Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7]([I:13])=[CH:8][CH:9]=2)[O:4][C:3]=1[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:16]([O:30][CH3:31])[CH:15]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:40](Cl)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>CC(C)=O>[CH2:40]([O:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7]([I:13])=[CH:8][CH:9]=2)[O:4][C:3]=1[C:14]1[CH:15]=[C:16]([O:30][CH3:31])[C:17]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:18]([O:20][CH3:21])[CH:19]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: ClCc1ccccc1
Reactant: COc1cc(-c2oc3cc(I)ccc3c(=O)c2O)cc(OC)c1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(-c2oc3cc(I)ccc3c(=O)c2OCc2ccccc2)cc(OC)c1OCc1ccccc1
Yield: 103.3 %

Procedure:
A stirring suspension of 3-hydroxy-7-iodo-(4-benzyloxy-3,5-dimethoxyphenyl)-chromen-4-one (5 g, 9 mmol), potassium carbonate (6.2 g, 45 mmol, 4.8 equ), potassium iodide (0.64 A, 4 mmol, 0.4 equ) and benzyl chloride (1.7 ml, 15 mmol, 1.6 equ) in acetone (150 ml) under nitrogen was heated to reflux for 19 hours. The reaction was filtered and the filtrate concentrated in vacuo to give an cream solid. This solid was recrystallised from isopropanol to give 35 (5.77 g, 99%) as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=2)[C:10]([C:18](=[O:22])[C:19]([OH:21])=[O:20])=[C:9]1[CH2:23]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K].[C:26]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:38]3[CH:39]=[CH:40][C:35]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:36][CH:37]=3)=[CH:14][CH:15]=2)[C:10]2[C:18](=[O:22])[C:19](=[O:21])[O:20][CH2:23][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C(=O)c1c(CO)n(Cc2ccccc2)c2ccc(Br)cc12
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Agent: [K]
Product: O=C1OCc2c(c3cc(-c4ccc(-c5ccccc5)cc4)ccc3n2Cc2ccccc2)C1=O

Procedure:
The title compound was prepared from [1-benzyl-5-bromo-2-(hydroxymethyl)-1H-indol-3-yl](oxo)acetic acid, potassium salt and 4-biphenylboronic acid in substantially the same manner, as described in step 4 of Example 9. The product was obtained as a white solid, mp: 254–255° C.; Mass spectrum (ESI, [M+H]+) m/z 444. 1H NMR (400 MHz, DMSO-d6) δ 8.26(s, 1H), 7.75–7.68 (m, 8H), 7.45–7.43 (m, 2H), 7.36–7.23 (m, 6H), 5.89 (s, 2H), 5.53 ppm (s, 2H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)(=[O:7])=[O:6].[CH3:14][N:15]1[C:19]([SH:20])=[N:18][N:17]=[N:16]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[S:5]([CH2:4][CH2:3][CH2:2][S:20][C:19]1[N:15]([CH3:14])[N:16]=[N:17][N:18]=1)(=[O:7])=[O:6]
Reactant: Cn1nnnc1S
Reactant: O=S(=O)(CCCCl)c1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1nnnc1SCCCS(=O)(=O)c1ccccn1
Yield: 33.4 %

Procedure:
2-Pyridyl 3-chloropropyl sulfone (2.2 g) and 1-methyl-5-mercapto-1,2,3,4-tetrazole (1.2 g) are dissolved in acetone (50 ml). Potassium carbonate (1.4 g) is added to the solution and the mixture is refluxed for 5 hours. Acetone is distilled off and water is added to the residue. The mixture is extracted with chloroform. The chloroform solution is washed with saturated aqueous sodium chloride and dried over magnesium sulfate. Chloroform is distilled off and the residue is purified by column chromatography (Kieselgel 60). The column is eluted with chloroform-methanol and the product is recrystallized from ethanol to obtain 3-(1-methyl-1,2,3,4-tetrazol-5-yl)thiopropyl 2-pyridyl sulfone (1 g) as colorless prisms, m.p. 98.5°-101° C.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1.Cl[C:34]([CH2:36][O:37]C(=O)C)=[O:35]>>[OH:37][CH2:36][C:34]([N:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1)=[O:35]
Reactant: CC(=O)OCC(=O)Cl
Reactant: O=C(N[C@@H]1CCNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Agent: Cl
Product: O=C(N[C@@H]1CCN(C(=O)CO)C1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12

Procedure:
Starting from 4-(5-cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-pyrrolidin-3-ylamide hydrochloride (example A142) and acetic acid chlorocarbonyl-methyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [Cl-].[CH:2]1([CH2:7][NH2+:8][CH2:9][CH2:10]Cl)[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[N:20]=[C:21]=[S:22]>>[CH3:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[N:20]=[C:21]1[N:8]([CH2:7][CH:2]2[CH2:6][CH2:5][CH2:4][CH2:3]2)[CH2:9][CH2:10][S:22]1
Reactant: ClCC[NH2+]CC1CCCC1
Reactant: Cc1cccc(N=C=S)c1C
Agent: [Cl-]
Product: Cc1cccc(N=C2SCCN2CC2CCCC2)c1C

Procedure:
2-Hydroxyethylamine was reacted with cyclopentylmethyl bromide according to Method B2a to give N-cyclopentylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclopentylmethyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2,3-dimethylphenyl isothiocyanate to give 2-(2,3-dimethylphenylimino)-3-(cyclopentylmethyl)-1,3-thiazolidine.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH2:14][C:15]([O:17]C)=[O:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=1[N+:28]([O-:30])=[O:29].C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>C(#N)C.O>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:20]2[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=2[N+:28]([O-:30])=[O:29])[CH:10]([CH2:14][C:15]([OH:17])=[O:16])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CC1CN(Cc2ccccc2)CCN1
Reactant: COc1ccc([N+](=O)[O-])c(F)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1ccc([N+](=O)[O-])c(N2CCN(Cc3ccccc3)CC2CC(=O)O)c1
Temperature: 90 °C

Procedure:
To a solution of Example 12C (0.907 g, 3.65 mmol) in acetonitrile (11.69 mL) was added 2-fluoro-4-methoxy-1-nitrobenzene (0.50 g, 2.92 mmol) and potassium carbonate (2.019 g, 14.61 mmol) in water (2.92 mL) followed by 18-crown-6 (0.039 g, 0.146 mmol), and the mixture was heated with an oil bath at 90° C. (reflux) for 24 hours. The solvent was evaporated and water was added followed by dichloromethane. The water phase was washed three times with dichloromethane to remove starting material and then acidified with 1 N HCl until pH=1. The acid product was extracted three times with dichloromethane, dried quickly with sodium sulfate and concentrated to give the title compound. MS (ESI) m/z 386.1 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].N1C=CN=C1.[C:21]([Si:25]([CH3:28])([CH3:27])Cl)([CH3:24])([CH3:23])[CH3:22]>C(Cl)Cl>[Si:25]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)NCCCCCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCCCCO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 87 %

Procedure:
To a solution of tert-butyl 6-hydroxyhexylcarbamate (21 mmol) in CH2Cl2 (30 ml) was added imidazole (27 mmol) at 0° C. The reaction mixture was kept at 25° C. and stirred for 20 min, then cooled to 0° C. To the resulting reaction mixture was added tert-butyldimethylchlorosilane (23 mmol) dropwise over 30 min at 0° C. The reaction mixture was allowed to warm to 25° C. and stirred for 16 h and then filtered. The filtrate was washed with 1 N HCl (2×25 ml) and brine (30 ml), dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by SiO2 flash column (eluent: petroleum ether and then CH2Cl2). Yield 6.53 g (87% yield).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1.[N-:12]=[N+:13]=[N-:14].[Na+]>CS(C)=O>[N:12]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1)=[N+:13]=[N-:14]
Reactant: Fc1cccc(C(F)(F)F)n1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=Nc1cccc(C(F)(F)F)n1
Temperature: 80 °C
Yield: 71.2 %

Procedure:
A mixture of 82.5 grams (g) of 2-fluoro-6-(trifluoromethyl)pyridine (0.5 mole), 65 g of sodium azide (1.0 mole) and 400 milliliters (ml) of dimethylsulfoxide (DMSO) was heated to a temperature of 80° C. for 18 hours. The mixture was allowed to cool and then poured into 1500 ml of ice water. This resulting mixture was then extracted 4 times with 300 ml of pentane each time. The pentane extracts were combined, washed with 500 ml of a saturated NaCl solution and dried with MgSO4. The pentane was then carefully evaporated leaving 67 g of the desired 2-azido-6-(trifluoromethyl)pyridine as a light yellow oil having an RI of 1.4771 @25° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](Cl)=[N:5][C:6]([Cl:12])=[N:7]2.C(N(CC)CC)C.[CH2:21]([CH2:23][NH2:24])[OH:22]>ClCCl>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([NH:24][CH2:23][CH2:21][OH:22])=[N:5][C:6]([Cl:12])=[N:7]2
Reactant: Clc1nc(Cl)c2c(Br)cccc2n1
Reactant: NCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: OCCNc1nc(Cl)nc2cccc(Br)c12
Reaction time: 0.5 h

Procedure:
To a stirred mixture of 5-bromo-2,4-dichloroquinazoline (2.3 g, 8.2 mmol) and triethylamine (1.5 ml, 11 mmol) in dichloromethane (100 ml) was added ethanolamine (0.64 ml, 11 mmol), and the mixture was stirred for 30 min. The solvent was evaporated and the residue treated with a mixture of water (30 ml) and ether (20 ml) giving the title compound as a crystalline precipitate which was collected by filtration and dried, m.p. 165°-67° C.
Reaction SMILES: [O:1]=[C:2]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13])[CH2:3][CH2:4][C:5]([OH:7])=O.[NH:14]1[CH2:20][CH2:19][CH2:18][C@H:15]1[CH2:16][OH:17].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[O:1]=[C:2]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13])[CH2:3][CH2:4][C:5]([N:14]1[CH2:20][CH2:19][CH2:18][C@H:15]1[CH2:16][OH:17])=[O:7]
Reactant: O=C(O)CCC(=O)N1CCCC1=O
Reactant: OC[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C1CCCN1C(=O)CCC(=O)N1CCC[C@H]1CO
Reaction time: 3 h

Procedure:
A solution of 4-oxo-4-(2-oxo-1-pyrrolidinyl)butyric acid (5.02 g), L-prolinol (2.74 g) and HOBt (3.72 g) in DMF (50 ml) was cooled to -25° C. and DCC (5.64 g) was added thereto. After 3 hours' stirring at a temperature of -25°-0° C., the mixture was stirred at room temperature for 15 hours. The precipitated dicyclohexylurea was filtered off, and the filtrate was concentrated. The residue was dissolved in chloroform and washed with 1N hydrochloric acid, a saturated aqueous solution of sodium bicarbonate and saturated brine in sequence. The organic layer was dried over magnesium sulfate, followed by concentration. The residue was purified by silica gel column chromatography (chloroform-methanol) to give 3.41 g of N-[(4-oxo-4-(2-oxo-1-pyrrolidinyl)butanoyl]-L-prolinol.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([OH:20])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([O:28][C:29]([N:31]1[CH2:37][CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O.ON1C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1>O1CCCC1>[CH2:21]([O:28][C:29]([N:31]1[CH2:37][CH2:36][CH2:35][N:34]([C:18](=[O:20])[C@H:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=2)[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:33][CH2:32]1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(OCc1ccccc1)N1CCCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N1CCCN(C(=O)OCc2ccccc2)CC1
Yield: 97.7 %

Procedure:
15.29 g of N-tert-butoxycarbonyltyrosine and 12.73 g of N-benzyloxycarbonylhomopiperazine were dissolved in 280 ml of tetrahydrofuran, to the solution were added 8.09 g of 1-hydroxybenzotriazole hydrate and 11.77 g of DCC at a room temperature with stirring, and the reaction mixture was stirred for 16 hours. The reaction mixture was evaporated to remove the solvent under a reduced pressure, to the residue was added benzene, and insoluble matter was filtered by suction and washed with benzene. The benzene layers were combined and evaporated off under a reduced pressure. The resulting residue was applied to a silica gel column and eluted with chloroform/methanol (100:1), to obtain 26.42 g of the title compound in colorless amorphous form.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([Cl:31])[CH:30]=1)[C:25](O)=O>>[Cl:21][C:22]1[CH:23]=[C:24]([C:25]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:19])([F:20])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)[N:16]=2)[CH:28]=[C:29]([Cl:31])[CH:30]=1
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3cc(Cl)cc(Cl)c3)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 241 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 3,5-dichlorobenzoic acid: MS (APCl) m/z 439 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][NH:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23][CH2:24][N:25]1[C:29](=[O:30])[C:28]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]2[C:26]1=[O:35]>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH2:22][CH2:23][CH2:24][N:25]2[C:29](=[O:30])[C:28]3[C:27](=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:26]2=[O:35])[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC1CCNC1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC1CCN(CCCN2C(=O)c3ccccc3C2=O)C1
Yield: 65.3 %

Procedure:
Dimethylformamide (200 ml) was added to 3-(tert-butoxycarbonylaminomethyl)pyrrolidine (14 g), and potassium carbonate (30 g) and N-(3-bromopropyl)phthalimide (18 g) were added at room temperature with stirring, and the mixture was stirred at room temperature for 8 hr. The reaction mixture was concentrated under reduced pressure, and aqueous potassium carbonate solution was added to the residue. The mixture was extracted with ethyl acetate. The mixture was dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography to give 17 g of 2-(3-(3-tert-butoxycarbonylaminomethylpyrrolidin-1-yl)propyl)-2,3-dihydro-1 H-isoindole-1,3-dione.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([CH:18]=[CH:19][CH:20]=2)[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:4][C@H:3]1[O:21][CH2:22][CH3:23].[CH2:24]([C:26]1[NH:30][C:29]([C:31](O)=[O:32])=[N:28][C:27]=1[C:34]([F:37])([F:36])[F:35])[CH3:25].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[CH2:24]([C:26]1[NH:30][C:29]([C:31]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[CH:9]=[C:10]([CH:18]=[CH:19][CH:20]=3)[C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[CH2:4][C@H:3]2[O:21][CH2:22][CH3:23])=[O:32])=[N:28][C:27]=1[C:34]([F:36])([F:37])[F:35])[CH3:25]
Reactant: CCO[C@@H]1CN(c2cccc(C(=O)OC(C)(C)C)c2)CC[C@@H]1N
Reactant: CCc1[nH]c(C(=O)O)nc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCO[C@@H]1CN(c2cccc(C(=O)OC(C)(C)C)c2)CC[C@@H]1NC(=O)c1nc(C(F)(F)F)c(CC)[nH]1
Yield: 83 %

Procedure:
The same operation as in Example (1g) was performed using tert-butyl cis(±)-3-(4-amino-3-ethoxypiperidin-1-yl)benzoate obtained in Example (48e) (about 0.22 mmol), 5-ethyl-4-(trifluoromethyl)-1H-imidazole-2-carboxylic acid obtained by the method described in Example (39e) (40 mg, 0.19 mmol), WSC hydrochloride (120 mg, 0.63 mmol) and HOBT (40 mg, 0.30 mmol), to obtain 81.0 mg of the title compound (83%).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:16](=[O:20])[N:17]([CH3:19])[CH3:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(C)(C)C.[ClH:22].O1CCOCC1>>[ClH:22].[NH2:7][C@@H:8]([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:16]([N:17]([CH3:19])[CH3:18])=[O:20]
Reactant: CN(C)C(=O)C(Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CN(C)C(=O)[C@@H](N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(1-Dimethylcarbamoyl-2-phenyl-ethyl)-carbamic acid tert-butyl ester (8.6 g, 29 mmol) was dissolved in 4 M HCl-dioxane (110 ml) at 0° C. and the mixture stirred at 25° C. for 1 hour. The mixture was concentrated and the solids triturated with ether. Yield, 6.2 g, 92%; PBMS 193 (MH+, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][N:8]2[C:12]3[NH:13][CH:14]=[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:16](=O)[C:11]=3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.O=P(Cl)(Cl)[Cl:27]>ClCCCl>[Cl:27][C:16]1[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][C:6]3[CH:23]=[CH:24][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:9]=[CH:10][C:11]=12
Reactant: CCOC(=O)c1c[nH]c2c(cnn2Cc2ccc(OC)cc2)c1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: CCOC(=O)c1cnc2c(cnn2Cc2ccc(OC)cc2)c1Cl
Temperature: 90 °C
Yield: 86.8 %

Procedure:
To a solution of ethyl 1-(4-methoxybenzyl)-4-oxo-4,7-dihydro-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (4.0 g, 13 mmol) in 1,2-dichloroethane (9.8 mL) was added POCl3 (2.4 mL, 26 mmol). The resulting mixture was heated at 90° C. for 3 h. After cooling, the most volatile were removed by vacuum, and the residue was diluted with EtOAc and washed with aq. Na2CO3 solution. The organic layer was washed water and brine, dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using CombiFlash® apparatus, eluting with 10 to 60% EtOAc in hexanes, to give the sub-title compound (3.9 g, 95%). LCMS calc. for C17H17ClN3O3 (M+H)+: m/z=346.1. Found: 346.1.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH:6]1[C:7]2[C:14](=O)[NH:13][CH:12]=[N:11][C:8]=2[NH:9][N:10]=1.CN(C)C1C=CC=CC=1>>[Cl:3][C:14]1[N:13]=[CH:12][N:11]=[C:8]2[NH:9][N:10]=[CH:6][C:7]=12
Reactant: O=c1[nH]cnc2[nH]ncc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: Clc1ncnc2[nH]ncc12
Reaction time: 0.25 h
Yield: 56.1 %

Procedure:
Phosphorus oxychloride (300 mL, 3.2 mol) was added to allopurinol (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA 20 g, 0.15 mol) and then N,N-dimethylaniline (30 mL, 0.24 mol) was added at room temperature. The resulting mixture was heated at reflux for 90 min and then cooled. The solvent was removed under vacuum. The residue was co-evaporated twice with toluene, and the resulting dark colored syrup was poured into a mixture of ice and water (500 mL). The mixture was stirred for 15 min, then transferred to a separatory funnel and extracted with ether (4×500 mL) and ethyl acetate (2×500 mL). The combined organic layers were washed twice with ice-water, dried (sodium sulfate), and concentrated to approximately 1.5 L. Charcoal was added to the slightly purple solution and the mixture was filtered through Celite. The Celite was washed with ethyl acetate and the combined filtrates were evaporated to dryness to give 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (13 g, 56%) as a pale green solid. 1H NMR (300 MHz, DMSO-d6) δ 8.44 (s, 1H), 8.81 (s, 1H), 14.50 (br s, 1H).
Reaction SMILES: [P:1]([O-:5])([O-:4])([OH:3])=[O:2].[K+].[K+].C([O-])(=O)C.[Ca+2:12].C([O-])(=O)C>>[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[Ca+2:12].[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[Ca+2:12].[Ca+2:12]
Reactant: O=P([O-])([O-])O
Agent: CC(=O)[O-]
Agent: [Ca+2]
Agent: [K+]
Product: O=P([O-])([O-])[O-]

Procedure:
Catalyst A was prepared by adding an aqueous solution of dipotassium hydrogen phosphate (1.0 mole) with vigorous stirring to an aqueous solution of calcium acetate (1.67 moles) to obtain a calcium phosphate gel having a Ca/P atomic ratio of 1.67. After standing overnight, the gel was recovered by filtration and washed by slurrying in a 3500 ml portion of water and filtered. The wash treatment was done three times. Finally, the filter cake was additionally washed by pulling 10 liters of distilled water through it. About 1/4 of the wet cake was reslurried in 1000 ml of distilled water and to the stirred slurry was added 16 g of barium nitrate dissolved in 300 ml of distilled water. The mixture was allowed to stand for two days with occasional stirring. Then to the well-stirred slurry was slowly added a mixture of 145 g nickel nitrate and 16 g barium nitrate dissolved in 600 ml of hot distilled water and 100 g potassium carbonate dissolved in 250 ml of distilled water. The resulting mixture was filtered to obtain a cake which was reslurried in about 3500 ml of distilled water and filtered. This operation was repeated and finally about 3 liters of distilled water was pulled through the filter cake. The cake was dried overnight at 220° F., crushed to pass a 40 mesh screen and calcined in air at 800° F. for 3 hours. The cooled product was mixed with 3 weight percent polyethylene powder and pilled to 1/8-inch size at 100 psig. The pills were heated at about 800° F. in hydrogen for about 20 minutes to obtain the finished catalyst. This invention catalyst, as analyzed, contained 16.3 weight percent barium and 26.9 weight percent nickel based on the total weight of the catalyst composite. The surface area of the catalyst was about 80 square meters per gram, as determined by nitrogen absorption, the pore volume was about 0.2 ml per gram as determined by water absorption, and the apparent bulk density was 0.94 gram per ml.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH2:19][CH2:20]OS(C)(=O)=O)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[NH:26]1[CH2:29][CH2:28][CH2:27]1>CC(N(C)C)=O.CCOCC.C([O-])([O-])=O.[Na+].[Na+]>[N:26]1([CH2:20][CH2:19][C:18]#[C:17][C:15]2[CH:14]=[CH:13][C:12]3[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=4)=[N:9][S:10][C:11]=3[CH:16]=2)[CH2:29][CH2:28][CH2:27]1
Reactant: CS(=O)(=O)OCCC#Cc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Reactant: C1CNC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)N(C)C
Product: Brc1ccc(-c2nsc3cc(C#CCCN4CCC4)ccc23)cc1
Yield: 34.9 %

Procedure:
73 mg (0.16 mmol) Methanesulfonic acid 4-[3-(4-bromo-phenyl)-benzo[d]isothiazol-6-yl]-but-3-ynyl ester in 1 ml DMA were treated with 35 μl (0.5 mmol) azetidine for 48 h. The solution was diluted with ether and aqueous Na2CO3, the phases were separated and the inorganic layer was extracted with ether. The combined organic phases were washed with brine, dried over Na2SO4. Column chromatography on silica gel with a gradient CH2Cl2 to CH2Cl2:MeOH 8:1 gave 22.2 mg (33%) 6-(4-Azetidin-1-yl-but-1-ynyl)-3-(4-bromo-phenyl)-benzo[d]isothiazole as brown oil, MS: 397(MH+, 1Br).