Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:11][C:10]([NH2:12])=[N:9][C:8]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:5][N:4]=[N:3]1.[C:19](Cl)(=[O:23])[CH:20]([CH3:22])[CH3:21]>>[CH3:1][N:2]1[C:6]([C:7]2[S:11][C:10]([NH:12][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])=[N:9][C:8]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[N:5][N:4]=[N:3]1
Reactant: CC(C)C(=O)Cl
Reactant: Cn1nnnc1-c1sc(N)nc1-c1ccccc1
Product: CC(C)C(=O)Nc1nc(-c2ccccc2)c(-c2nnnn2C)s1

Procedure:
Prepared from 5-(1-methyl-1H-tetrazol-5-yl)-4-phenyl-thiazol-2-ylamine and isobutyryl chloride.
Reaction SMILES: Br[C:2]([CH3:11])([CH3:10])[C:3]([NH:5][C:6]([NH:8][CH3:9])=[O:7])=[O:4].[Na+].[C:13]([O:16][CH2:17][C:18]1[CH2:19][S:20][C@@H:21]2[C@H:28]([NH:29][C:30](=[O:39])/[C:31](/[C:34]3[O:35][CH:36]=[CH:37][CH:38]=3)=[N:32]\[OH:33])[C:27](=[O:40])[N:22]2[C:23]=1[C:24]([O-:26])=[O:25])(=[O:15])[CH3:14].CCO>CS(C)=O>[C:13]([O:16][CH2:17][C:18]1[CH2:19][S:20][C@@H:21]2[C@H:28]([NH:29][C:30](=[O:39])/[C:31](/[C:34]3[O:35][CH:36]=[CH:37][CH:38]=3)=[N:32]\[O:33][C:2]([C:3]([NH:5][C:6]([NH:8][CH3:9])=[O:7])=[O:4])([CH3:11])[CH3:10])[C:27](=[O:40])[N:22]2[C:23]=1[C:24]([OH:26])=[O:25])(=[O:15])[CH3:14]
Reactant: CNC(=O)NC(=O)C(C)(C)Br
Reactant: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)/C(=N\O)c3ccco3)[C@H]2SC1
Agent: [Na+]
Solvent: CCO
Solvent: CS(C)=O
Product: CNC(=O)NC(=O)C(C)(C)O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1ccco1
Yield: 76 %

Procedure:
This compound was prepared from 1-(2-bromo-2-methylpropionyl)-3-methylurea and (6R,7R)-3-acetoxymethyl-7-[Z-2-(fur-2-yl)-2-hydroxyiminoacetamido]-ceph-3-em-4-carboxylic acid sodium salt by the method described in Example 1. [α]D22 +84.6° (c 0.65, DMSO), λmax (EtOH) 274 nm (ε 16,900), νmax (Nujol) 3340 (NH), 3700-2100 (bonded OH), 1790 (β-lactam), 1740 (OCOCH3), 1700 (CO2H), 1690, 1540 cm-1 (--CONH--, --CONHCONH--), τ (DMSO d6) 2.25, 3.2, 3.35 (fur-2-yl), 8.51, 8.52 (C(Me)2), 0.5 (--CONHCO), 1.75 (CONHMe), 7.28 (CONHMe), 4.1 (7 H), 4.75 (6 H), 6.28, 6.50 (2 CH2), 4.97, 5.29 (3 CH2), 7.9 (OCOCH3). Yield: 76%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:13]([CH2:23][O:24]CC3C=CC(OC)=CC=3)=[N:12][C:11]=2[CH:34]([CH3:36])[CH3:35])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(O)C.Cl>CO>[Cl:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:13]([CH2:23][OH:24])=[N:12][C:11]=2[CH:34]([CH3:36])[CH3:35])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: COc1ccc(COCc2nc(C(C)C)c(Sc3cc(Cl)cc(Cl)c3)n2CCc2ccccn2)cc1
Agent: Cl
Solvent: CO
Solvent: CCO
Product: CC(C)c1nc(CO)n(CCc2ccccn2)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 51.3 %

Procedure:
To 1.43 g of 5-(3,5-dichlorophenylthio)-4-isopropyl-2-(p-methoxybenzyloxymethyl)-1-(2-(2-pyridyl)ethyl)-1H-imidazole was added 20 ml of ethanol and 40 ml of 36% hydrochloric acid, and the mixture was stirred at 90° C. for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, an aqueous sodium hydrogen carbonate solution was added, and extracted with ethyl acetate. The extract was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate:methanol=10:1)to give 571 mg of 5-(3,5-dichlorophenylthio)-4-isopropyl-2-hydroxymethyl-1-(2-(2-pyridyl)ethyl)-1H-imidazole (112a)(yield 51%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[CH:25][CH:24]=1)[C@@H:3]([OH:21])[CH2:4][C@@H:5]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:35][O:36][C:37]([NH:39][C@@H:40]([C:44]([CH3:47])([CH3:46])[CH3:45])[C:41](O)=[O:42])=[O:38].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH2:6]([C@H:5]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])[CH2:4][C@H:3]([OH:21])[C@@H:2]([NH:1][C:41](=[O:42])[C@@H:40]([NH:39][C:37]([O:36][CH3:35])=[O:38])[C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[CH:25][CH:24]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@@H](N)Cc1ccc(-c2ccccn2)cc1
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.6 %

Procedure:
A solution containing the product from Example 23Q (0.442 g, 0.95 mmol) in THF (10 mL) was treated with the product from Example 1F (0.20 g, 1.06 mmol), DEPBT (0.45 g, 1.50 mmol), and N,N-diisopropylethylamine (0.85 mL, 4.88 mmol), stirred at 25° C. for 1 hour, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-75% ethyl acetate/dichloromethane to give the title compound (0.34 g, 56% yield).
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:12][C:11](=[O:13])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[CH2:1]([O:8][C@@H:9]1[CH2:12][C@H:11]([OH:13])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC(OCc2ccccc2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O[C@H]1C[C@@H](OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 91.8 %

Procedure:
A mixture of 3-benzyloxycyclobutan-1-one (0.92 g, 5.22 mmol) (Ogura et al., Bull. Chem. Soc. Jpn., 1984, 57, 1637-1642) and sodium borohydride (0.20 g, 5.29 mmol) in ethanol (15 ml) was stirred at room temperature for 3.5 h. The mixture was filtered, washing with ethanol, and the filtrate was concentrated. Filtration through a plug of silica, eluting with ethyl acetate, gave cis-3-benzyloxy-1-hydroxycyclobutane (0.854 g, 92%) as a colourless oil; 1H NMR (250 MHz, CDCl3) δ1.75-2.00 (2H, m), 2.65-2.79 (2H, m), 3.62 (1H, qn, J=7 Hz), 3.90 (1H, broad qn, J=7 Hz), 4.41 (2H, s), 7.23-7.47 (5H, m).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Br:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[C:20]([O:22][CH3:23])=[O:21])[C:14]([OH:16])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.[NH:49]1[C:57]2[CH:56]=[CH:55][CH:54]=[C:53]([CH2:58][NH2:59])[C:52]=2[CH:51]=[CH:50]1.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:23][O:22][C:20](=[O:21])[C:19]1[CH:18]=[CH:17][C:13]([C:14]([NH:59][CH2:58][C:53]2[CH:54]=[CH:55][CH:56]=[C:57]3[C:52]=2[CH:51]=[CH:50][NH:49]3)=[O:16])=[CH:12][C:11]=1[Br:10]
Reactant: NCc1cccc2[nH]ccc12
Reactant: COC(=O)c1ccc(C(=O)O)cc1Br
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)NCc2cccc3[nH]ccc23)cc1Br
Temperature: 25 °C
Reaction time: 24 h
Yield: 70 %

Procedure:
Diisopropylethylamine (2.3 mL, 13.2 mmol) was added dropwise to a solution of 3-bromo-4-(methoxycarbonyl)benzoic acid (Example 76; 861 mg, 3.32 mmol), O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (1.39 g, 3.65 mmol), 1H-indole-4-methanamine hydrochloride salt (Example 68; 528 mg, 3.98 mmol) and 1-hydroxybenzotriazole (493 mg, 3.65 mmol) in N,N-dimethylformamide (6.5 mL) at 0° C. The solution was allowed to warm to room temperature and then was stirred for 24 h. After the reaction mixture was concentrated under vacuum to remove most of the N,N-dimethylformamide, the residue was diluted with ethyl acetate (50 mL) and washed with 1N hydrochloric acid solution (10 mL), water (10 mL), saturated aqueous sodium bicarbonate solution (10 mL) and brine (10 mL). The organic layer was dried (MgSO4), filtered, evaporated and the residue was chromatographed (silica gel, 25-35% ethyl acetate in petroleum ether) to provide 2-bromo-4-[[[(1H-indol-4-yl)methyl]amino]carbonyl]benzoic acid methyl ester (900 mg, 70% yield) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([C:15]3[CH:20]=[CH:19][N:18]=[N:17][CH:16]=3)[CH:9]=2)=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].C(=O)([O-])[O-].[K+].[K+].[Cl:31][C:32]1[C:33](F)=[CH:34][C:35]([F:58])=[C:36]([S:38]([N:41]([CH2:47][C:48]2[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][C:49]=2[O:56][CH3:57])[C:42]2[S:43][CH:44]=[N:45][N:46]=2)(=[O:40])=[O:39])[CH:37]=1>CS(C)=O>[Cl:31][C:32]1[C:33]([O:14][C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:21]([F:22])([F:24])[F:23])[CH:4]=3)=[CH:9][C:10]=2[C:15]2[CH:20]=[CH:19][N:18]=[N:17][CH:16]=2)=[CH:34][C:35]([F:58])=[C:36]([S:38]([N:41]([CH2:47][C:48]2[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][C:49]=2[O:56][CH3:57])[C:42]2[S:43][CH:44]=[N:45][N:46]=2)(=[O:39])=[O:40])[CH:37]=1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Reactant: Oc1ccc(-c2ccc(Cl)c(C(F)(F)F)c2)cc1-c1ccnnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(-c4ccc(Cl)c(C(F)(F)F)c4)cc3-c3ccnnc3)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
4′-Chloro-3-(pyridazin-4-yl)-3′-(trifluoromethyl)biphenyl-4-ol (Preparation 56, 88 mg, 0.25 mmol) was dissolved in DMSO (1 mL), potassium carbonate (69 mg, 0.5 mmol) was added followed by 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide (Preparation 16, 127 mg, 0.27 mmol). The reaction was stirred at room temperature for 3 hours and then partitioned between ethyl acetate (50 mL) and water (50 mL). The organic phase was separated and washed with water (2×50 mL), dried over MgSO4, filtered and evaporated. The crude product was chromatographed on silica eluting with a gradient of heptane:ethyl acetate 100:0 to 20:80 to give the title compound (135 mg, 0.17 mmol, 69%) as a white solid.
Reaction SMILES: [NH2:1][CH:2]([CH:7]([OH:23])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:3]([O:5][CH3:6])=[O:4].C(N(CC)CC)C.[C:31](Cl)(=[O:47])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]>C1C=CC=CC=1>[C:31]([NH:1][CH:2]([CH:7]([OH:23])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:3]([O:5][CH3:6])=[O:4])(=[O:47])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]
Reactant: CCCCCCCCCCCCCCCC(O)C(N)C(=O)OC
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCC(=O)NC(C(=O)OC)C(O)CCCCCCCCCCCCCCC
Reaction time: 3 h
Yield: 87 %

Procedure:
10.7 g (0.033 mole) of methyl 2-amino-3-hydoxyoctadecanoate prepared according to Example 1 are dissolved in 200 cm3 of dry benzene and then 3.28 g of triethylamine are added. 8.92 g (0.033 mole) of palmitoyl chloride dissolved in 60 cm3 of benzene are added dropwise to this solution between 20 and 35° C. After 3 hours' stirring, the triethylamine hydrochloride is removed by filtration at 40° C. The organic phase is washed twice with 100 cm3 of water. The benzene solution is dried over sodium sulphate and then part of the benzene is removed by evaporation. 16.3 g of methyl 2-hexadecanoylamino-3-hydroxyoctadecanoate are isolated by crystallization.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[F:6][C:7](=[C:12]([F:14])[F:13])[CH2:8][C:9](Cl)=[O:10]>C(OCC)(=O)C>[F:6][C:7](=[C:12]([F:14])[F:13])[CH2:8][C:9]([N:1]1[CH:5]=[N:4][CH:3]=[N:2]1)=[O:10]
Reactant: c1nc[nH]n1
Reactant: O=C(Cl)CC(F)=C(F)F
Solvent: CCOC(C)=O
Product: O=C(CC(F)=C(F)F)n1cncn1
Yield: 94.2 %

Procedure:
To a solution of 1,2,4-triazole (1.38 g, 20 mmol) in ethyl acetate (100 mL) was added 3,4,4-trifluoro-3-butenoyl chloride (1.59 g, 10 mmol) at r.t. with stirring. The mixture was stirred for 30 min and filtered. The residue obtained after evaporation of the solvent was redissolved in dichloromethane (25 mL) and filtered. Evaporation of the solvent gave 1.8 g (94%) of the desired product as a clear oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14]([O:16]C)=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-:3])=[O:2].[Li+].[OH-]>CO.O>[N+:1]([C:4]1[CH:5]=[C:6]([C:14]([OH:16])=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-:3])=[O:2]
Reactant: COC(=O)c1cc([N+](=O)[O-])cc2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc([N+](=O)[O-])cc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
To methyl 3-nitro-1-naphthoate (2.5 g, 0.011 mole) (Aldrich) in MeOH/H2O (40 ml) (1:1) was added LiOH (1.8 g, 4 equivalents). The solution was stirred overnight at room temperature. The solvent was removed under a stream of N2. The residue was dissolved in H2O and the solution acidified with concentrated HCl. The resulting precipitate was filtered, washed with H2O and dried to yield 3-nitro-1-naphthoic acid (2.18 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2=[O:12].O1C2=CC3C(=O)C(=O)NC=3C=C2OCC1.Br[CH:29]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.BrCC1OC(C(F)(F)F)=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH:29]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:8](=[O:11])[C:7]2=[O:12]
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: O=C1Nc2c(F)cccc2C1=O
Agent: FC(F)(F)c1ccc(CBr)o1
Agent: O=C1Nc2cc3c(cc2C1=O)OCCO3
Product: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2c(F)cccc21

Procedure:
Following the procedure as described in PREPARATION 26A and making non-critical variations using 7-fluoroisatin to replace 2,3-dihydro-6H-[1,4]dioxino[2,3-f]indole-7,8-dione, and bromodiphenylmethane to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, 7-fluoro-1-(diphenylmethyl)-1H-indole-2,3-dione was obtained (80%): MS (ES+) m/z 353.7 (M+23).
Reaction SMILES: [C:1]([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:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:24])=[CH:18][CH:17]=1)#[N:2].[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35]>C(O)C.O1CCCC1.[C].[Pd]>[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35].[NH2:2][CH2:1][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:17]=[CH:18][C:19]([NH:22][C:23]([NH:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:24])=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccccc4)cc3)c2cc1C#N
Agent: [Pd]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccccc4)cc3)c2cc1CN
Reaction time: 8 h

Procedure:
After dissolving the N-[4-(6-cyano-7-methoxyquinolin-4-yloxy)phenyl]-N′-phenylurea (100 mg) synthesized in Example 37 in an ethanol (5 ml) and tetrahydrofuran (5 ml) mixed solvent, there were added trifluoroacetic acid (0.5 ml) and 50% palladium-carbon (50 mg), and the mixture was stirred overnight under a hydrogen atmosphere. After filtering off the palladium carbon, the filtrate was concentrated. The obtained residue was washed with tetrahydrofuran to obtain the title compound (70 mg).
Reaction SMILES: [N:1]1([CH:6]2[CH2:10][CH2:9][C:8](=[O:11])[CH2:7]2)[CH:5]=[CH:4][CH:3]=[N:2]1.[BH4-].[Na+].Cl.C([O-])(O)=O.[Na+]>CO>[N:1]1([C@@H:6]2[CH2:10][CH2:9][C@H:8]([OH:11])[CH2:7]2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=C1CCC(n2cccn2)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Product: O[C@H]1CC[C@@H](n2cccn2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.9 %

Procedure:
To a solution of 3-(1H-pyrazol-1-yl)cyclopentan-1-one (14.09 g, 93.8 mmol) in MeOH (150 ml) was added portionwise NaBH4 (1.77 g. 46.8 mmol) at 0° C., and stirred for 30 min at room temperature. The reaction mixture was poured into 0.5M HCl and basified with sat. NaHCO3 aq. and then extracted with CH2Cl2. The organic layer was dried over anhyd Na2SO4 followed by the removal of solvent. The crude product was purified by column chromatography (Hexane/EtOAc=2/1→1/1) to yield cis-3-(1H-pyrazol-1-yl)cyclopentanol (10.41 g, 73%) as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[N:21]1[CH:26]=[CH:25][N:24]=[CH:23][C:22]=1[C:27](Cl)=[O:28].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:16][CH2:17][N:18]([C:27]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][N:21]=3)=[O:28])[CH2:19][CH2:20]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=C(Cl)c1cnccn1
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)c2cnccn2)CC1
Reaction time: 2 h
Yield: 70.7 %

Procedure:
1-(5-Chloro-8-piperazin-1-ylquinolin-7-yl)ethanone (0.030 g, 0.10 mmol, from Example 47, Step 1) was combined with pyrazine-2-carbonyl chloride (0.022 g, 0.16 mmol) and triethylamine (0.043 mL, 0.31 mmol) in methylene chloride (1.0 mL) at room temperature and stirred for 2 hours. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4, concentrated and purified on silica gel (eluting with 0 to 5% methanol in dichloromethane) to give the desired product (28 mg, 68%). LCMS calculated for C20H19ClN5O2 (M+H)+: m/z=396.1; Found: 396.1.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH:6]2[CH:8]([C:9]3[NH:17][C:16]4[C:15](=[O:18])[N:14]([CH2:19][CH2:20][CH3:21])[C:13](=[O:22])[N:12]([CH2:23][CH2:24][CH3:25])[C:11]=4[N:10]=3)[CH:3]1[CH2:4][CH2:5]2.[BH4-].[Na+]>CO>[OH:1][CH:2]1[CH2:7][CH:6]2[CH:8]([C:9]3[NH:17][C:16]4[C:15](=[O:18])[N:14]([CH2:19][CH2:20][CH3:21])[C:13](=[O:22])[N:12]([CH2:23][CH2:24][CH3:25])[C:11]=4[N:10]=3)[CH:3]1[CH2:4][CH2:5]2
Reactant: CCCn1c(=O)c2[nH]c(C3C4CCC3C(=O)C4)nc2n(CCC)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCn1c(=O)c2[nH]c(C3C4CCC3C(O)C4)nc2n(CCC)c1=O

Procedure:
8-(2-Oxo-bicyclo[2.2.1]hept-7-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (200 mg) was reduced using NaBH4 (44 mg) in MeOH (10 ml). Yield 120 mg. Mass (ES+ 347).
Reaction SMILES: [CH2:1]([O:3][CH:4]=[CH:5][Sn](CCCC)(CCCC)CCCC)[CH3:2].[NH2:19][C:20]1[N:36]=[C:35]([CH2:37][O:38][CH3:39])[CH:34]=[CH:33][C:21]=1[C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29](Br)=[CH:28][CH:27]=1)=[O:23].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[F-].[K+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN1CCCC1=O>[NH2:19][C:20]1[N:36]=[C:35]([CH2:37][O:38][CH3:39])[CH:34]=[CH:33][C:21]=1[C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29](/[CH:5]=[CH:4]\[O:3][CH2:1][CH3:2])=[CH:28][CH:27]=1)=[O:23]
Reactant: COCc1ccc(C(=O)NCc2ccc(Br)cc2)c(N)n1
Reactant: CCCC[Sn](C=COCC)(CCCC)CCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN1CCCC1=O
Product: CCO/C=C\c1ccc(CNC(=O)c2ccc(COC)nc2N)cc1
Temperature: 125 °C
Reaction time: 1 h
Yield: 40.7 %

Procedure:
A mixture of (2-ethoxy-vinyl)-tributyl-stannane (37 mg, 0.10 mmol) synthesized according to WO02/018368, 2-amino-N-(4-bromo-benzyl)-6-methoxymethyl-nicotinamide (30 mg, 0.086 mmol) described in Preparation Example A+-23, tri-o-tolylphosphine (6.5 mg, 0.021 mmol), palladium acetate (0.96 mg, 0.0043 mmol), tetrabutylammonium chloride (24 mg, 0.086 mmol) and N-methylpyrrolidinone (1 mL) was stirred at 125° C. for 1 hour. The reaction solution was allowed to cool, an aqueous solution of potassium fluoride was added on an ice bath, the solution was filtered through Celite pad. The filtrate was partitioned with ethyl acetate. The organic layer was separated, washed with brine, then, evaporated in vacuo. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=1:2), and the title compound (12 mg, 0.035 mmol, 35%) was obtained as a colorless solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([OH:12])[CH:6]=[C:7]([CH3:11])[C:8]=1[N:9]=O)[CH3:2].C.[H][H]>O1CCCC1.[Pd]>[CH2:1]([C:3]1[CH:4]=[C:5]([OH:12])[CH:6]=[C:7]([CH3:11])[C:8]=1[NH2:9])[CH3:2]
Reactant: CCc1cc(O)cc(C)c1N=O
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCc1cc(O)cc(C)c1N

Procedure:
88.7 g (537.6 mmol) of the 3-ethyl-4-nitroso-5-methylphenol prepared in stage 1 are catalytically hydrogenated in 1 liter of tetrahydrofuran (THF) with molecular hydrogen under 5 bar at 20°-25° C. 10 g of 5% palladium on active charcoal (Pd-C) are used as catalyst. The hydrogen uptake is 77% of theory. The catalyst is filtered off, the filtrate is evaporated and the residue is recrystallised from methanol. Yield 51.2 g (63.2% of theory); melting point 167°-170° C.
Reaction SMILES: N12CCCNC1=NCCC2.[CH3:11][C:12]1[CH:24]=[CH:23][C:15]([CH:16]=[C:17]([CH2:21]C)[N+]([O-])=O)=[CH:14][CH:13]=1.[CH2:25]([O:27][C:28](=[O:32])[CH2:29][N+:30]#[C-:31])[CH3:26]>C(O)(C)C.C1COCC1>[CH2:25]([O:27][C:28]([C:29]1[NH:30][CH:31]=[C:17]([CH3:21])[C:16]=1[C:15]1[CH:23]=[CH:24][C:12]([CH3:11])=[CH:13][CH:14]=1)=[O:32])[CH3:26]
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: CCC(=Cc1ccc(C)cc1)[N+](=O)[O-]
Agent: C1CN=C2NCCCN2C1
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CCOC(=O)c1[nH]cc(C)c1-c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
1,5,7-Triazabicyclo[4.4.0]dec-5-ene on polystyrene (5.36 g, 2.6 mmol/g, 13.9 mmol) was added to a reaction mixture of 4-methyl-β-ethyl-β-nitrostyrene (1.23 g, 6.94 mmol) and isocyanoacetic acid ethyl ester (788 mg, 6.90 mmol) in isopropanol (5 mL) and THF (5 mL) and the reaction mixture was stirred overnight at RT under nitrogen as protective gas. The reaction mixture was filtered out and the residue washed with isopropanol and THF. The desired product 4-methyl-3-p-tolyl-1H-pyrrole-2-carboxylic acid ethyl ester (1.42 g, 85% of theoretical) was obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:18]3[S:19][C:20]([CH2:22][O:23][CH3:24])=[CH:21][C:17]=3[O:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:25]>>[ClH:25].[CH3:24][O:23][CH2:22][C:20]1[S:19][C:18]2[C:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[N:15][O:16][C:17]=2[CH:21]=1
Reactant: COCc1cc2onc(C3CCN(C(=O)OC(C)(C)C)CC3)c2s1
Agent: Cl
Product: COCc1cc2onc(C3CCNCC3)c2s1
Reaction time: 8 h

Procedure:
Stir a solution of 4-(5-methoxymethyl-thieno[2,3-d]isoxazol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (2.21 g, 6.68 mmol, 1.00 equivalents) and hydrochloric acid (1.0 M in diethly ether, 35 mL) overnight to form a suspension. Add additional hydrochloric acid (1.0 M in diethyl ether, 10 mL). Stir the suspension overnight, filter and wash the solid with ether. Collect the solid and dry to yield the desired product as a dark blue solid. LC/MS (ESI), m/e 253 (MH+), retention time 1.17 minutes. Condition II.