Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:39])[CH2:18][N:19]1[CH2:25][CH2:24][CH:23]([CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])[C:22]2[CH:34]=[CH:35][CH:36]=[CH:37][C:21]=2[C:20]1=[O:38].[ClH:40]>C(O)(=O)C.O1CCOCC1.O>[Cl-:40].[C:27]([CH2:26][CH:23]1[C:22]2[CH:34]=[CH:35][CH:36]=[CH:37][C:21]=2[C:20](=[O:38])[N:19]([CH2:18][C:17]([NH:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][NH:10][C:2]2[NH2+:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=2)=[O:39])[CH2:25][CH2:24]1)([OH:29])=[O:28]
Reactant: CC(C)(C)OC(=O)CC1CCN(CC(=O)NCCCCCNc2nc3ccccc3[nH]2)C(=O)c2ccccc21
Reactant: Cl
Solvent: CC(=O)O
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CC1CCN(CC(=O)NCCCCCNC2=Nc3ccccc3[NH2+]2)C(=O)c2ccccc21
Product: [Cl-]

Procedure:
Analagously to Example II, the tert-butyl ester (Example XIII) in glacial acetic acid was cleaved using 4N HCl in dioxane. After stripping off the solvent, the residue was dissolved in water, clarified using active carbon and then lyophilized; 0.67 g of white amorphous residue; ESI-MS [M+H+]: 478.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.Cl[C:21](Cl)([O:23]C(=O)OC(Cl)(Cl)Cl)Cl.[NH:32]1[CH2:36][CH:35]=[C:34]([O:37][S:38]([C:41]([F:44])([F:43])[F:42])(=[O:40])=[O:39])[CH2:33]1>ClCCl>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([C:21]([N:32]2[CH2:36][CH:35]=[C:34]([O:37][S:38]([C:41]([F:42])([F:43])[F:44])(=[O:39])=[O:40])[CH2:33]2)=[O:23])[CH2:3][CH2:2]1
Reactant: O=S(=O)(OC1=CCNC1)C(F)(F)F
Reactant: c1ccc2c(c1)NCCO2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(N1CC=C(OS(=O)(=O)C(F)(F)F)C1)N1CCOc2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 116.2 %

Procedure:
2.7 g of 3,4-dihydro-2H-benzo[1,4]oxazine and 50 ml of dichloromethane are introduced into a 250 ml three-necked flask equipped with a magnetic stirrer and placed under an inert atmosphere. After cooling to +4° C., 9.92 ml of diisopropylethylamine and 2.97 g of triphosgene are successively added. The reaction medium is stirred at ambient temperature for 3 h. 4.52 ml of diisopropylethylamine and 3.04 g of trifluoromethanesulfonic acid 2,5-dihydro-1H-pyrrol-3-yl ester are then introduced and the mixture is stirred at ambient temperature for 18 h. The reaction medium is washed with a saturated aqueous sodium hydrogencarbonate solution; the aqueous phase is extracted twice with ethyl acetate. The organic phases are combined, dried over sodium sulfate and concentrated under reduced pressure. The residue is chromatographed on silica gel eluted with a gradient of ethyl acetate from 0% to 10% in dichloromethane. 4.4 g of trifluoromethanesulfonic acid 1-(2,3-dihydrobenzo[1,4]oxazine-4-carbonyl)-2,5-dihydro-1H-pyrrol-3-yl ester are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:37](=[O:43])OC(Cl)(Cl)Cl)Cl.[CH2:45]([N:47]([CH2:51][CH3:52])[CH2:48][CH2:49][NH2:50])[CH3:46]>C(Cl)(Cl)Cl.O>[CH2:45]([N:47]([CH2:51][CH3:52])[CH2:48][CH2:49][NH:50][C:37]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:17][C:18]=1[N+:23]([O-:25])=[O:24])=[O:43])[CH3:46]
Reactant: CCN(CC)CCN
Reactant: COc1cc2nccc(Oc3ccc(N)c([N+](=O)[O-])c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCN(CC)CCNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 45.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-nitroaniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml) to prepare a solution. A solution of triphosgene (131 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, N1,N1-diethyl-1,2-ethanediamine (51 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (65 mg, yield 46%).
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][C:17]=2[NH:22][C:23]([C:25]2[N:26]=[C:27](Br)[S:28][C:29]=2[NH:30]C(=O)OC(C)(C)C)=[O:24])[CH2:12][CH2:11]1)=O)CCC.[C:39]1(B(O)O)[CH2:44][CH2:43][CH2:42][CH2:41][CH:40]=1>>[NH2:30][C:29]1[S:28][C:27]([C:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH:40]=2)=[N:26][C:25]=1[C:23]([NH:22][C:17]1[CH:18]=[N:19][N:20]([CH3:21])[C:16]=1[N:13]1[CH2:12][CH2:11][CH:10]([CH2:9][NH2:8])[CH2:15][CH2:14]1)=[O:24]
Reactant: CCCCOC(=O)NCC1CCN(c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC1
Reactant: OB(O)C1=CCCCC1
Product: Cn1ncc(NC(=O)c2nc(C3=CCCCC3)sc2N)c1N1CCC(CN)CC1
Yield: 26 %

Procedure:
Following Example 278, Suzuki coupling of tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamate and cyclohex-1-ene-1-boronic acid gave 265 as a pale brown solid (21 mg, 26% over two steps). 1H NMR (400 MHz, d6-DMSO) δ 8.61 (s, 1H), 7.43 (s, 1H), 7.26 (s, 2H), 6.25 (s br, 1H), 3.64 (s, 3H), 3.07-2.94 (m, 4H), 2.47 (d, J=6.1 Hz, 4H), 2.19 (s, 2H), 1.77 (d, J=12.2 Hz, 2H), 1.73-1.58 (m, 4H), 1.34-1.14 (m, 3H). Alkyl NH2 not seen. LCMS (ES+) m/z 416 (M+1)
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]([CH2:15][C:16]#[CH:17])[C:5](=[O:18])[C:4]=1[CH3:19])[CH3:2].[CH3:20][O-:21].[Na+].CI.[CH3:25][OH:26]>>[CH3:20][O:21][C:16]([O:26][CH3:25])([CH3:17])[CH2:15][N:6]1[C:5](=[O:18])[C:4]([CH3:19])=[C:3]([CH2:1][CH3:2])[N:8]=[C:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C[O-]
Reactant: C#CCn1c(-c2ccccc2)nc(CC)c(C)c1=O
Reactant: CO
Agent: [Na+]
Solvent: CI
Product: CCc1nc(-c2ccccc2)n(CC(C)(OC)OC)c(=O)c1C

Procedure:
To a stirred suspension of 4.51 g (17.9 mmol) of 6-ethyl-5-methyl-2-phenyl-3-propargyl-4(3H)-pyrimidinone (Compound 5) in 30 mL of methanol was added 7.50 g (34.7 mmol) of a 25% by weight solution of sodium methoxide in methanol. The mixture was warmed until homogeneous and 2.2 mL (35.3 mmol) of methyl iodide was added. The mixture was refluxed for 4 h and then rotovapped to remove the bulk of the methanol. The residue was partitioned between 100 mL of water and two 100 mL portions of ether. The combined ether layers were washed with 50 mL of brine and dried over MgSO4. Removal of the solvent afforded 4.35 g of a yellow oil. Flash chromatography on a column of 50 g of silica gel, eluting with 20, 30, 40 and 50% ether in hexanes furnished 3.30 g (58%) of 3-(2,2-dimethoxypropyl)-6-ethyl-5-methyl-2-phenyl- 4(3H)-pyrimidinone (compound 36), mp 80°-83° C. 1H-NMR (CDCl3) δ1.15(3H,s), 1.25(3H,t), 2.15(3H,s), 2.65(2H,q), 2.85(6H,s), 4.4(2H,m), 7.45(5H,s).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:12][S:13]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH2:23])(=[O:15])=[O:14]>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([NH:23][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][S:13]([CH3:12])(=[O:15])=[O:14])=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: CS(=O)(=O)Cc1ccccc1N
Reactant: Clc1nc2c(Br)cccn2n1
Product: CS(=O)(=O)Cc1ccccc1Nc1cccn2nc(Cl)nc12

Procedure:
164 a) A suspension of o-Nitrobenzylbromide (5.71 g, 26.4 mmol) and sodium methanesulfinate (4.0 g, 40.0 mmol) in ethanol (70 mL) was stirred at room temperature for 18 hours. The volatiles were evaporated under reduced pressure. To the residue was added water (50 mL) and stirred for 30 minutes. The suspension was filtered, rinsed with water and air dried. 1-Methanesulfonylmethyl-2-nitro-benzene was isolated as a yellow solid (5.36 g, 94%). MP=115-117° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.10 (d, J=8.1 Hz, 1H), 7.74-7.65 (m, 2H), 7.62-7.58 (m, 1H), 4.80 (s, 2H), 2.91 (s, 3H). 164 b) 2-Methanesulfonylmethyl-phenylamine was prepared from 1-methanesulfonylmethyl-2-nitro-benzene (1.0 g, 4.6 mmol) in a manner analogous to Example 111a. Product isolated as an off-white solid (0.84 g, 98%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.20 (t, J=7.5 Hz, 1H), 7.09 (d, J=7.5 Hz, 1H), 6.86-6.76 (m, 2H), 4.30 (s, 2H), 4.28 (br s, 2H), 2.87 (s, 3H). MS=186 (MH)+. 164 c) (2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-methanesulfonylmethyl-phenyl)-amine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (500.0 mg, 2.151 mmol) and 2-methanesulfonylmethyl-phenylamine (440.0 mg, 2.375 mmol) in a manner analogous to Example 2d. Product isolated as a tan solid (0.62 g, 51%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.02 (d, J=5.9 Hz, 1H), 7.71 (s, 1H), 7.53 (d, J=8.3 Hz, 1H), 7.47-7.41 (m, 3H), 6.89-6.81 (m, 2H), 4.41 (s, 2H), 2.93 (s, 3H). MS=337, 339 (MH)+. 164 d) N(8)-(2-Methanesulfonylmethyl-phenyl)-N(2)-[4-(4-methyl-piperazin-1-yl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepare from (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-methanesulfonylmethyl-phenyl)-amine (75.0 mg, 0.223 mmol) and 4-(4-Methyl-piperazin-1-yl)-phenylamine (47.0 mg, 0.246 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a brown foam (0.013 g, 12%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.96 (d, J=6.8 Hz, 1H), 7.70 (s, 1H), 7.56 (d, J=8.2 Hz, 1H), 7.51 (d, J=8.8 Hz, 2H), 7.43-7.37 (m, 2H), 7.18 (t, J=7.4 Hz, 1H), 6.96 (d, J=8.8 Hz, 2H), 6.83 (d, J=7.8 Hz, 1H), 6.70 (s, 1H), 6.67 (t, J=7.1 Hz, 1H), 4.45 (s, 2H), 3.18-3.13 (m, 4H), 2.94 (s, 3H), 2.62-2.57 (m, 4H), 2.36 (s, 3H). MS=492 (MH)+.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([F:13])([F:12])[F:11])[CH2:7][CH2:6][NH:5][CH2:4][CH:3]1[NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].[F:22][C:23]1[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:24]=1[CH:25]=O.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(O)(=O)C>[F:22][C:23]1[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][N:5]1[CH2:4][CH:3]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[C:2](=[O:1])[N:8]([CH2:9][C:10]([F:11])([F:12])[F:13])[CH2:7][CH2:6]1
Reactant: CC(C)(C)OC(=O)NC1CNCCN(CC(F)(F)F)C1=O
Reactant: O=Cc1cccc(F)c1F
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CN(Cc2cccc(F)c2F)CCN(CC(F)(F)F)C1=O
Reaction time: 0.5 h
Yield: 88.6 %

Procedure:
A mixture of tert-butyl 7-oxo-1-(2,2,2-trifluoroethyl)-1,4-diazepan-6-ylcarbamate (51 mg, 0.16 mmol), 2,3-difluorobenzaldehyde (0.053 mL, 0.49 mmol), and sodium cyanoborohydride (31 mg, 0.49 mmol) in methanol (5 mL) was adjusted to pH 4 with acetic acid. After 0.5 h, saturated aqueous sodium bicarbonate was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. Purification by silica gel chromatography [100% dichloromethane→95% dichloromethane/5% (10% ammonium hydroxide/methanol)] gave the title compound (62 mg). MS 438 (M+1).
Reaction SMILES: [C:1]([C:6]1[C:18]([CH3:19])=[CH:17][C:9]2[N:10]([CH3:16])[C:11]([C:13]([OH:15])=[O:14])=[N:12][C:8]=2[CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[C:20](#N)[CH3:21].C(N(CC)CC)C.C(OC(OCC)=O)(=O)OCC>C(OCC)(=O)C>[C:1]([C:6]1[C:18]([CH3:19])=[CH:17][C:9]2[N:10]([CH3:16])[C:11]([C:13]([O:15][CH2:20][CH3:21])=[O:14])=[N:12][C:8]=2[CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CC#N
Reactant: CCCC(=O)c1cc2nc(C(=O)O)n(C)c2cc1C
Agent: CCOC(=O)OC(=O)OCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCC(=O)c1cc2nc(C(=O)OCC)n(C)c2cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6.0 g of 5-butyryl-1,6-dimethyl-benzimidazole-2-carboxylic acid are introduced, in the course of 15 minutes, into a mixture of 150 ml of acetonitrile, 15 ml of triethylamine and 18.5 g of diethyl pyrocarbonate, while stirring at room temperature. The mixture is left to stand overnight, the acetonitrile is stripped off under reduced pressure, the residue is taken up in ethyl acetate and the resulting solution is washed with water, dried over sodium sulphate and evaporated to dryness. Ethyl 5-butyryl-1,6-dimethyl-benzimidazole-2-carboxylate, which is initially obtained as an oil but soon crystallises, is filtered off. When recrystallised from ethyl acetate/cyclohexane, it melts at 106°-108°.
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[N:10]=2)=[C:5]([C:22]([NH2:24])=[O:23])[CH:4]=1)#[CH:2].[C:25]([O:31][CH2:32][N:33]=[N+:34]=[N-:35])(=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>CN(C=O)C.O>[C:25]([O:31][CH2:32][N:33]1[CH:2]=[C:1]([C:3]2[S:7][C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]4[CH2:17][CH2:18][O:19][CH2:20][CH2:21]4)[N:10]=3)=[C:5]([C:22]([NH2:24])=[O:23])[CH:4]=2)[N:35]=[N:34]1)(=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27]
Reactant: C#Cc1cc(C(N)=O)c(Nc2cccc(CN3CCOCC3)n2)s1
Reactant: CC(C)(C)C(=O)OCN=[N+]=[N-]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)C(=O)OCn1cc(-c2cc(C(N)=O)c(Nc3cccc(CN4CCOCC4)n3)s2)nn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Ethynyl-2-{[6-(morpholin-4-ylmethyl)pyridin-2-yl]amino}thiophene-3-carboxamide (86 mg, 0.25 mmol) and azidomethyl pivalate (59 mg, 0.38 mmol) were combined in DMF (1.0 mL). CuSO4.5H2O (6.3 mg, 0.025 mmol) in water (0.2 mL) and sodium ascorbate (20 mg, 0.10 mmol) in water (0.2 mL) were added, and the reaction mixture was stirred at room temperature overnight. The reaction was concentrated to dryness, combined with MeOH and silica gel, and evaporated. Flash chromatography (dry load, 0-10% MeOH/EtOAc) afforded the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)[C:4]1=[O:17])[CH3:2].S1C=CC=C1.CO.[H][H]>C(O)C.[Pd]>[NH2:14][C:11]1[CH:10]=[CH:9][C:8]([N:5]2[CH2:6][CH2:7][N:3]([CH2:1][CH3:2])[C:4]2=[O:17])=[CH:13][CH:12]=1
Reactant: [H][H]
Reactant: CCN1CCN(c2ccc([N+](=O)[O-])cc2)C1=O
Agent: [Pd]
Solvent: CCO
Solvent: c1ccsc1
Solvent: CO
Product: CCN1CCN(c2ccc(N)cc2)C1=O
Yield: 93 %

Procedure:
A mixture of 12 parts of 1-ethyl-3-(4-nitrophenyl)-2-imidazolidinone, 1 part of a solution of thiophene in ethanol 4% and 200 parts of methanol was hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 9.6 parts (93%) of 1-(4-aminophenyl)-3-ethyl-2-imidazolidinone (18).
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[CH3:23][O:24][CH2:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([C:36](O)=[O:37])=[CH:28][CH:27]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:36]([C:29]2[C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:26]([CH2:25][O:24][CH3:23])=[CH:27][CH:28]=2)=[O:37])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: COCc1ccc(C(=O)O)c2ccccc12
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: COCc1ccc(C(=O)NC(Cc2ccc(C(F)(F)F)cc2)C(O)c2ccc(F)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (300 mg, 0.96 mmol) in acetonitrile (30 ml) were added 4-((methyloxy)methyl)-1-naphthalenecarboxylic acid (207 mg, 0.96 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (275 mg, 1.44 mmol) and 1-hydroxy-1H-benzotriazole (147 mg, 0.96 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml), and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-2:1) and recrystallized from ethyl acetate-hexane to give the title compound (340 mg, 69%).
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[Cl:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[N:25][CH:26]=1>>[Cl:20][C:21]1[CH:22]=[C:23]([C:2]2[C:3]([F:19])=[CH:4][C:5]([F:18])=[C:6]([C@:8]3([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]3)[CH:7]=2)[CH:24]=[N:25][CH:26]=1
Reactant: OB(O)c1cncc(Cl)c1
Reactant: C[C@]1(c2cc(Br)c(F)cc2F)N=C(N)OCC1(F)F
Product: C[C@]1(c2cc(-c3cncc(Cl)c3)c(F)cc2F)N=C(N)OCC1(F)F

Procedure:
In a manner analogous to that described in Example 31, the cross-coupling reaction of (R)-4-(5-bromo-2,4-difluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A6.2) and 5-chloropyridin-3-ylboronic acid yielded the title compound as a pale yellow solid. MS (ISP): m/z=373.8 [M+H]+.
Reaction SMILES: [O:1]=[C:2]([O:23][C@@H:24]1[CH:29]2[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]2)[CH2:25]1)[CH:3]([NH:10][C:11]1[CH:12]=[C:13]([CH:20]=[CH:21][CH:22]=1)[C:14]([O:16]CC=C)=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.N1CCCCC1>C1COCC1>[O:1]=[C:2]([O:23][CH:24]1[CH:29]2[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]2)[CH2:25]1)[C@H:3]([NH:10][C:11]1[CH:12]=[C:13]([CH:20]=[CH:21][CH:22]=1)[C:14]([OH:16])=[O:15])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C=CCOC(=O)c1cccc(NC(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)c1
Solvent: C1CCOC1
Solvent: C1CCNCC1
Product: O=C(O)c1cccc(N[C@@H](C(=O)OC2CN3CCC2CC3)c2ccccc2)c1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 39.5 %

Procedure:
To a solution of allyl 3-(2-oxo-1-phenyl-2-((R)-quinuclidin-3-yloxy)ethyl-amino)benzoate (I4) (1.40 g, 3.33 mmol) in dry THF (45 ml), were added tetrakis-(triphenylphosphine)palladium(0) (1.15 g, 1.00 mmol) and piperidine (0.99 ml, 1.00 mmol) and the reaction mixture was stirred at 60° C. for 1.5 hours. The solvent was removed in vacuo and the crude was purified by flash chromatography (DCM/MeOH=9/1 to MeOH) to obtain (R)-3-(2-oxo-1-phenyl-2-(quinuclidin-3-yloxy)ethylamino)benzoic acid (500 mg, 39.5% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C:18]([C:23]([OH:25])=[O:24])([C:20]([OH:22])=[O:21])[O:19][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:30]([CH:32]([CH2:35][CH3:36])[CH2:33]O)[CH3:31].Cl.[K+].[Br-]>C(Cl)(Cl)Cl>[CH2:30]([CH:32]([CH2:35][CH3:36])[CH2:33][O:24][C:23]([C:18]1([C:20]([O:22][CH2:8][CH:4]([CH2:5][CH3:6])[CH2:3][CH3:2])=[O:21])[O:17][C:16]2[CH:26]=[CH:27][C:13]([CH2:12][C@H:11]([NH:10][CH2:9][C@@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[OH:29])[CH3:28])=[CH:14][C:15]=2[O:19]1)=[O:25])[CH3:31]
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Reactant: CCC(CC)CO
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CCC(CC)COC(=O)C1(C(=O)OCC(CC)CC)Oc2ccc(C[C@@H](C)NC[C@H](O)c3cccc(Cl)c3)cc2O1

Procedure:
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and 2-ethylbutanol according to the procedure of Example 1 as an off-white gum (HCl salt); 1H NMR (CDCl3) δ 0.80-0.95 (m, 12H), 1.25-1.45 (m, 10H), 1.50-1.65 (m, 3H), 2.75-2.85 (m, 1H), 3.10-3.40 (m, 1H), 3.47-3.49 (m, 2H), 4.25 (d, 5H), 5.50 (d, 1H), 6.70-6.80 (m, 1H), 6.80-6.90 (m, 2H), 7.20-7.45 (m, 3H), 7.46 (s, 1H), 8.74 (bs, 1 H), 10.06 (bs, 1H); IR (KBr): 2964 cm-1 (--OH), 1766 cm-1 (C=O); MS (ES) m/z 590.4 (MH+); [α]D25 -21° (c, 1.0, CHCl3). Anal. Calcd. for C32H44ClNO7 ·HCl: C, 61.34; H, 7.08; N, 2.24; Cl, 11.32. Found: C, 61.09; H, 7.46; N, 2.12; Cl, 10.77.
Reaction SMILES: Cl.C([O:9][C:10]1[CH:11]=[C:12]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[N:23]2[CH2:28][CH2:27][N:26]([CH2:29][C:30]3[N:34]([CH2:35][C:36]4[CH:41]=[CH:40][C:39]([C:42]#[N:43])=[C:38]([F:44])[CH:37]=4)[CH:33]=[N:32][CH:31]=3)[CH2:25][C:24]2=[O:45])[CH:13]=[CH:14][CH:15]=1)C1C=CC=CC=1.[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49].[H][H]>CO.CCOC(C)=O.[Pd]>[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49].[OH:9][C:10]1[CH:11]=[C:12]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[N:23]2[CH2:28][CH2:27][N:26]([CH2:29][C:30]3[N:34]([CH2:35][C:36]4[CH:41]=[CH:40][C:39]([C:42]#[N:43])=[C:38]([F:44])[CH:37]=4)[CH:33]=[N:32][CH:31]=3)[CH2:25][C:24]2=[O:45])[CH:13]=[CH:14][CH:15]=1
Reactant: N#Cc1ccc(Cn2cncc2CN2CCN(c3cc(Cl)ccc3-c3cccc(OCc4ccccc4)c3)C(=O)C2)cc1F
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Cn2cncc2CN2CCN(c3cc(Cl)ccc3-c3cccc(O)c3)C(=O)C2)cc1F
Reaction time: 4 h

Procedure:
To a solution of the crude product from Step F (ca 1.68 mmol) in 25 mL of 1:1 MeOH/EtOAc was added trifluoroacetic acid (0.10 mL) and 10% palladium on carbon (800 mg). The solution was stirred under a balloon atmosphere of hydrogen at room temperature. After 4 hours, the solution was filtered through celite, the filter pad was rinsed with 1:1 MeOH/THF, and the filtrate was concentrated in vacuo. The crude material containing the titled product was used in the next reaction without further purification.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]4[CH2:23][CH2:24][CH2:25][C@H:13]4[C:12]=23)[N:4]=1.[CH2:26]([NH:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH3:29]>CN(C)C=O>[CH2:26]([N:30]([CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]4[CH2:23][CH2:24][CH2:25][C@H:13]4[C:12]=23)[N:4]=1)[CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH3:29]
Reactant: O=C1c2ccccc2-n2cnc(-c3noc(CCl)n3)c2[C@@H]2CCCN12
Reactant: CCCCNCCCC
Solvent: CN(C)C=O
Product: CCCCN(CCCC)Cc1nc(-c2ncn3c2[C@@H]2CCCN2C(=O)c2ccccc2-3)no1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.4 %

Procedure:
A solution of 711 mg (2.0 mmol) of (S)-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one in 10 ml of N,N-dimethylformamide was treated with 1.0 ml (6.0 mmol) of dibutylamine and stirred at room temperature under argon for 3 hrs. The solution was evaporated, the residue was triturated in 10 ml of water and the crystals were filtered off under suction. The crude product was dissolved in methylene chloride, the solution was dried with sodium sulfate, whereupon it was chromatographed on 30 g of silica gel (methylene chloride/acetone 9:1, then 4:1). There was obtained 0.73 g of (S)-1-(5-dibutylaminomethyl-1,2,4-oxadiazol-3-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one, which was converted in 10 ml of acetonitrile with ethereal hydrochloric acid into the hydrochloride. By crystallization from hot ethyl acetate there was obtained 0.75 g (77%) of (S)-1-(5-dibutylaminomethyl-1,2,4-oxadiazol-3-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one hydrochloride (1:1) of m.p. 115°-123° (dec.).