Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl>[N:22]1([C:20]([C:11]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[O:21])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCOCC2)(c2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(N1CCOCC1)C1(c2ccccc2)CCNCC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 90.3 %

Procedure:
4-(Morpholin-4-ylcarbonyl)-4-phenyl-1-piperidinecarboxylic acid tert-butyl ester (907 mg) was dissolved in methylene chloride (6 ml) and trifluoroacetic acid (1 ml) was added thereto. The mixture was stirred at room temperature for 10 hr. After completion of the reaction, a 10% aqueous sodium hydroxide solution was added, and the mixture was extracted three times with methylene chloride. The organic layer was dried and the solvent was evaporated under reduced pressure to give 4-(morpholin-4-ylcarbonyl)-4-phenylpiperidine (600 mg, yield 91%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[Cu](C#N)[C:11]#[N:12]>CN(C)C=O>[Cl:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([C:11]#[N:12])[N:3]=1
Reactant: N#C[Cu]C#N
Reactant: Cc1cc(Cl)nc(Br)c1
Solvent: CN(C)C=O
Product: Cc1cc(Cl)nc(C#N)c1
Yield: 54 %

Procedure:
To a solution of 20.7 g of 2-bromo-6-chloro-4-methylpyridine in 100 ml anhydrous N,N-dimethylformamide 9.9 g of copper cyanide was added. The reaction mixture was heated to reflux for 7 hours. After cooling, the mixture was filtered through a silica gel column with 500 ml ethyl acetate. The obtained solution was washed with a saturated aqueous solution of sodium chloride. The solvent was removed in vacuo and the residue purified by silica gel column chromatography using hexane/ethyl acetate. 1:1. 7.6 g (54%) of the title compound was obtained as a white solid of melting point 133° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]([OH:29])=O)=[C:22]([F:30])[CH:21]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[NH:31]1[CH2:34][CH2:33][CH2:32]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:31]1([C:27](=[O:29])[CH2:26][C:23]2[CH:24]=[CH:25][C:20]([O:19][CH2:18][CH2:17][C@@H:15]3[CH2:16][C@@H:14]3[CH:11]3[CH2:10][CH2:9][N:8]([C:5]4[N:6]=[CH:7][C:2]([Cl:1])=[CH:3][N:4]=4)[CH2:13][CH2:12]3)=[CH:21][C:22]=2[F:30])[CH2:34][CH2:33][CH2:32]1
Reactant: C1CNC1
Reactant: O=C(O)Cc1ccc(OCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1ccc(OCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)cc1F)N1CCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of [4-(2-{(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethoxy)-2-fluorophenyl]acetic acid (100 mg, 0.230 mmol) in 1 ml of anhydrous DMF at RT was added azetidine (13.2 mg, 0.230 mmol) and N,N-diisopropylethylamine (0.201 ml, 1.15 mmol). o-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (175 mg, 0.461 mmol) was added to the solution and the mixture stirred at RT for 4 hrs. The mixture was filtered and purified by reverse-phase HPLC (SunFire Prep C18 OBD 5 um 19×100 mm column; 35-75% acetonitrile in 0.1% formic acid in water gradient) to give the title compound. LC/MS (m/z): 473.1 (M+H)+. GPR119 Human EC50: 0.19 nM
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][CH:9]([CH:44]([F:46])[F:45])[CH2:10][C:11]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][C:12]=1[CH2:13][NH:14][C:15](=[O:38])[C@@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[C:21](=[O:37])[C@H:22]([NH:29]C(OC(C)(C)C)=O)[CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>C(Cl)Cl>[NH2:29][C@H:22]([CH:23]1[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1)[C:21]([N:17]1[CH2:18][CH2:19][CH2:20][C@H:16]1[C:15]([NH:14][CH2:13][C:12]1[CH:39]=[C:40]([Cl:43])[CH:41]=[CH:42][C:11]=1[CH2:10][CH:9]([NH2:8])[CH:44]([F:46])[F:45])=[O:38])=[O:37]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1CC(N)C(F)F)C1CCCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(Cc1ccc(Cl)cc1CNC(=O)[C@@H]1CCCN1C(=O)[C@H](N)C1CCCCC1)C(F)F

Procedure:
TFA (0.65 mL) was added to a stirred solution of N-[2-(2-amino-3,3-difluoropropyl)-5-chlorobenzyl]-1-{(2R)-2-[(tert-butoxycarbonyl)amino]-2-cyclohexylethanoyl}-L-prolinamide (0.080 g, 0.14 mmol) in CH2Cl2 (0.7 mL). After 1 h the solvent was evaporated in vacuo and the residue was partitioned between EtOAc and saturated aqueous Na2CO3. The organic layer was dried (Na2SO4) and evaporated in vacuo. The residue was partitioned between EtOAc and 1M HCl. The aqueous layer was evaporated in vacuo to give the HCl salt of the title compound as an off white solid; MS m/z=471.5.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH3:35][N:36]([CH3:42])[C@@H:37]1[CH2:41][CH2:40][NH:39][CH2:38]1>>[F:34][C:2]([F:33])([F:1])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:39]4[CH2:40][CH2:41][C@@H:37]([N:36]([CH3:42])[CH3:35])[CH2:38]4)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: CN(C)[C@@H]1CCNC1
Product: CN(C)[C@@H]1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)C1

Procedure:
5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-1,3-thiazol-4(5H)-one was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and (3R)Dimethyl-pyrrolidin-3-yl-amine following General Procedure C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[O:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[C:6]=2[N:7]=1.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:5]2[O:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2oc3ccccc3c2n1
Reactant: C1COCCN1
Solvent: CO
Product: Clc1nc(N2CCOCC2)c2oc3ccccc3c2n1
Temperature: 25 °C

Procedure:
2,4-dichlorobenzofuro[3,2-d]pyrimidine (61 mg, 0.255 mmol, 1.0 eq) was dissolved in MeOH (2 mL) and morpholine (49.1 mL, 562 μmol, 2.2 eq) was added. The reaction mixture was hated to reflux for 30 minutes and then cooled to room temperature. Solvents were removed in vacuo and the residue was purified by silica gel chromatography (gradient from 100% hexane in EtOAc to 50% hexane) and a colorless solid was obtained (59.4 mg, 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[Cl:10][C:11]1[CH:32]=[CH:31][CH:30]=[CH:29][C:12]=1[CH2:13][C:14]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:20](=[O:22])[CH3:21])[CH2:15][CH2:16][C:17]([OH:19])=[O:18].[OH-].[Na+]>C(O)C.O>[Cl:10][C:11]1[CH:32]=[CH:31][CH:30]=[CH:29][C:12]=1[CH2:13][C:14]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:20](=[O:22])[CH:21]=[CH:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([Cl:1])[CH:3]=1)[CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: CC(=O)C(CCC(=O)O)(Cc1ccccc1Cl)c1ccccc1
Reactant: O=Cc1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCC(Cc1ccccc1Cl)(C(=O)C=Cc1cccc(Cl)c1)c1ccccc1
Temperature: 25 °C

Procedure:
m-Chlorobenzaldehyde (3.5 g., 0.025 mole) in ethanol (10 ml.) is added to a solution of levo-4-(o-chlorobenzyl)-4-phenyl-5-oxohexanoic acid (4.89 g., 0.015 mole) and sodium hydroxide (0.8 g., 0.02 mole) in water (50 ml.). The resulting mixture is heated on a steam bath for 24 hours. The reaction solution is cooled to room temperature, diluted with water (300 ml.), and extracted with ether to remove the excess m-chlorobenzaldehyde. Ether is expelled from the aqueous phase by warming. The solution is cooled in an ice bath, acidified with dilute hydrochloric acid (10 ml.), and the off-white solid that precipitates is filtered and air-dried. Several recrystallizations from n-butyl chloride yields 3.15 g. of material with m.p. 170°-172°C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[C:16]([O:19][CH2:20][C:21]2[N:22]=[C:23]([CH3:26])[S:24][CH:25]=2)[CH:15]=[CH:14][CH:13]=3)=[O:9])[CH2:3][CH2:2]1.[C@H:27]1([CH2:37]O)[C@@H:36]2[N:31]([CH2:32][CH2:33][CH2:34][CH2:35]2)[CH2:30][CH2:29][CH2:28]1>>[CH:27]1([CH2:37][N:1]2[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]3[NH:11][C:12]4[C:17]([CH:18]=3)=[C:16]([O:19][CH2:20][C:21]3[N:22]=[C:23]([CH3:26])[S:24][CH:25]=3)[CH:15]=[CH:14][CH:13]=4)=[O:9])[CH2:3][CH2:2]2)[CH:36]2[N:31]([CH2:32][CH2:33][CH2:34][CH2:35]2)[CH2:30][CH2:29][CH2:28]1
Reactant: OC[C@@H]1CCCN2CCCC[C@H]12
Reactant: Cc1nc(COc2cccc3[nH]c(C(=O)NC4CCNCC4)cc23)cs1
Product: Cc1nc(COc2cccc3[nH]c(C(=O)NC4CCN(CC5CCCN6CCCCC56)CC4)cc23)cs1

Procedure:
This compound is synthesized from 4-(2-methyl-thiazol-4-ylmethoxy)-1H-indole-2-carboxylic acid piperidin-4-ylamide, (167, preparation see below) and (1R,9aR)-1-(octahydro-quinolizin-1-yl)-methanol analogously to the method described in example 127.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C@H:5]([CH:46]([CH3:48])[CH3:47])[CH2:6][C@H:7]([OH:45])[C@@H:8]([NH:16][C:17]([C@@H:19]([NH:26][C:27]([C@@H:29]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[CH2:20][C:21]1[N:22]=[CH:23][NH:24][CH:25]=1)=[O:18])[CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.CCN(C(C)C)C(C)C.[CH2:58]([N:62]=[C:63]=[O:64])[CH2:59][CH2:60][CH3:61]>C(O)C>[CH2:58]([NH:62][C:63](=[O:64])[NH:2][CH2:3][CH2:4][C@H:5]([CH:46]([CH3:48])[CH3:47])[CH2:6][C@H:7]([OH:45])[C@@H:8]([NH:16][C:17]([C@@H:19]([NH:26][C:27]([C@@H:29]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:41])[CH3:42])[CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:28])[CH2:20][C:21]1[N:22]=[CH:23][NH:24][CH:25]=1)=[O:18])[CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[CH2:59][CH2:60][CH3:61]
Reactant: CCCCN=C=O
Reactant: CC(C)[C@@H](CCN)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCCCNC(=O)NCC[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.6 %

Procedure:
0.100 g (0.145 mmol) of t-butyl [(S)-α-[[(S)-1-[[(1S,2S,4S)-6-amino-1-(cyclohexylmethyl)-2-hydroxy-4-isopropylhexyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]carbamate hydrochloride in 1 ml of ethanol is treated with 0.05 ml (0.25 mmol) of Hunig base, cooled to 0° and treated with 0.018 ml (0.16 mmol) of butyl isocyanate in 1 ml of ethanol. Then, the reaction mixture is stirred at room temperature for 2 hours and subsequently evaporated under reduced pressure. Chromatography of the residue on 5 g of silica gel with a mixture of methylene chloride and isopropanol as the eluting agent yields 0.063 g of t-butyl [(S)-α-[[(S)-1-[[(1S,2S,4S)-6-(3-butylureido)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropylhexyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]carbamate as an amorphous solid, MS: 754 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:4][CH2:5][OH:6].[C:19](OC(=O)C)(=[O:21])C>C(O)=O>[CH:19]([NH:1][CH2:2][C:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH2:4][CH2:5][OH:6])=[O:21]
Reactant: CC(=O)OC(C)=O
Reactant: NCC(CCO)(c1ccccc1)c1ccccc1
Solvent: O=CO
Product: O=CNCC(CCO)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
In formic acid (100 ml) was dissolved 4-amino-3,3-diphenylbutanol (reference compound 7-1) (17.1 g) followed by addition of acetic anhydride (16 ml) and the mixture was stirred at room temperature for 7 hours. The reaction mixture was concentrated to dryness and the residue was distributed between chloroform and water. The aqueous layer was made basic with aqueous ammonia and extracted with chloroform. The extract was dried over anhydrous sodium sulfate and concentrated to dryness. The residue was dissolved in ethanol (50 ml) and the solution was stirred with 1N-sodium hydroxide solution (60 ml) at room temperature for 15 minutes. To this reaction mixture was added water and the resulting crystals were recovered by filtration. The crystals were washed serially with water and ethyl acetate to provide the title compound (16 g) as colorless powder.
Reaction SMILES: CCN=C=NCCCN(C)C.[CH2:12]([NH2:18])[C:13]1[O:17][CH:16]=[CH:15][CH:14]=1.[CH2:19]([O:21][C:22]([C:24]1[C:25]([C:46]2[CH:54]=[CH:53][C:49]([C:50](O)=[O:51])=[CH:48][CH:47]=2)=[C:26]2[C:41](=[O:42])[N:40]3[CH2:43][CH2:44][CH2:45][N:39]3[C:27]2=[N:28][C:29]=1[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)=[O:23])[CH3:20].C1C=CC2N(O)N=NC=2C=1.O>CN(C=O)C>[F:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][CH2:30][C:29]2[N:28]=[C:27]3[N:39]4[CH2:45][CH2:44][CH2:43][N:40]4[C:41](=[O:42])[C:26]3=[C:25]([C:46]3[CH:54]=[CH:53][C:49]([C:50]([NH:18][CH2:12][C:13]4[O:17][CH:16]=[CH:15][CH:14]=4)=[O:51])=[CH:48][CH:47]=3)[C:24]=2[C:22]([O:21][CH2:19][CH3:20])=[O:23])=[CH:33][CH:34]=1
Reactant: CCOC(=O)c1c(CCc2ccc(F)cc2)nc2c(c1-c1ccc(C(=O)O)cc1)c(=O)n1n2CCC1
Reactant: NCc1ccco1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(CCc2ccc(F)cc2)nc2c(c1-c1ccc(C(=O)NCc3ccco3)cc1)c(=O)n1n2CCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 33.3 %

Procedure:
EDCI (31 mg, 0.16 mmol) was added to a solution of furfuryl amine (14 mg, 0.15 mmol), the product from Step E (71 mg, 0.15 mmol) and HOBT.H2O (20 mg, 0.15 mmol) in DMF (2.5 mL). The reaction was stirred 4 h at rt and then concentrated at reduced pressure. The remaining material was dissolved in CH2Cl2, washed with water, dried, filtered and concentrated. Chromatography on silica gel afforded the title compound as a yellow solid (30 mg, 0.05 mmol, 33%): 1H NMR (400 MHz, DMSO-d6) δ 9.06 (t, 1H, J=6), 7.89 (d, 2H, J=8), 7.56 (br s, 1H), 7.38 (d, 2H, J=8), 7.22 (br t, 2H J˜8), 7.07 (t, 2H, J=9), 6.37 (br s, 1H), 6.26 (d, 1H, J=3), 4.46 (d, 2H, J=6), 3.90 (m, 4H), 3.77 (t, 2H, J=7), 3.06 (m, 2H), 2.99 (m, 2H), 2.54 (quint., 2H, J=7), 0.78 (t, 3H, J=7) ppm; ESI-MS m/z 569 (M+H)+;
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=2[C:10](=O)[CH2:9]1.[C:20]([NH:23][NH2:24])([NH2:22])=[NH:21].[ClH:25].Cl.O>C(O)C>[ClH:25].[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=2[C:10](=[N:24][NH:23][C:20]([NH2:22])=[NH:21])[CH2:9]1
Reactant: Cc1ccnc2c1C(=O)CC(c1ccccc1Br)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1ccnc2c1C(=NNC(=N)N)CC(c1ccccc1Br)C2
Yield: 74.2 %

Procedure:
A mixture of 7-(2-bromophenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.49 g), aminoguanidine hydrochloride (0.19 g), concentrated hydrochloric acid (0.39 ml), water (0.39 ml) and ethanol (50 ml) was refluxed for 6.5 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The solution was washed with ethyl acetate. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethanol-water to give 7-(2-bromophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 66) (0.47 g) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5](CBr)=[CH:4][CH:3]=1.[CH2:10]([N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[CH2:23][OH:24])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[CH2:23][O:24][C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: OCC1CCCCN1Cc1ccccc1
Product: Fc1ccc(OCC2CCCCN2Cc2ccccc2)cc1

Procedure:
Following the procedure for Example 139, 4-fluorobenzylbromide and 1-benzyl-2-(hydroxymethyl)-piperidine were reacted to give 1-benzyl-2-(4'-fluorophenoxymethyl) piperidine.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[O:3]1.[NH:19]1[CH2:23][C@H:22]([OH:24])[C@@H:21]([OH:25])[CH2:20]1>>[OH:25][C@@H:21]1[C@@H:22]([OH:24])[CH2:23][N:19]([C:13]([C:12]2[CH:11]=[CH:10][C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:1])([CH3:18])[O:3]3)=[CH:17][CH:16]=2)=[O:15])[CH2:20]1
Reactant: CC1(C)OB(c2ccc(C(=O)O)cc2)OC1(C)C
Reactant: O[C@H]1CNC[C@@H]1O
Product: CC1(C)OB(c2ccc(C(=O)N3C[C@H](O)[C@@H](O)C3)cc2)OC1(C)C

Procedure:
The title compound was prepared by the procedure as described in Example 101 (Step H) using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid and (3S,4S)-pyrrolidine-3,4-diol.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:17][NH:18]CC3C=CC(OC)=CC=3OC)=[N:15][CH:16]=[C:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]([OH:36])([C:32]([F:35])([F:34])[F:33])=[O:31].C([SiH](CC)CC)C>C(Cl)Cl>[F:33][C:32]([F:35])([F:34])[C:30]([OH:36])=[O:31].[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:17][NH2:18])=[N:15][CH:16]=[C:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CNCc2ncc3n2CCN(Cc2ccccc2)C3)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1ncc2n1CCN(Cc1ccccc1)C2
Temperature: 55 °C

Procedure:
A flask was charged with 1-(7-benzyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)-N-(2,4-dimethoxybenzyl)methanamine (1.0 g, 2.6 mmol, prepared using H from 7-benzyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-3-carbaldehyde [WO 03/076427, Preparation 138] with 2,4-dimethoxybenzylamine), DCM (20 mL) and TFA (10 mL). To the mixture was added triethylsilane (0.50 mL, 3.1 mmol) and the mixture was heated to about 55° C. for about 6 h. The solvents were removed under reduced pressure to give (7-benzyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)methanamine 2,2,2-trifluoroacetate (1.6 g) as a crude material that was used directly without further purification: LC/MS (Table 2, Method h) Rt=1.65 min; MS m/z: 243 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][CH2:12][CH:11]([OH:15])[CH2:10]2)[C:5]([F:16])=[CH:4][N:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[CH2:10]2)[C:5]([F:16])=[CH:4][N:3]=1
Reactant: OC1CCC[C@H](Nc2nc(Cl)ncc2F)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=C1CCC[C@H](Nc2nc(Cl)ncc2F)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 93 %

Procedure:
To 700 ml DCM solution of 7.9 g (32.16 mmol) (3S)-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]cyclohexanol, 29a, (7.90 g, 32.16 mmol) in CH2Cl2 (700 mL) was added Dess-Martin reagent (17.73 g, 41.81 mmol). The reaction mixture was stirred at room temperature for 20 hours until TLC chromatography indicated reaction was complete. The reaction mixture was filtered through a pad of celite, and the resulting filtrate was washed with 200 mL of aqueous saturated NaHCO3 solution and 200 mL brine. The organic phase was dried with MgSO4, filtered and the solvent was removed under reduced pressure. The product was purified by silica gel chromatography (50% EtOAc/hexanes) to afford 7.3 g of the desired product, 29b (93% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2.[CH3:15]O>>[CH3:15][O:13][C:12]([C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH2:1])[CH:3]=2)[CH:8]=1)=[O:14]
Reactant: Nc1ccc2cc(C(=O)O)ccc2c1
Reactant: CO
Product: COC(=O)c1ccc2cc(N)ccc2c1

Procedure:
6-Amino-naphthalene-2-carboxylic acid (561 mg, 3 mmol) was esterified with MeOH using Method B to give the title compound.
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])[CH:5]=1.[C:40]([O:44][C:45](=[O:57])[CH2:46][N:47]1C=C2[C:49](C=CC=C2N)=[N:48]1)([CH3:43])([CH3:42])[CH3:41]>>[C:40]([O:44][C:45](=[O:57])[CH2:46][N:47]1[C:4]2[C:5](=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]3[N:19]=[C:18]([CH:20]4[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]4)[C:17]4[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=4[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:34])([CH3:33])[CH3:35])[C:14]3=[O:37])[CH:7]=[CH:8][CH:9]=2)[CH:49]=[N:48]1)([CH3:43])([CH3:42])[CH3:41]
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Reactant: CC(C)(C)OC(=O)Cn1cc2c(N)cccc2n1
Product: CC(C)(C)OC(=O)Cn1ncc2c(NC(=O)CN3N=C(C4CCCCC4)c4ccccc4N(CC(=O)C(C)(C)C)C3=O)cccc21

Procedure:
The title compound was obtained as the trifluoroacetate salt by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1), except that (4-amino-indazol-2-yl)-acetic acid tert-butyl ester (prepared in two steps from 4-nitro-indazole) was used instead of 3-amino-benzoic acid methyl ester in step e, followed by reaction of the product obtained, in place of (4-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-indazol-1-yl)-acetic acid tert-butyl ester (Example 130, step a), according to the method of Example 130, step b. 1H NMR (CDCl3) 10.04-9.95 (2H, br s), 9.06 (1H, s), 8.13 (1H, s), 7.53-7.20 (6H, m), 7.06 (1H, d, 6), 5.26 (2H, s), 4.80 (1H, d, 18), 4.63 (1H, d, 18), 4.29 (2H, s), 2.81-2.78 (1H, m), 2.07-1.67 (6H, m), 1.37-1.19 (13H, m). Found: C, 56.82; H, 5.42; N, 11.88%; C31H36N6O5.CF3CO2H.0.7H2O requires: C, 56.72; H, 5.53; N, 12.03%.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]([CH3:18])[C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)=[CH:9][C:8]=1[C:21]#[N:22]>>[C:21]([C:8]1[CH:9]=[C:10]([C:13]2[N:17]([CH3:18])[C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)[CH:11]=[CH:12][C:7]=1[NH:6][S:2]([CH3:1])(=[O:4])=[O:3])#[N:22]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1c(C#N)ccc1-c1ccc(N)c(C#N)c1
Product: Cn1c(C#N)ccc1-c1ccc(NS(C)(=O)=O)c(C#N)c1
Yield: 74 %

Procedure:
This compound was prepared according to the procedure of Example 48 using methane-sulfonyl chloride (0.044 mL, 0.6 mmol) and 5-(4-amino-3-cyanophenyl)-1-methyl-1H-pyrrole-2-carbonitrile (0.100 g, 0.45 mmol) to afford the title compound (0.100 g, 50%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[C:9](=[O:21])[N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH2:11][C:4]=12.[H-].[Na+].FC(F)CN1[CH2:32][CH2:31][C:30]2(N3C(=O)C(NC4N=CN=C(NC(C5CC5)=O)C=4OC)=CC(C)=C3C(=O)N2)[CH2:29][CH2:28]1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[C:9](=[O:21])[N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:11]3([CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[C:4]=12
Reactant: COc1c(NC(=O)C2CC2)ncnc1Nc1cc(C)c2n(c1=O)C1(CCN(CC(F)F)CC1)NC2=O
Reactant: COc1ccc(CN2Cc3c(OC)ccnc3C2=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)c3nccc(OC)c3C23CCCCC3)cc1
Reaction time: 0.33 h

Procedure:
To a solution of 4-methoxy-6-(4-methoxybenzyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (2, 1.0 mmol, 1 eq) in tetrahydrofuran (25 mL) add sodium hydride (2.5 mmol, 2.5 eq) at 0° C. Stir the mixture for 20 min and then add 1,5-dibromo pentane (3, 1.5 mmol, 1.5 eq) and stir for 8 h. After completion quench the mixture with water at 0° C. and add ethyl acetate. Separate the layer and remove the solvent to get crude. Purify the crude by silica gel column chromatography to afford 4′-methoxy-6′-(4-methoxybenzyl)spiro[cyclohexane-1,5′-pyrrolo[3,4-b]pyridin]-7′(6′H)-one (4).