Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[N:4][CH:5]=[C:6]([Cl:8])[N:7]=1.[CH:10]1(B(O)O)[CH2:12][CH2:11]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>O>[Cl:1][C:2]1[C:3]([CH:10]2[CH2:12][CH2:11]2)=[N:4][CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: OB(O)C1CC1
Reactant: Clc1cnc(I)c(Cl)n1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Clc1cnc(C2CC2)c(Cl)n1
Temperature: 110 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
A mixture of 3,5-dichloro-2-iodopyrazine (2 g), cyclopropylboronic acid (750 mg), tetrakistriphenylphosphine palladium (0) (1.68 g), potassium phosphate (3.09 g), toluene (40 mL), and water (4 mL) was stirred at 110° C. overnight. After leaving to be cooled, the insoluble matter was removed by decantation, followed liquid separation by the addition of ethyl acetate and water. The organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=98:2) to obtain 3,5-dichloro-2-cyclopropylpyrazine (784 mg) as a colorless oily material.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[C:9]([CH3:11])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.O[CH2:13][C@@H:14]1[CH2:18][CH2:17][CH2:16][N:15]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[C:3]2[CH:10]=[C:9]([CH3:11])[N:8]([CH2:13][C@@H:14]3[CH2:18][CH2:17][CH2:16][N:15]3[C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cc1cc2c(Cl)ncnc2[nH]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc2c(Cl)ncnc2n1C[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To the solution of 4-chloro-6-methyl-7H-pyrrolo[2,3-d]pyrimidine (1.0 g, 5.97 mmol, 1.0 eq) and (S)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (1.32 g, 6.57 mmol, 1.1 eq) and PPh3 (3.03 g, 11.94 mmol, 2.0 eq) in THF (50 mL), DIEA (2.08 g, 11.94 mmol, 2.0 eq) was added at 0° C. The resulted mixture was stirred and warmed to RT for 12 h. Solvent was removed and purified by column chromatography (eluting with 10% EtOAc in PE) to afford (S)-tert-butyl 2-((4-chloro-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrrolidine-1-carboxylate as a white solid (2.08 g, 100% in yield).
Reaction SMILES: [CH:1]1([N:7]2[CH:16](O)[CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)C.Cl>O>[CH:1]1([N:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1c2ccccc2CC(O)N1C1CCCCC1
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=c1c2ccccc2ccn1C1CCCCC1
Yield: 88.3 %

Procedure:
The compound (22 mg) obtained in step (b) just above was stirred in a mixed solution of ethanol:concentrated hydrochloric acid=10:1 at room temperature for 30 min. Water was added to the reaction solution. The mixture was extracted with ethyl acetate, and then dried over anhydrous magnesium sulfate. The solvent was then removed by distillation. The residue was purified by chromatography on silica gel (hexane:ethyl acetate=1:1) to give 2-cyclohexyl-2H-isoquinolin-1-one (18 mg).
Reaction SMILES: ClC1C=C(Cl)C=CC=1C[O:10][C@@H:11]1[C@@H:15]([CH2:16][O:17]CC2C=CC(Cl)=CC=2Cl)[O:14][C@@H:13]([N:27]2[CH:39]=[C:31]3[CH:32]=[CH:33][C:34]4[CH2:35][NH:36][N:37]=[CH:38][C:29]([C:30]=43)=[N:28]2)[C@:12]1([CH3:41])[OH:40].B(Cl)(Cl)Cl.CO>C(Cl)Cl>[CH3:41][C@@:12]1([OH:40])[C@H:11]([OH:10])[C@@H:15]([CH2:16][OH:17])[O:14][C@H:13]1[N:27]1[CH:39]=[C:31]2[CH:32]=[CH:33][C:34]3[CH2:35][NH:36][N:37]=[CH:38][C:29]([C:30]=32)=[N:28]1
Reactant: C[C@@]1(O)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1cc2ccc3c-2c(n1)C=NNC3
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1cc2ccc3c-2c(n1)C=NNC3
Temperature: -78 °C
Reaction time: 2.5 h
Yield: 20.1 %

Procedure:
To compound 24.1 (160 mg, 0.25 mmol) in CH2Cl2 (10 mL) at −78° C. was added 1M solution of boron trichloride in CH2Cl2 dropwise over 5 minutes and the solution stirred at −78° C. for 2.5 h and then at −25° C. for 3 hr. To this mixture was added 25 mL of 1:1 v/v CH2Cl2:MeOH and the solution stirred at −15° C. for 30 minutes. The mixture was brought to room temperature and the solvent was evaporated under reduced pressure. The residue was co-evaporated with MeOH (5×10 mL) and a 10 mL MeOH solution was neutralized with NH4OH and evaporated again. The residue was adsorbed on 2 g silica gel and loaded on a silica column and eluted successively with 50:1,20:1 and 15:1 CH2Cl2:MeOH. Fractions eluting at 20:1 and 15:1 were collected, Pooling of fraction and evaporation gave 16 mg product 24.2. 1H NMR (DMSO-d6) δ 8.10 (s, 1H), 7.51 (s, 1H), 7.30 (t, 1H), 6.61 (d, J 9 Hz, 1H), 6.11 (s, 1H), 5.71 (dt, J 6, 12 Hz, 1H), 5.08 (m, 3H), 3.86 (m, 5H), 3.78 (m, 1H), 0.72 (s, 31).
Reaction SMILES: [CH2:1]1[CH:3]([CH:4]([OH:7])C#N)[CH2:2]1.[N+:8]([CH3:11])([O-:10])=[O:9].C(N(CC)CC)C>CO>[N+:8]([CH2:11][CH:4]([CH:3]1[CH2:1][CH2:2]1)[OH:7])([O-:10])=[O:9]
Reactant: N#CC(O)C1CC1
Reactant: C[N+](=O)[O-]
Solvent: CO
Solvent: CCN(CC)CC
Product: O=[N+]([O-])CC(O)C1CC1

Procedure:
Example 319 A) To cyclopropyl carboxaldehyde in MeOH is added nitromethane and triethylamine. After stirring, the solvent is removed in vacuo and the residue is dissolved in CH2Cl2. The 2-nitro-1-cyclopropylethanol is isolated from the methylene chloride solution and added to a mixture of sodium acetate and acetic anhydride under N2After stirring, the mixture is diluted with water and extracted with EtOAc. The combined extracts are washed with brine, dried over MgSO4 and the solvent is removed in vacuo. The 2-nitroethenylcyclopropane is used without further purification.
Reaction SMILES: [C:1]([O:7][C@@H:8]1[C@@H:13]([O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])[C@H:12]([O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[C@@H:11]([CH2:28][O:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[O:10][C@H:9]1[O:36][C:37]1[C:45]2[C:40](=[N:41][CH:42]=[CH:43][C:44]=2[CH2:46][CH2:47][C:48]2[CH:53]=[CH:52][C:51]([O:54][C:55](=[O:60])[C:56]([CH3:59])([CH3:58])[CH3:57])=[CH:50][CH:49]=2)[NH:39][N:38]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH:68]([CH3:70])[CH3:69]>CC(C)=O>[CH:68]([N:39]1[C:40]2=[N:41][CH:42]=[CH:43][C:44]([CH2:46][CH2:47][C:48]3[CH:49]=[CH:50][C:51]([O:54][C:55](=[O:60])[C:56]([CH3:59])([CH3:58])[CH3:57])=[CH:52][CH:53]=3)=[C:45]2[C:37]([O:36][C@@H:9]2[O:10][C@H:11]([CH2:28][O:29][C:30](=[O:35])[C:31]([CH3:33])([CH3:34])[CH3:32])[C@@H:12]([O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[C@H:13]([O:14][C:15](=[O:20])[C:16]([CH3:17])([CH3:19])[CH3:18])[C@H:8]2[O:7][C:1](=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5])=[N:38]1)([CH3:70])[CH3:69]
Reactant: CC(C)I
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2n[nH]c3nccc(CCc4ccc(OC(=O)C(C)(C)C)cc4)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CC(C)n1nc(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)c2c(CCc3ccc(OC(=O)C(C)(C)C)cc3)ccnc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-4-[2-(4-pivaloyloxyphenyl)ethyl]-1H-pyrazolo-[3,4-b]pyridine (84 mg) in acetone (1.5 mL) were added cesium carbonate (0.11 g) and 2-iodopropane (0.03 mL), and the mixture was stirred at room temperature for 2 days. The reaction mixture was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=10/1-2/1) to give 1-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-4-[2-(4-pivaloyloxyphenyl)ethyl]-1H-pyrazolo[3,4-b]pyridine (61 mg). This material was dissolved in methanol (2 mL). To the solution was added sodium methoxide (28% methanol solution, 0.04 mL), and the mixture was stirred at 60° C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol) to give the title compound (26 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[CH2:8][NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1.C([O-])([O-])=O.[K+].[K+].[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=1>CC#N.O>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][N:9]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)[CH2:32][C:31]1[CH:34]=[CH:35][C:28]([F:27])=[CH:29][CH:30]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: COc1ccc(NCc2c(Cl)cncc2Cl)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1ccc(N(Cc2ccc(F)cc2)Cc2c(Cl)cncc2Cl)cc1OC
Temperature: 120 °C

Procedure:
Intermediate B1 (480 mg, 1.5 mmoles) was dissolved in CH3CN (7.5 mL). Solid K2CO3 (518 mg, 3.75 mmoles), solid KI (250 mg, 1.5 mmoles) and neat 4-fluoro-benzyl-bromide (0.191 mL, 1.5 mmoles) were added, and the mixture was heated in a sealed vial in a microwave oven at 120° C. for 30+30 minutes. The reaction mixture was diluted with water (40 mL) and extracted with AcOEt (3×40 mL). The organic layer was washed with brine, dried over Na2SO4, and evaporated to dryness. The crude was purified by flash chromatography (SiO2, petroleum ether/AcOEt from 9/1 to 7/3). The title compound was obtained as a light-yellow solid in amount of 407 mg.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[C@@H:21]([OH:22])[C:20](=[O:23])[NH:19][C:18]3[CH:24]=[CH:25][CH:26]=[CH:27][C:17]=3[S:16]2)=[CH:11][CH:10]=1.Cl.[CH3:29][N:30]([CH2:34][CH2:35]Cl)[CH2:31][CH2:32][CH3:33]>CC(C)=O>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C@H:15]2[C@@H:21]([OH:22])[C:20](=[O:23])[N:19]([CH2:35][CH2:34][N:30]([CH3:29])[CH2:31][CH2:32][CH3:33])[C:18]3[CH:24]=[CH:25][CH:26]=[CH:27][C:17]=3[S:16]2)=[CH:13][CH:14]=1
Reactant: COc1ccc([C@@H]2Sc3ccccc3NC(=O)[C@@H]2O)cc1
Reactant: CCCN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCN(C)CCN1C(=O)[C@H](O)[C@H](c2ccc(OC)cc2)Sc2ccccc21
Reaction time: 8 h
Yield: 92.5 %

Procedure:
5.05 g of potassium carbonate are added to a mixture of 10.0 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 6.57 g of 2-(N-methyl-N-n-propylamino)ethyl chloride hydrochloride and 100 ml of acetone. The mixture is refluxed under stirring overnight. After the reaction, the mixture is treated in the same manner as described in Example 28-(1). 12.3 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(N-methyl-N-n-propylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are thereby obtained as an oil. Yield: 92%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=S.C(N(CC)CC)C.CS(Cl)(=O)=O>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:17])([F:19])[F:18])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[N:22]=[C:23]=[N:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)CNC(=S)Nc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CN=C=Nc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100.3 %

Procedure:
A solution of N-{{2-chloro-5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-4-fluorophenyl}(thiocarbamoyl)}glycine, ethyl ester (5.0 g, 10.4 mmol) in methylene chloride is treated sequentially with triethylamine (4.3 mL, 31.1 mmol), 4-dimethylaminopyridine (0.05 g) and methanesulfonyl chloride (1.6 mL, 20.7 mmol) stirred at room temperature for 10 minutes, and partially concentrated in vacuo to obtain a heterogeneous mixture. The heterogeneous mixture is placed onto silica gel and eluted with methylene chloride. The resultant solution is concentrated in vacuo to give the title product as an amber syrup (4.68 g) which is identified by 1H and 13C NMR spectral analyses.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:6](=[O:23])[C:5]2([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[Cl:38])[NH:24][C:25]([N:27]([CH2:30][CH3:31])[CH2:28][CH3:29])=[O:26].[H][H]>CCO.C1COCC1.[Ni]>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([S:11]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=3)[C:5]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[Cl:38])([NH:24][C:25]([N:27]([CH2:28][CH3:29])[CH2:30][CH3:31])=[O:26])[C:6]2=[O:23])(=[O:13])=[O:12])=[CH:15][CH:16]=1
Reactant: CCN(CC)C(=O)NC1(c2ccccc2Cl)C(=O)N(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)c2ccc(Cl)cc21
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Solvent: C1CCOC1
Product: CCN(CC)C(=O)NC1(c2ccccc2Cl)C(=O)N(S(=O)(=O)c2ccc(N)cc2)c2ccc(Cl)cc21

Procedure:
7.6 g of the compound obtained in EXAMPLE 12 in 100 ml of EtOH and 50 ml of THF are reduced with hydrogen under a pressure of 50 bar for 6 hours at RT, in the presence of 2 g of Raney nickel. The mixture is filtered on Celite and the filtrate is evaporated under vacuum. The residue is chromatographed on silica using a DCM/AcOEt mixture (95/5; v/v) as the eluent to give the expected product after crystallization from a DCM/ iso ether mixture. m=3.2 g. M.p.=210° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][N:12]=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:19][CH2:20][C@@H:21]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH3:22].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(#N)CC>O>[CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][N:12]=[C:11]([O:19][CH2:20][C@@H:21]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH3:22])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1OCc1ccccc1
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC#N
Product: C[C@@H](COc1ncc([N+](=O)[O-])c(OCc2ccccc2)n1)NC(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 1 h
Yield: 16.7 %

Procedure:
A mixture of 4-(benzyloxy)-2-chloro-5-nitropyrimidine (670 mg), tert-butyl ((2S)-1-hydroxypropan-2-yl)carbamate (530 mg), potassium phosphate (642 mg) and propionitrile (10 mL) was stirred at 50° C. for 1 hr, and then at 100° C. for 5 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The combined organic layer were washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (170 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][S:22]([C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1)(=[O:24])=[O:23]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][C:25]([S:22]([CH2:21][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=3)(=[O:24])=[O:23])=[CH:26][CH:27]=2)=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cc2ccccn2)cc1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(S(=O)(=O)Cc2ccccn2)cc1

Procedure:
1 g of 2-(bromomethyl)pyridine hydrobromide was reacted with methyl 4-mercaptobenzoate via Procedure Q to afford methyl 4-(pyridin-2-ylmethylthio)benzoate. 500 mg of methyl 4-(pyridin-2-ylmethylthio)benzoate was reacted via Procedure R to give methyl 4-(pyridin-2-ylmethylsulfonyl)benzoate. 470 mg of methyl 4-(pyridin-2-ylmethylsulfonyl)benzoate was hydrolyzed via Procedure M to give 4-(pyridin-2-ylmethylsulfonyl)benzoic acid. 70 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(pyridin-2-ylmethylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(pyridin-2-ylmethylsulfonyl)benzamide. MS (Q1) 464.1 (M)+.
Reaction SMILES: Cl.[NH:2]([C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][N:18]3C(=O)C4=CC=CC=C4C3=O)[CH:12]=2)[N:10]=1)[C:3]([NH2:5])=[NH:4].Cl>O.C(O)C.[OH-].[Na+]>[NH:2]([C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH2:18])[CH:12]=2)[N:10]=1)[C:3]([NH2:5])=[NH:4]
Reactant: N=C(N)Nc1nc(-c2cccc(CN3C(=O)c4ccccc4C3=O)c2)cs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N=C(N)Nc1nc(-c2cccc(CN)c2)cs1
Yield: 35.9 %

Procedure:
A mixture of 2-guanidino-4-(3-phthalimidomethylphenyl)thiazole hydrochloride (0.7 g.) in water (30 ml.) and ethanol (30 ml.) and sufficient aqueous sodium hydroxide to give pH 12 was heated under reflux for 30 minutes. The pH was adjusted to approximately 3 with concentrated hydrochloric acid and the mixture heated under reflux for a further 30 minutes. The pH was then adjusted to 12 with dilute sodium hydroxide solution and the mixture extracted with ethyl acetate (50 ml.). This extract was evaporated to dryness to give 2-guanidino-4-(3-aminomethylphenyl)thiazole (0.15 g.), m.p. 155°-160° C. (decomp.).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[N:3]=1.Cl.[NH:19]1[CH2:24][CH2:23][CH2:22][CH:21]([NH:25][C:26]2[N:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=2)[CH2:20]1.C(N(CC)C(C)C)(C)C>CS(C)=O>[C:32]([C:29]1[CH:28]=[CH:27][C:26]([NH:25][CH:21]2[CH2:22][CH2:23][CH2:24][N:19]([C:2]3[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[C:4]([C:10]4[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=4[Cl:17])[N:3]=3)[CH2:20]2)=[N:31][CH:30]=1)#[N:33]
Reactant: N#Cc1ccc(NC2CCCNC2)nc1
Reactant: N#Cc1ccc(-c2ccc(Cl)cc2Cl)nc1Cl
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(NC2CCCN(c3nc(-c4ccc(Cl)cc4Cl)ccc3C#N)C2)nc1
Temperature: 120 °C

Procedure:
60 mg (0.21 mmol) of 2-chloro-6-(2,4-dichlorophenyl)pyridine-3-carbonitrile, 63 mg (0.25 mmol) of 6-(piperidin-3-ylamino)pyridine-3-carbonitrile hydrochloride (Example 10A) and 0.184 ml (1.06 mmol) of N,N-diisopropylethylamine were initially charged in 2 ml of DMSO. The mixture was heated at 120° C. in a microwave for 30 min. The crude product was purified by means of preparative HPLC (method 13). 61 mg (64% of theory) of the product were obtained in solid form.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.I[C:18]1[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[N:22][CH:23]=1>>[CH:1]1([N:5]2[CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][C:13]([O:16][C:18]4[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[N:22][CH:23]=4)=[CH:12][C:9]=3[CH2:10][CH2:11]2)[CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccc(I)cn1
Reactant: Oc1ccc2c(c1)CCN(C1CCC1)CC2
Product: N#Cc1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)cn1

Procedure:
The title compound (E206) was prepared from 3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ol (E3) and 5-iodo-2-pyridinecarbonitrile (Biochemical Journal, 1973, 131(4), 625) according to the method outlined for E177a; MS (ES+) m/e 320 [M+H]+.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:32]=[CH:31][CH:30]=[CH:29][C:23]=2[O:24][CH2:25][CH:26]2[CH2:28][O:27]2)[CH:13]=[C:14]([O:16][CH3:17])[CH:15]=1>O1CCCC1>[OH:4][CH2:3][CH2:2][N:1]([CH2:28][CH:26]([OH:27])[CH2:25][O:24][C:23]1[CH:29]=[CH:30][CH:31]=[CH:32][C:22]=1[CH2:21][CH2:20][CH2:19][CH2:18][C:12]1[CH:13]=[C:14]([O:16][CH3:17])[CH:15]=[C:10]([O:9][CH3:8])[CH:11]=1)[CH2:5][CH2:6][OH:7]
Reactant: OCCNCCO
Reactant: COc1cc(CCCCc2ccccc2OCC2CO2)cc(OC)c1
Solvent: C1CCOC1
Product: COc1cc(CCCCc2ccccc2OCC(O)CN(CCO)CCO)cc(OC)c1
Temperature: 50 °C
Reaction time: 24 h
Yield: 73.8 %

Procedure:
530 mg of diethanolamine were added to a solution of 345 mg of 2-{2-[4-(3,5-dimethoxyphenyl)butyl]phenoxymethyl}oxirane [prepared as described in Example 11(a)] in 10 ml of tetrahydrofuran, and the resulting mixture was stirred at 50° C. for 24 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 7:1 by volume mixture of methylene chloride and methanol as the eluent, to give 333 mg of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]([F:14])([F:13])[C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8]Cl>CO>[CH3:1][NH:2][CH2:8][C:7]1[CH:10]=[CH:11][CH:12]=[C:5]([C:4]([F:14])([F:13])[F:3])[CH:6]=1
Reactant: CN
Reactant: FC(F)(F)c1cccc(CCl)c1
Solvent: CO
Product: CNCc1cccc(C(F)(F)F)c1
Temperature: 50 °C

Procedure:
To a solution of methylamine 2M in MeOH (61.5 mL, 123.3 mmol), MeOH (30 mL) was added. The mixture was heated at 50° C. under stirring and 3-(trifluoromethyl)benzyl chloride (1.6 mL, 10.3 mmol) dissolved in MeOH (10 mL) were added. The reaction mixture was stirred at this temperature for 5 h. The solvent was removed under vacuo, then NaOH 1M was added and the aqueous layer was extracted with DCM. The organic layer was filtered through a phase separator and concentrated in vacuo to give 2.19 g of a colourless oil. 1H NMR (400 MHz, CDCl3) δ ppm 7.69 (s, 1H), 7.57 (d, 1H), 7.49 (t, 2H), 3.88 (s, 2H), 2.56, (s, 3H). UPLC-MS: Rt=0.39; m/z (ES+): 190 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[F:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:27]=1[CH2:28][NH:29][CH2:30]2>CN(C=O)C>[Cl:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:27]=1[CH2:28][N:29]([C:15]1[C:16]([F:18])=[C:17]3[C:12]([C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9][N:8]3[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:13][C:14]=1[F:20])[CH2:30]2
Reactant: Clc1cccc2c1CNC2
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(F)c(F)cc2c1=O
Solvent: CN(C)C=O
Product: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(N3Cc4cccc(Cl)c4C3)c(F)cc2c1=O
Yield: 34.5 %

Procedure:
170 mg of 1-(4-fluorophenyl)-6,7,8-trifluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 260 mg of 4-chloroisoindoline, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 82 mg of the target compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:16][CH2:15][N:14](O)[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[Ni]>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:16][CH2:15][NH:14][CH2:13]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H]1CCN(O)C1)OCc1ccccc1
Agent: [Ni]
Solvent: CCO
Product: O=C(N[C@@H]1CCNC1)OCc1ccccc1
Yield: 81 %

Procedure:
The crude (R)-3-(benzyloxycarbonylamino)-N-hydroxy-pyrrolidine obtained above (1.4 g) was dissolved in ethanol (10 ml). Raney nickel (about 2 g) was added to this mixture. The reaction was degassed under reduced pressure and hydrogen supply (three times) and subsequently put under hydrogen atmosphere (1 bar). The reaction was over after 6 hours, yielding crude (R)-3-(benzyloxycarbonylamino)-pyrrolidine which was further processed in situ, in that di-tert-butyl dicarbonate (1.0 g, 4.58 mmol) was added; the mixture was stirred for one hour. The solvent was removed and the residue taken up in an n-hexane/AcOEt mixture (1:1, 20 ml) and filtered through a silicagel pad. The silica was washed with n-hexane/AcOEt mixture (1:1; 250 ml). The organic phases were evaporated. The compound was obtained as a colorless oil (1.125 g; yield 81%) in good purity, i.e. at least 90–95%, rendering the compound sufficiently pure for further reaction, e.g. in Example 3.