Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[Li+].[Cl:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[CH2:27][C:26]2[C@H:21]([CH2:22][CH2:23][C:24](=[O:28])[CH:25]=2)[C@@H:20]2[C@@H:11]1[C@H:12]1[C@@:16]([CH2:18][C@@H:19]2[F:29])([CH3:17])[C:15](=[O:30])[CH2:14][CH2:13]1.C(=O)(O)[O-].[Na+].Cl>C(#N)C.[Cu](Br)Br.O>[Cl:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[CH2:27][C:26]2[CH:25]=[C:24]([OH:28])[CH:23]=[CH:22][C:21]=2[C@@H:20]2[C@@H:11]1[C@H:12]1[C@@:16]([CH2:18][C@@H:19]2[F:29])([CH3:17])[C:15](=[O:30])[CH2:14][CH2:13]1
Reactant: C[C@]12C[C@H](F)[C@H]3[C@@H]([C@H](CCCCCCCl)CC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Agent: Br[Cu]Br
Agent: Cl
Agent: O=C([O-])O
Solvent: CC#N
Solvent: O
Product: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCCCl)[C@H]3[C@@H]1CCC2=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 22.7 %

Procedure:
28.1 g of copper(II) bromide and 5.4 g of lithium bromide in 105 ml of anhydrous acetonitrile are added to 25.2 g of 7α-(6-chlorohexyl)-11β-fluor-estr-4-ene-3,17-dione in 175 ml of anhydrous acetonitrile at 80° C. After 15 minutes, the reaction mixture is cooled to 0° C., and 250 ml of saturated sodium bicarbonate solution is added in drops. Then, the solution is stirred into 1 liter of water, brought to pH=6 with 2N hydrochloric acid, extracted 3 times with ethyl acetate, washed with common salt solution, dried on magnesium sulfate and concentrated by evaporation in a vacuum. Chromatography of the crude product on silica gel with a hexane-ethyl acetate gradient yields 5.7 g of 7α-(6-chlorohexyl)-11β-fluoro-3-hydroxy-estra-1,3,5(10)-trien-17-one as a foam.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]#[N:27])[CH:21]=2)=[C:16]([F:28])[CH:15]=1)[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-:31].[K+].[K+].OO>CS(C)=O.O>[C:1]([O:5][C:6](=[O:29])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26](=[O:31])[NH2:27])[CH:21]=2)=[C:16]([F:28])[CH:15]=1)[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:3])([CH3:4])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)CCN(Cc1ccc(-c2cccc(C#N)c2)c(F)c1)C(=O)OC(C)(C)C
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)CCN(Cc1ccc(-c2cccc(C(N)=O)c2)c(F)c1)C(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 99.9 %

Procedure:
(3′-Cyano-2-fluoro-biphenyl-4-ylmethyl)-(3-methyl-butyl)-carbamic acid tert-butyl ester (I-5d: 1.20 g, 3.02 mmol) was dissolved in dimethyl sulfoxide (5.5 ml) and treated with potassium carbonate (0.502 g, 3.6 mmol) and 0.250 ml of a 30% hydrogen peroxide solution. After 18 hours, the reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound (1.25 g, 99%), which was pure enough to be taken on and used directly in the next reaction.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C@@H:17]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][N:30]=2)=[CH:24][CH:23]=1)[C:18]([OH:20])=[O:19]>CS(C)=O>[C:18]([C@@H:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][N:30]=2)=[CH:24][CH:23]=1)([OH:20])=[O:19]
Reactant: Cc1ccnc(Oc2ccc(C[C@H](N)C(=O)O)cc2)c1
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Solvent: CS(C)=O
Product: Cc1ccnc(Oc2ccc(C[C@H](Nc3nc4ccc(Cl)cc4cc3C(=O)O)C(=O)O)cc2)c1

Procedure:
In close analogy to the procedure described in Example 109c, 2,6-dichloroquinoline-3-carboxylic acid is reacted with (S)-2-amino-3-[4-(4-methyl-pyridin-2-yloxy)-phenyl]-propionic acid (prepared by analogy to Example 109a,b) in DMSO to provide the title compound in good yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:12][CH2:13][CH2:14][Cl:15])[C:9]([OH:11])=O)=[N:6][CH:7]=1.CCN(CC)CC.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[Br:47][C:48]1[CH:53]=[CH:52][C:51]([NH2:54])=[CH:50][CH:49]=1>C(Cl)Cl>[Br:47][C:48]1[CH:53]=[CH:52][C:51]([NH:54][C:9](=[O:11])[CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)[CH2:12][CH2:13][CH2:14][Cl:15])=[CH:50][CH:49]=1
Reactant: Nc1ccc(Br)cc1
Reactant: O=C(O)C(CCCCl)c1ccc(Br)cn1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Br)cc1)C(CCCCl)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(5-Bromo-pyridin-2-yl)-5-chloro-pentanoic acid (1.9 g, 6.5 mmol), Et3N (3.6 mL, 26 mmol), and Pybrop (6 g, 13 mmol) in CH2Cl2 (30 mL) was added 4-bromo-phenylamine (1.45 g, 8.45 mmol). This mixture was stirred overnight at room temperature and then evaporated. The mixture was redissolved in EtOAc (40 mL) and washed with 2N HCl (20 mL×3), brine, 5% NaHCO3 (20 mL×3), brine, dried with Na2SO4, filtered and evaporated. The residue was purified by column chromatography on silica gel using hexane/EtOAc to give a white solid (1.63 g, 56% for two steps). MS: calc'd 444 (MH+), exp 444 (MH+). 1H NMR (400 MHz, CDCl3-d) 9.65 (broad s, 1H), 8.72 (d, 1H, J=2.0 Hz), 8.06 (d, 1H, J=8.4 Hz), 7.53-7.41 (m, 4H), 4.18-4.08 (m, 1H), 3.66-3.54 (m, 2H), 2.45-2.35 (m, 1H), 2.21-2.11 (m, 1H), 1.98-1.87 (m, 1H), 1.83-1.72 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:3]=1[O:4][C:5]1[C:10]([C:11]2[C:19]3[C:14](=[C:15]([O:20]C)[N:16]=[CH:17][CH:18]=3)[N:13]([CH3:22])[CH:12]=2)=[CH:9][C:8]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[C:7]([F:28])[CH:6]=1.Cl.O1CCOCC1>>[F:1][C:2]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:3]=1[O:4][C:5]1[C:10]([C:11]2[C:19]3[CH:18]=[CH:17][NH:16][C:15](=[O:20])[C:14]=3[N:13]([CH3:22])[CH:12]=2)=[CH:9][C:8]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[C:7]([F:28])[CH:6]=1
Reactant: COc1nccc2c(-c3cc(NS(C)(=O)=O)c(F)cc3Oc3ccc(F)cc3F)cn(C)c12
Agent: Cl
Solvent: C1COCCO1
Product: Cn1cc(-c2cc(NS(C)(=O)=O)c(F)cc2Oc2ccc(F)cc2F)c2cc[nH]c(=O)c21
Temperature: 70 °C
Yield: 68.5 %

Procedure:
The product from Example 11E (0.120 g, 0.252 mmol) and 4 M hydrogen chloride in dioxane (10 mL, 40.0 mmol) were combined and heated at 70° C. for 24 hours, cooled and concentrated. The residue was purified by reverse phase HPLC (C18, CH3CN/water (0.1% TFA), 10-100%) to afford the title compound (0.080 g, 68%). 1H NMR (300 MHz, DMSO-d6) δ ppm 10.95 (d, J=5.43 Hz, 1H) 9.57 (s, 1H) 7.41-7.55 (m, 3H) 7.23-7.34 (m, 1H) 7.05-7.15 (m, 1H) 6.86-6.93 (m, 1H) 6.79 (d, J=11.19 Hz, 1H) 6.51 (d, J=5.76 Hz, 1H) 4.09 (s, 3H) 3.03 (s, 3H). MS (ESI+) m/z 464 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]([CH3:23])[S:13]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])C>[OH-].[Na+]>[CH3:23][N:12]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:24])=[O:3]
Reactant: CCOC(=O)CCCCCCCN(C)S(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(S(=O)(=O)N(C)CCCCCCCC(=O)O)cc1

Procedure:
The ester of 8-[Methyl-(toluene-4-sulfonyl)-amino]-octanoic acid ethyl ester was hydrolyzed in aqueous sodium hydroxide to obtain 8-[Methyl-(toluene-4-sulfonyl)-amino]-octanoic acid
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:24][C:25]4[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=4)=[N:18][CH:19]=[C:20]([CH:23]=3)[CH:21]=O)[N:10]=2)=CC=1.[NH2:44][C@H:45]([CH3:48])[CH2:46][OH:47]>>[NH2:8][C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]2[CH:23]=[C:20]([CH2:21][NH:44][C@H:45]([CH3:48])[CH2:46][OH:47])[CH:19]=[N:18][C:17]=2[NH:24][C:25]2[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[N:10]=1
Reactant: C[C@@H](N)CO
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C=O)cnc3Nc3ccc(OC)nc3)n2)cc1
Product: COc1ccc(Nc2ncc(CN[C@H](C)CO)cc2-c2nc(C)nc(N)n2)cn1

Procedure:
The title compound was synthesized following an analogous procedure to Example 220 using 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)nicotinaldehyde (0.230 g, 0.398 mmol) and (R)-2-aminopropanol (Aldrich, St. Louis, Mo.) (0.047 mL, 0.597 mmol). 1H NMR (400 MHz, d6-DMSO) δ 11.82 (s, 1H); 8.93 (d, J=2.35 Hz, 1H); 8.60-8.80 (m, 2H); 8.56 (d, J=2.54 Hz, 1H); 8.38 (d, J=2.54Hz, 1H); 8.13 (dd, J=8.90, 2.84 Hz, 1H); 7.76-7.95 (m, 2H); 6.85 (d, J=8.80 Hz, 1H); 4.17 (t, J=5.67 Hz, 2H); 3.85 (s, 3H); 3.50-3.56 (m, 2H); 3.22-3.32 (m, 1H); 2.44 (s, 3H); 1.26 (d, J=6.65 Hz, 3H). m/z (ESI, +ve ion) 397.1 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[C:13]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)=[N:12]2)[CH2:7][CH2:6]1)=[O:4].[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][C:30]1=[O:38].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:28][O:27][C:21]1[CH:20]=[C:19]([C:13]2[C:14]([CH3:18])([CH3:17])[C:15](=[O:16])[N:11]([CH:8]3[CH2:7][CH2:6][N:5]([C:3](=[O:4])[CH2:2][N:29]4[C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[CH2:31][C:30]4=[O:38])[CH2:10][CH2:9]3)[N:12]=2)[CH:24]=[CH:23][C:22]=1[O:25][CH3:26]
Reactant: O=C1Cc2ccccc2N1
Reactant: COc1ccc(C2=NN(C3CCN(C(=O)CCl)CC3)C(=O)C2(C)C)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(C2=NN(C3CCN(C(=O)CN4C(=O)Cc5ccccc54)CC3)C(=O)C2(C)C)cc1OC

Procedure:
0.5 g 2-[1-(chloroacetyl)piperidin-4-yl]-5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (compound A1), 0.16 g 1,3-dihydro-2H-indol-2-one and 0.7 g K2CO3 in 20 ml of acetonitrile is heated to reflux for 10 h. The acetonitrile is removed in vacuo and the residue dissolved in 70 ml of ethyl acetate and washed four times with 30 ml of water. The organic layer is dried over MgSO4 and concentrated in vacuo. The title product is isolated by column chromatography (silica gel, eluent: ethyl acetate to ethyl acetate/methanol 4:1).
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([NH:12][C:13]([N:15]3C=CN=C3)=[S:14])=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[NH4+]>C(O)C>[C:1]1([C:7]2[S:11][C:10]([NH:12][C:13]([NH2:15])=[S:14])=[N:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: S=C(Nc1nnc(-c2ccccc2)s1)n1ccnc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Product: NC(=S)Nc1nnc(-c2ccccc2)s1
Temperature: 90 °C

Procedure:
1.0 g of the crude mixture with N-(5-phenyl-1,3,4-thiadiazole-2-yl)-1H-imidazole-1-carbothioamide was combined with 0.536 g (6.96 mmol) ammonium acetate in 4 ml ethanol. The reaction mixture was heated in the microwave (at 100 Watt) for 30 minutes at 90° C. After completion of the reaction, the solvent was distilled off under vacuum, and water was added to the residue formed. After extraction with CH2Cl2 and drying of the organic phase with magnesium sulfate, the product crystallized out of the organic solvent and, after filtration, was washed with diethylether. 0.52 g of the N-(5-phenyl-1,3,4-thiadiazole-2-yl)-thiourea was obtained.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[CH3:10][C:11]1[C:12]([NH2:26])=[N:13][C:14]2([C:24]3[C:19](=[CH:20][CH:21]=[C:22]([NH2:25])[CH:23]=3)[O:18][CH2:17][CH2:16]2)[N:15]=1>>[NH2:26][C:12]1[C:11]([CH3:10])=[N:15][C:14]2([C:24]3[C:19](=[CH:20][CH:21]=[C:22]([NH:25][C:7]([C:5]4[S:6][C:2]([CH3:1])=[CH:3][CH:4]=4)=[O:9])[CH:23]=3)[O:18][CH2:17][CH2:16]2)[N:13]=1
Reactant: CC1=NC2(CCOc3ccc(N)cc32)N=C1N
Reactant: Cc1ccc(C(=O)O)s1
Product: CC1=NC2(CCOc3ccc(NC(=O)c4ccc(C)s4)cc32)N=C1N
Yield: 55.8 %

Procedure:
The title compound (45.5 mg, 57% yield) was prepared as described for Example 13a starting from 5-methylthiophene-2-carboxylic acid (32.1 mg, 0.23 mmol) and 5′-methylspiro[chroman-4,2′-imidazole]-4′,6-diamine (Intermediate 30, 52 mg, 0.23 mmol): 1H NMR (500 MHz, DMSO-d6) δ ppm 1.91 (m, 2 H), 2.23 (s, 3 H), 2.47 (s, 3 H), 4.39 (m, 2 H), 6.55 (s, 2 H), 6.73 (d, 1 H), 6.78 (d, 1 H), 6.86 (dd, 1 H), 7.50 (dd, 1 H), 7.73 (d, 1 H), 9.86 (s, 1 H); MS (ES+) m/z 355 [M+H]+.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:8]([C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Br)=[CH:13][CH:12]=1)([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].C(C(C)=O)C>C(OCC)(=O)C>[N+:8]([C:11]1[CH:18]=[CH:17][C:14]([CH2:15][O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:13][CH:12]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(COc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 15.5 h
Yield: 90.6 %

Procedure:
A mixture of phenol (11.3 g), 4-nitrobenzyl bromide (25.9 g), potassium carbonate (16.6 g) and methyl ethyl ketone (100 ml) was stirred for 15.5 hours at 80° C. Ethyl acetate was added thereto, the insoluble material was removed by filtration, the solvent was evaporated in vacuo, and the resulting residue was recrystallized from hexane-ethyl acetate to provide the title compound (pale yellow powder) (24.9 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[CH2:26][O:27][C:28]([CH3:51])([CH3:50])[C:29]([F:49])([F:48])[C@:30]([C:33]3[CH:38]=[C:37](B4OCC(C)(C)CO4)[CH:36]=[CH:35][C:34]=3[F:47])([CH3:32])[N:31]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.O1CCCC1.Cl[C:58]1[O:59][C:60]2[CH:66]=[C:65]([Cl:67])[CH:64]=[CH:63][C:61]=2[N:62]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([C:9]([NH:24][C:25]2[CH2:26][O:27][C:28]([CH3:50])([CH3:51])[C:29]([F:49])([F:48])[C@:30]([C:33]3[CH:38]=[C:37]([C:58]4[O:59][C:60]5[CH:66]=[C:65]([Cl:67])[CH:64]=[CH:63][C:61]=5[N:62]=4)[CH:36]=[CH:35][C:34]=3[F:47])([CH3:32])[N:31]=2)([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:21][CH:20]=1
Reactant: Clc1ccc2nc(Cl)oc2c1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(B4OCC(C)(C)CO4)ccc3F)C(F)(F)C(C)(C)OC2)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(NC2=N[C@](C)(c3cc(-c4nc5ccc(Cl)cc5o4)ccc3F)C(F)(F)C(C)(C)OC2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 85 °C
Yield: 43.6 %

Procedure:
A dried pressure tube was consecutively charged with [bis-(4-methoxy-phenyl)-phenyl-methyl]-{(R)-5-[5-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-2-fluoro-phenyl]-6,6-difluoro-5,7,7-trimethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-yl}-amine (intermediate B10.1) (100 mg, 127 μmol), tetrahydrofuran (3 ml), 2,6-dichlorobenzo[d]oxazole (31.6 mg, 165 μmol), cesium carbonate (165 mg, 507 μmol) and water (1.5 ml). The tube was flushed with argon, thereafter [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (11 mg, 12.7 μmol) was added, the tube was sealed and the reaction mixture heated at 85° C. for 64 hours. For the workup, the reaction mixture was evaporated at reduced pressure and the residue directly purified by chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to 80:20 as the eluent. The [bis-(4-methoxy-phenyl)-phenyl-methyl]-{(R)-5-[5-(6-chloro-benzo oxazol-2-yl)-2-fluoro-phenyl]-6,6-difluoro-5,7,7-trimethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-yl}-amine (41 mg, 44% yield) was obtained as a white solid. MS (ISP): m/z=740.4 [M+H]+ and 742.3 [M+2+H]+.
Reaction SMILES: [C:1]([C:3]1[C:8]([OH:9])=[CH:7][C:6]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[N:12]3[CH:21]=[CH:22][N:23]=[C:11]23)=[C:5]([F:24])[CH:4]=1)#[N:2].[CH2:25](Br)[C:26]#[CH:27].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:3]1[C:8]([O:9][CH2:27][C:26]#[CH:25])=[CH:7][C:6]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([C:17]([F:18])([F:20])[F:19])[N:12]3[CH:21]=[CH:22][N:23]=[C:11]23)=[C:5]([F:24])[CH:4]=1)#[N:2]
Reactant: N#Cc1cc(F)c(-n2c(=O)cc(C(F)(F)F)n3ccnc23)cc1O
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CCOc1cc(-n2c(=O)cc(C(F)(F)F)n3ccnc23)c(F)cc1C#N

Procedure:
A mixture of 8-(4-cyano-2-fluoro-5-hydroxyphenyl)-7,8-dihydro-5-trifluoromethylimidazo[1,2-a]pyrimidin-7-one (0.23 g), propargyl bromide (0.16 g), potassium carbonate (0.14 g) and acetonitrile (15 ml) was heated to reflux for 2 hours. The solvent was distilled off under reduced pressure. The residue was added with water and extracted with ethyl acetate. The extract layer was washed with water and dried on anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was recrystallized from diisopropyl ether to give the compound of interest (0.17 g) as a milk white crystal.
Reaction SMILES: [CH3:1][C:2]([S@@:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[CH:8](=O)[CH3:9]>ClCCl.[O-]S([O-])(=O)=O.[Cu+2]>[CH:8](=[N:7][S:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])[CH3:9]
Reactant: CC=O
Reactant: CC(C)(C)[S@@](N)=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC=NS(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (S)-(−)-2-methyl-2-propanesulfinamide (1.0 g, 8.25 mmol) and acetaldehyde (2.0 mL, 35.61 mmol) in dichloromethane (20 mL) at ambient temperature under nitrogen atmosphere was added CuSO4 (2.9 g, 18.15 mmol). The mixture was stirred at ambient temperature for 18 h. The reaction was filtered through celite and the filtrate solvent was removed under reduced pressure. N-ethylidene-2-methyl-2-propanesulfinamide was obtained as a clear colorless oil (1.18 g; 1H NMR, 400 MHz, CDCl3, 8.8 ppm (q, 11H), 2.24 ppm (d, 3H), 1.2 ppm (s, 9H)).
Reaction SMILES: C(S)C([O-])=O.[OH:6][C@@H:7]1[CH2:30][CH2:29][C@@:28]2([CH3:31])[C@H:9]([CH2:10][C@@H:11]([OH:33])[C@@H:12]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:32])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:23])[CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH2:8]1.Cl>>[OH:6][C@@H:7]1[CH2:30][CH2:29][C@@:28]2([CH3:31])[C@H:9]([CH2:10][C@H:11]([OH:33])[C@@H:12]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:32])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:23])[CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH2:8]1
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: Cl
Agent: O=C([O-])CS
Product: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 12 h
Yield: 70 %

Procedure:
The organism Clostridium absonum (VPI 6903A) is maintained in a chopped meat culture at 4° C. A volume of 1 ml. taken from this chopped meat starter culture is introduced into a 40 ml. volume of freshly autoclaved brain-heart infusion (Barto Brain Heart Infusion B37, Difco Laboratories) broth containing 0.1% thioglycollate. The culture is grown for 12 hours at 37° C., after which it is transferred into 1.0 liter of brain-heart infusion broth containing 0.1% thioglycollate and 5×10-4M 3α, 7α-dihydroxy-5β-cholanoic acid (Chenodeoxycholic Acid). The resultant culture is allowed to grow for 12 hours at 37° C., at which time it is then acidified to pH 3 with HCl and extracted three times with ether. The combined ether extracts were then washed with water, dried over sodium sulfate and evaporated to dryness in vacuo to yield 160 mg of 3α, 7β-dihydroxy-5β-cholanoic acid (yield by thin layer chromatography=70-80%).
Reaction SMILES: CN(C=O)C.[CH2:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1.I[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>CC([O-])=O.CC([O-])=O.[Pd+2].O.ClCCl>[C:16]1([C:7]2[CH2:8][C:9]3[C:14]([CH:6]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C1=Cc2ccccc2C1
Reactant: Ic1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: C1=C(c2ccccc2)Cc2ccccc21

Procedure:
20 ml of DMF, 2.2 g (20 mmol) of indene, 2.2 ml (20 mmol) of iodo-benzene, 2 ml of triethylamine and 0,134 (0,6 mmol) of Pd(OAc)2 were stirred under reflux for 10 hours. The resulting mixture was poured into the mixture of 50 ml of dicloromethane and 50 ml of water. Organic layer was separated, washed twice with water, filtered and dried over Na2SO4. Dicloromethane was removed and the residue was recrystallized from 20 ml of EtOH. The yeld of product was 65 %.
Reaction SMILES: [Br:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:23][CH3:24])[C:10]([N:11]([CH2:19][CH:20]3[CH2:22][CH2:21]3)C(=O)OC(C)(C)C)=[C:6]2[CH:5]=[CH:4][CH:3]=1.Cl.C(OCC)(=O)C.[OH-].[Na+]>C(OCC)(=O)C>[Br:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:23][CH3:24])[C:10]([NH:11][CH2:19][CH:20]3[CH2:21][CH2:22]3)=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: CCc1nn2c(Br)cccc2c1N(CC1CC1)C(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCc1nn2c(Br)cccc2c1NCC1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of crude tert-butyl N-(7-bromo-2-ethylpyrazolo[1,5-a]pyridin-3-yl)-N-cyclopropylmethylcarbamate dissolved in ethyl acetate (10 mL) was added 4N hydrochloric acid/ethyl acetate (30 mL), and the reaction mixture was stirred for 2 hours at room temperature. After completion of the reaction, a 5N aqueous sodium hydroxide solution was added to the reaction mixture while cooling with ice for neutralization. The reaction mixture was extracted with ethyl acetate, and after washing the organic extract with water and brine, it was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (20 g) and the title compound (479 mg) was obtained as a yellow oil from the ethyl acetate:n-hexane (1:3) fraction.
Reaction SMILES: C[O:2][C:3](=[O:34])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:23](=[O:33])[NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=2)=[CH:20][C:21]=1[Br:22])=[O:16])[CH2:5][NH:6][C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8].O.[OH-].[Li+].Cl>C1COCC1.O>[Br:22][C:21]1[CH:20]=[C:19]([C:23](=[O:33])[NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=2)[S:18][C:17]=1[C:15]([NH:14][C@@H:4]([CH2:5][NH:6][C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8])[C:3]([OH:34])=[O:2])=[O:16]
Reactant: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1sc(C(=O)NCc2cccc(O)c2)cc1Br
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NC[C@H](NC(=O)c1sc(C(=O)NCc2cccc(O)c2)cc1Br)C(=O)O)c1cccs1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of (S)-2-{[3-Bromo-5-(3-hydroxy-benzylcarbamoyl)-thiophene-2-carbonyl]-amino}-3-[(thiophene-2-carbonyl)-amino]-propionic acid methyl ester (24.2 mg, 0.043 mmol) in THF (3 mL) was added a solution of lithium hydroxide monohydrate (120 mg, 2.87 mmol) in water (4 mL). The mixture was then stirred at room temperature 15 h. The mixture was then acidified with 1N HCl and extracted with EtOAc (×3). The extracts were combined, washed with water and brine, dried over sodium sulfate, filtered, and evaporated to pure product, 20.6 mg (87%). MS m/e 553.8 (M+H+).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)=[C:15]3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.C([O:37][CH2:38][C:39](Cl)=[O:40])(=O)C>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:38](=[O:37])[CH2:39][OH:40])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:33])[NH:14][C:15]=23)[CH2:31][CH2:32]1
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ccnc2c1C(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ccnc2c1C(=O)N[C@H]1CC[C@@H](NC(=O)CO)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-fluorophenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f9) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.