Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[CH2:13][C:7]1([CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)[C:6]2=[N:17]S(C(C)(C)C)=O.CCOCC>O1CCOCC1>[Br:2][C:3]1[CH:4]=[C:5]2[C:14]([CH2:13][C:7]3([C:6]2=[NH:17])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]3)=[CH:15][CH:16]=1
Reactant: CC(C)(C)S(=O)N=C1c2cc(Br)ccc2CC12CCOCC2
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: N=C1c2cc(Br)ccc2CC12CCOCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
HCl (4M in 1,4-dioxane) (0.683 mL, 2.73 mmol) was added to a solution of N-(5-bromo-2′,3′,5′,6′-tetrahydrospiro[indene-2,4′-pyran]-3(1H)-ylidene)-2-methylpropane-2-sulfinamide (Example 25 Step 1, 105 mg, 0.27 mmol) in anhydrous 1,4-dioxane (1 mL) and the resulting mixture was stirred under a nitrogen atmosphere at r.t. overnight. Et2O (3 mL) was added, the precipitate was filtered off, washed with Et2O and then dissolved in DCM (5 mL) and sat. aq. NaHCO3 (5 mL). The mixture was poured into a phase separator, the organic layer was collected and concentrated to give the title compound that was used in the next step without any further purification.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[N:17]=[C:16]([C:18]4[C:19]([C:27]5[CH:32]=[CH:31][CH:30]=[C:29]([N+:33]([O-])=O)[CH:28]=5)=[N:20][N:21]5[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=45)[CH:15]=[CH:14][N:13]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[S-2].[Na+].[Na+]>C(O)C.O>[NH2:33][C:29]1[CH:28]=[C:27]([C:19]2[C:18]([C:16]3[CH:15]=[CH:14][N:13]=[C:12]([NH:11][C:9]4[CH:8]=[CH:7][C:6]5[O:1][CH2:2][CH2:3][O:4][C:5]=5[CH:10]=4)[N:17]=3)=[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][N:21]3[N:20]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: O=[N+]([O-])c1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)OCCO4)n2)c1
Agent: [Na+]
Agent: [S-2]
Solvent: O
Solvent: CCO
Product: Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)OCCO4)n2)c1
Temperature: 80 °C
Yield: 99.6 %

Procedure:
To a solution of N-(2,3-dihydro-1,4-benzodioxin-6-yl)-4-[2-(3-nitrophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine (1.09 g, 2.3 mmol) in ethanol (2 mL) was added sodium sulfide nonhydrate (2.76 g, 11.5 mmol) in H2O (2 mL). The mixture was heated at 80° C. for 16 h, allowed to cool to rt and filtered. The filtrate was concentrated to afford the product (1 g) as a yellow solid. 1H NMR (400 MHz, d6-DMSO) 69.29 (s, 1H), 8.76 (d, 1H, J=7.2), 8.51 (d, 1H, J=8.8), 8.15 (d, 1H, J=5.2), 7.39-7.43 (m, 1H), 7.35 (m, 1H), 7.04-7.12 (m, 3H), 6.76-6.72 (m, 2H), 6.65-6.62 (m, 2H), 6.43 (d, 1H, J=5.2), 5.21 (s, 2H), 4.16-4.20 (m, 4H).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[CH:14][C:13]=1[OH:22])(=[O:11])[CH3:10].C([O-])([O-])=O.[Cs+].[Cs+].C>CN(C=O)C.C1(C)C=CC=CC=1>[C:9]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[CH:14][C:13]=1[O:22][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)Nc1ccc(C(C)=O)c(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(=O)Nc1ccc(C(C)=O)c(OCc2ccccc2)c1
Reaction time: 18 h
Yield: 52.6 %

Procedure:
Benzyl bromide (4.84 mL, 6.97 g, 40.76 mmol) was added dropwise over 5 minutes to a mixture of give N-(4-acetyl-3-hydroxy-phenyl)-acetamide (7.50 g, 38.82 mmol) and Cs2CO3 (25.30 g, 77.64 mmol) in DMF (175 mL) at room temperature. After stirring for 18 hours, the solvent was removed in vacuo, and the residue stirred vigourously with water (200 mL) and DCM (200 mL) until dissolution was complete. The layers were separated, and the aqueous further extractede with DCM (2×200 mL). The combined organic layers were dried (MgSO4) and the solvents removed in vacuo. The residue was taken up in PhMe (150 mL) and evaporated to dryness, whereupon crystals started to form. The mixture was re-suspended in PhMe (100 mL) and refluxed for 1 hr with activated charcoal (5 g). The hot solution was filtered and allowed to cool. The product was collected by filtration to give N-(4-acetyl-3-benzyloxy-phenyl)-acetamide (5.79 g, 53%) as colourless crystals; δH (CDCl3) 7.83 (1H, m), 7.76 (1H, d, J=8.5 Hz), 7.58 (1H, br s), 7.45-7.32 (6H, m), 6.74 (1H, dd, J=8.5, 1.9 Hz), 5.15 (2H, s), 2.56 (3H, s), 2.19 (3H, s); LCMS retention time 2.33 min, M+H+ 284.3.
Reaction SMILES: Br.[CH3:2][N:3]1[CH2:8][CH2:7][C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([OH:9])[CH:5](Br)[CH2:4]1.[OH-].[Na+].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:2][N:3]1[CH2:8][CH2:7][C:6]2([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:5]([O:9]2)[CH2:4]1
Reactant: CN1CCC(O)(c2ccccc2)C(Br)C1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CN1CCC2(c3ccccc3)OC2C1
Reaction time: 0.5 h

Procedure:
A solution of 1-methyl-3-bromo-4-phenyl-4-piperidinol hydrobromide (4.10 g; 11.7 mmoles, described in Example 5) in water (5 ml) is cooled to 0°-5° C. Cold 10% aqueous sodium hydroxide solution (10 ml; 25 mmoles) is added dropwise with vigorous mechanical stirring, over a period of ten minutes. The solution is stirred for 30 min. and potassium carbonate is added to the solution at a temperature below 10° C. When the solution is saturated the solids are collected by filtration and crystallized from hexane at -70° C. to give the title compound, mp 44°-45° C. (R. E. Lyle and W. E. Krueger, supra, reported mp 43°-45° C.).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCOCC1.Br[C:27]1[N:35]2[C:30]([CH:31]=[N:32][C:33]([NH:36][C:37]3[CH:42]=[CH:41][C:40]([CH:43]4[CH2:48][CH2:47][N:46]([CH2:49][C:50]([NH2:52])=[O:51])[CH2:45][CH2:44]4)=[CH:39][CH:38]=3)=[N:34]2)=[CH:29][CH:28]=1.[CH3:53][N:54]([CH3:71])[CH2:55][C:56]1[CH:61]=[CH:60][C:59](B2OC(C)(C)C(C)(C)O2)=[CH:58][CH:57]=1.Cl.C(=O)([O-])[O-].[Na+].[Na+].O.O1CCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:53][N:54]([CH2:55][C:56]1[CH:61]=[CH:60][C:59]([C:27]2[N:35]3[C:30]([CH:31]=[N:32][C:33]([NH:36][C:37]4[CH:42]=[CH:41][C:40]([CH:43]5[CH2:48][CH2:47][N:46]([CH2:49][C:50]([NH2:52])=[O:51])[CH2:45][CH2:44]5)=[CH:39][CH:38]=4)=[N:34]3)=[CH:29][CH:28]=2)=[CH:58][CH:57]=1)[CH3:71]
Reactant: NC(=O)CN1CCC(c2ccc(Nc3ncc4ccc(Br)n4n3)cc2)CC1
Reactant: CN(C)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CN(C)Cc1ccc(-c2ccc3cnc(Nc4ccc(C5CCN(CC(N)=O)CC5)cc4)nn23)cc1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
Palladium Acetate (8.5 mg, 0.000038 mol), Triphenylphosphine (27.4 mg, 0.000105 mol) and 1,4-Dioxane (2.8 mL, 0.036 mol) were combined in a flask and stirred for 10 minutes. 2-{4-[4-(7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino)-phenyl]-piperidin-1-yl}-acetamide (157 mg, 0.000366 mol), Dimethyl-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-benzyl]-amine; hydrochloride (224 mg, 0.000753 mol), and 1.50 M of Sodium carbonate in Water (2.2 mL, 0.0033 mol) and Tetrahydrofuran (3.0 mL, 0.037 mol). were added. The reaction was heated at 80° C. for 3 days, then purified by preparatory HPLC and lyophilized to yield an orange solid, 2-(4-{4-[7-(4-Dimethylaminomethyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-1-yl)-acetamide; compound with 3 trifluoroacetic acids (4 mg, 1%). LCMS: m/z=484.18 (M+H+); 1H NMR (400 MHz, DMSO-d6) δ 9.95 (br s, 1H), 9.55 (m, 2H), 9.02 (s, 1H), 8.33 (d, 2H, J=8.2 Hz), 8.00 (m, 1H), 7.73 (m, 3H), 7.65 (m, 3H), 7.28 (d, 1H, J=4.8 Hz), 7.18 (d, 2H, J=8.4 Hz), 6.99 (d, 1H, J=4.8 Hz), 4.36 (m, 2H), 3.94 (m, 2H), 3.16 (m, 2H), 2.75 (m, 7H), 1.99 (m, 4H), 1.30 (s, 2H).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Si:11]([O:18][C@@H:19]1[C@H:23]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[C@@H:22]([CH2:32][OH:33])[O:21][C@H:20]1[N:34]1[CH:39]=[CH:38][C:37](=[O:40])[N:36]([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=2)[C:35]1=[O:50])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C>[Si:25]([O:24][C@H:23]1[C@@H:19]([O:18][Si:11]([C:14]([CH3:16])([CH3:15])[CH3:17])([CH3:12])[CH3:13])[C@H:20]([N:34]2[CH:39]=[CH:38][C:37](=[O:40])[N:36]([CH2:41][C:42]3[CH:43]=[CH:44][C:45]([O:48][CH3:49])=[CH:46][CH:47]=3)[C:35]2=[O:50])[O:21][C@H:22]1[CH:32]=[O:33])([C:28]([CH3:29])([CH3:30])[CH3:31])([CH3:27])[CH3:26]
Reactant: COc1ccc(Cn2c(=O)ccn([C@@H]3O[C@H](CO)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(Cn2c(=O)ccn([C@@H]3O[C@@H](C=O)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 95.1 %

Procedure:
Following the literature procedure (Myers, A. G.; Gin, D. Y.; Rogers, D. H., J. Amer. Chem. Soc., 1994, 116, 4697-4718), anhydrous dimethyl sulfoxide (3.35 ml, 47.23 mmole) was added dropwise to a solution of oxalyl chloride (14.2 ml, 28.34 mmole, 2.0 M solution in methylene chloride, Aldrich) in anhydrous methylene chloride (50 ml) under argon at −78° C. The resulting mixture was stirred at −78° C. for 45 min, and was transferred via cannula to a cooled (−78° C.) solution of 1-[(2R,3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(hydroxymethyl)tetrahydro-2-furanyl]-3-(4-methoxybenzyl)-2,4(1H,3H)-pyrimidinedione (5.6 g, 9.45 mmole, obtained from Reference Example 2) in anhydrous methylene chloride (50 ml) under argon. The resulting mixture was stirred at −78° C. for 1 h, and triethylamine (9.9 ml, 70.8 mmole) was added all at once. The mixture was stirred at −78° C. for 1.5 h under argon, and diluted with ethyl acetate (500 ml). The organic layer was washed with saturated sodium bicarbonate aqueous solution and saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness in vacuo. Toluene was added to the residue, and evaporated in vacuo. This procedure was repeated for two more times, to give 1-[(2R,3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-[3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl]-tetrahydro-furan-2-carbaldehyde as pale yellow solid (5.31 g, 95%). This material was used in its crude form in the following experiment. MS (ES): m/z 591.3 (M+H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH:14]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:22](=O)([O:28]C(C)(C)C)[O:23][C:24]([CH3:27])([CH3:26])[CH3:25]>ClCCl>[C:24]([O:23][C:22]([N:12]1[CH2:11][CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([Cl:2])=[CH:4][CH:5]=2)[CH2:14][CH2:13]1)=[O:28])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: Clc1ccc(C2=CCNCC2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 110.3 %

Procedure:
4-(4-Chlorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (Lancaster, 1.00 g, 4.35 mmol), triethylamine (0.92 g, 9.13 mmol), and di-tert-butyl carbonate (Aldrich, 1.04 g, 4.78 mmol) were combined in dichloromethane (100 mL) and stirred at room temperature for 14 hours. The mixture was washed with saturated aqueous ammonium chloride solution (30 mL), water (30 mL), saturated sodium chloride solution (30 mL) and dried over anhydrous magnesium sulfate. The mixture was filtered and concentrated in vacuo to give 4-(4-chlorophenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.41 g, 100%) of as a viscous yellow oil, which was used without further purification. 4-(4-Chlorophenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (334 mg, 1.14 mmoL) was dissolved in acetone/water (1:1, 10 mL), and N-methylmorpholine-N-oxide (Aldrich, 462 mg, 3.42 mmoL) and a catalytic amount of osmium tetroxide (Aldrich) were added. The mixture was stirred at room temperature for 3 hours. A saturated aqueous solution of sodium sulfite (2 mL) was added, and the mixture was stirred for 30 minutes at room temperature. The mixture was diluted with ethyl acetate (10 mL) and water (5 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with brine and dried over anhydrous magnesium sulfate. The mixture was filtered and concentrated in vacuo to give cis-[rac]-4-(4-chlorophenyl)-3,4-dihydroxypiperidine-1-carboxylic acid tert-butyl ester (364 mg, 1.11 mmol, 97%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17]([CH2:19][O:20][C:21](=[O:23])[CH3:22])=[O:18])[C@@H:13]([OH:24])[C@H:12]2[OH:25])=[C:4](Cl)[N:3]=1.[NH2:27][C@@H:28]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:29][OH:30].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17]([CH2:19][O:20][C:21](=[O:23])[CH3:22])=[O:18])[C@@H:13]([OH:24])[C@H:12]2[OH:25])=[C:4]([NH:27][C@H:28]([CH2:29][OH:30])[CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:3]=1
Reactant: N[C@H](CO)Cc1ccccc1
Reactant: CC(=O)OCC(=O)N[C@H]1C[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](O)[C@@H]1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCC(=O)N[C@H]1C[C@@H](n2cnc3c(N[C@H](CO)Cc4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reaction time: 8 h

Procedure:
The title compound is prepared by combining acetic acid [(1S,2R,3S,4R)-4-(2,6-dichloro-purin-9-yl)-2,3-dihydroxy-cyclopentyl-carbamoyl]-methyl ester (1 equivalent) and (S)-2-amino-3-phenyl-propan-1-ol 1 equivalent) in dichloromethane with triethylamine (1.1 equivalents) and stirring overnight. The reaction is diluted with dichloromethane, and washed consecutively with 0.1M hydrochloric acid, water and brine, before drying over magnesium sulfate. Filtration and removal of the volatile components under reduced pressure, affords the title compound.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5](O)=[O:6].C(Cl)(=O)C([Cl:13])=O>C1C=CC=CC=1>[F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5]([Cl:13])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CCC(F)(F)F
Solvent: c1ccccc1
Product: O=C(Cl)CCC(F)(F)F
Reaction time: 20 h

Procedure:
4,4,4-Trifluorobutyric acid (5.8 g, 0.041 mole) was dissolved in benzene (30 ml). Oxalyl chloride (6.2 g, 0.049 mole) was added and the reaction stirred for 20 hrs. The benzene and excess oxalyl chloride was removed by distillation to give the title compound.
Reaction SMILES: N1C=CC([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13]2[N:19]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4[S:28][CH:29]=[CH:30][N:31]=4)[CH:22]=3)[C:18](=[O:32])[CH2:17][CH2:16][CH2:15][CH2:14]2)=CC=1.C([Sn](CCCC)(CCCC)[C:38]1[S:42][CH:41]=[N:40][CH:39]=1)CCC.O.CCOC(C)=O>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[S:28]1[CH:29]=[CH:30][N:31]=[C:27]1[C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[CH2:20][N:19]1[CH:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:38]2[S:42][CH:41]=[N:40][CH:39]=2)[CH2:14][CH2:15][CH2:16][CH2:17][C:18]1=[O:32]
Reactant: O=C1CCCCC(c2ccccc2-c2ccncc2)N1Cc1cccc(-c2nccs2)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1CCCCC(c2ccccc2-c2cncs2)N1Cc1cccc(-c2nccs2)c1
Temperature: 75 °C

Procedure:
A mixture of 7-(2-bromophenyl)-1-(3-(thiazol-2-yl)benzyl)azepan-2-one (preparation described in example 450; 50 mg; 0.11 mmol), commercially available 5-(tributylstannyl)thiazole (51 mg; 0.13 mmol), and PdCl2(PPh3)2 (8 mg; 0.011 mmol) in THF (1 ml) was heated to 75° C., under nitrogen, for 17 h. After cooling to rt, water and AcOEt were added. The separated aq. layer was further extracted with AcOEt. The mixed organic layers were washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.80 min.; [M+H]+: 446.11 g/mol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:10])=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.[I-].[K+].Br[CH2:29][CH2:30][CH:31]=[C:32]1[C:38]2[CH:39]=[CH:40][CH:41]=[N:42][C:37]=2[CH2:36][O:35][C:34]2[CH:43]=[CH:44][C:45]([C:47]([OH:50])([CH3:49])[CH3:48])=[CH:46][C:33]1=2>C(O)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([CH2:29][CH2:30][CH:31]=[C:32]3[C:38]4[CH:39]=[CH:40][CH:41]=[N:42][C:37]=4[CH2:36][O:35][C:34]4[CH:43]=[CH:44][C:45]([C:47]([OH:50])([CH3:49])[CH3:48])=[CH:46][C:33]3=4)[CH2:14][CH2:13]2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccc(Cl)cc1)NC1CCNCC1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Solvent: Cc1cccc(C)n1
Product: CC(C)(O)c1ccc2c(c1)C(=CCCN1CCC(NC(=O)Cc3ccc(Cl)cc3)CC1)c1cccnc1CO2
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of 2-(4-chloro-phenyl)-N-piperidin-4-yl-acetamide (0.2 g, 0.8 mmol) in isopropanol (6.0 mL) was added 2,6-lutidine (0.095 mL, 0.8 mmol) and catalytic potassium iodide. This mixture was heated to 80° C. and treated with 2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.15 g, 0.4 mmol) in portions over 2 h. The solution was then stirred at 80° C. for an additional 18 h. The reaction mixture was concentrated in vacuo, then purified by flash chromatography on silica gel (gradient elution from 95% ethyl acetate/5% methanol to 90% ethyl acetate/20% methanol) to yield the title compound.
Reaction SMILES: [OH-].[Na+].C([O-])=O.[Na+].Br[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>[Pd].O>[C:8]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Brc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [Na+]
Solvent: O
Product: c1ccc(-c2ccccc2)cc1

Procedure:
A mixture comprising 4 parts of sodium diisopropyl naphthalene sulphonate, 1.2 parts of 3% palladium on carbon catalyst, 20 parts of sodium hydroxide, 80 parts of water, 6.8 parts of sodium formate and 15.7 parts of bromobenzene is stirred and heated for 4 hours under reflux. The mixture is then allowed to cool to 90°, a further charge of 6.8 parts of sodium formate is added, and the mixture is reheated and stirred under reflux for a further 16 hours. The mixture is then steam distilled until 800 parts of distillate are collected. The distillate is extracted with chloroform and the chloroform solution, is shown by gas chromatography to contain benzene and biphenyl but no bromobenzene. The chloroform solution is then concentrated by distillation, yielding 5.01 parts of biphenyl, melting at 69°-70°.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:14]=[C:13]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[C:11]([NH:20][C@H:21]([CH3:24])[CH2:22][OH:23])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:25]N1C(=O)CCC1=O>C(Cl)Cl>[CH2:1]([S:8][C:9]1[N:14]=[C:13]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:12]([Cl:25])=[C:11]([NH:20][C@H:21]([CH3:24])[CH2:22][OH:23])[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: C[C@H](CO)Nc1cc(NS(C)(=O)=O)nc(SCc2ccccc2)n1
Solvent: ClCCl
Product: C[C@H](CO)Nc1nc(SCc2ccccc2)nc(NS(C)(=O)=O)c1Cl

Procedure:
The title compound of Example 3 (0.4 g) was dissolved in DCM (20 ml) and treated with N-chlorosuccinimide (0.14 g) for 2 h. The volatiles were removed in vacuo and the residue purified by reverse phase HPLC ((gradient 95% to 20% 0.02M ammonium hydroxide/acetonitrile) to yield the title compound as a white solid. Yield: 0.25 g.
Reaction SMILES: [BH4-].[Na+].[C:3]1([S:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CO.C1COCC1.O.O.O.O.O.O.[Ni](Cl)Cl>[C:3]1([S:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(Sc2ccccc2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(Sc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Nickel chloride hexahydrate (41 g, 172.5 mmol), then sodium borohydride (19.5 g, 0.516 mmol) were added to a solution of 4-nitrophenyl phenyl sulfide Compound 161a (20 g, 86.5 mmol) in a mixture of MeOH (200 mL) and THF (75 mL) at 0° C. under nitrogen over a period of 1 hr. The mixture was stirred for 30 mins at 0° C. and the reaction was quenched slowly with aqueous 10% NH4Cl, neutralized with ammonium hydroxide and partitioned between ethyl acetate and water. The organic layer was dried (Na2SO4), then filtered and the solvent evaporated in vacuo to yield 4-phenylsulfanyl-phenylamine Compound 161b (15.08 g, 87%), as a solid. MS (ES+) m/z 202.1 (M+H+). 1H NMR (400 MHz, CDCl3) δ 7.32-7.29 (2H, m), 7.22-7.18 (2H, m), 7.13-7.09 (3H, m), 6.68-6.66 (2H, m), 3.79 (2H, br s)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C@H:14]1[CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]1=[O:24])=[O:12])=[CH:5]2.C[O-].[Na+].Br[CH2:29][C:30]#[N:31].Cl>O1CCCC1.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C@H:14]1[CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:29][C:30]#[N:31])[C:15]1=[O:24])=[O:12])=[CH:5]2
Reactant: N#CCBr
Reactant: O=C(N[C@H]1Cc2ccccc2NC1=O)c1cc2cc(Cl)ccc2[nH]1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#CCN1C(=O)[C@@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)Cc2ccccc21
Temperature: 25 °C
Yield: 26.8 %

Procedure:
(S)-3-(5-chloroindole-2-carbonylamino)-3,4-dihydrocarbostyril (Example 4, 13.4 mg) was dissolved in tetrahydrofuran (5 mL) at room temperature under argon with stirring. After cooing to 0° C., sodium methoxide (4.3 mg) was added, followed 2 h later by bromoacetonitrile (7.2 mg). This was warmed to room temperature over 2 h, and 2 h later water (15 mL), 1.0 M aqueous hydrochloric acid (1 mL), and ethyl acetate (20 mL) were added. The organic phase was separated, washed with brine, and dried over anhydrous sodium sulfate. After solvent evaporation under vacuum, the crude product was purified by reverse phase preparative HPLC to provide the title compound (4 mg). HPLC/MS [M+H]+, 379; HPLC/MS [M+Na]+, 401.
Reaction SMILES: C(O[C:6](=[O:31])[NH:7][C@H:8]([C:10](=[O:30])[NH:11][C@H:12]([B:17]1[O:25][C@H:24]2[C@:19]([CH3:29])([C@H:20]3[CH2:26][C@@H:22]([CH2:23]2)[C:21]3([CH3:28])[CH3:27])[O:18]1)[CH2:13][CH:14]([CH3:16])[CH3:15])[CH3:9])(C)(C)C.[C:32]1([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[CH:37]=[CH:36][CH:35]=[C:34]([NH:38][C@@H:39]([CH2:43][C:44]2[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[C:46]([O:52][CH3:53])[CH:45]=2)C(O)=O)[CH:33]=1>>[C:32]1([C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=2)[CH:37]=[CH:36][CH:35]=[C:34]([NH:38][C@@H:39]([CH2:43][C:44]2[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[C:46]([O:52][CH3:53])[CH:45]=2)[C:6]([NH:7][C@H:8]([C:10](=[O:30])[NH:11][C@H:12]([B:17]2[O:25][C@H:24]3[C@:19]([CH3:29])([C@H:20]4[CH2:26][C@@H:22]([CH2:23]3)[C:21]4([CH3:27])[CH3:28])[O:18]2)[CH2:13][CH:14]([CH3:16])[CH3:15])[CH3:9])=[O:31])[CH:33]=1
Reactant: CC(C)C[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Reactant: COc1ccc(C[C@H](Nc2cccc(-c3ccccc3)c2)C(=O)O)cc1OC
Product: COc1ccc(C[C@H](Nc2cccc(-c3ccccc3)c2)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)B2O[C@@H]3C[C@@H]4C[C@@H](C4(C)C)[C@]3(C)O2)cc1OC

Procedure:
The title compound is prepared as described in example 1 but using {(S)-1-[(R)-3-Methyl-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-butylcarbamoyl]-ethyl}-carbamic acid tert-butyl ester and (S)-2-(Biphenyl-3-ylamino)-3-(3,4-dimethoxyphenyl)-propionic acid.