Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]([CH2:11][CH3:12])[C@@H:3]([CH3:10])[C:4]([N:6]([O:8][CH3:9])[CH3:7])=[O:5].N1C(C)=CC=CC=1C.[CH2:21]([Si:23](OS(C(F)(F)F)(=O)=O)([CH2:26][CH3:27])[CH2:24][CH3:25])[CH3:22]>ClCCl>[CH3:9][O:8][N:6]([CH3:7])[C:4](=[O:5])[C@H:3]([CH3:10])[C@@H:2]([O:1][Si:23]([CH2:26][CH3:27])([CH2:24][CH3:25])[CH2:21][CH3:22])[CH2:11][CH3:12]
Reactant: CC[C@H](O)[C@@H](C)C(=O)N(C)OC
Reactant: CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC[C@H](O[Si](CC)(CC)CC)[C@@H](C)C(=O)N(C)OC
Reaction time: 5 h
Yield: 99 %

Procedure:
The above (2R,3S)-3-hydroxy-N-methoxy-N,2-dimethylpentanamide (7.3 g, 41.7 mmol) was dissolved in dichloromethane (150 ml), followed by addition of 2,6-lutidine (10.2 ml, 87 mmol) and trifluoromethanesulfonic acid triethylsilyl ester (14.1 ml, 62 mmol) while ice cooling, and the reaction solution was stirred for five hours. The reaction solution was diluted with dichloromethane and washed with a saturated ammonium chloride aqueous solution and brine. After the organic layer was dried over anhydrous sodium sulfate and the drying agent was filtered off, the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Merck, commercial name Silica Gel 60, 230-400 mesh; hexane:ethyl acetate=10:1) to obtain the title compound (11.95 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[C:14]2[C:9]=1[CH2:10][N:11]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1)[C:12](=[O:30])[N:13]2[C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:29].[CH3:40][CH:41]1[NH:46][CH2:45][CH2:44][N:43](C(OC(C)(C)C)=O)[CH2:42]1.BrC1C=C(OC)C=C2C=1CCC(=O)N2C1C(Cl)=CC=CC=1Cl>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([S:18]([N:46]2[CH2:45][CH2:44][NH:43][CH2:42][CH:41]2[CH3:40])(=[O:20])=[O:19])[CH:15]=[C:14]2[C:9]=1[CH2:10][N:11]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1)[C:12](=[O:30])[N:13]2[C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:29]
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1
Reactant: COc1ccc(CN2Cc3c(-c4ccccc4Cl)cc(S(=O)(=O)Cl)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Agent: COc1cc(Br)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)CC2
Product: COc1ccc(CN2Cc3c(-c4ccccc4Cl)cc(S(=O)(=O)N4CCNCC4C)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1

Procedure:
The 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-3-(4-methoxybenzyl)-7-[(2-methylpiperazin-1-yl)sulfonyl]-3,4-dihydroquinazolin-2(1H)-one was prepared from 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-3-(4-methoxybenzyl)-2-oxo-1,2,3,4-tetrahydroquinazoline-7-sulfonyl chloride (COMPOUND CCC8) and tert-butyl 3-methylpiperazine-1-carboxylate by a procedure analogous to that described in EXAMPLE CCC25, STEP B. Mass spectrum (ESI) 729 (M-t-Bu+1).
Reaction SMILES: C1(C)C=CC=CC=1[NH:7][N:8]=[C:9]([C:12]#[N:13])[C:10]#[N:11].N[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1.C(#N)CC#N.O.[NH2:29][NH2:30]>>[C:19]1([CH3:22])[CH:20]=[CH:21][CH:16]=[CH:17][C:18]=1[NH:7][N:8]=[C:9]1[C:10]([NH2:11])=[N:30][N:29]=[C:12]1[NH2:13]
Reactant: Cc1ccc(N)cc1
Reactant: Cc1ccccc1NN=C(C#N)C#N
Reactant: NN
Solvent: N#CCC#N
Solvent: O
Product: Cc1ccccc1NN=C1C(N)=NN=C1N
Temperature: 25 °C

Procedure:
4-(o-tolylhydrazono)-4H-pyrazole-3,5-diamine was prepared using 92 mg (0.5 mmol) of 2-(o-tolylhydrazono)-malononitrile, which was derived from 4-toluidine (107 μL, 1.0 mmol) and malononitrile (1.5 mmol), and hydrazine hydrate. Very little solid had formed after heating the reaction at 75° C. for 1 hr, however, analysis of the reaction solution by TLC indicated that no starting material remained. The solution was allowed to cool to ambient temperature and the solvent was evaporated. The residue was dissolved in ethyl acetate and then precipitated by the addition of hexanes. The resulting solid was isolated by filtration and dried to yield 43 mg (40%) of the compound as a yellow solid.
Reaction SMILES: N1C2C(=CC=CC=2)C=NC=1.[Cl:11][C:12]1[CH:13]=[C:14]([C:16]([F:20])=[CH:17][C:18]=1[Cl:19])[NH2:15].Cl[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([N+:32]([O-:34])=[O:33])[CH:30]=2)[N:25]=[CH:24][N:23]=1>>[Cl:11][C:12]1[CH:13]=[C:14]([NH:15][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([N+:32]([O-:34])=[O:33])[CH:30]=3)[N:25]=[CH:24][N:23]=2)[C:16]([F:20])=[CH:17][C:18]=1[Cl:19]
Reactant: O=[N+]([O-])c1ccc2ncnc(Cl)c2c1
Reactant: Nc1cc(Cl)c(Cl)cc1F
Agent: c1ccc2ncncc2c1
Product: O=[N+]([O-])c1ccc2ncnc(Nc3cc(Cl)c(Cl)cc3F)c2c1

Procedure:
In one particular, which includes a quinazoline that is substituted by one reactive group at position 6 thereof, 3,4-dichloro-6-fluoroaniline is reacted with 4-chloro-6-nitroquinazoline, so as to produce 4-[(3,4-dichloro-6-fluorophenyl)amino]-6-nitroquinazoline, which is reduced, by means of an ethanolic solution of hydrazine hydrate and Raney®Nickel, so as to produce 4-[(3,4-dichloro-6-fluorophenyl)amino]-6-aminoquinazoline. Then, the 4-[(3,4-dichloro-6-fluorophenyl)amino]-6-aminoquinazoline is reacted with a carbon-11 labeled acryloyl chloride so as to produce a carbon-11 labeled N-{4-[(3,4-dichloro-6-fluorophenyl)amino]quinazoline-6-yl}acrylamide (carbon-11 labeled Compound 3).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][Si:5]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].[CH3:15][O:16][CH2:17][CH2:18][O:19][CH3:20].[OH:21][C:22]([CH3:40])([CH3:39])[C:23]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][O:34][CH2:35][CH:36]2[CH2:38][O:37]2)=[CH:27][CH:26]=1)=[O:24]>CC(O)C>[OH:21][C:22]([CH3:39])([CH3:40])[C:23]([C:25]1[CH:30]=[CH:29][C:15]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH:32]([OH:31])[CH2:33][N:1]([CH2:38][CH:36]([OH:37])[CH2:35][O:34][CH2:33][CH2:32][O:31][C:28]2[CH:29]=[CH:30][C:25]([C:23](=[O:24])[C:22]([OH:21])([CH3:40])[CH3:39])=[CH:26][CH:27]=2)[CH2:2][CH2:3][CH2:4][Si:5]([O:12][CH2:13][CH3:14])([O:6][CH2:7][CH3:8])[O:9][CH2:10][CH3:11])=[CH:27][CH:26]=1)=[O:24]
Reactant: CC(C)(O)C(=O)c1ccc(OCCOCC2CO2)cc1
Reactant: CCO[Si](CCCN)(OCC)OCC
Reactant: COCCOC
Solvent: CC(C)O
Product: CCO[Si](CCCN(CC(O)COCCOc1ccc(C(=O)C(C)(C)O)cc1)CC(O)COCCOc1ccc(C(=O)C(C)(C)O)cc1)(OCC)OCC

Procedure:
To a mixture of 5.09 g (23 mmol) of 3-aminopropyltriethoxysilane, 30 ml of 1,2-dimethoxyethane and 30 ml of 2-propanol is added 8.99 g (32.1 mmol) of the compound prepared in Example 1A. The reaction mixture is heated at a gentle reflux for 23 hours. Solvent is evaporated to afford 14.37 g of a pale yellow oil corresponding to a mixture of the title compounds.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:9][OH:10].C[O-].[Na+].O>CN(C=O)C>[Br:1][C:2]1[C:3]([O:10][CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ncccc1Br
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ncccc1Br
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 95.3 %

Procedure:
Under an argon atmosphere, to a solution of 3-bromo-2-chloropyridine (4.76 g) in DMF (30 mL) was added 28% sodium methoxide methanol solution (5.73 g) at room temperature, and the mixture was stirred at 80° C. for 30 min. Water was added at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a crude product of the title compound (4.43 g) as a pale-yellow oil. This compound was used for the next step without further purification.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:10]=1[CH:11]=O.Cl.[NH2:19][OH:20].O>ClCCl>[Cl:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:10]=1[CH:11]=[N:19][OH:20]
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: NO
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: ON=Cc1c(Cl)cccc1Cl
Reaction time: 8 h
Yield: 132.9 %

Procedure:
Alternate procedure: Add triethylamine (23.1 g, 229 mmol) dropwise to a solution of 2,6-dichloro-benzaldehyde (20.0 g, 114 mmol) and hydroxylamine hydrochloride (10.3 g, 149 mmol) in dichloromethane (200 mL). Stir the reaction mixture for 8 h. Add water (200 mL). Separate the phases and extract the aqueous phase with dichloromethane (100 mL). Wash the combined organic phases with water (100 mL). Concentrate the combined organic phases to provide 28.8 g (94%) of the title compound.
Reaction SMILES: [H-].[Na+].[C:3]([O:12][CH2:13][CH:14]=[CH2:15])(=[O:11])[CH2:4][C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6].Cl[CH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1.Cl>O1CCOCC1.C1COCC1.O>[CH3:25][O:24][C:22]([C:21]1[CH:26]=[CH:27][C:18]([CH2:17][CH:4]([C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6])[C:3]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])=[CH:19][CH:20]=1)=[O:23]
Reactant: COC(=O)c1ccc(CCl)cc1
Reactant: C=CCOC(=O)CC(=O)OCC=C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: C1CCOC1
Product: C=CCOC(=O)C(Cc1ccc(C(=O)OC)cc1)C(=O)OCC=C
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
14.42 g (0.36 mol) of sodium hydride are added in portions to a solution of 56.7 g (0.3 mol) of diallyl malonate in 375 ml of dioxane and 75 ml of THF at 0° C. After warming to room temperature, the mixture is stirred at 40° C. for 1 hour. Subsequently, 111.88 g (0.6 mol) of methyl 4-chloromethylbenzoate, dissolved in 375 ml of dioxane, are slowly added dropwise at 40° C., and the reaction solution is stirred at 110° C. overnight. After cooling to room temperature, the reaction mixture is added to 1200 ml of water. Care must be taken during this that the pH is <7 (where appropriate, a few ml of 1 M hydrochloric acid are metered in to about pH 2). The mixture is then extracted three times with ethyl acetate, and the combined organic phases are washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the solvent is concentrated to dryness in vacuo. The resulting crude product is purified by flash chromatography (mobile phase: petroleum ether/ethyl acetate 10:1; 3 kg of silica gel). 85.4 g (0.26 mol, 85% yield) of a colorless solid are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](O)C(=[C:9]([O:11][CH3:12])[CH:10]=1)C=O.[C:14]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1CCCCC1.C(#N)C>[C:14]([C:22]1[C:23](=[O:24])[O:25][C:26]2[C:4]([CH:5]=1)=[C:3]([O:2][CH3:1])[CH:10]=[C:9]([O:11][CH3:12])[CH:27]=2)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1cc(O)c(C=O)c(OC)c1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Solvent: CC#N
Solvent: C1CCNCC1
Product: COc1cc(OC)c2cc(C(=O)c3ccccc3)c(=O)oc2c1

Procedure:
A mixture of 18.2 g 4,6-dimethoxysalicylaldehyde, 20.0 g ethyl benzoylacetate, 20 ml acetonitrile and 30 drops piperidine was heated gently on a hot plate for 45 minutes. After cooling the product was collected and recrystallized twice from acetonitrile and once from benzene containing a small amount of acetonitrile. m.p. 178° C.-179° C.
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[C:11](=[O:23])[N:12]([CH3:22])[C:13]3[C:18]([C:19]=2[O:20]C)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[OH-].[Na+]>>[C:1]1([NH:7][C:8]([C:10]2[C:11](=[O:23])[N:12]([CH3:22])[C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[N:12]1[CH:13]=[CH:18][CH:19]=[CH:10][CH:11]=1
Reactant: COc1c(C(=O)Nc2ccccc2)c(=O)n(C)c2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(=O)c(C(=O)Nc2ccccc2)c(O)c2ccccc21
Product: c1ccncc1
Temperature: 25 °C

Procedure:
A mixture of one part of N-phenyl-1,2-dihydro-4-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide (prepared according to Example 6) and 5 parts of 5 molar aqueous hydrochloric acid is refluxed for 2.5 h, cooled to room temperature and then neutralized with aqueous sodium hydroxide solution. The crystalline product obtained is filtered off and recrystallized from pyridine to give N-phenyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide (1) (the same compound as 1:1). M. p. 199°-200° C.
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[Mg].[F:10][C:11]1[CH:24]=[CH:23][C:22]2[S:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([Cl:25])[CH:19]=3)[C:14](=[O:26])[C:13]=2[CH:12]=1>O1CCCC1>[Cl:25][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[C:14]([CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1)([OH:26])[C:13]1[CH:12]=[C:11]([F:10])[CH:24]=[CH:23][C:22]=1[S:21]2
Reactant: O=c1c2ccc(Cl)cc2sc2ccc(F)cc12
Reactant: CN1CCC(Cl)CC1
Agent: [Mg]
Solvent: C1CCOC1
Product: CN1CCC(C2(O)c3ccc(Cl)cc3Sc3ccc(F)cc32)CC1

Procedure:
The Grignard reagent prepared from 5.9 g. (0.044 mol) of 4-chloro-N-methylpiperidine and 1.1 g. (0.044 mol) of magnesium turnings of tetrahydrofuran is treated with 5.8 g. (0.022 mol) and the above-prepared thioxanthone. The mixture is refluxed for four hours and worked up by the usual procedure to yield 6-chloro-2-fluoro-9-(1-methyl-4-piperidyl)-thioxanthene-9-ol, m.p. 133°-142° C.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5].C(Cl)CCl.O[C@H:13]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:14][NH:15][C:16]([C@@H:18]([CH2:27][CH:28]=[CH2:29])[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:17].CCN(C(C)C)C(C)C>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:1]([O:7][C@H:13]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH2:14][NH:15][C:16]([C@@H:18]([CH2:27][CH:28]=[CH2:29])[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:17])(=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5]
Reactant: C=CCCC(=O)O
Reactant: C=CC[C@@H](CC(=O)OC(C)(C)C)C(=O)NC[C@H](O)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCC(=O)O[C@@H](CNC(=O)[C@@H](CC=C)CC(=O)OC(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.6 %

Procedure:
To a solution of 4-pentenoic acid (0.335 mL, 3.28 mmol) in DMF (31.6 mL) cooled in an ice/water bath was added EDC (630 mg, 3.28 mmol) and the resulting solution was stirred 30 min. (S)-tert-butyl 3-((R)-2-hydroxy-2-phenylethylcarbamoyl)hex-5-enoate (730 mg, 2.19 mmol), iPr2NEt (1.14 mL, 6.57 mmol) and DMAP (26.7 mg, 0.219 mmol) were subsequently added and the reaction mixture was slowly warmed to rt and stirred for 16 h at which point LC-MS analysis indicated complete consumption of starting material. The reaction mixture was diluted with saturated NH4Cl and EtOAc and the layers separated. The aqueous was extracted 2× with EtOAc and the combined organic extracts were washed with 1N HCl and brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified using silica gel chromatography (MeOH/CH2Cl2 gradient) to yield 670 mg of desired product as a colorless oil in 74% yield. LRMS (M+Na)+: 430.0.
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([C:19]([Cl:22])=[CH:20][CH:21]=1)[C:7](C1C=CC(Cl)=C([N+]([O-])=O)C=1)=[O:8])([O-])=O.[Cl:23]C1C=CC=CC=1C(C1C=CC(Cl)=CC=1)=O>ClC1C=CC=CC=1>[Cl:22][C:19]1[CH:20]=[CH:21][CH:4]=[CH:5][C:6]=1[C:7]([Cl:23])=[O:8]
Reactant: O=C(c1ccc(Cl)c([N+](=O)[O-])c1)c1cc([N+](=O)[O-])ccc1Cl
Reactant: O=C(c1ccc(Cl)cc1)c1ccccc1Cl
Solvent: Clc1ccccc1
Product: O=C(Cl)c1ccccc1Cl

Procedure:
For example, 3,3'-dinitro-4,4'-dichlorobenzophenone can be prepared in a yield of 95 to 98% by nitrating 4,4'-dichlorobenzophenone [E. R. Kofanov et al., J. Org. Chem. USSR, 15, 98-100 (1979)]. 5,3'-Dinitro-2,4'-dichlorobenzophenone can be prepared in a high yield by nitrating 2,4'-dichlorobenzophenone [E. H. Faith et al., J. Am. Chem. Soc., 77, 543 (1955)]. 3,3'-Dinitro-4-chlorobenzophenone can be prepared in a high yield by nitrating 4-chlorobenzophenone [G. S. Mironov et al., J. Org. Chem. USSR, 8, 1538 (1972)]. 3,4'-Dinitro-4-chlorobenzophenone can be prepared by nitrating 4-halogeno-4'-nitrobenzophenone obtained by the condensation reaction between p-nitrobenzoyl chloride and chlorobenzene [P. T. Montagne et al., Ber., 49, 2267-2270 (1916); G. S. Mironov et al., J. Org. Chem. USSR, 8, 1538-1543 (1972)]. 3,3'-Dinitro-6,4'-dichlorobenzophenone can be prepared in a high yield by nitrating 2,4'-dichlorobenzophenone obtained by the condensation reaction between 2-chlorobenzoyl chloride and chlorobenzene [H. F. Faith et al., J. Am. Chem. Soc., 77, 543 (1955)].
Reaction SMILES: [OH:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12].[C:14](OCC)(=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16].[O-]CC.[Na+]>C(O)C>[CH:8]([C:7]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:2]=1[O:1][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:12][C:11]2=[O:13])([CH3:10])[CH3:9]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1cccc(C(C)C)c1O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc(=O)c2cccc(C(C)C)c2o1
Temperature: 25 °C

Procedure:
To a solution of Example 13A (2.048 g, 11.5 mmol) in ethanol (60 mL)was added diethyl oxalate (3.43 mL, 25.3 mmol) and sodium ethoxide (21% in EtOH, 12.9 mL, 34.5 mmol) and the mixture was refluxed for 30 minutes. The mixture was cooled to ambient temperature, partitioned between diethyl ether (150 mL) and water (150 mL). Hydrochloric acid (12N, 3 mL) was added and the separated organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford ethyl 8-isopropyl-4-oxo-4H-chromene-2-carboxylate. After dissolving the intermediate in acetic acid (45 mL) and 12N hydrochloric acid (7.5 mL), the mixture was heated to reflux for 5.5 hours then cooled to ambient temperature. Water (400 mL) was added and the mixture was extracted with ethyl acetate (400 mL). The combined organic layers were washed with water (400 mL) and brine, dried over anhydrous sodium sulfate and filtered. The solution was concentrated under reduced pressure and vacuum dried overnight to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.32 (d, 6H), 3.56 (m, 1H), 6.91 (s, 1H), 7.48 (t, 1H), 7.78 (dd, 1H), 7.89 (dd, 1H). MS (ESI) m/z 232.94 (M+H)+.
Reaction SMILES: Cl[Si:2]([NH:5][C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])[CH3:3].[C:10]1([CH:16]([K])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1>[C:6]([NH:5][Si:2]([CH3:4])([CH3:3])[CH:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)N[Si](C)(C)Cl
Reactant: [K]C(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)N[Si](C)(C)C(c1ccccc1)c1ccccc1

Procedure:
To a solution of 4.1 g (24.7 mmol) of ClSiMe2NHCMe3 in 80 mL of THF were added 3.735 g (18.1 mmol) of solid diphenylmethyl potassium. The orange color of the diphenylmethyl potassium disappeared instantly and precipitate formed rapidly. The reaction mixture was stirred for several days. The solvent was removed under reduced pressure and the residue was extracted with hexane and the solvent was removed under reduced pressure. The yellow liquid product was subjected to vacuum pumping to remove the excess ClSiMe2NHCMe3. The yield was 4.786 g, 88.9 percent.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1.[CH2:12]([S:18](Cl)(=[O:20])=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].O>N1C=CC=CC=1>[CH2:12]([S:18]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1)(=[O:20])=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: Cc1nc2cc(N)ccc2o1
Reactant: CCCCCCS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCS(=O)(=O)Nc1ccc2oc(C)nc2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 29.6 g of 5-amino-2-methylbenzoxazole in 100 ml pyridine cooled to 0° C. was added 41.3 g hexanesulfonyl chloride. After 1 hour stirring at 0° C., a reddish precipitate formed. The reaction mixture was stirred at room temperature for 2 days and then poured into 1.4 1 of water and stirred for 2 hours. A heavy oil deposited and the supernatant was decanted. The oil was dissolved in 1.0 1 dichloromethane, which was extracted with 4×200 ml of 1N hydrochloric acid, then dried over magnesium sulfate. The solvent was removed, leaving a reddish brown liquid of 5-hexylsulfonamido-2-methylbenzoxazole (Intermediate A).
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:18][CH2:17][C:16]2[S:15][C:14]3[N:13]=[CH:12][N:11]=[C:10]([O:19][CH:20]4[CH2:25][CH2:24][CH:23]([N:26]5[CH2:31][CH2:30][NH:29][C:28](=[O:32])[CH2:27]5)[CH2:22][CH2:21]4)[C:9]=3[C:8]1=2)(=O)=O.[C-:33]#[N:34].[Na+]>CS(C)=O.CN(C1C=CN=CC=1)C.C(Cl)Cl>[O:32]=[C:28]1[NH:29][CH2:30][CH2:31][N:26]([CH:23]2[CH2:24][CH2:25][CH:20]([O:19][C:10]3[C:9]4[C:8]5[C@@H:7]([CH2:6][C:33]#[N:34])[CH2:18][CH2:17][C:16]=5[S:15][C:14]=4[N:13]=[CH:12][N:11]=3)[CH2:21][CH2:22]2)[CH2:27]1
Reactant: CS(=O)(=O)OC[C@H]1CCc2sc3ncnc(OC4CCC(N5CCNC(=O)C5)CC4)c3c21
Reactant: [C-]#N
Agent: CN(C)c1ccncc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: N#CC[C@H]1CCc2sc3ncnc(OC4CCC(N5CCNC(=O)C5)CC4)c3c21
Temperature: 80 °C
Reaction time: 2 h
Yield: 85.3 %

Procedure:
To a solution of [(3S)-12-[[4-(3-oxopiperazin-1-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]methyl methanesulfonate (450 mg, 0.94 mmol, 1.00 equiv) in DMSO (10 mL) was added NaCN (276 mg, 5.63 mmol, 6.00 equiv) and DMAP (11 mg, 0.094 mmol, 0.10 equiv) at room temperature. The resulting solution was stirred for 2 h at 80° C. After cooling to r.t, the resulting solution was diluted with DCM (100 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography on silica gel with DCM/MeOH (10:1) to afford 330 mg (86%) of 2-[(3R)-12-[[4-(3-oxopiperazin-1-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]acetonitrile as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[O:16][C:6]2=[CH:7][C:8]3[C:9]([CH3:15])=[CH:10][CH:11]=[N:12][C:13]=3[CH:14]=[C:5]2[C@@H:4]([NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@@H:3]1[OH:26].C(O)(=O)/C=C\C(O)=O.CCCCCC>C(OCC)(=O)C>[CH3:1][C:2]1([CH3:27])[O:16][C:6]2=[CH:7][C:8]3[C:9]([CH3:15])=[CH:10][CH:11]=[N:12][C:13]=3[CH:14]=[C:5]2[CH:4]([NH:17][CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:3]1[OH:26]
Reactant: Cc1ccnc2cc3c(cc12)OC(C)(C)[C@@H](O)[C@@H]3NCCc1ccccc1
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1ccnc2cc3c(cc12)OC(C)(C)C(O)C3NCCc1ccccc1
Temperature: 0 °C
Yield: 72 %

Procedure:
To a solution of (±)-trans-2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinolin-3-ol (219 mg, 0.60 mmol) in ethyl acetate (3 mL), a solution of maleic acid (77 mg, 0.66 mmol) in ethyl acetate (1 mL) was added dropwise, the resulting reaction solution was cooled to 0° C., hexane (10 mL) was added thereto, and precipitated solid was filtered off to obtain 2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinolin-3-ol 3/2 maleate (yield: 72%).
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])[N:10]=2)=CC=1>CO.[Pd]>[F:18][C:15]([F:16])([F:17])[C:13]1[CH:12]=[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]([F:26])([F:28])[F:27])[N:10]=[C:9]([NH2:8])[CH:14]=1
Reactant: COc1ccc(CNc2cc(C(F)(F)F)cc(-c3ccccc3C(F)(F)F)n2)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1cc(C(F)(F)F)cc(-c2ccccc2C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of (4-methoxy-benzyl)-[4-trifluoromethyl-6-(2-trifluoromethyl-phenyl)-pyridin-2-yl]amine (1.00 g, 2.34 mmol, prepared as described in STEP B above) in MeOH (20 mL) was added, the flask was flushed well with Ar, Pd/C (500 mg, 0.235 mmol, 5% on carbon) was added, and the flask was flushed with Ar and fitted with an H2 balloon. The resulting mixture stirred at room temperature for 4 h. The balloon was removed, the flask was flushed again with Ar, the mixture was filtered through diatomaceous earth, and the filter cake was washed well with MeOH. The filtrate was concentrated in vacuo to yield 4-trifluoromethyl-6-(2-trifluoromethyl-phenyl)-pyridin-2-ylamine as a tan solid. 1H-NMR (400 MHz, CDCl3) δ: 7.81 (d, J=7.6 Hz, 1H), 7.64-7.76 (m, 2H), 7.59 (d, J=7.1 Hz, 1H), 7.25 (s, 1H), 6.79 (s, 1H), 3.22 (br. s., 4H).