Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([N:16]3[C:20](=[O:21])[NH:19][C:18]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)=[N:17]3)=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.[CH:29]1([C:32]([NH2:34])=[O:33])[CH2:31][CH2:30]1.C([O-])([O-])=O.[Cs+].[Cs+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:28][C:25]1[CH:26]=[CH:27][C:22]([C:18]2[NH:19][C:20](=[O:21])[N:16]([C:12]3[N:13]=[C:14]([CH3:15])[C:9]([O:8][C:6]4[CH:5]=[CH:4][N:3]=[C:2]([NH:34][C:32]([CH:29]5[CH2:31][CH2:30]5)=[O:33])[CH:7]=4)=[CH:10][CH:11]=3)[N:17]=2)=[CH:23][CH:24]=1
Reactant: Cc1nc(-n2nc(-c3ccc(F)cc3)[nH]c2=O)ccc1Oc1ccnc(Cl)c1
Reactant: NC(=O)C1CC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1nc(-n2nc(-c3ccc(F)cc3)[nH]c2=O)ccc1Oc1ccnc(NC(=O)C2CC2)c1
Temperature: 110 °C
Yield: 25.7 %

Procedure:
A suspension of Example A8 (0.250 g, 0.628 mmol), cyclopropane carboxamide (0.100 g, 1.175 mmol), Cs2CO3 (0.400 g, 1.228 mmol) and X-Phos (0.012 g, 0.025 mmol) in dioxane (20 mL) was purged with argon for 5 minutes. To the reaction mixture was added Pd2(dba)3 (0.012 g, 0.013 mmol) and the mixture wass heated in a reclosable sealed tube (100 mL) at 110° C. for 8 h. The solids from the reaction mixture was filtered and washed with DCM and THF. The filtrate was evaporated and the residue subjected to chromatography using (0-100% EtOAc/DCM) to provide N-(4-((6-(3-(4-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methylpyridin-3-yl)oxy)pyridin-2-yl)cyclopropanecarboxamide (0.072 g, 24%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 12.73 (s, 1H), 10.89 (s, 1H), 8.21 (d, J=5.7 Hz, 1H), 7.98-7.93 (m, 3H), 7.75 (d, J=8.8 Hz, 1H), 7.59 (d, J=2.4 Hz, 1H), 7.40 (t, J=8.8 Hz, 2H), 6.71 (dd, J=5.7, 2.4 Hz, 1H), 2.33 (s, 3H), 1.95 (t, J=6.1 Hz, 1H), 0.75 (d, J=6.2 Hz, 4H), MS (ESI) m/z: 447.2 (M+H+).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:19][CH:18]=3)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1)=[O:2].S(=O)(=O)([OH:31])N.Cl([O-])=O.[Na+]>O1CCCC1.O>[CH3:28][O:27][C:25]([CH2:24][CH2:23][C:20]1[CH:19]=[CH:18][C:17]([O:16][CH2:15][C:11]2[CH:10]=[C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:1]([OH:31])=[O:2])[CH:4]=3)[CH:14]=[CH:13][CH:12]=2)=[CH:22][CH:21]=1)=[O:26]
Reactant: NS(=O)(=O)O
Reactant: COC(=O)CCc1ccc(OCc2cccc(-c3cccc(C=O)c3)c2)cc1
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CCc1ccc(OCc2cccc(-c3cccc(C(=O)O)c3)c2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 98.5 %

Procedure:
To a solution of methyl 4-[(3′-formyl-[1,1′-biphenyl]-3-yl) methoxy]benzenepropanoate (0.48 g, 1.3 mmol) in tetrahydrofuran (5 mL) and water (2 mL) was added sulfamic acid (0.15 g, 1.3 mmol), and a solution of sodium chlorite (0.17 g, 1.5 mmol) in water (1.5 mL) was added. The mixture was stirred at room temperature for 15 hrs., and water was added. The mixture was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure to give the title compound 0.50 g (quantitative).
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[OH:6][CH2:7][CH:8]1[CH2:13][CH2:12][C:11]([CH3:20])([C:14]([O:16][CH2:17][CH:18]=[CH2:19])=[O:15])[CH2:10][CH2:9]1.Cl>N1C=CC=CC=1>[S:1]([O:6][CH2:7][CH:8]1[CH2:13][CH2:12][C:11]([CH3:20])([C:14]([O:16][CH2:17][CH:18]=[CH2:19])=[O:15])[CH2:10][CH2:9]1)([CH3:4])(=[O:3])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: C=CCOC(=O)C1(C)CCC(CO)CC1
Agent: Cl
Solvent: c1ccncc1
Product: C=CCOC(=O)C1(C)CCC(COS(C)(=O)=O)CC1

Procedure:
4.5 ml of mesyl chloride was added to a solution of 2.1 g of allyl 4-hydroxymethyl-1-methyl-1-cyclohexanecarboxylate (Example 44) in 50 ml of pyridine. The solution was reacted for 3 hours at room temperature. After reaction, 100 ml of 2N hydrochloric acid was added to the reaction solution. The solution was extracted three times with 30 ml of ethyl acetate. The organic layer obtained was washed once with an aqueous sodium hydrogencarbonate solution and twice with an aqueous sodium chloride solution, and was dried over magnesium sulfate. Thereafter, the solvent was removed in vacuo. The oily substance obtained was subjected to column chromatography using 20 g of silica gel. From the fraction eluted with hexane and ethyl acetate=2:1, the solvent was removed in vacuo, yielding 2 g of allyl 4-mesyloxymethyl-1-methyl-1-cyclohexanecarboxylate as a pale yellow oil, which had the following physiochemical properties:
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1.[NH2:13][C:14]([NH2:16])=[S:15]>C(O)C>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][C:3]2[N:13]=[C:14]([NH2:16])[S:15][CH:2]=2)=[CH:6][CH:7]=1
Reactant: O=C(CBr)Cc1ccc(Cl)cc1
Reactant: NC(N)=S
Solvent: CCO
Product: Nc1nc(Cc2ccc(Cl)cc2)cs1
Temperature: 85 °C
Yield: 86 %

Procedure:
A mixture of 1-bromo-3-(4-chlorophenyl)propan-2-one (25.4 grams, 103 mmol) and thiourea (8.59 g, 113 mmol) in ethanol (1.51 L) was heated at 85° C. for 2 hours. The reaction was cooled and concentrated in vacuo and the residue was taken up in ethyl acetate (300 mL) and saturated sodium bicarbonate (100 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO4, filtered, and concentrated in vacuo. The residue was recrystallized from ethyl acetate/hexanes to give 19.9 grams of the title compound as a tan powder (86% yield). LC/MS (FA) ES+ 225. 1H NMR (300 MHz, CDCl3) δ: 7.29-7.24 (m, 2H), 7.20-7.15 (m, 2H), 6.04 (m, 1H), 5.00 (bs, m, 2H), 3.83 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[O:9])[O:5][C:6]=1Br.[CH3:10][O:11][N:12]=[C:13]1[C:21]2[C:16](=[CH:17][C:18](B(O)O)=[CH:19][CH:20]=2)[CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[O:9])[O:5][C:6]=1[C:18]1[CH:17]=[C:16]2[C:21](=[CH:20][CH:19]=1)[C:13](=[N:12][O:11][CH3:10])[CH2:14][CH2:15]2
Reactant: O=Cc1cc(Br)c(Br)o1
Reactant: CON=C1CCc2cc(B(O)O)ccc21
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CON=C1CCc2cc(-c3oc(C=O)cc3Br)ccc21
Temperature: 25 °C
Yield: 35.2 %

Procedure:
A degassed mixture of the product of Step 3 (6.6 g, 26.0 mmol), 1-methoxyimino-indan-5-boronic acid (5.3 g, 26.0 mmol) and potasium carbonate (28 g, 202 mmol) in ethylene glycol dimethyl ether (150 ml) and water (75 ml) was treated with bis(triphenylphosphine) palladium (II) chloride (1.05 g, 1.5 mmol), then heated under reflux for 6 hours. After cooling to room temperature, the mixture was filtered through celite and the filtrate diluted with water and ethyl acetate. The organic phase was separated, washed with water and brine, dried, concentrated in vacuo and the residue purified by silica gel chromatography eluting with dichloromethane to give the title compound (3.06 g, 35%); MS(ES+) m/e 334/336 [M+H]+.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]([O:9][C:10]([NH:12][C@@H:13]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:25]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:24]=1)[C:14]([O:16][C@H:17]([CH3:21])[C@H:18]([OH:20])[CH3:19])=[O:15])=[O:11])([CH3:8])([CH3:7])[CH3:6].N1C=CC=CC=1>ClCCl>[C:5]([O:9][C:10]([NH:12][C@@H:13]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:25]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:24]=1)[C:14]([O:16][C@H:17]([CH3:21])[C@H:18]([O:20][C:1](=[O:3])[CH3:2])[CH3:19])=[O:15])=[O:11])([CH3:7])([CH3:8])[CH3:6]
Reactant: C[C@@H](O)[C@@H](C)OC(=O)[C@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)NC(=O)OC(C)(C)C
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)O[C@H](C)[C@@H](C)OC(=O)[C@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
Acetyl chloride (0.39 mL, 5.5 mmol) and (1R,2R)-2-hydroxy-1-methylpropyl (2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethoxy)phenyl]propanoate (32) (2.0 g, 3.6 mmol) were dissolved in 25 mL of anhydrous dichloromethane. A solution of pyridine (0.5 mL, 5.5 mmol) in dichloromethane was added dropwise at 0° C. The mixture was stirred at room temperature for 2 hours. The product was extracted with dichloromethane, washed with 5% NaHCO3, 10% citric acid, and dried over Na2SO4. After concentration and drying under vacuum, the crude product (33) (2.0 g, 95% yield) was isolated and used in the next reaction without further purification. 1H NMR (400 MHz, CDCl3): δ 1.11 (d, J=6.4 Hz, 3H), 1.15 (d, J=6.4 Hz, 3H), 1.43 (s, 9H), 2.05 (s, 3H), 2.95 (dd, J=13.6, 6.4 Hz, 1H), 3.00 (dd, J=13.6, 6.4 Hz, 1H), 4.50 (dd, J=13.6, 6.4 Hz, 1H), 4.93 (m, 2H), 4.98 (d, 1H, NH), 5.12 (s, 4H), 6.66 (dd, J=8.0, 2.0 Hz, 1H), 6.77 (d, J=2.0 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H), 7.29-7.45 (m, 10H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:8]=2[N:9]=1.[CH2:15]([N:17]=[C:18]=[O:19])[CH3:16]>C(O)C>[Cl:14][C:11]1[CH:12]=[CH:13][C:7]2[S:6][C:5]([S:4][CH2:3][CH2:2][NH:1][C:18]([NH:17][CH2:15][CH3:16])=[O:19])=[N:9][C:8]=2[CH:10]=1
Reactant: NCCSc1nc2cc(Cl)ccc2s1
Reactant: CCN=C=O
Solvent: CCO
Product: CCNC(=O)NCCSc1nc2cc(Cl)ccc2s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89 %

Procedure:
Dissolved in 10 ml of ethanol was 1.00 g (4.09 mmol) of 2-(2-aminoethylthio)-5-chlorobenzothiazole, and 0.36 ml (4.55 mmol) of ethyl isocyanate were added to the solution, which was stirred at room temperature for 15 minutes. The precipitated white crystals were then filtered out to obtain 1.15 g of the title compound (89% yield).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3/[CH:16]=[CH:17]/[C:18]([O:20]CC3C=CC=CC=3)=[O:19])[N:9]([CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])[C:8]=2[CH3:34])[CH:5]=[CH:4][N:3]=[CH:2]1>[Pd]>[C:18]([CH2:17][CH2:16][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[C:7]([CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)=[C:8]([CH3:34])[N:9]2[CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])([OH:20])=[O:19]
Reactant: COC(=O)CCn1c(C)c(Cn2ccnc2)c2c(/C=C/C(=O)OCc3ccccc3)cccc21
Agent: [Pd]
Product: COC(=O)CCn1c(C)c(Cn2ccnc2)c2c(CCC(=O)O)cccc21
Yield: 72.5 %

Procedure:
Hydrogenation of benzyl (E)-3-[3-(1H-imidazol-1-ylmethyl)-1-(2-methoxycarbonylethyl)-2-methyl-1H-indol-4-yl]-2-propenoate (1.40 g) in the presence of 10% palladium on carbon(0.15 g) according to the method of Preparation 21 gave the title compound (0.82 g), m.p. 136°-138° C.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27](=[O:29])[CH3:28])[CH:21]=2)[S:5][C:6]=1[C:7]1[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:9]=[CH:10][N:11]=1.[CH3:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[C:33]([C:45]([F:48])([F:47])[F:46])=[N:32]1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:30][N:31]1[CH:35]=[C:34]([C:2]2[N:3]=[C:4]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27](=[O:29])[CH3:28])[CH:21]=3)[S:5][C:6]=2[C:7]2[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:9]=[CH:10][N:11]=2)[C:33]([C:45]([F:48])([F:47])[F:46])=[N:32]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)c(C(F)(F)F)n1
Reactant: CC(=O)Nc1cc(-c2nc(Br)c(-c3nccn3COCC[Si](C)(C)C)s2)ccn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: CC(=O)Nc1cc(-c2nc(-c3cn(C)nc3C(F)(F)F)c(-c3nccn3COCC[Si](C)(C)C)s2)ccn1

Procedure:
N-(4-(4-bromo-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)thiazol-2-yl)pyridin-2-yl)acetamide (70.0 mg, 0.120 mmol), 1-methyl-3-trifluoromethyl-1H-pyrazole-4-boronic acid pinacol ester (0.0708 g, 0.241 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloride (4.95 mg, 0.00602 mmol) and sodium carbonate (38.3 mg, 0.361 mmol) in DME (1.2 mL) was degassed with argon. Water (0.5 mL) was added to the above mixture. The mixture was irradiated in microwave at 125° C. for 30 min. At that time, LCMS showed the desired product. Reaction mixture was filtered, the filtrate was evaporated to dryness, dissolved in DCM (1.20 mL) and treated with TFA (1.20 mL). This mixture was stirred at room temperature overnight. At that time, LCMS indicated formation of the desired product. The mixture was evaporated to dryness in vacuo, the residue was taken up by DMSO and purified using preparative HPLC to give product as yellow powder (16.3 mg, 31.2%). LCMS: (AA) ES+, 434, 435. 1H NMR (400 MHz, d4-methanol) δ: 8.67 (br, 1H) 8.38 (dd, 1H) 7.87 (s, 1H) 7.63 (dd, 1H) 7.14 (d, 2H) 3.98 (s, 3H) 2.19 (s 3H).
Reaction SMILES: Cl.Cl[C:3]1[N:8]=[CH:7][N:6]=[C:5]([N:9]2[C:13](=[O:14])[C:12]([N:15]3[CH:19]=[CH:18][N:17]=[CH:16]3)=[CH:11][NH:10]2)[CH:4]=1.Cl.[F:21][C:22]1([F:27])[CH2:26][CH2:25][NH:24][CH2:23]1.C(N(C(C)C)C(C)C)C>O1CCCC1>[F:21][C:22]1([F:27])[CH2:26][CH2:25][N:24]([C:3]2[N:8]=[CH:7][N:6]=[C:5]([N:9]3[C:13](=[O:14])[C:12]([N:15]4[CH:19]=[CH:18][N:17]=[CH:16]4)=[CH:11][NH:10]3)[CH:4]=2)[CH2:23]1
Reactant: FC1(F)CCNC1
Reactant: O=c1c(-n2ccnc2)c[nH]n1-c1cc(Cl)ncn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=c1c(-n2ccnc2)c[nH]n1-c1cc(N2CCC(F)(F)C2)ncn1

Procedure:
100 mg (0.3 mmol) of the compound from Example 13A, 58 mg (0.4 mmol) of 3,3-difluoropyrrolidine hydrochloride and 175 ml (130 mg, 1.0 mmol) of N-ethyl-N-(propan-2-yl)propane-2-amine are initially charged in 2 ml of tetrahydrofuran and reacted in a single mode microwave (Emrys Optimizer) at 120° C. for 1 h. After concentration under reduced pressure, the residue is taken up in acetonitrile/water and purified by preparative HPLC (RP 18 column; mobile phase: acetonitrile/water gradient). Yield: 111 mg (99% of theory)
Reaction SMILES: [O:1]=[C:2]1[C:15]2[C:14]3[S:13][C:12]4=[CH:16][CH2:17][CH2:18][CH:19]=[C:11]4[CH:10]=[C:9]([C:20]([OH:22])=[O:21])[C:8]=3[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.[OH-].[Na+].[BH4-].[Na+]>O>[OH:1][CH:2]1[C:15]2[C:14]3[S:13][C:12]4=[CH:16][CH2:17][CH2:18][CH:19]=[C:11]4[CH:10]=[C:9]([C:20]([OH:22])=[O:21])[C:8]=3[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1
Reactant: O=C(O)C1=CC2=CCCC=C2Sc2c1ccc1c2C(=O)CC1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C1=CC2=CCCC=C2Sc2c1ccc1c2C(O)CC1
Reaction time: 0.25 h

Procedure:
A suspension of 1-oxo-2,3,9,10-tetrahydro-1H-benzo[b]indeno[5,4-f]thiepin-6-carboxylic acid (3.10 g, 10 mmole) in water (60 ml) was stirred during the addition of 1N sodium hydroxide solution (10 ml). After stirring for 15 minutes the mixture was treated with sodium borohydride (0.95 g, 25 mmole) in portions and the reaction mixture was stirred at room temperature overnight. Careful acidification of the mixture with 10% hydrochloric acid precipitated the racemic title compound which was collected by filtration and washed well with water.
Reaction SMILES: [OH-].[K+].[CH3:3][S:4][CH:5]1[NH:8][C:7](=[O:9])[CH2:6]1.I[CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=[O:13]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.C(OCC)(=O)C>[CH3:3][S:4][CH:5]1[N:8]([CH2:11][C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[O:13])[C:7](=[O:9])[CH2:6]1
Reactant: O=C(CI)OCc1ccc([N+](=O)[O-])cc1
Reactant: CSC1CC(=O)N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CSC1CC(=O)N1CC(=O)OCc1ccc([N+](=O)[O-])cc1
Yield: 25.5 %

Procedure:
Powdery potassium hydroxide (36 mg, 0.64 mmole) and tetrabutylammonium bromide (21 mg) were suspended in tetrahydrofuran (3 ml). To the suspension was slowly added dropwise a solution of 4-methylthio-2-azetidinone (72.5 mg, 0.62 mmole) and p-nitrobenzyl iodoacetate (493 mg, 1.25 mmoles) in tetrahydrofuran (1 ml) at -20° C., with stirring. The temperature of the mixture was elevated to room temperature step by step and the mixture was stirred at room temperature for 1.5 hours. After completion of the reaction, the mixture was diluted with ethyl acetate and subjected to a natural filtration. The filtrate was concentrated under reduced pressure and the resulting residue was purified by preparative thin layer chromatography (eluent: a 1:1 by volume mixture of ethyl acetate and benzene), to give 49 mg of the desired compound as crystals.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH3:40])[C:4]([C:34]2[N:38]([CH3:39])[N:37]=[CH:36][CH:35]=2)=[CH:5][C:6]=1[C:7]([NH:9][C@@H:10]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([F:33])([F:32])[F:31])[CH2:11][N:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22])=[O:8].C1C(=O)N([Cl:48])C(=O)C1>O1CCCC1>[Cl:1][C:2]1[N:3]([CH3:40])[C:4]([C:34]2[N:38]([CH3:39])[N:37]=[CH:36][C:35]=2[Cl:48])=[CH:5][C:6]=1[C:7]([NH:9][C@@H:10]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([F:33])([F:32])[F:31])[CH2:11][N:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22])=[O:8]
Reactant: Cn1nccc1-c1cc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)c(Cl)n1C
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: Cn1ncc(Cl)c1-c1cc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)c(Cl)n1C
Reaction time: 1 h

Procedure:
A solution of 2-chloro-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-1-methyl-5-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrole-3-carboxamide (125 mg, 0.22 mmol) and NCS (29 mg, 0.22 mmol) in tetrahydrofuran (2.2 ml) was stirred at 70° C. in a sealed tube. LCMS showed a 1:1 mixture of two chlorination products along with starting material. Additional NCS (29 mg, 0.22 mmol) was added and the solution stirred an additional 1 h where LCMS showed complete conversion to the two chlorination products. The resulting solution was partitioned between DCM-H2O and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated, dry loaded onto silica and purified by column chromatography (2% MeOH in DCM (1% NH4OH)) affording an inseparable mixture of the desired title compound along with a chloro-regioisomer: LCMS (ES) m/e 604, 606 (M, M+2)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C@H:4]([CH2:20][SH:21])[NH:5][CH2:6][C:7]([S:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)([CH3:9])[CH3:8].[C:23](N1C=CN=C1)(N1C=CN=C1)=[S:24]>C(Cl)(Cl)Cl>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][S:10][C:7]([CH3:9])([CH3:8])[CH2:6][N:5]2[C@H:4]([C:3]([O:2][CH3:1])=[O:22])[CH2:20][S:21][C:23]2=[S:24])=[CH:17][CH:16]=1
Reactant: COC(=O)[C@H](CS)NCC(C)(C)SCc1ccc(OC)cc1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@@H]1CSC(=S)N1CC(C)(C)SCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
To a solution of N-[2-(4-methoxybenzylthio)-2-methylpropyl]-L-cysteine methyl ester (5.0 g) in chloroform (90 ml), thiocarbonyldiimidazole (3.0 g) was added and the mixture was stirred for 1 hr at room temperature. The reaction mixture was washed with 3N hydrochloric acid, water and then saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The crude product was recrystallized from ethyl acetate to give 5.1 g (91%) of the titled compound.
Reaction SMILES: C[N:2](C)[CH:3]=[N:4][C:5]([C:7]1[C:12]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][C:10](=[O:20])[N:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:8]=1)=O.O=C1N(C2C=CC=CC=2)[N:33]=C(C(N)=O)C(SC2C=CC=CC=2)=C1.COC(OC)N(C)C>>[C:21]1([N:9]2[C:10](=[O:20])[CH:11]=[C:12]([S:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:7]([C:5]3[N:4]=[CH:3][NH:2][N:33]=3)=[N:8]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CN(C)C=NC(=O)c1nn(-c2ccccc2)c(=O)cc1Sc1ccccc1
Reactant: NC(=O)c1nn(-c2ccccc2)c(=O)cc1Sc1ccccc1
Agent: COC(OC)N(C)C
Product: O=c1cc(Sc2ccccc2)c(-c2nc[nH]n2)nn1-c1ccccc1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
Preparation of N,N-dimethyl-N′-[(6-oxo-1-phenyl-4-phenylsulfanyl-1,6-dihydropyridazin-3-yl)carbonyl]formamidine: A mixture of 6-oxo-1-phenyl-4-phenylsulfanyl-1,6-dihydropyridazine-3-carboxamide (193 mg, 0.6 mmol) and N,N-dimethylformamide dimethyl acetal (1 mL) was stirred at 120° C. for 1 h and then evaporated in vacuo. The residue was crystallized on treatment with Et2O (10 mL) to yield the desired product as a white crystalline substance (196 mg, 88%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:50])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23]CC3C=CC=CC=3)[C:18]=2[O:31]CC2C=CC=CC=2)[CH:7]=[C:6]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH:5]=1.[H][H]>[Pd]>[CH3:1][O:2][C:3](=[O:50])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[C:18]=2[OH:31])[CH:7]=[C:6]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH:5]=1
Reactant: [H][H]
Reactant: CCCCCCCCCCOc1cc(OCCCCCCc2cccc(OCc3ccccc3)c2OCc2ccccc2)cc(C(=O)OC)c1
Agent: [Pd]
Product: CCCCCCCCCCOc1cc(OCCCCCCc2cccc(O)c2O)cc(C(=O)OC)c1
Reaction time: 4.5 h
Yield: 87.4 %

Procedure:
A mixture of 0.7 g of 3-(decyloxy)-5-[[6-[2,3-bis(phenylmethoxy) phenyl]hexyl]oxy]benzoic acid methyl ester and 0.3 g of 10% palladium on carbon was stirred in a hydrogen atmosphere until uptake ceased after 4.5 hours. After the usual workup, the crude product was triturated with hexane and filtered to give 0.45 g (87% yield, mp 71°-72°) of 3-(decyloxy)-5-[[6-(2,3-dihydroxyphenyl) hexyl]oxy]benzoic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([S:12]([N:15]3[CH2:20][CH2:19][CH2:18][C:17](=O)[CH2:16]3)(=[O:14])=[O:13])[C:6]=2[CH:5]=[CH:4][N:3]=1.Cl.[CH2:23]([NH2:29])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C([BH3-])#N.[Na+]>CO>[Cl:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([S:12]([N:15]3[CH2:20][CH2:19][CH2:18][CH:17]([NH:29][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:16]3)(=[O:14])=[O:13])[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: O=C1CCCN(S(=O)(=O)c2cccc3c(Cl)nccc23)C1
Reactant: CCCCCCN
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCCCCCNC1CCCN(S(=O)(=O)c2cccc3c(Cl)nccc23)C1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
To 50 ml of methanol were added 2.47 g of the thus obtained 1-(1-chloro-5-isoquinolinesulfonyl)-3-piperidone, 1.11 g of n-hexylamine hydrochloride and 0.50 g of sodium cyanoborohydride, followed by stirring at 20° C. for 15 hours. The methanol was removed under reduced pressure, and 50 ml of chloroform was added to the resultant product. Then, the mixture was washed twice with 50 ml each of water and then washed once with 50 ml of a 50% aqueous sodium hydrogencarbonate solution, and dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain a residue. The residue thus obtained was subjected to purification by silica gel column chromatography (Wacogel C-200, 100 g; solvent: chloroform) to obtain 2.54 g of 1-(1-chloro-5-isoquinolinesulfonyl)-3-hexylaminopiperidine [Compound (98)]. Compound (98) was analyzed to give the following data.