Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)=[O:7].[NH:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31](=[O:34])[CH2:32][CH3:33])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1>>[O:7]=[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)[CH2:5][CH2:4][CH2:3][CH2:2][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31](=[O:34])[CH2:32][CH3:33])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1
Reactant: O=C(CCCCCl)c1cccc(C(F)(F)F)c1
Reactant: CCC(=O)Nc1cccc(C2CCNCC2)c1
Product: CCC(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(C(F)(F)F)c3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 using 5-chloro-1-[3-(trifluoromethyl)phenyl]-1-pentanone and N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 461.2 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:18])[O:3][C:4]1[C:9]2[O:10][CH:11]([CH3:15])[C:12](=[O:14])[NH:13][C:8]=2[CH:7]=[C:6]([CH:16]=O)[CH:5]=1.[CH2:19]([NH:21][C:22](=[O:35])[C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1)[CH3:20]>>[F:1][CH:2]([F:18])[O:3][C:4]1[C:9]2[O:10][CH:11]([CH3:15])[C:12](=[O:14])[NH:13][C:8]=2[CH:7]=[C:6]([CH2:16][N:32]2[CH2:31][CH2:30][N:29]([C:26]3[CH:25]=[CH:24][C:23]([C:22]([NH:21][CH2:19][CH3:20])=[O:35])=[CH:28][CH:27]=3)[CH2:34][CH2:33]2)[CH:5]=1
Reactant: CC1Oc2c(cc(C=O)cc2OC(F)F)NC1=O
Reactant: CCNC(=O)c1ccc(N2CCNCC2)cc1
Product: CCNC(=O)c1ccc(N2CCN(Cc3cc4c(c(OC(F)F)c3)OC(C)C(=O)N4)CC2)cc1

Procedure:
Using 403A and N-ethyl-4-(piperazin-1-yl)benzamide 283 in the general procedure for reductive aminations, the title compound was obtained as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09 (t, J=7.20 Hz, 3H) 1.43 (d, J=6.82 Hz, 3H) 2.46-2.49 (m, 4H) 3.19-3.29 (m, 6H) 3.43 (s, 2H) 4.70-4.77 (m, 1H) 6.80 (s, 2H) 6.93 (d, J=8.84 Hz, 2H) 6.95-7.34 (m, 1H) 7.71 (d, J=9.09 Hz, 2H) 8.17 (t, J=5.56 Hz, 1H) 10.80 (s, 1H). ESI-MS: m/z 475.4 (M+H)+. mp 219.3-223.8° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][CH:9]1[C:14](=[O:15])[NH:13][N:12]=[C:11]2[CH2:16][O:17][C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[C:21]([NH:28][C:29]4([CH3:33])[CH2:32][NH:31][CH2:30]4)=[CH:20][C:19]=3[N:10]12.C=O.[BH3-][C:37]#N.[Na+]>CO.CC(O)=O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:37][N:31]1[CH2:30][C:29]([NH:28][C:21]2[C:22]([C:24]([F:25])([F:27])[F:26])=[CH:23][C:18]3[O:17][CH2:16][C:11]4=[N:12][NH:13][C:14](=[O:15])[C@H:9]([CH3:8])[N:10]4[C:19]=3[CH:20]=2)([CH3:33])[CH2:32]1.[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:2][N:31]1[CH2:30][C:29]([NH:28][C:21]2[C:22]([C:24]([F:25])([F:27])[F:26])=[CH:23][C:18]3[O:17][CH2:16][C:11]4=[N:12][NH:13][C:14](=[O:15])[C@@H:9]([CH3:8])[N:10]4[C:19]=3[CH:20]=2)([CH3:33])[CH2:32]1
Reactant: [BH3-]C#N
Reactant: CC1C(=O)NN=C2COc3cc(C(F)(F)F)c(NC4(C)CNC4)cc3N21
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1C(=O)NN=C2COc3cc(C(F)(F)F)c(NC4(C)CN(C)C4)cc3N21
Product: C[C@H]1C(=O)NN=C2COc3cc(C(F)(F)F)c(NC4(C)CN(C)C4)cc3N21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 12 %
Yield: 12 %

Procedure:
To a mixture of 1-methyl-9-((3-methylazetidin-3-yl)amino)-8-(trifluoromethyl)-3,5-dihydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-2(1H)-one trifluoroacetic acid (Example #100, Step C, 0.120 g, 0.250 mmol) in MeOH (5 mL) and AcOH (0.5 mL) was added paraformaldehyde (neat, 0.060 g, 2 mmol). The reaction mixture was stirred at ambient temperature for 30 min then NaBH3CN (0.126 g, 2 mmol) was added and the reaction mixture was heated at 50° C. for 5 h. The reaction mixture was cooled to ambient temperature and the solvent was removed in vacuo. The residue was purified by preparative HPLC (Table 3, Method 18) and further separated by chiral SFC (Table 2, Method 11) to give (S)-9-((1,3-dimethylazetidin-3-yl)amino)-1-methyl-8-(trifluoromethyl)-3,5-dihydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-2(1H)-one trifluoroacetic acid (Example #101-1, Enantiomer 1, SFC (Table 1, Method 16) Rt=5.21 min, 0.019 g, 12%) and (R)-9-((1,3-dimethylazetidin-3-yl)amino)-1-methyl-8-(trifluoromethyl)-3,5-dihydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-2(1H)-one trifluoroacetic acid (Example #101-2, Enantiomer 2, SFC (Table 1, Method 16) Rt=5.89 min, 0.020 g, 12%) as white solids.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:18]1[S:22][CH:21]=[CH:20][C:19]=1CBr.CO.[CH2:27](Cl)Cl>CN(C=O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:27][C:18]2[S:22][CH:21]=[CH:20][CH:19]=2)=[C:4]([Cl:11])[N:3]=1
Reactant: BrCc1ccsc1
Reactant: ClCCl
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: Nc1nc(Cl)c2ncn(Cc3cccs3)c2n1

Procedure:
A mixture of 2-amino-6-chloropurine (Aldrich Chemical Co.) (7.47 g; 0.44 mol), potassium carbonate (6.64 g; 0.048 mol), and 3-thenylbromide (see U.S. Pat. No. 3,746,724) (7.8 g; 0.044 mol) in DMF (200 ml) was stirred under nitrogen at room temperature for 48 hours. The mixture was filtered and the filtrate evaporated to dryness under vacuum, ethyl ether was added and the precipitate was collected by filtration to give a mixture of 7- and 9-substituted chloropurines. A sample of pure 9isomer was prepared by chromatography on silica gel with 5% methanol/methylene chloride as the eluting solvent to separate it from the 7-isomer. Analytical sample was obtained by crystallization from acetonemethanol mixture, yield 2.36 g, mp softens at 185° C. (dec) and then melts at 203°-204° C. (dec).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5](C(Cl)(Cl)Cl)[O:4][N:3]=1.[CH2:11]1[O:20][C:14]2([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[O:13][CH2:12]1>C(O)C>[CH2:11]1[O:20][C:14]2([CH2:19][CH2:18][N:17]([C:5]3[O:4][N:3]=[C:2]([CH3:1])[N:6]=3)[CH2:16][CH2:15]2)[O:13][CH2:12]1
Reactant: Cc1noc(C(Cl)(Cl)Cl)n1
Reactant: C1CC2(CCN1)OCCO2
Solvent: CCO
Product: Cc1noc(N2CCC3(CC2)OCCO3)n1
Yield: 19.5 %

Procedure:
3-Methyl-5-trichloromethyl-1,2,4-oxadiazole (Moussebois and Eloy, Helv. Chim. Acta 1964, 47, 838) (1 g, 5 mmol) and 4-piperidone ethylene ketal (1.5 g, 10 mmol) in ethanol (20 ml) were heated reflux overnight. The solvent was evaporated and the residue taken up in dichloromethane and filtered. The filtrate was washed with dilute HCl, dried over sodium sulphate and evaporated to leave a pale yellow oil (0.22 g). The acid washing was neutralised with solid sodium bicarbonate and extracted with dichloromethane. Evaporation gave further oil (0.17 g, total 0.39 g), MS (+EI) 225 (M+).
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]1)=O.O.[NH2:18][NH2:19]>O>[CH3:12][N:9]1[CH2:10][CH2:11][CH:6]([C:4]2[C:3]3[C:2](=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:19][N:18]=2)[CH2:7][CH2:8]1
Reactant: NN
Reactant: CN1CCC(C(=O)c2ccccc2F)CC1
Solvent: O
Product: CN1CCC(c2n[nH]c3ccccc23)CC1
Yield: 23.7 %

Procedure:
An autoclave was charged with 10.0 g of 4-(2-fluorobenzoyl)-1-methylpiperidine and 14 ml of hydrazine hydrate. The reaction was heated at 150° for 20 hrs, cooled, and poured into water. The resultant solid was collected. The solid was recrystallized twice from toluene to yield 2.4 g (23.7%) of product, mp 168°-170° C.
Reaction SMILES: C([O:3][C:4]([CH2:6][C:7]1[CH:8]=[C:9]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][C:14]=2[CH2:22][NH:23][CH2:24][CH3:25])[CH:10]=[N:11][CH:12]=1)=[O:5])C.C(N(C(C)C)CC)(C)C.[CH:35]1([C:38](Cl)=[O:39])[CH2:37][CH2:36]1>C(Cl)Cl>[C:4]([CH2:6][C:7]1[CH:8]=[C:9]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][C:14]=2[CH2:22][N:23]([C:38]([CH:35]2[CH2:37][CH2:36]2)=[O:39])[CH2:24][CH3:25])[CH:10]=[N:11][CH:12]=1)([OH:3])=[O:5]
Reactant: O=C(Cl)C1CC1
Reactant: CCNCc1cc(C(=O)O)ccc1-c1cncc(CC(=O)OCC)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN(Cc1cc(C(=O)O)ccc1-c1cncc(CC(=O)O)c1)C(=O)C1CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-(5-Ethoxycarbonylmethyl-pyridin-3-yl)-3-ethylaminomethyl-benzoic acid (0.347 g, 1.0 mmol) and diisopropylethylamine (0.44 mL, 2.5 mmol) were combined in CH2Cl2 (75 mL). Cyclopropanecarbonyl chloride (0.12 mL, 1.3 mmol) was added slowly, and the reaction was stirred at room temperature for 10 minutes. The mixture was quenched with H2O (100 mL), and the product was extracted with CH2Cl2. The combined organic layers were washed with brine and concentrated. The crude material was dissolved in MeOH (75 mL), 1N aqueous LiOH (5 mL) was added and stirred at room temperature for 3 hours. Additional 1N aqueous LiOH (1 mL) was added and the reaction was stirred at room temperature for 3 days. The mixture was quenched with 1N aqueous HCl (5 mL) and extracted with EtOAc. The combined organic layers were washed with H2O and brine, and then concentrated to give 4-(5-carboxymethyl-pyridin-3-yl)-3-[(N-cyclopropanecarbonyl-N-ethyl-amino)-methyl]-benzoic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[C:20]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:19]=2)[C:10]=1[C:11]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOC(C)=O.[Pt]=O>[NH2:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][C:13]2[CH:14]=[CH:15][CH:16]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:10]=2[C:11]#[N:12])=[CH:19][C:20]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: N#Cc1c(Cc2ccc([N+](=O)[O-])c(OCc3ccccc3)c2)cccc1OCc1ccccc1
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: N#Cc1c(Cc2ccc(N)c(OCc3ccccc3)c2)cccc1OCc1ccccc1

Procedure:
To a solution of 2-benzyloxy-6-(3-benzyloxy-4-nitrobenzyl) -benzonitrile (0.564 g, 1.25 mmol) in EtOAc (50 mL), under N2, is added platinum oxide (0.112 g, 0.493 mmol). The suspension is stirred under an H2 atmosphere. Upon consumption of the starting material by LC/MS, the reaction mixture is passed through a plug of Celite and concentrated. Purification of the residue by flash chromatography (15-20% EtOAc/hexanes) affords 2-(4-amino-3-benzyloxybenzyl)-6-benzyloxybenzonitrile as a yellow oil: MS (M+H)+=421.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[CH2:11](Br)[CH:12]=[CH2:13].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:13]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=2)[CH:5]=[N:6]1)[CH:12]=[CH2:11]
Reactant: C=CCBr
Reactant: Brc1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCn1ncc2cc(Br)ccc21
Yield: 35.9 %

Procedure:
5-Bromoindazole (Bioorg. Med. Chem. Lett., 11:1153-1156 (2001)) (3.94 g, 20.0 mmol), allyl bromide (2.6 mL, 30 mmol) and potassium carbonate (4.15 g, 30.0 mmol) were heated in DMF (25 mL) at 100° C. for 18 hours. The reaction was cooled, filtered through celite, and the solids were washed with EtOAc. The solution was concentrated to near dryness and then partitioned between EtOAc and water. The organic phase was washed with NaHCO3, dried (MgSO4), concentrated, and purified by column chromatography (silica gel, 7% EtOAc/hexanes) to provide the N1 isomer (faster eluting) 1-allyl-5-bromo-1H-indazole (1s) (1.7 g, 36% yield). 1H NMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 7.88 (d, J=2.3 Hz, 1H), 7.44 (dd, J=8.6, 1.6 Hz, 1H), 7.29 (d, J=8.6 Hz, 1H), 6.06-5.97 (m, 1H), 5.24 (dd, J=10.2, 1.6 Hz, 1H), 5.12 (d, J=16.4 Hz, 1H), 5.01-5.00 (m, 2H); MS (ESI+) m/z 237, 239 (M+H, Br pattern) detected; HPLC (5 to 95%) 2.98 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([N:18]3[C:22]4[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=4[N:20]=[C:19]3[C:28]([OH:31])([CH3:30])[CH3:29])[CH2:14][CH2:13]1)[CH2:5]2.C(N(CC)C(C)C)(C)C.Cl[C:42]([O:44][CH3:45])=[O:43]>C1COCC1>[CH3:45][O:44][C:42](=[O:43])[NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([CH2:11][N:12]1[CH2:13][CH2:14][CH:15]([N:18]3[C:22]4[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=4[N:20]=[C:19]3[C:28]([OH:31])([CH3:29])[CH3:30])[CH2:16][CH2:17]1)[CH2:5]2
Reactant: COC(=O)Cl
Reactant: Cc1ccc2c(c1)nc(C(C)(C)O)n2C1CCN(CC2Cc3ccc(N)cc3C2)CC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Nc1ccc2c(c1)CC(CN1CCC(n3c(C(C)(C)O)nc4cc(C)ccc43)CC1)C2
Reaction time: 8 h
Yield: 43.7 %

Procedure:
To a solution of 2-{1-[1-(5-amino-indan-2-ylmethyl)-piperidin-4-yl]-5-methyl-1H-benzoimidazol-2-yl}-propan-2-ol (36 mg, 0.096 mmol), N,N-diisopropylethylamine (37 mg, 0.29 mmol) in THF (3 mL) was added methyl chloroformate (9 mg, 0.11 mmol). After stirring overnight, the reaction mixture was quenched with silica-supported diamine-3 (95 mg, Silicycle) to scavenge the excessive amount of methyl chloroformate. The mixture was filtered and concentrated in vacuo, and the residue was purified by flash chromatography eluent to afford (2-{4-[2-(1-hydroxy-1-methyl-ethyl)-5-methyl-benzoimidazol-1-yl]-piperidin-1-ylmethyl}-indan-5-yl)-carbamic acid methyl ester (20 mg, 59%) as white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[N:9]=[CH:8][N:7](COC(=O)C(C)(C)C)[C:6]2=[O:29]>N>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[N:9]=[CH:8][NH:7][C:6]2=[O:29]
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCn1cncn1
Agent: N
Product: COc1cc2c(=O)[nH]cnc2cc1OCCn1cncn1
Yield: 96.6 %

Procedure:
A solution of 6-methoxy-3-((pivaloyloxy)methyl)-7-(2-(1,2,4-triazol-1-yl)ethoxy)-3,4-dihydroquinazolin-4-one (1.6 g, 4 mmol) in saturated methanolic ammonia (25 ml) was stirred at ambient temperature for 2 days. The volatiles were removed by evaporation, the solid residue was triturated with ether, collected by filtration and dried under vacuum to give 6-methoxy-7-(2-(1,2,4-triazol-1-yl)ethoxy)-3,4-dihydroquinazolin-4-one (1.11 g, 98%)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][NH:25][CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[C:29]1([S:35][CH2:36][C:37](Cl)=[O:38])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:26][CH3:27])[C:37](=[O:38])[CH2:36][S:35][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OCC)ccc1OC
Reactant: O=C(Cl)CSc1ccccc1
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)CSc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester and (phenylthio)acetyl chloride.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8]2[CH:13]=[N:12][CH:11]=[C:10]([C:14]3[CH:15]=[N:16][N:17]4[CH:22]=[CH:21][N:20]=[CH:19][C:18]=34)[N:9]=2)[CH2:2]1.O=C1CCC(=O)N1[O:30][C:31](=O)[CH2:32][C:33]#[N:34].C(N(CC)CC)C>C(Cl)Cl>[O:30]=[C:31]([N:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8]2[CH:13]=[N:12][CH:11]=[C:10]([C:14]3[CH:15]=[N:16][N:17]4[CH:22]=[CH:21][N:20]=[CH:19][C:18]=34)[N:9]=2)[CH2:2]1)[CH2:32][C:33]#[N:34]
Reactant: N#CCC(=O)ON1C(=O)CCC1=O
Reactant: c1cn2ncc(-c3cncc(N[C@@H]4CCCNC4)n3)c2cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CCC(=O)N1CCC[C@@H](Nc2cncc(-c3cnn4ccncc34)n2)C1
Yield: 55.9 %

Procedure:
A solution of (R)—N-(piperidin-3-yl)-6-(pyrazolo[1,5-a]pyrazin-3-yl)pyrazin-2-amine (Preparation 30b, 0.23 g, 0.78 mmol), 3-[(2,5-dioxopyrrolidin-1-yl)oxy]-3-oxopropane nitrile (prepared as described in BE875054(A1), 0.17 g, 0.94 mmol)) and triethylamine (0.13 mL, 0.94 mmol) in methylene chloride (10 mL) was stirred overnight at ambient temperature. After evaporation of the solvent, the crude mixture was purified by flash chromatography (95:5 to 93:7 methylene chloride/methanol) to yield the title compound (0.158 g, 38%) as a pale yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH2:8][CH2:9][OH:10])[CH:2]=1.[Cl:11][C:12]1[C:13]([N:18]2[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][C@@H:19]2[CH3:31])=[N:14][CH:15]=[CH:16][N:17]=1>>[ClH:11].[CH3:31][C@H:19]1[CH2:20][NH:21][CH2:22][CH2:23][N:18]1[C:13]1[C:12]([O:10][CH2:9][CH2:8][O:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[N:17][CH:16]=[CH:15][N:14]=1
Reactant: OCCOc1cccnc1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1nccnc1Cl
Product: C[C@H]1CNCCN1c1nccnc1OCCOc1cccnc1
Product: Cl
Yield: 58 %

Procedure:
The title compound was prepared starting from 2-(3-pyridyloxy)ethanol (from Example 150, Step 1) and 3-chloro-2-[4-tert-butoxycarbonyl-(2S)-methyl-1-piperazinyl]pyrazine (prepared according to the procedure of Example 172, Step 2, with the exception that (2S)-methyl piperazine was substituted for (2R)-methylpiperazine). MS m/z 316 (M+H)+. Yield 58%; mp 170-172° C. Anal. (C16H21N5O2.1.45HCl) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:14]3[CH:15]=[C:16]([C:19]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)(O)[C:20]4[N:24]([CH3:25])[CH:23]=[N:22][CH:21]=4)[CH:17]=[CH:18][C:13]=3[N:12]([CH3:34])[C:11](=[O:35])[CH2:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.S(Cl)([Cl:38])=O>>[Cl:38][C:19]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)([C:20]1[N:24]([CH3:25])[CH:23]=[N:22][CH:21]=1)[C:16]1[CH:17]=[CH:18][C:13]2[N:12]([CH3:34])[C:11](=[O:35])[CH2:10][N:9]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:14]=2[CH:15]=1
Reactant: CN1C(=O)CN=C(c2cccc(Cl)c2)c2cc(C(O)(c3ccc(Cl)cc3)c3cncn3C)ccc21
Reactant: O=S(Cl)Cl
Product: CN1C(=O)CN=C(c2cccc(Cl)c2)c2cc(C(Cl)(c3ccc(Cl)cc3)c3cncn3C)ccc21
Temperature: 5 °C
Reaction time: 6 h

Procedure:
5-(3-chlorophenyl)-7-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one (see Example B8) (0.0075 mol) was added portionwise at 5° C. to thionyl chloride (40 ml). The mixture was stirred at 5° C. for 6 hours. The solvent was evaporated till dryness. The product was used without further purification, yielding 7-[chloro(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-5-(3-chlorophenyl)-1,3dihydro-1-methyl-2H-1,4-benzodiazepin-2-one.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[N:12]3[N:24]=[CH:25][CH:26]=[C:11]3[N:10]=2)[CH2:4][CH2:3]1.[I:27]Cl>C(Cl)Cl>[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[N:12]3[N:24]=[CH:25][C:26]([I:27])=[C:11]3[N:10]=2)[CH2:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](Nc2cc(NCc3cccc(Cl)c3)n3nccc3n2)CC1
Reactant: ClI
Solvent: ClCCl
Product: N[C@H]1CC[C@H](Nc2cc(NCc3cccc(Cl)c3)n3ncc(I)c3n2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of {5-[(trans-4-aminocyclohexyl)amino](pyrazolo[1,5-a]pyrimidin-7-yl)}[(3-chlorophenyl)methyl]amine (41.8 mg) in CH2Cl2 (565 μL) was added ICl (169 μL, 1.0 M in CH2Cl2), and the resulting mixture was stirred at room temperature for 4 h in the dark. The reaction was quenched with saturated aqueous Na2S2O3. The resulting precipitate was collected by filtration. After extraction of filtrate by CH2Cl2, the combined organic layer was washed with saturated aqueous NaCl. To this solution, the precipitate collected above was dissolved, and the solvent was removed in vacuo. The residue was purified by preparative HPLC, and the fraction contained the title compound was basified (pH 9) with saturated aqueous NaHCO3. After extraction with CH2Cl2, combined organic layer was dried over Na2SO4. The solvent was removed in vacuo, and the title compound (23.11 mg, 41% yield) was obtained as a white solid. The 1H-NMR, HPLC retention time and ESI/MS data for this compound are shown below.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][NH:10][CH2:11][C:12]2[C:17]([CH:18]([CH3:20])[CH3:19])=[CH:16][CH:15]=[CH:14][N:13]=2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[OH:21][N:22]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH:30]=O)[C:23]1=[O:32].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:11][C:12]2[C:17]([CH:18]([CH3:20])[CH3:19])=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:30][CH2:29][CH2:28][CH2:27][N:24]2[CH2:25][CH2:26][N:22]([OH:21])[C:23]2=[O:32])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: O=CCCCN1CCN(O)C1=O
Reactant: Cc1cnc(CNCc2ncccc2C(C)C)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cnc(CN(CCCCN2CCN(O)C2=O)Cc2ncccc2C(C)C)c(C)c1

Procedure:
Using General Procedure B: Reaction of (3,5-Dimethyl-pyridin-2-ylmethyl)-(3-isopropyl-pyridin-2-ylmethyl)-amine and 4-(3-Hydroxy-2-oxo-imidazolidin-1-yl)-butyraldehyde with NaBH(OAc)3 in CH2Cl2 gave COMPOUND 153 as a colorless oil. 1H NMR (CDCl3) δ 0.98 (d, 6H, J=6.9 Hz), 1.28-1.46 (m, 4H), 2.19 (s, 3H), 2.28 (s, 3H), 2.53 (dd, 2H, J=7.2, 7.2 Hz), 2.93 (septet, 1H, J=6.9 Hz), 3.05 (t, 2H, J=7.2 Hz), 3.14 (t, 2H, J=7.2 Hz), 3.41 (t, 2H, J=7.2 Hz), 3.72 (s, 4H), 7.14 (dd, 1H, J=7.5, 4.8 Hz), 7.25 (s, 1H), 7.51 (dd, 1H, J=7.5, 1.2 Hz), 8.10 (br s, 1H), 8.19 (s, 1H), 8.33 (dd, 1H, J=4.8, 1.2 Hz); 13C NMR (CDCl3) δ 18.29 (2 carbons), 23.52 (2 carbons), 24.17, 25.51, 27.48, 41.29, 44.36, 48.91, 54.31, 58.75, 59.38, 123.20, 132.28, 133.29, 133.85, 139.13, 144.34, 145.95, 146.48, 154.29, 156.08, 165.16; ES-MS m/z 426 (M+H). Anal. Calcd. For C24H35N5O2.1.2H2O: C, 64.46; H, 8.43; N, 15.66. Found: C, 64.57; H, 8.03; N, 15.28.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[NH:34][C:35]([C:37]1([C:40](=[O:49])[NH:41][C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)[CH2:39][CH2:38]1)=[O:36])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([N:12](C(OC2C=CC=CC=2)=O)[C:13](=O)[O:14]C2C=CC=CC=2)[CH:7]=1.Cl.Cl.Cl.[CH3:53][N:54]([CH3:65])[CH:55]1[CH2:58][N:57]([CH:59]2[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]2)[CH2:56]1.C(N(CC)CC)C.O>CN(C)C=O>[CH3:53][N:54]([CH3:65])[CH:55]1[CH2:56][N:57]([CH:59]2[CH2:64][CH2:63][N:62]([C:13]([NH:12][C:8]3[CH:7]=[C:6]([O:5][C:4]4[CH:31]=[CH:32][C:33]([NH:34][C:35]([C:37]5([C:40]([NH:41][C:42]6[CH:43]=[CH:44][C:45]([F:48])=[CH:46][CH:47]=6)=[O:49])[CH2:39][CH2:38]5)=[O:36])=[C:2]([F:1])[CH:3]=4)[CH:11]=[CH:10][N:9]=3)=[O:14])[CH2:61][CH2:60]2)[CH2:58]1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Reactant: CN(C)C1CN(C2CCNCC2)C1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CN(C)C1CN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)C5(C(=O)Nc6ccc(F)cc6)CC5)c(F)c4)ccn3)CC2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 64.6 %

Procedure:
To a solution of phenyl N-[4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate (50.0 mg) in N,N-dimethylformamide (2.0 ml) were added N,N-dimethyl-N-[1-(piperidin-4-yl)azetidin-3-yl]amine trihydrochloride (79.9 mg), triethylamine (0.105 ml) and water (0.050 ml), followed by stirring at room temperature for 12 hr. The reaction mixture was partitioned between ethyl acetate and a 1N aqueous solution of sodium hydroxide. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate, then ethyl acetate:methanol=20:1). Fractions containing the target compound were concentrated. To the residue was added diethyl ether:hexane=1:3, and the precipitate was collected by filtration. This was washed with hexane and dried under aeration to provide the titled compound as white powder (30.8 mg, 64.8%).