Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([OH:9])[CH2:5][C:6]([CH3:8])=[CH2:7].[CH3:16][C:17]([NH2:21])([C:19]#[CH:20])[CH3:18].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:8][C:6](=[CH2:7])[CH2:5][C:4]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([OH:9])[CH2:3][CH2:2][NH:21][C:17]([CH3:18])([C:19]#[CH:20])[CH3:16]
Reactant: C#CC(C)(C)N
Reactant: C=C(C)CC(O)(CCCl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C#CC(C)(C)NCCC(O)(CC(=C)C)c1ccccc1
Temperature: 80 °C
Yield: 42.6 %

Procedure:
A stirred mixture of 1-chloro-5-methyl-3-phenylhex-5-en-3-ol (550 mg, 2.45 mmol), 1,1-dimethylpropargylamine (204 mg, 2.45 mmol), KI (447 mg, 2.7 mmol), i-Pr2NEt (05 mL, 2.7 mmol) and dry DMF (3 mL) was heated at 80° C. in an oil bath for 24 h. The mixture was concentrated to leave a brown oil which was purified by chromatography on a 12-g silica cartridge eluted with a 0-10% MeOH in CH2Cl2 gradient to afford 5-methyl-1-(2-methylbut-3-yn-2-ylamino)-3-phenylhex-5-en-3-ol (283 mg, 42%) as a brown solid which was used in the next step without further purification. LC-MS Method 1 tR=1.08 min, m/z=272.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[F:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:20])[C:15](=[O:21])[C:14]([C:22]#[N:23])=[C:13]2[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>N1C=CC=CC=1>[F:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:20])[C:15](=[O:21])[C:14]([C:22]#[N:23])=[C:13]2[N:24]1[CH2:25][CH2:26][N:27]([C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[O:7])[CH2:28][CH2:29]1
Reactant: Cn1c(=O)c(C#N)c(N2CCNCC2)c2cc(F)ccc21
Reactant: O=C(Cl)c1ccco1
Solvent: c1ccncc1
Product: Cn1c(=O)c(C#N)c(N2CCN(C(=O)c3ccco3)CC2)c2cc(F)ccc21
Temperature: 0 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
2-Furoyl chloride (148 μL, 1.5 mmol) was added to a stirred solution of Compound 50 (286 mg, 1.0 mmol) in pyridine (5 mL) under argon at 0° C. The solution was allowed to come to room temperature and further stirred overnight. The solution was poured into ice water and the solids formed were filtered. The solids were washed by excess water, dried, and recrystallized by ethyl acetate to yield 333 mg (87%) of white solids. M.P. 263° C. 1H NMR (DMSO-d6): δ 3.58 (s, 3H), 3.62 (m, 4H), 3.95 (m, 4H), 6.66 (d, J=3.6 Hz, 1H), 7.08 (d, J=3.4 Hz, 1H), 7.65 (m, 3H), 7.88 (s, 1H). EIMS m/z 403 (M+23). Anal. (C20H17FN4O3) C, H, N.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].C(N(C(C)C)C(C)C)C.[C:19]([C:22]1[N:27]=[C:26]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][C:37]([CH2:40][C:41](O)=[O:42])=[CH:36][C:35]=3[Cl:44])=[CH:30][CH:29]=2)[C:25]([CH3:45])=[N:24][C:23]=1[CH3:46])(=[O:21])[NH2:20].Cl.CN(C)CCCN=C=NCC.N1(O)C2C=CC=CC=2N=N1>CN(C=O)C>[C:19]([C:22]1[N:27]=[C:26]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][C:37]([CH2:40][C:41]([NH:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:42])=[CH:36][C:35]=3[Cl:44])=[CH:30][CH:29]=2)[C:25]([CH3:45])=[N:24][C:23]=1[CH3:46])(=[O:21])[NH2:20]
Reactant: Cc1nc(C)c(-c2ccc(-c3ccc(CC(=O)O)cc3Cl)cc2)nc1C(N)=O
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCNC(=O)Cc1ccc(-c2ccc(-c3nc(C(N)=O)c(C)nc3C)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 150.4 %

Procedure:
A mixture of ethyl 3-aminopropanoate hydrochloride (88 mg, 0.57 mmol) and N-ethyl-N-isopropylpropan-2-amine (99 μL, 0.57 mmol) in DMF (342 μL) were treated with a solution of 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)acetic acid (Example 1; 205 mg, 0.52 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (124 mg, 0.65 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (70.0 mg, 0.52 mmol) and N-ethyl-N-isopropylpropan-2-amine (99 μL, 0.57 mmol) in DMF (2049 μL) at RT. The resulting solution was stirred at RT for 20 hours. The reaction mixture was evaporated to dryness and redissolved in DCM (5 mL), and washed with water (5 mL). The organic layer was evaporated to afford ethyl 3-(2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)acetamido)propanoate (387 mg, 151%) which was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13]([NH2:15])[C:12]([NH2:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17](OC)(OC)OC>C1COCC1.C(O)(C(F)(F)F)=O>[CH2:1]([O:8][C:9]1[N:14]=[C:13]2[NH:15][CH:17]=[N:16][C:12]2=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(OC)OC
Reactant: Nc1ccc(OCc2ccccc2)nc1N
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: c1ccc(COc2ccc3nc[nH]c3n2)cc1
Reaction time: 24 h
Yield: 81.1 %

Procedure:
To a solution of 6-(benzyloxy)pyridine-2,3-diamine (19.31 g, 89.71 mmol) in THF (300 mL) was added trimethyl orthoformate 99% (99.16 ml, 897.1 mmol) and TFA (345 μL, 4.49 mmol) at room temperature. After stirring for 24 h the solvent was removed under reduced pressure. The residue was taken up in 2 M HCl and EtOAc. The two layers were separated. The organic layer was washed with 2 M HCl and the combined aqueous layers were then made basic by the careful addition of 2 N NaOH. The precipitate was collected by vacuum filtration to give the title compound as a white solid (16.39 g). LCMS m/z=226.3, [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 5.40 (s, 2H), 6.91 (d, J=9.1 Hz, 1H), 7.32 (m, 1H), 7.38 (m, 2H), 7.48 (m, 2H), 8.09 (d, J=9.1 Hz, 1H), 8.79 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([C:21]([OH:23])=O)[N:18]([CH3:20])[N:19]=3)=[C:11]([CH2:24][OH:25])[O:10][N:9]=2)=[CH:4][CH:3]=1.O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.[NH2:46][CH:47]1[CH2:51][CH2:50][O:49][CH2:48]1.[Cl-].[Na+]>C1COCC1>[O:49]1[CH2:50][CH2:51][CH:47]([NH:46][C:21]([C:17]2[N:18]([CH3:20])[N:19]=[C:15]([O:14][CH2:13][C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[N:9][O:10][C:11]=3[CH2:24][OH:25])[CH:16]=2)=[O:23])[CH2:48]1
Reactant: Cn1nc(OCc2c(-c3ccc(F)cc3)noc2CO)cc1C(=O)O
Reactant: NC1CCOC1
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cn1nc(OCc2c(-c3ccc(F)cc3)noc2CO)cc1C(=O)NC1CCOC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.7 %

Procedure:
To a solution of 5-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid (100 mg, 0.29 mmol) in THF (10 mL) was added 1-hydroxybenzotriazole hydrate (45.0 mg, 0.29 mmol), N-ethyldiisopropylamine (126 μL, 0.76 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidazole hydrochloride (56.3 mg, 0.29 mmol) and rac-3-aminotetrahydrofuran (25.1 mg, 0.29 mmol) and the resulting mixture stirred overnight at room temperature. The reaction mixture was then poured into aqueous sodium chloride (saturated) and the mixture was extracted with ethyl acetate. The combined organic layers were then washed with water and saturated sodium hydrogen carbonate solution and then dried over sodium sulfate, filtered and evaporated. Concentration and purification by chromatography (silica, dichloromethane:methanol=99:1 to 95:5) afforded the title compound (60 mg, 50%) as a white solid. MS: m/e=415.1 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10](=[O:16])[N:9]([CH3:17])[C:8]=2[CH:7]=[C:6]1[N:18]1[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:19]1.[Br:36]N1C(=O)CCC1=O.S([O-])(O)(=O)=O.[K+]>CN(C)C=O>[Br:36][C:7]1[C:8]2[N:9]([CH3:17])[C:10](=[O:16])[N:11]([CH3:15])[C:12](=[O:14])[C:13]=2[N:5]([CH2:4][C:3]2[CH:32]=[CH:33][CH:34]=[CH:35][C:2]=2[Cl:1])[C:6]=1[N:18]1[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:30])[CH3:28])[CH2:19]1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1c(=O)c2c(cc(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n2Cc2ccccc2Cl)n(C)c1=O
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(c(Br)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n2Cc2ccccc2Cl)n(C)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
To a solution of tert-butyl {(3R)-1-[5-(2-chlorobenzyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate (1.00 g) in N,N-dimethylformamide (20 ml) was added N-bromosuccinimide (392 mg), and the resulting mixture was stirred overnight at room temperature. The reaction solution was adjusted to pH 2 with a 10% aqueous potassium hydrogensulfate solution and extracted with ethyl acetate (200 ml). The organic layer was washed with a 10% aqueous potassium hydrogensulfate solution and a saturated aqueous sodium chloride solution, dried over sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=2/1) to obtain the title compound (1.143 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13](Cl)[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1B(O)O>>[CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]([C:23]2[CH:22]=[CH:21][C:20]([Cl:19])=[CH:25][C:24]=2[Cl:26])[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1c(Cl)ccnc1OCc1ccccc1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Product: O=[N+]([O-])c1c(-c2ccc(Cl)cc2Cl)ccnc1OCc1ccccc1
Yield: 51 %

Procedure:
2-Benzyloxy-4-chloro-3-nitro-pyridine (Wilde, et. al. WO 99/01454, which is incorporated herein by reference in its entirety) (11 g, 41.6 mmol) and 2,4-dichlorophenylboronic acid (11.9 g, 62.3 mmol) were treated substantially as described in Part A of Example 19a to give 8.0 g (51%) of 2-benzyloxy-4-(2,4-dichloro-phenyl)-3-nitro-pyridine: MS (AP) m/z 375.2 [(M+H)+, 100].
Reaction SMILES: [S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([CH2:20][NH:21][C:22]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=S)[N:19]=[C:14]2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2]>C1COCC1.CCOC(C)=O.C(O[Hg]OC(=O)C)(=O)C>[CH:24]1([C:22]2[N:19]3[C:14]4[CH:13]=[CH:12][N:11]([S:1]([C:4]5[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=5)(=[O:3])=[O:2])[C:15]=4[N:16]=[CH:17][C:18]3=[CH:20][N:21]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(CNC(=S)C4CCCCC4)cnc32)cc1
Agent: CC(=O)O[Hg]OC(C)=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2cnc(C4CCCCC4)n23)cc1
Reaction time: 0.5 h
Yield: 25 %

Procedure:
To a solution of N #5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)cyclohexanecarboxamide (0.081 g, 0.196 mmol) in THF (1 mL) at ambient temperature was added 2,4-bis(4-phenoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (0.104 g, 0.196 mmol, TCI). After about 15 h, the reaction mixture was concentrated under reduced pressure. The residue was suspended in EtOAc/DCM (1:1) and filtered through a plug of silica gel (5 g) eluting with EtOAc/DCM (1:1, approximately 100 mL). Concentration of the filtrate provided the crude N-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)cyclohexanecarbothioamide. The crude thioamide was dissolved in THF (1 mL) and diacetoxymercury (0.0626 g, 0.196 mmol) was added. After about 30 min at ambient temperature, additional diacetoxymercury (0.0626 g, 0.196 mmol) was added. After about 4 h, the reaction mixture was diluted with EtOAc, filtered, concentrated under reduced pressure, and purified by silica gel chromatography eluting with a gradient of 50-95% EtOAc in heptane to provide 1-cyclohexyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine as a yellow oil (0.020 g, 25%): LC/MS (Table 2, Method a) Rt=2.77 min; MS m/z: 395 (M+H)+.
Reaction SMILES: C(O)(=O)C.[N:5]1([C:11]2[C:12](=[O:18])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]Cl.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][N:8]1[CH2:7][CH2:6][N:5]([C:11]2[C:12](=[O:18])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:10][CH2:9]1
Reactant: O=c1cccccc1N1CCNCC1
Reactant: COc1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CC#N
Product: COc1cccc(CN2CCN(c3cccccc3=O)CC2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-(1-piperazinyl)-2,4,6-cycloheptatriene-1-one acetic acid salt (0.171 g, 0.680 mmol, example 2a), 3-methoxybenzyl chloride (0.118 g, 0.750 mmol) and potassium carbonate (0.276 g, 2.00 mmol) in acetonitrile (2.00 mL) was stirred at room temperature for 16 h. The solvent was removed in vacuo. The residue was triturated with dichloromethane and filtered. The filtrate was concentrated in vacuo to dryness and the residue was subjected to preparative thin layer chromatography using ethyl acetate:methanol (9:1) as the eluent. The title compound was obtained as a yellow oil (0.095 g, 45%); MS (FAB) 311 (M+ +1).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[CH3:15][N:16]1[CH:23]2[CH:19]([N:20]([C:24]3[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=3)[CH2:21][CH2:22]2)[CH2:18][CH2:17]1>>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:30][C:27]2[CH:26]=[CH:25][C:24]([N:20]3[CH2:21][CH2:22][CH:23]4[N:16]([CH3:15])[CH2:17][CH2:18][CH:19]34)=[CH:29][CH:28]=2)=[O:12])=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(C(=O)O)cc1
Reactant: CN1CCC2C1CCN2c1ccc(N)cc1
Product: CCCCOc1ccc(C(=O)Nc2ccc(N3CCC4C3CCN4C)cc2)cc1

Procedure:
4-Butoxybenzoic acid was reacted with 4-(4-methylhexahydropyrrolo[3,2-b]pyrrol-1-yl)phenylamine by method E. The product with the molecular weight of 393.53 (C24H31N3O2); MS (ESI): 394 (M+H+) was obtained in this way.
Reaction SMILES: C([O:8][C:9](=[O:31])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:30])[CH:16]([CH:26]([CH2:28][CH3:29])[CH3:27])[NH:17][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)C1C=CC=CC=1.[H][H]>CO.[C].[Pd]>[C:18]([NH:17][CH:16]([C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[C:9]([OH:31])=[O:8])=[O:30])[CH:26]([CH2:28][CH3:29])[CH3:27])(=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: [H][H]
Reactant: CCC(C)C(NC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCC(C)C(NC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
N-benzoyl-D,L-isoleucyl-L-proline benzyl ester (1.1 g) was dissolved in methanol (15 ml), and 10% palladium-carbon (120 mg) was added. The resulting mixture aerated with hydrogen was allowed to react at room temperature for 3 h, filtered and concentrated under reduced pressure to remove the solvent to give a colourless sticky matter (1.04 g, 99%), which was directly used for the next reaction.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][O:6][C:7]2[CH:32]=[CH:31][C:10]([C:11]([NH:13]/[C:14](/[C:25]([NH:27][CH2:28][CH2:29][OH:30])=[O:26])=[CH:15]\[C:16]3[CH:21]=[CH:20][C:19]([CH:22]4[CH2:24][CH2:23]4)=[CH:18][CH:17]=3)=[O:12])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh].C(O)C.C1COCC1>[CH:22]1([C:19]2[CH:20]=[CH:21][C:16]([CH2:15][CH:14]([NH:13][C:11](=[O:12])[C:10]3[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)=[CH:32][CH:31]=3)[C:25]([NH:27][CH2:28][CH2:29][OH:30])=[O:26])=[CH:17][CH:18]=2)[CH2:23][CH2:24]1
Reactant: O=C(NCCO)/C(=C/c1ccc(C2CC2)cc1)NC(=O)c1ccc(OCCC2CC2)cc1
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(NC(Cc1ccc(C2CC2)cc1)C(=O)NCCO)c1ccc(OCCC2CC2)cc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 53.7 %

Procedure:
To an ethanol:THF (4:1, V/V, 7.5 mL) solution of 4-(2-cyclopropylethoxy)-N-((Z)-2-(4-cyclopropylphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide (165 mg, 0.380 mmol) prepared in Example 1 (1d) was added tris(triphenylphosphine)rhodium(I) chloride (71 mg, 0.076 mmol). The mixture was stirred under a hydrogen atmosphere (rubber balloon) at 60° C. for 5 hours. The reaction solution was cooled to room temperature, and the solvent was evaporated. The residue was purified by alumina column chromatography (ethyl acetate to ethyl acetate:methanol, 10:1, V/V) to give 89 mg of the title compound (white powder, yield: 54%).
Reaction SMILES: C([NH:8][CH2:9][C@@H:10]1[C@@H:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C@H:14]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C@@H:13]([O:28][C@@H:29]([C:31]2[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[C:33]([C:41]([F:44])([F:43])[F:42])[CH:32]=2)[CH3:30])[CH2:12][CH2:11]1)C1C=CC=CC=1>C(O)C.[OH-].[OH-].[Pd+2]>[NH2:8][CH2:9][C@@H:10]1[C@@H:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C@H:14]([C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)[C@@H:13]([O:28][C@@H:29]([C:31]2[CH:32]=[C:33]([C:41]([F:42])([F:43])[F:44])[CH:34]=[C:35]([C:37]([F:40])([F:38])[F:39])[CH:36]=2)[CH3:30])[CH2:12][CH2:11]1
Reactant: CCOC(=O)[C@@H]1[C@@H](CNCc2ccccc2)CC[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccc(F)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)[C@@H]1[C@@H](CN)CC[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccc(F)cc1
Reaction time: 16 h
Yield: 70 %

Procedure:
To a solution of the crude oil from Step D (0.15 g, 0.24 mmol) in 40 mL ethanol was added 0.1 g (20% by weight) of 10% Pd(OH)2—C. The mixture was hydrogenated at 50 PSi for 16 hr at room temperature. The catalyst was filtered through a filter aid pad. The solvent of the filtrate was removed under vacuum to give the title compound (0.09 g) which was used without further purification. 1H-NMR (CDCl3) δ: 7.71 (1H, s), 7.20 (2H, s), 7.00 (2H, m), 6.85 (2H, m), 4.45 (1H, q, J=6.4 Hz), 3.83 (2H, m), 3.35 (1H, m), 3.00-2.86 (2H, m), 2.75 (1H, m), 2.52 (1H, t, J=11.0 Hz), 2.40 (1H, m), 2.25 (1H, m), 1.58 (1H, m), 1.40 (1H, m), 1.33 (3H, d, J=6.4 Hz), 0.88 (3H, t, J=7.1 Hz). MS: (MH)+ 536.5.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[NH3:24]>>[CH2:22]([O:21][C:19]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH2:24])=[CH:10][C:9]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:8][CH:7]=2)=[O:20])[CH3:23]
Reactant: CCOC(=O)c1cnc2ccc(Oc3ccccc3)cc2c1Cl
Reactant: N
Product: CCOC(=O)c1cnc2ccc(Oc3ccccc3)cc2c1N

Procedure:
Prepared as in Example 1a from ethyl 4-chloro-6-phenoxyquinoline-3-carboxylate (Example 8b) and ammonia as a off-white solid (82%). 1H NMR (400 MHz, DMSO-d6) δ 1.35 (t, J=8.0 Hz, 3H), 4.35 (q, J=8.0 Hz, 2H), 7.05 (d, J=8.0 Hz, 2H), 7.15 (t, J=8.0 Hz, 1H), 7.40 (m, d, 2H), 7.46 (dd, J=8.0 Hz, 1H), 7.87 (d, J=8.0 Hz, 1H), 8.13 (d, J=4.0 Hz, 1H), 8.27 (bs, 2H), 8.87 (s, 1H). MS 309 (MH+).
Reaction SMILES: Br.[NH2:2][C:3]1[C:8]([CH:9]=O)=[CH:7][C:6]([Br:11])=[CH:5][N:4]=1.C(N(CC)CC)C.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.[BH4-].[Na+]>CO>[Br:11][C:6]1[CH:7]=[C:8]([CH2:9][NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:3]([NH2:2])=[N:4][CH:5]=1
Reactant: NCCCN1CCOCC1
Reactant: Nc1ncc(Br)cc1C=O
Agent: Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: Nc1ncc(Br)cc1CNCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 53.6 %

Procedure:
To a solution of 2-amino-5-bromo-pyridine-3-carbaldehyde hydrobromide (4.30 g, 15.3 mmol) in MeOH (100 mL) was added triethylamine (4.3 mL, 31 mmol) and the mixture was stirred at room temperature for 10 min. The resulting suspension was treated with 4-(3-aminopropyl)morpholine (2.5 mL, 17 mmol) and the mixture was stirred for 7 h. TLC analysis indicated remaining starting material. Additional 4-(3-aminopropyl)morpholine (1.0 mL, 6.8 mmol) was added, and the mixture was allowed to stir overnight at room temperature. The mixture was cooled and then NaBH4 (0.87 g, 23.0 mmol) was added in two portions. The mixture was stirred at room temperature for 4 h. The solvent was removed in vacuo. Purification by column chromatography (silica gel, CH2Cl2/MeOH/Et3N, 97/2.5/0.5 to 85/14.5/0.5) gave the title compound (2.70 g, 54%) as a brown oil: MS (ESI) m/e 329 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[N:28]=[C:27]2[CH2:29][N:30]([CH3:33])[C:31](=[O:32])[C:26]2=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[N:28]=[C:27]3[CH2:29][N:30]([CH3:33])[C:31](=[O:32])[C:26]3=[CH:25][CH:24]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CN1Cc2nc(Cl)ccc2C1=O
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CN1Cc2nc(Nc3sc(-c4c(F)cc(C(C)(C)O)cc4F)cc3C(N)=O)ccc2C1=O

Procedure:
The title compound was prepared according to the general procedure in Example 1 Step 5 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (75 mg, 0.240 mmol) and 2-chloro-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (43.8 mg, 0.240 mmol) as the starting materials.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:37])([F:36])[F:35])[CH2:18][C:19]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=3)=O)=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9].Cl.[NH2:39][OH:40].C([O-])(O)=O.[Na+]>>[F:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:37])([F:35])[F:36])[CH2:18]/[C:19](=[N:39]\[OH:40])/[C:21]3[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: NO
Reactant: Cc1cc(C(=O)CC(c2ccc(-c3ccc(C(=O)O)c(F)c3)cc2)c2ccccc2C(F)(F)F)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(CC(c2ccc(-c3ccc(C(=O)O)c(F)c3)cc2)c2ccccc2C(F)(F)F)=N/O)ccn1

Procedure:
In analogy to example 132, step 6, from 3-fluoro-4′-[3-(2-methyl-pyridin-4-yl)-3-oxo-1-(2-trifluoromethyl-phenyl)-propyl]-biphenyl-4-carboxylic acid and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a white solid, MS (ESI−): m/z=521.2 ([M−H]−).
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][CH2:10][CH:9]([CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][C:16]([C:20]4[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=4)=[CH:15][C:14]=3[Cl:27])[C:8]2=[O:28])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:30]([CH3:37])([CH3:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:34]([O:33][C:31](=[O:32])[C:30]([O:26][C:23]1[CH:24]=[CH:25][C:20]([C:16]2[CH:15]=[C:14]([Cl:27])[C:13]([CH2:12][CH:9]3[CH2:10][CH2:11][N:7]([CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[C:8]3=[O:28])=[C:18]([Cl:19])[CH:17]=2)=[CH:21][CH:22]=1)([CH3:37])[CH3:36])[CH3:35]
Reactant: O=C1C(Cc2c(Cl)cc(-c3ccc(O)cc3)cc2Cl)CCN1C1CCCCC1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(-c2cc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)cc1
Yield: 104.3 %

Procedure:
Combine 1-Cyclohexyl-3-(3,5-dichloro-4′-hydroxy-biphenyl-4-ylmethyl)-pyrrolidin-2-one (prep 55) (0.15 g, 0.36 mmol), ethyl 2-bromoisobutyrate (0.28 g, 1.43 mmol) and Cs2CO3 (0.35 g, 1.07 mmol) in DMF (7 mL) and heat to 60° C. for 16 hours. Cool the reaction, extract with diethyl ether and water, dry (Na2SO4) and then purify by normal phase chromatography (30 to 80% gradient of ethyl acetate in hexanes) to afford 200 mg (100%) of the title compound: LC-MS (ES +) m/z=exact mass calcd for C29H35Cl2NO4 531, found 532 and 534 (M+1 and M+3, 100%).