Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:26])=[C:12]3[CH:18]=[C:17]([CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:36]([CH3:38])[CH3:37].O>CN(C=O)C>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:26])[C:12]3[CH:18]=[C:17]([CH2:19][N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)[S:16][C:13]=3[N:14]([CH:36]([CH3:38])[CH3:37])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(CN3CCOCC3)cc2c1O
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)sc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 38 %

Procedure:
N-(4-Chlorobenzyl)-4-hydroxy-2-(4-morpholinylmethyl)thieno[2,3-b]pyridine-5-carboxamide (418 mg) from Example No. 41 and potassium carbonate (152 mg) are suspended in DMF (10 mL) and to the mixture is added 2-bromopropane (103 μL). The reaction mixture is stirred at room temperature for 4 h. Additional 2-bromopropane (103 μL) is added and the mixture is heated to 60° C. for 20 h. The reaction mixture is allowed to cool to room temperature, is poured into water (25 mL), and then extracted with EtOAc (3×25 mL). The organic layer is dried (Na2SO4) and concentrated. The resulting crude solid is purified by recrystallization from ethanol to afford 173 mg (38%) of the title compound as a white solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([OH:28])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:29][C:30]([F:41])([F:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C@H:37](O)[CH3:38].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([O:28][C@H:37]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[C:30]([F:29])([F:40])[F:41])[CH3:38])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: C[C@@H](O)c1ccccc1C(F)(F)F
Reactant: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1O[C@@H](C)c1ccccc1C(F)(F)F

Procedure:
In a similar manner as described for example B31, 441 mg of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-hydroxythiophene-2-carboxylate, 300 mg of (1R)-1-[2-(trifluoromethyl)phenyl]ethanol, 672 mg of triphenylphosphine (polymer bound, ˜3 mmol/g) and 484 mg of di-tert-butyl azodicarboxylate in 12 ml anhydrous dichloromethane yield the title compound.
Reaction SMILES: C(=O)([O-])[O-:2].[Na+].[Na+].[CH3:7][C:8]1([CH3:15])[O:14][CH2:13][CH:12]=[CH:11][CH2:10][O:9]1.C(#N)C1C=CC=CC=1.OO>CO>[CH3:7][C:8]1([CH3:15])[O:14][CH2:13][CH:12]2[CH:11]([O:2]2)[CH2:10][O:9]1
Reactant: O=C([O-])[O-]
Reactant: CC1(C)OCC=CCO1
Agent: OO
Agent: [Na+]
Solvent: N#Cc1ccccc1
Solvent: CO
Product: CC1(C)OCC2OC2CO1
Yield: 70 %

Procedure:
To a suspension of sodium carbonate (37 g, 0.35 mole) in a mixture of the dioxepin (II) (158.7 g, 1.26 mole), benzonitrile (127.9 g, 1.26 mole) and methanol (150 ml), was added 30% aqueous hydrogen peroxide (42.2 g, 1.24 mole) during 30 min at such a rate that the temperature stayed below 80°. The mixture was kept at 80° with an oil bath for 2 hr, by which time 99% of the hydrogen peroxide added had reacted. The mixture was decanted and, then, subjected to fractional distillation first at 60 mm, then at 20 mm and finally at 6 mm. The fraction boiling at 75°-85° at 6 mm was refractionated at 6 mm to obtain the product (III) as a colorless liquid. (125.5 g) (70% yield). b.p. 82°-87°/6 mm.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[C:3](=[O:8])[NH:2]2.N1C=CC=CC=1.[C:15](Cl)(=[O:17])[CH3:16].O>C(#N)C>[C:15]([N:2]1[C:3](=[O:8])[CH:4]2[CH2:7][CH:1]1[CH:6]=[CH:5]2)(=[O:17])[CH3:16]
Reactant: CC(=O)Cl
Reactant: O=C1NC2C=CC1C2
Solvent: CC#N
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)N1C(=O)C2C=CC1C2
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 77.8 %

Procedure:
100 g of (±)-2-azabicyclo[2.2.1]hept-5-en-3-one were dissolved in acetonitrile (800 ml) and pyridine (161.26 ml) under nitrogen. At 12° C., 104.5 g of acetyl chloride were added dropwise over the course of 2 hours. The mixture was then stirred at room temperature for 4.5 hours. 800 ml of water were added to the mixture, and the acetonitrile was evaporated off in vacuo. The aqueous phase was extracted 3 times with 400 ml of ethyl acetate. The combined org. phases were washed with 1N HCl (400 ml), water (400 ml), saturated NaCl (400 ml), dried with magnesium sulphate and completely evaporated. The residue was taken up in methylene chloride and filtered through silica gel. The filtrate was concentrated and the product was purified by distillation. 107.76 g of product were obtained as a clear liquid. The yield was 71%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([N+:23]([O-:25])=[O:24])=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1.C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([N+:23]([O-:25])=[O:24])=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:18]=1)=[O:6]
Reactant: COc1ccccc1C(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1C(=O)Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1

Procedure:
2-Methoxy-benzoyl chloride was condensed with 5-Amino-2-nitrobenzotrifluoride in dichloromethane in presence of triethylamine as acid scavenger to yield 2-Methoxy-N-(4-nitro-3-trifluromethyl-phenyl)-benzamide. The reaction mixture was then concentrated in vacuo and the residue was extracted into ethyl acetate. The ethyl acetate layer was washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulphate and finally concentrated in vacuo. The residue obtained was chromatographed over silica gel to afford the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:10][NH:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:25]I.[OH-].[K+].Cl>CS(C)=O.C(OCC)C.O>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:10][N:11]([CH3:25])[C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CI
Reactant: O=C(NCC(c1ccc(Cl)c(Cl)c1)N1CCCC1)c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOCC
Product: CN(CC(c1ccc(Cl)c(Cl)c1)N1CCCC1)C(=O)c1ccccc1
Temperature: 23 °C
Yield: 40.5 %

Procedure:
A solution of N-[2-(3,4-dichlorophenyl)-2-pyrrolidin-1-yl-ethyl]benzamide (260 mg) in dimethylsulfoxide (1.5 mL) and methyl iodide (230 mg) were added to a solution of KOH (190 mg) in dimethylsulfoxide (0.7 mL). The reaction was stirred at 23° C. for 3/4 hour, was poured into water (10 mL), and extracted with dichloromethane (20 mL). The organic layer was washed (brine), dried and evaporated to a gold oil. Chromatography, with ethyl acetate:hexane (50:50 then 75:25) as the eluent, gave an oil, which was dissolved in diethylether and treated with hydrochloric acid (g)/diethylether to provide the title compound as a white solid (60 mg); mp 199-202° C.; MS: m/z=377(M+1); NMR: 1.98 (m,1), 2.12 (m,2), 2.35 (m,1), 2.54 (s,3,), 2.61 (m,1), 3.35 (m,2), 3.88 (t,1), 4.13 (m,1), 4.63 (m,2), 7.2 (dd,1), 7.26 (s,1), 7.53 (d,1), 7.79 (broad s,1), 8.11 (broad s,1), 13.23 (broad s,1). Analysis Calculated: C, 57.43; H, 5.6; N, 6.7; Found: C, 57.59; H, 5.61; N, 6.35.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH:13]([OH:21])[CH:12]2[N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:30]I>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH:13]([O:21][CH3:30])[CH:12]2[N:22]([CH3:27])[S:23]([CH3:26])(=[O:24])=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C1c2cc(OCc3ccccc3)ccc2OC(C)(C)C1O)S(C)(=O)=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1C(N(C)S(C)(=O)=O)c2cc(OCc3ccccc3)ccc2OC1(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
0.5 g (1.3 mmol) of N-(6-benzyloxy-3-hydroxy-2,2-dimethylchroman-4-yl)-N-methyl-methanesulfonamide (Example 1g) dissolved in 4 ml of DMF was added dropwise to a suspension of 0.05 g (1.7 mmol) of sodium hydride in 3 ml of DMF. The mixture was stirred at RT for 30 min, 0.25 g (1.8 mmol) of methyl iodide was added, and the mixture was stirred at RT for another 3 h. The reaction mixture was concentrated under reduced pressure, the residue was taken up in water and EA and the organic phase was washed with dilute hydrochloric acid and saturated sodium bicarbonate solution. Drying over magnesium sulfate and concentration under reduced pressure gave 0.52 g of N-(6-benzyloxy-3-methoxy-2,2-dimethylchroman-4-yl)-N-methyl-methanesulfonamide, m.p. 119-121° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]=[CH:6][N:7]([CH2:9][CH2:10][CH2:11][NH:12][C:13]([CH2:22][CH3:23])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14][CH3:15])[CH:8]=1.[CH3:24][O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>>[CH2:14]([C:13]([NH:12][CH2:11][CH2:10][CH2:9][N:7]1[CH:8]=[C:4]([CH2:3][CH2:2][NH:1][C:30](=[O:31])[C:29]2[CH:33]=[CH:34][C:26]([O:25][CH3:24])=[CH:27][CH:28]=2)[N:5]=[CH:6]1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:22][CH3:23])[CH3:15]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CCC(CC)(NCCCn1cnc(CCN)c1)c1ccccc1
Product: CCC(CC)(NCCCn1cnc(CCNC(=O)c2ccc(OC)cc2)c1)c1ccccc1

Procedure:
3-[4-(2-Aminoethyl) imidazol-1-yl]-N-(1-ethyl-1-phenylpropyl)propylamine (0.5 g) was reacted with 4-methoxybenzoyl chloride (0.29 g) in a similar manner to Example 55 to give N-(2-{1-[3-(1-ethyl-1-phenylpropylamino)propyl]-imidazol-4-yl}ethyl)-4-methoxybenzamide, as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([OH:13])=O)[NH:8]2)=[CH:4][CH:3]=1.[CH3:14][N:15]([CH3:21])[C@H:16]1[CH2:20][CH2:19][NH:18][CH2:17]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:18]3[CH2:19][CH2:20][C@H:16]([N:15]([CH3:21])[CH3:14])[CH2:17]3)=[O:13])[NH:8]2)=[CH:4][CH:3]=1
Reactant: CN(C)[C@H]1CCNC1
Reactant: O=C(O)c1cc2ccc(Cl)cc2[nH]1
Product: CN(C)[C@H]1CCN(C(=O)c2cc3ccc(Cl)cc3[nH]2)C1

Procedure:
The title compound is synthesized by condensation of 6-chloro-1H-indole-2-carboxylic acid and dimethyl-(S)-pyrrolidin-3-yl-amine analogously to the preparation of Example 2 as a colorless solid; ES-MS: M+=292.2; HPLC: AtRet=3.15 min.
Reaction SMILES: C([Li])CCC.CCCCCC.[CH3:12][S:13]([C:16]1[N:17]=[CH:18][N:19]2[CH:23]=[CH:22][S:21][C:20]=12)(=[O:15])=[O:14].[CH2:24]([Sn:28](Cl)([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH3:27].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[CH3:12][S:13]([C:16]1[N:17]=[CH:18][N:19]2[C:23]([Sn:28]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:24][CH2:25][CH2:26][CH3:27])=[CH:22][S:21][C:20]=12)(=[O:14])=[O:15]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CS(=O)(=O)c1ncn2ccsc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC[Sn](CCCC)(CCCC)c1csc2c(S(C)(=O)=O)ncn12
Reaction time: 0.5 h

Procedure:
A 1.6 N n-butyllithium/n-hexane solution (0.7 ml) was added to a solution of 202 mg of 7-methanesulfonylimidazo[5,1-b]thiazole in 20 ml of dry THF in an argon atmosphere at −70° C. The mixture was stirred at the same temperature for 30 min. Tri-n-butylstannyl chloride (0.3 ml) was added thereto. A saturated aqueous ammonium chloride solution was added to the reaction mixture. Ethyl acetate was then added thereto. The mixture was washed with water and saturated brine in that order. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation. The residue was purified by column chromatography on silica gel (hexane:methyl acetate=2:1) to give 110 mg of the title compound.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[H-].[Na+].Cl[C:8]1[C:9]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[N:10][S:11][N:12]=1.O>O1CCCC1>[CH2:1]([O:4][C:8]1[C:9]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[N:10][S:11][N:12]=1)[C:2]#[CH:3]
Reactant: Clc1nsnc1-c1cccnc1
Reactant: C#CCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C#CCOc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.6 %

Procedure:
To a solution of propargyl alcohol (420 mg, 7.5 mmol) and sodium hydride (180 mg, 7.5 mmol) in dry tetrahydrofuran was added a solution of 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (490 mg, 2.5 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 2 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to yield 530 mg (98%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([Cl:18])[CH:12]=2)=[CH:6][C:3]=1[C:4]#N.[CH2:19]([Mg]Br)[CH3:20].C1C[O:26]CC1>>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([Cl:18])[CH:12]=2)=[CH:6][C:3]=1[C:4](=[O:26])[CH2:19][CH3:20]
Reactant: CC[Mg]Br
Reactant: N#Cc1cc(Nc2ccc(F)c(Cl)c2)ccc1N
Reactant: C1CCOC1
Product: CCC(=O)c1cc(Nc2ccc(F)c(Cl)c2)ccc1N
Temperature: 25 °C
Reaction time: 48 h
Yield: 38 %

Procedure:
To a stirred solution of 2-amino-5-[(3-chloro-4-fluorophenyl)amino]benzonitrile (5.90 g, 22.5 mmol) in THF (120 mL) at 0° C. was slowly added ethyl magnesium bromide (80 mL, 80.0 mmol). The solution was stirred at room temperature for 2 days and quenched with 1N HCl. The resulting mixture was made alkaline with sodium bicarbonate solution (sat.) and extracted several times with ethyl acetate. The combined organic layers were dried over magnesium sulfate. Flash silica gel column separation using 20% ethyl acetate/hexane followed by trituration with ether gave 1-{2-amino-5-[(3-chloro-4-fluorophenyl)amino]phenyl}propan-1-one as a yellow solid (2.48 g, 38%). 1H NMR (DMSO-d6): δ 7.78 (s, 1H), 7.48 (d, J=2.5 Hz, 1H), 7.18 (t, J=9.1 Hz, 1H), 7.12 (dd, J=8.8, 2.6 Hz, 1H), 7.04 (s, 2H), 6.81 (m, 1H), 6.79 (d, J=8.8 Hz, 1H), 6.73 (m, 1H), 2.93 (q, J=7.2 Hz, 2H), 1.07 (t, J=7.1 Hz, 3H); MS (ESI) m/z 293/295 ([M+H]+); MS (ESI) m/z 291/293 ([M−H]−); Anal. calcd for C15H14ClFN2O: C, 61.54; H, 4.82; N, 9.57. Found: C, 61.55; H, 4.68; N, 9.47.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:26](OC2C=CC([N+]([O-])=O)=CC=2)=[O:27])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].CCOCC>CN(C)C=O>[C:13]([O:17][C:18]([N:20]1[CH2:21][CH2:22][N:23]([C:26]([N:1]2[CH2:2][CH2:3][CH:4]([C:7]3[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=3)[CH2:5][CH2:6]2)=[O:27])[CH2:24][CH2:25]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: c1cc(C2CCNCC2)ccn1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)N2CCC(c3ccncc3)CC2)CC1
Temperature: 105 °C
Yield: 46.7 %

Procedure:
4-(4-Pyridyl)piperidine (2.44 g) was added to a stirred suspension of 1-t-butoxycarbonyl-4-(4-nitrophenoxycarbonyl)piperazine (5.26 g) in dimethylformamide (90 mL) at 25° C. The reaction mixture was heated at 105° C. for 18 hours. The dimethylformamide was evaporated and water (500 mL) added, The aqueous phase was extracted with ethyl acetate. The organic phase was washed with 1M sodium hydroxide solution (5×100 mL) and saturated brine (2×100 mL), dried and evaporated, The residue was purified by chromatography on silica gel using a mixture of dichloromethane: methanol: 0.88 ammonia (94:5:1) as eluent to give a yellow oil. Trituration with ether gave, as a pale yellow solid, 1-t-butoxycarbonyl-4-[4-(4-pyridyl)-1-piperidylcarbonyl]piperazine (2.62 g); mp 143-4° C.; NMR (CDCl3) 1.44(s, 9H), 1.58-1.78(m, 2H), 1.78-1.92(d, 2H), 2.60-2.75(m, 1H), 2.80-2.96 (m, 2H), 3.92-3.25(t, 4H), 3.38-3.50(m, 4H), 3.82(d, 2H), 7.10(d, 2H), 8.51(d, 2H); EI-MS m/z 375(M+H).
Reaction SMILES: [NH:1]([C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[C@H:2]([C:6]([N:8]1[CH2:29][CH2:28][CH2:27][C@H:9]1[C:10]([NH:12][C@H:13]([C:17]([N:19]1[CH2:26][CH2:25][CH2:24][C@H:20]1[C:21](O)=[O:22])=[O:18])[CH:14]([CH3:16])[CH3:15])=[O:11])=[O:7])[CH:3]([CH3:5])[CH3:4].[CH3:40]N1CCOCC1.[N+](=C)=[N-].[ClH:50]>O1CCOCC1>[NH:1]([C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[C@H:2]([C:6]([N:8]1[CH2:29][CH2:28][CH2:27][C@H:9]1[C:10]([NH:12][C@H:13]([C:17]([N:19]1[CH2:26][CH2:25][CH2:24][C@H:20]1[C:21]([CH2:40][Cl:50])=[O:22])=[O:18])[CH:14]([CH3:15])[CH3:16])=[O:11])=[O:7])[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C(=O)N1CCC[C@H]1C(=O)O
Reactant: CN1CCOCC1
Reactant: Cl
Agent: C=[N+]=[N-]
Solvent: C1COCCO1
Product: CC(C)[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C(=O)N1CCC[C@H]1C(=O)CCl

Procedure:
10 (1.1 g, 2.01 mmol) was treated as described for 13 using CAIBE (0.263 ml, 2.01 mmol), NMM (0.223 ml, 2.02 mmol), diazomethane (10 mmol in 13.3 ml ether) and 5 ml of HCl in dioxane (7.6M).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][CH2:12][CH2:13][OH:14])([O-])=[O:2].Cl.[H][H].[CH3:18][OH:19]>[Pd]>[OH2:2].[OH:14][CH2:13][CH2:12][CH2:11][N:10]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:1][C:18]1=[O:19]
Reactant: O=[N+]([O-])c1ccccc1NCCCO
Reactant: [H][H]
Reactant: CO
Agent: [Pd]
Agent: Cl
Product: O
Product: O=c1[nH]c2ccccc2n1CCCO

Procedure:
A solution of 180 parts of 3-[(2-nitrophenyl)amino]-1-propanol in 200 parts of methanol and 100 parts of a hydrochloric acid solution 10N is hydrogenated at normal pressure and at a temperature at 50° C., in the presence of 5 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen (3 moles) is taken up, hydrogenation is stopped. The catalyst is filtered off and the filtrate is evaporated. The residue (mainly 3-[(2-aminophenyl)amino]-1-propanol hydrochloride) is dissolved in 500 parts of water. To this solution is added a solution of 88.8 parts of potassium isocyanate in 150 parts of water and the whole is stirred and refluxed for 15 hours. The reaction mixture is cooled and the product is extracted with trichloromethane. The extract is dried and evaporated. The residue is dissolved in 250 parts of boiling water, treated with activated charcoal and crystallized at room temperature. The precipitate is filtered off and recrystallized from 400 parts of water, followed by recrystallization from ethyl acetate, yielding 58 parts of 1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one hydrate; mp. 48°-65° C.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]([OH:15])=O)[CH:3]=1.S([O:21][CH3:22])(OC)(=O)=O.[C:23](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:23])=[C:4]([C:13]([O:21][CH3:22])=[O:15])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: COS(=O)(=O)OC
Reactant: O=C(O)c1cc(Br)c2ccccc2c1O
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(Br)c2ccccc2c1OC
Temperature: 25 °C

Procedure:
To a solution of 4-bromo-1-hydroxy-2-naphthoic acid (see Example 1, 1.63 g, 6.10 mmol) in 35 mL of acetone was added dimethyl sulfate (1.75 mL, 18.3 mmol) and potassium carbonate (2.95 g, 21.4 mmol). The reaction was heated to reflux for 14 hours, cooled to room temperature, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-20% ethyl acetate in hexanes to provide methyl 4-bromo-1-methoxy-2-naphthoate that gave a proton NMR spectra consistent with theory.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([S:7][CH3:8])[C:3]=1[C:9]#[N:10].[CH3:11][N:12]=[C:13]=[O:14]>C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC.O1CCCC1>[CH3:11][NH:12][C:13]([NH:1][C:2]1[S:6][N:5]=[C:4]([S:7][CH3:8])[C:3]=1[C:9]#[N:10])=[O:14]
Reactant: CSc1nsc(N)c1C#N
Reactant: CN=C=O
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: C1CCOC1
Product: CNC(=O)Nc1snc(SC)c1C#N
Reaction time: 8 h

Procedure:
A solution of 27.4 g of 5-amino-4-cyano-3-(methylthio)isothiazole, 9.7 g of methyl isocyanate, and 50 drops of dibutyltin diacetate in 150 ml of tetrahydrofuran was heated under reflux during 16 hours. Comparative thin-layer chromatography indicated the reaction to be 50% complete. An additional 10 ml of methyl isocyanate and 20 drops of dibutyltin diacetate were added and the heating continued for eight hours. Comparative thinlayer chromatography indicated that the reaction was still only 50% complete. An additional 10 g of methyl isocyanate were added to the reaction mixture, and the heating was continued overnight. The solid was isolated from the slurry by filtration to give a first crop of 1-methyl-3-(4-cyano-3-(methylthio)-5-isothiazolyl)urea, m.p. 250° (resolidified and m.p. 290°-292°). The filtrate was evaporated to give a tan solid. This solid was recrystallized from ethanol to give a second crop of product. The mother liquor was concentrated to give a third crop. The total yield was 33.4 g of 1-methyl-3-(4-cyano-3-(methylthio)-5-isothiazollyl)urea. Recrystallization from ethanol gave a solid, m.p. 248°-250°, resolidified, m.p. 286°. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: CO[C:3]1[CH:10]=[C:9]([C:11]#[C:12][Si:13]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[C:8]([O:23][CH2:24][CH3:25])=[CH:7][C:4]=1[CH:5]=O.[CH2:26]([O:28][C:29]1[CH:43]=[C:42]([I:44])[C:41]([O:45][CH3:46])=[CH:40][C:30]=1[CH2:31]P(=O)(OCC)OCC)[CH3:27].[H-].[Na+].O1CCC[CH2:50]1>>[CH2:26]([O:28][C:29]1[CH:43]=[C:42]([I:44])[C:41]([O:45][CH3:46])=[CH:40][C:30]=1/[CH:31]=[CH:5]/[C:4]1[C:3]([CH3:50])=[CH:10][C:9]([C:11]#[C:12][Si:13]([CH:14]([CH3:16])[CH3:15])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])=[C:8]([O:23][CH2:24][CH3:25])[CH:7]=1)[CH3:27]
Reactant: CCOc1cc(I)c(OC)cc1CP(=O)(OCC)OCC
Reactant: CCOc1cc(C=O)c(OC)cc1C#C[Si](C(C)C)(C(C)C)C(C)C
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: CCOc1cc(/C=C/c2cc(OC)c(I)cc2OCC)c(C)cc1C#C[Si](C(C)C)(C(C)C)C(C)C

Procedure:
The 2-methoxy-5-ethoxy-4-((tri-iso-propylsilyl)ethynyl)benzaldehyde and diethyl 2-ethoxy-4-iodo-5-methoxybenzylphosphonate can be added to a solution containing sodium hydride (NaH) dissolved in tetrahydrofuran (THF), yielding (E)-(4-(2-ethoxy-4-iodo-5-methoxystyryl)-(2-ethoxy-5-methylphenyl)ethynyl)tri-iso-propylsilane.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][C:15]=3[CH3:23])=[CH:7][C:6]=2[C:5]2[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:4]=2[N:3]=1.S(Cl)([Cl:31])=O>>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([Cl:31])=[O:19])=[CH:16][C:15]=3[CH3:23])=[CH:7][C:6]=2[C:5]2[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:4]=2[N:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(=O)O)cc3C)cc12
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(=O)Cl)cc3C)cc12
Temperature: 25 °C

Procedure:
A solution of 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylbenzoic acid (from the previous step) in thionyl chloride was stirred at 60° C. for 3 hour. After cooling to ambient temperature, the reaction mixture was concentrated en vaccuo. The crude material was used for next step without purification.