Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][CH:6]([C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][CH:9]=1)[CH3:7])[CH:2]([CH3:4])[CH3:3].CO.O.[OH-].[Li+]>O1CCCC1>[CH2:1]([O:5][CH:6]([C:8]1[CH:9]=[CH:10][C:11]([C:12]([OH:14])=[O:13])=[CH:16][CH:17]=1)[CH3:7])[CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)c1ccc(C(C)OCC(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)COC(C)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.1 %

Procedure:
To a solution of methyl 4-(1-isobutoxyethyl)benzoate (180 mg, 0.76 mmol) in tetrahydrofuran:methanol:water=3:1:1 (4 mL) was added lithium hydroxide (100 mg, 2.4 mmol). The mixture was stirred at room temperature for 2 hours. The suspension was concentrated in vacuum and quenched with aqueous 1N hydrochloric acid (5 mL). The residue was taken up with water (50 mL) and extracted with dichloromethane (50 mL). The combined extract was dried over sodium sulphate, evaporated and purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give the product 4-(1-isobutoxyethyl)benzoic acid (132 mg, 78%) as pale solid.
Reaction SMILES: [OH:1][C:2]1[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][C:4](=[O:13])[CH:3]=1.[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][CH:27]=[C:26]2[CH2:32][CH2:33][NH:34][C:35](=[O:37])[CH3:36]>>[OH:1][C:2]1[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][C:4](=[O:13])[C:3]=1[CH:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:27]1[NH:28][C:29]2[C:25]([C:26]=1[CH2:32][CH2:33][NH:34][C:35](=[O:37])[CH3:36])=[CH:24][C:23]([CH3:22])=[CH:31][CH:30]=2
Reactant: O=Cc1ccccc1
Reactant: O=C1C=C(O)C(c2ccccc2)C1
Reactant: CC(=O)NCCc1c[nH]c2ccc(C)cc12
Product: CC(=O)NCCc1c(C(C2=C(O)C(c3ccccc3)CC2=O)c2ccccc2)[nH]c2ccc(C)cc12

Procedure:
Using general procedure C, 3-hydroxy-4-phenyl-cyclopent-2-enone (Lit. 17) was reacted with benzaldehyde and N-[2-(5-methyl-1H-indol-3-yl)-ethyl]-acetamide (Lit. 7) to give the title compound as orange solid. MS: 479.0 ([M+H]+).
Reaction SMILES: [CH2:1]([N:8]1[C@H:12]([C:13]([OH:15])=[O:14])[C@H:11]([C:16]([OH:18])=[O:17])[N:10]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:9]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:27]1[CH:32]=CC=C[CH:28]=1.S(=O)(=O)(O)O.[CH2:38](O)[CH2:39][CH3:40]>>[CH2:19]([N:10]1[C@H:11]([C:16]([O:18][CH2:28][CH2:27][CH3:32])=[O:17])[C@H:12]([C:13]([O:15][CH2:38][CH2:39][CH3:40])=[O:14])[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]1=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: c1ccccc1
Reactant: CCCO
Reactant: O=C(O)[C@@H]1[C@H](C(=O)O)N(Cc2ccccc2)C(=O)N1Cc1ccccc1
Agent: O=S(=O)(O)O
Product: CCCOC(=O)[C@@H]1[C@H](C(=O)OCCC)N(Cc2ccccc2)C(=O)N1Cc1ccccc1

Procedure:
A mixture of cis-1,3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylic acid (35.4 g), benzene (500 ml), n-propanol (45 ml) and conc. sulfuric acid (5.0 g) was refluxed for 14 hours, cooled, washed successively with water, 5% aqueous sodium hydroxide and water, and then concentrated under reduced pressure to give oily product of di-n-propyl cis-1,3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylate (42.3 g). IR (neat, cm-1): 2970, 1750, 1710, 1445, 1420, 1360, 1210, 1055, 750, 700.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([N:19]=[N+:20]=[N-:21])=[CH:15][CH:14]=2)=[CH:11][N:10]=[C:9]1[NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:30]([C:32]1[CH:37]=[C:36](F)[CH:35]=[C:34](F)[CH:33]=1)#[CH:31].O=[C:41]1O[C@H:46]([C@H:48](CO)O)[C:44]([O-])=[C:42]1O.[Na+]>O.CCO.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:12]([C:13]2[CH:14]=[CH:15][C:16]([N:19]3[CH:31]=[C:30]([C:32]4[CH:37]=[CH:36][C:35]([CH2:41][CH2:42][CH2:44][CH2:46][CH3:48])=[CH:34][CH:33]=4)[N:21]=[N:20]3)=[CH:17][CH:18]=2)=[CH:11][N:10]=[C:9]1[NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1cc(F)cc(F)c1
Reactant: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Reactant: CC(C)(C)OC(=O)Nc1ncc(-c2ccc(N=[N+]=[N-])cc2)n1C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: CCCCCc1ccc(-c2cn(-c3ccc(-c4cnc(NC(=O)OC(C)(C)C)n4C(=O)OC(C)(C)C)cc3)nn2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 593.7 %

Procedure:
5-(4-azidophenyl)-2-tert-butoxycarbonylaminoimidazole-1-carboxylic acid tert-butyl ester (0.080 g, 0.200 mmol), 1-ethynyl-3,5-difluorobenzene (0.035 g, 0.26 mmol), CuSO4.5H2O (0.097 g, 0.040 mmol), and sodium ascorbate (0.004 g, 0.020 mmol) were all charged in a reaction vessel and dissolved in a 1:1:1 mixture of H2O (0.75 mL), EtOH 0.75 mL), and CH2Cl2 (0.75 mL). The reaction was stirred at ambient temperature for 16 h. After the reaction was quenched with sat. NaHCO3 and diluted with EtOAc (50 mL). The organic layer was washed with sat. NaHCO3 (3×20 mL) before being dried (Na2SO4), filtered and evaporated to dryness. The crude product was purified by column chromatography (10%-30% EtOAc/Hexanes) to afford 0.068 g (44%) of 2-tert-butoxycarbonylamino-5-{4-[4-(4-pentylphenyl)-[1,2,3]triazol-1-yl]phenyl}imidazole-1-carboxylic acid tert-butyl ester as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 9.60 (s, 1H), 9.29 (s, 1H), 8.01 (m, 3H), 7.98 (d, 2H, J=6.0 Hz), 7.85 (d, 2H, J=5.6 Hz), 7.32 (d, 2H, J=5.4 Hz), 2.62 (t, 2H, J=5.1 Hz), 1.59 (s, 9H), 1.47 (m, 2H), 1.45 (s, 9H), 1.30 (m, 4H), 0.87 (m, 3H); 13C NMR (75 MHz, DMSO-d6) δ 152.8, 147.2, 142.3, 139.9, 135.5, 128.9, 127.8, 127.6, 125.9, 120.1, 118.9, 113.5, 85.5, 80.0, 38.7, 31.3, 30.8, 27.9, 27.3, 21.9, 13.9; HRMS (ESI) calcd for C32H40N6O4 (M+) 572.3111. found 572.3113.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:27])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][O:29][C:30](=O)[O:31]C.[H-].[K+]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:27])[C@H:17]([C:30]([O:29][CH3:28])=[O:31])[CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)OC
Reactant: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@H]2[C@@H]3CCc4cc(OCc5ccccc5)ccc4[C@H]3CC[C@]2(C)C1=O
Yield: 90 %

Procedure:
A solution of 3-benzyloxy-1,3,5(10)-estratrien-17-one (2) (4.00 g, 11.1 mmol) in dry THF (5 mL) was added over a period of 30 min to a solution of dimethylcarbonate (2.34 mL, 27.8 mmol) and potassium hydride (1.42 g, 34.7 mmol) in dry THF (40 mL). Then, the mixture was heated to reflux for a period of 3 h. Most of the solvent was then evaporated and the residue was diluted with ethyl acetate (100 mL) and treated with a saturated ammonium chloride solution (50 mL). The organic phase was washed with water (6×40 mL), dried and evaporated to give a yellowish solid. Trituration of the residue with a mixture of acetone:hexanes (1:1) yielded the title compound in 90% yield as a white solid.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]#[C:12][C:13]1[C:22]([O:23][CH3:24])=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[N:16][N:17]=[C:18]2[CH2:25][C:26]1[C:31]([Cl:32])=[CH:30][N:29]=[CH:28][C:27]=1[Cl:33])[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.[Pd]>[CH2:1]([N:8]([CH2:10][CH:11]=[CH:12][C:13]1[C:22]([O:23][CH3:24])=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[N:16][N:17]=[C:18]2[CH2:25][C:26]1[C:31]([Cl:32])=[CH:30][N:29]=[CH:28][C:27]=1[Cl:33])[CH3:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nncc2c1C#CCN(C)Cc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nncc2c1C=CCN(C)Cc1ccccc1
Yield: 60.8 %

Procedure:
A solution of benzyl-{3-[1(3,5-dichloro-pyridin-4-ylmethyl)-6-methoxy-phthalazin-5-yl]-prop-2-ynyl}-methyl-amine (0.17 g, 0.36 mmoles), prepared as described in example 74, in THF (5 ml) and 10% Pd/C (0.07 g) was charged in a Parr apparatus at 2.7 atmospheres for 1.5 hours. The mixture was filtered over celite and dried to give an oil which was flash chromatographed (eluent: CH2Cl2/CH3OH/NH3 98:2:0.2, then 98:2:0.5). The resultant oil was crystallised from isopropyl ether to give 0.105 g of the title compound (yield: 61%)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:9]([CH3:23])[NH:8][C:7]=1[NH2:24])=[O:5])[CH3:2].CO[CH:27](OC)[N:28]([CH3:30])[CH3:29]>CCOCC>[CH2:1]([O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:9]([CH3:23])[NH:8][C:7]=1[N:24]=[CH:27][N:28]([CH3:30])[CH3:29])=[O:5])[CH3:2]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)C1=C(C)NC(N)=C(C(=O)OCC)C1c1ccccc1
Solvent: CCOCC
Product: CCOC(=O)C1=C(C)NC(N=CN(C)C)=C(C(=O)OCC)C1c1ccccc1
Reaction time: 1 h

Procedure:
15 g (45 mmols) of 2-amino-4-phenyl-6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester were warmed to 100° C. together with 10 g (84 mmols) of dimethylformamide dimethyl acetal and the mixture was stirred for about 60 minutes at this temperature. The reaction mass solidified whilst cooling and was suspended in a little ether, filtered off and recrystallised from ethanol. Melting point: 131° C. Yield: 13.7 g (79%)
Reaction SMILES: [Cl:1]C1C=CC(C(F)(F)F)=CN=1.[ClH:12].[F:13][C:14]([F:35])([F:34])[C:15]1[CH:16]=[CH:17][C:18]([O:21][C:22]2[CH:33]=[CH:32][C:25]([O:26][CH:27]([CH3:31])[C:28]([Cl:30])=[O:29])=[CH:24][CH:23]=2)=[N:19][CH:20]=1>BrC(CC)C(O)=O>[ClH:1].[Cl:12][C:17]1[C:18]([O:21][C:22]2[CH:33]=[CH:32][C:25]([O:26][CH:27]([CH3:31])[C:28]([Cl:30])=[O:29])=[CH:24][CH:23]=2)=[N:19][CH:20]=[C:15]([C:14]([F:34])([F:35])[F:13])[CH:16]=1
Reactant: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)C(=O)Cl
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: CCC(Br)C(=O)O
Agent: Cl
Product: CC(Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1)C(=O)Cl

Procedure:
By using 2-chloro-5-trifluoromethylpyridine instead of 2,3-dichloro-5-trifluoromethylpyridine in the above (b), 2-(4-(5-trifluoromethyl-2-pyridyloxy)phenoxy)propionic acid chloride hydrochloride was obtained.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[C:6]([C:32]([F:35])([F:34])[F:33])=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11]([C:15]([NH:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16])=[C:10]([O:26][CH2:27][C:28]([F:31])([F:30])[F:29])[CH:9]=[CH:8]2.Cl[C:37]([O:39][CH3:40])=[O:38]>C1COCC1>[CH3:3][O:4][C:5]1[C:6]([C:32]([F:33])([F:34])[F:35])=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11]([C:15]([N:17]([C:37]([O:39][CH3:40])=[O:38])[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:20])=[O:16])=[C:10]([O:26][CH2:27][C:28]([F:29])([F:30])[F:31])[CH:9]=[CH:8]2
Reactant: COc1ccc2c(C(=O)NCC(=O)OC(C)(C)C)c(OCC(F)(F)F)ccc2c1C(F)(F)F
Reactant: COC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)N(CC(=O)OC(C)(C)C)C(=O)c1c(OCC(F)(F)F)ccc2c(C(F)(F)F)c(OC)ccc12
Temperature: 55 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (80% by weight dispersion in mineral oil, 381 mg, 1.1 eq) was added to a stirred solution of N-[[6-methoxy-2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]glycine, 1,1-dimethylethyl ester (5.56 g, 11.5 mmol) in anhydrous THF (90 mL) at room temperature under a dry nitrogen atmosphere. The reaction was heated at 55° C. for 2 hours, then cooled to 0° C. in an ice bath. A solution of methyl chloroformate (1.21 mL, 1.36 eq) in anhydrous THF (30 mL) was slowly added to the 0° C. reaction mixture over 25 minutes. After 10 minutes, the reaction was warmed to room temperature. After 1 hour, the reaction was quenched with saturated aqueous ammonium chloride (1 mL), diluted with ether (100 mL) and preabsorbed onto silica gel. The product was flash chromatographed (4:1 petroleum ether:ethyl acetate, silica) to provide the title compound as white flakes (4.42 g, 71%), m.p. 53°-54° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:11][CH:10]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 50 °C
Yield: 100.1 %

Procedure:
A mixture of methyl 4-hydroxy-benzoate (10.0 g, 0.066 mol) and potassium carbonate (20.9 g, 0.098 mol), were taken in acetone (50 ml) and heated at 50° C. for 1 hour. To the reaction mixture, benzyl bromide (8.6 ml, 0.072 mol) was added and heated at 80° C. for 5 hours. The mixture was cooled to room temperature and filtered, washed with acetone. Solvent was removed to obtain pure 4-benzyloxy-benzoic acid methyl ester as white solid (16 g, 100%).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[NH:13][C:12]1=[O:19])[CH2:8]2.Br[CH2:21][CH:22]1[CH2:25][CH2:24][CH2:23]1>>[CH:1]12[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH:2]1[N:11]1[CH:15]=[C:14]([CH:16]([CH3:17])[CH3:18])[N:13]([CH2:21][CH:22]3[CH2:25][CH2:24][CH2:23]3)[C:12]1=[O:19])[CH2:10]2
Reactant: BrCC1CCC1
Reactant: CC(C)c1cn(C2C3CC4CC(C3)CC2C4)c(=O)[nH]1
Product: CC(C)c1cn(C2C3CC4CC(C3)CC2C4)c(=O)n1CC1CCC1

Procedure:
This material was obtained in analogy to the procedure outlined in example 23 from 1-adamantan-2-yl-4-isopropyl-1,3-dihydro-imidazol-2-one (obtained in example 8, 100 mg) by alkylation with bromomethylcyclobutane (86 mg). 1-Adamantan-2-yl-3-cyclobutylmethyl-4-isopropyl-1,3-dihydro-imidazol-2-one was obtained as a light yellow oil (51 mg). MS (EI): 328.3 (M+).
Reaction SMILES: [Li]CCCC.[Cl:6][C:7]1[CH:8]=[C:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=[N:11][CH:12]=1.[CH:21](OC)=[O:22].C([O-])(O)=O.[Na+]>C1COCC1.CC(C)=O.CCCCCC>[Cl:6][C:7]1[C:8]([CH:21]=[O:22])=[C:9]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:10]=[N:11][CH:12]=1
Reactant: COC=O
Reactant: Clc1cncc(OCc2ccccc2)c1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1c(Cl)cncc1OCc1ccccc1
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 75 %

Procedure:
To a stirred solution of dilsopropylamine (4.5 mL, 31.78 mmol) in anhydrous tetrahydrofuiran (20 mL) under nitrogen atmosphere at −5° C. was added dropwise n-BuLi in hexanes (2.5 M solution, 12.8 mL, 31.78 mmol) maintaining internal temperature of the reaction mixture below 0° C. The reaction mixture was stirred at −10° C. for 10 minutes, then at 0° C. for 30 minutes. This was cooled to −78° C. and a solution of Example 236A (5.8 g, 26.5 mmol) in anhydrous tetrahydroffiran (30 mL) was added slowly. Stirring at −78° C. was continued for 1 hour. Then the reaction was quenched with dropwise addition of methyl formate (5 mL, 79.5 mmol) in anhydrous THF (15 mL) and stirred at −78° C. for 3.5 hours. Internal temperature of the reaction mixture was maintained at or below −74° C. throughout the reaction. After 3.5 hours, the reaction mixture was poured into an ice cold saturated aqueous solution of NaHCO3 (200 mL) and stirred for 15 minutes. The mixture was partitioned with ethyl acetate (250 mL), organic layer was separated and washed with brine (2×60 mL). The dried (MgSO4) organic layer was concentrated under reduced pressure to obtain the crude product (8.5 g). The title compound was obtained in 75% yield (4.2 g) by flash chromatography on silica gel eluting with 6% acetone-hexane.
Reaction SMILES: [CH:1]1([NH:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)CC[CH2:4][CH2:3][CH2:2]1.N.[H][H].[O:17]1CCCC1>>[CH:8]1([N:7]2[CH2:4][CH2:3][CH2:2][C:1]2=[O:17])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: C1CCC(NC2CCCCC2)CC1
Reactant: C1CCOC1
Reactant: [H][H]
Agent: N
Product: O=C1CCCN1C1CCCCC1
Temperature: 225 °C
Yield: 8.8 %

Procedure:
5 g (0.05 mol) of MAA, 100 g of tetrahydrofuran, 9 g (0.06 mol) of dicyclohexylamine, 4 g of ammonia and 10 g of catalyst B were introduced into an autoclave fitted with a gas-distribution stirrer. The autoclave was subsequently heated to 225° C., and hydrogen was injected into the autoclave at a pressure of 200 bar. When take-up of hydrogen was no longer observed, the reaction was terminated. Analysis of the reaction mixture by gas chromatography gave a yield of 8.8% of N-cyclohexylpyrrolidone.
Reaction SMILES: [C:1]([C:5]1N=C(N2CC[C@H](O)C2)[C:8]2[C:9](=[N:11][N:12]([CH2:14]C3C(C)=NON=3)N=2)[N:10]=1)(C)(C)C.[C:27]([C:31]1[N:32]=[C:33]([N:40]2[CH2:44][CH2:43][C@H:42]([O:45]C(=O)C(F)(F)F)[CH2:41]2)[C:34]2[N:39]=[N:38][NH:37][C:35]=2[N:36]=1)([CH3:30])([CH3:29])[CH3:28].ClCC1N(C)N=C(C)N=1>>[C:27]([C:31]1[N:32]=[C:33]([N:40]2[CH2:44][CH2:43][C@H:42]([OH:45])[CH2:41]2)[C:34]2[C:35](=[N:37][N:38]([CH2:1][C:5]3[N:12]([CH3:14])[N:11]=[C:9]([CH3:8])[N:10]=3)[N:39]=2)[N:36]=1)([CH3:29])([CH3:28])[CH3:30]
Reactant: CC(C)(C)c1nc(N2CC[C@H](OC(=O)C(F)(F)F)C2)c2nn[nH]c2n1
Reactant: Cc1nonc1Cn1nc2nc(C(C)(C)C)nc(N3CC[C@H](O)C3)c2n1
Agent: Cc1nc(CCl)n(C)n1
Product: Cc1nc(Cn2nc3nc(C(C)(C)C)nc(N4CC[C@H](O)C4)c3n2)n(C)n1

Procedure:
In analogy to the procedure described for the synthesis of (S)-1-[5-tert-Butyl-2-(4-methyl-furazan-3-ylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-ol (example 73), the title compound was prepared from Trifluoro-acetic acid (S)-1-(5-tert-butyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)-pyrrolidin-3-yl-ester and 5-(chloromethyl)-1,3-dimethyl-1H-1,2,4-triazole and isolated as colorless gum. MS (m/e): 372.3 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[C:5]([Cl:8])=[N:6][CH:7]=1.[NH4+].[Cl-]>CCO.O.[Fe]>[Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1cc(Br)cnc1Cl
Temperature: 25 °C
Yield: 90.8 %

Procedure:
To a solution of 5-bromo-2-chloro-3-nitropyridine (10.0 g, 42.1 mmol) in EtOH (70 ml) and H2O (14 ml) was added iron (11.7 g, 211 mmol) and NH4Cl (6.76 g, 126 mmol) at room temperature. The mixture was refluxed for 1 hour, and then cooled to room temperature, filtered through a Celite pad and washed with EtOH. The filtrate was concentrated in vacuo. The residue was treated with saturated aq. NaHCO3, and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (Hexane:EtOAc=3:1) to give 5-bromo-2-chloropyridin-3-amine (7.93 g, 91%) as a white solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 5.89 (2H, s), 7.30 (1H, d, J=2.0 Hz), 7.66 (1H, d, J=2.4 Hz).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][C:11]1[C:12]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:13][C:14]([NH:18][CH:19]2[CH2:24][CH2:23][N:22]([C@H:25]3[CH2:30][CH2:29][C@H:28]([O:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:26]3)[CH2:21][CH2:20]2)=[C:15]([OH:17])[CH:16]=1.[Cl:39][C:40](Cl)([O:42]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[ClH:39].[CH3:10][C:11]1[C:12]([S:35]([CH3:38])(=[O:36])=[O:37])=[CH:13][C:14]2[N:18]([CH:19]3[CH2:20][CH2:21][N:22]([C@H:25]4[CH2:26][CH2:27][C@H:28]([O:31][CH2:32][CH2:33][CH3:34])[CH2:29][CH2:30]4)[CH2:23][CH2:24]3)[C:40](=[O:42])[O:17][C:15]=2[CH:16]=1
Reactant: CCCO[C@H]1CC[C@H](N2CCC(Nc3cc(S(C)(=O)=O)c(C)cc3O)CC2)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCO[C@H]1CC[C@H](N2CCC(n3c(=O)oc4cc(C)c(S(C)(=O)=O)cc43)CC2)CC1
Product: Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Hunig's base (0.01 mL, 0.06 mmol) was added to a solution of 5-methyl-4-(methylsulfonyl)-2-({1-[trans-4-(propyloxy)cyclohexyl]-4-piperidinyl}amino)phenol (D89, 14 mg, 0.03 mmol) in DCM (3 mL) at rt under Ar. The reaction was cooled to 0° C. and the triphosgene (5 mg, 0.02 mmol) was added. The mixture was stirred for 2 h at 0° C. The reaction was quenched with sat. NaHCO3 (5 mL) and partitioned between DCM and H2O. The aqueous layer was extracted with DCM (2×) and the combined organics were dried (Na2SO4) and concentrated by rotary evaporation to give a yellow oil, which was purified via flash column chromatography (silica, DCM to 0.5% NH3/9.5% MeOH/90% DCM) to give the free base of the title compound as a pale yellow oil. HCl (0.1 mL, 0.1 mmol, 1 M in Et2O) was added to a solution of the free base in DCM (0.5 mL) and the solvent was removed by rotary evaporation. The resulting solid was triturated with Et2O to give 6-methyl-5-(methylsulfonyl)-3-{1-[trans-4-(propyloxy)cyclohexyl]-4-piperidinyl}-1,3-benzoxazol-2(3H)-one hydrochloride (E31; 11 mg, 62%) as a cream solid.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][C:10]([F:13])([F:12])[C:9](=[O:14])[N:8]([CH3:15])[C:7]3[CH:16]=[N:17][C:18]([NH:20][C:21]4[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=4)=[N:19][C:6]2=3)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.CN(C(=[N+](C)C)ON1C2=NC=CC=C2N=N1)C.F[P-](F)(F)(F)(F)F.Cl.[CH:62]1[C:74]2[CH:73]([CH2:75][O:76][C:77](=[O:85])[NH:78][CH:79]3[CH2:84][CH2:83][NH:82][CH2:81][CH2:80]3)[C:72]3[C:67](=[CH:68][CH:69]=[CH:70][CH:71]=3)[C:66]=2[CH:65]=[CH:64][CH:63]=1>C(OCC)(=O)C.CN(C)C=O>[CH:62]1[C:74]2[CH:73]([CH2:75][O:76][C:77](=[O:85])[NH:78][CH:79]3[CH2:80][CH2:81][N:82]([C:25](=[O:26])[C:24]4[CH:28]=[CH:29][C:21]([NH:20][C:18]5[N:17]=[CH:16][C:7]6[N:8]([CH3:15])[C:9](=[O:14])[C:10]([F:12])([F:13])[CH2:11][N:5]([CH:1]7[CH2:4][CH2:3][CH2:2]7)[C:6]=6[N:19]=5)=[CH:22][CH:23]=4)[CH2:83][CH2:84]3)[C:72]3[C:67](=[CH:68][CH:69]=[CH:70][CH:71]=3)[C:66]=2[CH:65]=[CH:64][CH:63]=1
Reactant: CN1C(=O)C(F)(F)CN(C2CCC2)c2nc(Nc3ccc(C(=O)O)cc3)ncc21
Reactant: O=C(NC1CCNCC1)OCC1c2ccccc2-c2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1C(=O)C(F)(F)CN(C2CCC2)c2nc(Nc3ccc(C(=O)N4CCC(NC(=O)OCC5c6ccccc6-c6ccccc65)CC4)cc3)ncc21
Reaction time: 0.25 h
Yield: 50.1 %

Procedure:
A mixture of 0.250 g (0.62 mmole) of 4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-benzoic acid (I-11), 0.250 g (2.48 mmole) of triethylamine, 0.319 g (0.74 mmole) of N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-methanaminium, hexafluorophosphate(1-) (1:1) and 5 mL of dimethylformamide was stirred for 15 minutes and then 0.267 g (0.74 mmole) of 4-piperidinyl-carbamic acid 9H-fluoren-9-ylmethyl ester monohydrochloride was added. The mixture was stirred for 3 hours, then taken up in 100 mL of ethyl acetate and washed twice with 100 mL of water and then 100 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with hexane-ethyl acetate (gradient 50:50-0:100) to give 0.220 g of {1-[4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-benzoyl]-piperidin-4-yl}-carbamic acid 9H-fluoren-9-ylmethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[NH2:11].C(N(CC)CC)C.[C:20](Cl)(=[O:24])[CH2:21][CH2:22][CH3:23]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[NH:11][C:20](=[O:24])[CH2:21][CH2:22][CH3:23]
Reactant: COC(=O)c1ccc(C)cc1N
Reactant: CCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)Nc1cc(C)ccc1C(=O)OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 103.9 %

Procedure:
To a 0° C. solution of 2-amino-4-methyl-benzoic acid methyl ester (1.5 g, 9.0 mmol) and triethylamine (1.4 g, 13.5 mmol) in methylene chloride (30.0 mL) is added butyryl chloride (1.2 g, 10.8 mmol) dropwise. The mixture is stirred at 0° C. for 30 min and is quenched with saturated sodium bicarbonate (10 mL). The organic phase is washed with brine (20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to a residue. The residue is purified by flash chromatography to afford the title compound as syrup (2.2 g, 100%). LC-ES/MS m/e 236.3 (M+1).