Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([N:13]3C(=O)C4=CC=CC=C4C3=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.O.NN.Cl>C(O)C>[NH2:13][CH:10]1[CH2:9][CH2:8][N:7]([CH2:6][C:5]2[CH:24]=[CH:25][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:12][CH2:11]1
Reactant: O=C1c2ccccc2C(=O)N1C1CCN(Cc2ccc(F)cc2)CC1
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: NC1CCN(Cc2ccc(F)cc2)CC1
Yield: 91.7 %

Procedure:
To a solution of 1-(p-fluorobenzyl)-4-phthalimidopiperidine (3.0 g, 8.9 mmol) in ethanol (30 ml) was added hydrazine monohydrate (0.7 ml) and the mixture was heated under reflux for 3 hours. After allowed to cool, to the reaction mixture was added 5N hydrochloric acid (50 ml) and insolubles were filtered off. Then, the filtrate was washed with chloroform (30 ml×3). The aqueous layer was neutralized with potassium carbonate and then extracted with chloroform (50 ml×4). After drying over anhydrous magnesium sulfate, the solvent was distilled off to give 1.7 g of the title compound. Yield=94%.
Reaction SMILES: [CH3:1][C:2]([CH3:46])=[CH:3][CH2:4][CH2:5]/[C:6](/[CH3:45])=[CH:7]/[CH2:8][CH2:9]/[C:10](/[CH3:44])=[CH:11]/[CH2:12][CH2:13]/[C:14](/[CH3:43])=[CH:15]/[CH2:16][CH2:17]/[C:18](/[CH3:42])=[CH:19]/[CH2:20][CH2:21]/[C:22](/[CH3:41])=[CH:23]/[CH2:24][CH2:25]/[C:26](/[CH3:40])=[CH:27]/[CH2:28][CH2:29]/[C:30](/[CH3:39])=[CH:31]/[CH2:32][CH2:33]/[C:34](/[CH3:38])=[CH:35]/[CH2:36][OH:37].[C:47](Cl)(=[O:54])[C:48]1[CH:53]=[CH:52][CH:51]=[N:50][CH:49]=1>N1C=CC=CC=1.CCCCCC>[C:47]([O:37][CH2:36][CH:35]=[C:34]([CH3:38])[CH2:33][CH2:32][CH:31]=[C:30]([CH3:39])[CH2:29][CH2:28][CH:27]=[C:26]([CH3:40])[CH2:25][CH2:24][CH:23]=[C:22]([CH3:41])[CH2:21][CH2:20][CH:19]=[C:18]([CH3:42])[CH2:17][CH2:16][CH:15]=[C:14]([CH3:43])[CH2:13][CH2:12][CH:11]=[C:10]([CH3:44])[CH2:9][CH2:8][CH:7]=[C:6]([CH3:45])[CH2:5][CH2:4][CH:3]=[C:2]([CH3:46])[CH3:1])(=[O:54])[C:48]1[CH:53]=[CH:52][CH:51]=[N:50][CH:49]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CO
Solvent: c1ccncc1
Solvent: CCCCCC
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCOC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10 Grams of solanesol were dissolved in 50 ml of pyridine and the solution was added with a solution of 4.5 g of nicotinic acid chloride in pyridine dropwise over 30 minutes. After completion of the addition, the mixture was stirred at room temperature for two hours to complete the reaction. The reaction product was diluted with n-hexane, washed with water and concentrated. The concentrate was purified by chromatography with 80 g of silica gel in n-hexane/ether solvent mixture as elution solvent to obtain a white yellow waxy final product.
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[N+:15]([O-])([O-:17])=[O:16].[Na+]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[NH:12]2)=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16]
Reactant: Fc1ccc2c(c1)[nH]c1ccccc12
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=[N+]([O-])c1cc2c(cc1F)[nH]c1ccccc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 45.1 %

Procedure:
3-Fluoro-benzohydrazine (3.3 g) and cyclohexanone (2.2 g) were added to ethanol (30 ml) and the mixture was stirred for 2 hours under reflux. The reaction mixture was concentrated and the resulting residue was recrystallized from hexane to obtain 7-fluoro-carbazole (1.81 g, 48%). Then, concentrated sulfuric acid (20 ml) was cooled to 0° C. and added with 7-fluoro-carbazole (2.1 g) and sodium nitrate (900 mg), and then the mixture was stirred for 10 minutes. The reaction mixture was poured on an ice layer and filtered to obtain 7-fluoro-6-nitro-carbazole (1.1 g, 42%). The resulting 7-fluoro-6-nitro-carbazole (500 mg) and KOH (200 mg) were stirred in acetonitrile as a solvent, and then the mixture was added dropwise with 2-iodopropane (500 mg) and stirred for 8 hours. The reaction mixture was added with water and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography (adsorbent: silica gel, developing solvent: ethyl acetate/hexane) to obtain 7-fluoro-1-isopropyl-6-nitro-carbazole (254 mg, 43%). The resulting 7-fluoro-1-isopropyl-6-nitro-carbazole (500 mg) and Fe (400 mg) were stirred in i-PrOH/water solvent (1:1) under reflux. The reaction mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography (adsorbent: silica gel, developing solvent: ethyl acetate/hexane) to obtain 6-amino-7-fluoro-isopropyl-carbazole (290 mg, 65%). The resulting amino compound (500 mg) was dissolved in chloroform (10 ml), and the solution was added dropwise with phenyl chloroformate (190 mg) and stirred for 2 hours. The reaction mixture was added with water and extracted. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography (adsorbent: silica gel, developing solvent: ethyl acetate/hexane) to obtain phenylurethane (263 mg, 61%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([CH3:27])[CH:21]=2)[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].Cl.[Cl:35][CH2:36][CH2:37][N:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1.Cl>C1C=CC=CC=1.CC(C)=O>[ClH:35].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:36][CH2:37][N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)=[C:22]([CH3:27])[CH:21]=2)[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: ClCCN1CCCC1
Reactant: COc1ccc(C(c2ccc(O)c(C)c2)c2cccc3ccccc23)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: c1ccccc1
Product: COc1ccc(C(c2ccc(OCCN3CCCC3)c(C)c2)c2cccc3ccccc23)cc1

Procedure:
A mixture of (4-methoxyphenyl)-(3-methyl-4-hydroxyphenyl)-naphth-1-yl-methane (0.3 gm, 0.008 mol), anhydrous K2CO3 (2.0 gm), 1-(2-chloroethyl)pyrrolidine hydrochloride (0.3 gm, 0.0017 mol) and anhydrous acetone (25 ml) was refluxed for 10 hrs, K2CO3 was filtered off, acetone was distilled off, and the residue was diluted with water. The reaction mixture was extracted with ethyl acetate washed with water, dried over Na2SO4 and concentrated to give an oil. This oil was passed through basic alumina using benzene as eluent. Solvent was distilled off. The oil thus obtained was treated with ethanolic HCl. The solvent was evaporated and compound was crystallized with absolute alcohol and anhydrous ether to give the title compound as a salt of general formula I. Yield 170 mg(46%).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[CH2:18]([O:21][CH3:22])[C:19]#[CH:20].O>C(COC)OC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:22][O:21][CH2:18][C:19]#[C:20][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1nc(-c2ccccc2)sc1Br
Reactant: C#CCOC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)c1nc(-c2ccccc2)sc1C#CCOC
Temperature: 25 °C
Yield: 87.1 %

Procedure:
Nitrogen was bubbled through a solution of Ethyl 5-bromo-2-phenylthiazole-4-carboxylate (13.1 g, 41.9 mmol) and methyl propargyl ether (7.1 mL, 83.9 mmol) in dimethoxyethane (DME) (200 mL). Dichlorobis(triphenylphosphine)palladium (II) (1.47 g, 2.2 mmol), copper (I) iodide (0.2 g, 1.1 mmol), and TEA (29 mL, 210 mmol) were added and the reaction mixture was heated at reflux for 16 h. The reaction mixture was cooled to room temperature, poured into H2O (200 mL) and extracted with EtOAc (2×200 mL). The combined organics were washed with brine, dried (MgSO4), and concentrated. The crude product was purified by MPLC eluting with pentane/EtOAc (0-50% gradient) to give ethyl 5-(3-methoxyprop-1-ynyl)-2-phenylthiazole-4-carboxylate as a tan solid (11 g, 88% yield).
Reaction SMILES: [CH:1]1([CH2:6][OH:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:8][S:9](Cl)(=[O:11])=[O:10].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:8][S:9]([O:7][CH2:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: OCC1CCCC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CS(=O)(=O)OCC1CCCC1
Temperature: 4 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
Cyclopentanemethanol (50.0 g; 0.484 mol) and methane-sulfonyl chloride (67.0 g; 0.581 mol) in toluene (500 ml) were stirred and cooled to 4° C. Triethylamine (68.0 g; 0.678 mol) was added dropwise with external cooling so that the reaction temperature remained below 20° C. The reaction mixture is stirred under dry nitrogen at room temperature overnight. The reaction mixture was quenched with water (500 ml) and ether (500 ml), the organic phase separated, washed with water (500 ml) and saturated brine (500 ml) and dried (MgSO4). The solution is filtered and the solvent evaporated, to afford cyclopentylmethyl methanesulfonate (86.0 g; 100% yield) as a colorless liquid. NMR - d(CDCl3 ; 60 MHz) 0.8-2.6 (9H, m), 3.1 (3H, s) and 4.15 (2H, d, J=8 Hz).
Reaction SMILES: [CH:1]1([O:6][C:7]2[C:12]([O:13][CH:14]([F:16])[F:15])=[CH:11][CH:10]=[CH:9][C:8]=2/[CH:17]=[CH:18]/[C:19]2[N:20]=[C:21]3[N:25]([C:26]=2[C:27]([OH:29])=O)[CH:24]=[CH:23][S:22]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:30][C:31]([F:39])([F:38])[C:32]1[N:33]=[C:34]([NH2:37])[S:35][CH:36]=1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C1COCC1.CN(C=O)C>[CH:1]1([O:6][C:7]2[C:12]([O:13][CH:14]([F:16])[F:15])=[CH:11][CH:10]=[CH:9][C:8]=2/[CH:17]=[CH:18]/[C:19]2[N:20]=[C:21]3[N:25]([C:26]=2[C:27]([NH:37][C:34]2[S:35][CH:36]=[C:32]([C:31]([F:39])([F:38])[F:30])[N:33]=2)=[O:29])[CH:24]=[CH:23][S:22]3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1nc(C(F)(F)F)cs1
Reactant: O=C(O)c1c(/C=C/c2cccc(OC(F)F)c2OC2CCCC2)nc2sccn12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Nc1nc(C(F)(F)F)cs1)c1c(/C=C/c2cccc(OC(F)F)c2OC2CCCC2)nc2sccn12

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 5 (365 mg, 0.868 mmol) with 4-(trifluoromethyl)-1,3-thiazol-2-amine (157 mg, 0.965 mmol) in the presence of EDCI hydrochloride (333 mg, 1.737 mmol) and DMAP (98 mg, 0.868 mmol) in a mixture of THF and DMF (1:1, 6 mL) to give 34 mg of the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.75-1.85 (m, 8H), 4.70-4.78 (m, 1H), 7.18 (t, J=74.7 Hz, 1H), 7.20-7.5 (m, 2H), 7.40-7.46 (m, 1H), 7.53 (d, J=15.9 Hz, 1H), 7.60-7.70 (m, 1H), 7.79 (d, J=15.0 Hz, 1H), 8.05-8.12 (m, 2H), 13.03 (br s, 1H); APCI-MS (m/z) 571.07 (MH)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:17]1[C:18]2[C:19](=[C:23]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=3)[N:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:32])[N:25]=2)[N:20]=[CH:21][N:22]=1>CN(C)C=O.C(OC)(C)(C)C>[CH2:3]([N:10]1[CH2:14][CH2:13][CH:12]([O:15][C:17]2[C:18]3[C:19](=[C:23]([C:33]4[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=4)[N:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[Cl:32])[N:25]=3)[N:20]=[CH:21][N:22]=2)[CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: OC1CCN(Cc2ccccc2)C1
Reactant: Clc1ccc(-c2c3ncnc(Cl)c3nn2-c2ccccc2Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: Clc1ccc(-c2c3ncnc(OC4CCN(Cc5ccccc5)C4)c3nn2-c2ccccc2Cl)cc1
Reaction time: 2 h
Yield: 31.3 %

Procedure:
Sodium hydride (24 mg of a 60% dispersion in mineral oil, 0.6 mmol) was added to a solution of 1-benzylpyrrolidin-3-ol (0.1 ml, 0.6 mmol) in dimethylformamide (1 ml), and the resultant mixture was stirred at room temperature for 5 min. Next, 7-chloro-3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidine 1-2A-1c (50 mg, 0.13 mmol) was added in one portion, and the mixture was stirred for 2 hours. The reaction mixture was diluted with methyl tert-butyl ether and washed with water (3×). The organic phase was dried over anhydrous magnesium sulfate and concentrated. Purification of the residue by flash column chromatography (50% ethyl acetate in hexanes) provided the title compound 7-(1-benzylpyrrolidin-3-yloxy)-3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidine 7A-1 (21 mg): MS: 516.1 (M+1)+; 1H NMR (400 MHz, CDCl3) δ 8.6 (s, 1H), 7.5 (m, 6H), 7.3 (m, 7H), 5.8 (m, 1H), 3.7 (s, 2H), 3.2 (m, 1H), 2.9 (m, 1H), 2.8 (m, 1H), 2.7 (m, 1H), 2.5 (m, 1H), 2.2 (m, 1H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[OH:11])[CH3:2].[C:12](O)(=[O:14])C>>[CH2:1]([C:3]1[CH:8]=[C:7]([CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[OH:11])[CH:12]=[O:14])[CH3:2]
Reactant: CC(=O)O
Reactant: CCc1cccc(CC)c1O
Product: CCc1cc(C=O)cc(CC)c1O
Temperature: 120 °C
Yield: 39.9 %

Procedure:
To a solution of 2,6-diethylphenol (3.80 g, 25.3 mmol) in acetic acid (30 mL) hexamethylenetetraamine (5.3 g, 37.9 mmol) is added and the mixture is heated to 120° C. A first fraction of the solvent is distilled off (Dean-Stark), then the mixture is refluxed for 3 h. The mixture is cooled to rt, diluted with water (100 mL) and extracted twice with EA (2×200 mL). The organic extracts are washed with sat. aq. NaHCO3, dried and the solvent is removed in vacuo. The crude product is purified by column chromatography eluting with DCM containing 2% of methanol to give 3,5-diethyl-4-hydroxybenzaldehyde (1.8 g) as colourless solid; 1H NMR (CDCl3): δ 9.85 (s, 1H), 7.57 (s, 2H), 5.32 (s, 1H), 2.69 (q, J=7.6 Hz, 2H), 1.30 (t, J=7.6 Hz, 3H).
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:11]C(=O)C)[CH2:4][C:5]1[CH:10]=[N:9][CH:8]=[CH:7][N:6]=1.[ClH:15]>>[ClH:15].[ClH:15].[NH2:11][CH:3]([CH2:4][C:5]1[CH:10]=[N:9][CH:8]=[CH:7][N:6]=1)[CH2:2][OH:1]
Reactant: CC(=O)NC(CO)Cc1cnccn1
Agent: Cl
Product: NC(CO)Cc1cnccn1

Procedure:
A solution of 11 g of N-[(1RS)-1-hydroxymethyl-2-(2-pyrazinyl)ethyl]acetamide in 30 cm3 of 5N hydrochloric acid is heated at a temperature in the region of 115° C. for 18 hours. The reaction mixture is concentrated under reduced pressure (1 kPa) at a temperature in the region of 40° C. 7.9 g of (2RS)-2-amino-3-(2-pyrazinyl)-1-propanol dihydrochloride are obtained in the form of a black paste [mass spectrum: DCI m/z=154 MH+]
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:12][CH:11]2[CH2:13]Br)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([NH:22][CH2:23][CH2:24][NH:25][CH3:26])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:1]1([S:7]([NH:10][CH:11]2[CH2:13][N:22]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:23][CH2:24][N:25]([CH3:26])[CH2:12]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CNCCNCc1ccccc1
Reactant: O=S(=O)(c1ccccc1)N1CC1CBr
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CN1CCN(Cc2ccccc2)CC(NS(=O)(=O)c2ccccc2)C1
Reaction time: 5 h
Yield: 22.3 %

Procedure:
A mixture of 1-benzenesulfonyl-2-bromomethylethylenimine (27.2 g), N-benzyl-N'-methylethylenediamine (16.2 g), triethylamine (19.9 g) and chloroform (350 ml) is refluxed with stirring for 5 hours. The solvent is evaporated under reduced pressure, and the residue is purified by silica gel chromatography to give the title compound (7.9 g) as an oil.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]([N:20]([CH3:22])[CH3:21])=[O:19])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.[N:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31][CH:30]=1>>[CH3:21][N:20]([CH3:22])[C:18]([N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:8][C:6]3[N:7]=[C:2]([C:33]4[CH:34]=[N:29][CH:30]=[N:31][CH:32]=4)[N:3]=[C:4]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:5]=3[CH:10]=2)[CH2:13][CH2:14]1)=[O:19]
Reactant: CN(C)C(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Reactant: OB(O)c1cncnc1
Product: CN(C)C(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(-c4cncnc4)nc3s2)CC1

Procedure:
4-((2-Chloro-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)-N,N-dimethylpiperazine-1-carboxamide was reacted with pyrimidine-5-boronic acid in General Procedure A. Purification on silica yielded 268. NMR (CDCl3): 2.55-2.57 (m, 4H, 2×CH2), 2.84 (s, 6H, 2×CH3), 3.31-3.33 (m, 4H, 2×CH2), 3.80 (s, 2H, CH2), 3.90-3.92 (m, 4H, 2×CH2), 3.99-4.02 (m, 4H, 2×CH2), 7.19 (s, H, ArH), 9.28 (s, H, ArH), 9.69 (s, 2H, 2×ArH). MS: (ESI+): MH+=469.24
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([Cl:8])=[C:4](Cl)[N:3]=1.[CH2:10]([N:12]1[CH2:18][CH2:17][C:16]2[CH:19]=[C:20]([NH2:23])[CH:21]=[CH:22][C:15]=2[CH2:14][CH2:13]1)[CH3:11].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:23][C:20]2[CH:21]=[CH:22][C:15]3[CH2:14][CH2:13][N:12]([CH2:10][CH3:11])[CH2:18][CH2:17][C:16]=3[CH:19]=2)[C:5]([Cl:8])=[CH:6][N:7]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CCN1CCc2ccc(N)cc2CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CCN1CCc2ccc(Nc3nc(Cl)ncc3Cl)cc2CC1
Temperature: 80 °C
Yield: 539.7 %

Procedure:
2,5,6-trichloropyrimidine (200 mg, 0.15 mmol) and 3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (209 mg, 1.10 mmol) were mixed with N,N-diisopropylethylamine (211 mg, 1.63 mmol) in 8 mL isopropyl alcohol and heated at 80° C. for 24 hours. The reaction was concentrated and the organics were partitioned between dichloromethane and saturated sodium bicarbonate solution. The organic layer was separated, was dried (sodium sulfate), and was concentrated. Chromatography on silica (1% to 20% methanol:dichloromethane gradient elution) afforded 273 mg (74%) of (2,5-dichloro-pyrimidin-4-yl)-(3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)-amine as a tan foam. MS: 338.55 (M+H).
Reaction SMILES: [CH:1]([C:3]1[CH:14]=[CH:13][C:6]([CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1)=O.C(O)(=O)[CH2:16][C:17]([OH:19])=[O:18].N1CCCCC1.Cl>N1C=CC=CC=1>[CH3:12][O:11][C:9]([CH2:8][CH2:7][C:6]1[CH:13]=[CH:14][C:3]([CH:1]=[CH:16][C:17]([OH:19])=[O:18])=[CH:4][CH:5]=1)=[O:10]
Reactant: O=C(O)CC(=O)O
Reactant: COC(=O)CCc1ccc(C=O)cc1
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: COC(=O)CCc1ccc(C=CC(=O)O)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
A solution of methyl 4-formylhydrocinnamate (2.30 g), malonic acid (2.50 g) and piperidine (0.1 ml) in 12 ml pyridine was stirred at 100° C. for 2 hours, and subsequently at 140° C. for 2 hours. After addition of 100 ml ice-cold water, 210 ml of 0.5 mol/l hydrochloric acid was added dropwise to the reaction mixture to precipitate a solid, which was then filtered, washed with water, and dried by heating under reduced pressure to give 4-[2-(methoxycarbonyl)ethyl]cinnamic acid (2.38 g, 84%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14](O)=[O:15])[CH:12]=2)[C:7]([C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])=[C:6]1[CH2:22][CH2:23][CH3:24].O[N:30]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.N>CN(C)C=O>[Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([NH2:30])=[O:15])[CH:12]=2)[C:7]([C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])=[C:6]1[CH2:22][CH2:23][CH3:24]
Reactant: On1nnc2ccccc21
Reactant: CCCc1c(C(=O)C(C)C)c2ccc(C(=O)O)cc2n1Cc1ccccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Product: CCCc1c(C(=O)C(C)C)c2ccc(C(N)=O)cc2n1Cc1ccccc1Cl
Temperature: 20 °C
Yield: 82.2 %

Procedure:
To a solution of 1-(2-chlorobenzyl)-3-isobutyryl-2-propylindole-6-carboxylic acid (150 mg) in dimethylformamide (3 ml) were added 1-hydroxybenzotriazole (102 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (109 mg). After stirred at 20° C. over night, the resulting mixture was poured into 28% aqueous ammonia (5 ml). The mixture was partitioned between ethyl acetate and water, and the organic phase was washed with 1N hydrochloric acid and brine, dried over sodium sulfate and evaporated in vacuo. The crystalline residue was recyrystallized from a mixture of ethyl acetate and hexane to give 1-(2-chlorobenzyl)-3-isobutyryl-2-propylindole-6-carboxamide (123 mg) as colorless crystals.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[CH:4][C:3]=1[CH3:12].[Cu][C:14]#[N:15]>CC(N(C)C)=O>[CH3:12][C:3]1[CH:4]=[C:5]([CH3:11])[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[C:14]#[N:15]
Reactant: N#C[Cu]
Reactant: Cc1cc(C)c(Cl)c([N+](=O)[O-])c1
Solvent: CC(=O)N(C)C
Product: Cc1cc(C)c(C#N)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 23.1 %

Procedure:
To a solution of 4,6-dimethyl-2-nitroaniline (3 g, 18.07 mmol) in acetic acid (20 mL) and 6 N HCl (60 mL) at 0° C. was added a solution of sodium nitrite (2.18 g, 31.62 mmol) in water (5 mL). The reaction mixture was stirred at 0° C. for 30 min after completion of addition and copper (I) cyanide (3.24 g, 3 mmol) was added pinch by pinch. The resulting mixture was stirred at 0° C. for 5 h and at room temperature for an additional 2 h. The mixture was passed through a Celite pad, extracted with EtOAc (3×100 mL), and concentrated using a rotary evaporator to afford a solid residue. The solid was further purified by column (SiO2, hexanes/EtOAc=7:1) to yield 2-chloro-1,5-dimethyl-3-nitro-benzene (2.6 g, 81%) as a light yellow solid. A solution of 2-chloro-1,5-dimethyl-3-nitro-benzene (2.6 g, 15.7 mmol) and copper (I) cyanide (7.05 g, 78.3 mmol) in DMAC (20 mL) was stirred at reflux for 14 h. The reaction mixture was cooled to room temperature, quenched by adding water (30 mL), filtered through a Celite pad, extracted with EtOAc (3×100 mL), and concentrated using a rotary evaporator to afford a solid residue. The solid was further purified by column (SiO2, hexanes/EtOAc=6:1) to yield 0.64 g of 2,4-dimethyl-6-nitro-benzonitrile (23%). A solution of 2,4-dimethyl-6-nitro-benzonitrile (1.1 g, 6.24 mmol) in MeOH (20 mL) and water (10 mL) was mixed with hydrogen peroxide (10 mL), DMSO (10 mL) and potassium hydroxide (0.636 g, 11.36 mmol). The reaction mixture was stirred at 60° C. for 3 h, diluted with water (100 mL), extracted with EtOAc (3×100 mL), and concentrated using a rotary evaporator to afford 4,6-dimethyl-2-nitrobenzamide (0.52 g, 43%). A solution of 4,6-dimethyl-2-nitrobenzamide (0.52 g, 2.68 mmol) in MeOH (30 mL) was mixed with palladium carbon (0.25 g). The resulting suspension was stirred at room temperature under hydrogen for 14 h. The mixture was passed through a Celite pad, concentrated using a rotary evaporator to afford 2-amino-4,6-dimethylbenzamide (0.42 g, 95%).
Reaction SMILES: I[C:2]1[N:6]2[CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:21][Si:22]([C:25]#[CH:26])([CH3:24])[CH3:23]>>[F:18][C:17]([F:20])([F:19])[C:14]1[CH:15]=[CH:16][C:11]([C:8]2[CH:9]=[CH:10][C:5]3[N:6]([C:2]([C:26]#[C:25][Si:22]([CH3:24])([CH3:23])[CH3:21])=[CH:3][N:4]=3)[CH:7]=2)=[CH:12][CH:13]=1
Reactant: C#C[Si](C)(C)C
Reactant: FC(F)(F)c1ccc(-c2ccc3ncc(I)n3c2)cc1
Product: C[Si](C)(C)C#Cc1cnc2ccc(-c3ccc(C(F)(F)F)cc3)cn12
Yield: 88.3 %

Procedure:
Prepared from 3-iodo-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (example C.24 step 2) (2.3 g, 6 mmol) and trimethylsilylacetylene (1.64 mL, 12 mmol) as described in example C.20 step 4. Obtained the title compound as a yellow solid (1.9 g, 89%). MS (ISP) 359.1 [(M+H)+].