Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[C:18]([O:20][CH:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH:19]=2)[NH:16][C:15]([C:27](O)=[O:28])=[CH:14]3)=[CH:6][CH:5]=1.O.O[N:32]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.N>CN(C)C=O.O>[CH3:1][O:2][CH2:3][C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[C:18]([O:20][CH:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[CH:19]=2)[NH:16][C:15]([C:27]([NH2:32])=[O:28])=[CH:14]3)=[CH:6][CH:5]=1
Reactant: COCc1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C(=O)O)cc3c2)cn1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: O
Solvent: CN(C)C=O
Product: COCc1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C(N)=O)cc3c2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 136.2 %

Procedure:
To a solution of 5-{[6-(methoxymethyl)pyridin-3-yl]oxy}-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indole-2-carboxylic acid (2.2 g) in N,N-dimethylformamide (20 mL) were added 1-hydroxybenzotriazole monohydrate (1.27 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.6 g) and 25% aqueous ammonia (10 mL) and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was crystallized from diethyl ether to give the title compound (2.99 g, yield 45%) as white crystals.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[NH:3]1.[CH2:17]=O.[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([OH:29])[C:27]#[CH:28])=[CH:22][CH:21]=1>O1CCOCC1.O>[F:19][C:20]1[CH:21]=[CH:22][C:23]([CH:26]([OH:29])[C:27]#[C:28][CH2:17][N:10]2[CH2:9][CH2:8][CH:7]([N:6]3[C:5]4[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=4[NH:3][C:2]3=[O:1])[CH2:12][CH2:11]2)=[CH:24][CH:25]=1
Reactant: C=O
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: C#CC(O)c1ccc(F)cc1
Solvent: O
Solvent: C1COCCO1
Product: O=c1[nH]c2ccccc2n1C1CCN(CC#CC(O)c2ccc(F)cc2)CC1
Temperature: 80 °C

Procedure:
To a solution of 4-(2-keto-1-benzimidazolinyl)piperidine (0.625 g) in a mixture of dioxane (10 ml), water (2 ml), and 37% formalin (0.40 g), there were added a solution of 3-(p-fluorophenyl)-3-hydroxy-1-propyne (0.45 g) in dioxane (2 ml) and a solution of cupric sulfate pentahydrate (30 mg) in water (1 ml) under ice-cooling. The resulting mixture was heated at 80° C for 4 hours and, after cooling, the resulting mixture was filtered and the filtrate was concentrated under reduced pressure and extracted with chloroform. The chloroform extracts were dried over magnesium sulfate. After evaporation of the solvent, the residual oil was chromatographed on silica gel to afford 1-[4-(p-fluorophenyl)-4-hydroxy-2-butynyl]-4-(2-keto-1-benzimidazolinyl)piperidine as oily substance. νOHneat or νNHneat 3200 cm-1, νC=Oneat 1680 cm-1.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[C:7]([CH:19]=[CH:20][C:21]=1[N+:22]([O-])=O)[O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][N:10]=1)[CH3:3].[Cl-].[Ca+2].[Cl-].C(O)C>[Fe].O>[CH3:3][CH:2]([O:4][C:5]1[CH:6]=[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:16])=[O:17])=[CH:11][N:10]=2)[CH:19]=[CH:20][C:21]=1[NH2:22])[CH3:1]
Reactant: CC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)cn2)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)cn2)ccc1N
Temperature: 80 °C
Reaction time: 3 h
Yield: 87.7 %

Procedure:
A mixture of 2-[3-(1-methylethoxy)-4-nitrophenoxy]-5-(methylsulfonyl)pyridine (39.89 g), iron powder (31 g), calcium chloride (1.3 g), ethanol (400 mL) and water (100 mL) was stirred at 80° C. for 3 h. The mixture was filtered through celite and the filtrate was concentrated under reduced pressure. Water and brine were added to the residue. The mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated. The residual solid was washed with diethyl ether-hexane to give the title compound (32 g, 88%) as a brownish solid. MS 323 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[NH:10][C:11]([NH:13][CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:12].[C:19]([C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:31]=1[OH:32])[C:26]([OH:28])=O)([CH3:22])([CH3:21])[CH3:20].[CH:37]1(N=C=NC2CCCCC2)CCCC[CH2:38]1>ClCCl>[Cl:9][C:5]1[C:6]([Cl:8])=[CH:7][C:2]([NH:1][C:26](=[O:28])[C:25]2[CH:24]=[C:23]([C:19]([CH3:20])([CH3:21])[CH3:22])[C:31]([OH:32])=[C:30]([C:33]([CH3:34])([CH3:36])[CH3:35])[CH:29]=2)=[C:3]([NH:10][C:11]([NH:13][CH2:14][CH2:18][CH2:17][CH2:16][CH2:15][CH2:37][CH3:38])=[O:12])[CH:4]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: Nc1cc(Cl)c(Cl)cc1NC(=O)NC1CCCC1
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Solvent: ClCCl
Product: CCCCCCCNC(=O)Nc1cc(Cl)c(Cl)cc1NC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Yield: 161.5 %

Procedure:
1-(2-amino-4,5-dichlorophenyl)-3-cyclopentylurea (0.48 g), 3,5-di-t-butyl-4-hydroxybenzoic acid (0.38 g) and dicyclohexylcarbodiimide (0.37 g) were stirred in dichloromethane (35 ml) at room temperature for 3 hrs. After filtering off the insolubles and distilling off the solvent, the residue was purified by a silica gel column chromatography (chloroform:ethyl acetate=20:1) to give N-[4,5-dichloro-2-(3-heptylureido)phenyl]-3,5-di-t-butyl-4-hydroxybenzamide (1.35 g, 68%) as crystals.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[H][H].[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[CH2:14]I)[CH3:11]>CN(C)C=O.O>[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[CH2:14][N:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1)[CH3:11]
Reactant: c1cc[nH]c1
Reactant: [H][H]
Reactant: CCOC(CI)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(Cn1cccc1)OCC
Temperature: 25 °C
Yield: 95 %

Procedure:
To a cold solution (-5° C. to 0° C.) of sodium hydride in anhydrous dimethylformamide (11.8 g, 245.9 mmol), pyrrole (15.0 g, 223.6 mmol) in dry dimethylformamide was slowly added while stirring vigorously. The reaction was completed, and the temperature raised to room temperature. After hydrogen is fully evolved, iodoacetaldehyde diethyl acetal was added (65.5 g, 268.1 mmol) to the reaction mixture. The reaction mixture was allowed to reflux for 5 hours or until there was no further advance of the reaction. The reaction mixture was cooled to room temperature, poured onto 50 mL of water, extracted with ether, dried over MgSO4, and concentrated. The product was purified by column chromatography [silica gel, hexane] to give the title compound, 1-(2,2-diethoxyethyl)pyrrole, (95%), ms 183 (M+).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7]O[C:9]2=[O:14])([O-:3])=[O:2].[CH3:15][C:16]1([CH3:23])[O:20][CH:19]([CH2:21][NH2:22])[CH2:18][O:17]1.CO>>[CH3:15][C:16]1([CH3:23])[O:20][CH:19]([CH2:21][N:22]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[CH:13][C:4]=3[N+:1]([O-:3])=[O:2])[C:9]2=[O:14])[CH2:18][O:17]1
Reactant: CC1(C)OCC(CN)O1
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Solvent: CO
Product: CC1(C)OCC(Cn2ccc3c([N+](=O)[O-])cccc3c2=O)O1

Procedure:
5-Nitro-isochromen-1-one (8 g, 0.04 mol) and (2,2-dimethyl-1,3-dioxolan-4-yl)methanamine (5 g, 0.04 mol) were refluxed in methanol (40 mL, 1 mol) for 2 hours. The volatiles were removed via rotovapor, and the residue was purified via flash column chromatography (330 g of silica gel, 0-50% EtOAc/Hexane) to give a bright yellow solids.
Reaction SMILES: [CH:1]1([CH:6]=[CH:7][C:8]#[N:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:16]1[CH:20]=[C:19]([C:21]2[C:22]3[CH:29]=[CH:28][N:27]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:23]=3[N:24]=[CH:25][N:26]=2)[CH:18]=[N:17]1>C(#N)C>[CH:1]1([CH:6]([N:16]2[CH:20]=[C:19]([C:21]3[C:22]4[CH:29]=[CH:28][N:27]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:23]=4[N:24]=[CH:25][N:26]=3)[CH:18]=[N:17]2)[CH2:7][C:8]#[N:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Reactant: N#CC=CC1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)C4CCCC4)c3)ncnc21
Temperature: 65 °C
Reaction time: 12 h
Yield: 97.8 %

Procedure:
Method B. Into a four-neck 250 mL round bottom flask equipped with a stir bar, thermocouple, condenser and nitrogen inlet was charged (35)-cyclopentyl-3-{4-[7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]pyrazol-1-yl}propionitrile ((S)-10, 13.9 g, 31.5 mmol), acetonitrile (84 mL) and 3-cyclopentylacrylonitrile (8, a mixture of E and Z isomers, 3.82 g, 31.5 mmol, 1.0 equiv) at room temperature. The resulting mixture was then treated with cesium carbonate (Cs2CO3, 2.57 g, 7.88 mmol, 0.25 equiv) at room temperature. The reaction mixture was warmed to 65° C. and checked after 12 hours by chiral HPLC to determine the enantiomeric ratio of compound (R)-10 to compound (S)-10. When the ratio of compound (R)-10 to compound (S)-10 reached to one to one, the reaction mixture was then allowed to cool to room temperature gradually and stirred at room temperature for 24 to 48 h. The reaction mixture was monitored by HPLC to determine the level of 4-(1H-pyrazol-4-yl)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (5). The reaction was considered complete when the level of compound 5 was found to be ≦2% by HPLC area %. The reaction mixture was then filtered through a Celite pad to remove insoluble solids present in the reaction solution. The filtrates were then concentrated under reduced pressure to remove about 40 mL of solvent. The concentrated solution was diluted with ethyl acetate (40 mL) and washed with 1 N aqueous HCl solution (40 mL). The two layers were separated, and the aqueous acid wash solution was back extracted with ethyl acetate (20 mL). The combined organic fractions were washed with 1 M aqueous sodium bicarbonate (NaHCO3) solution (45 mL) and 20% (w/w) brine solution (40 mL). The organic fraction was dried over magnesium sulfate (MgSO4) and concentrated under reduced pressure to afford the crude racemic 3-cyclopentyl-3-{4-[7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]pyrazol-1-yl}propionitrile (9, racemic SEM-protected compound, 13.6 g, 13.9 g theoretical, 97.8%) as an amber oil, which was found to be identical to the material made by Method A. This crude product was found to be pure enough (>96 area % by HPLC) and was directly used in the subsequent chiral separation without further purification.
Reaction SMILES: [OH:1][C@H:2]1[CH:16]=[C:15]2[C@:5]([CH3:17])([CH2:6][C:7]3[C:8](=[CH:14]2)[O:9][C:10](=[O:13])[C:11]=3[CH3:12])[C@@H:4]([CH3:18])[C@H:3]1[O:19][C:20](=[O:23])[CH2:21][CH3:22].N1C=CC=CC=1.[CH:30]1([C:33](Cl)=[O:34])[CH2:32][CH2:31]1>>[CH:30]1([C:33]([O:1][C@H:2]2[CH:16]=[C:15]3[C@:5]([CH3:17])([CH2:6][C:7]4[C:8](=[CH:14]3)[O:9][C:10](=[O:13])[C:11]=4[CH3:12])[C@@H:4]([CH3:18])[C@H:3]2[O:19][C:20](=[O:23])[CH2:21][CH3:22])=[O:34])[CH2:32][CH2:31]1
Reactant: O=C(Cl)C1CC1
Reactant: CCC(=O)O[C@H]1[C@@H](O)C=C2C=C3OC(=O)C(C)=C3C[C@]2(C)[C@H]1C
Solvent: c1ccncc1
Product: CCC(=O)O[C@H]1[C@@H](OC(=O)C2CC2)C=C2C=C3OC(=O)C(C)=C3C[C@]2(C)[C@H]1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.3 %

Procedure:
The title compound (70 mg, 96%) was prepared in the same manner as in Example A3, except that the compound (60 mg, 0.19 mmol) prepared in Example A2, anhydrous pyridine (151 μl, 1.87 mmol), and cyclopropanecarbonyl chloride (68 μl, 0.75 mmol) were stirred at 25° C. for 30 min and the purification was performed by column chromatography on silica gel (toluene:ethyl acetate=20:1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH2:8][CH3:9].[OH:10][C:11]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14].[CH2:21](OCC)[CH3:22]>CC(=O)CC>[CH2:21]([O:10][C:11]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:12]=1[C:13]([O:15][CH2:8][CH3:9])=[O:14])[CH3:22]
Reactant: CCI
Reactant: O=C(O)c1ccc(I)cc1O
Reactant: CCOCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)c1ccc(I)cc1OCC
Temperature: 80 °C
Yield: 49 %

Procedure:
Potassium carbonate (100 g, 724 mmol) and iodoethane (29.1 mL, 364 mmol) were added to a mechanically stirred solution of 2-hydroxy-4-iodobenzoic acid (16.0 g, 60.6 mmol, prepared according to Singh, S.; et al. J. Med. Chem. 1997, 40, 2472-2481) in 2-butanone (250 mL). The resulting mixture was heated at 80° C. for 16 h and then allowed to cool. Diethyl ether (250 mL) was added to the reaction vessel and the supernatant was transferred to a separatory funnel. Diethyl ether (250 mL) was again added to the reaction vessel to wash the remaining solid and the supernatant was again transferred to the separatory funnel. Water (400 mL) was added and the phases were separated. The aqueous phase was washed twice with diethyl ether (500 mL, 200 mL) and then the combined organic phases were washed with water (400 mL), brine (400 mL), dried over magnesium sulfate and concentrated. Purification of the crude residue by flash column chromatography (silica gel, eluting with 10% ethyl acetate in hexanes) gave ethyl 2-ethoxy-4-iodobenzoate as an off-white solid (9.50 g, 49%).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.[Cl:10][S:11](O)(=[O:13])=[O:12].S(Cl)(Cl)(=O)=O>ClCCl>[F:1][C:2]([F:9])([F:8])[C:3]1[S:4][C:5]([S:11]([Cl:10])(=[O:13])=[O:12])=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)Cl
Reactant: FC(F)(F)c1cccs1
Solvent: ClCCl
Solvent: O=S(=O)(Cl)Cl
Product: O=S(=O)(Cl)c1ccc(C(F)(F)F)s1

Procedure:
5-trifluoromethyl-thiophene-2-sulfonylchloride was prepared from commercially available 2-trifluoromethyl-thiophene through reaction with chlorosulfonic acid in dichloromethane and subsequent silica gel chromatography (1H-NMR of the sulfonylchloride (CDCl3, 400 MHz): δ [ppm] 7.9 (1H, d), 7.5 (1H, d)).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:22](=[O:23])[C:11]2=[CH:12][C:13]([CH:20]=O)=[C:14]3[N:19]([C:10]2=[N:9]1)[CH:18]=[CH:17][CH:16]=[CH:15]3.[CH3:24][C:25]1[CH:30]=[CH:29][N:28]=[C:27]([C:31]2([C:37]#[N:38])[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:26]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl.C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:22](=[O:23])[C:11]2=[CH:12][C:13]([CH2:20][N:34]3[CH2:35][CH2:36][C:31]([C:27]4[CH:26]=[C:25]([CH3:24])[CH:30]=[CH:29][N:28]=4)([C:37]#[N:38])[CH2:32][CH2:33]3)=[C:14]3[N:19]([C:10]2=[N:9]1)[CH:18]=[CH:17][CH:16]=[CH:15]3
Reactant: O=Cc1cc2c(=O)n(-c3ccccc3F)nc-2n2ccccc12
Reactant: Cc1ccnc(C2(C#N)CCNCC2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: CC#N
Product: Cc1ccnc(C2(C#N)CCN(Cc3cc4c(=O)n(-c5ccccc5F)nc-4n4ccccc34)CC2)c1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
2-(2-Fluorophenyl)-3-oxo-2,3-dihydropyrazolo[4,3-c]quinolizine-5-carbaldehyde (0.025 g, 0.081 mmol) was suspended in a mixture of 1,2-dichloroethane (2 mL) and acetonitrile (4 mL) containing powdered 4 Å molecular sieves and treated with 4-(4-methylpyridin-2-yl)piperidine-4-carbonitrile (0.018 g, 0.094 mmol. 1.2 equiv), acetic acid (0.028 mL, 0.49 mmol, 6.0 equiv), and sodium triacetoxyborohydride (0.034 g, 0.16 mmol, 2.0 equiv). After stirring at ambient temperature for 60 hours, the mixture was poured into saturated aqueous sodium bicarbonate and extracted with dichloromethane (2×).
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[CH:14][C:13]=1[CH:20]=[CH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:7])(C)(C)C.Cl.[N:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][CH:37](C(O)=O)[CH2:36][CH2:35]2)=[CH:30][CH:29]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)CC)C>Cl.O1CCOCC1>[C:18]([C:16]1[CH:15]=[CH:14][C:13]([CH:20]=[CH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:12]([O:11][CH2:10][CH2:9][NH:8][C:6]([CH:37]2[CH2:36][CH2:35][N:34]([C:31]3[CH:32]=[CH:33][N:28]=[CH:29][CH:30]=3)[CH2:39][CH2:38]2)=[O:7])[CH:17]=1)#[N:19]
Reactant: O=C(O)C1CCN(c2ccncc2)CC1
Reactant: CCOC(=O)C=Cc1ccc(C#N)cc1OCCNC(=O)OC(C)(C)C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCOC(=O)C=Cc1ccc(C#N)cc1OCCNC(=O)C1CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3.0 g (8.33 mmol) of ethyl 3-[2-(2-(t-butoxycarbonylamino)ethoxy)-4-cyanophenyl]acrylate was dissolved in a mixture of 20 ml of 4 N solution of hydrogen chloride in dioxane and 10 ml of dioxane. The obtained solution was stirred at room temperature for 4 hours. The solvent was evaporated and the residue was dissolved in 50 ml of DMF. 2.22 g (9.17 mmol) of 1-(4-pyridyl)-4-piperidinecarboxyic acid hydrochloride, 4.27 g (9.17 mmol) of bromotripyrrolidinophosphonium hexafluorophosphate and 3.48 ml (25.0 mmol) of triethylamine were added to the obtained solution, and they were stirred at room temperature for 3 days. The solvent was evaporated, and the obtained crude product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC([N:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH:17]([CH3:22])[CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:21][N:18]1[CH2:19][CH2:20][NH:15][CH2:16][CH:17]1[CH3:22]
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1CNCCN1C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (15 mL) was added to 3,4-dimethylpiperazine-1-carboxylic acid tert-butyl ester (3.10 g) obtained from Referential Example 83 in methylene chloride (30 mL) at room temperature, followed by stirring for 1 hour. The residue obtained by removal through evaporation of the reaction solvent under reduced pressure was crystallized from chloroform-ether, and the crystals were recovered by filtration, to thereby give the title compound (2.756 g, 56%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-])=O)=[C:6]([OH:9])[C:7]=1[Cl:8].[Sn](Cl)Cl.[OH-].[Na+].C(OCC)(=O)C>C(O)C>[NH2:10][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[C:7]([Cl:8])[C:6]=1[OH:9]
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1O
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(Cl)c(Cl)c1O
Temperature: 80 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
A mixture of 5,6-dichloro-2-nitrophenol(1.8 g, 8.7 mmol) and tin (II) chloride (5.8 g, 26.1 mmol) in ethanol(50 mL) was heated at 80° C. under argon. After 2 hours, the starting material had disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH, before being extrated with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/CH2Cl2) gave the desired product(1.4 mg, 90%). 1H NMR (CD3OD): δ 6.71 (d, 1H), 6.45 (d, 1H).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][N:16]=2)[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])=S.C([NH:24][NH2:25])=O.[CH2:26]1COCC1>C([O-])(=O)C.[Hg+]>[CH3:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]2[CH:12]=[C:7]([CH:6]=[C:5]([C:3]3[N:2]([CH3:26])[CH:1]=[N:25][N:24]=3)[CH:14]=2)[C:8]([O:10][CH3:11])=[O:9])=[N:16][CH:17]=1
Reactant: CNC(=S)c1cc(C(=O)OC)cc(-c2ccc(C)cn2)c1
Reactant: NNC=O
Reactant: C1CCOC1
Agent: CC(=O)[O-]
Agent: [Hg+]
Product: COC(=O)c1cc(-c2ccc(C)cn2)cc(-c2nncn2C)c1
Temperature: 40 °C
Reaction time: 16 h

Procedure:
To a solution of methyl 3-[(methylamino)carbonothioyl]-5-(5-methylpyridin-2-yl)benzoate (0.90 g, 3.00 mmol) in THF (30 mL) was added formic hydrazide (0.54 g, 8.99 mmol) and mercury acetate (1.72 g, 5.39 mmol) and the mixture heated to 40° C. After 16 h, the reaction was cooled to ambient temperature, filtered and concentrated. The organic residue was dissolved in 100 ml of dichloromethane and washed with 50 mL of saturated aqueous sodium bicarbonate (2×). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (100% dichloromethane→90% dichloromethane/methanol) to give the title compound (0.37 g). MS 309.1 (M+1).
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]3[S:23][C:22]([CH2:24][N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[CH:21][C:10]=3[N:11]=[C:12]([C:14]3[CH:15]=[N:16][C:17]([NH2:20])=[N:18][CH:19]=3)[N:13]=2)[CH2:4][CH2:3]1.[CH3:31][N:32]([CH3:37])[CH2:33][C:34](O)=[O:35]>>[NH2:20][C:17]1[N:18]=[CH:19][C:14]([C:12]2[N:13]=[C:8]([N:5]3[CH2:4][CH2:3][O:2][CH2:7][CH2:6]3)[C:9]3[S:23][C:22]([CH2:24][N:25]4[CH2:26][CH2:27][N:28]([C:34](=[O:35])[CH2:33][N:32]([CH3:37])[CH3:31])[CH2:29][CH2:30]4)=[CH:21][C:10]=3[N:11]=2)=[CH:15][N:16]=1
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCNCC4)cc3n2)cn1
Reactant: CN(C)CC(=O)O
Agent: Cl
Product: CN(C)CC(=O)N1CCN(Cc2cc3nc(-c4cnc(N)nc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
The HCl salt of 5-(4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidin-2-yl)pyrimidin-2-amine (100 mg) was reacted with N,N-dimethylglycine via General Procedure B to generate 38.3 mg of 105. MS (Q1) 498.3 (M)+.
Reaction SMILES: [CH:1]([Si:4]([CH:35]([CH3:37])[CH3:36])([CH:32]([CH3:34])[CH3:33])[N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15]([C:17]3[S:21][C:20]([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=4)=[N:19][C:18]=3[CH2:29][CH2:30]O)=[O:16])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)([CH3:3])[CH3:2].CCN(CC)CC>C(Cl)Cl.CCOC(C)=O.CS(Cl)(=O)=O>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C:20]2[S:21][C:17]3[C:15](=[O:16])[N:14]([C:10]4[CH:9]=[C:8]5[C:13](=[CH:12][CH:11]=4)[N:5]([Si:4]([CH:35]([CH3:37])[CH3:36])([CH:1]([CH3:2])[CH3:3])[CH:32]([CH3:34])[CH3:33])[CH:6]=[CH:7]5)[CH2:30][CH2:29][C:18]=3[N:19]=2)=[CH:23][CH:24]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(NC(=O)c3sc(-c4ccc(Cl)cc4)nc3CCO)ccc21
Agent: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(N3CCc4nc(-c5ccc(Cl)cc5)sc4C3=O)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Dissolve 2-(4-chloro-phenyl)-4-(2-hydroxy-ethyl)-thiazole-5-carboxylic acid (1-triisopropylsilanyl-1H-indol-5-yl)-amide in CH2Cl2 (25 mL) and add Et3N (0.33 mL, 2.36 mmol) and methanesulfonyl chloride (0.16 mmol, 2.13 mmol). Stir the mixture at room temperature for 2 h, then add additional Et3N (0.33 mL, 2.36 mmol) and methanesulfonyl chloride (0.16 mmol, 2.13 mmol). Stir the mixture for an additional 2 h, dilute with EtOAc (50 mL), then wash with water (20 mL) and brine (20 mL). Dry, filter and concentrate the organic solution then and purify the crude material by flash chromatography, using a linear gradient of 100% hexanes to 50% EtOAc/hexanes as eluent, to give the title compound (1.15 g, 100%). MS (ES+) 536.1 (M+1)+. 1H NMR (400 MHz, CDCl3) δ: 7.93 (d, 2H, J=8.3 Hz), 7.56 (d, 1H, J=1.8 Hz), 7.50 (d, 1H, J=8.8 Hz), 7.44 (d, 2H, J=8.3 Hz), 7.27 (d, 1H, J=3.1 Hz), 7.14-7.10 (m, 1H), 6.61 (d, 1H, J=2.6 Hz), 4.16 (t, 2H, J=6.8 Hz), 3.29 (t, 2H, J=7.0 Hz), 1.73-1.65 (m, 3H), 1.14 (d, 18H, J=7.5 Hz).
Reaction SMILES: Cl.C[O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][C@H:10]([NH:15][CH2:16][CH2:17][CH3:18])[C@@H:11]2[CH3:14])=[CH:6][CH:5]=1.C(O)C.C(OCC)C.[BrH:27]>>[BrH:27].[OH:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][C@H:10]([NH:15][CH2:16][CH2:17][CH3:18])[C@@H:11]2[CH3:14])=[CH:6][CH:5]=1
Reactant: CCCN[C@H]1CCc2ccc(OC)cc2[C@H]1C
Agent: Br
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: CCCN[C@H]1CCc2ccc(O)cc2[C@H]1C
Yield: 70 %

Procedure:
cis-7-Methoxy-1-methyl-2-(n-propylamino) tetralin hydrochloride (100 mg, 0.37 mmol) was heated in 48% aqueous HBr for 3 h at 120° C. under N2. The volatiles were evaporated from the faint pink solution and the residue was treated twice with ethanol followed by evaporation, giving a faint pink residue which was dissolved in abs. ethanol. Dry abs. ethyl ether was added to the solution, yielding white crystals which were then recrystallized from MeOH-ethyl ether, yielding the desired product (75 mg, 70% yield), m.p. 262°-263° C.