Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][CH:12]1[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:14][CH2:13]1)=S.[S]>[Hg]=O.O1CCCC1>[NH:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:9]1[NH:11][CH:12]1[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:14][CH2:13]1
Reactant: CCOC(=O)N1CCCC(NC(=S)Nc2ccccc2N)CC1
Agent: O=[Hg]
Agent: [S]
Solvent: C1CCOC1
Product: CCOC(=O)N1CCCC(Nc2nc3ccccc3[nH]2)CC1
Reaction time: 3 h
Yield: 81 %

Procedure:
A mixture of 33.6 parts of ethyl 4-[[[(2-aminophenyl)amino]thioxomethyl]amino]hexahydro-1H-azepine-1-carboxylate, 26 parts of mercury(II) oxide, 0.1 parts of sulfur and 450 parts of tetrahydrofuran was stirred for 3 hours at reflux temperature. The reaction mixture was filtered while hot over diatomaceous earth and the filtrate was evaporated. The residue was boiled in acetonitrile. The product was filtered off and dried, yielding 24.5 parts (81.0%) of ethyl 4-(1H-benzimidazol-2-yl-amino)hexahydro-1H-azepine-1-carboxylate; mp. 174.6° C. (compound 10).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:19]=[C:18]([C:20]([OH:22])=O)[O:17][N:16]=1.F[B-](F)(F)F.[N:28]1(OC(N(C)C)=[N+](C)C)[C:32]2[CH:33]=[CH:34][CH:35]=CC=2N=[N:29]1.C(N(CC)C(C)C)(C)C.Cl.NN1CCCC1>CN(C=O)C>[N:28]1([NH:29][C:20]([C:18]2[O:17][N:16]=[C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=4)=[N:5][O:6][C:2]=3[CH3:1])[CH:19]=2)=[O:22])[CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1onc(-c2ccccn2)c1COc1cc(C(=O)O)on1
Agent: Cl
Agent: F[B-](F)(F)F
Agent: NN1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2ccccn2)c1COc1cc(C(=O)NN2CCCC2)on1
Reaction time: 4 h
Yield: 57.4 %

Procedure:
To a solution of 3-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid (100 mg, 0.33 mmol) in DMF (5 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (160 mg, 0.5 mmol), N,N-diisopropyl ethyl amine (280 μL, 1.7 mmol) and N-aminopyrrolidine HCl (61 mg, 0.50 mmol). The resulting reaction mixture was for 4 h at room temperature. Concentration and purification by chromatography (silica, dichloromethane:methanol=1:0 to 8.5:1.5) afforded the title compound (70 mg, 57%) as a white solid. MS: m/e=370.2 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7]C(=O)OC(C)(C)C)[N:4]=[C:3]1[CH3:15].[ClH:16]>ClCCl.O1CCOCC1>[ClH:16].[CH3:1][N:2]1[CH:6]=[C:5]([NH2:7])[N:4]=[C:3]1[CH3:15]
Reactant: Cc1nc(NC(=O)OC(C)(C)C)cn1C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1nc(N)cn1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 55 %

Procedure:
To a solution of 337b (1.2 g, 5.68 mmol) in dichloromethane (5.0 mL) was added 3M HCl in dioxane (5.0 mL). This mixture was stirred at room temperature for 4 h and concentrated under reduced pressure. The crude product was washed by ethyl acetate to afford 337c (450 mg, 55%) as a pale yellow solid, which was used in the next step without further purification. MS-ESI: [M+H]+ 112.2
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[N:10]=1)[C:5]([OH:7])=[O:6].[CH:12](O)([CH3:14])[CH3:13]>OS(O)(=O)=O>[CH:12]([O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([CH3:11])[N:10]=[C:2]([Cl:1])[CH:3]=1)([CH3:14])[CH3:13]
Reactant: Cc1cc(C(=O)O)cc(Cl)n1
Reactant: CC(C)O
Agent: O=S(=O)(O)O
Product: Cc1cc(C(=O)OC(C)C)cc(Cl)n1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
To a suspension of 2-chloro-6-methyl-isonicotinic acid (20.0 g, 117 mmol) in isopropanol (80 mL), H2SO4 (5 mL) is added dropwise. The mixture becomes warm (40° C.). The mixture is stirred for 24 h at rt, then at 90° C. for 28 h before the solvent is removed in vacuo. The residue is dissolved in diethyl ether (200 mL), washed with sat. aq. NaHCO3-solution (3×50 mL) followed by brine (3×50 mL), dried over Na2SO4, filtered and concentrated to give 2-chloro-6-methyl-isonicotinic acid isopropyl ester (21.0 g) as a colourless oil which slowly crystallises; LC-MS: tR=0.97 min, [M+1]+=214.05.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:12]([O:14][CH:15]([O:18][CH2:19][CH3:20])[CH2:16][NH2:17])[CH3:13].CCN=C=NCCCN(C)C>C(Cl)Cl>[Br:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([NH:17][CH2:16][CH:15]([O:18][CH2:19][CH3:20])[O:14][CH2:12][CH3:13])=[O:6])=[C:2]([Cl:1])[CH:10]=1
Reactant: O=C(O)c1ccc(Br)cc1Cl
Reactant: CCOC(CN)OCC
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CCOC(CNC(=O)c1ccc(Br)cc1Cl)OCC
Reaction time: 4 h
Yield: 99.9 %

Procedure:
To a suspension of 2-chloro-4-bromobenzoic acid (10.0 g, 42.47 mmol) in CH2Cl2 (1000 mL) was added aminoacetaldehyde diethyl acetal (5.1 mL, 46.72 mmol) and WSC (9.77 g, 50.96 mmol) at room temperature, and stirred for 4 hours. The mixture was washed with water (100 mL), dried over MgSO4. Removal of the solvent, gave title compound (14.88 g, 100% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH:6]=[CH:7][CH2:8][N:9]2[C:14](=[O:15])[C:13]([NH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][C:11]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)=[N:10]2)=[CH:4][CH:3]=1.[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38]Br>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][CH2:8][N:9]2[C:14](=[O:15])[C:13]([N:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:38][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][N:32]=3)=[CH:12][C:11]([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)=[N:10]2)=[CH:30][CH:31]=1
Reactant: CCOC(=O)Nc1cc(-c2ccc(OC)cc2)nn(CC=Cc2ccc(Cl)cc2)c1=O
Reactant: BrCc1ccccn1
Product: CCOC(=O)N(Cc1ccccn1)c1cc(-c2ccc(OC)cc2)nn(CC=Cc2ccc(Cl)cc2)c1=O
Yield: 97 %

Procedure:
2-(4-Chlorocinnamyl)-4-ethoxycarbonylamino-6-(4-methoxyphenyl)-2H-pyridazin-3-one (70 mg) and 2-pyridylmethyl bromide were processed as in Example 116 (stirred at 70° C. for 4 hours), whereby the title compound (82 mg, 97.0%) was obtained.
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH:6]=[N:5][CH:4]=1)=[CH2:2]>CO.[C].[Pd]>[CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:16][CH2:15]2)[CH:6]=[N:5][CH:4]=1)[CH3:2]
Reactant: C=Cc1cncc2cccc(NC3CCN(C(=O)OC(C)(C)C)CC3)c12
Agent: [Pd]
Solvent: CO
Product: CCc1cncc2cccc(NC3CCN(C(=O)OC(C)(C)C)CC3)c12
Yield: 90.5 %

Procedure:
A solution (2 ml) of Intermediate 81 (103 mg) in methanol was vigorously stirred in the presence of 10% palladium carbon catalyst (16.5 mg) at room temperature under hydrogen atmosphere of ordinary pressure. The reaction mixture was filtered through Celite, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain the title compound (93.7 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:12])[C:7]=1[CH2:8][C:9]([OH:11])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:33]([CH2:36][CH:37]([CH3:39])[CH3:38])[CH2:34][NH2:35])[CH:30]=[CH:31][CH:32]=1>C1COCC1>[Cl:12][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C:9]([NH:35][CH2:34][CH:33]([C:29]1[CH:30]=[CH:31][CH:32]=[C:27]([O:26][CH3:25])[CH:28]=1)[CH2:36][CH:37]([CH3:39])[CH3:38])=[O:11]
Reactant: O=C(O)Cc1c(Cl)cncc1Cl
Reactant: COc1cccc(C(CN)CC(C)C)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1cccc(C(CNC(=O)Cc2c(Cl)cncc2Cl)CC(C)C)c1
Yield: 97.4 %

Procedure:
By working in a way similar to that described in example 4 but using (3,5-dichloropyridin-4-yl)-acetic acid (2.06 g, 10 mmoles), carbonyldiimidazole (1.78 g, 11 mmoles), THF (30 ml) and 2-(3-methoxy-phenyl)-4-methyl-pentylamine (2.07 g, 10 mmoles), obtained as described in example 21, 3.85 g of the title compound were obtained (yield: 97.6%), m.p.: 98-99° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:14]#[N:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.Br.C(O)(=[O:25])C>>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:9][CH2:10][C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:14]([NH2:15])=[O:25])[CH2:12][CH2:13]2)=[N:6][CH:7]=1
Reactant: N#CC1(c2ccccc2)CCN(c2ncc(Br)cn2)CC1
Reactant: CC(=O)O
Agent: Br
Product: NC(=O)C1(c2ccccc2)CCN(c2ncc(Br)cn2)CC1
Temperature: 0 °C

Procedure:
A solution of 1-(5-bromopyrimidin-2-yl)-4-phenylpiperidine-4-carbonitrile (0.31 g, 0.9 mmol) in HBr-acetic acid (12 mL) was refluxed for 16 h. After completion of reaction (by TLC), the mixture was poured into 100 mL of ice cold water and extracted with EtOAc (3×150 mL). The combined organics were washed with brine, dried over anhydrous Na2SO4, filtered and evaporated to obtain the desired product as a white solid (0.12 g). MS: 361.15 [M+H]+.
Reaction SMILES: [CH2:1]([CH:6]1[O:11][C:10]2[CH:12]=[CH:13][C:14]([C:16]([OH:18])=O)=[CH:15][C:9]=2[CH2:8][O:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].C(Cl)(Cl)Cl.ClC(OCC)=O.[NH3:29]>C(N(CC)CC)C>[CH2:1]([CH:6]1[O:11][C:10]2[CH:12]=[CH:13][C:14]([C:16]([NH2:29])=[O:18])=[CH:15][C:9]=2[CH2:8][O:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCC1OCc2cc(C(=O)O)ccc2O1
Reactant: N
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCC1OCc2cc(C(N)=O)ccc2O1
Temperature: 0 °C

Procedure:
A mixture of 3.0 g of 2-pentyl-1,3-benzodioxan-6-carboxylic acid (prepared in accordance with Example 12), 60 ml of chloroform and 2.2 ml of triethylamine is cooled to 0° C. 1.5 ml of ethyl chloroformate are added dropwise while stirring. The mixture is stirred at 0° C. for 1 hour and then ammonia gas is conducted in. The mixture is stirred at room temperature for 5 hours and then evaporated. The residue is stirred up with 100 ml of water and the suspension is suction filtered. The material on the suction filter is dried and boiled up with hexane. There is obtained 2-pentyl-1,3-benzodioxan-6-carboxamide as a beige powder; m.p. 162.5°-163° C.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][C:13]([C:15]#[N:16])=[CH:14][C:6]=2[N:5]([C:17]([CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[O:18])[C@H:4]1[CH3:25].[C:26]([N:33]([CH3:39])[C@H:34]([C:36](O)=[O:37])[CH3:35])([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[C:15]([C:13]1[CH:12]=[CH:11][C:7]2[NH:8][C:9](=[O:10])[C@@H:3]([NH:2][C:36](=[O:37])[C@@H:34]([N:33]([CH3:39])[C:26](=[O:27])[O:28][C:29]([CH3:30])([CH3:32])[CH3:31])[CH3:35])[C@H:4]([CH3:25])[N:5]([C:17]([CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])[C:6]=2[CH:14]=1)#[N:16]
Reactant: C[C@H]1[C@H](N)C(=O)Nc2ccc(C#N)cc2N1C(=O)C1CCOCC1
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](C(=O)N[C@@H]1C(=O)Nc2ccc(C#N)cc2N(C(=O)C2CCOCC2)[C@H]1C)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.8 %

Procedure:
To a 0° C. solution of (3S,4S)-3-amino-4-methyl-2-oxo-5-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile hydrochloride (218 mg, 598 μmol) in DMF (1.99 ml) was added Boc-N-methyl-L-alanine (134 mg, 657 μmol), N,N-diisopropylethylamine (414 μl, 2.39 mmol), and HBTU (249 mg, 657 μmol). The reaction was stirred at rt for 30 min, then diluted with EtOAc, washed with H2O, sat. aq. NaHCO3, and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(S)-1-((2S,3S)-8-cyano-2-methyl-4-oxo-1-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (239 mg, 78%) as a white solid. MS m/z 536 (MNa)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.N1CCCCC1.[CH3:21][Si:22]([C:25]#[CH:26])([CH3:24])[CH3:23].CCN(CC)CC>CCOCC.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.[Cu]I>[CH3:14][N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:4]=[CH:3][C:2]([C:26]#[C:25][Si:22]([CH3:24])([CH3:23])[CH3:21])=[CH:7][N:6]=2)[CH2:9][CH2:10]1
Reactant: CN1CCN(c2ccc(Br)cn2)CC1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCNCC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CN1CCN(c2ccc(C#C[Si](C)(C)C)cn2)CC1
Temperature: 90 °C
Yield: 60.8 %

Procedure:
A mixture of 1-(5-bromopyridin-2-yl)-4-methylpiperazine (501.7 mg, 1.96 mmol), PdCl2(PPh3)2 (51.1 mg, 0.073 mmol) and copper(I) iodide (39.9 mg, 0.21 mmol) was flushed with argon for 10 min prior to addition of piperidine (1.25 mL, 12.7 mmol) and trimethylsilylacetylene (1.40 mL, 9.9 mmol). The resulting mixture was heated at 90° C. in a sealed vial for 3 d. The reaction mixture was cooled to room temperature and the volatiles were removed in vacuo. Chromatography on Biotage (silica, SNAP-25 g, 5-15% MeOH in DCM) yielded an impure product. A second chromatography on Biotage (silica, SNAP-25 g, 0-3% Et3N in Et2O) gave 1-methyl-4-(5-((trimethylsilyl)ethynyl)pyridin-2-yl)piperazine (325.7 mg, 61%). 1H NMR (400 MHz, CDCl3) δ ppm 8.29 (d, J=1.3 Hz, 1 H), 7.53 (dd, J=8.9, 2.4 Hz, 1 H), 6.55 (d, J=8.8 Hz, 1 H), 3.67-3.52 (m, 4 H), 2.57-2.44 (m, 4 H), 2.35 (s, 3 H); MS ESI [M+H]+ 274.0, calcd for [C15H23N3Si+H]+ 274.2.
Reaction SMILES: [OH:1][CH:2]([CH2:17][OH:18])[CH2:3][N:4]1[C:13]2[C:12](=[O:14])[N:10]([CH3:11])[C:9](=[O:15])[N:8]([CH3:16])[C:7]=2[N:6]=[CH:5]1.[Cl:19][C:20]1[CH:30]=[CH:29][C:23]([O:24][CH2:25][C:26](O)=[O:27])=[CH:22][CH:21]=1.O>C1(C)C(C)=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:19][C:20]1[CH:30]=[CH:29][C:23]([O:24][CH2:25][C:26]([O:18][CH2:17][CH:2]([OH:1])[CH2:3][N:4]2[C:13]3[C:12](=[O:14])[N:10]([CH3:11])[C:9](=[O:15])[N:8]([CH3:16])[C:7]=3[N:6]=[CH:5]2)=[O:27])=[CH:22][CH:21]=1
Reactant: O=C(O)COc1ccc(Cl)cc1
Reactant: Cn1c(=O)c2c(ncn2CC(O)CO)n(C)c1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: Cn1c(=O)c2c(ncn2CC(O)COC(=O)COc2ccc(Cl)cc2)n(C)c1=O
Yield: 79 %

Procedure:
27.0 g (0.1 mol) 7-(2,3-dihydroxypropyl)-theophylline and 18.6 g (0.1 mol) p-chlorophenoxyacetic acid were heated in 100 ml xylene for 8 hours in a water separator with the addition of 0.9 g p-toluenesulfonic acid. After cooling down, the xylene was decanted and the residue dissolved in hot isopropanol. After addition of a little water the monoester crystallized out slowly. The yield was 33.4 g (79% yield) of 1-(7-theophyllinyl)-2-hydroxy-3-propyl (p-chlorophenoxyacetate) with a melting point of 81°-83°C.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:35][CH:36]([CH3:41])[CH2:37][C:38](O)=[O:39].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[F:17][C:15]1[CH:14]=[N:13][C:12]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)=[C:11]([CH:16]=1)[C:10]([NH:9][C@H:6]1[CH2:7][CH2:8][C@@H:3]([NH:2][C:38](=[O:39])[CH2:37][CH:36]([CH3:41])[CH3:35])[CH2:4][CH2:5]1)=[O:27]
Reactant: CC(C)CC(=O)O
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](N)CC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](NC(=O)CC(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 64 h

Procedure:
N-(cis-4-Amino-cyclohexyl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide hydrochloride (100 mg, 0.243 mmol) was dissolved in dimethylformamide (1 ml) and triethylamine (100 μl, 0.729 mmol) was added followed by 3-methylbutyric acid (32 μl, 0.291 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (56 mg, 0.291 mmol) and 1-hydroxybenzotriazole (39 mg, 0.291 mmol). The reaction was stirred under nitrogen at room temperature for 64 h and the solvent was removed under reduced pressure. The residue was partitioned between sat. sodium bicarbonate solution (5 ml) and ethyl acetate (10 ml) and the aqueous phase was extracted with ethyl acetate (3×10 ml). The combined organic extracts were washed with water (2×5 ml), brine (5 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was triturated with diethylether (5 ml) to give 5-Fluoro-N-[cis-4-(3-methyl-butyrylamino)-cyclohexyl]-2-(3-methylsulfanyl-phenoxy)-nicotinamide (112 mg) as a white solid.
Reaction SMILES: C[N:2]1[CH2:15][CH2:14][C:12]2=[C:13]3[C:8](=[CH:9][CH:10]=[CH:11]2)[CH:7]2[CH2:16][CH2:17][CH2:18][CH:6]2[N:5]3[CH2:4][CH2:3]1.ClC(OC(Cl)C)=O>ClC(Cl)C>[CH2:4]1[N:5]2[C:13]3[C:8]([CH:7]4[CH2:16][CH2:17][CH2:18][CH:6]42)=[CH:9][CH:10]=[CH:11][C:12]=3[CH2:14][CH2:15][NH:2][CH2:3]1
Reactant: CN1CCc2cccc3c2N(CC1)C1CCCC31
Agent: CC(Cl)OC(=O)Cl
Solvent: CC(Cl)Cl
Product: c1cc2c3c(c1)C1CCCC1N3CCNCC2
Temperature: 25 °C
Yield: 73.9 %

Procedure:
To a solution of 3-methyl-2,3,4,5,9,10,11,11a-octahydro-1H,8bH-cyclopenta[b][1,4]diazocino[7,8,1-hi]indole (0.40 g, 1.6 mmole) in dichloroethane (80 mL) was added 1-chloroethyl chloroformate (1.2 mL, 10.8 mmole) and the solution refluxed for 24 hours under nitrogen. The reaction mixture was cooled to room temperature and the solvent removed in vacuo and replaced with methanol (200 mL) and refluxed for another 3 hours under nitrogen. The solvent was removed in vacuo and the residue purified by flash column chromatography (silica gel, 1.5% methanol in dichloromethane) to provide 0.27 g of the title compound as an off-white solid. A THF solution of this compound was further treated with hydrogen chloride to provide 0.22 g of a hydrochloride salt, mp 137-140° C. MS (ESI) m/z 229 ([M+H]+).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[Cl:13])=[O:5].[BH4-].[Na+].Cl>CO>[NH2:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[Cl:13])[OH:5]
Reactant: NCC(=O)c1cccc(Cl)c1Cl
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NCC(O)c1cccc(Cl)c1Cl
Reaction time: 8 h

Procedure:
Under argon, 300 mg (1.25 mmol) of the compound of Example 41A were initially charged in 2 ml of methanol. 189 mg (5.0 mmol) of sodium borohydride were added and the mixture was stirred overnight. 1 N hydrochloric acid was added slowly until the evolution of gas had ceased, and the methanol was then removed on a rotary evaporator. The aqueous residue was made alkaline by addition of sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulphate and freed from the solvent on a rotary evaporator. The residue (189 mg, 74% of theory) corresponded to the title compound.
Reaction SMILES: [F:1][CH:2]([F:25])[O:3][C:4]1[CH:24]=[CH:23][C:7]([CH2:8][C:9]2[C:10]([CH3:22])=[C:11]([CH3:21])[C:12]([CH:19]=O)=[C:13]([CH:18]=2)[C:14](OC)=[O:15])=[CH:6][CH:5]=1.[NH2:26][C@@H:27]1[C@@H:32]([OH:33])[CH2:31][CH2:30][O:29][CH2:28]1>C1COCC1>[F:1][CH:2]([F:25])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]2[CH:18]=[C:13]3[C:12]([CH2:19][N:26]([C@@H:27]4[C@@H:32]([OH:33])[CH2:31][CH2:30][O:29][CH2:28]4)[C:14]3=[O:15])=[C:11]([CH3:21])[C:10]=2[CH3:22])=[CH:23][CH:24]=1
Reactant: N[C@H]1COCC[C@@H]1O
Reactant: COC(=O)c1cc(Cc2ccc(OC(F)F)cc2)c(C)c(C)c1C=O
Solvent: C1CCOC1
Product: Cc1c(Cc2ccc(OC(F)F)cc2)cc2c(c1C)CN([C@H]1COCC[C@@H]1O)C2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.1 %

Procedure:
To a solution of methyl 5-(4-(difluoromethoxy)benzyl)-2-formyl-3,4-dimethylbenzoate (0.04 g) in THF (2.00 mL) was added (3S,4S)-3-aminotetrahydro-2H-pyran-4-ol (0.01 g) under argon atmosphere, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated, and the residue was diluted with acetic acid (2.00 mL). Sodium triacetoxyborohydride (0.03 g) was added thereto under argon atmosphere, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.02 g).
Reaction SMILES: C(SCCCC)CCC.[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Li].[C:17]([O:21][C:22](=[O:36])[CH:23]=[CH:24][CH2:25][C:26]1[CH:27]=[C:28]2[C:32](=[C:33]([CH3:35])[CH:34]=1)[NH:31][N:30]=[CH:29]2)([CH3:20])([CH3:19])[CH3:18]>CCOCC>[C:17]([O:21][C:22](=[O:36])[CH2:23][CH:24]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][N:10]=1)[CH2:25][C:26]1[CH:27]=[C:28]2[C:32](=[C:33]([CH3:35])[CH:34]=1)[NH:31][N:30]=[CH:29]2)([CH3:19])([CH3:20])[CH3:18]
Reactant: [Li]c1ccccn1
Reactant: Cc1cc(CC=CC(=O)OC(C)(C)C)cc2cn[nH]c12
Solvent: CCOCC
Solvent: CCCCSCCCC
Product: Cc1cc(CC(CC(=O)OC(C)(C)C)c2ccccn2)cc2cn[nH]c12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a 50-mL oven-dried flask was added di-n-butylsulfide (261 mg, 1.781 mmol, 6.4 equiv) and cuprous iodide (170 mg, 0.891 mmol, 3.2 equiv) under nitrogen. Anhydrous ether (1 mL) was added and the suspension was cooled to 0° C. before the solution of 2-pyridinyl lithium was added via canuula. A yellowish brown precipitate was formed. After stirring at 0° C. for 15 min, the cooling bath was removed and 4-(7-methyl-1H-indazol-5-yl)-but-2-enoic acid tert-butyl ester (75.8 mg, 0.278 mmol, 1.0 equiv) in anhydrous ether (1 mL) was added via syringe. The dark solution was stirred at room temperature for 40 min. LCMS indicated the formation of the desired product. The reaction mixture was then partitioned between an aqueous ammonium hydroxide/ammonium chloride solution and ethyl acetate (upon shaking, the solids gradually dissolved to a blue aqueous solution). The layers were separated and the organic layer was washed with water, brine, dried over sodium sulfate and concentrated in vacuo to an oil. Careful flash column chromatography (5% methanol in methylene chloride) afforded the desired product (10.4 mg, 11%) which was carried on without farther purification. MS (ESI) 352 (M H)+, 296 (M-tBu)+.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][N:9]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[C:8]2=[O:18])=[C:4]([O:21][C:22]([F:25])([F:24])[F:23])[CH:3]=1.[CH3:26][O:27][C:28]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)=[O:29].O1CCOCC1.C([O-])(=O)C.[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CS(C)=O>[CH3:26][O:27][C:28]([C:30]1[CH:35]=[CH:34][C:33]([C:2]2[CH:20]=[CH:19][C:5]([CH2:6][CH:7]3[CH2:11][CH2:10][N:9]([CH:12]4[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]4)[C:8]3=[O:18])=[C:4]([O:21][C:22]([F:25])([F:24])[F:23])[CH:3]=2)=[CH:32][CH:31]=1)=[O:29]
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: O=C1C(Cc2ccc(Br)cc2OC(F)(F)F)CCN1C1CCCCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: COC(=O)c1ccc(-c2ccc(CC3CCN(C4CCCCC4)C3=O)c(OC(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.2 %

Procedure:
Combine 3-(4-bromo-2-(trifluoromethoxy)benzyl)-1-cyclohexylpyrrolidin-2-one (9.68 g, 23.0 mmol), 4-(methoxycarbonyl)phenylboronic acid (8.29 g, 46.1 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) (2.87 g, 3.9 mmol), dioxane (400 mL) and DMSO (8 mL) in a 1 L flask equipped with a magnetic stir bar, reflux condenser, and N2 inlet. Add potassium acetate (9.04 g, 92.1 mmol) and heat to 80° C. while stirring for 2 hours. Cool to room temperature, filter through silica gel and rinse with ethyl acetate (400 mL). Wash with water (2×400 mL) and saturated sodium chloride solution (1×400 mL), then dry over anhydrous magnesium sulfate and concentrate to an oil. Purify the crude product via silica gel chromatography eluting with 10% to 20% ethyl acetate in hexanes to afford 9.86 g (90%) of the product as a white solid. MS (m/z): 476 (M+1).