Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][NH2:41])=[CH:33][CH:32]=2)=[C:28]([CH:42]([CH3:44])[CH3:43])[NH:27][N:26]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:52][S:53](Cl)(=[O:55])=[O:54].Cl>ClCCl>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][NH:41][S:53]([CH3:52])(=[O:55])=[O:54])=[CH:33][CH:32]=2)=[C:28]([CH:42]([CH3:44])[CH3:43])[NH:27][N:26]=1)(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCN)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCNS(C)(=O)=O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-aminopropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole (0.36 g) in dichloromethane (6 mL) were added triethylamine (0.2 mL) and methanesulfonyl chloride (0.05 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 0.5 mol/L hydrochloric acid, and the resulting mixture was extracted with ethylacetate. The organic layer was washed with water, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/3-ethyl acetate) to give 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-isopropyl-4-({4-[3-(methanesulfonylamino)-propoxy]phenyl}methyl)-1H-pyrazole (255 mg). This material was dissolved in methanol (6 mL). To the solution was added sodium methoxide (28% methanol solution, 0.11 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol) to give the title compound (0.16 g).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([O:13][CH3:14])[CH2:9][C@H:8]2[CH2:15][NH:16][C:17](=[O:19])[CH3:18])[C:3]1=[O:20].C(N(CC)CC)C.Cl[C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([C:39]([F:42])([F:41])[F:40])[CH:37]=2)[N:32]=[CH:31][N:30]=1>CC(O)C>[CH3:14][O:13][C@H:10]1[CH2:9][C@@H:8]([CH2:15][NH:16][C:17](=[O:19])[CH3:18])[C@@H:7]([N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][C:29]3[C:38]4[C:33](=[CH:34][CH:35]=[C:36]([C:39]([F:41])([F:42])[F:40])[CH:37]=4)[N:32]=[CH:31][N:30]=3)[C:3]2=[O:20])[CH2:12][CH2:11]1
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Reactant: CO[C@@H]1CC[C@H](N2CC[C@H](N)C2=O)[C@H](CNC(C)=O)C1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CO[C@@H]1CC[C@H](N2CC[C@H](Nc3ncnc4ccc(C(F)(F)F)cc34)C2=O)[C@H](CNC(C)=O)C1
Reaction time: 8 h
Yield: 80.7 %

Procedure:
A sample of the N-(((1S,2S,5R)-2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5-methoxycyclohexyl)methyl)acetamide (220 mg, 0.776 mmol) was dissolved in 2-propanol (10 ml) at room temperature. To this solution was added triethylamine (0.433 ml, 3.11 mmol), followed by 4-chloro-6-(trifluoromethyl)quinazoline (235 mg, 1.009 mmol). The reaction mixture was stirred overnight. It was concentrated and chromatographed (120 g silica gel eluting with 5% followed by 10% MeOH in CH2Cl2) to afford the title compound (300 mg, 0.626 mmol, 81% yield) as a white solid. LC/MS found [M+H]+=480.4. 1H-NMR (400 MHz, CDCl3), δ ppm: 8.6 (s, 1H), 8.51 (s, 1H), 7.92 (br s, 1H), 7.87-7.82 (m, 2H), 6.28 (br s, 1H), 5.00 (dd, J=16.02, 8.65 Hz, 1H), 4.36-4.35 (m, 1H), 3.72-3.68 (m, 1H), 3.63-3.56 (m, 1H), 3.37-3.23 (m, 2H), 3.31 (s, 3H), 3.18-3.13 (m, 1H), 2.69-2.66 (m, 1H), 2.12-2.07 (m, 1H), 2.06-1.89 (m, 4H), 1.96 (s, 3H), 1.74-1.67 (m, 1H), 1.57-1.51 (m, 1H), 1.30-1.28 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:10]=[C:6]2[C:5]([C:17]([OH:19])=O)=[CH:4][C:3]=1[Cl:20].[CH2:21]([N:25]1[CH2:30][CH2:29][CH:28]([CH2:31][NH2:32])[CH2:27][CH2:26]1)[CH2:22][CH2:23][CH3:24]>>[NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:10]=[C:6]2[C:5]([C:17]([NH:32][CH2:31][CH:28]2[CH2:29][CH2:30][N:25]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:26][CH2:27]2)=[O:19])=[CH:4][C:3]=1[Cl:20]
Reactant: Nc1c(Cl)cc(C(=O)O)c2nc(-c3ccccc3)cn12
Reactant: CCCCN1CCC(CN)CC1
Product: CCCCN1CCC(CNC(=O)c2cc(Cl)c(N)n3cc(-c4ccccc4)nc23)CC1

Procedure:
The title compounds were prepared according to the procedure described in the step 3 in EXAMPLE 5 from 5-amino-6-chloro-2-phenylimidazo[1,2-a]pyridine-8-carboxylic acid (EXAMPLE 22, Step 2) and 1-(1-butyl-4-piperidinyl)methanamine (EXAMPLE 1, METHOD A, Step 5).
Reaction SMILES: Cl[C:2]1[C:12]2[CH2:11][CH2:10][C@H:9]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:8]=[CH:7][C:6]=2[C:5]([O:19][CH3:20])=[C:4]([N+:21]([O-])=O)[CH:3]=1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[CH3:20][O:19][C:5]1[C:6]2[CH2:7][CH2:8][C@@H:9]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH2:10][CH2:11][C:12]=2[CH:2]=[CH:3][C:4]=1[NH2:21]
Reactant: [H][H]
Reactant: COc1c([N+](=O)[O-])cc(Cl)c2c1C=C[C@@H](N1CCOCC1)CC2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COc1c(N)ccc2c1CC[C@@H](N1CCOCC1)CC2
Reaction time: 16 h

Procedure:
A mixture of 4-((S)-4-Chloro-1-methoxy-2-nitro-6,7-dihydro-5H-benzocyclohepten-7-yl)-morpholine (12 mg, 0.035 mmol) and 20% Pd(OH)2/C (9 mg) in Methanol (4 mL), was placed under a blanket of Hydrogen at atmospheric pressure. After 16 h, the reaction was filtered and concentrated under reduced pressure to give (S)-1-Methoxy-7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[CH:12]=[C:13]([CH:28]=[CH:29][C:30]=2[N+:31]([O-])=O)[O:14][CH2:15][CH2:16][O:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1COCC1.C(O)C.[Pd]>[NH2:31][C:30]1[CH:29]=[CH:28][C:13]([O:14][CH2:15][CH2:16][O:17][S:18]([C:21]2[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=2)(=[O:19])=[O:20])=[CH:12][C:11]=1[CH2:10][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:8])=[O:9]
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc([N+](=O)[O-])c(CS(=O)(=O)c3ccccc3)c2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)OCCOc2ccc(N)c(CS(=O)(=O)c3ccccc3)c2)cc1
Yield: 94.9 %

Procedure:
A solution of toluene-4-sulfonic acid 2-(3-benzenesulfonylmethyl-4-nitro-phenoxy)-ethyl ester (13.1 g, 26.7 mmol) in THF (350 mL) and ethanol (250 mL) was added to 10% palladium on carbon (5.8 g) and hydrogenated on the Parr apparatus with for one hour (starting pressure of 30-40 psi.). The mixture was filtered over Celite, concentrated and dried in vacuo at 80° C. for 30 minutes to yield toluene-4-sulfonic acid 2-(4-amino-3-benzenesulfonylmethyl-phenoxy)-ethyl ester as a light yellow solid (11.7 g, 95.1%): MP: 144-6° C.; Mass spectrum (+EI, [M+H]+) m/z 462.
Reaction SMILES: C(OC1C=CC=CC=1N1CCCN(C[CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:31]=[C:30]3[C:25]([CH:26]=[CH:27][C:28](=[O:32])[NH:29]3)=[CH:24][CH:23]=2)CC1)C.[Br:33]CCCBr.C([O-])([O-])=O.[K+].[K+]>CCO.O>[Br:33][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:31]=[C:30]2[C:25]([CH:26]=[CH:27][C:28](=[O:32])[NH:29]2)=[CH:24][CH:23]=1
Reactant: CCOc1ccccc1N1CCCN(CCCCOc2ccc3ccc(=O)[nH]c3c2)CC1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=c1ccc2ccc(OCCCBr)cc2[nH]1
Yield: 54.6 %

Procedure:
A mixture of intermediate 14 (193 mg, 1.2 mmol), 1,3-dibromopropane (0.37 mL, 3.6 mmol) and anhydrous K2CO3 (166 mg, 1.2 mmol) was dissolved in EtOH and the solution was heated to reflux overnight. The solution was diluted with water and extracted with EtOAc. The combined organic layers were washed with saturated aq NaHCO3, brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by flash chromatography on silica gel column (elution with PE/EtOAc=2:1) to give 7-(3-bromopropoxy)quinolin-2(1H)-one (intermediate 32) (185 mg, 55%) as a white solid.
Reaction SMILES: [C:1]1([C:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[CH:18](OC)[N:19]([CH3:21])[CH3:20]>>[CH3:18][N:19]([CH3:21])[CH:20]=[C:9]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:8]
Reactant: O=C(Cc1ccccc1)c1ccccc1
Reactant: COC(OC)N(C)C
Product: CN(C)C=C(C(=O)c1ccccc1)c1ccccc1

Procedure:
25.00 g of benzyl phenyl ketone was mixed with 92 ml of N,N-dimethylformamide dimethyl acetal and then heated at reflux for one hour. Almost all of N,N-dimethylformamide dimethyl acetal was evaporated under reduced pressure and the deposited crystal was washed with diethyl ether. After drying, 31.40 g of the desired compound was obtained as a pale yellow crystal having a melting point of 128 to 130° C.
Reaction SMILES: [F:1][C:2]1[C:3]([N:15]=CN(C)C)=[N:4][C:5](=[O:14])[N:6]([CH:8]2[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]2)[CH:7]=1.[CH:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1>C(Cl)Cl.CN(C)C=O>[NH2:15][C:3]1[C:2]([F:1])=[CH:7][N:6]([CH:8]2[CH2:12][CH2:11][CH:10]([O:13][C:33](=[O:34])[NH:32][C:29]3[CH:28]=[CH:27][C:26]([C:23]4[CH:24]=[CH:25][CH:20]=[CH:21][CH:22]=4)=[CH:31][CH:30]=3)[CH2:9]2)[C:5](=[O:14])[N:4]=1
Reactant: O=C=Nc1ccc(-c2ccccc2)cc1
Reactant: CN(C)C=Nc1nc(=O)n(C2CCC(O)C2)cc1F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Nc1nc(=O)n(C2CCC(OC(=O)Nc3ccc(-c4ccccc4)cc3)C2)cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 38.2 %

Procedure:
A solution of N′-[5-fluoro-1-(3-hydroxy-cyclopentyl)-2-oxo-1,2-dihydro-pyrimidin-4-yl]-N,N-dimethyl-formamidine (0.050 g, 0.186 mmol) in CH2Cl2 (2 mL) and anhydrous dimethylformamide (1 mL) was treated with 4-biphenyl isocyanate (0.039 g, 0.2 mmol). The mixture was stirred at room temperature under nitrogen for 5 hours, then quenched by the addition of acetic acid (0.5 mL) and stirred 10 minutes. The mixture was concentrated in vacuo, loaded on silica gel, and chromatographed on silica gel (10 g SiO2, 8:1 ethyl acetate/methanol) to afford biphenyl-4-yl-carbamic acid 3-(4-amino-5-fluoro-2-oxo-2H-pyrimidin-1-yl)-cyclopentyl ester 31 as a white solid (0.029 g, 38%).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:16])[C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[C:8]([O:10]CC)=O.[CH3:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20].Cl>O1CCCC1>[CH3:16][N:4]([CH3:3])[C:5]1[CH:6]=[C:7]([C:8](=[O:10])[CH2:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:14][CH:15]=1
Reactant: CC(=O)C(C)(C)C
Reactant: CCOC(=O)c1cccc(N(C)C)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)c1cccc(C(=O)CC(=O)C(C)(C)C)c1
Reaction time: 3 h
Yield: 74.8 %

Procedure:
Into a 100 ml three-necked flask equipped with a stirrer, a dropping funnel, a reflux condenser, and a nitogen-inlet tube, were charged 2.08 gm (31 mmol) of 60% sodium hydride and 5.0 gm (26 mmol) of ethyl 3-dimethylaminobenzoate. The mixture was dispersed in 40 ml of tetrahydrofuran and heated under refluxing. To the mixture was dropwise added 3.0 gm (30 mmol) of pinacolone and the mixture was heated with stirring for 3 hours. After cooling, 50 ml of 1N hydrochloric acid was added to the reaction mixture, and the organic layer was extracted twice with chloroform. The extract was thoroughly washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by evaporation to obtain an yellow oil. The oily substance was submitted to the Kugelrohr distillation at 200° C., 1 mmHg, and crystallized from hexane to give 4.81 gm (yield: 75%) of yellow solid product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](Cl)=[N:8][CH:9]=1)([O-:3])=[O:2].[C@H:11]1([NH2:18])[CH2:16][CH2:15][C@H:14]([NH2:17])[CH2:13][CH2:12]1>C(O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:17][C@H:14]2[CH2:15][CH2:16][C@H:11]([NH2:18])[CH2:12][CH2:13]2)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: CCO
Product: N[C@H]1CC[C@H](Nc2ccc([N+](=O)[O-])cn2)CC1

Procedure:
A solution of 5-nitro-2-chloropyridine (2.50 g) and trans-1,4-cyclohexanediamine (5.40 g) in ethanol (15 ml)tetrahydrofuran (10 ml) was stirred at room temperature for 5 days. The precipitates were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent: chloroform-methanol-concentrated aqueous ammonia (20:4:1)) and crystallized from ethyl acetate to obtain N-(5-nitro-2-pyridyl)-trans-1,4-cyclohexanediamine (Reference Example 3-1 in Table 5).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH2:29][CH3:30])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[F:31][C:32]([F:36])([F:35])[CH2:33]I>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH2:29][CH3:30])[C:16]3[CH2:22][CH2:21][N:20]([CH2:33][C:32]([F:36])([F:35])[F:31])[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4CC)n2)CCNC3)cc1
Reactant: FC(F)(F)CI
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4CC)n2)CCN(CC(F)(F)F)C3)cc1

Procedure:
Compound ha was synthesized using the general procedure described in Example 5 but by reacting (S)-1-ethyl-3-(4-(4-(3-ethylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea with 1,1,1-trifluoro-2-iodoethane instead of benzyl chloroformate: LC-MS: m/z=+493 (M+H)−.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:12](=[O:15])[CH2:13]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([NH:30][C:31]1[CH:47]=[CH:46][C:34]([O:35][CH2:36][CH2:37][NH:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:33][CH:32]=1)(=[O:29])[CH3:28].C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C(O)(C)C>[CH2:39]([N:38]([CH2:37][CH2:36][O:35][C:34]1[CH:33]=[CH:32][C:31]([NH:30][C:27](=[O:29])[CH3:28])=[CH:47][CH:46]=1)[CH2:13][C:12](=[O:15])[C:11]1[CH:16]=[CH:17][C:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Reactant: CC(=O)Nc1ccc(OCCNCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCO
Product: CC(=O)Nc1ccc(OCCN(CC(=O)c2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)Cc2ccccc2)cc1
Temperature: 25 °C
Yield: 66.9 %

Procedure:
A mixture of 3,4-dibenzyloxyphenacyl bromide (32.8 g.), N-[2-(4-acetamidophenoxy)ethyl]benzylamine (22.8 g.), anhydrous sodium carbonate (8.4 g.) and ethanol (1 liter) was boiled under reflux for 2 hours, then filtered hot to remove the inorganic sediment and evaporated in vacuo to afford a thick syrup. The latter was dissolved in hot isopropanol and the solution cooled, the precipitated solid then being collected by filtration. To a hot solution of the solid in fresh isopropanol were added a few milliliters of ethyl acetate, and the solution was then allowed to cool to room temperature. The crystallized solid was collected by filtration, washed in diethyl ether and dried. Recrystallization from an isopropanol/ethyl acetate mixture afforded N-benzyl-N-(3,4-dibenzyloxybenzoyl)methyl-2-(4-acetamidophenoxy)ethylamine (32.8 g.), m.p. 104°-6° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([OH:20])=O)=[N:8][C:9]=2[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:3][CH2:2]1.[NH2:21][C@@H:22]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:23]([NH2:25])=[O:24]>>[C:23]([C@@H:22]([NH:21][C:18]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[N:8]=1)=[O:20])[CH2:26][CH:27]([CH3:29])[CH3:28])(=[O:24])[NH2:25]
Reactant: CC(C)C[C@H](N)C(N)=O
Reactant: O=C(O)c1ccc(C2CC2)c(Cc2ccc(F)cc2)n1
Product: CC(C)C[C@H](NC(=O)c1ccc(C2CC2)c(Cc2ccc(F)cc2)n1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acid and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials, MS (EI): m/e=384.2 [M+H]+.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([CH:14]([C:16]3[CH:17]=[C:18]([Cl:30])[C:19]([C:28]#[N:29])=[C:20]4[C:26]=3[O:25][CH:24]([CH3:27])[CH2:23][NH:22][CH2:21]4)[CH3:15])[N:11]=[C:12]([CH3:13])[C:5]=12.O=[C:32]1[CH2:35][CH:34]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[CH2:33]1.C([BH3-])#N.[Na+]>CO.O>[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([CH:14]([C:16]3[C:26]4[O:25][CH:24]([CH3:27])[CH2:23][N:22]([CH:32]5[CH2:35][CH:34]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:41])([CH3:40])[CH3:42])[CH2:33]5)[CH2:21][C:20]=4[C:19]([C:28]#[N:29])=[C:18]([Cl:30])[CH:17]=3)[CH3:15])[N:11]=[C:12]([CH3:13])[C:5]=12
Reactant: CC(C)(C)OC(=O)NC1CC(=O)C1
Reactant: Cc1nn(C(C)c2cc(Cl)c(C#N)c3c2OC(C)CNC3)c2ncnc(N)c12
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1nn(C(C)c2cc(Cl)c(C#N)c3c2OC(C)CN(C2CC(NC(=O)OC(C)(C)C)C2)C3)c2ncnc(N)c12
Temperature: 60 °C

Procedure:
9-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-2-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile bishydrochloride (20 mg, 0.05 mmol) from Example 59, step 1, was dissolved in methanol (1.1 mL), and the tert-butyl (3-oxocyclobutyl)carbamate (0.019 g, 0.10 mmol) was added, followed by the sodium cyanoborohydride (0.0063 g, 0.10 mmol). The reaction was heated to 60° C. for 2 h, allowed to cool, diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to give tert-butyl {3-[9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-cyano-2-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]cyclobutyl}carbamate. LCMS calculated for C28H36ClN8O3 (M+H)+: m/z=567.2; found: 567.3.
Reaction SMILES: [C:1](OC)(=[O:6])[CH2:2][C:3]([CH3:5])=O.[H-].[Na+].C([Li])CCC.[C:16]1([CH2:22][CH2:23][C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:25])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCCCCC.O1CCCC1>[C:26]1([C:24]2([CH2:23][CH2:22][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[O:25][C:1](=[O:6])[CH:2]=[CH:3][CH2:5]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)CC(C)=O
Reactant: O=C(CCc1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1C=CCC(CCc2ccccc2)(c2ccccc2)O1

Procedure:
The title compound was prepared as described in General Method 1 using 25 mmol of methyl acetoacetate, 27.5 mmol of NaH 60% dispersion in oil, 26.25 mmol of 1.6M n-butyl lithium in hexane, 25 mmol of 3-phenylpropiophenone and 70 mL of tetrahydrofuran. Upon concentrating the reaction a solid precipitated out which was triturated with ether and filtered (m.p. 130°-130.55,° C.). 1H NMR (CDCl3) δ 2.2-2.4 (m, 2 H), 2.4-2.6 (m, 1 H), 2.6-2.8 (m, 1 H), 2.9 (d, 1 H), 3.0 (d, 1 H), 3.3 (d, 1 H), 3.4 (d, 1 H), 7.0-7.5 (m, 15 H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH:5]([CH3:9])[C:6]([OH:8])=O.C(Cl)Cl.[C:13]([O:17][C:18]([N:20]1[C:24]([NH2:25])=[CH:23][C:22]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[N:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C.Cl>>[C:13]([O:17][C:18]([N:20]1[C:24]([NH:25][C:6](=[O:8])[CH:5]([CH3:9])[CH2:4][CH2:3][CH2:2][Br:1])=[CH:23][C:22]([C:26]2[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=2)=[N:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(CCCBr)C(=O)O
Reactant: CC(C)(C)OC(=O)n1nc(-c2ccc(Cl)cc2)cc1N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(CCCBr)C(=O)Nc1cc(-c2ccc(Cl)cc2)nn1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.2 %

Procedure:
To a solution of 5-bromo-2-methyl-pentanoic acid (1.79 g, 9.2 mmol, 1 eq) in anhydrous DCM (8 mL) oxalyl chloride (1.0 mL, 12.0 mmol, 1.3 eq) was added dropwise and the mixture was stirred at room temperature for 16 hours. After evaporation of the solvent and the excess oxalyl chloride, the residue was dissolved in anhydrous DCM (8 mL) and a solution of 5-amino-3-(4-chloro-phenyl)-pyrazole-1-carboxylic acid tert-butyl ester (2.7 g, 9.2 mmol, 1.0 eq) and triethylamine (1.7 mL, 12 mmol, 1.3 eq) was added dropwise at 0° C. The mixture was allowed to reach room temperature and stirred at room temperature for 24 hours, after which another 0.5 eq of activated 5-bromo-2-methyl-pentanoic acid was added. HCl 1M was added; the crude was extracted with DCM and purified through SiO2 column (eluent DCM) to give 3.3 g (yield 97%) of the title product.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[O:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[CH2:7][C:6](=O)[CH2:5]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:3])[C:6]1[CH2:5][O:4][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[CH:7]=1
Reactant: CNC
Reactant: O=C1COc2ccccc2C(=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CN(C)C1=CC(=O)c2ccccc2OC1

Procedure:
Dimethylamine is introduced while stirring into a boiling solution of 52.8 g (0.3 mole) 2,3,4,5-tetrahydro-1-benzoxepin-3,5-dione and a spatula tip of p-toluene sulfonic acid in 225 ml toluene. The water of reaction is separated by a water separator. After the reaction has ended, the solution is concentrated, the remaining residue is filtered under suction and recrystallized from chloroform/ether. 42 g (69% of the theoretical yield) of 3-dimethylamino-1-benzoxepin-5(2H)-one are obtained. This compound displays a melting point of 136-136° C.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[N:8]=1)=O.[NH:26]([C:28]1[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[CH:29]=1)[NH2:27]>>[CH3:34][C:30]1[CH:29]=[C:28]([N:26]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:15]=[CH:16][C:17]([O:20][C:21]([F:24])([F:22])[F:23])=[CH:18][CH:19]=4)[N:8]=3)=[CH:4][CH:3]=[N:27]2)[CH:33]=[CH:32][N:31]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)ccc1=O
Reactant: Cc1cc(NN)ccn1
Product: Cc1cc(-n2nccc2-c2nn(-c3ccc(OC(F)(F)F)cc3)ccc2=O)ccn1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-8) and 4-hydrazino-2-methylpyridine according to the method described for example 91. MS: M=414.2 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=2)=[CH:8][C:9]=1[NH:10]C(OC(C)(C)C)=O)=[O:4].FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=2)=[CH:8][C:9]=1[NH2:10])=[O:4]
Reactant: COC(=O)c1sc(-c2ccc(F)cn2)cc1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1sc(-c2ccc(F)cn2)cc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-tert-butoxycarbonylamino-5-(5-fluoropyridin-2-yl)-thiophene-2-carboxylic acid methyl ester (80 mg) in dichloromethane (1.35 mL) was mixed with trifluoroacetic acid (0.15 mL) and stirred at room temperature overnight. The solvent was then removed in vacuo, and the residue was taken up again in dichloromethane and washed twice with saturated NaHCO3 solution and once with water. The dichloromethane phase was dried over sodium sulfate and concentrated. The product with the molecular weight of 252.27 (C11H9FN2O2S) was obtained in this way; MS (ESI): 253 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]=1[CH:16]=O>>[N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]=1[CH2:16][NH:1][CH2:2][CH2:3][CH2:4][OH:5]
Reactant: NCCCO
Reactant: O=Cc1ccc2ccccc2n1
Product: OCCCNCc1ccc2ccccc2n1

Procedure:
prepared by reaction of 3-amino-propan-1-ol with quinoline-2-carbaldehyde