Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=4)=[CH:13][CH:14]=3)[CH2:9]2)[N:5]=[C:4]([NH2:25])[N:3]=1.[CH3:26][N:27]1[CH2:33][CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH3:26][N:27]1[CH2:33][CH2:32][CH2:31][N:30]([C:2]2[CH:7]=[C:6]([N:8]3[CH:17]([CH3:18])[CH2:16][C:15]4[C:10](=[CH:11][C:12]([C:19]5[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=5)=[CH:13][CH:14]=4)[CH2:9]3)[N:5]=[C:4]([NH2:25])[N:3]=2)[CH2:29][CH2:28]1
Reactant: CN1CCCNCC1
Reactant: CC1Cc2ccc(-c3cnn(C)c3)cc2CN1c1cc(Cl)nc(N)n1
Product: CC1Cc2ccc(-c3cnn(C)c3)cc2CN1c1cc(N2CCCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 118 starting from 4-chloro-6-[3-methyl-7-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl]pyrimidin-2-amine and 1-methyl-1,4-diazepane (Aldrich, Cat. No. 186090). LCMS (M+H)+: m/z=433.3.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]([C@@H:20]([NH:22][C:23]3[N:31]=[CH:30][N:29]=[C:28]4[C:24]=3[N:25]=[CH:26][N:27]4C3CCCCO3)[CH3:21])=[N:10][C:9]=2[CH:8]=[CH:7][C:6]=1[F:38])=[O:4]>CO.Cl.O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:11]([CH:20]([NH:22][C:23]3[N:31]=[CH:30][N:29]=[C:28]4[C:24]=3[N:25]=[CH:26][NH:27]4)[CH3:21])=[N:10][C:9]=2[CH:8]=[CH:7][C:6]=1[F:38])=[O:4]
Reactant: COC(=O)c1c(F)ccc2nc([C@H](C)Nc3ncnc4c3ncn4C3CCCCO3)n(-c3ccccc3)c12
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)c1c(F)ccc2nc(C(C)Nc3ncnc4[nH]cnc34)n(-c3ccccc3)c12
Yield: 50.2 %

Procedure:
A solution of 5-fluoro-3-phenyl-2-{(S)-1-[9-(tetrahydropyran-2-yl)-9H-purin-6-ylamino]ethyl}-3H-benzoimidazole-4-carboxylic acid methyl ester (50 mg, 0.097 mmol) in MeOH (2 mL) and 4N HCl in dioxane (0.5 ml) was stirred at RT for 30 min then the volatiles were removed under reduced pressure. The resulting residue was dissolved in a minimum amount of MeOH and EtOAc. A solid precipitated on standing and was collected by filtration to afford 197 (21 mg, 46%). LCMS (Method K): RT 3.28 min [M+H]+ 432.1. 1H NMR (DMSO-d6, 400 MHz): δ 12.65 (1H, s), 9.92 (1H, br s), 8.61 (1H, s), 8.50 (1H, s), 7.89 (1H, dd, J=8.90, 4.75 Hz), 7.59-7.48 (2H, m), 7.45-7.30 (3H, m), 7.25 (1H, dd, J=10.49, 8.90 Hz), 5.51-5.40 (1H, m), 3.09 (3H, s), 1.65 (3H, d, J=6.84 Hz)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([S:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.[NH2:14][C:15]1[NH:16][C:17](=[O:23])[NH:18][C:19](=[O:22])[C:20]=1[NH2:21].O>CN(C)C=O>[NH2:14][C:15]1[NH:16][C:17](=[O:23])[NH:18][C:19](=[O:22])[C:20]=1[NH:21][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([S:12][CH3:13])=[CH:11][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(SC)ccc1C(=O)O
Reactant: Nc1[nH]c(=O)[nH]c(=O)c1N
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(SC)ccc1C(=O)Nc1c(N)[nH]c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Twenty grams of 2-methoxy-4-methylmercapto-benzoic acid is dissolved in 260 ml of dimethylformamide, mixed with 13 gm of N,N'-carbonyl-diimidazole, and stirred for 30 minutes at ambient temperature. Then, 13 gm of 4,5-diamino-pyrimidin-2,6-dione are added, and the reaction mixture is refluxed for three hours with stirring. After cooling, it is poured into 1 liter of water. The product precipitated is suction filtered, washed with water, and dried at 70° C. in a circulating air drier.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>C1COCC1>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:17]=2)=[O:32])=[CH:26][CH:25]=1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4ccc(Cl)cc4)c3)c2cc1OC
Temperature: 80 °C

Procedure:
In a sealed reaction vessel, 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (100 mg, 0.34 mmol) was dissolved in 10 mL of dry THF. To this solution was added 4-chlorophenyl isocyanate (61 mg, 0.4 mmol). The reaction was heated to 80° C. for 2 hours. The solution was then concentrated to dryness and purified by silica gel chromatography eluting with an ethyl acetate/dichloromethane gradient 5-30% over 16 column volumes. The major peak was concentrated and recrystallized with ethyl acetate/hexanes, and the solid collected by vacuum filtration to give 26.53 mg. 1H (DMSO-d6) 8.9 (m, 2H), 8.5 (s, 1H), 7.8-7.2 (m, 9H), 6.9 (m, 1H), 4.1 (s, 6H)
Reaction SMILES: [CH2:1]([C:5]1[C:13]([CH3:14])=[CH:12][C:8]([C:9]([NH2:11])=O)=[CH:7][N:6]=1)[CH:2]([CH3:4])[CH3:3].N1C=CC=CC=1>C(Cl)Cl>[CH2:1]([C:5]1[C:13]([CH3:14])=[CH:12][C:8]([C:9]#[N:11])=[CH:7][N:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: Cc1cc(C(N)=O)cnc1CC(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(C#N)cnc1CC(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.7 %

Procedure:
To a solution of 6-isobutyl-5-methyl-nicotinamide (1.89 g, 9.85 mmol) in DCM (40 mL) and pyridine (2.83 g, 39.4 mmol), TFA anhydride (5.17 g, 24.6 mmol) is added portionwise at 0° C. The mixture is stirred at rt for 24 h, diluted with DCM and washed with water, 4% aq. citric acid solution followed by sat. aq. NaHCO3 solution. The org. extract is dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 9:1 to give 6-isobutyl-5-methyl-nicotinonitrile (1.35 g) as a white solid; LC-MS: tR=0.89 min, [M+1]+=175.11.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([S:10][CH2:11][CH2:12][CH3:13])[N:7]=[C:6](Cl)[CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C@@H:68]([NH2:72])([CH2:70][CH3:71])[CH3:69]>CCOCC.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([S:10][CH2:11][CH2:12][CH3:13])[N:7]=[C:6]([NH:72][CH:68]([CH2:70][CH3:71])[CH3:69])[CH:5]=1
Reactant: CC[C@H](C)N
Reactant: CCCSc1cc(C(=O)OC)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCCSc1cc(C(=O)OC)cc(NC(C)CC)n1
Temperature: 90 °C
Reaction time: 18 h
Yield: 55 %

Procedure:
Add 2-chloro-6-propylsulfanyl-isonicotinic acid methyl ester (1.35 g, 5.49 mmol) palladium acetate (0.123 g, 0.549 mmol, 0.1 eq.), racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.342 g, 0.549 mmol, 0.1 eq.), cesium carbonate (2.68 g, 8.24 mmol, 1.5 eq.) and toluene (20 mL) into a sealed vessel flushed with nitrogen. Slowly add (S)-sec-butylamine (0.824 mL, 8.24 mmol) and heat and stir the reaction mixture at 90° C. for 18 h. Cool the reaction mixture to room temperature, dilute with ether and filter through a filtering agent. Concentrate the filtrate and purify (silica gel chromatography, eluting with the 5:95 to 10:90 ethyl acetate:hexanes) to give the title compound (55%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:16])([O:10][CH2:11][C@@H:12]([OH:15])[CH2:13][OH:14])[CH3:9])=[CH:4][CH:3]=1.N1C=CN=C1.[C:22]([Si:26](Cl)([CH3:28])[CH3:27])([CH3:25])([CH3:24])[CH3:23].O>O1CCCC1.CN(C)C1C=CN=CC=1>[C:22]([Si:26]([CH3:28])([CH3:27])[O:14][CH2:13][C@H:12]([OH:15])[CH2:11][O:10][C:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)([CH3:16])[CH3:9])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(OC[C@@H](O)CO)c1ccc(F)cc1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(OC[C@@H](O)CO[Si](C)(C)C(C)(C)C)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 82.6 %

Procedure:
To a solution of (S)-3-[1-(4-fluoro-phenyl)-1-methyl-ethoxy]-propane-1,2-diol (0.46 g) in tetrahydrofuran (6 ml) were added imidazole (0.32 g) and 4-dimethylaminopyridine (catalytic amount). The mixture was cooled to 0° C. and a solution of tert-butyl(chloro)dimethylsilane (0.32 g) in tetrahydrofuran (2 ml) was added dropwise. After 2 hours at 0° C., the reaction mixture was allowed to stir at room temperature for 16 hours. Water was added and the mixture was extracted twice with diethylether. The combined organic layers were dried (MgSO4) and evaporated. The crude product was purified by column chromatography (SiO2; gradient: heptane/EtOAc 90:10->75:25) to give (R)-1-(tert-butyl-dimethyl-silanyloxy)-3-[1-(4-fluorophenyl)-1-methyl-ethoxy]-propan-2-ol (0.57 g, 83%) as a colorless liquid. 1H NMR (300 MHz, CDCl3, δ): 0.00 (s, 6H), 0.82 (s, 9H), 1.48 (s, 6H), 2.49 (bs, 1H), 3.15 (d, J=4 Hz, 2H), 3.56 (t, J=4 Hz, 2H), 3.68 (m, 1H)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([OH:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2].Br[CH2:17][CH2:18][CH2:19][Cl:20].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:17][CH2:18][CH2:19][Cl:20])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(O)ccc2[nH]1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)c1cc2cc(OCCCCl)ccc2[nH]1
Temperature: 80 °C
Reaction time: 160 h
Yield: 0.1 %

Procedure:
To a solution of ethyl-5-hydroxyindole-2-carboxylate (15 g, 73 mmol, 1.0 eq.) and 1-bromo-3-chloropropane (8.8 mL, 88 mmol, 1.2 eq.) in 2-butanone (200 mL) was added potassium carbonate (12.1 g, 88 mmol, 1.2 eq.). The reaction mixture was stirred 160 h at 80° C. The reaction mixture was cooled down and partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and brine then dried over sodium sulfate, filtered and concentrated in vacuo. The crude mixture was purified by column chromatography on silica eluting with cyclohexane/ethyl acetate 9:1 to yield 15.3 mg (74%) of the title compound as a light yellow solid. MS (m/e): 282.7 (MH+, 100%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([NH:11][S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:9]2[C:5]([CH:6]=[C:7]([C:20](=[S:22])[NH2:21])[NH:8]2)=[CH:4][CH:3]=1.Br[CH:24]([CH:27]=O)[CH:25]=[O:26].CN(C)C(=O)C>O>[Cl:1][C:2]1[C:10]([NH:11][S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:9]2[C:5]([CH:6]=[C:7]([C:20]3[S:22][C:24]([CH2:25][OH:26])=[CH:27][N:21]=3)[NH:8]2)=[CH:4][CH:3]=1
Reactant: NC(=S)c1cc2ccc(Cl)c(NS(=O)(=O)c3cccs3)c2[nH]1
Reactant: O=CC(Br)C=O
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=S(=O)(Nc1c(Cl)ccc2cc(-c3ncc(CO)s3)[nH]c12)c1cccs1
Temperature: 90 °C
Reaction time: 3 h
Yield: 53.6 %

Procedure:
A mixture of 6-chloro-7-[(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (0.75 g), bromomalonaldehyde (0.45 g) and N,N-dimethylacetamide (10 mL) was stirred at 90° C. for 3 hr. Water was added to the reaction mixture, and the obtained crystals were filtrated, washed with water and dried. To a mixture of the obtained crystals, tetrahydrofuran (10 mL) and methanol (5 mL) was added sodium borohydride (84 mg) at 0° C., and the mixture was stirred at the same temperature for 30 min. To the reaction mixture was added 10% aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography and the title compound (0.46 g, yield 55%) was obtained as pale-yellow crystals from a fraction eluted with tetrahydrofuran-hexane (3:1, volume ratio). melting point 197-199° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([CH2:17][CH2:18][CH2:19][CH2:20]OS(C)(=O)=O)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:26]([NH:28][CH2:29][CH2:30][OH:31])[CH3:27]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([CH2:17][CH2:18][CH2:19][CH2:20][N:28]([CH2:26][CH3:27])[CH2:29][CH2:30][OH:31])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)OCCCCc1ccc2c(-c3ccc(Cl)cc3)nsc2c1
Reactant: CCNCCO
Product: CCN(CCO)CCCCc1ccc2c(-c3ccc(Cl)cc3)nsc2c1

Procedure:
According to the method in example 23, Methanesulfonic acid 4-[3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl]-butyl ester and 2-Ethylaminoethanol were converted to yield 2-({4-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-butyl}-ethyl-amino)-ethanol, MS: 389 (MH+, 1Cl).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:11])[CH:10]=1)[C:5]([OH:7])=O.[CH2:12]([O:14][C:15](=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=1)[CH3:13]>>[CH2:12]([O:14][C:15](=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:5](=[O:7])[C:4]2[CH:3]=[C:2]([F:1])[CH:10]=[C:9]([Br:11])[CH:8]=2)[CH:18]=1)[CH3:13]
Reactant: CCOC(=O)Cc1cccc(N)c1
Reactant: O=C(O)c1cc(F)cc(Br)c1
Product: CCOC(=O)Cc1cccc(NC(=O)c2cc(F)cc(Br)c2)c1

Procedure:
3-Fluoro-5-bromobenzoic acid (123 mg, 0.56 mmol) was coupled with ethyl ester (6) (100 mg, 0.56 mmol) following Method C to give the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17](#[N:21])[CH2:18][C:19]#[N:20].C(O)C.[BH4-].[Na+]>O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][CH:18]([C:17]#[N:21])[C:19]#[N:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCC#N
Reactant: O=Cc1cccc(OCc2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#CC(C#N)Cc1cccc(OCc2ccccc2)c1
Yield: 91.6 %

Procedure:
Using 1.06 g of 3-(benzyloxy)benzaldehyde, 0.33 g of malononitrile, 8 ml of ethanol, 1.5 ml of water and 57 mg of sodium borohydride, and according to the process described in the REFERENCE PRODUCTION EXAMPLE 19, there was obtained 1.20 g of (3-(benzyloxy)benzyl)malononitrile (the intermediate (31)).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:15]=[CH:16][CH:17]=2)[CH2:8][CH2:7]1.[Cl:24][C:25]1[CH:40]=[CH:39][C:28]([O:29][C:30]2[N:38]=[CH:37][CH:36]=[CH:35][C:31]=2[C:32](Cl)=[O:33])=[CH:27][CH:26]=1>C1COCC1.C(Cl)Cl>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([O:29][C:30]2[N:38]=[CH:37][CH:36]=[CH:35][C:31]=2[C:32]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[CH2:7][CH2:8][CH:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:21])[CH3:22])[CH:13]=3)[CH2:10][CH2:11]2)=[O:33])=[CH:39][CH:40]=1
Reactant: O=C(Cl)c1cccnc1Oc1ccc(Cl)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCN)CC2)c1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCNC(=O)c3cccnc3Oc3ccc(Cl)cc3)CC2)c1

Procedure:
Prepared by Procedure Q2 (THF/DCM, 1:3) and Scheme AT using N-{3-[1-(4-aminobutyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 2-(4-chlorophenoxy)nicotinoyl chloride: ESMS m/e: 549.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24]Br)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[C:27]1([SH:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[H-].[Na+]>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][S:33][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CBr)c1
Reactant: Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CSc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2′-bromomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester (0.103 g, 0.24 mmol) and thiophenol (0.03 mL, 0.26 mmol) in 1,4-dioxane (2 mL) was added sodium hydride (60% in mineral oil; 0.013 g, 0.29 mmol), and the reaction was stirred for 30 minutes at room temperature. The mixture was partitioned between EtOAc and H2O, and the aqueous layer was acidified and extracted three times with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:25]([CH2:26][C:27]([OH:29])=O)[C:24]3[C:19](=[C:20]([O:30][CH3:31])[CH:21]=[CH:22][CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.Cl.[N:65]1([CH2:70][CH2:71][C@H:72]2[CH2:77][CH2:76][C@H:75]([NH2:78])[CH2:74][CH2:73]2)[CH2:69][CH2:68][CH2:67][CH2:66]1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:25]([CH2:26][C:27]([NH:78][C@H:75]3[CH2:76][CH2:77][C@H:72]([CH2:71][CH2:70][N:65]4[CH2:69][CH2:68][CH2:67][CH2:66]4)[CH2:73][CH2:74]3)=[O:29])[C:24]3[C:19](=[C:20]([O:30][CH3:31])[CH:21]=[CH:22][CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)(=[O:10])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: N[C@H]1CC[C@H](CCN2CCCC2)CC1
Reactant: COc1cccc2c1-c1ccccc1N(S(=O)(=O)c1ccc(Cl)c(Cl)c1)C2CC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cccc2c1-c1ccccc1N(S(=O)(=O)c1ccc(Cl)c(Cl)c1)C2CC(=O)N[C@H]1CC[C@H](CCN2CCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of [5-(3,4-dichloro-benzenesulfonyl)-10-methoxy-5,6-dihydro-phenanthridin-6-yl]-acetic acid (Example 17/d) (0.163 g, 0.34 mmol), triethylamine (0.3 mL, 2.1 mmol) and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) (0.152 g, 0.4 mmol) in dry dimethyl formamide (10 mL) was stirred at room temperature for five minutes before trans-4-(2-pyrrolidin-1-yl-ethyl)-cyclohexylamine dihydrochloride (Reference Example 4) (0.09 g, 0.34 mmol) was added. The pH of the reaction mixture was adjusted to 8 by addition of triethylamine, the so obtained mixture was stirred at room temperature overnight, then concentrated in vacuo. The residue was treated with saturated sodium hydrogencarbonate solution (30 mL), the precipitated crystals were filtered off, washed with water and dried. The crude product was purified by column chromatography using Kieselgel 60 (0.040-0.063 mm) (Merck) as adsorbent, and chloroform:methanol:NH4OH=9:1:0.1 as eluent. The product was crystallized with diethyl ether to yield 0.135 g (60%) of the title compound. MS (EI) 657.2 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([OH:20])[C:17]([OH:19])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1C[CH2:24][CH2:23][CH2:22]1>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C@H:16]2[CH2:17][O:19][C:23]([CH3:24])([CH3:22])[O:20]2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: O=C(O)[C@@H](O)Cc1ccc(OCc2ccccc2)cc1
Product: CC1(C)OC[C@H](Cc2ccc(OCc3ccccc3)cc2)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
A solution of (S)-3-(4-benzyloxy-phenyl)-2-hydroxy-propionic acid (3.1 g, 11.38 mmol) in tetrahydrofuran (50 mL) was treated with a solution of borane tetrahydrofuran complex in tetrahydrofuran (1.0 M, 22.7 mL, 22.76 mmol) at 0° C. The mixture was allowed to slowly warm to room temperature and stirred at this temperature for 2 h. The resulting mixture was carefully quenched with 1N aqueous sodium hydroxide and treated with ethyl acetate. The layers were separated and the aqueous layer extracted twice more with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was immediately treated with excess acetone dimethyl ketal and a catalytic amount of p-toluene sulfonic acid. The mixture was treated with ethyl acetate and water. The aqueous layer made basic with solid potassium carbonate (pH=9), and extracted with ethyl acetate. The organic layers were combined and dried over sodium sulfate, filtered and concentrated in vacuo which afforded (S)-4-(4-benzyloxy-benzyl)-2,2-dimethyl-[1,3]dioxolane (3.1 g, 91%) as a white solid.
Reaction SMILES: CC(C)([O-])C.[K+].[NH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1.[Cl:17][C:18]1[CH:19]=[N:20][CH:21]=[C:22](Cl)[CH:23]=1>CN1CCCC1=O>[Cl:17][C:18]1[CH:23]=[C:22]([C:9]2[N:8]([NH2:7])[C:16]3[C:11]([CH:10]=2)=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:21]=[N:20][CH:19]=1
Reactant: Clc1cncc(Cl)c1
Reactant: Nn1ccc2ccccc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Nn1c(-c2cncc(Cl)c2)cc2ccccc21
Yield: 100.3 %

Procedure:
Potassium tert-butoxide (12.7) was added to a 0° C. solution of N-aminoindole (6.0 g) in 1-methyl-2-pyrrolidinone (150 ml). After stirring for thirty minutes, 3,5-dichloropyridine (7.5 g) was added and the resulting mixture was stirred at room temperature for five hours. The reaction mixture was quenched with water, diluted with ethyl acetate (500 ml) and washed with brine (3×500 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give an oil. Purification of the oil by flash chromatography (silica, 0-2% methanol/dichloromethane) afforded the title compound (11.1 g), m.p. 154°-156° C.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([NH:5][C@@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[CH2:8][CH2:7]1)=[O:4].C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]([F:17])([F:18])[C:3]([NH:5][C@@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C@H:9]([OH:16])[CH2:8][CH2:7]1)=[O:4]
Reactant: O=C1CC[C@H](NC(=O)C(F)(F)F)c2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CC[C@@H](O)c2ccccc21)C(F)(F)F
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 87.5 %

Procedure:
Degassed DMF (argon sparged, 100 mL) was added to Intermediate 1b (8.00 g, 31.3 mmol) and [N-[(1R,2R)-2-(amino-κN)-1,2-diphenylethyl]-4-methylbenzenesulfonamidato-κN]chloro[(1,2,3,4,5,6-η)-1-methyl-4-(1-methylethyl)benzene]-ruthenium (Strem Chemicals Inc.; 594 mg, 0.93 mmol). Triethylamine (8.66 mL, 62.6 mmol) was added slowly to ice cold formic acid (2.34 mL, 62.6 mmol) and stirred for 20 min; this was then added to the DMF solution. The reaction was heated to 60° C. for 18 h. After cooling, the mixture was partitioned between DCM (200 mL) and water (600 mL). The aqueous layer was extracted DCM (3×) and the combined organic layers washed with brine, dried (MgSO4) and concentrated in vacuo. Purification by FCC, using 0-100% EtOAc in cyclohexane, afforded the title compound (7.10 g, 27.4 mmol, 88%). 1H NMR (400 MHz, CDCl3): 1.88-1.92 (1H, d, J=4.8 Hz), 1.98-2.18 (4H, m), 4.80-4.88 (1H, m), 5.165-5.24 (1H, m), 6.70-6.80 (1H, br s), 7.25-7.30 (1H, m), 7.30-7.40 (2H, m), 7.45-7.50 (1H, m).