Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C@:4]23[CH2:30][CH2:29][C@@H:28]([C:31]([CH3:33])=[CH2:32])[C@@H:5]2[C@@H:6]2[C@@:19]([CH3:22])([CH2:20][CH2:21]3)[C@@:18]3([CH3:23])[C@@H:9]([C@:10]4([CH3:27])[C@@H:15]([CH2:16][CH2:17]3)[C:14]([CH3:25])([CH3:24])[C:13](=[O:26])[CH2:12][CH2:11]4)[CH2:8][CH2:7]2)[CH2:3][CH2:2]1.[Cl:34][C:35]1[CH:36]=[CH:37][C:38]([N:41]([S:49]([C:52]([F:55])([F:54])[F:53])(=[O:51])=[O:50])S(C(F)(F)F)(=O)=O)=[N:39][CH:40]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1COCC1>[F:53][C:52]([F:55])([F:54])[S:49]([O:26][C:13]1[C:14]([CH3:24])([CH3:25])[C@H:15]2[C@:10]([CH3:27])([CH2:11][CH:12]=1)[C@@H:9]1[C@:18]([CH3:23])([C@@:19]3([CH3:22])[C@H:6]([CH2:7][CH2:8]1)[C@H:5]1[C@H:28]([C:31]([CH3:33])=[CH2:32])[CH2:29][CH2:30][C@:4]1([NH:1][CH2:2][CH2:3][N:41]([C:38]1[CH:37]=[CH:36][C:35]([Cl:34])=[CH:40][N:39]=1)[S:49]([C:52]([F:53])([F:54])[F:55])(=[O:50])=[O:51])[CH2:21][CH2:20]3)[CH2:17][CH2:16]2)(=[O:51])=[O:50]
Reactant: O=S(=O)(N(c1ccc(Cl)cn1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: C=C(C)[C@@H]1CC[C@]2(N3CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CCC(=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C)[C@@H]1CC[C@]2(NCCN(c3ccc(Cl)cn3)S(=O)(=O)C(F)(F)F)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(OS(=O)(=O)C(F)(F)F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: -78 °C

Procedure:
(1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-3a-(aziridin-1-yl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)octadecahydro-1H-cyclopenta[a]chrysen-9(5bH)-one (353 mg, 0.781 mmol) was mixed with N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-((trifluoromethyl)sulfonyl)methanesulfonamide (338 mg, 0.860 mmol) in THF (2 mL) under nitrogen. The solution was stirred at −78° C. under nitrogen. A 0.5 M stock solution of potassium bis(trimethylsilyl)amide (1.875 mL, 0.938 mmol) was added, and the mixture was stirred at −78° C. for an hour. The desired product was purified by silica gel chromatography eluted with mixture of ethyl acetate and hexanes (230 mg, 35%). MS: m/e 844.3/846.3 (M+H)+, 6.47 min (method 15). 1H NMR (400 MHz, CHLOROFORM-d) δ (key fingerprint signals) 8.45 (d, J=2.0 Hz, 1H), 7.76 (dd, J=8.7, 2.6 Hz, 1H), 7.48 (d, J=8.5 Hz, 1H), 5.57 (d, J=6.5 Hz, 1H), 4.80-4.57 (m, 3H), 3.71-3.65 (m, 1H), 2.80-2.73 (m, 1H), 2.73-2.49 (m, 2H), 2.45-2.29 (m, 1H), 2.26-2.12 (m, 2H), 2.08-1.94 (m, 2H), 1.93-1.80 (m, 2H), 1.80-1.72 (m, 3H), 1.71-1.65 (m, 6H). 19F NMR (376 MHz, CHLOROFORM-d) δ −74.84 (s), −74.85 (s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[CH2:23][CH2:22][C:21](=[O:24])[C:20]4[N:25]([CH3:28])[CH:26]=[CH:27][C:19]=4[S:18]3(=[O:30])=[O:29])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[BH4-].[Na+].[Cl-].[NH4+].C(=O)([O-])O.[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[CH2:23][CH2:22][CH:21]([OH:24])[C:20]4[N:25]([CH3:28])[CH:26]=[CH:27][C:19]=4[S:18]3(=[O:30])=[O:29])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Cn1ccc2c1C(=O)CCN(CCCN1CCN(c3ccc(F)cc3)CC1)S2(=O)=O
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Cl-]
Solvent: CCO
Product: Cn1ccc2c1C(O)CCN(CCCN1CCN(c3ccc(F)cc3)CC1)S2(=O)=O
Yield: 74.7 %

Procedure:
To a suspension of 240 mg (0.57 mmol) of Compound 23 in 5 ml of ethanol, 200 mg (5.3 mmol) of sodium borohydride were added gradually under ice-cooled stirring. The resulting mixture was stirred under ice cooling for 1 hour and further at room temperature for 4 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture under ice cooling, followed by the addition of a saturated aqueous solution of sodium hydrogencarbonate so that the mixture was alkalinized. The water layer was extracted with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluent: methanol/methylene chloride=1/20), whereby 186 mg of the title compound were obtained (yield: 77%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH:10]([C:12]1[C:20]2[C:15](=[CH:16][C:17]([N+:21]([O-:23])=[O:22])=[CH:18][CH:19]=2)[N:14]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[N:13]=1)=[CH2:11].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(C(C)C)CC)(C)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:8][C:6]1[CH:5]=[C:4]([CH3:9])[N:3]=[C:2]([CH:11]=[CH:10][C:12]2[C:20]3[C:15](=[CH:16][C:17]([N+:21]([O-:23])=[O:22])=[CH:18][CH:19]=3)[N:14]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[N:13]=2)[CH:7]=1
Reactant: C=Cc1nn(C2CCCCO2)c2cc([N+](=O)[O-])ccc12
Reactant: Cc1cc(C)nc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C)nc(C=Cc2nn(C3CCCCO3)c3cc([N+](=O)[O-])ccc23)c1
Temperature: 110 °C
Yield: 68 %

Procedure:
A suspension of 2-bromo-4,6-dimethylpyridine (2.42 g, 13 mmol), 3-vinyl-6-nitro-1-(tetrahydro -pyran-2-yl)-1H-indazole (2.37 g, 8.67 mmol), palladium acetate (0.145 g, 0.65 mmol), tri-ortho-tolylphosphine (0.791 g, 2.6 mmol), and diisopropylethylamine (2.4 mL, 13.8 mmol) in aqueous DMF (85%, 34.5 mL) was degassed with Argon bubbling for 5 minutes followed by sonication for 5 minutes before heating in microwave apparatus (300 watts, 10% power) at 110° C. for 40 minutes. After cooling, the mixture was dropped into cold water. The resulting yellow ppt was collected by filtration. The solids were dissolved in ethyl acetate, dried (sodium sulfate), and concentrated under reduced pressure. The residue was purified on silica gel using a gradient of 0 to 20% ethyl acetate in a mixture of chloroform and hexanes (1:1) as eluent. Product from chromatography was triturated with MTBElhexanes to obtain clean product as yellow solid. Mother liquor was repurified in a similar fashion on silica gel followed by trituration to obtain product in a 68% yield. 1H NMR (CDCl3): δ 8.54 (1H, s), 8.15 (1H, d, J=9.4 Hz), 8.08 (1H, dd, J=9.04,1.9 Hz), 7.87 (1H, d, J=16.6 Hz), 7.55 (1H, d, J=16.6 Hz), 7.14 (1H, s), 6.90 (1H, s), 5.82 (1H, dd, J=9.0, 3.0 Hz), 4.08–4.01 (1H, m), 3.84–3.76 (1H, m), 2.56 (3H, s), 2.62–2.54 (1H, m), 2.34 (3H, s), 2.24–2.10 (2H, m), 1.88–1.68 (3H, m).
Reaction SMILES: [O:1]1[CH2:21][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=2)=[CH:7][C:6]=1[N+:18]([O-:20])=[O:19].[C:22]([NH2:26])([CH3:25])([CH3:24])[CH3:23]>CO>[C:22]([NH:26][CH2:21][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=2)=[CH:7][C:6]=1[N+:18]([O-:20])=[O:19])([CH3:25])([CH3:24])[CH3:23]
Reactant: O=C1CCC(c2ccc(OCC3CO3)c([N+](=O)[O-])c2)=NN1
Reactant: CC(C)(C)N
Solvent: CO
Product: CC(C)(C)NCC(O)COc1ccc(C2=NNC(=O)CC2)cc1[N+](=O)[O-]
Yield: 70.4 %

Procedure:
A stirred mixture of crude 6-[4-(2,3-epoxypropoxy)-3-nitrophenyl]-4,5-dihydro-3(2H)-pyridazinone (3.3 g, 0.011 mole), methanol (70 ml), and t-butylamine (7.2 ml, 0.068 mole), was gently heated under reflux for 105 minutes. The filtered solution was evaporated under reduced pressure to an orange coloured foam (4 g, 97%). The crude base (3.77 g) was digested with water (200 ml) and glacial acetic acid added to pH 4, then the solution filtered and washed with dichloromethane (3 × 100 ml). The aqueous phase was treated with potassium carbonate solution to pH 9, then extracted with dichloromethane and the combined organic extracts washed with a little water. Evaporation of the dried solution gave crude 6-[4-(3-t-butylamino-2-hydroxypropoxy)-3-nitrophenyl]-4,5-dihydro-3(2H)-pyridazinone (2.82 g, m.p. about 92°-105°C). After two recrystallisations from ethyl acetate the free base (m.p. about 124°C) was converted into its hydrochloride m.p. 260°-262°C. The pure hydrochloride recrystallised from methanol-ether, had m.p. 263°-265°C (decomposition).
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16](=[O:18])[CH3:17])=[C:11]([CH3:19])[CH:10]=1.[ClH:20]>C(#N)C.[Cu](Cl)Cl>[Cl:20][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16](=[O:18])[CH3:17])=[C:11]([CH3:19])[CH:10]=1
Reactant: Cl
Reactant: CC(=O)c1c(C)cc(N)cc1C
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: CC(=O)c1c(C)cc(Cl)cc1C
Temperature: 0 °C
Yield: 76 %

Procedure:
Anhydrous copper(II) chloride (98.9 g, 0.74 mol) was mixed with tert-butyl nitrite (94.8 g, 0.83 mol) in acetonitrile (1.02 L). The solution was cooled to 0° C. and slowly added with 1-(4-amino-2,6-dimethylphenyl)ethanone (100 g, 0.61 mol) in a period of 5.0 min. After the addition was completed, the reaction mixture was warmed to room temperature, and was poured into an aqueous hydrochloric acid solution (20%, 1.0 L). The solution was extracted with EtOAc (800 mL), and the organic layer was separated, washed with H2O (1.0 L), dried over MgSO4 (s), and concentrated under reduced pressure. The liquid was distilled to give 1-(4-chloro-2,6-dimethylphenyl)ethanone (85.0 g) as yellow oil in 76% yield: 1H NMR (500 MHz, CDCl3) δ 7.02 (s, 2H), 2.45 (s, 3H), 2.22 (s, 6H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:7][CH:6]=1)=[O:4].[C:19]([C:23]1[CH:46]=[CH:45][C:26]([C:27]([NH:29][C@H:30]([C:41]([O:43][CH3:44])=[O:42])[CH2:31][C:32]2[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[CH:34][CH:33]=2)=[O:28])=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(#N)C>[C:19]([C:23]1[CH:46]=[CH:45][C:26]([C:27]([NH:29][C@H:30]([C:41]([O:43][CH3:44])=[O:42])[CH2:31][C:32]2[CH:33]=[CH:34][C:35]([C:36]([O:38][CH2:2][C:3]([C:5]3[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:7][CH:6]=3)=[O:4])=[O:37])=[CH:39][CH:40]=2)=[O:28])=[CH:25][CH:24]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CCCCCCCOc1ccc(C(=O)CBr)cc1
Reactant: COC(=O)[C@H](Cc1ccc(C(=O)O)cc1)NC(=O)c1ccc(C(C)(C)C)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CC#N
Product: CCCCCCCOc1ccc(C(=O)COC(=O)c2ccc(C[C@H](NC(=O)c3ccc(C(C)(C)C)cc3)C(=O)OC)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 49 %

Procedure:
A solution of 2-bromo-1-(4-(heptyloxy)phenyl)ethanone, INT-4 (166 mg, 0.45 mmol) in acetonitrile (1 mL) was added to a solution of (S)-4-(2-(4-(tert-butyl)benzamido)-3-methoxy-3-oxopropyl)benzoic acid INT-1 (190 mg, 0.50 mmol) and TEA (75.0 μl, 0.54 mmol) in acetonitrile (4 mL). The reaction mixture was stirred at room temperature for 18 h then poured onto 0.5 M citric acid (30 mL) and extracted with EA (3×25 mL). The combined organics were dried over MgSO4, filtered and concentrated. The residue was triturated with Et2O (10 mL) and the filtrate concentrated to afford 159 mg (49%) of (S)-2-(4-(heptyloxy)phenyl)-2-oxoethyl 4-(2-(4-(tert-butyl)benzamido)-3-methoxy-3-oxopropyl)benzoate as a white solid. LCMS-ESI (m/z) calculated for C37H45NO7: 615.8. found 616.0 [M+H]+, tR=2.76 min. (Method 4).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:45]=[CH:44][C:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([NH:31][C:32](=[O:41])[C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)[C:24]([O:26]C(C)(C)C)=[O:25])=[CH:18][C:17]=2[O:42][CH3:43])=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:45]=[CH:44][C:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([NH:31][C:32](=[O:41])[C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)[C:24]([OH:26])=[O:25])=[CH:18][C:17]=2[O:42][CH3:43])=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccc(C(=O)Oc2ccc(CC(NC(=O)c3ccc(OC)cc3)C(=O)OC(C)(C)C)cc2OC)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCOc1ccc(C(=O)Oc2ccc(CC(NC(=O)c3ccc(OC)cc3)C(=O)O)cc2OC)cc1
Temperature: 30 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
A crude solution of 4-(3-(tert-butoxy)-2-(4-methoxybenzamido)-3-oxopropyl)-2-methoxyphenyl 4-(heptyloxy)benzoate in DCM (1 mL) was treated with TFA (0.1 mL) and stirred overnight at 30° C. The solvent was evaporated and the residue was purified by preparative HPLC to give 16.9 mg (48%) of 3-(4-((4-(heptyloxy)benzoyl)oxy)-3-methoxyphenyl)-2-(4-methoxybenzamido)propanoic acid 2. LCMS-ESI (m/z) calculated for C32H37NO8: 563; found 564 [M+H]+, tR=11.01 min (Method 2). 1H NMR (400 MHz, DMSO) δ 12.79 (s, 1H), 8.57 (d, J=8.1 Hz, 1H), 8.00 (d, J=9.0 Hz, 2H), 7.82 (d, J=8.9 Hz, 2H), 7.13 (d, J=1.7 Hz, 1H), 7.11-7.03 (m, 3H), 6.99 (d, J=8.9 Hz, 2H), 6.92 (dd, J=8.1, 1.7 Hz, 1H), 4.61 (ddd, J=10.8, 8.1, 4.4 Hz, 1H), 4.07 (t, J=6.5 Hz, 2H), 3.80 (s, 3H), 3.69 (s, 3H), 3.20 (dd, J=13.8, 4.2 Hz, 1H), 3.08 (dd, J=13.7, 10.7 Hz, 1H), 1.84-1.66 (m, 2H), 1.51-1.17 (m, 8H), 0.87 (t, J=6.9 Hz, 3H).
Reaction SMILES: C1C2C(COC([N:18]3[CH2:22][CH2:21][CH2:20][C@H:19]3[C@H:23]([O:44][CH3:45])[C@@H:24]([CH3:43])[C:25]([NH:27][C@H:28]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:26])=O)C3C(=CC=CC=3)C=2C=CC=1.C(NCC)C>ClCCl>[CH3:45][O:44][C@@H:23]([C@@H:19]1[CH2:20][CH2:21][CH2:22][NH:18]1)[C@@H:24]([CH3:43])[C:25]([NH:27][C@H:28]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:26]
Reactant: CO[C@H]([C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C)[C@@H]1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Solvent: CCNCC
Solvent: ClCCl
Product: CO[C@@H]([C@@H]1CCCN1)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirring solution of #120 (2.87 g, 4.68 mmol, 1.00 eq.) in 20 mL of dichloromethane, diethylamine (10 mL, 95 mM, 20.5 eq.) was added. The reaction was allowed to stir at room temperature for 2 hours. Another (10 mL, 95 mmol, 20.5 eq.) of diethylamine was added and the reaction was allowed to stir at room temperature for 3 more hours. Reaction was concentrated in vacuo and placed underneath high vacuum producing #121 (1.8 g, quant.) yellow white oil solid mix. LC-MS (Protocol Q): m/z 391.1 [M+H+] retention time=1.05 minutes.
Reaction SMILES: C(CS[C:6](=[S:12])[S:7][CH2:8][C:9]([OH:11])=O)(O)=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:25]1[C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=[C:27]([S:33]([NH2:36])(=[O:35])=[O:34])[CH:26]=1.Cl.C(N(CC)C(C)C)(C)C.Cl>O1CCCC1>[S:33]([C:27]1[CH:26]=[CH:25][C:30]([CH2:31][N:32]2[C:9](=[O:11])[CH2:8][S:7][C:6]2=[S:12])=[CH:29][CH:28]=1)(=[O:34])(=[O:35])[NH2:36]
Reactant: NCc1ccc(S(N)(=O)=O)cc1
Reactant: O=C(O)CSC(=S)SCC(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: NS(=O)(=O)c1ccc(CN2C(=O)CSC2=S)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.7 %

Procedure:
To a solution of bis(carboxymethyl)trithiocarbonate (200 mg) in tetrahydrofuran (10 ml) was added carbonyldiimidazole (291 mg), and the mixture was stirred at room temperature. After 2 hr, to the reaction mixture were added homosulfamine hydrochloride (200 mg) and N,N-diisopropylethylamine (155 mg), and the mixture was stirred overnight at 70° C. 2N Hydrochloric acid (10 ml) was added thereto under ice cooling, the mixture was extracted twice with ethyl acetate (40 ml), and the extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=2:1) to give 3-(4-sulfamoylbenzyl)-2-thioxothiazolidin-4-one (189 mg).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17][CH:16]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>ClCCl.[Cl-].[Na+].O>[CH2:6]([O:13][C:14](=[O:23])[C:15]1[CH:16]=[CH:17][C:18]([CH2:21][O:22][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:19][CH:20]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(OCc1ccccc1)c1ccc(CO)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)OCc1ccc(C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 73 %

Procedure:
Under ice cooling, methanesulfonyl chloride (2.1 mL, 27 mmol) was added to a solution of 4-hydroxymethylbenzoic acid benzyl ester (Reference Compound No. 7-1, 6.0 g, 24.8 mmol) and triethylamine (7.6 mL, 54 mmol) in dichloromethane (60 mL), and then the reaction mixture was stirred at room temperature for 50 minutes. Brine (0.30 L) was added to the reaction solution, and the mixture was extracted with chloroform (0.15 L) four times. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 5.8 g of the title reference compound as yellow oil. (Yield 73%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:19]=[C:18]([OH:20])[C:17]3[C:12](=[C:13]([CH:24]=O)[CH:14]=[C:15]([N+:21]([O-:23])=[O:22])[CH:16]=3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:26]([O:28][C:29]([CH:31]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:30])[CH3:27]>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:19]=[C:18]([OH:20])[C:17]3[C:12](=[C:13]([CH:24]=[CH:31][C:29]([O:28][CH2:26][CH3:27])=[O:30])[CH:14]=[C:15]([N+:21]([O-:23])=[O:22])[CH:16]=3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=Cc1cc([N+](=O)[O-])cc2c(O)nc(Nc3ccc(Cl)c(Cl)c3)nc12
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCCl
Product: CCOC(=O)C=Cc1cc([N+](=O)[O-])cc2c(O)nc(Nc3ccc(Cl)c(Cl)c3)nc12
Reaction time: 0.5 h

Procedure:
A solution of 2-((3,4-dichlorophenyl)amino)-4-hydroxy-6-nitroquinazoline-8-carbaldehyde (100 mg) and ethoxycarbonylmethylene triphenylphosphorane (100 mg) in 1,2-dichloroethane (5 mL) was stirred at room temperature for 1 h. The mixture was concentrated to an oil, which was purified by preparative high pressure liquid chromatography (21.4 mm i.d.×30 cm Dynamax 300 Å C18 column; 30-90% CH3CN/H2O (+0.1% (v/v) CF3CO2H) gradient over 30 min, then to 100% CH3CN over 5 min; 15.0 mL/min flow; 1.0 min (15 mL) fractions). Fractions containing the desired product, as determined by analytical HPLC, were concentrated to afford the title compound as a crystalline yellow solid which was isolated by filtration and dried. Yield 14.2 mg. 1H NMR (300 MHz, CDCl3): δ8.79 (d, J=2.4 Hz, 1H); 8.61 (d, J=2.4 Hz, 1H), 8.20 (d, J=16.2 Hz, 1H); 7.72-7.52 (m, 3H), 6.98 (d, J=16.2 Hz, 1H), 4.20 (q, J=7.2 Hz, 2H); 1.27 (t, J=7.2 Hz, 3H). HPLC (Method A): 8.45 min. MS (APCI+): m/z 449, 451.
Reaction SMILES: [CH2:1]([N:8]1[CH2:31][CH:30]([C:32]([OH:34])=O)[O:29][C:10]2([CH2:15][CH2:14][N:13]([C:16](=[O:28])[C:17]3[CH:22]=[CH:21][C:20]([O:23][CH:24]([CH3:26])[CH3:25])=[C:19]([CH3:27])[CH:18]=3)[CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:35][CH2:36][C:37](=[O:39])[CH3:38].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CC1CCCO1>>[CH2:36]([NH:35][C:32]([CH:30]1[O:29][C:10]2([CH2:11][CH2:12][N:13]([C:16](=[O:28])[C:17]3[CH:22]=[CH:21][C:20]([O:23][CH:24]([CH3:25])[CH3:26])=[C:19]([CH3:27])[CH:18]=3)[CH2:14][CH2:15]2)[CH2:9][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:31]1)=[O:34])[C:37]([CH3:38])=[O:39]
Reactant: CC(=O)CN
Reactant: Cc1cc(C(=O)N2CCC3(CC2)CN(Cc2ccccc2)CC(C(=O)O)O3)ccc1OC(C)C
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CC1CCCO1
Product: CC(=O)CNC(=O)C1CN(Cc2ccccc2)CC2(CCN(C(=O)c3ccc(OC(C)C)c(C)c3)CC2)O1
Temperature: 75 °C
Yield: 41 %

Procedure:
To 8-benzyl-3-(4-isopropoxy-3-methyl-benzoyl)-11-oxa-3,8-diazaspiro[5.5]undecane-10-carboxylic acid (201 mg, 0.43 mmol), 1-aminopropan-2-one (47 mg, 0.43 mmol) and T3P (641 μL of 50% w/w, 1.08 mmol) was added 2-methyltetrahydrofuran (1 mL) and the reaction mixture was then heated at 75° C. for 2 hours. The reaction mixture was cooled to room temperature and partitioned between EtOAc/saturated aq. NaHCO3. The layers were separated and the aqueous layer was extracted with EtOAc (2×). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to a dark foam. The crude product was purified by silica gel column chromatography using 20-70% EtOAC in DCM as eluent to afford N-acetonyl-8-benzyl-3-(4-isopropoxy-3-methyl-benzoyl)-11-oxa-3,8-diazaspiro[5.5]undecane-10-carboxamide (92 mg, 41%) as a yellow solid. ESI-MS m/z calc. 521.6. found 522.5 (M+1)+; Retention time: 1.48 minutes (3 min run).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[CH2:6][C:5]1=[O:15])(=[O:3])[CH3:2].[CH3:16][CH2:17][O:18][C:19](OCC)(OCC)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(OC(=O)C)(=O)C>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:19]([O:18][CH2:17][CH3:16])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]1=[O:15])(=[O:3])[CH3:2]
Reactant: COc1ccc2c(c1)N(C(C)=O)C(=O)C2
Reactant: CCOC(OCC)(OCC)c1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CCOC(=C1C(=O)N(C(C)=O)c2cc(OC)ccc21)c1ccccc1

Procedure:
Prepared from 1-acetyl-6-methoxy-2-indolinone, triethyl orthobenzoate and acetic anhydride
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([CH:20]([OH:23])[CH:21]=[CH2:22])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.[Li]OC(C)=O.O.[Li+].[Cl-].I[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH:39]([CH3:44])[C:40]([O:42][CH3:43])=[O:41]>[N+](CCCC)(CCCC)(CCCC)CCCC.[Cl-].CC([O-])=O.CC([O-])=O.[Pd+2].C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([C:20](=[O:23])[CH2:21][CH2:22][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[CH:39]([CH3:44])[C:40]([O:42][CH3:43])=[O:41])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: C=CC(O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Reactant: COC(=O)C(C)c1ccccc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Product: COC(=O)C(C)c1ccccc1CCC(=O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A degassed suspension of the product of Step 1 (15.0 g, 46.6 mmol), n-Bu4NCl (25.9 g, 93 mmol), LiOAc·H2O (7.7 g, 115 mmol), LiCl (1.98 g, 93 mmol), Pd(OAc)2 (0.315 g, 1.4 mmol), and methyl 2-(2-iodo-phenyl)propanoate in DMf (90 mL) was stirred for 2 hours at 100° C. The dark red solution was then cooled to 0° C. and poured into saturated NaHCO3 solution (500 mL). The product was extracted with EtOAc and the organic layer was washed with H2O followed by brine. The solvent was removed under vacuum and the residue was purified by flash chromatography (EtOAc:hexane 1:10, 1:5 and 3:10) to give a pale yellow foam (18.9 g).
Reaction SMILES: [CH2:1]([Li])CCC.[Cl:6][C:7]1[CH:11]=[C:10]([CH:12]=O)[NH:9][C:8]=1[C:14]([O:16][CH3:17])=[O:15]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Cl:6][C:7]1[CH:11]=[C:10]([CH:12]=[CH2:1])[NH:9][C:8]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: [Li]CCCC
Reactant: COC(=O)c1[nH]c(C=O)cc1Cl
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1cc(Cl)c(C(=O)OC)[nH]1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 40.7 %

Procedure:
A suspension of methyl(triphenyl)phosphonium bromide (3.97 g, 11.1 mmol) in 20 mL of THF was cooled to −78° C. n-Butyllithium (1.6 M in Hexanes, 6.93 mL, 11.1 mmol) was added and the resulting yellow solution stirred for 20 minutes. A THF solution of methyl 3-chloro-5-formyl-1H-pyrrole-2-carboxylate (0.522 g, 2.78 mmol) was added and the reaction was warmed to RT. The reaction mixture was partitioned between EtOAc and water and the layers were separated. The organic layer was dried over MgSO4, filtered and the solvent evaporated. Purification was accomplished by silica gel column chromatography (EtOAc/hexanes) to afford the title compound (0.210 g, 40%) as a white solid. 1H NMR (400 MHz, Acetone-d6) δ ppm 11.05 (br. s., 1H), 6.62 (dd, 1H), 6.42 (d, 1H), 5.83 (d, 1H), 5.25 (d, 1H), 3.79 (s, 3H). LCMS: m/z=184.6 (M−1).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)(=[S:3])[NH2:2].[Cl:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18](=O)[CH2:19]Br>>[Cl:14][C:15]1[CH:16]=[C:17]([C:18]2[N:2]=[C:1]([C:4]3[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=3)[S:3][CH:19]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)c1ccc(C(N)=S)cc1
Reactant: O=C(CBr)c1cccc(Cl)c1
Product: COC(=O)c1ccc(-c2nc(-c3cccc(Cl)c3)cs2)cc1
Yield: 72 %

Procedure:
In the same manner as in Example 28, methyl 4-thiocarbamoylbenzoate was reacted with 3-chlorophenacyl bromide to obtain methyl 4-[4-(3-chlorophenyl)-2-thiazolyl]benzoate. The product was recrystallized from ethanol. Yield: 72%. Pale yellow prisms. Melting point: 150 to 151° C.