Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: IC.[NH2:3][C:4]1[N:5]=[CH:6][C:7]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([C:27]3([C:33]#[N:34])[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]3)[CH:22]=2)=[N:8][C:9]=1[C:10]1[O:14][N:13]=[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:11]=1.[CH2:35](N(CC)CC)C>C(Cl)(Cl)Cl>[NH2:3][C:4]1[N:5]=[CH:6][C:7]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([C:27]3([C:33]#[N:34])[CH2:32][CH2:31][CH2:30][N:29]([CH3:35])[CH2:28]3)[CH:22]=2)=[N:8][C:9]=1[C:10]1[O:14][N:13]=[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:11]=1
Reactant: N#CC1(c2cc(-c3cnc(N)c(-c4cc(-c5ccccc5)no4)n3)ccn2)CCCNC1
Reactant: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: CI
Product: CN1CCCC(C#N)(c2cc(-c3cnc(N)c(-c4cc(-c5ccccc5)no4)n3)ccn2)C1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
Iodomethane (17.09 mg, 7.496 μL, 0.1204 mmol) w as added to a stirred solution of 3-[4-[5-amino-6-(3-phenylisoxazol-5-yl)pyrazin-2-yl]-2-pyridyl]piperidine-3-carbonitrile (51 mg, 0.1204 mmol) and triethyl amine (30.46 mg, 41.96 μL, 0.3010 mmol) in chloroform (1 mL) and the reaction stirred at ambient temperature for 23 hours. A further portion of iodomethane (213.6 mg, 93.68 μL, 1.505 mmol) was added and the reaction stirred at ambient temperature for a further 5.5 hours. The solvent was removed in vacuo and the residue re-dissolved in dichloromethane and filtered. The filtrate was concentrated in vacuo and the residue purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 0%-100% B (solvent A: 10 mM ammonium formate in water; solvent B: 10 mM ammonium formate in 1:1 MeOH:CH3CN) over 14 minutes at 25 mL/min]. The relevant fractions were concentrated in vacuo and partitioned between dichloromethane/saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer extracted with dichloromethane (×3). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The residue was freeze-dried to give 3-[4-[5-amino-6-(3-phenylisoxazol-5-yl)pyrazin-2-yl]-2-pyridyl]-1-methyl-piperidine-3-carbonitrile Compound I-37 as a yellow solid (14.1 mg, 27% Yield). 1H NMR (400.0 MHz, DMSO-d6) δ 1.96-1.71 (m, 4H), 2.20 (s, 3H), 2.21-2.19 (m, 1H), 2.68 (br d, 1H), 2.75 (br d, 1H), 3.22-3.20 (m, 1H), 7.21 (br s, 2H), 7.51-7.44 (m, 3H), 7.68 (s, 1H), 7.94-7.91 (m, 2H), 8.00 (dd, 1H), 8.12 (s, 1H), 8.59 (d, 1H) and 8.93 (s, 1H) ppm LC/MS m/z 438.2 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=1)([OH:3])=[O:2].[N+:13]([O-])([OH:15])=[O:14]>FC(F)(F)C(O)=O>[C:1]([C:4]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=1)([OH:3])=[O:2]
Reactant: O=C(O)c1ccc2c(c1)OCO2
Reactant: O=[N+]([O-])O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cc2c(cc1[N+](=O)[O-])OCO2
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
To 5-carboxy-1,3-benzodioxole (50 g, 300 mmol) in trifluoroacetic acid (400 mL) at 0° C. was added HNO3 (38 mL, 900 mmol) dropwise. The reaction mixture was stirred at 0° C. for 1 hour, then warmed to ambient temperature and stirred for 3 hours. The mixture was poured into ice water and the resulting precipitate was collected by filtration. The solid was air dried overnight to afford 58 g (92% yield) of 5-carboxy-6-nitro-1,3-benzodioxole as a yellow solid; NMR (DMSO-d6) 7.6 (s, 1), 7.3 (s, 1), 6.3 (s, 2) ppm.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][OH:15].O[C:17]1[CH:21]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[O:19][N:18]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:17]1[CH:21]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[O:19][N:18]=1
Reactant: COC(=O)c1cc(O)no1
Reactant: Cc1oc(-c2ccccc2)nc1CCO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)c1cc(OCCc2nc(-c3ccccc3)oc2C)no1
Reaction time: 15 h
Yield: 104.3 %

Procedure:
To a mixture of 2-(5-methyl-2-phenyl-4-oxazolyl)ethanol (5.64 g), methyl 3-hydroxy-5-isoxazolecarboxylate (8.00 g), tributylphosphine (15.9 g) and tetrahydrofuran (200 mL) was added a solution (100 mL) of 1,1′-(azodicarbonyl)dipiperidine (19.9 g) in tetrahydrofuran at room temperature and the mixture was stirred for 15 hrs. The precipitated crystals were removed by filtration and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to give crystals (9.50 g, 73%) of methyl 3-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-5-isoxazolecarboxylate from a fraction eluted with ethyl acetate-hexane (1:3, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 90-91° C.
Reaction SMILES: CN1CCCCC1.[CH:8]([O:11][C:12]([NH:14][C@H:15]([C:19]([OH:21])=O)[CH:16]([CH3:18])[CH3:17])=[O:13])([CH3:10])[CH3:9].ClC(OCC(C)C)=O.[Cl:30][C:31]1[C:32]([O:39][CH2:40][CH:41]([NH2:43])[CH3:42])=[N:33][CH:34]=[N:35][C:36]=1[CH2:37][CH3:38]>C(Cl)Cl.O>[Cl:30][C:31]1[C:32]([O:39][CH2:40][CH:41]([NH:43][C:19](=[O:21])[C@H:15]([CH:16]([CH3:17])[CH3:18])[NH:14][C:12]([O:11][CH:8]([CH3:9])[CH3:10])=[O:13])[CH3:42])=[N:33][CH:34]=[N:35][C:36]=1[CH2:37][CH3:38]
Reactant: CCc1ncnc(OCC(C)N)c1Cl
Reactant: CC(C)OC(=O)N[C@H](C(=O)O)C(C)C
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCCCC1
Solvent: ClCCl
Solvent: O
Product: CCc1ncnc(OCC(C)NC(=O)[C@@H](NC(=O)OC(C)C)C(C)C)c1Cl
Temperature: -20 °C
Reaction time: 1 h
Yield: 43.6 %

Procedure:
0.34 g of N-methylpiperidine was added to a solution containing 0.7 g of N-isopropoxycarbonyl-L-valine dissolved in 50 ml of methylene chloride, at -20° C. After the mixture was stirred for 10 minutes at the same temperature, 0.47 g of isobutyl chloroformate was added to the mixture, and stirred for 1 hour at -20° C. 0.74 g of 1-(5-chloro-6-ethyl-4-pyrimidinyloxy)-2-propylamine was added to this mixture at -60° C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 20 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The obtained crude crystal was purified by column chromatography on silica gel, thus obtaining 0.6 g of the desired product in the form of a white prism-shaped crystal (yield: 43%).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C:7]2[C:11]([C:12]#[N:13])=[C:10]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[S:9][C:8]=2[C:20]([O:22]CC)=[O:21])=[CH:4][C:3]=1[F:27].O1CCCC1.CO.[OH-].[Na+].O>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C:7]2[C:11]([C:12]#[N:13])=[C:10]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[S:9][C:8]=2[C:20]([OH:22])=[O:21])=[CH:4][C:3]=1[F:27]
Reactant: CCOC(=O)c1sc(N2CCOCC2)c(C#N)c1Cc1ccc(Cl)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1c(N2CCOCC2)sc(C(=O)O)c1Cc1ccc(Cl)c(F)c1
Temperature: 25 °C
Yield: 66.3 %

Procedure:
To a solution of ethyl 3-(4-chloro-3-fluorobenzyl)-4-cyano-5-morpholin-4-ylthiophene-2-carboxylate in tetrahydrofuran (5.64 mL, 69.6 mmol) was added methanol (2.5 mL, 62 mmol) and 1 M sodium hydroxide in water (4.23 mL, 4.23 mmol) and the resulting suspension was stirred at room temp. The reaction was stirred for 16 hours at room temperature. Volatiles were then removed in vacuo, and the residue diluted with EtOAc (30 mL). Mixture was then transferred to a separatory funnel containing 1N HCl (5.0 mL) and water (10 mL), at which time the pH of aqueous layer was measured at ˜2.0. Layers were separated, and the aqueous layer was extracted 3×20 mL with EtOAc. Combined organic layers were dried over Na2SO4, filtered, concentrated in vacuo. Resulting residue was adsorbed to celite, and the resulting solid was placed into a dryload cartridge and purified via column chromatography (gradient elution, 0-5% MeOH:CH2Cl2) to afford 3-(4-chloro-3-fluorobenzyl)-4-cyano-5-morpholin-4-ylthiophene-2-carboxylic acid (94) as a white solid (0.128 g, yield 66.3%). LCMS: (FA) ES+ 381, 383; 1H NMR (400 MHz, DMSO) δ 13.25 (s, 1H), 7.52 (dd, J=8.1, 8.1, 1H), 7.22 (dd, J=1.9, 10.5, 1H), 7.05 (dd, J=1.5, 8.3, 1H), 4.31 (s, 2H), 3.80-3.65 (dd, J=4.5, 5.2, 4H), 3.59-3.47 (dd, J=4.5, 5.2, 4H).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:10]([CH3:11])=[C:9]([CH:12]=O)[NH:8][C:7]=1[CH3:14])([OH:3])=[O:2].[I:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[CH2:19]2.N1CCCCC1>C(O)C>[I:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2=[CH:12][C:9]1[NH:8][C:7]([CH3:14])=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:10]=1[CH3:11]
Reactant: O=C1Cc2cc(I)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)O
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3ccc(I)cc32)c(C)c1CCC(=O)O
Yield: 71.1 %

Procedure:
3-(2-Carboxyethyl)-2,4-dimethyl-5-formylpyrrole (97.5 mg), 130 mg 5-iodo-2-oxindole, and 75 μL of piperidine in 3 mL of ethanol were stirred at 95° C. for 5 hours. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven overnight to give 155 mg of the title compound (71%) as an orange solid.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH2:10][CH2:11][CH3:12])=[N:5][CH:6]=[CH:7][CH:8]=1.[CH2:13]([O:15][C:16](=[O:28])[CH2:17][CH2:18][C:19]1[CH:24]=[C:23]([F:25])[C:22]([OH:26])=[C:21]([F:27])[CH:20]=1)[CH3:14]>>[CH2:13]([O:15][C:16](=[O:28])[CH2:17][CH2:18][C:19]1[CH:24]=[C:23]([F:25])[C:22]([O:26][CH2:2][C:3]2[C:4]([S:9][CH2:10][CH2:11][CH3:12])=[N:5][CH:6]=[CH:7][CH:8]=2)=[C:21]([F:27])[CH:20]=1)[CH3:14]
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Reactant: CCCSc1ncccc1CCl
Product: CCCSc1ncccc1COc1c(F)cc(CCC(=O)OCC)cc1F
Yield: 79 %

Procedure:
3-Chloromethyl-2-propylsulfanyl-pyridine (0.1 g, 0.49 mmol) obtained in Step C of Preparation Example 14 and 3-(3,5-difluoro-4-hydroxy-phenyl)-propionic acid ethyl ester obtained in Step D of Preparation Example 2 were used to react in the same manner as in Step A of Example 1 to obtain the title compound (0.155 g, 79%).
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:8][CH2:7][CH:6]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:5][CH2:4]1.[Si]([Cl:34])(C)(C)C>C(OCC)(=O)C>[ClH:34].[CH3:29][N:2]([CH3:1])[C:3]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:8][CH2:7][CH:6]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:5][CH2:4]1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)C1(c2ccccc2)CCC(c2[nH]c3ccccc3c2CCC(=O)O)CC1
Solvent: CCOC(C)=O
Product: Cl
Reaction time: 16 h

Procedure:
3-[2-(4-Dimethylamino-4-phenylcyclohexyl)-1H-indol-3-yl]propionic acid (more polar diastereomer) (419 mg, 1.08 mmol) was dissolved in ethyl acetate (50 ml). Me3SiCl (276 μl, 1.16 mmol) was added dropwise at RT and the mixture was stirred for 16 h. The solvent was distilled off on a rotary evaporator and Example 153 (458 mg, m.p. 242-245° C., 100%) was obtained as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[C:11]([NH2:20])=[N:12][C:13]([NH2:19])=[N:14]3)[CH2:3][CH2:2]1.[F:21][C:22]1[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25]>>[NH2:19][C:13]1[N:12]=[C:11]([NH2:20])[C:10]2[C:15](=[CH:16][CH:17]=[CH:18][C:9]=2[O:8][CH2:7][CH:4]2[CH2:5][CH2:6][N:1]([C:24]([C:23]3[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:22]=3[F:21])=[O:25])[CH2:2][CH2:3]2)[N:14]=1
Reactant: O=C(Cl)c1cccc(F)c1F
Reactant: Nc1nc(N)c2c(OCC3CCNCC3)cccc2n1
Product: Nc1nc(N)c2c(OCC3CCN(C(=O)c4cccc(F)c4F)CC3)cccc2n1
Yield: 74 %

Procedure:
The amidation of 5-(piperidin-4-ylmethoxy)quinazoline-2,4-diamine (50 mg; 0.18 mmol) was carried out using 2,3-difluorobenzoyl chloride (65 mg; 0.37 mmol) via Method AA to yield 114 mg. (74% yield). 1HNMR (400 MHz, DMSO-d6) δ 7.51 (q, J=8.8 Hz, 1H), 7.33 (m, 2H), 7.2 (m, 3H), 6.77 (d, J=8.4 Hz, 1H), 6.54 (d, J=8.0 Hz, 1H), 5.94 (br s, 2H), 4.54 (br d, J=12.8 Hz, 1H), 4.03 (d, J=6.0 Hz, 2H), 3.44 (d, J=14.0 Hz, 1H), 3.14 (t, J=12.4 Hz, 1H), 2.88 (m, 1H), 2.23 (s, 1H), 1.9 (d, J=12.4 Hz, 1H), 1.75 (d, J=10.8 Hz, 1H), 1.26 (m, 2H). MS m/z (ESI) 414 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([O:8][CH2:9][C@@:10]1([C:23]#[C:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[O:14][C@@H:13](OC(OC(C)(C)C)=O)[CH:12]=[CH:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:29]1[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]1=[O:31]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[C:1]([O:5][C:6]([O:8][CH2:9][C@@:10]1([C:23]#[C:24][Si:25]([CH3:26])([CH3:27])[CH3:28])[O:14][C@@H:13]([N:29]2[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]2=[O:31])[CH:12]=[CH:11]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)OC[C@]1(C#C[Si](C)(C)C)C=C[C@H](OC(=O)OC(C)(C)C)O1
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1cn([C@H]2C=C[C@@](C#C[Si](C)(C)C)(COC(=O)OC(C)(C)C)O2)c(=O)[nH]c1=O
Yield: 78.5 %

Procedure:
(2S,5R)-5-t-Butoxycarbonyloxymethyl-5-(2-trimethylsilylethynyl)-2-t-butoxycarbonyloxy-2,5-dihydrofuran (β/α=>99/1) (2.0 g) was added to a glass reactor, and the atmosphere of the reactor was changed to nitrogen. To the reactor, thymine (3.1 g) and N,N′-dimethylformamide (40 mL) were added under stirring. To the resultant mixture, tetrakis(triphenylphosphine)palladium(0) (560 mg) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated, and the residue was purified through silica gel column chromatography, to thereby yield 1.6 g of (2R,5R)-5-t-butoxycarbonyloxymethyl-5-(2-trimethylsilylethynyl)-2-(thymin-1-yl)-2,5-dihydrofuran (yield: 78%, β/α=>99/1). The 1H-NMR data of the compound are as follows.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[O:14][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:12][C:11]=1[CH2:21][CH2:22][O:23][C:24]1[CH:37]=[CH:36][C:27]([CH2:28][CH:29]2[S:33][C:32](=[O:34])[NH:31][C:30]2=[O:35])=[CH:26][CH:25]=1.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:9][C:10]1[O:14][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:12][C:11]=1[CH2:21][CH2:22][O:23][C:24]1[CH:37]=[CH:36][C:27]([CH2:28][CH:29]2[S:33][C:32](=[O:34])[NH:31][C:30]2=[O:35])=[CH:26][CH:25]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CC2SC(=O)NC2=O)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1NC(=O)C(Cc2ccc(OCCc3nc(-c4ccccc4)oc3CBr)cc2)S1

Procedure:
N-Bromosuccinimide (2.75 g) was added portionwise to a solution of 5-{4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyl}-2,4-thiazolidinedione (6.0 g) and α,α'-azobisisobutyronitrile (0.5 g) in carbon tetrachloride(150 ml) under reflux. After refluxing for another 10 minutes, the reaction mixture was washed with water and dried (MgSO4). The solvent was distilled off to give 5-{4-[2-(5-bromomethyl-2-phenyl-4-oxazolyl)ethoxy]benzyl}-2,4-thiazolidinedione as a crude oily substance (about 8 g). IR (neat) cm-1 : 1750, 1690. NMRδ(ppm) in CDCl3 : 3.03 (2 HtJ=7 Hz), 2.9 to 3.2 (1H, m), 3.48 (1H, d.d, J=14 and 5 Hz), 4.24 (2H, t, J=7 Hz), 4.45 (1h, d.d, J=9 and 5 Hz), 4.61 (2H, s), 6.81 (2H, d, J=9 Hz), 7.10 (2H, d, J=9 Hz), 7.4 (3H, m), 8.0 (2H, m), 8.70 (1H, broad s).
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:29])([CH3:28])[O:6][CH2:7][CH:8]([NH:19][C:20](=[O:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:9]([NH:11]CC1C=CC=CC=1)[CH3:10])([CH3:4])[CH3:3]>CO.[OH-].[OH-].[Pd+2]>[NH2:11][CH:9]([CH3:10])[CH:8]([NH:19][C:20](=[O:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:7][O:6][Si:5]([C:2]([CH3:1])([CH3:3])[CH3:4])([CH3:28])[CH3:29]
Reactant: CCCCCCC(=O)NC(CO[Si](C)(C)C(C)(C)C)C(C)NCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCCCCCC(=O)NC(CO[Si](C)(C)C(C)(C)C)C(C)N
Reaction time: 18 h
Yield: 102.2 %

Procedure:
A mixture of 28c (208.6 g, 0.50 mmol) and 104 mg of Pd(OH)2 in 15 mL of methyl alcohol is shaken in a Parr apparatus under hydrogen pressure for 18 h. The reaction mixture is filtered through diatomaceous earth and the filtrate concentrated to give 169 mg of the desired product 25c as an oil. NMR δ 0.84 (s, 9H), 1.05 (d, 3H), 1.60 (m, 2H), 2.10 (t, 2H), 3.31 (m, 1H), 6.47 (br d, 1H).
Reaction SMILES: Br[C:2]1[C:10]2[NH:9][C:8]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH2:13][CH2:12]4.[N:18]1[C:27]2[C:22](=[CH:23][C:24](B3OC(C)(C)C(C)(C)O3)=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1>>[N:18]1[C:27]2[C:22](=[CH:23][C:24]([C:2]3[C:10]4[NH:9][C:8]5[CH:11]6[CH2:17][CH2:16][N:14]([CH2:15][C:7]=5[C:6]=4[CH:5]=[CH:4][CH:3]=3)[CH2:13][CH2:12]6)=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: CC1(C)OB(c2ccc3ncccc3c2)OC1(C)C
Reactant: Brc1cccc2c3c([nH]c12)C1CCN(CC1)C3
Product: c1cnc2ccc(-c3cccc4c5c([nH]c34)C3CCN(CC3)C5)cc2c1

Procedure:
7-Bromo-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (146 mg, 0.5 mmol, Example 1B) was coupled with 6-quinolineboronic acid pinacol ester (191 mg, 0.75 mmol, Aldrich) following the procedure described in Example 4. Purification by preparative reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 40-99% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] gave the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 1.99-2.18 (m, 4 H) 3.02-3.30 (m, 5 H) 4.29 (s, 2 H) 7.10-7.24 (m, 2 H) 7.36 (d, J=8 Hz, 1 H) 7.58 (dd, J=8, 4 Hz, 1 H) 8.04-8.10 (m, 1 H) 8.13-8.22 (m, 2 H) 8.45 (d, J=8 Hz, 1 H) 8.86 (dd, J=4, 2 Hz, 1 H); MS (DCI/NH3) m/z 340 (M+H)+.
Reaction SMILES: [OH-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[C:14]([C:16]([NH:18][C:19]3[C:20]([CH3:30])=[C:21]([CH:26]=[CH:27][C:28]=3[CH3:29])[C:22]([O:24]C)=[O:23])=[O:17])[C:13]([CH3:31])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.CO>C1COCC1>[OH:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[C:14]([C:16]([NH:18][C:19]3[C:20]([CH3:30])=[C:21]([CH:26]=[CH:27][C:28]=3[CH3:29])[C:22]([OH:24])=[O:23])=[O:17])[C:13]([CH3:31])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1
Reactant: COC(=O)c1ccc(C)c(NC(=O)c2nc(N3CCC(O)CC3)ccc2C)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(N2CCC(O)CC2)nc1C(=O)Nc1c(C)ccc(C(=O)O)c1C
Reaction time: 16 h
Yield: 41.1 %

Procedure:
A solution of aqueous 2N NaOH (2.00 ml) is added to a stirred solution of methyl 3-[[6-(4-hydroxy-1-piperidyl)-3-methyl-pyridine-2-carbonyl]amino]-2,4-dimethyl-benzoate (0.21 g, 0.52 mmol) in THF:MeOH (3 ml:1 ml). After 16 h at ambient temperature, the organic solvent is removed under reduced pressure and the residue is diluted with water, acidified to pH 6 with aqueous 1N HCl, and extracted with ethyl acetate (2×20 ml). The organic layers are combined and dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure and the resulting precipitate is triturated with pentane and filtered to afford the title compound as a white solid (0.082 g, 39%). Mass spectrum (m/z): 384.2 (M+1).
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:11]1[CH:12]=[C:13]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:14]2[O:19][CH2:18][CH2:17][N:16]([CH2:20][C:21]#[N:22])[C:15]=2[CH:23]=1)(=[O:10])[CH3:9].[Br:28]N1C(=O)CCC1=O.C(OCC)(=O)C>O1CCCC1>[Br:28][CH2:9][C:8]([C:11]1[CH:12]=[C:13]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:14]2[O:19][CH2:18][CH2:17][N:16]([CH2:20][C:21]#[N:22])[C:15]=2[CH:23]=1)=[O:10]
Reactant: CC(=O)c1cc2c(c(C(C)(C)C)c1)OCCN2CC#N
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(C(=O)CBr)cc2c1OCCN2CC#N
Reaction time: 0.5 h
Yield: 49 %

Procedure:
Triethylamine (0.76 ml, 5.5 mmol) and tert-butyl dimethylsilyltrifluoromethanesulfonate (0.73 g, 5.5 mmol) were added to a solution of [6-acetyl-8-(tert-butyl)-3,4-dihydro-2H-1,4-benzoxazin-4-yl]methyl cyanide (0.5 g, 1.8 mmol) in tetrahydrofuran (50 ml) while cooling on ice and the mixture was stirred at the same temperature for 30 minutes, after which N-bromosuccinimide (0.49 g, 2.7 mmol) was added and stirring was continued for 30 minutes. Ethyl acetate was added, the reaction mixture was washed with brine and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and then the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (310 mg) as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][CH:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[CH3:30][C:31]([CH3:33])=O>>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][CH:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[CH2:15][O:16][CH2:17][CH:18]3[CH2:19][CH2:20][N:21]([CH:31]([CH3:33])[CH3:30])[CH2:22][CH2:23]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: O=C(NC(COCC1CCNCC1)c1ccccn1)c1ccc2c(Cl)c[nH]c2c1
Product: CC(C)N1CCC(COCC(NC(=O)c2ccc3c(Cl)c[nH]c3c2)c2ccccn2)CC1
Yield: 69.7 %

Procedure:
Using alkylation method A, 3-chloro-N-[1-(2-pyridinyl)-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide (170 mg, 0.41 mmol) and acetone (1.2 mL, 16.8 mmol) afforded 130 mg (70%) of the title compound.
Reaction SMILES: ClC1C=[C:10]2[C:5]([CH:6]=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=3)[CH2:17][OH:18])=[N:9]2)=CC=1.CC(C[AlH]CC(C)C)C.ClCCl>C1(C)C=CC=CC=1>[N:9]1[CH:10]=[CH:5][CH:6]=[CH:7][C:8]=1/[CH:12]=[CH:13]/[C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][OH:18]
Reactant: OCc1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: OCc1cccc(/C=C/c2ccccn2)c1
Temperature: -70 °C

Procedure:
The methyl benzoate (Example 37b part ii) (2.25 g, 9.4 mmol) was dissolved in dry toluene (60 ml) and cooled to -70° C. under nitrogen. 1M DIBAL in dichloromethane (18.8 ml, 18.8 mmol) was added over 15 minutes and the reaction mixture allowed to warm up to -30° C. for 30 minutes. The reaction was quenched by careful addition of methanol (8 ml), then water, and after filtration through Celite the organic phase was evaporated in vacuo.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:18]([OH:20])=O)=[C:4]([NH:8][C:9]([CH:11]2[C:13]([CH3:15])([CH3:14])[C:12]2([CH3:17])[CH3:16])=[O:10])[S:5][C:6]=1[CH3:7].C([N:24](CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH4+].[OH-]>O1CCCC1>[CH3:1][C:2]1[C:3]([C:18]([NH2:24])=[O:20])=[C:4]([NH:8][C:9]([CH:11]2[C:13]([CH3:15])([CH3:14])[C:12]2([CH3:17])[CH3:16])=[O:10])[S:5][C:6]=1[CH3:7]
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1sc(NC(=O)C2C(C)(C)C2(C)C)c(C(=O)O)c1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1sc(NC(=O)C2C(C)(C)C2(C)C)c(C(N)=O)c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Example 9B (0.30 g, 1.0 mmol) and N,N-diisopropylethylamine (0.21 mL, 1.2 mmol) in 5 mL tetrahydrofuran was added o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 0.41 g, 1.1 mmol). The mixture stirred for 2 hours at ambient temperature, and 5 mL of NH4OH was added and the reaction mixture stirred for an additional 1 hour. The mixture was concentrated under reduced pressure and the residue was dissolved in 10 mL CH2Cl2. NH4Cl (5 mL) was added, the layers were separated and the aqueous layer was extracted 2×5 mL CH2Cl2. The combined organics were dried over anhydrous Na2SO4, filtered, concentrated, and purified via column chromatography (SiO2, 50% hexanes:ethyl acetate) to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.15 (s, 1H), 1.21 (s, 6H), 1.32 (s, 6H), 2.26 (s, 3H), 2.30 (s, 3H), 5.60-5.84 (m, 2H), 11.88 (s, 1H); MS (DCI/NH3) m/z 295 (M+H)+; anal. calculated for C15H22N2O2S: C, 61.19; H, 7.53; N, 9.52. Found: C, 61.28; H, 7.74; N, 9.44.