Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]4[CH2:30][CH2:29][C:27](=[O:28])[NH:26][C:24]=4[CH:25]=3)[CH2:11][CH2:10]2)[C:4]([Cl:8])=[C:5]([Cl:7])[CH:6]=1.[H-].[Na+].[I-].[Na+].[OH2:35].O1[CH2:41][CH2:40][O:39][CH2:38]C1>>[C:40]([O:39][CH2:38][N:26]1[C:24]2[C:23](=[CH:22][CH:21]=[C:20]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][N:12]3[CH2:13][CH2:14][N:9]([C:3]4[CH:2]=[CH:1][CH:6]=[C:5]([Cl:7])[C:4]=4[Cl:8])[CH2:10][CH2:11]3)[CH:25]=2)[CH2:30][CH2:29][C:27]1=[O:28])(=[O:35])[CH2:41][CH2:22][CH2:21][CH2:20][CH2:25][CH2:24][CH2:23][CH2:30][CH3:29]
Reactant: O
Reactant: C1COCCO1
Reactant: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Product: CCCCCCCCCC(=O)OCN1C(=O)CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70 %

Procedure:
The chloromethyl ester above is dried over 4 Å molecular sieves. A solution of aripiprazole (45 grams, 0.1 mol) in 1,4-dioxane (800 mL) was sonicated to dissolve the aripiprazole completely, and then treated with NaH (38 g, 0.95 mol, 60% dispersion) in one portion. After stirring this reaction mixture for 15 minutes at room temperature, the reaction mixture was treated dropwise with chloromethyl ester (0.3 mol.) and a catalytic amount of sodium iodide (0.05 mol.). The resultant cloudy mixture was heated to 90° C. for 2 hours, cooled to ambient temperature and poured into water. The product was extracted with ethyl acetate, and the combined ethyl acetate layers washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Column chromatography over silica gel provided the desired product (12.5 gram, 70% yield). 1H NMR (CDCl3, 300 MHz) δ 0.87 (t, 3H), 1.20 (m, 12H), 1.63 (m, 2H), 1.70 (m, 2H), 1.83 (m, 2H), 2.35 (t, 2H), 2.50 (t, 2H), 2.68 (m, 6H), 2.86 (t, 2H), 3.08 (m, 4H), 3.97 (t, 2H), 5.92 (s, 2H), 6.58 (dd, 1H), 6.61 (d, 1H), 6.94 (dd, 1H), 7.06 (d, 1H), 7.14-7.17 (m, 2H); m/z (M+H) 632.88.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[C:30]([O:32][CH2:33][CH3:34])=[O:31].[CH3:35][C:36]1[N:44]=[CH:43][CH:42]=[CH:41][C:37]=1[C:38](O)=[O:39]>ClCCl.O.C(N(CC)CC)C>[CH3:35][C:36]1[N:44]=[CH:43][CH:42]=[CH:41][C:37]=1[C:38]([N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:39]
Reactant: CCOC(=O)C1CCCCN1
Reactant: Cc1ncccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)C1CCCCN1C(=O)c1cccnc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.3 %

Procedure:
150.8 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 60.3 g of 1-hydroxybenzotriazole hydrate are added to a suspension of 82.4 g of ethyl piperidine-2-carboxylate in 500 cm3 of dichloromethane. The solution remains milky and 45 g of 2-methylnicotinic acid are added. The solution becomes clear and 161 cm3 of triethylamine are added. The mixture is kept stirred at ambient temperature overnight. The mixture is hydrolysed with 2×1 liter of water. The organic phase is then dried over magnesium sulphate and evaporated at reduced pressure (2.7 kPa). The oil obtained is chromatographed on a column of 8 cm diameter containing 900 g of silica (0.04-0.02). Elution is carried out with ethyl acetate, 70-cm3 fractions being collected. The homogeneous fractions are combined and concentrated at reduced pressure (2.7 kPa). 81.86 g of ethyl N-(2-methylnicotinoyl)piperidine-2-carboxylate are thus obtained in the form of a colourless oil (Rf=0.21; thin layer chromatography on silica gel; ethyl acetate eluent).
Reaction SMILES: [C:1]([C:4]1[C:5](=[S:15])[S:6][S:7][C:8]=1[C:9]1[CH:14]=[N:13][CH:12]=[CH:11][N:10]=1)(O)=[O:2].C(OC([N:21]1C2C(=CC=CC=2)C=CC1OCC)=O)C.N>C(Cl)Cl.CO.CN(C)C=O>[C:1]([C:4]1[C:5](=[S:15])[S:6][S:7][C:8]=1[C:9]1[CH:14]=[N:13][CH:12]=[CH:11][N:10]=1)(=[O:2])[NH2:21]
Reactant: O=C(O)c1c(-c2cnccn2)ssc1=S
Reactant: CCOC(=O)N1c2ccccc2C=CC1OCC
Agent: N
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NC(=O)c1c(-c2cnccn2)ssc1=S
Temperature: 20 °C
Reaction time: 5 h
Yield: 51.6 %

Procedure:
A suspension of 4-carboxy-5-(pyrazin-2-yl)-1,2-dithiole-3-thione (12.8 g) [prepared as described in Example 32] and 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (13.25 g) in methylene chloride (40 cc) is stirred for 5 hours at a temperature of about 20° C. A solution (15 cc) of 4N ammonia in methanol is added over a period of 10 minutes to the solution obtained, and the reaction mixture is stirred for a further 5 minutes at a temperature of about 20° C. The insoluble product is filtered off and washed successively with methylene chloride (50 cc), saturated aqueous sodium bicarbonate solution (25 cc), water (4 × 100 cc) and then ethyl acetate (15 cc). The residue obtained is dissolved at a temperature of about 100° C. in dimethylformamide (100 cc) and the solution, which is filtered hot, is then poured into distilled water (200 cc). After cooling to a temperature of about 20° C., the insoluble product is filtered off and washed with ethyl acetate (2 × 10 cc) to give 4-carbamoyl-5-(pyrazin-2-yl)-1,2-dithiole-3-thione (6.58 g) melting at 267° C.
Reaction SMILES: C([C:4]1[CH:5]=[C:6]([NH:10]/[C:11](=[C:18]2\[C:19](=[O:27])[NH:20][C:21]3[C:26]\2=[CH:25][CH:24]=[CH:23][CH:22]=3)/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:8][CH:9]=1)(O)=O.[CH2:28]([O:30][C:31](=[O:35])CNC)[CH3:29].CN([C:39]([O:43]N1N=NC2C=CC=CC1=2)=[N+:40]([CH3:42])[CH3:41])C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(N(CC)CC)C>[CH2:28]([O:30][C:31]([CH2:42][N:40]([CH3:41])[C:39]([C:4]1[CH:5]=[C:6]([NH:10]/[C:11](=[C:18]2\[C:19](=[O:27])[NH:20][C:21]3[C:26]\2=[CH:25][CH:24]=[CH:23][CH:22]=3)/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:8][CH:9]=1)=[O:43])=[O:35])[CH3:29]
Reactant: CCOC(=O)CNC
Reactant: O=C1Nc2ccccc2/C1=C(/Nc1cccc(C(=O)O)c1)c1ccccc1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CN(C)C(=O)c1cccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)c1

Procedure:
Prepared analogously to Example 21 from (Z)-3-[1-(3-carboxyphenylamino)-1-phenyl-methylidene]-2-indolinone, sarcosine ethyl ester, TBTU, HOBt and triethylamine in DMF.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@@H:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:26]=[CH:25][C:24](SC)=[CH:23][N:22]=3)=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:30]1C=C(C=CC=1)C(OO)=O.[O-:40][S:41]([O-:43])=O.[Na+].[Na+]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@@H:10]([C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21]3[N:22]=[CH:23][C:24]([S:41]([CH3:30])(=[O:43])=[O:40])=[CH:25][N:26]=3)=[CH:18][CH:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CSc1cnc(Nc2ccc([C@H]3CN(C(=O)OC(C)(C)C)CCO3)cc2)nc1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Nc3ncc(S(C)(=O)=O)cn3)cc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (S)-2-[4-(5-methylsulfanyl-pyrimidin-2-ylamino)-phenyl]-morpholine-4-carboxylic acid tert-butyl ester (72 mg) in dichloromethane (5 ml) was added 3-chloroperoxybenzoic acid (77.2 mg). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was then poured into saturated aq. Na2SO3 solution and extracted twice with dichloromethane. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to afford (S)-2-[4-(5-methanesulfonyl-pyrimidin-2-ylamino)-phenyl]-morpholine-4-carboxylic acid tert-butyl ester (84 mg, quant.) as a light brown foam which was used in the next step without further purification. MS (ISP): 435.2 ([M+H]+), 379.2 ([M+H—C4H8]+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:16]2[C:25]3[CH2:24][CH2:23][C:22](=[O:26])[CH2:21][C:20]=3[CH:19]=[CH:18][CH:17]=2)[C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].C([C:31]([O:33][CH3:34])=[O:32])#N.C(O)(=O)C>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:16]2[CH:17]=[CH:18][CH:19]=[C:20]3[C:25]=2[CH2:24][CH2:23][C:22]([OH:26])=[C:21]3[C:31]([O:33][CH3:34])=[O:32])[C:10](=[O:15])[C:11]([F:13])([F:12])[F:14])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(N(C(=O)C(F)(F)F)c2cccc3c2CCC(=O)C3)cc1
Reactant: COC(=O)C#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)C1=C(O)CCc2c1cccc2N(C(=O)C(F)(F)F)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
A solution of N-(4-cyanophenyl)-2,2,2-trifluoro-N-(5,6,7,8-tetrahydro-6-oxo-1-naphthyl)acetamide (1.17 g, 3.27 mmol) in THF (15 ml) was added dropwise over a 15 minute period to a stirred suspension of 80% NaH (0.30 g, 10 mmol) (Aldrich) in methyl cyanoformate (1.5 ml, 19 mmol) (Aldrich) and THF (15 ml) under nitrogen. The reaction mixture was stirred 30 minutes at room temperature then quenched with acetic acid (0.7 ml, 12 mmol). The solution was concentrated in vacuo onto silica gel (3 g) and the absorbed material purified by chromatography on silica gel (30 g) eluting with ether:hexane (1:4 to 1:3) to give methyl 5-(N-(4-cyanophenyl)-2,2,2-trifluoroacetamido)-3,4-dihydro-2-hydroxy-1-naphthalene carboxylate (0.64 g). 1H NMR (CDCl3, 200 MHz) δ: 2.5-2.9 (m, 4H, CH2CH2), 3.93 (s, 3H, CH3), 7.10 (d, J=8 Hz, 1H, Ar), 7.32 (t, J=8 Hz, 1H, Ar), 7.39 (d, J=9 Hz, 2H, Ar), 7.64 (d, J=9 Hz, 2H, Ar), 7.82 (d, J=8 Hz, 1H, Ar), 13.35 (s, 1H, OH). Anal. Calculated for C21H15F3N2O4: C, 60.58; H, 3.63; N, 6.73. Found: C, 60.66; H, 3.66; N, 6.68.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][N:13]2[C:17]([SH:18])=[N:16][N:15]=[N:14]2)[CH2:6][CH2:5]1.CC(O[CH2:23][C:24]1[CH2:33][S:32][C@@H:27]2[C@H:28]([NH2:31])[C:29](=[O:30])[N:26]2[C:25]=1[C:34]([OH:36])=[O:35])=O.C(=O)(O)[O-].[Na+]>O>[NH2:31][CH:28]1[C:29](=[O:30])[N:26]2[C:25]([C:34]([OH:36])=[O:35])=[C:24]([CH2:23][S:18][C:17]3[N:13]([CH2:12][CH2:11][CH2:10][N:7]4[CH2:6][CH2:5][N:4]([CH3:3])[CH2:9][CH2:8]4)[N:14]=[N:15][N:16]=3)[CH2:33][S:32][C@H:27]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CN1CCN(CCCn2nnnc2S)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CN1CCN(CCCn2nnnc2SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)CC1
Temperature: 64 °C
Reaction time: 2 h
Yield: 34.5 %

Procedure:
To a solution of 1-[3-(4-methyl-1-piperazinyl)propyl]-1H-tetrazole-5-thiol.dihydrochloride (75.32 g) in water (6 l) was added 7-aminocephalosporanic acid (60.0 g) and the mixture was adjusted to pH 5.4 with a saturated aqueous solution of sodium bicarbonate and stirred for 2 hours at 64° C. The reaction mixture was cooled and adjusted to pH 6.84 with a saturated aqueous solution of sodium bicarbonate. The resulting mixture was subjected to column chromatography (CM-Cephadex, H-type: 3 l), eluting with water, 0.5% aqueous solution of sodium chloride and 2% aqueous solution of sodium chloride. The fiactions containing the object compound were collected. The resulting mixture (about 7 l) was adjusted to pH 4.5 with a saturated aqueous solution of sodium bicarbonate and then subjected to column chromatography (Non-ion adsorption resin, Diaion HP 20 prepared by Mitsubishi Chemical Industries: 3 l) and eluting with water, 2% isopropyl alcohol and 15% isopropyl alcohol. The fractions containing the object compound were collected and then concentrated. The concentrate was lyophilized to give a powder of 7-amino-3-[1-[3-(4-methyl-1-piperazinyl) propyl]-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (34.6 g).
Reaction SMILES: [O:1]1[CH2:25][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH:22]3[O:24][CH2:23]3)=[CH:16][CH:15]=2)([CH3:13])[CH3:12])=[CH:7][CH:6]=1.[CH3:26][C:27]1([CH3:39])[NH:36][C:35]([CH3:38])([CH3:37])[CH2:34][C:29]2([O:33][CH2:32][CH2:31][O:30]2)[CH2:28]1>C(O)(C)(C)C>[OH:1][CH:2]([CH2:25][N:36]1[C:35]([CH3:38])([CH3:37])[CH2:34][C:29]2([O:30][CH2:31][CH2:32][O:33]2)[CH2:28][C:27]1([CH3:39])[CH3:26])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH:22]([OH:24])[CH2:23][N:36]3[C:27]([CH3:39])([CH3:26])[CH2:28][C:29]4([O:30][CH2:31][CH2:32][O:33]4)[CH2:34][C:35]3([CH3:38])[CH3:37])=[CH:18][CH:19]=2)([CH3:13])[CH3:12])=[CH:9][CH:10]=1
Reactant: CC1(C)CC2(CC(C)(C)N1)OCCO2
Reactant: CC(C)(c1ccc(OCC2CO2)cc1)c1ccc(OCC2CO2)cc1
Solvent: CC(C)(C)O
Product: CC(C)(c1ccc(OCC(O)CN2C(C)(C)CC3(CC2(C)C)OCCO3)cc1)c1ccc(OCC(O)CN2C(C)(C)CC3(CC2(C)C)OCCO3)cc1

Procedure:
To 50 ml of t-butanol were added 3.5 g of 2,2-bis[p-(2,3-epoxypropoxy)phenyl]propane and 5.0 g of 7,7,9,9-tetramethyl-1,4-dioxa-8-azaspiro[4.5]decane; the mixture was then reacted following the procedure described in Example 21 to give the desired Compound No. 126 in the form of a white powder having an Rf value of 0.38 on thin-layer chromatography on silica gel developed with a 20:2:1 by volume mixture of benzene, ethyl acetate and triethylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:28]1([C:33](Cl)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1>O1CCCC1>[CH:28]1([C:33](=[O:34])[CH:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[C:10]([NH:12][C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[O:11])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=C(Cl)C1CCCC1
Reactant: O=C(Cc1ccc(Cl)c(Cl)c1)Nc1nccs1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Nc1nccs1)C(C(=O)C1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 39.9 %

Procedure:
To a solution of rac-2-(3,4-dichloro-phenyl)-N-thiazol-2-yl-acetamide (185 mg, 0.64 mmol) in tetrahydrofuran (15 mL), previously cooled to −78° C., was added slowly a 1.0 M solution of lithium bis(trimethylsilyl)amide (1.3 mL, 1.3 mmol). The solution was stirred for 15 min at −78° C., then cyclopentanecarbonyl chloride (0.08 mL, 0.64 mmol) was dropwise added. The reaction mixture was stirred for an additional 60 min at −78° C. before it was quenched by the addition of a saturated ammonium chloride solution (10 mL). The mixture was then extracted with ethyl acetate (3×10 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The product was purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) to afford 3-cyclopentyl-2-(3,4-dichloro-phenyl)-3-oxo-N-thiazol-2-yl-propionamide (98 mg, 40% yield) as a yellow-orange solid: EI-HRMS m/e calcd for C17H16N2O2SCl2 (M+) 382.0309, found 382.0309.
Reaction SMILES: [C:1]([O:4]CC(=O)CC1C=CC(Cl)=C(Cl)C=1)(=[O:3])[CH3:2].[CH2:17]([O:24][C:25]([N:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([CH2:36][C:37](=[O:40])[CH2:38]Cl)=[CH:28]1)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)(=O)C.C(N(CC)CC)C>>[C:1]([O:4][CH2:38][C:37](=[O:40])[CH2:36][C:29]1[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:27]([C:25]([O:24][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:26])[CH:28]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)Cc1ccc(Cl)c(Cl)c1
Reactant: O=C(CCl)Cc1cn(C(=O)OCc2ccccc2)c2ccccc12
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CC(=O)OCC(=O)Cc1cn(C(=O)OCc2ccccc2)c2ccccc12
Yield: 44 %

Procedure:
The procedure described above for the synthesis of 3-(3,4-dichlorophenyl)-2-oxopropyl acetate was followed, reacting 3-[1-(benzyloxycarbonyl)indol-3-yl]-1-chloropropan-2-one (19.28 g, 56.4 mmol) with acetic acid (6.5 mL, 6.8 g, 0.11 mol) and triethylamine (15.7 mL, 11.4 g, 0.113 mol). Flash chromatography over silica gel (25% ethyl acetate in hexanes) gave pure product as an orange oil that solidified under vacuum to a yellow solid (9.06 g, 44% yield): 1H NMR (400 MHz, CDCl3) δ 2.15 (s, 3H) 3.81 (d, J=0.8 Hz, 2H) 4.73 (s, 2H) 5.45 (s, 2H) 7.26-7.30 (m, 1H) 7.32-7.51 (m, 7H) 7.62 (s, 1H) 8.18 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[CH:18]([F:20])[F:19])[N:3]=1.[NH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1.[Li+].CC([N-]C(C)C)C.CC(O)=O>C1COCC1.O>[Cl:8][C:6]1[N:5]=[C:4]([N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[CH:18]([F:20])[F:19])[N:3]=[C:2]([NH:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH:7]=1
Reactant: Nc1cccnc1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)cc(Cl)n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: FC(F)c1nc2ccccc2n1-c1nc(Cl)cc(Nc2cccnc2)n1
Reaction time: 0.17 h
Yield: 67 %

Procedure:
1-(4,6-Dichloro-2-pyrimidinyl)-2-(difluoromethyl)-1H-benzimidazole (International Publ. No. WO 2002/088112, the disclosure of which is incorporated herein by reference in its entirety) (0.315 g, 1 mmol) was added to a mixture of 3-aminopyridine (0.28 g, 3 mmol) and LDA (1.5 mL, 2 M in THF, 3 mmol) in 10 mL THF at room temperature. After 10 min, the mixture was neutralized with HOAc, diluted with water, extracted with EtOAc, and dried (Na2SO4). Chromatography on silica, eluting with CH2Cl2/EtOAc (3:2) gave a solid, which was recrystallized from i-Pr2O to give 0.252 g (67% yield) of 6-chloro-2-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-N-(3-pyridinyl)-4-pyrimidinamine: mp (i-Pr2O) 233-236° C.; 1H NMR (DMSO-d6) δ 10.42 (br, 1H), 8.72 (d, J=2.3 Hz, 1H), 8.43 (dd, J=4.7, 1.4 Hz, 1H), 8.26 (m, 1H), 8.01 (ddd, J=8.3, 2.5, 1.5 Hz, 1H), 7.86 (m, 1H), 7.62 (t, JHF′=52.9 Hz, 1H), 7.48-7.42 (m, 3H), 6.86 (s, 1H); Anal. Calcd. for C17H11ClF2N6: C, 54.8; H, 3.0; N, 22.55. Found: C, 54.75; H, 3.0; N, 22.7%.
Reaction SMILES: [NH:1]1[C:5]2[C:6]3[N:14]=[CH:13][CH:12]=[CH:11][C:7]=3[NH:8][CH2:9][CH2:10][C:4]=2[CH:3]=[N:2]1.C(N(CC)CC)C.[F:22][C:23]1[CH:24]=[CH:25][C:26]([CH3:41])=[C:27]([CH:40]=1)[C:28]([NH:30][C:31]1[N:36]=[CH:35][C:34]([C:37](Cl)=[O:38])=[CH:33][CH:32]=1)=[O:29].[OH-].[Na+]>ClCCl.CO>[NH:1]1[C:5]2[C:6]3[N:14]=[CH:13][CH:12]=[CH:11][C:7]=3[N:8]([C:37]([C:34]3[CH:33]=[CH:32][C:31]([NH:30][C:28](=[O:29])[C:27]4[CH:40]=[C:23]([F:22])[CH:24]=[CH:25][C:26]=4[CH3:41])=[N:36][CH:35]=3)=[O:38])[CH2:9][CH2:10][C:4]=2[CH:3]=[N:2]1
Reactant: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)Cl)cn1
Reactant: c1cnc2c(c1)NCCc1cn[nH]c1-2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)N2CCc3cn[nH]c3-c3ncccc32)cn1

Procedure:
To a solution of 2 mmol 1,4,5,6-tetrahydropyrazolo[3,4-d]pyrido[3,2-b]azepine and 10 mmol of triethylamine in 25 ml of dichloromethane is added 4.2 mmol of 6-[(5-fluoro-2-methylbenzoyl)amino]pyridine-3-carbonyl chloride. After stirring over the mixture is worked-up as described for Example 1 and the initial solid treated with 1N NaOH in methanol as described for Example 1 to give the product as a solid.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([CH:22]([CH3:24])[CH3:23])=[CH:6][CH:7]=[C:8]([CH3:21])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:20])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:19])[CH2:17][Cl:18])C.[H-].C([Al+]C(C)C)(C)C.O>C1(C)C=CC=CC=1>[Cl:18][CH2:17][C:16]([CH3:19])=[CH:15][CH2:14][CH2:13][C:12]([CH3:20])=[CH:11][CH2:10][CH2:9][C:8]([CH3:21])=[CH:7][CH:6]=[C:5]([CH:22]([CH3:23])[CH3:24])[CH2:4][OH:3]
Reactant: CCOC(=O)C(=CC=C(C)CCC=C(C)CCC=C(C)CCl)C(C)C
Agent: CC(C)[Al+]C(C)C
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=CCCC(C)=CCCC(C)=CC=C(CO)C(C)C)CCl
Reaction time: 0.5 h
Yield: 83.7 %

Procedure:
14-Chloro-2-(1-methylethyl)-5,9,13-trimethyl-2,4,8, 12-tetradecatetraenoic acid ethyl ester (670 mg, 1.81 mmol) is dissolved in dry toluene (200 ml) under argon atmosphere and to the solution is gradually added a 1 M solution of diisopropylaluminum hydride in toluene (4 ml) while cooling and stirring on ethanol-dry ice bath. After 30 minutes, disappearance of the starting compound is confirmed. To the mixture is added water (1.5 ml), and after removing the bath, the mixture is thoroughly stirred. To the mixture is added a drying agent (anhydrous magnesium sulfate) and the mixture is further stirred. The mixture is filtered and concentrated and the resulting residue is chromatographed (n-hexane/ethyl acetate=12:1) on silica gel column to give the desired alcohol, 14-chloro-2-(1-methylethyl)-5,9,13-trimethyl-2,4,8,12-tetradecatetraene-1-ol (492 mg, 79%) from the desired fraction.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[N:5][CH:4]=1)#[CH:2].[OH:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:39])[C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[C:33](I)[CH:32]=3)=[CH:25][C:24]=2[C:40]([F:43])([F:42])[F:41])[CH2:18][CH2:17]1>>[N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([C:1]#[C:2][C:35]2[CH:36]=[C:31]([CH:32]=[CH:33][C:34]=2[CH3:37])[C:30]([NH:29][C:26]2[CH:27]=[CH:28][C:23]([CH2:22][N:19]3[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][OH:13])[CH2:17][CH2:18]3)=[C:24]([C:40]([F:43])([F:42])[F:41])[CH:25]=2)=[O:39])=[CH:4][N:5]=1
Reactant: Cc1ccc(C(=O)Nc2ccc(CN3CCN(CCO)CC3)c(C(F)(F)F)c2)cc1I
Reactant: C#Cc1cnnc2ccccc12
Product: Cc1ccc(C(=O)Nc2ccc(CN3CCN(CCO)CC3)c(C(F)(F)F)c2)cc1C#Cc1cnnc2ccccc12

Procedure:
The title compound can be synthesized from 4-ethynylcinnoline and N-(4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-iodo-4-methylbenzamide in a manner similar to that described for Example 1.
Reaction SMILES: [CH:1](=[N:8][OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.ClN1C(=O)CCC1=O.[CH2:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:19]#[CH:20].C(N(CC)CC)C>CN(C=O)C.C(Cl)Cl>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:1]2[CH:20]=[C:19]([CH2:18][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[O:9][N:8]=2)[CH:3]=1
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: ON=Cc1cccnc1
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1cc(-c2cccnc2)no1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 59.2 %

Procedure:
To a solution of 33 (161 mg, 1.3 mmol) in anhydrous DMF (5 mL) at 0° C. was added N-chlorosuccinimide (202 mg, 1.3 mmol) portionwise over 20 min. The resultant solution was heated to 50° C. and stirred for 50 min. The solution was cooled to room temperature and transferred to a flask containing CH2Cl2 (3 mL). To the solution was added a solution of tert-butyl prop-2-ynylcarbamate (204 mg, 1.3 mmol) in CH2Cl2 (3 mL), the solution was cooled to 0° C. and triethylamine (0.18 mL, 1.3 mmol) was added dropwise, the ice bath was removed and the solution was stirred at ambient temperature for 3 h. To the solution was added saturated aqueous sodium bicarbonate (30 mL), the organic fraction was collected and the aqueous fraction was extracted with CH2Cl2 (2×15 mL), back washed with water (30 mL), and brine (30 mL), dried (Na2SO4), filtered and the solvent was removed in vacuo. The crude material was chromatographed on silica gel (EtOAc/Hex, 50/50, Rf=0.16) to afford the title compound 34 (212 mg, 59% yield) as a an off white solid: mp=67-69° C.; 1H NMR (CDCl3) δ 8.93 (br s, 1H), 8.62 (m, 1H), 8.05 (m, 1H), 7.34 (m, 1H), 6.50 (s, 1H); 5.63 (br s, 1H); 4.43 (d, J=6 Hz, 1H), 1.40 (s, 9H); LRMS (ESI) calcd for C14H18N3O3 [M+H]+ 276. found 276.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1.[CH3:26][C:27]1[CH:31]=[C:30]([CH3:32])[NH:29][N:28]=1>>[CH3:26][C:27]1[CH:31]=[C:30]([CH3:32])[N:29]([C:2]2[N:11]=[C:10]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:18][CH:19]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[N:28]=1
Reactant: Cc1cc(C)[nH]n1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: Clc1nc(Cl)c2ccccc2n1
Product: Cc1cc(C)n(-c2nc(Nc3ccc(N4CCOCC4)cc3)c3ccccc3n2)n1

Procedure:
Was prepared according to Method B from 2,4-dichloroquinazoline, N-(4-aminophenyl)-morpholine and 3,5-dimethylpyrazole. Mp. 268.2-270.4° C.