Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:31]=[CH:30][C:6]([O:7][C:8]2[CH:28]=[CH:27][C:11]([O:12][CH2:13][CH2:14][CH2:15][N:16]3C(=O)C4C(=CC=CC=4)C3=O)=[CH:10][C:9]=2[F:29])=[C:5]([OH:32])[CH:4]=1)[CH3:2].O.NN.Cl>CO>[NH2:16][CH2:15][CH2:14][CH2:13][O:12][C:11]1[CH:27]=[CH:28][C:8]([O:7][C:6]2[CH:30]=[CH:31][C:3]([CH2:1][CH3:2])=[CH:4][C:5]=2[OH:32])=[C:9]([F:29])[CH:10]=1
Reactant: CCc1ccc(Oc2ccc(OCCCN3C(=O)c4ccccc4C3=O)cc2F)c(O)c1
Agent: Cl
Agent: NN
Solvent: CO
Solvent: O
Product: CCc1ccc(Oc2ccc(OCCCN)cc2F)c(O)c1
Temperature: 0 °C
Yield: 41.7 %

Procedure:
To a solution of 2-{3-[4-(4-Ethyl-2-hydroxy-phenoxy)-3-fluoro-phenoxy]-propyl}-isoindole-1,3-dione (0.096 mmol; 42 mg) in methanol (2 mL), under argon, was added hydrazine monohydrate (0.21 mmol; 10 μL). The reaction was heated to reflux for 1 h 30. After cooling to 0° C., the mixture was hydrolysed with HCl 1N and filtered. The filtrate was basified with NaOH 0.1 N (pH=11) and extracted with chloroform (3*5 ml). Combined organic phases were dried over Na2SO4, concentrated in vacuo. The title compound (13 mg; 0.04 mmol; 44%) was obtained as yellow oil, after purification by preparative TLC (dichloromethane/methanol/NH4OH: 90/10/1).
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].C(OC([N:12]1[CH2:17][C@@H:16]([CH2:18]OS(C2C=CC(C)=CC=2)(=O)=O)[C@H:15]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][O:37][CH2:38][C@H:39]([O:41][CH2:42][CH3:43])[CH3:40])=[CH:32][CH:31]=2)[C@@H:14]([O:44][CH2:45][C:46]2[CH:47]=[CH:48][C:49]3[O:54][CH2:53][CH2:52][N:51]([CH2:55][CH2:56][CH2:57][O:58][CH3:59])[C:50]=3[CH:60]=2)[CH2:13]1)=O)(C)(C)C>CN1CCCN(C)C1=O.CC(OC)(C)C>[CH2:42]([O:41][C@H:39]([CH3:40])[CH2:38][O:37][CH2:36][C:33]1[CH:34]=[CH:35][C:30]([C@@H:15]2[C@@H:14]([O:44][CH2:45][C:46]3[CH:47]=[CH:48][C:49]4[O:54][CH2:53][CH2:52][N:51]([CH2:55][CH2:56][CH2:57][O:58][CH3:59])[C:50]=4[CH:60]=3)[CH2:13][NH:12][CH2:17][C@H:16]2[CH2:18][NH2:1])=[CH:31][CH:32]=1)[CH3:43]
Reactant: [N-]=[N+]=[N-]
Reactant: CCO[C@H](C)COCc1ccc([C@H]2[C@H](COS(=O)(=O)c3ccc(C)cc3)CN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Solvent: COC(C)(C)C
Product: CCO[C@H](C)COCc1ccc([C@H]2[C@H](CN)CNC[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4.57 mmol of sodium azide are added to a solution of 0.91 mmol of (3R,4R,5S)-4-[4-((R)-2-ethoxy-propoxymethyl)-phenyl]-3-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-5-(toluene-4-sulfonyloxymethyl)-piperidine-1-carboxylic acid tert-butyl ester (example 5d) in 5 ml of 1,3-dimethyl-tetrahydro-pyrimidin-2-one (DMPU) under argon at 50° C. After 2 h, the reaction mixture is cooled to RT, diluted with TBME, washed successively with H2O (2×) and brine, dried over Na2SO4 and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) as a pale yellow oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.27 (EtOAc/heptane 1:1); Rt=5.98 (gradient I).
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]([C:11]([O:13][CH3:14])=[O:12])=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1.Br[CH2:16][C:17]#[C:18][CH3:19].C(N(CC)C(C)C)(C)C>O1CCCC1>[Br:1][C:2]1[N:6]([CH2:16][C:17]#[C:18][CH3:19])[C:5]([C:7]([O:9][CH3:10])=[O:8])=[C:4]([C:11]([O:13][CH3:14])=[O:12])[N:3]=1
Reactant: COC(=O)c1nc(Br)[nH]c1C(=O)OC
Reactant: CC#CCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC#CCn1c(Br)nc(C(=O)OC)c1C(=O)OC
Yield: 75 %

Procedure:
A solution of 15.0 g (57.0 mmol) of dimethyl 2-bromo-imidazole-4,5-dicarboxylate, 5.15 ml (57.0 mmol) of 1-bromo-2-butyne and 50 ml of N,N-diisopropylethylamine in 280 ml of tetrahydrofuran was refluxed for one hour. The mixture was concentrated by evaporation, the residue combined with approx. 100 ml of water and extracted three times with 70 ml of ethyl acetate. The extracts were washed with 50 ml of water, dried and evaporated down. The crude product thus obtained was purified by column chromatography (silica gel; eluant:dichloromethane with 0–2% ethanol).
Reaction SMILES: Br[C:2]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7]C)=[O:5].[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C([O-])([O-])=O.[Na+].[Na+]>C(O)CCC>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:2]2[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCOC(=O)c1cccc([N+](=O)[O-])c1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: COC(=O)c1cccc([N+](=O)[O-])c1N1CCN(C(=O)OC(C)(C)C)CC1
Yield: 72 %

Procedure:
To a stirred solution of 736 mg (2.83 mmol) of ethyl 2-bromo-3-nitrobenzoate and 579 mg (3.1 mmol, 1.1 eq) of 1-tert-butyloxycarbonylpiperazine in n-butanol (6 mL) was added 330 mg (3.1 mmol, 1.1 eq) of Na2CO3. The mixture was heated to reflux for 4 h. The solvent was removed under reduced pressure. The crude product was partitioned between EtOAc (100 mL) and 20 mL of H2O. The organic layer was washed with H2O (2×20 mL), dried over Na2SO4 and concentrated. Column chromatography (silica, 10-20% EtOAc/hexanes) provided 744 mg (72%) of 4-(2-methoxycarbonyl-6-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester. TLC (silica, 20% EtOAc/hexanes): Rf=0.5. 1H NMR (400 MHz, CDCl3): 7.67 (dd, J=8.2, 1.4 Hz, 1H), 7.62 (dd, J=8.2, 1.4 Hz, 1H), 7.16 (t, J=8.2 Hz, 1H), 3.86 (s, 3H), 3.44-3.36 (m, 4H), 3.03-2.95 (m, 4H), 1.48 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:21])=[C:4]([F:20])[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[Cl:19])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(N(C(C)C)CC)(C)C.[CH3:31][C:32]1([CH3:40])[O:36][C@H:35]([CH2:37][O:38][NH2:39])[CH2:34][O:33]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCCC1>[Cl:1][C:2]1[C:3]([F:21])=[C:4]([F:20])[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[Cl:19])=[C:6]([CH:10]=1)[C:7]([NH:39][O:38][CH2:37][C@@H:35]1[CH2:34][O:33][C:32]([CH3:40])([CH3:31])[O:36]1)=[O:9]
Reactant: O=C(O)c1cc(Cl)c(F)c(F)c1Nc1ccc(I)cc1Cl
Reactant: CC1(C)OC[C@@H](CON)O1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC1(C)OC[C@@H](CONC(=O)c2cc(Cl)c(F)c(F)c2Nc2ccc(I)cc2Cl)O1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
A 1L single necked round-bottomed flask equipped with a magnetic stirrer was charged with a solution of 5-chloro-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-benzoic acid (59.6 g, 135 mmol) in dry tetrahydrofuran (300 mL). The solution was cooled to 0° C. in an ice-acetone bath. To this solution was added diisopropylethylamine (34.8 g, 270 mmol), (S)-O-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine (29.7 g, 202 mmol), 1-hydroxybenzotriazole (30.93 g, 202 mmol), and benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP) (89.32 g, 202 mmol). After 30 minutes, the cooling bath was removed, and the reaction was stirred at ambient temperature for 18 hrs. The solvent was evaporated in vacuo, and the residue was dissolved in diethyl ether. The organic solution was washed with 10% aqueous sodium hydroxide (3×500 mL) and brine, and dried (MgSO4). The solution was concentrated to afford 5-chloro-2-(2-chloro-4-iodo-phenylamino)-N-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-3,4-difluoro-benzamide (69.9 g) as a pale yellow solid that was used directly in the next hydrolysis reaction.
Reaction SMILES: O.NN.[Br:4][C:5]1[CH:6]=[CH:7][C:8]2[N:14]3[C:15]([CH2:18][O:19][N:20]4C(=O)C5=CC=CC=C5C4=O)=[N:16][N:17]=[C:13]3[CH2:12][N:11]=[C:10]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)[C:9]=2[CH:37]=1>C(O)C>[NH2:20][O:19][CH2:18][C:15]1[N:14]2[C:8]3[CH:7]=[CH:6][C:5]([Br:4])=[CH:37][C:9]=3[C:10]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)=[N:11][CH2:12][C:13]2=[N:17][N:16]=1
Reactant: O=C1c2ccccc2C(=O)N1OCc1nnc2n1-c1ccc(Br)cc1C(c1ccccn1)=NC2
Agent: NN
Solvent: CCO
Solvent: O
Product: NOCc1nnc2n1-c1ccc(Br)cc1C(c1ccccn1)=NC2

Procedure:
In the manner given in Example 2, a solution of hydrazine hydrate in ethanol is treated at 65° C. with 8-bromo-1-[(phthalimidooxy)methyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine to give 1-[(aminooxy)methyl]-8-bromo-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C@@H:33]([N:38]([CH3:46])[C:39](=[O:45])[C@H:40]([CH:42]([CH3:44])[CH3:43])[NH2:41])[C@@H:34]([CH3:37])[CH2:35][CH3:36])[CH2:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C@H:12]([O:31][CH3:32])[C@@H:13]([CH3:30])[C:14](=[O:29])[NH:15][C@H:16]([C:24]1[S:25][CH:26]=[CH:27][N:28]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:6].[C:47]([O:51][C:52]([N:54]1[CH2:59][CH2:58][CH2:57][CH2:56][C@:55]1([CH3:63])[C:60](O)=[O:61])=[O:53])([CH3:50])([CH3:49])[CH3:48].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>ClCCl>[CH3:1][O:2][C@@H:3]([C@@H:33]([N:38]([CH3:46])[C:39](=[O:45])[C@@H:40]([NH:41][C:60]([C@@:55]1([CH3:63])[CH2:56][CH2:57][CH2:58][CH2:59][N:54]1[C:52]([O:51][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:53])=[O:61])[CH:42]([CH3:44])[CH3:43])[C@@H:34]([CH3:37])[CH2:35][CH3:36])[CH2:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C@H:12]([O:31][CH3:32])[C@@H:13]([CH3:30])[C:14](=[O:29])[NH:15][C@H:16]([C:24]1[S:25][CH:26]=[CH:27][N:28]=1)[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:6]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@]1(C)C(=O)O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](N)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](NC(=O)[C@@]1(C)CCCCN1C(=O)OC(C)(C)C)C(C)C
Yield: 41.5 %

Procedure:
According to the general procedure D, from #86 (400 mg, 0.6 mmol, 1 eq.), #157 (146 mg, 0.6 mmol, 1 eq.), dichloromethane (10 mL), HATU (259 mg, 0.72 mmol, 1.2 eq.) and N,N-diisopropylethylamine (158 mg, 1.2 mmol, 2 eq.) was synthesized the crude desired material, which was purified by silica gel chromatography (Gradient: 0.01 to 0.05% methanol in dichloromethane) to afford #189 (220 mg, 37%) as a white solid. HPLC (Protocol W): m/z 883.7 [M+H+], retention time=4.12 minutes (purity=95%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:27])=[C:21]([CH:23]=[CH:24][C:25]=2[F:26])[NH2:22])[CH:5]=[CH:4][N:3]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=1[S:36](Cl)(=[O:38])=[O:37]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[N:10][C:9]=2[C:19]2[C:20]([F:27])=[C:21]([NH:22][S:36]([C:30]3[CH:31]=[C:32]([F:35])[CH:33]=[CH:34][C:29]=3[F:28])(=[O:38])=[O:37])[CH:23]=[CH:24][C:25]=2[F:26])[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccc(F)c(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F
Reactant: O=S(=O)(Cl)c1cc(F)ccc1F
Product: O=S(=O)(Nc1ccc(F)c(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1cc(F)ccc1F

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2,4-difluoroaniline (900 mg, 2.196 mmol) and 2,5-difluorobenzenesulfonyl chloride (0.355 mL, 2.64 mmol) the title compound of Step H was obtained as a light yellow solid (774 mg, 60% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.41 (d, J=5.5 Hz, 1H), 7.48-7.57 (m, 4H), 7.29 (t, J=8.8 Hz, 1H), 6.57 (d, J=5.5 Hz, 1H), 3.70-3.74 (m, 4H), 3.52-3.55 (m, 4H). MS (ESI): 585 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]3[CH2:12][NH:13][CH2:14][CH2:15][N:10]3[C:9](=[O:16])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:23]1[C:32]2[C:27](=[CH:28][C:29]([C:33](O)=[O:34])=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[C:17]1([C:7]2([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:11]3[CH2:12][N:13]([C:33]([C:29]4[CH:28]=[C:27]5[C:32](=[CH:31][CH:30]=4)[N:23]=[CH:24][CH:25]=[CH:26]5)=[O:34])[CH2:14][CH2:15][N:10]3[C:9](=[O:16])[O:8]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(O)c1ccc2ncccc2c1
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)C2CNCCN12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccc2ncccc2c1)N1CCN2C(=O)OC(c3ccccc3)(c3ccccc3)C2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.7 %

Procedure:
Hexahydro-1,1-diphenyl-3H-oxazolo[3,4-a]pyrazin-3-one (0.15 g, 0.51 mmol), quinoline-6-carboxylic acid (0.11 g, 0.63 mmol), 1-hydroxybenzotriazole (0.10 g, 0.74 mmol) were dissolved in N,N-dimethylformamide (5 mL). 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.15 g, 0.78 mmol) was added thereto, and the mixture was stirred at room temperature for 2 hours and 30 minutes. The reaction solution was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with a 1 N aqueous sodium hydroxide solution, water and saturated brine, and dried over magnesium sulfate. The solid was filtered off, and the filtrate was concentrated. The residue was purified with amino silica gel column chromatography (hexane:ethyl acetate=1:1 to ethyl acetate) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain the title compound (0.13 g, yield 57%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.[OH-].[Na+].C([O-])(=[O:17])C.[Na+].Cl>O>[OH:17][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1
Reactant: O=C(O)Cc1ccc(CBr)cc1
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)Cc1ccc(CO)cc1
Temperature: 25 °C
Yield: 55.1 %

Procedure:
A solution of 9.00 g (39.3 mmol) of p-bromomethylphenylacetic acid, 3.14 g (78.6 mmol) of sodium hydroxide and 3.54 g (43.2 mmol) of sodium acetate in 40 ml of water was stirred for 4 hours at 100° C. At the end of this time, it was cooled to room temperature and then acidified with 2N aqueous hydrochloric acid. It was then extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was recrystallized from a mixture of ethyl acetate and methylene chloride to give 3.60 g (yield 55%) of the title compound, melting at 136°-137° C.
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]([CH3:41])=[C:11]([CH3:40])[C:12]=1[C:13]([C:15]1[CH:34]=[CH:33][C:18]([O:19][S:20]([C:23]2[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[C:25]([OH:32])[CH:24]=2)(=[O:22])=[O:21])=[C:17]([CH:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)[CH:16]=1)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:42](OC(=O)C)(=[O:44])[CH3:43].[I-].[Mg+2].[I-]>CCOCC>[C:42]([O:32][C:25]1[CH:24]=[C:23]([S:20]([O:19][C:18]2[CH:33]=[CH:34][C:15]([C:13]([C:12]3[C:11]([CH3:40])=[C:10]([CH3:41])[O:9][C:8]=3[CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:14])=[CH:16][C:17]=2[CH:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)(=[O:22])=[O:21])[CH:31]=[CH:30][C:26]=1[C:27]([OH:29])=[O:28])(=[O:44])[CH3:43]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1oc(Cc2ccccc2)c(C(=O)c2ccc(OS(=O)(=O)c3ccc(C(=O)O)c(O)c3)c(C3CCCC3)c2)c1C
Agent: [I-]
Agent: [Mg+2]
Solvent: CCOCC
Product: CC(=O)Oc1cc(S(=O)(=O)Oc2ccc(C(=O)c3c(Cc4ccccc4)oc(C)c3C)cc2C2CCCC2)ccc1C(=O)O
Temperature: 25 °C
Yield: 80 %

Procedure:
A stirred solution containing 4-[4-(2-benzyl-4,5-dimethyl-furan-3-carbonyl)-2-cyclopentyl-phenoxysulfonyl]-2-hydroxy-benzoic acid (0.235 g, 0.409 mmol), acetic anhydride (3.3 mL) and magnesium iodide (0.113 g, 0.409 mmol) in ether (8 mL) was refluxed for 0.5 h. The reaction was allowed to cool to ambient temperature, quenched with H2O (100 mL), extracted with ether and concentrated. The mixed anhydride/product was dissolved in THF (6 mL), treated with H2O (6 mL) and refluxed for 0.5 h. The reaction was allowed to cool to ambient temperature, quenched with H2O (100 mL), extracted with ether and concentrated. Purification on 2% H3PO4 /MeOH treated silica gel, eluting with a 18 & 25% EtOAc/pet ether step gradient followed by crystallization from acetone/hexane gave 0.201 g (80%) of the title compound as an off white solid, mp 55-90° C. 1H NMR (DMSO-d6) δ 1.23-1.32 (m, 2 H), 1.50-1.53 (m, 2 H), 1.64-1.72 (m, 4 H), 1.76 (s, 3 H), 2.17 (s, 3 H), 2.23 (s, 3 H), 2.92 (quintet, 1 H), 3.79 (s, 2 H), 6.98-7.00 (m, 2 H), 7.15-7.23 (m, 4 H), 7.53 (dd, 1 H), 7.58 (d, 1 H), 7.84 (d, 1 H), 7.88 (dd, 1 H), 8.12 (d, 1 H) 13.7 (br s, 1 H). mass spectrum (-ESI) m/z 615 (M-H). Anal. Calcd. for C34H32O9S.0.5H2O: C, 65.27; H, 5.32; N, 0.00. Found: C, 65.33; H, 5.30; N, 0.03.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]2[CH:3]1[CH:4]2[C:8]([O:10]CC)=[O:9].Cl>[OH-].[Na+]>[O:1]=[C:2]1[CH2:7][CH2:6][CH:5]2[CH:3]1[CH:4]2[C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)C1C2CCC(=O)C21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C1C2CCC(=O)C21
Reaction time: 2.5 h

Procedure:
A mixture of 60 g of (1SR,5RS,6SR)ethyl 2-oxobicyclo[3.1.0]hexane-6-carboxylate and 300 ml of 1N sodium hydroxide was stirred at 25°-30° C. After 2.5 hours, concentrated hydrochloric acid was added to adjust the pH to 0.8-1.2. The resulting solution was extracted with ethyl acetate. The extracts were dried over magnesium sulfate, filtered, and concentrated to give 49.1 g (98%) of the crude material. Recrystallization from 100 ml of ethyl acetate gave the title compound, mp 123.5°-128° C.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.F[C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([NH:19][C:20]2[N:25]=[C:24]([C:26]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[NH:28][CH:27]=3)[CH:23]=[CH:22][N:21]=2)=[C:12]([O:35][CH3:36])[CH:11]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH3:1][N:2]([CH3:8])[C@@H:3]1[CH2:7][CH2:6][N:5]([C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([NH:19][C:20]3[N:25]=[C:24]([C:26]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[NH:28][CH:27]=4)[CH:23]=[CH:22][N:21]=3)=[C:12]([O:35][CH3:36])[CH:11]=2)[CH2:4]1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1nccc(-c2c[nH]c3ccccc23)n1
Reactant: CN(C)[C@@H]1CCNC1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N2CC[C@@H](N(C)C)C2)c([N+](=O)[O-])cc1Nc1nccc(-c2c[nH]c3ccccc23)n1
Temperature: 140 °C
Yield: 84.2 %

Procedure:
(3R)—N,N-Dimethylpyrrolidin-3-amine (92 mg, 0.81 mmol) was added to a mixture of N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1H-indol-3-yl)pyrimidin-2-amine (Intermediate 68, 404 mg, 0.73 mmol) and DIPEA (0.256 mL, 1.46 mmol) in DMA 3 mL. The mixture was then heated in a microwave at 140° C. for 0.5 h. Part-purification was achieved by ion-exchange chromatography, using an SCX column (20 g) and eluting with 0.35M methanolic ammonia. Appropriate fractions were combined and concentrated in vacuo to provide an orange/brown gum. This gum was triturated with ethanol (15 mL) to give a solid which was collected by filtration and dried under vacuum to give the title compound (291 mg, 84%) as an orange solid; 1H NMR: 1.82 (1H, dt), 2.12-2.20 (1H, m), 2.22 (6H, s), 2.73-2.83 (1H, m), 3.12-3.22 (2H, m), 3.22-3.27 (1H, m), 3.41-3.51 (1H, m), 3.97 (3H, s), 6.58 (1H, s), 7.07 (1H, t), 7.18 (1H, t), 7.26 (1H, d), 7.45 (1H, d), 8.00 (1H, s), 8.28-8.31 (2H, m), 8.35 (1H, d), 8.57 (1H, s), 11.78 (1H, s); m/z: ES+ MH+ 474.30.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[N:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:14][CH:15]=2)[N:7]=[C:6]([C:27](O)=[O:28])[CH:5]=1)[CH2:2][CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CN(C=O)C.[NH2:68][C@H:69]([CH2:74][C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][C:76]=1[Cl:81])[CH2:70][C:71]([OH:73])=[O:72].Cl>>[Cl:81][C:76]1[CH:77]=[CH:78][CH:79]=[CH:80][C:75]=1[CH2:74][C@@H:69]([NH:68][C:27]([C:6]1[CH:5]=[C:4]([CH2:1][CH2:2][CH3:3])[N:8]([CH2:9][C:10]2[CH:11]=[N:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:14][CH:15]=2)[N:7]=1)=[O:28])[CH2:70][C:71]([OH:73])=[O:72]
Reactant: CCCc1cc(C(=O)O)nn1Cc1ccc(-c2ccccc2-c2nnn[nH]2)nc1
Reactant: N[C@@H](CC(=O)O)Cc1ccccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(C(=O)N[C@@H](CC(=O)O)Cc2ccccc2Cl)nn1Cc1ccc(-c2ccccc2-c2nnn[nH]2)nc1
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A solution of 5-propyl-1-{6-[2-(1H-tetrazol-5-yl)phenyl]pyridin-3-ylmethyl}-1H-pyrazole-3-carboxylic acid (20 mg, 0.05 mmol), HATU (19.5 mg, 0.0514 mmol) and DIPEA (44.7 uL, 257 μmol) in DMF (1.59 mL, 20.5 mmol) was stirred to pre-activate the acid. After 30 minutes, (R)-3-amino-4-(2-chlorophenyl)butanoic acid.HCl (12.8 mg, 0.0514 mmol)) was added. The resulting solution was stirred overnight. The mixture was concentrated, re-dissolved in water/MeCN/TFA and purified using reverse phase liquid chromatography to yield the title compound (20.5 mg; 100% purity) as a TFA salt. MS m/z: [M+H]+ calcd for C30H29ClN8O3, 585.21; found 585.4.
Reaction SMILES: O=[C:2]1[CH:8]([CH2:9][C:10]([OH:12])=O)[CH2:7]C[S:5][C:4]2[S:13][CH:14]=[CH:15][C:3]1=2.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][NH2:24])=[CH:19][CH:18]=1>C(O)C>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:10](=[O:12])[CH2:9][CH:8]3[CH2:7][S:5][C:4]4[S:13][CH:14]=[CH:15][C:3]=4[C:2]3=[N:24]2)=[CH:19][CH:18]=1
Reactant: O=C(O)CC1CCSc2sccc2C1=O
Reactant: NNc1ccc(Cl)cc1
Solvent: CCO
Product: O=C1CC2CSc3sccc3C2=NN1c1ccc(Cl)cc1
Yield: 33.2 %

Procedure:
A mixture of 3.7 g of 4-oxo-4,5,6,7-tetrahydrothieno[2,3-b]thiepin-5-acetic acid and 2.6 g of 4-chlorophenylhydrazine in 50 ml of ethanol is refluxed under heating for 6.5 hours. Then, the reaction mixture is concentrated under reduced pressure. The resulting residue is dissolved in 40 ml of acetic acid and the mixture is further refluxed under heating for 1.5 hours. After cooling, the mixture is concentrated under reduced pressure, and the residue is subjected to column chromatography on silica gel and eluted with chloroform. The crystals obtained from the fraction are recrystallized from a mixed solvent of chloroform and ethanol to give 1.7 g of 2-(4-chlorophenyl)-4,4a,5,6-tetrahydrothieno[2',3':2,3]thiopyrano[4,5-c]pyridazin-3(2H)-one as pale brown crystals, melting at 134°-135° C.
Reaction SMILES: [N+:1]([C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[C:6]([CH3:11])[N:5]=1)([O-])=O.C>CO>[NH2:1][C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[C:6]([CH3:11])[N:5]=1
Reactant: Cc1ccc(O)c([N+](=O)[O-])n1
Solvent: CO
Product: Cc1ccc(O)c(N)n1

Procedure:
3.5 g of 2-nitro-3-hydroxy-6-methylpyridine in 50 ml of methanol are placed under hydrogen pressure in the presence of one gram of palladinized charcoal. The mixture is stirred and filtered. The methanol is evaporated.
Reaction SMILES: [CH3:1][O:2][C@H:3]([C@@H:14]([CH3:20])[C@@H:15]([O:18][CH3:19])[C:16]#[CH:17])[C@@H:4]([CH3:13])[CH2:5][O:6]C(=O)C(C)(C)C.C[O-].[Na+]>CO>[CH3:1][O:2][C@H:3]([C@@H:14]([CH3:20])[C@@H:15]([O:18][CH3:19])[C:16]#[CH:17])[C@@H:4]([CH3:13])[CH2:5][OH:6]
Reactant: C#C[C@H](OC)[C@H](C)[C@@H](OC)[C@@H](C)COC(=O)C(C)(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C#C[C@H](OC)[C@H](C)[C@@H](OC)[C@@H](C)CO
Reaction time: 8 h

Procedure:
To 2,2-Dimethyl-propionic acid (2S,3S,4R,5R)-3,5-dimethoxy-2,4-dimethyl-hept-6-ynyl ester (750 mg, 2.64 mmol) in anhydrous methanol (10 ml) at room temperature and under an atmosphere of nitrogen was added sodium methoxide (30% wt in MeOH, 3.8 ml, 21.1 mmol). The reaction was stirred overnight, quenched with saturated ammonium chloride and extracted with dichloromethane (3×). The combined organic layers were dried by passing through a hydrophobic frit and concentrated in vacuo. The product was purified by flash chromatography (SiO2, iHex/EtOAc, 6:1 then 2:1) to afford 500 mg (94%) as a clear oil. 1H NMR (300 MHz, CDCl3) δ 3.86 (dd, J=9.4 Hz, 2.1 Hz, 1H), 3.75-3.60 (m, 2H), 3.49 (s, 3H), 3.48 (m, 1H), 3.46 (s, 3H), 2.59 (m, 1H), 2.49 (d, J=2.1 Hz, 1H), 2.03-1.84 (m, 2H), 1.04 (d, J=7.0 Hz, 3H), 0.90 (d, J=7.0 Hz, 3H).