Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C@H:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[C@@H:7]([NH:16][CH2:17][C@@H:18]([OH:30])[C@@H:19]([NH2:29])[CH2:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=2)[CH2:6]1)[CH:2]=[CH2:3].[CH2:31]([C@H:35]1[CH2:39][CH2:38][N:37]([C@@H:40]([CH2:44][CH:45]=[CH2:46])[C:41](O)=[O:42])[C:36]1=[O:47])[CH2:32][CH2:33][CH3:34].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([O:4][C@H:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[C@@H:7]([NH:16][CH2:17][C@@H:18]([OH:30])[C@@H:19]([NH:29][C:41](=[O:42])[C@@H:40]([N:37]2[CH2:38][CH2:39][C@H:35]([CH2:31][CH2:32][CH2:33][CH3:34])[C:36]2=[O:47])[CH2:44][CH:45]=[CH2:46])[CH2:20][C:21]2[CH:22]=[C:23]([F:28])[CH:24]=[C:25]([F:27])[CH:26]=2)[CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CC[C@@H](C(=O)O)N1CC[C@H](CCCC)C1=O
Reactant: C=CCO[C@@H]1C[C@H](NC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c2cc(OC)ccc21
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCO[C@@H]1C[C@H](NC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)[C@H](CC=C)N2CC[C@H](CCCC)C2=O)c2cc(OC)ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.2 %

Procedure:
Step J (1): A mixture of (2R,3S)-1-((1S,3R)-3-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-ylamino)-3-amino-4-(3,5-difluorophenyl)butan-2-ol (51 mg, 0.122 mmol) from stepE(2), (S)-2-((S)-3-butyl-2-oxopyrrolidin-1-yl)pent-4-enoic acid (31 mg, 0.128 mmol) from stepB(5), EDC (25 mg, 0.128 mmol), HOBt (17 mg, 0.128 mmol), and DIEA (108 μL, 0.610 mmol) were mixed in 2 mL of DMF and stirred at room temperature for 24 h. Purified using reverse phase preparatory HPLC to give 61 mg of (S)—N-((2S,3R)-4-((1S,3R)-3-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-ylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)-2-((S)-3-butyl-2-oxopyrrolidin-1-yl)pent-4-enamide as clear viscous residue (TFA salt). A 2 mg sample was free based by passage through basic alumina (activated, Brockmann I), using methanol as an eluant: LC-MS (M+H)+=640.6; 1H NMR (500 MHz, CDCl3) δ 7.27-7.37 (m, 1H), 6.78-6.93 (m, 2H), 6.69-6.80 (m, 2H), 6.55-6.67 (m, 1H), 5.81-6.08 (m, 1H), 5.52-5.72 (m, 1H), 5.31 (dd, J=17.09, 1.53 Hz, 1H), 5.18 (dd, J=10.38, 1.22 Hz, 1H), 4.91-5.14 (m, 2H), 4.65-4.86 (m, 1H), 4.49 (dd, J=9.77, 6.10 Hz, 1H), 3.97-4.22 (m, 3H), 3.75-3.87 (m, 3H), 3.34-3.55 (m, 1H), 2.99-3.33 (m, 2H), 2.84-3.00 (m, 1H), 2.53-2.86 (m, 4H), 2.19-2.52 (m, 2H), 2.00-2.19 (m, 1H), 1.69-1.93 (m, 2H), 1.42-1.72 (m, 5H), 1.17-1.40 (m, 5H), 0.98-1.15 (m, 1H), 0.79-0.96 (m, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[O:16])=[CH:13][N:12]=[C:11]([NH:25][CH:26]2[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]2)[N:10]=1.C(N(CC)CC)C.Cl[C:40]([O:42][CH3:43])=[O:41]>ClCCl>[CH3:43][O:42][C:40]([N:28]1[CH2:29][CH2:30][CH2:31][CH:26]([NH:25][C:11]2[N:10]=[C:9]([NH2:8])[C:14]([C:15](=[O:16])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])=[CH:13][N:12]=2)[CH2:27]1)=[O:41]
Reactant: COC(=O)Cl
Reactant: COc1ccccc1C(=O)c1cnc(NC2CCCNC2)nc1N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: COC(=O)N1CCCC(Nc2ncc(C(=O)c3ccccc3OC)c(N)n2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
To a solution of [4-amino-2-(piperidin-3-ylamino)-pyrimidin-5-yl]-(2-methoxy-phenyl)-methanone trifluoroacetic acid salt (42 mg, Example 53) in dichloromethane (3 mL) were added triethylamine (48 mg, Aldrich) and methyl chloroformate (6.1 mg, Aldrich) at 0° C. After stirring for 1 hour at 0° C., the reaction mixture was concentrated in vacuo and crude product was purified on silica gel with 95:5 of dichloromethane/methanol to give 3-[4-amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-carboxylic acid methyl ester (20.5 mg). MS (M+H)+, 386. CDK4 IC50=0.459 μM; CDK1 IC50=0.469 μM; CDK2 IC50=0.713 μM; HCT 116 IC90=6.437 μM.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12]([C@H:14]1[C@@H:19]([NH2:20])[C@H:18]2[CH2:21][C@@H:15]1[CH2:16][CH2:17]2)=[O:13])[CH3:10].C([BH3-])#N.[Na+]>C(O)(=O)C.CO>[CH2:9]([O:11][C:12]([C@H:14]1[C@@H:19]([NH:20][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@H:18]2[CH2:21][C@@H:15]1[CH2:16][CH2:17]2)=[O:13])[CH3:10]
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1N
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
Benzaldehyde (0.454 mL, 4.47 mmol) and 10 drops glacial acetic acid were added sequentially to a solution of (1S,2R,3S,4R)-3-amino-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (prepared as described in Example 6k, 0.82 g, 4.47 mmol) in methanol (15 mL) at 25° C. Sodium cyanoborohydride (0.703 g, 11.2 mmol) was added, and the reaction mixture was stirred at 25° C. for 2 h, and then was partitioned between half-saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (2×150 mL). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (Teledyne Isco RediSep column; 0 to 35% ethyl acetate in hexanes) to afford the desired product, (1S,2R,3S,4R)-3-benzylamino-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (0.875 g, 3.22 mmol, 72%), as a clear oil. 1H NMR (400 MHz, CDCl3) δ: 1.06-1.16 (2H, m), 1.20-1.23 (2H, m), 1.28 (3H, t, J=7.0 Hz), 1.46-1.61 (2H, m), 1.93-1.97 (1H, m), 2.33-2.34 (1H, m), 2.43-2.44 (1H, m), 2.59-2.62 (1H, m), 2.98-3.00 (1H, m), 3.71 (1H, d, J=14.0 Hz), 3.85 (1H, d, J=13.3 Hz), 4.14 (2H, q, J=7.3 Hz), 7.20-7.24 (1H, m), 7.27-7.33 (4H, m).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:18][CH3:19])[C:4]2[C:9]([C:10](=[O:16])[C:11]=1[C:12]([NH:14][CH3:15])=[O:13])=[CH:8][CH:7]=[C:6](Cl)[N:5]=2.[CH3:20][C:21]([O:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])([CH3:24])[C:22]#[CH:23]>CN(C)C=O.C(N(CC)CC)C.C(OCC)(=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH2:18][CH3:19])[C:4]2[N:5]=[C:6]([C:23]#[C:22][C:21]([O:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])([CH3:24])[CH3:20])[CH:7]=[CH:8][C:9]=2[C:10](=[O:16])[C:11]=1[C:12](=[O:13])[NH:14][CH3:15]
Reactant: CCn1c(N)c(C(=O)NC)c(=O)c2ccc(Cl)nc21
Reactant: C#CC(C)(C)OCC(=O)OCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)COC(C)(C)C#Cc1ccc2c(=O)c(C(=O)NC)c(N)n(CC)c2n1
Temperature: 90 °C
Yield: 82.4 %

Procedure:
1.15 g (4.10 mmol) of 2-amino-7-chloro-1-ethyl-N-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide and 1.39 g (8.19 mmol) of ethyl [(1,1-dimethylprop-2-yn-1-yl)oxy]acetate are placed in a mixture of 10 ml of dimethylformamide and 10 ml of triethylamine. Argon is sparged into the reaction mixture for 15 minutes and then 0.031 g (0.16 mmol) of CuI and 0.144 g (0.20 mmol) of bis(triphenylphosphine)palladium(II) dichloride are successively added. The reaction mixture is heated at 90° C. for 15 hours. After returning to ambient temperature, the reaction mixture is poured onto a water/ice mixture. After separating them by settling, the black gum obtained is dissolved in ethyl acetate and then washed with water. The organic phase is dried over sodium sulfate, filtered and concentrated under vacuum. 1.4 g of a brown oil are obtained, which oil is purified by chromatography on silica (elution with a cyclohexane/ethyl acetate 30:70 to 20:80 gradient) to give 0.72 g of the expected product in the form of a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[F:13][C:14]1[C:19]([F:20])=[CH:18][C:17]([S:21](Cl)(=[O:23])=[O:22])=[C:16]([N+:25]([O-:27])=[O:26])[CH:15]=1.N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][S:21]([C:17]2[CH:18]=[C:19]([F:20])[C:14]([F:13])=[CH:15][C:16]=2[N+:25]([O-:27])=[O:26])(=[O:22])=[O:23])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1S(=O)(=O)Cl
Reactant: Nc1ccc(Cl)c2cccnc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cc(F)c(F)cc1S(=O)(=O)Nc1ccc(Cl)c2cccnc12
Yield: 14.2 %

Procedure:
In the similar fashion using route 14 general procedure 27, 5-chloro-quinolin-8-ylamine (Intermediate 27) (400 mg, 2.2 mmol), 4,5-difluoro-2-nitro-benzenesulfonyl chloride (Intermediate 219) (750 mg, 2.9 mmol), DMAP (cat.) and pyridine (5 ml) and DCM (5 ml) gave the title compound (125 mg, 14%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[C:15](=[O:17])[CH3:16].CC([N:21](C)C)=O.BrC(C)(C)C(N)=O.[OH-].[Na+]>O>[NH2:21][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[C:15](=[O:17])[CH3:16]
Reactant: CC(=O)c1ccc(N2CCN(C)CC2)cc1O
Reactant: CC(=O)N(C)C
Agent: CC(C)(Br)C(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)c1ccc(N2CCN(C)CC2)cc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.2 %

Procedure:
To a solution of 1-[2-hydroxy-4-(4-methyl-piperazin-1-yl)-phenyl]-ethanone (5.22 g, 22.2 mmol) in DMA (50 mL) NaOH (2.67 g, 66.6 mmol) was added. The mixture was stirred at room temperature for 1 h, after which time 11.1 g (66.7 mmol) of 2-bromo-2-methylpropanamide was added and the mixture was stirred at room temperature overnight. 8.01 g (200 mmol) of NaOH was added and the resulting mixture was stirred at 100° C. for 2 h, then 50 mL of water was added and the mixture was stirred at 100° C. for 1 h. After cooling to room temperature, the mixture was concentrated and then diluted with DCM and washed with water, dried over sodium sulfate and concentrated. The crude solid was purified by flash chromatography on silica gel (eluant: DCM/EtOH 95/5) to afford 1.51 g of the title compound (30% yield).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:10]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[O:12][N:11]=2)[CH:6]=[C:7](F)[CH:8]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].[NH:27]1[CH:31]=[CH:30][N:29]=[CH:28]1.CN(C)C=O>C(Cl)(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([C:10]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[O:12][N:11]=2)[CH:6]=[C:7]([N:27]2[CH:31]=[CH:30][N:29]=[CH:28]2)[CH:8]=1)#[N:2]
Reactant: N#Cc1cc(F)cc(-c2noc(-c3ccccn3)n2)c1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: N#Cc1cc(-c2noc(-c3ccccn3)n2)cc(-n2ccnc2)c1

Procedure:
In a screw cap vial equipped with stir bar added 3-(3-Cyano-5-fluorophenyl)-5-(2-Pyridyl)-1,2,4-oxadiazole (20 mg, 0.08 mmol), potassium carbonate (20.8 mg, 0.15 mmol), imidazole (7.7 mg, 0.11 mmol) and dimethylformamide (1 ml). Stirred the resulting mixture at 120° C. for 2 h. The reaction mixture was diluted with chloroform (30 ml) and washed with water (30 ml). The aqueous phase was re-extracted with chloroform (30 ml) and the combined organic phase was dried (sodium sulfate), filtered and concentrated in-vacuo. The crude residue was purified on silica gel using 1% methanol in dichloromethane to isolate the free base of the desired compound as a white solid. The free base was converted to it's hydrochloride salt (11.7 mg), white solid. 1H-NMR (DMSO), δ (ppm): 9.81 (s, 1H), 8.83 (m, 4H), 8.42 (m, 2H), 8.19 (dt, 1H), 7.92 (s, 1H), 7.80 (dd, 1H).
Reaction SMILES: [C@@H:1]1([N:9]2[CH:16]=[CH:15][C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.[C:17]1([C:23](Cl)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>N1C=CC=CC=1>[C:23]([O:7][CH2:6][C@H:5]1[O:8][C@@H:1]([N:9]2[CH:16]=[CH:15][C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:2][C@@H:3]1[OH:4])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=c1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: O=c1ccn([C@H]2C[C@H](O)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)c(=O)[nH]1
Yield: 96.3 %

Procedure:
2′-Deoxyuridine (1.00 g, 4.39 mmol) and triphenylmethylchloride (1.34 g, 4.83 mmol) were stirred in dry pyridine (20 ml) overnight at 50° C. under an atmosphere of nitrogen. The reaction mixture was then poured into ice-H2O (100 ml) with vigorous stirring and filtered. The precipitate was dissolved in EtOAc (100 ml) and the solution was washed with 0.5M HCl (100 ml) and H2O (100 ml), dried (Na2SO4) and reduced in vacuo. The residue was washed with toluene to leave the title compound (1.99 g, 97%) as a pale yellow solid. For analytical purposes, the compound was purified by gradient flash column chromatography, eluting with 5→10% MeOH/CHCl3.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.C([N:12]([CH2:15][CH3:16])CC)C.ClC(OCC)=O.N[C:24]1([OH:30])[CH2:29]CC[CH2:26][CH2:25]1>O1CCCC1>[OH:30][CH:24]1[CH2:29][CH2:16][CH:15]([NH:12][C:1]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[O:9])[CH2:26][CH2:25]1
Reactant: CCN(CC)CC
Reactant: NC1(O)CCCCC1
Reactant: O=C(O)c1cccnc1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Product: O=C(NC1CCC(O)CC1)c1cccnc1
Temperature: -4 °C
Reaction time: 2 h

Procedure:
Nicotinic acid (2.14 g, 0.017 mol) was suspended in 75 mL of dry tetrahydrofuran, then 1.76 g of freshly distilled triethylamine were added. The clear solution thus obtained was cooled to -4° C. in an ice bath under argon, then ethyl chloroformate (1.88 g, 0.014 mol) in 10 mL of tetrahydrofuran was added such that the temperature did not go above 0° C. The free aminocyclohexanol (2.0 g, 0.017 mol) was added as a powder to the cold reaction mixture, which was allowed to come to room temperature and stirred for 2 hours. The precipitate which formed was collected by filtration, dissolved in 28 mL of hot water and recrystallized as 3.25 g (85%) of fine colorless needles melting at 208°-210° C. and having the formula ##STR111## as confirmed by elemental analysis.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[CH3:14][N:15]1[CH:20]2[CH2:21][CH2:22][CH:16]1[CH2:17][C:18](=[O:23])[CH2:19]2>C(OCC)C>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:18]2([OH:23])[CH2:19][CH:20]3[N:15]([CH3:14])[CH:16]([CH2:22][CH2:21]3)[CH2:17]2)=[CH:8][CH:9]=1
Reactant: CN1C2CCC1CC(=O)C2
Reactant: Clc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CN1C2CCC1CC(O)(c1ccc(Cl)cc1)C2
Reaction time: 0.33 h
Yield: 76 %

Procedure:
2.5 M n-butyl lithium (17.96 mL, 40.90 mmol) was added to -70 ° C diethyl ether (35 mL) and 4-bromochlorobenzene (9.03 g, 47.15 mmol) in diethyl ether (20mL) was added dropwise over 20 minutes. The mixture was stirred in the cold for 20 minutes then 8-Methyl-8-aza-bicyclo[3.2.1]octan-3-one (5 g, 35.92 mmol) in diethyl ether (12 mL) was added dropwise over 5 minutes. Cooling bath was removed and when internal temperature of −20° C. was reached the solution was quenched with 1N hydrochloric acid (200 mL). The aqueous layer was raised to pH=10 with ammonium hydroxide and extracted with diethyl ether (three times, 200 mL each). The combined organic layers were washed with brine (100 mL), dried with magnesium sulfate and concentrated to yield racemic3-(4-Chloro-phenyl)-8-methyl-8-aza-bicyclo[3.2.1]octan-3-ol (6.87 g, contains 9% 8-Methyl-8-aza-bicyclo[3.2.1]octan-3-one) as a white solid. Solid was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH2:19][OH:20])[C:10]=1[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([N:27]=[C:28]=[O:29])[CH2:23][CH2:24][CH2:25][CH3:26].CO>C1COCC1>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH2:19][O:20][C:28](=[O:29])[NH:27][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:10]=1[CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(CO)nc2ccccc2c1OCc1ccccc1
Reactant: CCCCCN=C=O
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCNC(=O)OCc1nc2ccccc2c(OCc2ccccc2)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.7 %

Procedure:
To a solution of [4-(benzyloxy)-3-methylquinolin-2-yl]methanol (105 mg) in THF (3 mL) was added pentylisocyanate (45 mg), followed by stirring at room temperature for 1 hour. Pentylisocyanate (20 mg) was further added to the reaction mixture, followed by stirring at room temperature for 16 hours. Methanol (2 mL) was added to the reaction mixture, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform) to obtain [4-(benzyloxy)-3-methylquinolin-2-yl]methylpentylcarbamate (150 mg).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C([N:15]([CH2:26][CH3:27])[C:16](=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[CH3:24])C.C(C[CH2:31][N:32]1[CH2:36][CH2:35][C@@H:34]([OH:37])[CH2:33]1)#N>O1CCCC1.O>[OH:37][C@@H:34]1[CH2:35][CH2:36][N:32]([CH2:31][CH2:27][C:26]2[NH:15][C:16](=[O:25])[C:17]3[C:18]([CH:24]=2)=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=3)[CH2:33]1
Reactant: CCN(CC)C(=O)c1cccc(C)c1C
Reactant: N#CCCN1CC[C@@H](O)C1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cc1cccc2c(=O)[nH]c(CCN3CC[C@@H](O)C3)cc12
Temperature: -78 °C
Yield: 22.9 %

Procedure:
Diisopropylamine (122 mL) was dissolved in tetrahydrofuran (400 mL), and n-butyllithium (1.56 mol/L) (534 mL) was added dropwise to the solution under ice-cooling. The mixture was stirred under ice-cooling for 30 min, and then cooled to −78° C. A solution (150 mL) of N,N-diethyl-2,3-dimethylbenzamide (85.4 g) in tetrahydrofuran was added dropwise to the reaction mixture and the mixture was stirred at −78° C. for 0.5 hr. The reaction mixture was cooled to −78° C. and absolution (150 mL) of (R)-1-(2-cyanoethyl)-3-hydroxypyrrolidine (53 g) in tetrahydrofuran was added dropwise to the mixture. The reaction mixture was allowed to warm to room temperature. After the completion of the reaction, water was added to the reaction mixture and the organic layer was separated and concentrated. The residue was dissolved in chloroform and the solution was washed with saturated brine and dried over magnesium sulfate. The organic layer was extracted with 1N hydrochloric acid, and the layer was basified. The aqueous layer was extracted with chloroform and the extract was dried over magnesium sulfate. The solvent was concentrated and the obtained residue was purified by silica gel column chromatography to give (R)-3-[2-(3-hydroxypyrrolidin-1-yl)ethyl]-5-methyl-2H-isoquinolin-1-one (23.6 g).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:34](=[O:35])[N:6]2[C:7]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)=[O:22])=[C:8]([C:11]3[S:15][C:14]4=[C:16]([S:19][CH3:20])[N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Cl:36]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.ClCCl>C1C=CC=CC=1.[Cl-].[Na+].O>[Cl:36][C:18]1[N:13]2[C:14]([S:15][C:11]([C:8]3[C@H:9]([CH3:10])[C@@H:5]4[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:34](=[O:35])[N:6]4[C:7]=3[C:21]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([N+:31]([O-:33])=[O:32])=[CH:29][CH:30]=3)=[O:22])=[CH:12]2)=[C:16]([S:19][CH3:20])[N:17]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CSc1ncn2cc(C3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)sc12
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: ClCCl
Solvent: O
Product: CSc1nc(Cl)n2cc(C3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)sc12
Reaction time: 0.17 h
Yield: 27.5 %

Procedure:
4-Nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo-[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (109 mg) was dissolved in 10 ml of benzene at room temperature. N-Chlorosuccinimide (30 mg) and 5 mg of 2,2′-azobis(isobutyronitrile) were added to the solution. The mixture was stirred for 10 min. Dichloromethane (10 ml) and 10 ml of semisaturated brine were added thereto, followed by separation. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane:methanol=20:1) to give 32 mg of 4-nitrobenzyl(1S,5R,6S)-2-(5-chloro-7-methylthioimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][CH:15]=[CH:16][C:9]=23)[C:5]([C:17]2[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=2)=[N:4]1)[CH3:2].[C:24]([N:28]=[C:29]=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[CH3:25][C:24]([NH:28][C:29]([NH:21][C:20]1[CH:22]=[CH:23][C:17]([C:5]2[C:6]([C:8]3[CH:13]=[CH:12][N:11]=[C:10]4[NH:14][CH:15]=[CH:16][C:9]=34)=[CH:7][N:3]([CH2:1][CH3:2])[N:4]=2)=[CH:18][CH:19]=1)=[O:30])([CH3:27])[CH3:26]
Reactant: CC(C)(C)N=C=O
Reactant: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(N)cc2)n1
Product: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(NC(=O)NC(C)(C)C)cc2)n1

Procedure:
Following the procedure described in Example 1 with 4-[1-ethyl-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]aniline and tert-butyl isocyanate provided the title compound. ESMS [M+H]+: 403.2
Reaction SMILES: C[N:2](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][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.Cl.[F:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33]N)=[CH:29][CH:28]=1.CCN(CC)CC>C(O)C>[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)=[CH:29][CH:28]=1
Reactant: NNc1ccc(F)cc1
Reactant: CN(C)C=CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1-c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 29.7 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (337 mg, 1.0 mmol) in ethanol (100 mL) were added 4-fluorophenylhydrazine hydrochloride (244 mg, 1.5 mmol) and Et3N (0.28 mL, 2.0 mmol). The mixture was stirred at 100° C. for 3 h and the solvent was removed under reduced pressure. Preparative HPLC chromatography provided 3-[1-(4-fluorophenyl)-1H-pyrazol-5-yl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one as a pale brown solid (119 mg, 30%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[C:8]([NH2:11])[C:9]=1[NH2:10])=[O:4].CO[C:20](=N)[C:21]([Cl:24])([Cl:23])[Cl:22]>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([O:12][CH2:13][C:14]([F:17])([F:15])[F:16])=[C:8]2[C:9]=1[NH:10][C:20]([C:21]([Cl:24])([Cl:23])[Cl:22])=[N:11]2)=[O:4]
Reactant: COC(=N)C(Cl)(Cl)Cl
Reactant: COC(=O)c1sc(OCC(F)(F)F)c(N)c1N
Product: COC(=O)c1sc(OCC(F)(F)F)c2nc(C(Cl)(Cl)Cl)[nH]c12

Procedure:
2-Trichloromethyl-6-(2,2,2-trifluoro-ethoxy)-3H-thieno[3,4-d]imidazole-4-carboxylic acid methyl ester was prepared by a procedure according to example 100 (i) from 500 mg (1.85 mmol) 3,4-diamino-5-(2,2,2-trifluoro-ethoxy)-thiophene-2-carboxylic acid methyl ester and 328.0 μl (2.59 mmol) 2,2,2-trichloro-acetimidic acid methyl ester.