Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:42])[C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[O:22][CH2:23][C:24]([N:26]2[CH2:31][C@H:30]([CH3:32])[N:29]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[CH2:28][C@H:27]2[CH3:41])=[O:25])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClC(Cl)C.ClCCl>[Cl:21][C:19]1[CH:18]=[CH:17][C:16]([O:22][CH2:23][C:24]([N:26]2[CH2:31][C@H:30]([CH3:32])[N:29]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[CH2:28][C@H:27]2[CH3:41])=[O:25])=[C:15]([C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[O:42])[CH:20]=1
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1C(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
To a solution of (2R, 5S)-4-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester (0.110 g, 0.182 mmol) in dichloroethane (10 ml) was added trifluoroacetic acid (5 ml). The reaction was stirred for two hours at ambient temperature. The reaction was then diluted with dichloromethane and washed with 1N aqueous sodium hydroxide. The organics were dried over magnesium sulfate, filtered and concentrated to give the title compound (0.080 g, 87% yield).
Reaction SMILES: [Na+].[CH2:2]([O:4][C:5](=[O:14])[CH2:6][CH2:7][C:8]([CH3:13])([CH3:12])[C:9]([O-])=[O:10])[CH3:3].C(OC(Cl)=O)(C)C.[BH4-].[Na+].[Cl-].[NH4+]>C1COCC1.CN(C=O)C.C(OCC)(=O)C.CO>[OH:10][CH2:9][C:8]([CH3:12])([CH3:13])[CH2:7][CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:14]
Reactant: CCOC(=O)CCC(C)(C)C(=O)[O-]
Agent: CC(C)OC(=O)Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CCC(C)(C)CO
Temperature: 25 °C
Reaction time: 20 h
Yield: 75.1 %

Procedure:
To a solution of acid from Step 1 (2.92 g, 13.9 mmol) in a mixture of THF/DMF (5:1, 60 mL) was added isopropylchloroformate (2.71 mL, 20.9 mmol). After 20 h of stirring at room temperature, the solution was cooled to 0° C. and NaBH4 (1.06 g, 27.9 mmol) followed methanol (5 mL) was added to the solution. After 30 min of stirring, a saturated aqueous solution of ammonium chloride was added (20 mL) and followed by ethyl acetate (20 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with brine, dried with magnesium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (hexanes/ethyl acetate 95:5 to 60:40). After evaporation at low temperature, ethyl 5-hydroxy-4,4-dimethyl-pentanoate (1.82 g, 75% yield) was obtained as a volatile colorless oil.
Reaction SMILES: C(OC([NH:8][C:9]([NH:27]C(OC(C)(C)C)=O)=[N:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:12]=1)=O)(C)(C)C.[ClH:35]>ClCCl.O1CCOCC1>[ClH:35].[ClH:35].[CH3:26][O:25][C:23]([C:22]1[C:17]([C:13]2[CH:12]=[C:11]([NH:10][C:9]([NH2:27])=[NH:8])[CH:16]=[CH:15][CH:14]=2)=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:24]
Reactant: COC(=O)c1cccnc1-c1cccc(N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)c1cccnc1-c1cccc(NC(=N)N)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of N,N′-bis(tert-butoxycarbonyl)-N″-(3-(3-methoxycarbonylpyridin-2-yl)phenyl)guanidine (203 mg) in dichloromethane (2 ml) was added a solution of hydrogen chloride in 1,4-dioxane (4N, 4 ml), and the mixture was stirred at room temperature for 16 hours. The solvent was evaporated under reduced pressure. To the residue was added 5% ethanol in ethyl acetate (100 ml), and the precipitate was collected by filtration and dried under reduced pressure to give 3-(3-methoxycarbonylpyridin-2-yl)phenyl-guanidine dihydrochloride (142 mg).
Reaction SMILES: [OH:1][S:2]([OH:5])(=O)=[O:3].[C:6]1([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(OCC)C>[N:12]1([C:6]2[CH:11]=[CH:10][C:9]([S:2]([OH:5])(=[O:3])=[O:1])=[CH:8][CH:7]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=S(=O)(O)O
Reactant: c1ccc(N2CCCC2)cc1
Solvent: CCOCC
Product: O=S(=O)(O)c1ccc(N2CCCC2)cc1
Temperature: 170 °C
Reaction time: 3 h
Yield: 47.2 %

Procedure:
A solution of H2SO4 (6.8 g, 68.00 mmol) in diethylether (80 mL) was added to 1-phenylpyrrolidine (10 g, 68.03 mmol) in diethylether (20 mL) at 0° C. The diethylether was decanted, and the resulting solution was stirred for 3 hours at 170° C., then concentrated in vacuo to afford 7.3 g (43%) of 4-(pyrrolidin-1-yl)benzenesulfonic acid as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:15][CH:16]2[CH2:18][CH2:17]2)[C@H:10]([C:12]([OH:14])=O)[CH3:11])=[CH:5][C:4]=1[C:19]([F:22])([F:21])[F:20])#[N:2].[CH3:23][NH:24][CH3:25]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:15][CH:16]2[CH2:18][CH2:17]2)[C@H:10]([C:12]([N:24]([CH3:25])[CH3:23])=[O:14])[CH3:11])=[CH:5][C:4]=1[C:19]([F:22])([F:20])[F:21])#[N:2]
Reactant: C[C@@H](C(=O)O)N(CC1CC1)c1ccc(C#N)c(C(F)(F)F)c1
Reactant: CNC
Product: C[C@@H](C(=O)N(C)C)N(CC1CC1)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described in example 3 using N-[4-cyano-3-(trifluoromethyl)phenyl]-N-(cyclopropylmethyl)alanine and dimethylamine: 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J=8.8 Hz, 1H), 7.10 (d, J=2.5 Hz, 1H), 6.95 (dd, J=8.8, 2.6 Hz, 1H), 4.63 (q, J=6.6 Hz, 1H), 3.19 (m, 2H), 2.98 (s, 3H), 2.90 (s, 3H), 1.38 (d, J=6.8 Hz, 3H), 0.93 (m, 1H), 0.57 (m, 2H), 0.26 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C1(CN)CCCCC1.[O:17]=[C:18]1[C:26]2([CH2:30][O:29][C:28]3[CH:31]=[C:32]4[C:36](=[CH:37][C:27]2=3)[CH2:35][CH2:34][O:33]4)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]1[CH2:38][C:39]1[CH:47]=[CH:46][CH:45]=[CH:44][C:40]=1[C:41](O)=[O:42].O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:41](=[O:42])[C:40]2[CH:44]=[CH:45][CH:46]=[CH:47][C:39]=2[CH2:38][N:19]2[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:26]3([CH2:30][O:29][C:28]4[CH:31]=[C:32]5[C:36](=[CH:37][C:27]3=4)[CH2:35][CH2:34][O:33]5)[C:18]2=[O:17])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Reactant: Nc1cccc(Cl)c1
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: O=C(Nc1cccc(Cl)c1)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using 3-chloroaniline to replace cyclohexanemethylamine, and 2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, N-(3-chlorophenyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide was obtained (81%) as a colorless solid: mp>230° C.; 1H NMR (300 MHz, DMSO-d6) δ10.71 (s, 1H), 7.96-7.90 (m, 1H), 7.65-7.57 (m, 2H), 7.52-7.31 (m, 3H), 7.26-7.10 (m, 4H), 6.99 (dd, J=7.4, 7.4 Hz, 1H), 6.87 (d, J=7.8 Hz, 1H), 6.50 (s, 1H), 6.38 (s, 1H), 5.16-4.99 (m, 2H), 4.82 (d, J=9.4 Hz, 1H), 4.67 (d, J=9.4 Hz, 1H), 4.46 (t, J=8.8 Hz, 2H), 3.01-2.83 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ177.8, 167.8, 161.6, 161.2, 142.8, 140.9, 136.1, 134.5, 133.5, 132.7, 131.1, 130.8, 129.1, 128.5, 127.9, 127.4, 124.1, 123.9, 123.6, 120.9, 120.3, 119.8, 119.6, 118.7, 109.8, 92.9, 80.4, 72.6, 57.4, 41.7, 28.8; MS (ES+) m/z 523.1 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[S:7][C:6]=2[CH:16]=1.ClC1C=CC=C(C(OO)=O)C=1.[OH-:28].[Ca+2].[OH-:30]>C(Cl)Cl>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[S:7](=[O:30])(=[O:28])[C:6]=2[CH:16]=1
Reactant: Oc1ccc2c(c1)Sc1ccccc1CN2
Reactant: [OH-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Ca+2]
Solvent: ClCCl
Product: O=S1(=O)c2ccccc2C=Nc2ccc(O)cc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 10.11-dihydro-7-hydroxydibenzo [b,f][1,4]thiazepin (2.2 g,10 mmoles) and m-chloroperbenzoic acid (3.4 g,20 mmoles) in methylene chloride (250 ml) was stirred at 0° C. for 1 hour. The reaction mixture was treated with 4 g of calcium hydroxide for 15 minutes and was then filtered. The filtrate was chromatographed on silica gel, eluting with 5% methanol in chloroform, to yield the title compound, m.p. 202° (dec.).
Reaction SMILES: [CH3:1][C:2]12[CH2:11][C:6]3([CH2:12][CH3:13])[CH2:7][CH:8]([CH2:10][C:4]([CH3:14])([CH2:5]3)[CH2:3]1)[CH2:9]2.[Br:15]Br.S([O-])([O-])=O.[Na+].[Na+]>>[Br:15][C:8]12[CH2:10][C:4]3([CH3:14])[CH2:5][C:6]([CH2:12][CH3:13])([CH2:11][C:2]([CH3:1])([CH2:3]3)[CH2:9]1)[CH2:7]2
Reactant: CCC12CC3CC(C)(CC(C)(C3)C1)C2
Reactant: BrBr
Agent: O=S([O-])[O-]
Agent: [Na+]
Product: CCC12CC3(C)CC(C)(CC(Br)(C3)C1)C2
Reaction time: 4 h
Yield: 86 %

Procedure:
Mix 0.4 mol of 1,3-dimethyl-5-ethyl adamantane (III) with a ten times excess of bromine (4 mol). Heat slowly and stir for 4 hrs under reflux. Subsequently allow to cool and pour onto ice water. Decompose the excess bromine with sodium sulfite until discolouration of the aqueous solution. Then extract with ether, wash the combined organic phases with sodium bicarbonate solution, dry with magnesium sulfate, filter and evaporate to dryness under vacuum. Recrystallize the residue from methanol. (Yield: 86%).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH:19]=O)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[NH2:23][NH2:24]>C(O)C>[F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH:19]=[N:23][NH2:24])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: NN
Reactant: O=Cc1ccccc1OS(=O)(=O)c1ccc(C(F)(F)F)cc1
Solvent: CCO
Product: NN=Cc1ccccc1OS(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
A solution of 2-formylphenyl 4-(trifluoromethyl)benzenesulfonate (1.7 g, 5.1 mmol) in warm ethanol (100 mL) is added dropwise over 1 hour into a solution of hydrazine (6 equiv) in ethanol (5 mL). The reaction is stirred at room temperature overnight at which time the solvent is evaporated to dryness. The crude product is recrystallized from CH2Cl2/hexane to remove a dimer by-product. An 89% yield of 2-[hydrazonomethyl]phenyl 4-(trifluoromethyl)benzenesulfonate (4.65 g) is obtained.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]([C:27]2[C:36]([C:37]([O:39][CH3:40])=[O:38])=[C:35]3[C:30]([C:31]4[CH:43]=[CH:42][O:41][C:32]=4[CH2:33][O:34]3)=[CH:29][CH:28]=2)COCC[Si](C)(C)C)(=[O:17])=[O:16])=[C:11](/[CH:44]=[CH:45]\[CH2:46][N:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)[CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[F:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:27]2[C:36]([C:37]([O:39][CH3:40])=[O:38])=[C:35]3[C:30]([C:31]4[CH:43]=[CH:42][O:41][C:32]=4[CH2:33][O:34]3)=[CH:29][CH:28]=2)(=[O:16])=[O:17])=[C:11](/[CH:44]=[CH:45]\[CH2:46][N:47]2[CH2:48][CH2:49][O:50][CH2:51][CH2:52]2)[CH:10]=1
Reactant: COC(=O)c1c(N(COCC[Si](C)(C)C)S(=O)(=O)c2ccc(F)cc2/C=C\CN2CCOCC2)ccc2c1OCc1occc1-2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2/C=C\CN2CCOCC2)ccc2c1OCc1occc1-2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.7 %

Procedure:
TFA (2 mL) was added to a solution of methyl 7-{N-[4-fluoro-2-((Z)-3-{morpholin-4-yl}prop-1-enyl)benzenesulfonyl]-N-(2-trimethylsilanylethoxymethyl)amino]-4H-furo[2,3-c]chromene-6-carboxylate (Intermediate 52, 1.15 g) in DCM (20 mL). The reaction mixture was stirred at room temperature for 30 minutes. Aqueous potassium carbonate was added and the layers were separated. The organic layer was dried (Na2SO4), filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 20-80% to give methyl 7-{4-fluoro-2-[(Z)-3-(morpholin-4-yl)prop-1-enyl]benzenesulfonylamino}-4H-furo[2,3-c]chromene-6-carboxylate (0.412 g) as a yellow foam.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:36]([O:38]C)=[O:37])=[CH:12][C:13]=3[N:14]3[CH2:20][CH:19]([C:21]([NH:23][CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[O:22])[CH2:18][C:17]4[CH:30]=[C:31]([O:34][CH3:35])[CH:32]=[CH:33][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CI.[H-].[Na+].[CH3:44]NC(N)=O>CN(C=O)C.CO.CO.C(Cl)Cl>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:36]([OH:38])=[O:37])=[CH:12][C:13]=3[N:14]3[CH2:20][CH:19]([C:21]([N:23]([CH3:44])[CH:24]4[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)=[O:22])[CH2:18][C:17]4[CH:30]=[C:31]([O:34][CH3:35])[CH:32]=[CH:33][C:16]=4[C:15]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)NC1CCOCC1)Cc1cc(OC)ccc1-3
Reactant: CNC(N)=O
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc2c(c1)CC(C(=O)N(C)C1CCOCC1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)O)cc21

Procedure:
Prepared from Methyl 13-cyclohexyl-3-(methyloxy)-6-((tetrahydro-2H-pyran-4-ylamino)carbonyl)-6,7-dihydro-5H-indolo[2,1-a][2]benzazepine-10-carboxylate by methylation using MeI and NaH in DMF in a similar manner as described before; Analytical thin layer chromatography (5% MeOH/CH2Cl2) Rf=0.30; Analytical HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Flow Rate=5 ml/min, Column: Xterra MS C18 S7 3.0×50 mm; LC/MS: (ES+) m/z (M+H)+=531.21, HPLC Rt=1.998 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[F:14][C:15]([F:31])([F:30])[C:16]1[O:20][N:19]=[C:18]([C:21]2[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=2)[C:24](O)=[O:25])[N:17]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([C:24]([C:23]2[CH:27]=[CH:28][CH:29]=[C:21]([C:18]3[N:17]=[C:16]([C:15]([F:30])([F:14])[F:31])[O:20][N:19]=3)[CH:22]=2)=[O:25])[CH2:10][CH2:9]1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: Fc1ccccc1N1CCNCC1
Product: O=C(c1cccc(-c2noc(C(F)(F)F)n2)c1)N1CCN(c2ccccc2F)CC1
Yield: 28 %

Procedure:
This compound was synthesized from 1-(2-fluorophenyl)piperazine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described for example 37 step 3 (45 mg, yield 28%). 1H NMR (400 MHz, CDCl3) δ 8.21-8.20 (m, 2H), 7.68-7.60 (m, 2H), 7.11-6.94 (m, 4H), 4.01 (m, 2H), 3.63 (m, 2H), 3.20-3.06 (m, 4H). MS (ESI) m/z: Calculated for C20H16F4N4O2: 420.12. found: 421.2 (M+H)+
Reaction SMILES: [NH2:1][C@H:2]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[CH:25][CH:24]=1)[CH2:3][C@H:4]([OH:21])[C@@H:5]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:35][O:36][C:37]([NH:39][C@@H:40]([C:44]([CH3:47])([CH3:46])[CH3:45])[C:41](O)=[O:42])=[O:38].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH2:6]([C@H:5]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])[C@@H:4]([OH:21])[CH2:3][C@H:2]([NH:1][C:41](=[O:42])[C@@H:40]([NH:39][C:37]([O:36][CH3:35])=[O:38])[C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[CH:25][CH:24]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](N)Cc1ccc(-c2ccccn2)cc1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.5 %

Procedure:
A solution of the product of Example 1E (1.7 g) in THF (33 mL) was treated with the product of Example 1F (0.81 g, 4.3 mmol), DEPBT (1.5 g, 5.0 mmol), and N,N-diisopropylethylamine (2.9 mL, 16.6 mmol), stirred at 25° C. for 16 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-100% ethyl acetate/dichloromethane to give the title compound (1.55 g, 74% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH2:18][CH2:17][C:16](CC3C=CC=CC=3)(Br)[C:15](=[O:27])[C:8]=2[S:9][C:10]=1[NH:11][C:12](=[O:14])[CH3:13])=[O:5])[CH3:2].[Li+].[Br-].[NH4+].[Cl-]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH:18]=[C:17]([CH2:6][C:7]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:8]=3)[CH:16]=[C:15]([OH:27])[C:8]=2[S:9][C:10]=1[NH:11][C:12](=[O:14])[CH3:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(NC(C)=O)sc2c1CCC(Br)(Cc1ccccc1)C2=O
Agent: [Br-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(NC(C)=O)sc2c(O)cc(Cc3ccccc3)cc12
Temperature: 150 °C
Yield: 43.4 %

Procedure:
A suspension of the bromide 02-5 (8.5 g, 18.9 mmol), LiBr (1.8 g, 20.8 mmol, 1.1 equiv.), Li2CO3 (1.5 g, 20.8 mmol, 1.1 equiv.) and DMF (200 mL) was heated to 150° C. for 4 h under a N2-atmosphere. The reaction mixture was cooled to RT and poured into saturated aqueous NH4Cl (750 mL). The aqueous layer was extracted with EtOAc (3×200 mL). The combined organic layers were washed with H2O (3×200 mL), sat. aq. NH4Cl (200 mL) and dried over Na2SO4. The solvent was removed in vacuo to give the crude product. The solid was washed with Et2O (25 mL) to give 02-6 (1.52 g, 4.1 mmol, 22%). The filtrate was evaporated and the residue was purified by column chromatography (SiO2, EtOAc/hept=1/1) to give another fraction of 02-6 (2.5 g, 6.8 mmol, 36%) as a yellow solid (total yield: 4.3 g, 11.7 mmol, 62%).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH:8]([OH:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[CH3:14][N:15]1[CH:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:17]=[N:16]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>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].O>[F:10][C:9]([F:12])([F:11])[CH:8]([C:5]1[CH:6]=[N:7][C:2]([C:18]2[CH:17]=[N:16][N:15]([CH3:14])[CH:19]=2)=[CH:3][CH:4]=1)[OH:13]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: OC(c1ccc(Br)nc1)C(F)(F)F
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2ccc(C(O)C(F)(F)F)cn2)cn1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
In 1,4-dioxane (2.0 mL) was dissolved 1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethanol (98.6 mg, 0.385 mmol). To the solution were added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (120 mg, 0.578 mmol), cesium carbonate (188 mg, 0.578 mmol), tris(dibenzylideneacetone)dipalladium (5.3 mg, 0.0058 mmol), tricyclohexylphosphine (3.9 mg, 0.0139 mmol) and water (0.2 mL), and the mixture was stirred at 80° C. for 2 hours. Water was added to the reaction mixture. Extraction with ethyl acetate, washing with saturated brine and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=19/1) to give Compound A26 (94.5 mg, 950 yield).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([N+:20]([O-])=O)[C:12](=[O:19])[N:13]([CH2:15][CH2:16][O:17][CH3:18])[CH:14]=1>[Pt].C(O)(=O)C>[NH2:20][CH:11]1[CH2:10][CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])[CH2:14][N:13]([CH2:15][CH2:16][O:17][CH3:18])[C:12]1=[O:19]
Reactant: COCCn1cc(-c2cccc(F)c2F)cc([N+](=O)[O-])c1=O
Agent: [Pt]
Solvent: CC(=O)O
Product: COCCN1CC(c2cccc(F)c2F)CC(N)C1=O
Reaction time: 65 h

Procedure:
10% Platinum on carbon (320 mg) was added to a solution of 5-(2,3-difluorophenyl)-1-(2-methoxyethyl)-3-nitropyridin-2(1H)-one (300 mg, 0.967 mmol) in acetic acid (10 mL). The reaction vessel was evacuated and back-filled with nitrogen (3×), then back-filled with hydrogen (56 psi). After 65 h, the mixture was filtered and concentrated. MS 285 (M+1).
Reaction SMILES: [OH:1][C@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:23])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.[H][H]>C(O)C.[Pd]>[OH:1][C@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:23])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1
Reactant: [H][H]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Pd]
Solvent: CCO
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 96.2 %

Procedure:
A mixture of 3β-hydroxy-5-pregnen-20-one (980 mg, 316.5 g/m, 3.1 mmol) and 50 mg of 5% Pd/C in 50 mL of absolute ethyl alcohol was stirred under 1 atmosphere of hydrogen gas for 5 hours at room temperature. The reaction was filtered through a celite pad and the filtrate evaporated under reduced pressure to give 950 mg of 3β-hydroxy-5α-pregnan-20-one (96% yield).
Reaction SMILES: [CH2:1]([C:3]([C:14]1[S:18][C:17]2[CH:19]=[C:20]([C:23]([OH:25])=[O:24])[CH:21]=[CH:22][C:16]=2[CH:15]=1)([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([CH3:13])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].OS(O)(=O)=O.[C:31]([O-])(O)=O.[Na+]>CO>[CH3:31][O:24][C:23]([C:20]1[CH:21]=[CH:22][C:16]2[CH:15]=[C:14]([C:3]([CH2:4][CH3:5])([C:6]3[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([CH3:13])[CH:7]=3)[CH2:1][CH3:2])[S:18][C:17]=2[CH:19]=1)=[O:25]
Reactant: O=C([O-])O
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1cc2ccc(C(=O)O)cc2s1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: CCC(CC)(c1ccc(O)c(C)c1)c1cc2ccc(C(=O)OC)cc2s1
Yield: 98 %

Procedure:
A solution of 2-[1-ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-benzo[b]thiophene-6-carboxylic acid (3.98 g, 11.23 mmol) in MeOH (100 mL) is treated with H2SO4 (concentrated, 1.0 mL). The mixture is stirred at 80° C. for 8 h and neutralized with aqueous NaHCO3. The MeOH is removed under vacuum and the residue is extracted with EtOAc (2×100 mL). The combined organic layer is dried over Na2SO4, concentrated and purified by silica gel column chromatography (20% EtOAc/Hex) to give the product (4.05 g, 98%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.[B:9]([O-])([O-:14])[O:10]C(C)C.[Li]CCCC>C1COCC1>[F:8][C:6]1[CH:7]=[C:2]([B:9]([OH:14])[OH:10])[CH:3]=[N:4][CH:5]=1
Reactant: CC(C)OB([O-])[O-]
Reactant: Fc1cncc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1cncc(F)c1
Reaction time: 0.5 h

Procedure:
3-bromo-5-fluoropyridine (2a) (25 kg, 142 moles, 1.0 equiv.), THF (222.5 kg) and isopropyl borate (28 kg, 149.3 moles, 1.05 equiv.) were added to a 700 L low temperature reactor. The resulting mixture was cooled to −90° C.˜−80° C. while stirred. Then n-BuLi (40.2 kg, 2.5 M, 142 moles, 1.0 equiv.) was added dropwise (2 kg/h) maintaining the temperature below −87° C. After the addition was complete, the mixture was maintained at −88˜−83° C. for 2.5 h. When the reaction was deemed complete by HPLC analysis, it was quenched by addition of 9% aqueous HCl (7.7 kg). The mixture was transferred to a 1000 L glass-lined reactor and the temperature returned to −20˜−10° C. Additional HCl solution (122.3 kg) was then added until pH was adjusted to 1˜2 maintaining the temperature at 0˜10° C. The mixture was then held for 0.5 h in order to allow layers to separate. The organic layer was separated and washed with saturated brine (38 kg). It was stirred for 0.5 h and then held again for 0.5 h to allow layer separation. The aqueous layer was separated and the combined aqueous layers were extracted with EtOAc twice (51+25 kg). The organic phase was separated and pH was adjusted to a value of 6 by using 30% aqueous NaOH solution (27.4 kg). At this pH a solid precipitated out. The slurry was filtered by centrifuge and allowed to dry in a tray dryer at 40˜45° C. Title compound (2b) was obtained as a white solid (17.5 kg, 87.4%, purity: 98.6% AUC using method B).