Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]([CH3:32])([CH3:31])[O:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([C:23]3[CH2:28][CH2:27][C:26]([CH3:30])([CH3:29])[CH2:25][CH:24]=3)[CH:17]=2)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[K+].[C:34]([C:36]1[N:37]=[C:38]([C:49]([O-])=[O:50])[N:39]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[CH:40]=1)#[N:35].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([Si:5]([CH3:32])([CH3:31])[O:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:49]([C:38]3[N:39]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[CH:40]=[C:36]([C:34]#[N:35])[N:37]=3)=[O:50])=[C:18]([C:23]3[CH2:28][CH2:27][C:26]([CH3:30])([CH3:29])[CH2:25][CH:24]=3)[CH:17]=2)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: CC1(C)CC=C(c2cc(CN3CCN(CCO[Si](C)(C)C(C)(C)C)CC3)ccc2N)CC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)CC=C(c2cc(CN3CCN(CCO[Si](C)(C)C(C)(C)C)CC3)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Yield: 62 %

Procedure:
A solution of 4-{4-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-piperazin-1-ylmethyl}-2-(4,4-dimethyl-cyclohex-1-enyl)-phenylamine (as prepared in the previous step, 233 mg, 0.590 mmol) in CH2Cl2 (10 mL) was treated with 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in Example 1, step (d), 188 mg, 0.610 mmol), PyBroP (332 mg, 0.713 mmol), and DIEA (177 μL, 10.2 mmol) at RT for 1 h. The mixture was diluted with CH2Cl2 (40 mL) and washed with water (1×30 mL) and satd aq NaHCO3 (1×30 mL). The combined aqueous layers were extracted with CH2Cl2 (1×30 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification of the residue on a 20-g Isolute SPE column on a FlashMaster system with 10-25% EtOAc-hexane afforded the title compound (223 mg, 62%) as an off-white solid. Mass spectrum (ESI, m/z): Calcd. for C38H62N6O3Si2, 707.4 (M+H). found 707.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH3:18][C:19]1[NH:23][N:22]=[C:21]([CH:24]=O)[CH:20]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][NH:17][CH2:24][C:21]3[CH:20]=[C:19]([CH3:18])[NH:23][N:22]=3)[CH2:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(N2CCN(CCN)CC2)cc1
Reactant: Cc1cc(C=O)n[nH]1
Product: COc1ccc(N2CCN(CCNCc3cc(C)[nH]n3)CC2)cc1
Yield: 30.1 %

Procedure:
Compound 36 was prepared using the same method as that of Example 1 except that 4-(4-methoxyphenyl)piperazin-1-ylethylamine and 5-methylpyrazole-3-carbaldehyde were used.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:13][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([N:27]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=3)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:23][CH2:22]2)[CH2:10]1)=O)(C)(C)C.[C:44]1([S:50](Cl)(=[O:52])=[O:51])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>>[C:44]1([S:50]([NH:8][C@H:9]2[CH2:13][C@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C@@H:11]([CH2:20][N:21]3[CH2:22][CH2:23][CH:24]([N:27]([C:31]([O:33][CH2:34][C:35]4[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=4)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:25][CH2:26]3)[CH2:10]2)(=[O:52])=[O:51])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](NC(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](NS(=O)(=O)c3ccccc3)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(S)-((t-butoxycarbonyl)amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 33 in Step A and phenylsulfonyl chloride in Step B, the title compound was prepared.
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])[C:9](=[CH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)[NH:8][CH2:7][CH2:6]2.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:34]=[C:35]([O:39][CH3:40])[C:36]=1[O:37][CH3:38])[C:31](Cl)=[O:32].N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])/[C:9](=[CH:15]/[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)/[N:8]([C:31](=[O:32])[C:30]1[CH:29]=[C:28]([O:27][CH3:26])[C:36]([O:37][CH3:38])=[C:35]([O:39][CH3:40])[CH:34]=1)[CH2:7][CH2:6]2
Reactant: COc1ccc(C=C2NCCc3cc(OC)c(OC)cc32)cc1OC
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(/C=C2/c3cc(OC)c(OC)cc3CCN2C(=O)c2cc(OC)c(OC)c(OC)c2)cc1OC

Procedure:
A suspension of 6 parts of 3,4-dihydro-6,7-dimethoxy-1-[(3,4-dimethoxyphenyl)methylene]isoquinoline and 6 parts of 3,4,5-trimethoxybenzoyl chloride in 50 parts of pyridine is heated at the boiling point under reflux in a nitrogen atmosphere for 45 minutes, whereupon 180 parts of chloroform is introduced. The resultant solution is washed with water, dried over anhydrous sodium sulfate, and stripped of solvent by vacuum distillation. The residue is taken up in benzene; and the benzene solution is chromatographed on silica gel, using benzene and mixtures thereof with increasing amounts of ethyl acetate as developing solvents. From an eluate comprising 30% ethyl acetate in benzene, on evaporation of solvent, (Z)-1,2,3,4-tetrahydro-6,7-dimethoxy-2-(3,4,5-trimethoxybenzoyl)-1-[(3,4-dimethoxyphenyl)methylene]isoquinoline melting at 195°-200° is obtained as the residue.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:2].N1C=CC=CC=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH2:14]([O:13][C:11]([CH:10]1[CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][N:8]([S:23]([CH3:22])(=[O:25])=[O:24])[CH2:9]1)=[O:12])[CH3:15]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C1CNCC1C(=O)OCC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C1CN(S(C)(=O)=O)CC1C(=O)OCC
Reaction time: 2 h
Yield: 57.5 %

Procedure:
To a solution of (3RS,4RS)-pyrrolidine-3,4-dicarboxylic acid diethyl ester (2.04 g, 9.48 mmol) [Bull. Soc. Chim. Fr. 1988, 579] in dichloromethane (30 ml) was added pyridine (1.12 g, 14.22 mmol), N,N-dimethylaminopyridine (10 mg) and methanesulfonyl chloride (1.30 g, 11.38 mmol) and stirred for 2 h at RTThe solution was washed with 0.5 M aqueous HCl and water, dried and evaporated. Flash chromatography (EtOAc/hexane 1:1) gave 1.6 g (42%) of (3RS,4RS)-1-methanesulfonyl-pyrrolidine-3,4-dicarboxylic acid diethyl ester as a colorless solid, MS: 310 (M+NH4)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[C:27]([C:28]([O:30]CC)=O)=[C:26]([CH:33]=O)[N:25]=[C:24]([C:35]4[CH:40]=[CH:39][C:38]([C:41]([O:43][CH3:44])=[O:42])=[CH:37][CH:36]=4)[N:23]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:46][NH2:47]>C(O)C>[CH3:44][O:43][C:41]([C:38]1[CH:39]=[CH:40][C:35]([C:24]2[N:23]=[C:22]([NH:21][C:18]3[CH:17]=[CH:16][C:15]([CH2:14][N:11]4[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]4)=[CH:20][CH:19]=3)[C:27]3[C:28](=[O:30])[NH:47][N:46]=[CH:33][C:26]=3[N:25]=2)=[CH:36][CH:37]=1)=[O:42]
Reactant: NN
Reactant: CCOC(=O)c1c(C=O)nc(-c2ccc(C(=O)OC)cc2)nc1Nc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: CCO
Solvent: O
Product: COC(=O)c1ccc(-c2nc(Nc3ccc(CN4CCN(C(=O)OC(C)(C)C)CC4)cc3)c3c(=O)[nH]ncc3n2)cc1

Procedure:
Ethyl 4-(4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)phenylamino)-6-formyl-2-(4-(methoxycarbonyl)phenyl)pyrimidine-5-carboxylate (0.5 g, 0.82 mmol) was dissolved in ethanol (5 mL), hydrazine hydrate (60 μL, 1.24 mmol) was added and the mixture is refluxed for 2.5 hours. The reaction mixture was cooled to obtain a solid precipitate. The precipitate was filtered and the solid dried under vacuum (0.4 g). 1H NMR (400 MHz, DMSO-d6): δ 13.41 (s, 1H), 11.52 (s, 1H), 8.52 (d, J=8.4 Hz, 2H), 8.34 (s, 1H), 8.13 (d, J=8.8 Hz, 2H), 7.86 (d, J=8.8 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H), 3.90 (s, 3H), 3.51 (s, 2H), 3.29 (t, J=4.4 Hz, 4H), 2.34 (t, J=4.4 Hz, 4H), 1.39 (s, 9H); MS m/z 572.3 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[N:5][N:4]=[N:3]1.C([Li])CCC.[C:13]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[CH3:1][N:2]1[C:6]([CH2:7][C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[OH:20])=[N:5][N:4]=[N:3]1
Reactant: Cc1nnnn1C
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1nnnc1CC(O)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 21.9 %

Procedure:
A solution of 1,5-dimethyltetrazole (20 g; 0.204 mole) in dry THF (200 mL) was cooled to -78° C. and treated with n-butyllithium (91 mL of 2.5 molar solution in hexane; 0.227 mole) and the mixture stirred at -78° C. for 30 minutes. Benzophenone (31.1 g; 0.171 mole) was added and the mixture stirred at -78° C. for 30 minutes and allowed to warm up to 23° C. and stirred for 15 hours. The mixture was quenched with 2N HCl (100 mL) and extracted with EtOAc (3×150 mL). The combined organic layers were dried (MgSO4) and evaporated. The residue was crystallized from EtOAc-Hexane to afford the title compound as a white solid (10.5 g; 22%); m.p.=175°-176° C. (crystallized from EtOAc-hexane). MS (CI): m/e=281 for (M+H)+ ;
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([F:20])[CH:14]=2)=[C:10]([C:21]([OH:23])=[O:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO>[CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([F:20])[CH:14]=2)[C@H:10]([C:21]([OH:23])=[O:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C1=C(c2ccc(Cl)c(F)c2)CN(Cc2ccccc2)C1
Reactant: [H][H]
Solvent: CO
Product: O=C(O)[C@@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)c(F)c1

Procedure:
A 2-l Hastelloy C4 autoclave was charged under argon with 1-benzyl-4-(4-chloro-3-fluoro-phenyl)-2,5-dihydro-1H-pyrrole-3-carboxylic acid (30.0 g, 90.4 mmol), [Ru(OAc)2((R)-2-Furyl-MeOBIPHEP)] (275.5 mg, 0.36 mmol, S/C 250) and methanol (1.2 l). The asymmetric hydrogenation was run for 20 h at 30° C. under 40 bar of hydrogen (99.2% conversion). After the pressure was released, a sample of the white suspension was evaporated to dryness. Crude (S,S)-Id was obtained with 97.9% purity and >99.9% ee.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]([C:18](=O)[CH3:19])[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[CH:4][CH:3]=1.N.C([BH3-])#[N:25].[Na+]>CO.C(O)(=O)C>[NH2:25][CH:18]([CH3:19])[CH:7]([CH2:6][C:5]1[CH:21]=[CH:22][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]
Reactant: [BH3-]C#N
Reactant: CC(=O)C(Cc1ccc(Cl)cc1)C(=O)OCc1ccccc1
Agent: N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(N)C(Cc1ccc(Cl)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
Benzyl 2-(4-chlorobenzyl)-3-ketobutyrate (317 mg, 1 mmole, obtained from Step A) was added to a cooled mixture of 7M ammonia in MeOH (2.42 mL) and glacial acetic acid (1.6 mL). To this solution, at ˜10° C., was added sodium cyanoborohydride (101 mg, 1.75 mmol) in small portions. This mixture was stirred at room temperature for 40 h. The excess sodium cyanoborohydride was destroyed by the addition of 6M HCl (to pH 1). The residue obtained after removal of volatiles was taken up in a minimal amount of water and extracted with ether. The aqueous layer was basified to pH 10 using solid KOH. This layer was then saturated with sodium chloride and then extracted with EtOAc. Further analyses of the ether and the EtOAc layers suggest that the desired product resides the EtOAc layer. This material was used in the ensuing coupling reactions without further purification. Proton NMR spectrum show that the two pairs of diastereomers are obtained in ˜1:1 ratio, homogeneous by TLC, Rf=0.4 in 95:5 CH2Cl2:MeOH. LC/MS m/e=318 (M+1). 400 MHz 1H NMR (CDCl3) δ 1.27, 1.29 (2 d, J=7 Hz, 3H), 2.85 (m, 1H), 3.03 (m, 1H), 3.15 (m, 1H), 3.55 (m, 1H), 4.85 (br, 2H), 5.00-5.18 (m, 2H), 7.0-7.2 (m, 9H).
Reaction SMILES: [CH:1]([NH:3][CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)=[O:6])=[S:2].C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][C:25]([CH3:27])=[O:26]>CCOC(C)=O>[OH:26][C:25]1([CH3:27])[CH2:24][S:2][CH:1]=[N:3][CH:4]1[C:5]([O:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)=[O:6]
Reactant: CC(=O)CCl
Reactant: COc1ccc(COC(=O)CNC=S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COc1ccc(COC(=O)C2N=CSCC2(C)O)cc1
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
A mixture of p-methoxybenzyl N-thioformyl-glycinate (4.79 g., 20 mMols), anhydrous powdered K2CO3 (8.29 g., 60 mMols), Me2CO (50 ml.), and ClCH2COCH3 (2.0 ml., 25 mMols) is stirred in a capped flask at room temperature for 6.5 hrs. The mixture is diluted with EtOAc (100 ml.) and filtered. The filtrate is evaporated in vacuo to an oil which is taken up in Et2O, washed twice with H2O and brine, dried with MgSO4, filtered, and evaporated in vacuo to an orange semi-solid (5.36 g.). The crude product is dissolved in warm PhH (25 ml.) and the solution is left in a refrigerator. The pale yellow crystals of p-methoxybenzyl 5-hydroxy-5-methyl-5,6-dihydro-4H-1,3-thiazine-4-carboxylate (2.23 g.) are collected, washed with cold PhH and petroleum ether, and dried in vacuo: mp 102°-103° C. (micro hot stage); ir (CHCl3) 2.97, 5.82, 6.21, 6.62, 7.97, 8.51, 9.62, and 12.04μ; nmr (CDCl3) δ1.35 (s, 3, CH3), 2.75 (d of d, l, J=12 Hz and J=1Hz, SCH), 3.07 (d, l, J=12Hz, SCH), 3,25 (br s, l, OH), 3.82 (s, 3, OCH3), 4.17 (d of d, l, J=2Hz and J=1Hz, H4), 5.18 (s, 2, CH2Ar), 6.87 and 7.33 (two d's 4, J=9Hz, ArH), and 8.23 (d, l, J=2Hz, H2); mass spectrum m/e 295 (M+), 222, 131, and 121.
Reaction SMILES: CC([O:7][C:8]([C:10]1[N:15]2[C:16]([C@@H:18]([NH:19][C:20](/[C:22](/[C:26]3[O:30][CH:29]=[CH:28][CH:27]=3)=[N:23]\[O:24][CH3:25])=[O:21])[C@H:14]2[S:13][CH2:12][C:11]=1[CH2:31][O:32][C:33]([NH2:35])=[O:34])=[O:17])=[O:9])OC(C)=O.[O-]CC.[Na+].Cl>O1CCCC1.C(O)C>[CH3:25][O:24]/[N:23]=[C:22](\[C:20]([NH:19][C@@H:18]1[C:16](=[O:17])[N:15]2[C:10]([C:8]([OH:9])=[O:7])=[C:11]([CH2:31][O:32][C:33]([NH2:35])=[O:34])[CH2:12][S:13][C@H:14]12)=[O:21])/[C:26]1[O:30][CH:29]=[CH:28][CH:27]=1
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(C)OC(C)=O)=C(COC(N)=O)CS[C@H]12)c1ccco1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1ccco1
Temperature: -60 °C
Reaction time: 1 h

Procedure:
Cefuroxime axetil (20.4 gm, predominantly S-isomer) was dissolved in a mixture of tetrahydrofuran (204 ml) and ethyl alcohol (58 ml). The solution was cooled to −60° C., sodium ethoxide (6.59 gm) was added in portions and the reaction mixture was stirred for 1 hour. Aqueous hydrochloric acid was added and the procedure described in Example 1 was followed to obtain cefuroxime (15.67 gm).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]3[N:20]=[CH:19][N:18]=[C:17]([NH2:21])[CH:16]=3)[CH2:11][CH2:10]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:25]1[S:26][C:27]([C:30]#[N:31])=[CH:28][N:29]=1>>[N:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]3[N:20]=[CH:19][N:18]=[C:17]([NH:21][C:25]4[S:26][C:27]([C:30]#[N:31])=[CH:28][N:29]=4)[CH:16]=3)[CH2:11][CH2:10]2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: Nc1cc(N2CCN(CCN3CCOCC3)CC2)ncn1
Reactant: N#Cc1cnc(Cl)s1
Agent: [H-]
Agent: [Na+]
Product: N#Cc1cnc(Nc2cc(N3CCN(CCN4CCOCC4)CC3)ncn2)s1

Procedure:
6-[4-(2-morpholin-4-ylethyl)piperazin-1-yl]pyrimidin-4-amine 7-4 (1.5 g, 5.13 mmol), sodium hydride (0.41 g, 10.26 mmol) and 2-chloro-1,3-thiazole-5-carbonitrile 2-2 (0.74 g, 5.13 mmol) were treated as in Scheme 4 above. The product was purified on a silica column eluted with DCM:MeOH:NH4OH (95:5:0.5 and 9:1:0.1) and isolated directly from the appropriate fractions after they were concentrated and the residue was suspended in methanol and filtered. 1H-NMR (CDCl3): 9.27 ppm (s, 1H); 8.45 ppm (s, 1H); 7.90 ppm (s, 1H); 5.87 ppm (s, 1H); 3.72 ppm (m, 4H); 3.65 ppm (s, 4H); 2.57 ppm (m, 8H); 2.50 ppm (s, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=1)[CH:9]([C:12]1[CH:13]=[CH:14][C:15]2[CH:16]3[CH2:25][CH2:24][CH2:23][CH:17]3[C:18](=O)[NH:19][C:20]=2[CH:21]=1)[CH2:10][CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:43])=CC=1>C1COCC1>[C:1]([O:5][C:6]([N:8]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=1)[CH:9]([C:12]1[CH:13]=[CH:14][C:15]2[CH:16]3[CH2:25][CH2:24][CH2:23][CH:17]3[C:18](=[S:43])[NH:19][C:20]=2[CH:21]=1)[CH2:10][CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(c1ccc2c(c1)NC(=O)C1CCCC21)N(Cc1cccc(Cl)c1)C(=O)OC(C)(C)C
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CCC(c1ccc2c(c1)NC(=S)C1CCCC21)N(Cc1cccc(Cl)c1)C(=O)OC(C)(C)C

Procedure:
A solution of 260 mg (0.55 mmol) of 7-[1-(N-tert-butoxycarbonyl-3-chlorobenzylamino)propyl]-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one and 597 mg (1.48 mmol) of Lawesson's reagent in 30 ml of THF is refluxed for 1 hour. After concentration by evaporation in a vacuum, the residue is purified by column chromatography with hexane-ethyl acetate: 230 mg of product.
Reaction SMILES: [CH:1]([N:4]1[C:8]2[N:9]=[C:10]([C@H:14]3[C@H:18]([CH3:19])[CH2:17][NH:16][CH2:15]3)[NH:11][C:12](=[O:13])[C:7]=2[CH:6]=[N:5]1)([CH3:3])[CH3:2].[CH3:20][C:21]1[N:22]=[CH:23][C:24]([CH:27]=O)=[N:25][CH:26]=1>>[CH:1]([N:4]1[C:8]2[N:9]=[C:10]([C@H:14]3[C@H:18]([CH3:19])[CH2:17][N:16]([CH2:20][C:21]4[CH:26]=[N:25][C:24]([CH3:27])=[CH:23][N:22]=4)[CH2:15]3)[NH:11][C:12](=[O:13])[C:7]=2[CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: Cc1cnc(C=O)cn1
Reactant: CC(C)n1ncc2c(=O)[nH]c([C@@H]3CNC[C@H]3C)nc21
Product: Cc1cnc(CN2C[C@@H](C)[C@H](c3nc4c(cnn4C(C)C)c(=O)[nH]3)C2)cn1

Procedure:
Following the procedure for the preparation of 1-cyclopentyl-6-[(3,4-trans)-4-methyl-1-(pyridin-3-ylmethyl)pyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting 1-isopropyl-6-[(3S,4S)-4-methylpyrrolidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one and 5-methylpyrazine-2-carbaldehyde provided the title compound. 400 MHz 1H NMR (CDCl3) δ 11.4 (brs, 1H), 8.49 (s, 1H), 8.44 (s, 1H), 7.99 (s, 1H), 5.00-4.93 (m, 1H), 4.00-3.97 (m, 1H), 3.78-3.67 (m, 1H), 3.33 (t, J=8.3 Hz, 1H), 3.04 (d, J=9.9 Hz, 1H), 2.85-2.82 (m, 1H), 2.65-2.61 (m, 1H), 2.49 (s, 3H), 2.48-2.41 (m, 1H), 2.13 (t, J=8.5 Hz, 1H), 1.46 (dd, J=11.6,6.6 Hz, 6H), 1.17 (d, J=7.05 Hz, 3H). MS: (M+H m/z=368.1).
Reaction SMILES: Cl.[CH3:2][N:3]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])=[C:4]1[CH2:20][NH2:21].[C:22]([NH:32][CH2:33][C:34](O)=[O:35])([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>>[CH3:2][N:3]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])=[C:4]1[CH2:20][NH:21][C:34](=[O:35])[CH2:33][NH:32][C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23]
Reactant: Cn1c(CN)c(-c2ccccc2Cl)c2cc(Cl)ccc21
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: Cl
Product: Cn1c(CNC(=O)CNC(=O)OCc2ccccc2)c(-c2ccccc2Cl)c2cc(Cl)ccc21

Procedure:
Using 1-methyl-2-aminomethyl-3-o-chlorophenyl-5-chloroindole hydrochloride and N-carbobenzoxy-glycine, the reaction is effected as in Example 12 (1), whereby 1-methyl-2-(N-carbobenzoxy-glycylaminomethyl)-3-o-chlorophenyl-5-chloroindole is obtained as crystals melting at 96° to 98° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[NH:10][C:11]1([CH3:17])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][N:21]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[CH2:1]([O:8][C:9](=[O:18])[NH:10][C:11]1([CH3:17])[CH2:16][CH2:15][N:14]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][N:21]=2)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc(Cl)nc1
Reactant: CC1(NC(=O)OCc2ccccc2)CCNCC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(NC(=O)OCc2ccccc2)CCN(c2ccc(Cl)cn2)CC1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
To a stirred solution of (4-methyl-piperidin-4-yl)-carbamic acid benzyl ester (0.5 g, 2.02 mmol, Example 30B) in dioxane (5.0 mL) at room temperature was added 2,5-dichloro-pyridine (0.4 g, 2.79 mmol) and diisopropylethyl amine (0.2 mL, 1.1 mmol). The reaction mixture was stirred at 80° C. for 48 hours, concentrated under reduced pressure and purified by flash chromatography with 10% to 40% ethyl acetate in hexane to provide (5′-chloro-4-methyl-3,4,5,6-tetrahydro-2H-(1,2′)bipyridinyl-4-yl)-carbamic acid benzyl ester. MS (CI) m/z 360 (M+1)+; 1H NMR (300 MHz, CDCl3) δ ppm 8.01 (d, 1H), 7.49 (dd, 1H), 7.36-7.27 (m, 5H), 7.26 (m, 1H), 6.78 (d, 1H), 5.04 (s, 2H), 3.82 (m, 2H), 3.21 (m, 2H), 2.15 (m, 2H), 1.58 (m, 2H), 1.35 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([CH2:40][CH2:41][C:42]#[N:43])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:44][CH3:45])=[O:5])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].Cl.[NH2:53][OH:54]>C(O)C>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:27]=[C:28]([C:36]([F:39])([F:37])[F:38])[CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=3)[C:22]([CH2:40][CH2:41][C:42](=[NH:43])[NH:53][OH:54])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:44][CH3:45])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(CCC#N)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(CCC(=N)NO)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 80 °C
Reaction time: 31.5 h
Yield: 56.5 %

Procedure:
(2R,4S)-4-{[3,5-Bis(trifluoromethyl)benzyl]-[5-(2-cyanoethyl)-pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (500 mg) is dissolved in ethanol (5 ml), and thereto are added sodium carbonate (292 mg) and hydroxylamine hydrochloride (192 mg). The mixture is heated at 80° C. and stirred for 31.5 hours. The reaction solution is cooled to room temperature, and partitioned by adding water and ethyl acetate. The organic layer is washed with saturated brine, then dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; chloroform:methanol=1:0→19:1) to give (2R,4S)-4-([3,5-bis(trifluoromethyl)benzyl]-{5-[2-(N-hydroxycarbamimidoyl)ethyl]pyrimidin-2-yl})amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (297 mg) MS (m/z): 670 [M+H]+, and (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-carbamoylethyl)pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (140 mg) MS (m/z): 655 [M+H]+.