Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=2)[CH2:3][CH2:2]1.[NH2:19][C:20]1[C:25]2[CH:26]=[C:27]([CH2:29][CH:30]([NH:40]S(C3C=CC(OC4CCOCC4)=CC=3)(=O)=O)[C:31]([N:33]3[CH2:38][CH2:37][CH:36]([CH3:39])[CH2:35][CH2:34]3)=[O:32])[S:28][C:24]=2[CH:23]=[CH:22][N:21]=1>>[NH2:19][C:20]1[C:25]2[CH:26]=[C:27]([CH2:29][CH:30]([NH:40][S:15]([C:12]3[CH:13]=[CH:14][C:9]([CH2:8][O:7][CH:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)=[CH:10][CH:11]=3)(=[O:17])=[O:16])[C:31]([N:33]3[CH2:34][CH2:35][CH:36]([CH3:39])[CH2:37][CH2:38]3)=[O:32])[S:28][C:24]=2[CH:23]=[CH:22][N:21]=1
Reactant: CC1CCN(C(=O)C(Cc2cc3c(N)nccc3s2)NS(=O)(=O)c2ccc(OC3CCOCC3)cc2)CC1
Reactant: O=S(=O)(Cl)c1ccc(COC2CCOCC2)cc1
Product: CC1CCN(C(=O)C(Cc2cc3c(N)nccc3s2)NS(=O)(=O)c2ccc(COC3CCOCC3)cc2)CC1

Procedure:
This compound was prepared from 218 mg of 4-(tetrahydropyran-4-yloxymethyl)-benzene-sulfonyl chloride and 210 mg (0.5 mmol) 30a using the procedure described for 58c. Yield: 100 mg, m.p. 124-128° C., (+)-FAB-MS: 573 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].Br[CH2:34][CH2:35][OH:36]>>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:21][CH2:22][N:23]([CH2:34][CH2:35][OH:36])[CH2:24][CH2:25]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Reactant: OCCBr
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCN(CCO)CC4)cn3)nc2n1C1CCCC1
Yield: 34.8 %

Procedure:
Following General Procedure D, 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (34 mg, 0.072 mmol) and 2-bromo ethanol (9 mg, 0.216 mmol) gave 7-cyclopentyl-2-{5-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (12 mg, 32%). MS (ESI) m/z 479.3 (M+H)+
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:12])=[C:7]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH:6]=[CH:5]2.C([Li])CCC.[CH:26]([C:28]1[N:29]=[CH:30][N:31]([C:33]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:32]=1)=[O:27].[Cl-].[NH4+]>C1COCC1.CCCCCC>[Si:14]([O:13][C:7]1[C:8]([CH3:12])=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([CH:26]([C:28]1[N:29]=[CH:30][N:31]([C:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH:32]=1)[OH:27])[CH:11]=[CH:10]2)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: Cc1c(O[Si](C)(C)C(C)(C)C)ccc2cc(Br)ccc12
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1c(O[Si](C)(C)C(C)(C)C)ccc2cc(C(O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc12
Temperature: -70 °C
Reaction time: 1 h

Procedure:
6-Bromo-2-tert-butyldimethylsilyloxy-1-methylnaphthalene (35.1 g) was dissolved in THF (350 mL) and the solution was cooled to −70° C. A solution (1.6 M: 82 mL) of n-butyllithium in hexane was slowly added dropwise and the mixture was stirred for 1 hr. Then, a solution (300 mL) of 4-formyl-1-trityl-1H-imidazole (30.5 g) in THF was added dropwise. After stirring at −70° C. for 30 min., the reaction was stopped by adding 20% aqueous ammonium chloride. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give crude (6-tert-butyldimethylsilyloxy-5-methyl-2-naphthyl)(1-trityl-1H-imidazol-4-yl)methanol as an amorphous solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:18])=[C:6]([C:8](=[O:17])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[CH:7]=1.[C:19](OC(=O)CC)(=O)[CH2:20][CH3:21].Cl>C(N(CC)CC)C>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:18][C:19]([CH2:20][CH3:21])=[C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16])[C:8]2=[O:17]
Reactant: Cc1ccccc1CC(=O)c1cc(Br)ccc1O
Reactant: CCC(=O)OC(=O)CC
Agent: Cl
Solvent: CCN(CC)CC
Product: CCc1oc2ccc(Br)cc2c(=O)c1-c1ccccc1C
Temperature: 25 °C
Yield: 20.7 %

Procedure:
Intermediate 11 (3.0 g, 9.83 mmoles) was taken in a RB flask and to this triethylamine (25 ml) and propionic anhydride (4.00 g, 30.76 mmoles) were added and the mixture was refluxed for 24 h. After cooling to RT, the reaction mixture was acidified by the addition of 1N HCl solution, extracted with ethyl acetate, washed with sodium bicarbonate solution, dried with sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate:petroleum ether to afford the title compound as colourless liquid (0.700 g, 20% yield). 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 7.73(d, J=2.5Hz, 1H), 7.63(dd, J=8.7, 2.5 Hz, 1H), 7.34(t, J=4.8Hz, 1H), 7.22-7.14(m, 4H), 2.63(q, J=7.5Hz, 2H), 0.94(t, J=7.5Hz, 3H).
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9]([C:12]([CH3:17])([CH3:16])[C:13](N)=[O:14])=[CH:8][CH:7]=2)=[O:5])[CH2:3][CH2:2]1.[CH2:18]([OH:20])[CH3:19]>>[CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9]([C:12]([CH3:17])([CH3:16])[C:13]([O:20][CH2:18][CH3:19])=[O:14])=[CH:8][CH:7]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: CC(C)(C(N)=O)c1ccc(C(=O)C2CC2)cc1
Reactant: CCO
Product: CCOC(=O)C(C)(C)c1ccc(C(=O)C2CC2)cc1

Procedure:
Dissolve 2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionamide (100 mg) in ethanol and bubble in hydrochloride gas for 5 minutes while stirring. Reflux for 10 hours, distill off the ethanol and extract into ethyl acetate. Evaporate the solvent in vacuo to give the title compound as an oil (50 mg).
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:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=1.Cl.Cl.[CH3:26][N:27]1[CH:31]=[C:30]([NH2:32])[CH:29]=[N:28]1>>[CH3:26][N:27]1[CH:31]=[C:30]([NH:32][C:21]([C:18]2[CH:17]=[CH: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:20][N:19]=2)=[O:23])[CH:29]=[N:28]1
Reactant: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)O)nc1
Reactant: Cn1cc(N)cn1
Agent: Cl
Product: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)Nc2cnn(C)c2)nc1
Yield: 90 %

Procedure:
As described for example 7, 5-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridine-2-carboxylic acid (100 mg, 0.32 mmol) was converted, using 1-methyl-1H-pyrazol-4-ylamine dihydrochloride instead of isopropylamine, to the title compound (113 mg, 90%), which was obtained as a white solid. MS: m/e=391.1 [M+H]+.
Reaction SMILES: [Si]([O:18][C:19]1[C:24]([CH3:25])=[C:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][O:36][C:37]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)C(O)=[C:21]([O:57][CH3:58])[C:20]=1[O:59][CH3:60])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[C:61]([O:68][C:69]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[O:70])(OC(C)(C)C)=O.C(N(CC)CC)C>ClCCl>[C:72]([O:71][C:69]([O:68][C:61]1[C:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][O:36][C:37]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)=[C:24]([CH3:25])[C:19]([OH:18])=[C:20]([O:59][CH3:60])[C:21]=1[O:57][CH3:58])=[O:70])([CH3:73])([CH3:74])[CH3:75]
Reactant: COc1c(O)c(CCCCCCCCCCOC(c2ccccc2)(c2ccccc2)c2ccccc2)c(C)c(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1OC
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(O)c(C)c(CCCCCCCCCCOC(c2ccccc2)(c2ccccc2)c2ccccc2)c(OC(=O)OC(C)(C)C)c1OC
Temperature: 40 °C
Reaction time: 16 h
Yield: 150.3 %

Procedure:
A mixture of 4-tert-butyldiphenylsilyloxy-2,3-dimethoxy-5-methyl-6-(10-trityloxydecyl)phenol (8 g), di-tert-butyl dicarbonate (3 g), triethylamine (1 g) and dichloromethane (20 ml) was stirred at 40° C. for 16 hours. After concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (30 ml). Tetrabutylammonium fluoride trihydrate (2 g) was added, and the mixture was stirred at room temperature for 15 minutes. The solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography on silica gel and eluted with hexane/ethyl acetate (7:3) to obtain the desired compound (10 g).
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[N:10][C:9]([C:12]([OH:14])=O)=[N:8]2)[CH:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[C:47]([O:51][C:52]([N:54]1[CH2:59][CH2:58][NH:57][CH2:56][CH:55]1[CH3:60])=[O:53])([CH3:50])([CH3:49])[CH3:48]>C(Cl)Cl>[C:47]([O:51][C:52]([N:54]1[CH2:59][CH2:58][N:57]([C:12]([C:9]2[N:10]=[CH:11][N:7]([C:3]3[CH:2]=[C:1]([CH3:15])[CH:6]=[CH:5][CH:4]=3)[N:8]=2)=[O:14])[CH2:56][CH:55]1[CH3:60])=[O:53])([CH3:50])([CH3:48])[CH3:49]
Reactant: CC1CNCCN1C(=O)OC(C)(C)C
Reactant: Cc1cccc(-n2cnc(C(=O)O)n2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cccc(-n2cnc(C(=O)N3CCN(C(=O)OC(C)(C)C)C(C)C3)n2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2.00 g (9.84 mmol) 1-m-tolyl-1H-[1,2,4]-triazole-3-carboxylic acid was stirred with 3.30 g (10.3 mmol) TBTU and 2.50 mL (14.6 mmol) DIPEA in 30 mL DCM at RT. After 10 min, 2.05 g (9.84 mmol) 2-methyl-piperazine-1-carboxylic acid tert-butyl ester was added and the reaction mixture was stirred at RT for 12 h. The solvent was removed by distillation. The residue was taken up in water and extracted with EtOAc. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (EtOAc).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)[CH3:2].[C:11](OC(=O)C)(=[O:13])[CH3:12].C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>CN(C=O)C>[CH2:1]([N:3]([C:11](=[O:13])[CH3:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCNc1ccc(O)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCN(C(C)=O)c1ccc(O)cc1

Procedure:
Two g of p-ethylaminophenol (0.0146 moles) were dissolved in 50 ml DMF. To this was added 2.98 g of acetic anhydride (0.0292 moles). The mixture was heated at 60° for three hours and then poured over crushed ice. Sodium carbonate was added until a pH of approximately 10 was achieved. The solution and precipitated oil were extracted with chloroform, dried over anhydrous magnesium sulfate, and then evaporated to dryness leaving a residual oil. To this oil was added 5% sodium hydroxide, and the mixture was heated at 60° for one hour. The solution was cooled and then extracted with chloroform. The remaining aqueous phase was acidified with dilute HCl to achieve a pH of approximately 4, and then extracted with chloroform. The liquid was dried over anhydrous magnesium sulfate, and then evaporated to dryness. The residual brown solid material was recrystallized from an ethanol-water mixture to yield N-ethyl-4'-hydroxyacetanilide (melting point 183°-185° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][C:12]([CH2:14][CH2:15][NH:16][C:17]([C:19]3[NH:23][N:22]=[C:21]([C:24](O)=[O:25])[CH:20]=3)=[O:18])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][C:12]([CH2:14][CH2:15][NH:16][C:17]([C:19]3[NH:23][N:22]=[C:21]([C:24]([N:31]4[CH2:32][CH2:33][CH:28]([OH:27])[CH2:29][CH2:30]4)=[O:25])[CH:20]=3)=[O:18])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)c1cc(C(=O)NCCc2ccc(-c3ccc(Cl)c(Cl)c3)o2)[nH]n1
Reactant: OC1CCNCC1
Product: O=C(NCCc1ccc(-c2ccc(Cl)c(Cl)c2)o1)c1cc(C(=O)N2CCC(O)CC2)n[nH]1

Procedure:
The title compound was prepared as in Example 1 starting from 5-{2-[5-(3,4-dichlorophenyl)furan-2-yl]ethylcarbamoyl}-1H-pyrazole-3-carboxylic acid and 4-hydroxypiperidine. The crude product was purified by flash chromatography using CH2Cl2-MeOH (95:5) as an eluent. 1H NMR (400 MHz, CDCl3): 1.62 (1H, d), 1.65 (2H, m), 1.95 (2H, m), 3.00 (2H, t), about 3.57 (2H, m), 3.77 (2H, q), about 4.1 (3H, m), 6.20 (1H, d), 6.58 (1H, d), 7.03 (1H, s), about 7.6 (1H, broad s), 7.40 (1H, distorted d), 7.43 (1H, distorted dd), 7.74 (1H, d), 11.6 (1H, broad s).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:21]=[CH:22][CH:23]=1)[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([O:19]C)=[O:18])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)([O-:3])=[O:2]>[OH-].[Na+].CO>[N+:1]([C:4]1[CH:5]=[C:6]([CH:21]=[CH:22][CH:23]=1)[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([OH:19])=[O:18])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)([O-:3])=[O:2]
Reactant: COC(=O)c1ccc2c(c1)CCN2Cc1cccc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc2c(c1)CCN2Cc1cccc([N+](=O)[O-])c1

Procedure:
A suspension of the methyl ester (Example 32) (5.72 g) in 2N sodium hydroxide (35 ml) and methanol (140 ml) was heated under reflux for 6 hours. The reaction mixture was cooled and concentrated in vacuo. Acidification with aqueous hydrochloric acid and filtration gave 1-(3-nitrobenzyl)indoline-5-carboxylic acid, m.p. 259°-262° C.
Reaction SMILES: [CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][CH:13]=[C:9]2[N:8]([CH:14]2[CH2:23][CH2:22][C:17]3(OCC[O:18]3)[CH2:16][CH2:15]2)[C:7](=[O:24])[C:6]=1[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[C:33]([C:38]#[N:39])=[CH:34][CH:35]=[CH:36][CH:37]=2)=[C:28]([F:40])[CH:27]=1)[CH2:2][CH2:3][CH3:4].Cl.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][CH:13]=[C:9]2[N:8]([C@H:14]2[CH2:15][CH2:16][C@H:17]([OH:18])[CH2:22][CH2:23]2)[C:7](=[O:24])[C:6]=1[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[C:33]([C:38]#[N:39])=[CH:34][CH:35]=[CH:36][CH:37]=2)=[C:28]([F:40])[CH:27]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3C#N)c(F)c2)c(=O)n(C2CCC3(CC2)OCCO3)c2ccnn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCc1c(Cc2ccc(-c3ccccc3C#N)c(F)c2)c(=O)n([C@H]2CC[C@H](O)CC2)c2ccnn12
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of 4′-{[7-butyl-4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}-2′-fluorobiphenyl-2-carbonitrile (4.7 g) in tetrahydrofuran (40 mL) was added 3M hydrochloric acid (40 mL), and the mixture was stirred at 70° C. for 2 hr. The mixture was allowed to cool, and diluted with ethyl acetate, and the mixture was neutralized with 8M aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was dissolved in ethanol (20 mL)-tetrahydrofuran (20 mL). Thereto was added sodium borohydride (0.26 g) at 0° C. After stirring for 1 hr, ethyl acetate and saturated aqueous ammonium chloride solution were added. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (3.3 g, 98%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.[C:21](=[NH:34])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[C:22]1([C:21](=[N:34][C:2]2[N:7]=[CH:6][C:5]([CH:8]3[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]3)=[CH:4][CH:3]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)nc2)C1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(N=C(c3ccccc3)c3ccccc3)nc2)C1
Temperature: 100 °C
Yield: 22 %

Procedure:
To a stirred solution of tert-butyl (RS)-2-(6-chloropyridin-3-yl)morpholine-4-carboxylate (1.16 g) and benzophenone imine (977 μl) in toluene (35 ml) was added sodium tert-butoxide (597 mg). The reaction mixture was purged with argon for 10 min. (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (242 mg) and tris(dibenzylideneacetone)dipalladium(0) (107 mg) were added and the reaction mixture was heated at 100° C. overnight. The reaction mixture was then cooled to room temperature, poured into water and extracted twice with EtOAc. The organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 30% EtOAc in hexanes) to afford tert-butyl (RS)-2-(6-(diphenylmethyleneamino)pyridin-3-yl)morpholine-4-carboxylate (374 mg, 22%) as a yellow oil. MS (ISP): 444.2 ([M+H]+).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][N:5]1[C:13]2[CH2:12][CH2:11][N:10]([C:14](=[O:16])[CH3:15])[CH2:9][C:8]=2[C:7]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)=[N:6]1.[Cl:27][C:28]1[CH:42]=[CH:41][C:31]2[N:32]=[C:33]([N:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[S:34][C:30]=2[CH:29]=1>CCO>[Cl:27][C:28]1[CH:42]=[CH:41][C:31]2[N:32]=[C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:3][CH:2]([OH:1])[CH2:4][N:5]4[C:13]5[CH2:12][CH2:11][N:10]([C:14](=[O:16])[CH3:15])[CH2:9][C:8]=5[C:7]([C:17]5[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=5)=[N:6]4)[CH2:37][CH2:36]3)[S:34][C:30]=2[CH:29]=1
Reactant: Clc1ccc2nc(N3CCNCC3)sc2c1
Reactant: CC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC2CO2)C1
Solvent: CCO
Product: CC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC(O)CN2CCN(c3nc4ccc(Cl)cc4s3)CC2)C1
Temperature: 60 °C
Yield: 91.1 %

Procedure:
To a stirred solution of 144 mg (0.39 mmol) of 1-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone in 4 mL of EtOH was added 100 mg (0.39 mmol) 6-chloro-2-piperazin-1-yl-benzothiazole. The solution was heated to 60° C. overnight. The solvent was then removed by rotary evaporation and the crude product was purified by column chromatography (silica, 0-10% MeOH/EtOAc) to afford 220 mg (90%) of a white solid. MS (electrospray): exact mass calculated for C29H30ClF3N6O2S: 618.18; m/z found, 619.2 [M+H]+. HPLC (reverse phase conditions 40-90%): tR=8.27 min. 1H NMR (CDCl3, 400 MHz, a mixture of amide rotamers): 7.70 (d, J=8.34 Hz, 1H), 7.62 (m, 2H), 7.57 (d, J=8.59 Hz, 1H), 7.48 (d, J=2.53 Hz, 1H), 7.36 (d, J=8.59 Hz, 1H), 7.16 (dd, J=8.59, 2.53 Hz, 1H), 4.80 and 4.68 (A and B of AB quartet, J=15.92 Hz,1H), 4.58 (s,1H), 4.18-4.08 (m, 2H), 4.01-3.89 (m, 2H), 3.85-3.60 (m, 2H), 3.59-3.47 (m, 4H), 2.94-2.75 (m, 2H), 2.72-2.62 (m, 2H), 2.55-2.47 (m, 2H), 2.46-2.39 (m, 2H), 2.13 (s, 1.5H), 2.08 (s, 1.5H).
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[NH2:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([OH:30])[CH2:26][CH2:25]1>>[OH:30][C@H:27]1[CH2:28][CH2:29][C@H:24]([NH:23][C:2]2[C:3]([CH3:22])=[N:4][C:5]3[C:10]([N:11]=2)=[C:9]([C:12]2[NH:20][C:19]4[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=4[CH:13]=2)[CH:8]=[CH:7][CH:6]=3)[CH2:25][CH2:26]1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Reactant: N[C@H]1CC[C@H](O)CC1
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1N[C@H]1CC[C@H](O)CC1
Temperature: 100 °C

Procedure:
Prepared similarly to that described in Example 131 using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 48 mg, 0.162 mmol) and trans-4-aminocyclohexanol (32.7 mg, 0.283 mmol; Alfa Aesar, Ward Hill, Mass.), heating at 100° C. for 1 h. Purification by silica gel (100% DCM to 10% MeOH/DCM) provided 2-(3-((trans-4-hydroxycyclohexyl)amino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (54% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.34-1.57 (m, 4H) 1.93 (d, J=11.54 Hz, 2H) 2.09 (d, J=12.32 Hz, 2H) 2.54 (s, 3H) 2.92 (t, J=6.85 Hz, 2H) 3.42-3.54 (m, 3H) 3.91-4.04 (m, 1H) 4.60 (br. s., 1H) 6.75 (d, J=7.43 Hz, 1H) 6.94 (s, 1H) 7.08 (d, J=2.15 Hz, 1H) 7.32 (t, J=7.82 Hz, 1H) 7.57 (dd, J=8.02, 1.37 Hz, 1H) 7.89 (dd, J=7.53, 1.27 Hz, 1H) 11.96 (br. s., 1H). MS (ESI, pos. ion) m/z: 392.3 (M+1).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([NH2:6])=[N:2]1.[CH3:7][C:8]([CH3:10])=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C1COCC1>[CH:8]([NH:6][C:3]1[CH:4]=[CH:5][NH:1][N:2]=1)([CH3:10])[CH3:7]
Reactant: Nc1cc[nH]n1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)Nc1cc[nH]n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
To a mixture of 1H-pyrazol-3-ylamine (8.3 g, 100 mmol), acetone (7.4 mL, 100 mmol) and acetic acid (12 mL, 200 mmol) in THF (280 mL) was added, in portions, sodium triacetoxyborohydride (27 g, 120 mmol) while cooling with an ice-water bath. The mixture was stirred at room temperature for 1 h and then at 50° C. for 3 h. After cooling to room temperature, 10 N NaOH (40 mL) was added dropwise, and stirred gently for 1 h. The clear solution was isolated with decantation. The gummy residue was washed with THF (2×50 mL). All the THF solutions were combined and concentrated. The residue was purified by silica gel column chromatography (EtOAc), affording isopropyl-(1H-pyrazol-3-yl)-amine (8.5 g, 68%) as a colorless oil. 1H NMR (300 MHz, CDCl3): δ 7.34 (d, 1H), 5.62 (d, 1H), 3.58 (m, 1H), 1.22 (d, 6H).
Reaction SMILES: Cl[C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[CH3:19][C:20]1[CH:33]=[CH:32][C:23]([C:24]([NH:26][N:27]2[NH:31][CH:30]=[CH:29][S:28]2)=[O:25])=[CH:22][C:21]=1B1OC(C)(C)C(C)(C)O1>>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:17]=[CH:18][C:2]([C:21]3[CH:22]=[C:23]([C:24](=[O:25])[NH:26][N:27]4[NH:31][CH:30]=[CH:29][S:28]4)[CH:32]=[CH:33][C:20]=3[CH3:19])=[N:3][CH:4]=2)=[CH:10][CH:11]=1
Reactant: Cc1ccc(C(=O)NN2NC=CS2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: COc1ccc(NC(=O)c2ccc(Cl)nc2)cc1
Product: COc1ccc(NC(=O)c2ccc(-c3cc(C(=O)NN4NC=CS4)ccc3C)nc2)cc1

Procedure:
N-(4-Methoxyphenyl)-6-[2-methyl-5-(thiadiazol-2-ylcarbamoyl)-phenyl]-nicotinamide was prepared from 6-chloro-N-(4-methoxyphenyl)nicotinamide (Intermediate 2) and 4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-(thiadiazol-2-yl)-benzamide (Intermediate 12) using General Method B. LCMS: retention time 3.05 min, MH+446. NMR: δH [2H6]-DMSO 13.15, (1H, b), 10.41, (1H, s), 9.24, (2H, m), 8.45, (1H, dd), 8.28, (1H, s), 8.11, (1H, d), 7.88, (1H, d), 7.71, (2H, d), 7.56, (1H, d), 6.97, (2H, d), 3.76, (3H, s), 2.48, (3H, s).