Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[CH:9][C:7]=1[NH2:8].CO[C:19](=O)[CH2:20][C:21](=[O:28])[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1>>[CH3:16][O:15][C:10]1[C:11]([O:13][CH3:14])=[CH:12][C:6]2[C:2]3[N:3]([CH2:4][CH2:5][N:1]=3)[C:19](/[CH:20]=[C:21](/[C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)\[OH:28])=[N:8][C:7]=2[CH:9]=1
Reactant: COc1cc(N)c(C2=NCCN2)cc1OC
Reactant: COC(=O)CC(=O)c1cccnc1
Product: COc1cc2c(cc1OC)C1=NCCN1C(/C=C(\O)c1cccnc1)=N2
Reaction time: 1 h
Yield: 28.1 %

Procedure:
A mixture of 2-(4,5-dihydro-1H-imidazol-2-yl)-4,5-dimethoxyaniline (0.15 g, 0.68 mmol) and methyl-3-oxo-3(3-pyridinyl)propanoate (0.20 g, 1.12 mmol) was stirred at 155 for 1 hour. The reaction mixture was purified by column chromatography on silica-gel (dichloromethane/ methanol, 25/1) to give (Z)-2-(8,9-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1-(3-pyridinyl)ethenol (66.9 mg, 28%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:20][CH2:19][CH2:18][N:17]([CH3:21])[CH2:16][CH2:15]1)[CH:5]=O.[C:22]([C:26]1[CH:27]=[C:28]([NH2:33])[C:29]([NH2:32])=[CH:30][CH:31]=1)([CH3:25])([CH3:24])[CH3:23]>>[C:22]([C:26]1[CH:31]=[CH:30][C:29]2[NH:32][C:5]([C:4]3[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][CH2:13][N:14]4[CH2:20][CH2:19][CH2:18][N:17]([CH3:21])[CH2:16][CH2:15]4)=[C:2]([Cl:1])[CH:3]=3)=[N:33][C:28]=2[CH:27]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CN1CCCN(CCCOc2ccc(C=O)cc2Cl)CC1
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Product: CN1CCCN(CCCOc2ccc(-c3nc4cc(C(C)(C)C)ccc4[nH]3)cc2Cl)CC1
Yield: 34.1 %

Procedure:
This compound was prepared by the method described in Example 1, using 3-chloro-4-[3-(4-methyl-[1,4]diazepan-1-yl)-propoxy]-benzaldehyde (62 mg, 0.20 mmol, 1.0 equiv), 4-tert-butyl-benzene-1,2-diamine (33 mg, 0.20 mmol, 1.0 equiv), and Na2S2O5 (50 mg, 0.26 mmol, 1.3 equiv) in General Procedure 3. Purification by Method 2 afforded 31 mg (34%) of the title compound. MS (electrospray): mass calculated for C26H35ClN4O, 454.25; m/z found, 455.3 [M+H]+. 1H NMR (400 MHz, CD3OD): 8.12 (d, J=2.2 Hz, 1H), 7.98 (dd, J=8.6, 2.3 Hz, 1H), 7.6 (s, 1H), 7.52 (d, J=8.5 Hz, 1H), 7.37 (dd, J=8.6, 1.8 Hz, 1H), 7.22 (d, J=8.7 Hz, 1H), 4.19 (t, J=6.0 Hz, 2H), 2.84-2.74 (m, 10H), 2.40 (s, 3H), 2.08-1.97 (m, 2H), 1.90-1.83 (m, 2H), 1.41 (s, 9H).
Reaction SMILES: [Li+].CC(O[Al-](OC(C)(C)C)OC(C)(C)C)(C)C.[C:18]1([C:26](OCC)=[O:27])([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:20][CH2:19]1>C1COCC1.C(Cl)Cl>[CH2:24]([O:23][C:21]([C:18]1([CH2:26][OH:27])[CH2:20][CH2:19]1)=[O:22])[CH3:25]
Reactant: CCOC(=O)C1(C(=O)OCC)CC1
Agent: CC(C)(C)O[Al-](OC(C)(C)C)OC(C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)C1(CO)CC1
Reaction time: 4 h
Yield: 97.4 %

Procedure:
A solution of lithium aluminum-tri-tert-butoxyhydride 1.0M in THF (28.5 mL, 28.5 mmol) is added to a solution of diethyl 1,1-cyclopropanedicarboxylate (2.0 mL, 11.4 mmol) in anhydrous THF (85.0 mL). After stirring the reaction mixture for 4 h, 10 mL of lithium aluminum-tri-tert-butoxyhydride 1.0M solution in THF is added and the solution is stirred for 18 h. The reaction mixture is diluted with DCM, washed with 1N aqueous HCl solution, saturated aqueous NaHCO3 solution and brine. After drying the organic phase over anhydrous Na2SO4, removal of the solvent under reduced pressure affords 1.60 g of 1-hydroxymethyl-cyclopropanecarboxylic acid ethyl ester that is used in the next step without further purification. Yield: 85%. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.88 (2H, q, J=4.1 Hz), 1.21-1.33 (5H, m), 2.59 (1H, t, J=6.9 Hz), 3.63 (2H, d, J=7.2 Hz), 4.17 (2H, q, J=7.1 Hz).
Reaction SMILES: [Cl:1][CH2:2][CH2:3]SC1C=CC(C(O)=O)=CC=1.Cl[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([O:23]O)=[O:22])[CH:16]=1.[S:25]([O-:29])([O-])(=[O:27])=S.[Na+].[Na+]>C(Cl)Cl.O>[Cl:1][CH2:2][CH2:3][S:25]([C:20]1[CH:19]=[CH:18][C:17]([C:21]([OH:23])=[O:22])=[CH:16][CH:15]=1)(=[O:29])=[O:27]
Reactant: O=S([O-])([O-])=S
Reactant: O=C(O)c1ccc(SCCCl)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(O)c1ccc(S(=O)(=O)CCCl)cc1
Temperature: -10 °C

Procedure:
4-(2-Chloroethylsulfanyl)-benzoic acid (18.4 mmol) is suspended in methylene chloride (60 ml) and cooled to −10C. m-Chloroperbenzoic acid (38.6 mmol) are added dropwise in methylene chloride (60 ml) and the mixture is stirred for e hours at −10° C. The mixture is diluted methylene chloride (100 ml) and a 5% solution of sodium thiosulfate in water is added and the mixture vigorously stirred. The mixture is extracted, washed with water and and dried over sodium sulfate and evaporated. The crude product is recrystallized from ethylacetate and the solid filtered of and dried (vacuum). 2.19 g of a pale powder with mp. 142-144° C., Rf=0.37 (CH2Cl2/MeOH=9:1) is obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Cl:15])=[CH:10][CH:9]=2)=[O:5])C.Br[CH2:17][C:18]1[C:19]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:20]=2[S:21][CH:22]=1>>[Cl:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:17][C:18]1[C:19]3[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:20]=3[S:21][CH:22]=1)[C:6]([C:4]([OH:3])=[O:5])=[CH:14]2
Reactant: Fc1ccc2scc(CBr)c2c1
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2[nH]1
Product: O=C(O)c1cc2cc(Cl)ccc2n1Cc1csc2ccc(F)cc12

Procedure:
Using general procedure B, 5-chloro-1H-indole-2-carboxylic acid ethyl ester was coupled with 3-bromomethyl-5-fluoro-benzo[b]thiophene (Lit. 18) and the product obtained was hydrolyzed to give the title compound as white solid. MS: 358.1 ([M−H]−).
Reaction SMILES: C([O:3][CH:4]1[CH:8]([NH:9][C:10]([CH2:12][N:13]2[C:19](=[O:20])[CH:18]([NH:21][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:17][S:16](=[O:31])(=[O:30])[CH2:15][CH2:14]2)=[O:11])[CH2:7][C:6](=[O:32])[O:5]1)C.FC(F)(F)C(O)=O>C(#N)C.O>[OH:3][CH:4]1[CH:8]([NH:9][C:10]([CH2:12][N:13]2[C:19](=[O:20])[CH:18]([NH:21][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:17][S:16](=[O:31])(=[O:30])[CH2:15][CH2:14]2)=[O:11])[CH2:7][C:6](=[O:32])[O:5]1
Reactant: CCOC1OC(=O)CC1NC(=O)CN1CCS(=O)(=O)CC(NC(=O)c2ccccc2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: O=C(CN1CCS(=O)(=O)CC(NC(=O)c2ccccc2)C1=O)NC1CC(=O)OC1O
Reaction time: 3 h

Procedure:
A solution of N-{4-[(2-ethoxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl)-methyl]-1,1,5-trioxo-1λ6-[1,4]thiazepan-6-yl}-benzamide, 45, (0.03 g, 0.05 mmol) in acetonitrile/water is treated with trifluoroacetic acid. After stirring for 3 hours the solution is concentrated in vacuo and the crude product purified by preparative reverse phase HPLC to afford 0.02 g (77% -yield) of the desired product as a white solid.) 1H NMR (CD3OD): δ 7.90 (m, 2H), 7.62–7.46 (m, 3H), 5.46 (d, J=10.5 Hz, 1H), 4.61 (m, 1H), 4.51 (dd, J=16.3, 5.1 Hz, 1H), 4.36 (m, 2H), 4.02 (dd, J=16.0, 3.3 Hz, 1H), 3.84–3.64 (m, 3H), 3.42 (m, 1H), 3.26 (m, 1H), 2.68 (m, 1H), 2.52 (m, 1H); ESI MS 440.06 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[N:13]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[N:12]=[CH:11][CH:10]=2)=[C:5]([CH3:22])[N:4]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[C:3]1=[O:33].[S:34](=O)(=[O:37])([OH:36])[OH:35].O.C(OCC)(=O)C>C(#N)C>[C:18]([C:17]1[CH:16]=[CH:15][C:14]([N:13]2[C:9]([C:6]3[C:7](=[O:8])[N:2]([CH3:1])[C:3](=[O:33])[N:4]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[CH:24]=4)[C:5]=3[CH3:22])=[C:10]([S:34]([OH:37])(=[O:36])=[O:35])[CH:11]=[N:12]2)=[CH:21][CH:20]=1)#[N:19]
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: O=S(=O)(O)O
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1c(-c2c(S(=O)(=O)O)cnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
To a suspension of the compound prepared in Example 1 (2.0 g) in acetonitrile (20 ml) was added concentrated sulfuric acid (1.08 ml) and the resulting mixture was stirred with heating under reflux for three hours. The reaction mixture was cooled to room temperature and thereto were added water (40 ml) and ethyl acetate (40 ml×1, 20 ml×1) such that the intended products were extracted into an organic layer. The organic layer was washed with saturated saline (20 ml), dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. To the residue was added chloroform (10 ml) and the resulting mixture was stirred at 60° C. for thirty minutes. The mixture was stirred at room temperature overnight and the precipitated crystals were collected by filtration and washed with chloroform to afford 1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonic acid (2.06 g).
Reaction SMILES: [CH3:1][N:2](S(C1C=CC=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[Cl:23][C:24]1[C:29]([C:30]#[N:31])=[CH:28][CH:27]=[CH:26][N:25]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C1C(Cl)=CC=C(Cl)C=1>[Cl:11][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:12])[C:5]=1[C:4]1[N:31]=[C:30]([C:29]2[C:24]([Cl:23])=[N:25][CH:26]=[CH:27][CH:28]=2)[N:2]([CH3:1])[N:3]=1
Reactant: N#Cc1cccnc1Cl
Reactant: CN(N=C(Cl)c1c(Cl)cccc1Cl)S(=O)(=O)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccc(Cl)cc1
Product: Cn1nc(-c2c(Cl)cccc2Cl)nc1-c1cccnc1Cl
Yield: 37.3 %

Procedure:
In 50 ml of dichlorobenzene were dissolved 5.7 g of N-methyl-N-phenylsulfonyl-2,6-dichloro-benzohydrazonoyl chloride and 2.3 g of 2-chloro-3-cyanopyridine, to which was added 2.2 g of anhydrous aluminum chloride at room temperature with stirring. The resulting solution was raised to 120°-140° C. in an oil bath and stirred for 4 hours. After the completion of the reaction, the reaction solution was washed with a diluted alkali solution and further with a diluted hydrochloric acid solution. After the washing with water, the organic layer was dried over anhydrous magnesium sulfate and concentrated under a reduced pressure. The resulting concentrate was subjected to a chromatography of silica gel (trade mark: Wakogel C-200) using a mixed solution of hexane and ethyl acetate as a developing solvent to obtain 1.9 g (yield: 37.3%) of a desired light brown granular crystal (melting point: 133.0°-135.5° C.).
Reaction SMILES: O[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([P:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1.P(Cl)(Cl)[Cl:28]>C(Cl)(Cl)Cl>[Cl:28][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([P:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1
Reactant: ClP(Cl)Cl
Reactant: Oc1nccc(-c2cccc(P(c3ccccc3)c3ccccc3)c2)n1
Solvent: ClC(Cl)Cl
Product: Clc1nccc(-c2cccc(P(c3ccccc3)c3ccccc3)c2)n1
Yield: 90 %

Procedure:
5 mmol of 20 are dissolved in 50 ml of CHCl3 and mixed with 10 mmol of PCl3. It is refluxed for 30 min, the volatiles are removed in a vacuum and the colorless solid is washed with water. Recrystallization from chloroform gives 21 in a yield above 90%. ESI MS, m/z (%): 375.8154 (100) [M+H]+. 31P{1H} NMR (101.2 MHz, 25° C., DMSO-d6): δ −7.40.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#N)=[C:9]([O:15][CH3:16])[CH:8]=2)=[C:4]([O:19][C:20]([F:23])([F:22])[F:21])[CH:3]=1.[OH-:24].[K+].C(O)CO.[OH2:30]>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]([OH:30])=[O:24])=[C:9]([O:15][CH3:16])[CH:8]=2)=[C:4]([O:19][C:20]([F:23])([F:22])[F:21])[CH:3]=1
Reactant: O
Reactant: [OH-]
Reactant: COc1cc(Oc2ccc(Cl)cc2OC(F)(F)F)ccc1C#N
Agent: [K+]
Solvent: OCCO
Product: COc1cc(Oc2ccc(Cl)cc2OC(F)(F)F)ccc1C(=O)O
Temperature: 120 °C

Procedure:
To a solution of 4-[4-chloro-2-(trifluoromethoxy)phenoxy]-2-methoxybenzonitrile (Preparation 103, 230 mg, 0.66 mmol) in 10 mL of ethylene glycol/water (8:2) was added KOH flakes (380 mg, 6.6 mmol). The reaction mixture was heated to 120° C. for 64 hours. After cooling to room temperature the residue was partitioned between EtOAc (80 mL) and water (75 mL), the aqueous layer was separated, acidified with 2M HCl and extracted with EtOAc (2×50 mL). The organic layers were combined, dried over MgSO4 and evaporated in vacuo to yield 167 mg of the title compound as yellow oil.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:13]=[C:12]([CH:14]=[O:15])[N:11]([CH3:16])[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.[C:17]([O-:20])([O-])=[O:18].[K+].[K+].BrCC(OC(C)(C)C)=O>CC#N.C(Cl)Cl.FC(C(O)=O)(F)F>[CH:14]([C:12]1[N:11]([CH3:16])[CH:10]=[C:9]([S:6]([NH:5][CH2:1][C:17]([OH:20])=[O:18])(=[O:8])=[O:7])[CH:13]=1)=[O:15]
Reactant: O=C([O-])[O-]
Reactant: Cn1cc(S(=O)(=O)NC(C)(C)C)cc1C=O
Agent: CC(C)(C)OC(=O)CBr
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC#N
Product: Cn1cc(S(=O)(=O)NCC(=O)O)cc1C=O
Reaction time: 8 h

Procedure:
A solution of 0.8 g (3.3 mmol) N-(tert-butyl)-5-formyl-1-methyl-1H-pyrrole-3-sulfonamide, 1.2 g (9.8 mmol) K2CO3 and 1.4 g (7.2 mmol) tert-butyl bromoacetate in CH3CN was heated at reflux overnight Solvent was removed, and the residue was partitioned between EtOAc and water. The organic layer was separated and washed with brine. Drying (MgSO4) and removal of solvent gave an oil that was chromatographed by normal phase (100% CH2Cl2 followed by gradient elution to 20 EtOAc in CH2Cl2) to give material that was dissolved in 2 mL 1:1 CH2Cl2-TFA with stirring overnight. Solvent was removed to give the title compound as a solid, 1H NMR (DMSO) δ 9.6 (s, 1H), 7.4 (s, 1H), 7.2 (s, 1H), 4.1 (s, 3H), 3.9 (s, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]([N:15]([CH2:17][CH:18]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=2[CH3:35])[CH2:19][CH2:20][O:21]C2CCCCO2)[CH3:16])=[O:14])[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1)#[N:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+].C(Cl)Cl>CO>[C:1]([C:3]1[CH:4]=[C:5]([C:13]([N:15]([CH2:17][CH:18]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=2[CH3:35])[CH2:19][CH2:20][OH:21])[CH3:16])=[O:14])[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1)#[N:2]
Reactant: Cc1cc(F)ccc1C(CCOC1CCCCO1)CN(C)C(=O)c1cc(C#N)cc2c1CCCC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(F)ccc1C(CCO)CN(C)C(=O)c1cc(C#N)cc2c1CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.4 %

Procedure:
3-Cyano-N-[2-(4-fluoro-2-methylphenyl)-4-(tetrahydro-2H-pyran-2-yloxy)butyl]-N-methyl-5,6,7,8-tetrahydronaphthalene-1-carboxamide (460 mg, 0.96 mmol) was dissolved in methanol (10 mL) together with 4-toluenesulfonic acid (37 mg, 0.2 mmol) and the solution was stirred at room temperature overnight. An aqueous solution of NaHCO3 together with CH2Cl2 was added and the organic solution was then washed with brine, dried and the solvent removed by evaporation. There was obtained 350 mg (92%) of 3-cyano-N-[2-(4-fluoro-2-methylphenyl)-4-hydroxybutyl]-N-methyl-5,6,7,8-tetrahydronaphthalene-1-carboxamide as an oil. 1H NMR (300 MHz, CDCl3): 1.0-2.3 (cm, 6H), 2.4 (s, 3H), 2.6 (s, 3H), 2.7-4.5 (cm, 10H), 6.4-7.4 (cm, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:33]1([NH2:36])[CH2:35][CH2:34]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:36][CH:33]3[CH2:35][CH2:34]3)=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: NC1CC1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(Cn1c(-c2ccc(Cl)cc2)nc2cccnc21)NC1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.5 %

Procedure:
Under nitrogen bubbling, a mixture of 2-(4chlorophenyl)-3H-imidazo [4,5-b]pyridine-3-acetic acid (4.0 g, 0.014 mole) and 1,1'-carbonyldiimidazole (2.27 g, 0.014 mole) in 150 ml of tetrahydrofuran was stirred at room temperature for 3 hours. Then, under nitrogen atmosphere, cyclopropylamine (2.40 g, 0.042 mole) was added and the reaction mixture was allowed to stir at room temperature overnight. The tetrahydrofuran was evaporated and the residue was recrystallized from isopropyl alcohol with refrigeration. The solid was collected by filtration, washed with cold isopropyl alcohol and water, and dried under high vacuum at 50° C. over the weekend to give 2.4 g (53%) of title compound, mp 231°-232° C.
Reaction SMILES: [CH2:1]([S:8][C:9]1[S:19][C:12]2=[N:13][C:14](I)=[CH:15][C:16](=[O:17])[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:20]#[N:21].[Na+]>CN(C)C=O.O>[CH2:1]([S:8][C:9]1[S:19][C:12]2=[N:13][C:14]([C:20]#[N:21])=[CH:15][C:16](=[O:17])[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: O=c1cc(I)nc2sc(SCc3ccccc3)nn12
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(=O)n2nc(SCc3ccccc3)sc2n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 44.5 %

Procedure:
In 120 ml of dimethylformamide, 9 g of 90% pure 2-benzylthio-7-iodo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was dissolved, and 3.05 g of cuprous cyanide and 1.57 g of sodium cyanide were added thereto. The reaction mixture was heated to 100° C. and stirred at that temperature for 1 hour. After the reaction was finished, the reaction mixture was cooled, diluted with water and extracted with chloroform. The organic layer was washed with water, and the chloroform was distilled off. Water was added to the residue and the mixture was extracted with toluene. The organic layer was washed with water and dried over anhydrous sodium sulfate. Florisil® was added to the dried organic layer, and the organic layer was shaken well. After the Florisil® was separated, the solvent was distilled off, and thus 3.0 g of 2-benzylthio-7-cyano-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained. Yield 50%. (Florisil® (a registered trademark of Floridin Company) is a highly selective magnesium silicate absorbent.)
Reaction SMILES: [CH3:1][C:2]1[S:11][C:5]2[CH2:6][NH:7][CH2:8][CH:9]([OH:10])[C:4]=2[CH:3]=1.[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1F>>[ClH:12].[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[O:10][CH:9]1[CH2:8][NH:7][CH2:6][C:5]2[S:11][C:2]([CH3:1])=[CH:3][C:4]1=2
Reactant: Fc1cccc(Cl)c1Cl
Reactant: Cc1cc2c(s1)CNCC2O
Product: Cc1cc2c(s1)CNCC2Oc1cccc(Cl)c1Cl
Product: Cl

Procedure:
The same method as in Example 3 was conducted using 2-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 8) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 2,3-dichloro-1-fluorobenzene instead of 1,3-difluorobenzene to give the objective compound.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:18]=[C:19]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:30]I.O>CN(C=O)C.C(OCC)(=O)C>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:18]=[C:19]([N:23]([CH3:30])[S:24]([CH3:27])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CI
Reactant: CS(=O)(=O)Nc1cccc(C=C2c3ccccc3CCc3ccccc32)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1cccc(C=C2c3ccccc3CCc3ccccc32)c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
Dissolve N-[3-(10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-phenyl]-methanesulfonamide (10 mg, 0.265 mmol) in DMF (4 mL) and add NaH (13 mg of a 60% suspension in mineral oil, 0.318 mmol). Stir at room temperature for 50 min, then add MeI (33□L, 75 mg, 0.530 mmol). Stir at room temp for 1 h. Dilute reaction mixture with H2O and ethyl acetate. Separate layers, and wash organics with H2O. Dry organics (MgSO4) and concentrate to 101 mg (100%) of a pale yellow solid, mp 124.2° C. 1H NMR (CDCl3) δ 2.53 (s, 3H), 2.72-3.54 (br m, 4H), 6.74 (s, 1H), 6.78 (s, 1H), 6.91-7.43 (m, 11H); MS (ES) 412 (M+Na). HPLC shows 97% purity.
Reaction SMILES: [CH2:1]([N:3](CC)CC)[CH3:2].Cl.C(=N)(OCC)C.[NH:15]1[CH2:20][CH2:19][CH:18]([CH2:21][O:22][C:23]2[CH:24]=[C:25]([O:30][S:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[Cl:40])(=[O:33])=[O:32])[CH:26]=[C:27]([CH3:29])[CH:28]=2)[CH2:17][CH2:16]1>CN(C)C=O>[ClH:40].[C:1]([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][O:22][C:23]2[CH:24]=[C:25]([O:30][S:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[Cl:40])(=[O:32])=[O:33])[CH:26]=[C:27]([CH3:29])[CH:28]=2)[CH2:17][CH2:16]1)(=[NH:3])[CH3:2]
Reactant: CCN(CC)CC
Reactant: Cc1cc(OCC2CCNCC2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Agent: CCOC(C)=N
Agent: Cl
Solvent: CN(C)C=O
Product: CC(=N)N1CCC(COc2cc(C)cc(OS(=O)(=O)c3ccccc3Cl)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
Triethylamine (0.5 mL) and ethyl acetimidate hydrochloride (247 mg, 2.0 mmol) were added to a solution of 2-chlorobenzenesulfonic acid 3-[(piperidin-4-yl)methoxy]-5-methylphenyl ester (396 mg, 1.0 mmol), as prepared in the preceding step, in N,N-dimethylformamide (10 mL). The reaction mixture was stirred at room temperature overnight. The N,N-dimethylformamide was removed in vacuo and the residue partitioned between methylene chloride (200 mL) and 10% K2CO3 (50 mL). The organic phase was washed with 10% K2CO3 (2×50 mL) and dried over K2CO3. The solvent was removed in vacuo, HCl-methanol (30 mL) was added, and the solution was concentrated in vacuo. The residue was crystallized from methanol-ethyl acetate to give the title compound as white crystals (405 mg, 86%). 1H-NMR (300 MHz, DMSO-d6) δ 1.30 (m, 2 H), 1.82 (d, 2 H, J=7.0 Hz), 2.05 (m, 1 H), 2.20 (s, 3 H), 2.29 (s, 3 H), 3.16 (m, 2 H), 3.77 (d, 2 H, J=3.0 Hz), 3.92 (d, 1 H, J=6.5 Hz), 4.17 (d, 1 H, J=6.5 Hz), 6.46 (d, 1 H, J=2.5 Hz), 6.49 (s, 1 H), 7.59 (t, 1 H, J=8.0 Hz), 7.87 (m, 2 H), 7.95 (d, 1 H, J=8.0 Hz), 8.77 (br s, 1 H), and 9.35 (br s, 1 H). Mass spectrum (MALDI-TOF, sinapinic acid matrix) calcd. for C21H25N2O4SCl: 437.1 (M+H). Found: 436.8.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[CH:13]=[C:12]([O:14][C:15]3[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=3[C:17]([OH:19])=O)[CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1.C(N(CC)CC)C.C([Cl:36])(=O)OCC.[NH2:37][CH2:38][CH2:39][C:40]1[N:44]=[CH:43][NH:42][CH:41]=1>C1COCC1>[ClH:36].[ClH:36].[NH:42]1[CH:41]=[C:40]([CH2:39][CH2:38][NH:37][C:17](=[O:19])[C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[O:14][C:12]2[CH:11]=[CH:10][N:9]=[C:8]([NH:7][C:4]3[S:5][CH:6]=[C:2]([CH3:1])[N:3]=3)[CH:13]=2)[N:44]=[CH:43]1
Reactant: NCCc1c[nH]cn1
Reactant: CCOC(=O)Cl
Reactant: Cc1csc(Nc2cc(Oc3ccccc3C(=O)O)ccn2)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1csc(Nc2cc(Oc3ccccc3C(=O)NCCc3c[nH]cn3)ccn2)n1
Product: Cl
Yield: 101.3 %

Procedure:
Using the method of Example 32, 2-(2-(4-methylthiazol-2-ylamino)pyridin-4-yloxy)benzoic acid (0.1 g, 0.3055 mmol), triethylamine (0.2129 mL, 1.527 mmol), ethyl carbonochloridate (0.03213 mL, 0.3360 mmol), and histamine (0.1019 g, 0.9164 mmol) were reacted in THF (2 mL) to provide N-(2-(1H-imidazol-4-yl)ethyl)-2-(2-(4-methylthiazol-2-ylamino)pyridin-4-yloxy)benzamide dihydrochloride (0.084 g, 55.17% yield). 1H NMR (CDCl3) δ 8.38 (s, 1H), 8.08 (d, 1H), 7.76 (d, 1H), 7.51 (t, 1H), 7.39 (t, 1H), 7.06 (s, 1H), 7.02 (m, 2H), 6.89 (s, 1H), 6.55 (m, 2H), 3.81 (m, 2H), 3.16 (m, 2H), 2.45 (s, 3H); Mass spectrum (esi) m/z=421 (100) (M+H).