Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][C:8]2([C:22]([OH:24])=[O:23])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].I[CH3:27]>CN(C)P(=O)(N(C)C)N(C)C>[C:1]1([NH:7][C:8]2([C:22]([O:24][CH3:27])=[O:23])[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:12][CH2:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CI
Reactant: O=C(O)C1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Agent: [Na]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)C1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A solution of 62.3 parts of 4-(phenylamino)-1-(2-phenylethyl)-4-piperidinecarboxylic acid, sodium salt in 28.4 parts of iodomethane is stirred and heated to 100° C. After cooling to 10° C., there are added dropwise 340 parts of hexamethylphosphoric triamide (slightly exothermic reaction). Upon completion, stirring is continued for 24 hours at room temperature. The reaction mixture is poured onto water (800 parts) and the product is extracted with methylbenzene. The extract is washed with water, dried, filtered and evaporated. The oily residue solidifies on triturating in 2,2'-oxybispropane. The product is filtered off and crystallized from 2,2'-oxybispropane, yielding methyl 4-(phenylamino)-1-(2-phenylethyl)-4-piperidinecarboxylate; mp. 94.9° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][C:4]=1[O:18][CH3:19].[N:20]1[CH:25]=[CH:24][CH:23]=[C:22](B(O)O)[CH:21]=1.C([O-])([O-])=O.[K+].[K+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:19][O:18][C:4]1[CH:5]=[C:6]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:7]=[CH:8][C:3]=1[CH2:2][C:22]1[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=1
Reactant: OB(O)c1cccnc1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1CBr
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(-c2nc3ccccc3o2)ccc1Cc1cccnc1
Temperature: 80 °C

Procedure:
A mixture of 2-[4-(bromomethyl)-3-methoxyphenyl]-1,3-benzoxazole (190 mg, 0.58 mmol), 3-pyridylboronic acid (70 mg, 0.58 mmol), Pd(Ph3P)4 (70 mg, 0.06 mmol), K2CO3 (200 mg, 1.5 mmol), DME (6 mL) and H2O (3 mL) was degassed with bubbling Ar for 15 min. The mixture was heated at 80° C. for 1 h. The reaction was poured into H2O (40 mL) and extracted with CH2Cl2 (2×30 mL). The organic extracts were dried (MgSO4) and concentrated to afford a colorless solid. Purification of the solid by flash chromatography on silica gel (EtOAc:hexanes 3:1) afforded the desired 2-[3-methoxy-4-(pyridin-3-ylmethyl)phenyl]-1,3-benzoxazole as a yellow solid: 1H NMR (CDCl3, 300 MHz) δ 8.56 (br s, 1H), 8.45 (br d, 1H), 7.74–7.80 (m, 3H), 7.50–7.58 (m, 2H), 7.32–7.37 (m, 2H), 7.17–7.24 (m, 2H), 4.00 (s, 2H), 3.93 (s, 3H). MS (ESI) 317 (M+H)+.
Reaction SMILES: C(O[AlH-](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+].[CH3:18][C:19]1([CH3:29])[CH2:24][CH2:23][C:22](=[O:25])[CH:21]([CH2:26][CH:27]=[CH2:28])[CH2:20]1>O1CCCC1.C(OCC)(=O)C>[CH3:18][C:19]1([CH3:29])[CH2:24][CH2:23][C@@H:22]([OH:25])[C@H:21]([CH2:26][CH:27]=[CH2:28])[CH2:20]1
Reactant: C=CCC1CC(C)(C)CCC1=O
Agent: CC(C)(C)O[AlH-](OC(C)(C)C)OC(C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CC[C@@H]1CC(C)(C)CC[C@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
To a solution of lithium tri-tert-butoxyaluminohydride (460 mg) in dry tetrahydrofuran (3.5 ml) there was added a solution of 4,4-dimethyl-2-(2-propenyl)cyclohexanone (250 mg) at 0° C., and the mixture was stirred at room temperature for 2 hrs. The reaction was quenched by addition of water. The pH of the mixture was adjusted to pH 7 with 0.1N hydrochloric acid. The mixture was extracted with diethyl ether, and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. Purification of the residue by silica gel column chromatography (using n-hexane:ethyl acetate=20:1 as an eluent) gave (1R*,2R*)-4,4-dimethyl-2-(2-propenyl)cyclohexanol (185 mg, 73% yield) as a colorless oil; EI-MS: m/z 168 (M+); 1H-NMR (CDCl3)d: 0.90 (3H,s), 0.93 (3H,s), 1.2-1.8 (7H,m), 1.95 (1H,m), 2.46 (1H,m), 3.23 (1H,dt,J=5 & 11 Hz), 5.02 (1H,br.d,J=10 Hz), 5.06 (1H,br.d,J=17 Hz), 5.85 (1H,m).
Reaction SMILES: [CH:1]1([O:5][C:6]2[N:11]=[CH:10][C:9]([C:12](=O)[CH3:13])=[CH:8][C:7]=2[CH3:15])[CH2:4][CH2:3][CH2:2]1.[CH3:16][C:17]([S@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18]>>[CH:1]1([O:5][C:6]2[N:11]=[CH:10][C:9]([CH:12]([NH:22][S@@:20]([C:17]([CH3:19])([CH3:18])[CH3:16])=[O:21])[CH3:13])=[CH:8][C:7]=2[CH3:15])[CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)c1cnc(OC2CCC2)c(C)c1
Reactant: CC(C)(C)[S@](N)=O
Product: Cc1cc(C(C)N[S@](=O)C(C)(C)C)cnc1OC1CCC1
Yield: 76 %

Procedure:
The title compound is prepared in 76% yield (1.17 g, colorless oil) from 1-(6-cyclobutoxy-5-methylpyridin-3-yl)ethanone (1.03 g, 5.00 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide (909 mg, 7.50 mmol) in a similar manner to Step-4 of Amine-1.
Reaction SMILES: Cl[C:2]([CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:8][CH:7]([NH:22][C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[C:6]1=[O:33])=[O:3].[CH2:34]([NH2:36])[CH3:35]>>[C:27]1([CH2:26][O:25][C:23](=[O:24])[NH:22][CH:7]2[N:8]=[C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:5]([CH2:4][C:2]([NH:36][CH2:34][CH3:35])=[O:3])[C:6]2=[O:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)CN1C(=O)C(NC(=O)OCc2ccccc2)N=C(c2ccccc2)c2ccccc21
Reactant: CCN
Product: CCNC(=O)CN1C(=O)C(NC(=O)OCc2ccccc2)N=C(c2ccccc2)c2ccccc21

Procedure:
The products of Example 134 was carried out using equivalent amounts of 1,3-dihydro-1-chlorocarbonylmethyl-3(phenylmethyloxycarbonyl)amino-5-phenyl-2H-1,4-benzodiazepin-2-one and ethylamine. The product was purified by chromatography on silica gel (hexane-ethyl acetate elution). The combined product fractions were evaporated to dryness in vacuo and crystallized to give the title compound which was dried at 65° : m.p. 149° C.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][CH2:7][N:8]([CH2:10][CH2:11][C:12]([C:25]#[N:26])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-:30].[K+].[K+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][CH2:7][N:8]([CH2:10][CH2:11][C:12]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:25]([NH2:26])=[O:30])[CH3:9])=[CH:4][CH:3]=1
Reactant: CN(CCc1ccc(Cl)cc1)CCC(C#N)(c1ccccc1)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CN(CCc1ccc(Cl)cc1)CCC(C(N)=O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 3-[N-(4-chlorphenethyl)-N-methylamino]-1-cyano-1,1-diphenylpropane (0.2 g--Preparation 24) in 90% sulphuric acid (0.5 ml) was heated at 80°-85° c. for 3 hours. On cooling to room temperature, ice (10 g) was added and the mixture was basified (pH 10) by the addition of potassium carbonate. The mixture was extracted with dichloromethane (3×50 ml) and the combined dichloromethane extracts were washed with water (2×20 ml) then dried (Na2SO4) and concentrate in vacuo to give a gum. The gum was purified by column chromatography on silica eluting with hexane containing dichloromethane (25% up to 100%) followed by dichloromethane containing methanol (0% up to 5%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a gum, yield, 0.16 g.
Reaction SMILES: Br[C:2]1[C:7]2[NH:8][C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:13][C@H:12]3[CH3:24])=[N:10][C:6]=2[CH:5]=[C:4]([C:25]([F:28])([F:27])[F:26])[CH:3]=1.[F:29][C:30]([F:41])([F:40])[C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[Cl:23][C:22]1[C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:9]3[NH:8][C:7]4[C:2]([C:34]5[CH:35]=[CH:36][C:31]([C:30]([F:41])([F:40])[F:29])=[CH:32][CH:33]=5)=[CH:3][C:4]([C:25]([F:27])([F:28])[F:26])=[CH:5][C:6]=4[N:10]=3)[C@H:12]([CH3:24])[CH2:13]2)=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: C[C@@H]1CN(c2ncccc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(Br)c2[nH]1
Product: C[C@@H]1CN(c2ncccc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)c2[nH]1

Procedure:
7-Bromo-2-[(2R)-4-(3-chloropyridin-2-yl)-2-methylpiperazin-1-yl]-5-(trifluoromethyl)-1H-benzoimidazole (95 mg, 0.2 mmol, Example 77) and 4-(trifluoromethyl)phenylboronic acid (47 mg, 0.25 mmol, Aldrich) reacted under the conditions of Example 51a to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 515 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)=[N:8][C:7]=12)#[CH:2].Cl[C:27]1[S:28][C:29]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:30][N:31]=1>>[F:15][C:12]([F:14])([F:13])[C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:27]3[S:28][C:29]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:30][N:31]=3)=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[CH:10]=1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3cccc(C(F)(F)F)c3)nc12
Reactant: NS(=O)(=O)c1cnc(Cl)s1
Product: NS(=O)(=O)c1cnc(C#Cc2cnn3c(C(F)(F)F)cc(-c4cccc(C(F)(F)F)c4)nc23)s1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.10) (355 mg, 1.0 mmol) and 2-chloro-thiazole-5-sulfonamide (199 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (270 mg, 52%). MS (ISN) 516.1 [(M−H)−]; mp 251° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[Br:21][CH:22](Br)[CH3:23]>O>[Br:21][CH2:22][CH2:23][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: CC(Br)Br
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(OCCBr)cc1
Temperature: 30 °C
Reaction time: 0.75 h
Yield: 45.3 %

Procedure:
A mixture of 4-hydroxybenzaldehyde (10.0 g, 82 mmol) and potassium carbonate (46 g, 326 mmol) was placed into 2 L round bottom flask, and DMF (150 mL) was added. The mixture was stirred for 45 min. and dibromoethane (46 g) was added in one portion, then the reaction mixture was allowed to stir at 25-35° C. for 96 hrs under a nitrogen atmosphere. The reaction mixture was cooled to 25-35° C. and then poured into water (500 mL). The mixture was extracted with EtOAc (3×100 mL), combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography over silicagel by using 10-15% ethyl acetate/pet. ether to afford the title compound (8.50 g, 45%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.CCCCCC.C([Li])CCC.[CH3:19][C:20]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:21]=1[CH:22]=[O:23].O>C(OCC)C.O1CCCC1>[CH3:19][C:20]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:21]=1[CH:22]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[OH:23]
Reactant: Cc1cc([N+](=O)[O-])ccc1C=O
Reactant: Brc1ccccn1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc([N+](=O)[O-])ccc1C(O)c1ccccn1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
2-bromopyridine (0.9 ml) was dissolved in diethylether (30 ml), and the mixture was cooled to −78° C. under argon atmosphere. 1.6M n-butyllithium hexane solution (5.9 ml) was added dropwise to the solution, and the mixture was stirred for 30 minutes. The reaction solution was added dropwise to a solution of 2-methyl-4-nitrobenzaldehyde (1.3 g) in tetrahydrofuran (30 ml) at −78° C. The mixture was allowed to be at room temperature and stirred overnight, and water was added to the mixture. The mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane), to give (2-methyl-4-nitrophenyl)(pyridin-2-yl)methanol (0.84 g) as pale brown crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[O:5][CH2:6][CH:7](Cl)[CH3:8].[I-].[Na+].[NH4+:16].[OH-].Cl>C(OCC)C.O.C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[O:5][CH2:6][CH:7]([NH2:16])[CH3:8]
Reactant: Cc1cc(C)cc(OCC(C)Cl)c1
Reactant: [NH4+]
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: Cc1cc(C)cc(OCC(C)N)c1
Temperature: 130 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
A 100 ml autoclave was charged with 1.96 g (9.8 mmol) of 1-(3,5-dimethylphenoxy)-2-chloropropane, 10 ml of ethanol and 0.2 g of sodium iodide, and then 40 ml of a 28% ammonia aqueous solution was added. The mixture was continuously stirred at 130° C. for 8 hours to complete the reaction. After allowed to cool, the reaction mixture was transferred into a 500 ml beaker with 50 ml of water and 20 ml of diethyl ether. A 20% hydrochloric acid aqueous solution was added to the reaction mixture until it became acidic, and the mixture was washed with 20 ml of diethyl ether three times. While the water layer was cooled, a 20% sodium hydroxide aqueous solution was added to make it alkaline, and the water layer was subjected to extraction with 50 ml of diethyl ether three times, and dried over 10 g of anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure to give 1.48 g of 1-(3,5-dimethylphenoxy)-2-aminopropane (yield 83.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]([O:17][C:18]2[C:23]([Cl:24])=[CH:22][C:21]([NH:25]C(=O)C)=[CH:20][C:19]=2[Cl:29])[CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>Cl>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]([O:17][C:18]2[C:19]([Cl:29])=[CH:20][C:21]([NH2:25])=[CH:22][C:23]=2[Cl:24])[CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:4][CH:3]=1
Reactant: CC(=O)Nc1cc(Cl)c(OC(CCc2ccc(Cl)cc2)Cn2ccnc2)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Nc1cc(Cl)c(OC(CCc2ccc(Cl)cc2)Cn2ccnc2)c(Cl)c1
Yield: 248.8 %

Procedure:
A solution of 1-[4-(4-chlorophenyl)-2-(4-acetylamino-2,6-dichlorophenoxy)-n-butyl]imidazole (1.58 g) (prepared as in Example 1) in 15 ml of concentrated hydrochloric acid was heated at 90° C. for 1 day. The resulting solution was poured into 200 ml of aqueous potassium carbonate solution, extracted with ethyl acetate (3×75 ml) and the combined extracts dried (MgSO4) and evaporated. The resulting oil (1.3 g) was dissolved in ether and treated with ethereal hydrogen chloride until precipitation was complete. The product was filtered off and dried immediately in vacuo to give 1.4 g of 1-[4-(4-chlorophenyl)-2-(4-amino-2,6-dichlorophenoxy)-n-butyl]imidazole bis(hydrochloride), m.p. 119°-123° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][C:39]=1[O:40][CH3:41])[NH:36][CH:35]=[CH:34]2>CC(N(C)C)=O>[CH3:41][O:40][C:39]1[CH:38]=[C:37]2[C:33]([CH:34]=[CH:35][NH:36]2)=[CH:32][C:31]=1[O:30][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCCC1
Reactant: COc1cc2[nH]ccc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3cc4cc[nH]c4cc3OC)ncnc2cc1OCCCN1CCCCC1
Temperature: 95 °C
Reaction time: 2.5 h
Yield: 38.2 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (200 mg, 0.6 mmol), (prepared as described for the starting material in Example 67), potassium carbonate (248 mg, 1.8 mmol) and 5-hydroxy-6-methoxyindole (127 mg, 0.78 mmol) in DMA (4.0 ml) was stirred at 95° C. for 2.5 hours. The reaction mixture was allowed to cool to ambient temperature, filtered and the filtrate evaporated under vacuum. The residue was purified by silica column chromatography eluting with dichloromethane/methanol/0.880 aqueous ammonia (89/10/1) and the resulting oil triturated with diethyl ether to give 4-(6-methoxyindol-5-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline (106 mg, 38%).
Reaction SMILES: [O:1]=[C:2]([CH2:13][CH2:14][CH3:15])[CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5].CN(C)N>C1(C)C=CC=CC=1>[CH3:15][C:14]1[O:1][C:2]([CH2:13][CH2:14][CH3:15])=[C:3]([C:4]([NH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:5])[C:2](=[O:1])[CH:13]=1
Reactant: CCCC(=O)CC(=O)Nc1ccccc1
Agent: CN(C)N
Solvent: Cc1ccccc1
Product: CCCc1oc(C)cc(=O)c1C(=O)Nc1ccccc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 97.4 %

Procedure:
A mixture of 2.05 g (10 m mol) of 3-oxo-N-phenyl hexanamide (m.p. 77.0°~78.5° C.), 0.9 g (15 m mol) of N,N-dimethylhydrazine and 15 ml of toluene was stirred for 8 hours at 60° C. and further heated to a more elevated temperature to distill off the unreacted N,N-dimethylhydrazine and the resulted water together with about 2 ml of toluene. While refluxing, to the mixture was dropwise added a solution of 3.90 g (25 m mol) of 2-ethyl-2,6-dimethyl-4H-1,3-dioxin-4-one in 8 ml of toluene during 30 minutes. While refluxing for 2.5 hours, 3 ml of toluene was removed. After cooling to room temperature, the precipitated crystals were separated, washed and dried under vacuo to afford 1.32 g of the title compound (yield: 49%).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][CH:11]1[N:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:15]2[CH:25]=[CH:26][CH:27]=[CH:28][C:14]=2[NH:13][C:12]1=[O:29])=[O:9])([CH3:6])([CH3:5])[CH3:4].[I-].[Na+].Cl[CH2:33][C:34]([N:36]1[CH2:44][CH:43]2[CH2:45][CH:39]3[CH2:40][CH:41]([CH2:46][CH:37]1[CH2:38]3)[CH2:42]2)=[O:35]>CN(C)C=O>[CH:37]12[CH2:46][CH:41]3[CH2:40][CH:39]([CH2:45][CH:43]([CH2:42]3)[CH2:44][N:36]1[C:34]([CH2:33][N:13]1[C:14]3[CH:28]=[CH:27][CH:26]=[CH:25][C:15]=3[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])=[N:17][CH:11]([NH:10][C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:9])[C:12]1=[O:29])=[O:35])[CH2:38]2
Reactant: CC(C)(C)OC(=O)NC1N=C(c2ccccc2F)c2ccccc2NC1=O
Reactant: O=C(CCl)N1CC2CC3CC(C2)CC1C3
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1N=C(c2ccccc2F)c2ccccc2N(CC(=O)N2CC3CC4CC(C3)CC2C4)C1=O
Reaction time: 1 h
Yield: 120.8 %

Procedure:
To a suspension of sodium hydride (0.035 g of a 60% dispersion in mineral oil) in dry N,N-dimethylformamide (5 ml) was added dropwise a solution of (3RS)-3-tert-butoxycarbonylamino-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one (0.293 g) in dry N,N-dimethylformamide (2 ml) under stirring at cooling in an ice-bath. After completion of the addition, the mixture was allowed to stand to room temperature and stirred for 2 hours. To the the mixture was added sodium iodide (0.129 g) and followed dropwise a solution of N-chloromethylcarbonyl-2-azatricyclo-[4.3.1.14,8 ]undecane (0.215 g) in dry N,N-dimethylformamide (2 ml) under stirring at cooing in an ice-bath for 1 hour and then at room temperature overnight. The reaction mixture was concentrated in vacuo. The residue was treated with ethyl acetate and water. The organic layer was washed with water and dried over sodium sulfate. Removal of the solvent gave (3RS)-1-[(2-azatricyclo[4.3.1.14,8 ]undec-2-yl)carbonylmethyl]-3-tert-butoxycarbonylamino-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one (0.537 g), which was used in a following reaction step without further purification.
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16]2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].N1C=CC=CC=1.C1CCC(N=C=NC2CCCCC2)CC1.C(O)(C(F)(F)F)=O>CS(C)=O.C1(C)C=CC=CC=1>[CH2:1]([C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:19][CH2:18][C:17](=[O:20])[CH2:16]2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1ccc(N2CCC(O)C2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCc1ccc(N2CCC(=O)C2)cc1
Temperature: 25 °C
Yield: 84.4 %

Procedure:
To a solution of 1-(4-octylphenyl)pyrrolidin-3-ol (3.7 g, 13.43 mmol) in DMSO (50 ml) and Toluene (50.0 ml) at 0° C. was added pyridine (3.80 ml, 47.0 mmol), DCC (4.85 g, 23.51 mmol), and TFA (1.035 ml, 13.43 mmol). Following the addition the reaction mixture was allowed to warm to room temperature. After 5 h saturated NaCHCO3 was added to the reaction mixture and the suspension was filtered. The filtrate was partially concentrated in vacuo and the resulting dark oil was extracted with heptane. The heptane extracts were purified by silica gel chromatography eluting with EtOAc/Hep to provide 1-(4-octylphenyl)pyrrolidin-3-one (3.1 g, 11.34 mmol, 84% yield) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C@H:10]2[C@@H:14]([NH:15][C:16](=[O:30])[C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]4=[O:29])=[CH:19][CH:18]=3)[CH2:13][NH:12][CH2:11]2)=[O:8])=[CH:4][CH:3]=1.CCN(CC)CC.[C:38](OC(=O)C)(=[O:40])[CH3:39]>C1COCC1>[C:38]([N:12]1[CH2:13][C@H:14]([NH:15][C:16](=[O:30])[C:17]2[CH:18]=[CH:19][C:20]([N:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]3=[O:29])=[CH:21][CH:22]=2)[C@H:10]([NH:9][C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:8])[CH2:11]1)(=[O:40])[CH3:39]
Reactant: O=C(N[C@H]1CNC[C@H]1NC(=O)c1ccc(Cl)s1)c1ccc(-n2ccccc2=O)cc1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N1C[C@H](NC(=O)c2ccc(-n3ccccc3=O)cc2)[C@H](NC(=O)c2ccc(Cl)s2)C1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 44.4 %

Procedure:
To a solution of Example 75 (6 mg, 0.013 mmol) in THF (200 μl) at 0° C. was added Et3N (3 μl, 0.021 mmol) followed by the acetic anhydride (5 μl, 0.04 mmol). The reaction mixture was stirred at 0° C. for 5 minutes and then at rt for 10 minutes. The solvent was evaporated under pressure, and the residue was purified by preparative HPLC using 0 to 100% B over 10 minutes (Column, Luna 10μ, C18 25×100 mm; Solvent A, 10% ACN +90% H2O with 0.1% TFA; Solvent B, 90% ACN+10% H2O with 0.1% TFA) to afford the title compound (2.8 mg, 48%) as a white lyophilite. MS m/z 486 ([M+H]+).