Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC1C=CC=CC=1C1SC=C(CC(O)=O)N=1.C([O:19][C:20](=[O:34])[CH2:21][C:22]1[N:23]=[C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=2)[S:25][CH:26]=1)C.[Li+].[OH-]>>[OH:33][C:29]1[CH:28]=[C:27]([C:24]2[S:25][CH:26]=[C:22]([CH2:21][C:20]([OH:34])=[O:19])[N:23]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: CCOC(=O)Cc1csc(-c2cccc(O)c2)n1
Agent: O=C(O)Cc1csc(-c2ccccc2O)n1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)Cc1csc(-c2cccc(O)c2)n1
Yield: 99 %

Procedure:
The procedure used for the preparation of 5a was repeated with 4d (1.84 g, 7.00 mmol) and 2N LiOH (14.0 mL) to provide 5d (1.63 g, 99%) as a white solid, which was recrystallized from EtOAc/toluene. mp 172.0°-174.0° C.; IR (KBr) 3500-2400 (br), 3336 (br), 1689, 1442, 1276, 1231 cm-1 ; 1H NMR (DMSO-d6) δ3.72 (2H, s, CH2), 6.81 (1H, d, J=7.4 Hz, Ar), 7.19-7.30 (3H, m, Ar), 7.43 (1H, s), 9.67 (1H, br s, OH), 12.40 (1H, br s, CO2H); FDMS m/z 236 (M+ +1); Anal. Calcd for C11H9NO3S: C, 56.14; H, 3.86; N, 5.95. Found: C, 56.11; H, 3.73; N, 5.80.
Reaction SMILES: [CH2:1](I)[CH2:2][CH3:3].[O-]CC.[Na+].[CH2:9]([C:11]1[NH:15][N:14]=[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:12]=1)[CH3:10]>C(O)C>[CH2:2]([C:1]1[N:15]([CH2:11][CH2:9][CH3:10])[N:14]=[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:12]=1)[CH3:3]
Reactant: CCCI
Reactant: CCOC(=O)c1cc(CC)[nH]n1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCn1nc(C(=O)OCC)cc1CC
Reaction time: 8 h

Procedure:
Propyl iodide (0.43 mL, 4.46 mmol) and a solution of sodium ethoxide in ethanol (21%, 0.95 g, 3.27 mmol) were added to a solution of ethyl 5-ethyl-1H-pyrazole-3-carboxylate (0.5 g, 2.97 mmol) in ethanol (5 mL) at ambient temperature. The reaction was stirred overnight, and additional propyl iodide (0.05 mL) and sodium ethoxide in ethanol (21%, 0.1 g) were added. After 3 hours, the solvent was removed under reduced pressure and the residue was partitioned between an aqueous sodium chloride solution and methyl tert-butyl ether. The aqueous phase was extracted with methyl tert-butyl ether twice. The organic phases were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield impure ethyl 5-ethyl-1-propyl-1H-pyrazole-3-carboxylate.
Reaction SMILES: O[C:2]1([CH:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH2:5][CH2:4][CH2:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6]([CH2:5][CH2:4][CH:3]=[C:2]2[CH:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)=[CH:7][CH:8]=1
Reactant: COc1ccc2c(c1)C(O)(C1CCN(C)CC1)CCC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: COc1ccc2c(c1)C(C1CCN(C)CC1)=CCC2

Procedure:
A solution of 15 g of the oil obtained in Stage A, in 400 ml of anhydrous dichloromethane, is refluxed for 20 minutes in the presence of 11.4 g of para-toluenesulfonic acid.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:17]([NH:19][C@H:20]([C:31](O)=[O:32])[CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)=[O:18])[CH2:11][C:12]1[N:16]=[CH:15][NH:14][CH:13]=1)=[O:8].[CH3:34][O:35][C:36](=[O:41])[C@H:37]([CH2:39][OH:40])[NH2:38].C(N(CC)CC)C>C(#N)C>[CH3:34][O:35][C:36](=[O:41])[C@H:37]([CH2:39][OH:40])[NH:38][C:31](=[O:32])[C@H:20]([CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)[NH:19][C:17](=[O:18])[C@H:10]([CH2:11][C:12]1[N:16]=[CH:15][NH:14][CH:13]=1)[NH:9][C:7](=[O:8])[C@@H:2]1[CH2:3][CH2:4][C:5](=[O:6])[NH:1]1
Reactant: COC(=O)[C@@H](N)CO
Reactant: O=C1CC[C@@H](C(=O)N[C@@H](Cc2c[nH]cn2)C(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)O)N1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CO)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H]1CCC(=O)N1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
L-Pyroglutamyl-L-histidyl-L-tryptophan (IV) (0.452 g) and L-serine methyl ester (V) hydrochloride (0.155 g) in dry acetonitrile (50 ml) are treated with triethylamine (0.14 ml) and DCI (0.227 g) in dry acetonitrile (5 ml) at 0°C. After stirring at room temperature for 24 hours, the reaction mixture is evaporated to dryness. The residue is dissolved in methanol and the dicyclohexylurea is removed by filtration. The filtrate is concentrated to dryness to L-pyroglutamyl-L-histidyl-L-tryptophyl-L-serine methyl ester (VI).
Reaction SMILES: CN(OC)[C:3]([CH:5]1[CH:10]2[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]2)[CH2:6]1)=[O:4].[H-].C([Al+]CC(C)C)C(C)C.Cl.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH:3]([CH:5]1[CH:10]2[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]2)[CH2:6]1)=[O:4]
Reactant: CON(C)C(=O)C1CN2CCC1CC2
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: O=CC1CN2CCC1CC2
Temperature: -70 °C

Procedure:
(±) 3-(N-Methyl-N-methoxyaminocarbonyl)-1-azabicyclo[2.2.2]octane (D31) (6.0g, 0.03 moles) was dissolved in dry toluene (250ml) and cooled to -70° C. under a nitrogen atmosphere. Diisobutylaluminium hydride (1.5M solution in toluene (45ml, 0.068 moles) was added dropwise. The reaction was then allowed to warm to room temperature over a period of 2h. Hydrochloric acid (2N, 300ml) was added rapidly with vigorous stirring. The aqueous layer was saturated with potassium carbonate and the mixture extracted with chloroform (3×250ml). The combined extracts were dried (Na2SO4) and evaporated to dryness. The residue was distilled in a Kugelrohr to yield the title compound (D32) as a colourless oil (3.6g, 85%) b.p. 100° C. at 1.0
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([Cl:9])[S:8][C:4]=2[CH:3]=1.[CH3:12][C:13]([CH3:15])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C.O>[Cl:9][C:7]1[S:8][C:4]2[CH:3]=[C:2]([NH:1][CH:13]([CH3:15])[CH3:12])[CH:11]=[CH:10][C:5]=2[N:6]=1
Reactant: CC(C)=O
Reactant: Nc1ccc2nc(Cl)sc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Solvent: O
Product: CC(C)Nc1ccc2nc(Cl)sc2c1
Reaction time: 2 h

Procedure:
To a solution of (29) (0.2 mmol, 36.8 mg) in 2 ml dichloroethane was added 0.2 mmol acetone (14.5 μl), followed by 63.6 mg sodium triacetoxyborohydride, and 12 μl acetic acid. After 2 h, the solution was poured into water and extracted with ethyl acetate. The combined extracts were washed with water, dried over sodium sulfate, and the solvent removed by rotary evaporation.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([CH:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[N:5][CH:4]=1)=[O:2].O.O.P([O-])(O)(O)=[O:21].[Na+].CC(=CC)C.Cl([O-])=O.[Na+]>C(O)(C)(C)C.O>[C:13]([O:12][C:11]([NH:10][CH:8]([C:6]1[S:7][C:3]([C:1]([OH:21])=[O:2])=[CH:4][N:5]=1)[CH3:9])=[O:17])([CH3:16])([CH3:15])[CH3:14]
Reactant: O=P([O-])(O)O
Reactant: CC(NC(=O)OC(C)(C)C)c1ncc(C=O)s1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(NC(=O)OC(C)(C)C)c1ncc(C(=O)O)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
A mixture of tert-butyl 1-(5-formylthiazol-2-yl)ethylcarbamate (3.5 g, 0.014 mol), sodium dihydrogen phosphate dihydrate (2.9 g, 0.019 mol) and 2-methyl-2-butene (3.85 g, 0.055 mol) in tert-butyl alcohol (70 ml) and water (40 mL) was stirred at room temperature for 30 minutes. Sodium chlorite (3.22 g, 0.035 mol) was added and the reaction maintained at room temperature for an additional 2 hours. The reaction was concentrated, diluted with water (50 mL) and acidified (pH=4) with the addition of 3N H3PO4. The mixture was extracted with DCM, the organic layer dried over anhydrous Na2SO4 and evaporated to dryness to afford 2-(1-(tert-butoxycarbonylamino)ethyl)thiazole-5-carboxylic acid (2.35 g, 60%). LC-MS: (FA) ES+ 273.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:23][S:22][C@@H:9]2[C@H:10]([NH:13][C:14]([CH2:16][C:17]3[S:21][CH:20]=[CH:19][CH:18]=3)=[O:15])[C:11](=[O:12])[N:8]2[C:7]=1[C:24]([O-:26])=[O:25])=O.[Na+].[CH3:28][N:29]([CH3:39])[C:30](=[O:38])[CH2:31][N:32]1[C:36]([SH:37])=[N:35][N:34]=[N:33]1.[2H]C([2H])([2H])C(C([2H])([2H])[2H])=O>C(O)C>[S:21]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH2:16][C:14]([NH:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:24]([OH:26])=[O:25])=[C:6]([CH2:5][S:37][C:36]3[N:32]([CH2:31][C:30](=[O:38])[N:29]([CH3:28])[CH3:39])[N:33]=[N:34][N:35]=3)[CH2:23][S:22][C@H:9]12)=[O:15]
Reactant: CN(C)C(=O)Cn1nnnc1S
Reactant: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Agent: [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H]
Agent: [Na+]
Solvent: CCO
Product: CN(C)C(=O)Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Yield: 44.1 %

Procedure:
Prepared from sodium cephalothin and N,N-dimethyl-5-mercapto-1H-tetrazol-1-ylacetamide as described in example 12(b) in 44.1% yield; t.l.c. (SiO2 ; B.A.W; 12:3:5) Rf=0.35; λmax (95% ethanol) 271 nm (ε 8,390); δ(free acid) [(CD3)2CO] 2.33 and 3.27 (6H, 2×s -N(CH3)2), 3.85 (2H,s, C2 methylene), 4.00 (2H,s, --CH2CO--), 4.47 (2H,bs, --CH2S--), 5.20 (1H,d, J 5 Hz, C6 proton), 5.55 (2H,s, --CH2CON(CH3)2), 5.97 (1H,dd, J 5 and 9 Hz, C7 proton), 6.9-8.0 (4H,m, thienyl protons and --CO2H), 8.29 (1H,d, J 9 Hz, --CONH--).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:25]=[CH:24][C:12]([CH2:13][N:14]2[CH:18]=[C:17]([C:19](OCC)=[O:20])[N:16]=[N:15]2)=[CH:11][CH:10]=1.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]2[CH:18]=[C:17]([CH2:19][OH:20])[N:16]=[N:15]2)=[CH:24][CH:25]=1
Reactant: CCOC(=O)c1cn(Cc2ccc(OC)cc2)nn1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Cn2cc(CO)nn2)cc1
Yield: 94.2 %

Procedure:
To tetrahydrofuran (THF, 500 ml) was added carefully lithium aluminium hydride (7.3 g) with stirring. The resulting mixture was stirred at 0° C., to which was added dropwise a solution of ethyl 1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate (50.0 g) in THF (500 ml). The resulting mixture was stirred at room temperature for 30 minutes, and the reaction was stopped by careful addition of sodium sulfate decahydrate. The slurry mixture was stirred at room temperature for 2 hours further, filtered to remove solids, and the filtrate was concentrated in vacuo to afford [1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl]methanol (39.51 g, yield: 94%).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:16]=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20])[CH:14]=O.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.[OH-].[Na+]>C(#N)C>[CH3:22][O:21][C:17]1[CH:16]=[C:13]([C:14]2[NH:8][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=3[N:7]=2)[CH:12]=[C:11]([O:10][CH3:9])[C:18]=1[O:19][CH3:20]
Reactant: Nc1ccccc1N
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: COc1cc(-c2nc3ccccc3[nH]2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 14 %

Procedure:
To a solution of 1,2-phenylenediamine (30 mmole, 3.24 g) and 3,4,5-trimethoxybenzaldehyde (30 mmole, 5.89 g) in acetonitrile (75 ml) is added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (30 mmole, 6.81 g), and the mixture is stirred 18 hours at room temperature. Sodium hydroxide (0.5M, 120 ml) is added, and the mixture is stirred over night at room temperature. The dark precipitate is filtered off and is digested with ethanol (30 ml) to give the title product as a brown solid (14%). (R1=hydrogen, R2=3,4,5-trimethoxyphenyl, n=0). 1H-NMR (DMSO, TMS, δ): 3.74 (s, 3H, OCH3), 3.91 (s, 6H, OCH3), 7.20 (m, 2H, ar), 7.54 (s, 2H, ar), 7.61 (m, 2H, ar).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:8]([CH2:32][O:33][CH2:34][CH2:35][O:36][CH3:37])[S:9]([C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[N:29]=[CH:28][CH:27]=[CH:26][N:25]=4)=[CH:20][C:19]=3[CH:30]=[O:31])=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])=[N:4][O:5][C:6]=1[CH3:7].[BH4-].[Na+]>CO>[CH3:1][C:2]1[C:3]([N:8]([CH2:32][O:33][CH2:34][CH2:35][O:36][CH3:37])[S:9]([C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[N:25]=[CH:26][CH:27]=[CH:28][N:29]=4)=[CH:20][C:19]=3[CH2:30][OH:31])=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])=[N:4][O:5][C:6]=1[CH3:7]
Reactant: COCCOCN(c1noc(C)c1C)S(=O)(=O)c1ccccc1-c1ccc(-c2ncccn2)cc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COCCOCN(c1noc(C)c1C)S(=O)(=O)c1ccccc1-c1ccc(-c2ncccn2)cc1CO
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To N-(4,5-dimethyl-3-isoxazolyl)-2'-formyl-N-[(2-methoxyethoxy)methyl]-4'-(2-pyrimidinyl)[1,1'-biphenyl]-2-sulfonamide (460 mg, 0.88 mmol, prepared as described in Step C of Example 16) in 10 ml MeOH, NaBH4 (40 mg, 1.06 mmol) was added. The reaction mixture was stirred at room temperature for 1.5 hrs and concentrated. To the residue, 10 ml H2O and 50 ml EtOAc were added. The organic layer was separated, washed with H2O, brine, dried and concentrated to give N-(4,5-dimethyl-3-isoxazolyl)-2'-(hydroxymethyl)-N-[(2-methoxyethoxy)methyl]-4'-(2-pyrimidinyl)[1,1'-biphenyl]-2-sulfonamide.
Reaction SMILES: [CH:1]1([S:4]([NH:7][CH:8]2[CH2:12][CH:11]([C:13]([O:15]CC)=[O:14])[CH:10]([CH3:18])[CH2:9]2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>>[CH:1]1([S:4]([NH:7][CH:8]2[CH2:12][CH:11]([C:13]([OH:15])=[O:14])[CH:10]([CH3:18])[CH2:9]2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: CCOC(=O)C1CC(NS(=O)(=O)C2CC2)CC1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC1CC(NS(=O)(=O)C2CC2)CC1C(=O)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a flask containing ethyl 4-(cyclopropanesulfonamido)-2-methylcyclopentanecarboxylate (7.5 g, 27.3 mmol) was added aqueous NaOH (1N, 150 mL, 150 mmol). After stirring at ambient temperature for about 5 h, the reaction was acidified to about pH 1 with aqueous 6 N HCl and extracted with DCM (3×100 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give crude 4-(cyclopropanesulfonamido)-2-methylcyclopentanecarboxylic acid containing about 5 mol % DCM (6.6 g, 97%) as a white solid: 1H NMR (DMSO-d6) δ 12.09 (s, 1H), 7.11 (d, J=8.1 Hz, 1H), 3.66-3.53 (m, 1H), 2.78-2.68 (m, 1H), 2.50 (tq, J=5.1, 7.7 Hz, 1H), 2.29-2.17 (m, 1H), 2.17-2.01 (m, 2H), 1.82 (dt, J=9.9, 12.7 Hz, 1H), 1.24 (dt, J=8.9, 12.4 Hz, 1H), 0.98-0.85 (m, 7H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[C:4]([NH2:12])[N:3]=1.[OH-].[K+].[N+:15]([C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[C:20]([C:27]([F:30])([F:29])[F:28])[C:19]=1Cl)([O-:17])=[O:16].Cl>O.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[C:4]([NH:12][C:19]2[C:20]([C:27]([F:29])([F:30])[F:28])=[CH:21][C:22]([N+:24]([O-:26])=[O:25])=[CH:23][C:18]=2[N+:15]([O-:17])=[O:16])[N:3]=1
Reactant: Nc1nc(Cl)ccc1C(F)(F)F
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(C(F)(F)F)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(Nc2nc(Cl)ccc2C(F)(F)F)c(C(F)(F)F)c1
Reaction time: 3 h

Procedure:
In 20 ml. of dimethylformamide, 1.8 g. of 2-chloro-6-amino-5-trifluoromethylpyridine was dissolved and 1.0 g. of powdery potassium hydroxide was gradually added with stirring. After the addition, a solution of 2.7 g. of 2,4-dinitro-6-trifluoromethylchlorobenzene in 10 ml. of dimethylformamide was added dropwise at room temperature and the reaction was continued for about 3 hours. The reaction mixture was acidified with conc. HCl and was poured into water. The precipitate was filtered and recrystallized from methanol to obtain 2.9 g. of the object compound having the melting point of 129° to 131° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:15]=[C:14]3[S:16][C:17]([NH:19][C:20]([CH:22]4[CH2:24][CH2:23]4)=[O:21])=[N:18][C:13]3=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[N:25]([C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=1)=[C:26]=[O:27]>O1CCCC1>[F:8][C:7]1[CH:6]=[CH:5][C:4]([NH:9][C:10]2[N:15]=[C:14]3[S:16][C:17]([NH:19][C:20]([CH:22]4[CH2:23][CH2:24]4)=[O:21])=[N:18][C:13]3=[CH:12][CH:11]=2)=[CH:3][C:2]=1[NH:1][C:26](=[O:27])[NH:25][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:35])([F:37])[F:36])=[CH:30][CH:29]=1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: Nc1cc(Nc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)Nc1cc(Nc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.5 %

Procedure:
N-{5-[(3-Amino-4-fluorophenyl)amino][1,3]thiazolo[5,4-b]pyridin-2-yl}cyclopropanecarboxamide (100 mg, 0.30 mmol) produced in Example 12(v) was dissolved in tetrahydrofuran (10 ml), 1-isocyanato-4-(trifluoromethyl)benzene (84 mg, 0.45 mmol) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10/1) to give the title compound (47 mg, 30%) as a yellow-brown powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:9]1[N:13]([C@H:14]2[O:26][C@@H:25]([CH2:27][O:28]C(=O)C)[C@H:20]([O:21]C(=O)C)[C@@H:15]2[O:16]C(=O)C)[C:12]2[CH:32]=[C:33]([Cl:37])[C:34]([Cl:36])=[CH:35][C:11]=2[N:10]=1.C(O)C>ClCCl>[NH:1]([C:9]1[N:13]([C@H:14]2[O:26][C@@H:25]([CH2:27][OH:28])[C@H:20]([OH:21])[C@@H:15]2[OH:16])[C:12]2[CH:32]=[C:33]([Cl:37])[C:34]([Cl:36])=[CH:35][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: CC(=O)OC[C@@H]1O[C@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Solvent: ClCCl
Solvent: CCO
Product: OC[C@@H]1O[C@H](n2c(Nc3ccccc3)nc3cc(Cl)c(Cl)cc32)[C@@H](O)[C@H]1O
Temperature: 80 °C
Reaction time: 336 h
Yield: 5 %

Procedure:
Aniline (5 ml) and 2-bromo-5,6-dichloro-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole (0.6 g, 1.1 mmol) were combined with absolute ethanol (35 mL) and stirred at 80 ° C. for 14 days. The reaction mixture was concentrated and the aniline was distilled off under high vacuum at 80° C. The brown residue was dissolved in methanol (50 mL) and K2CO3 was added. This solution was stirred for 18 h. The solution was filtered, concentrated and purified on a silica gel column (2.5 cm×16 cm, 230-400 mesh) with 1:15 methanol:dichloromethane to give a white solid (0.024 g, 0.06 mmol, 5%). MS (AP+): m/z (rel. intensity) 410 (19.39, M+1); 1H NMR (DMSO-d6) d 9.09 (s, 1H, NH), 7.83 (s, 1H, Ar-H), 7.78 (d, 1H, Ar-H, J=7.9 Hz), 7.58 (s, 2H, Ar-H), 7.31 (t, 2H, Ar-H, J=7.9 Hz), 6.99 (t, 1H, Ar-H, J=7.5 Hz), 5.95 (d, 1H, H-1', J=7.8 Hz), 5.86 (t, 1H, OH, J=4.4 Hz), 5.38 (d, 1H, OH, J=7.6 Hz), 5.30 (d, 1H, OH, J=4.2 Hz), 4.33 (apparent dd, 1H, H-4', J=13.4 Hz, J=7.8 Hz), 4.11 (apparent t, 1H, H-2', J=4.8 Hz), 4.05 (s, 1H, H-4'), 3.79-3.71 (m, 2H, H-5').
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6](C)[CH2:5][N:4]([CH2:9][C:10]2[S:18][C:17]3[C:16]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[N:15][C:14]([C:25]4[CH:33]=[C:32]([F:34])[CH:31]=[C:30]5[C:26]=4[CH:27]=[CH:28][NH:29]5)=[N:13][C:12]=3[CH:11]=2)[CH2:3]1.C(OC(N1CCNCC1C)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[F:34][C:32]1[CH:31]=[C:30]2[C:26]([CH:27]=[CH:28][NH:29]2)=[C:25]([C:14]2[N:15]=[C:16]([N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[C:17]3[S:18][C:10]([CH2:9][N:4]4[CH2:5][CH2:6][NH:7][CH:2]([CH3:1])[CH2:3]4)=[CH:11][C:12]=3[N:13]=2)[CH:33]=1
Reactant: C[C@@H]1CN(Cc2cc3nc(-c4cc(F)cc5[nH]ccc45)nc(N4CCOCC4)c3s2)C[C@H](C)N1
Agent: CC1CNCCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1CN(Cc2cc3nc(-c4cc(F)cc5[nH]ccc45)nc(N4CCOCC4)c3s2)CCN1

Procedure:
Prepared according to the method used in the preparation of 6-(cis-3,5-dimethyl-piperazin-1-ylmethyl)-2-(6-fluoro-1H-indol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, using 2-methyl-piperazine-1-carboxylic acid tert-butyl ester in place of 2,6-dimethyl-piperazine, followed by BOC-deprotection using TFA:DCM (1:1). The title compound was obtained as a white solid (19.8 mg, 33%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]#[N:8])=[CH:2]1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH:14]=O>>[CH3:9][O:10][C:11]1[CH:12]=[C:13](/[CH:14]=[C:6](/[C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)\[C:7]#[N:8])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]
Reactant: COc1ccc(C=O)cc1OC
Reactant: N#CCc1ccsc1
Product: COc1ccc(/C=C(\C#N)c2ccsc2)cc1OC
Yield: 65.3 %

Procedure:
3-Thiopheneacetonitrile (246 mg) was condensed with 3,4-dimethoxybenzaldehyde (332 mg) through Method B (production step 2), to thereby yield the target product (yield: 354 mg, 65%).
Reaction SMILES: COC1C=CC(C[N:8]2[N:12]=[N:11][C:10]([CH2:13][C@H:14]3[CH2:19][CH2:18][C@H:17]([O:20][C:21]([N:23]4[CH2:32][CH2:31][C:30]5[C:25](=[CH:26][CH:27]=[C:28]([NH:33][C:34]([NH:36][C:37]6[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=6[F:43])=[O:35])[CH:29]=5)[CH2:24]4)=[O:22])[CH2:16][CH2:15]3)=[N:9]2)=CC=1.[H][H]>[C].[Pd].C(O)C>[N:11]1[NH:12][N:8]=[N:9][C:10]=1[CH2:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([O:20][C:21]([N:23]2[CH2:32][CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[C:28]([NH:33][C:34]([NH:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[F:43])=[O:35])[CH:29]=3)[CH2:24]2)=[O:22])[CH2:16][CH2:15]1
Reactant: [H][H]
Reactant: COc1ccc(Cn2nnc(C[C@H]3CC[C@H](OC(=O)N4CCc5cc(NC(=O)Nc6ccccc6F)ccc5C4)CC3)n2)cc1
Agent: [Pd]
Solvent: CCO
Product: O=C(Nc1ccc2c(c1)CCN(C(=O)O[C@H]1CC[C@H](Cc3nn[nH]n3)CC1)C2)Nc1ccccc1F

Procedure:
An ethanol (6 mL) suspension of trans-6-[3-(2-fluoro-phenyl)-ureido]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-[2-(4-methoxy-benzyl)-2H-tetrazol-5-ylmethyl]-cyclohexyl ester (333 mg) obtained in Example (44e) and palladium carbon (55 mg) was stirred at room temperature for 3 days in a hydrogen atmosphere. The reaction mixture was filtered through Celite and concentrated. The residue was purified by column chromatography (dichloromethane/ethyl acetate=5:1→1:1 and then dichloromethane/methanol=25:1→5:1) to obtain the title compound (22 mg, 8%) as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]([CH3:25])[CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:26]([O:28][CH3:29])=[O:27])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:36][CH2:37]I>CN(C)C=O.O>[CH2:36]([N:22]1[CH2:23][CH2:24][CH:19]([N:18]([CH3:25])[C:17]2[NH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:26]([O:28][CH3:29])=[O:27])[CH:14]=3)[NH:9][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:20][CH2:21]1)[CH3:37]
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N(C)C3CCNCC3)nc2c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1CCC(N(C)C2=C(c3ccc(F)cc3)Nc3ccc(C(=O)OC)cc3N2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.9 %

Procedure:
To a solution of methyl 2-(4-fluorophenyl)-3-[methyl(piperidin-4-yl)amino]quinoxaline-6-carboxylate (100 mg, 0.25 mmol) in N,N-dimethylformamide (30 mL) was added potassium carbonate (157.6 mg, 1.14 mmol) and CH3CH2I (71.32 mg, 0.46 mmol), and the reaction mixture was stirred overnight at room temperature. The reaction mixture was then diluted with water (200 mL) and extracted with dichloromethane (4×50 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (1% methanol in dichloromethane) to afford methyl 3-[(1-ethylpiperidin-4-yl)(methyl)amino]-2-(4-fluorophenyl)-1,4-dihydroquinoxaline-6-carboxylate as light yellow oil (53 mg, 46%).