Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH2:25])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].Br[CH2:27][CH:28]=[CH:29][CH3:30].[OH-].[Na+]>O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:20]([S:21](=[O:23])(=[O:24])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH:25][CH2:27][CH:28]=[CH:29][CH3:30])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC=CCBr
Reactant: CC(=O)Nc1ccc(Nc2c(N)cc(C(=O)O)cc2S(N)(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC=CCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Nc1ccc(NC(C)=O)cc1

Procedure:
The starting material is prepared as follows: To the stirred mixture of 5.5 g of 4-(4-acetamidophenylamino)-3-amino-5-sulfamoylbenzoic acid, 2.0 g of 1-bromo-2-butene, 30 ml of water and 10 ml of N aqueous sodium hydroxide, 4N aqueous sodium hydroxide is added dropwise in order to keep the pH of the mixture at 7.4 for 17 hours. It is filtered, the filtrate acidified with glacial acetic acid to pH = 4 and the precipitate formed filtered off. It is recrystallized from aqueous ethanol, to yield the 4-(4-acetamidophenylamino)-3-but-2-enylamino-5-sulfamoylbenzoic acid melting at about 230° with decomposition.
Reaction SMILES: C([O:4][CH2:5][C@@H:6]1[CH2:11][C@@H:10]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH2:9][C:8](=[O:20])[O:7]1)(=O)C>C1COCC1.CO.[Sn]>[Si:13]([O:12][C@@H:10]1[CH2:11][C@@H:6]([CH2:5][OH:4])[O:7][C:8](=[O:20])[CH2:9]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(=O)OC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Agent: [Sn]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC(=O)O[C@H](CO)C1
Reaction time: 8 h
Yield: 29.3 %

Procedure:
((2S,4R)-4-(tert-butyldimethylsilyloxy)-6-oxotetrahydro-2H-pyran-2-yl)methyl acetate (VI) (0.625 g, 80% purity, 1.65 mmol) was dissolved in THF (8 mL) and MeOH (8 mL). Tin catalyst (tBu2SnClOH)2 (94 mg, 0.1 eq) was added and the reaction was stirred overnight. Reaction was concentrated and purified by flash chromatography to give pure (4R,6S)-4-(tert-butyldimethylsilyloxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-2-one (VII) (126 mg, 30%). VII was found to contain less than 0.1% of enantiomer.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH:3]([NH:14][C:15]([C:17]1[O:18][C:19]2[CH:25]=[C:24]([C:26]([O:28]C(C)(C)C)=[O:27])[CH:23]=[CH:22][C:20]=2[CH:21]=1)=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1.FC(F)(F)C(O)=O>ClCCl>[F:34][C:2]([F:1])([F:33])[CH:3]([NH:14][C:15]([C:17]1[O:18][C:19]2[CH:25]=[C:24]([C:26]([OH:28])=[O:27])[CH:23]=[CH:22][C:20]=2[CH:21]=1)=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:11])([F:12])[F:13])[CH:5]=1
Reactant: CC(C)(C)OC(=O)c1ccc2cc(C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)oc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1ccc2cc(C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)oc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of tert-butyl 2-({2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}carbamoyl)-1-benzofuran-6-carboxylate (450 mg, 1.04 mmol) in dichloromethane (4.5 ml) was admixed at 0° C. with trifluoroacetic acid (0.46 ml, 6.0 mmol) and stirred at room temperature overnight. Subsequently, the reaction mixture was washed with water, and the organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue was filtered through silica gel, the filtercake was rinsed with ethyl acetate and methanol, and the filtrate was concentrated.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](Cl)=[N:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].[NH3:14]>O1CCCC1>[C:1]([C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7]([NH2:14])=[N:8][C:9]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: N
Reactant: CC(=O)c1cc(C#N)c(Cl)nc1C
Solvent: C1CCOC1
Product: CC(=O)c1cc(C#N)c(N)nc1C
Temperature: 80 °C

Procedure:
40 g (0.21 mol) of 5-acetyl-2-chloro-3-cyano-6-methyl-pyridine are dissolved in 800 ml of tetrahydrofuran, 200 ml of concentrated aqueous NH3 solution are added, and the mixture is heated at 80° C. in a stirred autoclave for two hours. After cooling, the mixture is concentrated and filtered, and the filter cake is extracted by boiling in acetonitrile and is filtered with suction.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:15][CH3:16])[C:13]=1[OH:14])[CH:6]=[CH:7][C:8]([OH:10])=[O:9].N1C=CN=C1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>CN(C)C=O>[CH3:16][O:15][C:12]1[CH:11]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:13]=1[O:14][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])/[CH:6]=[CH:7]/[C:8]([OH:10])=[O:9]
Reactant: COc1cc(C=CC(=O)O)cc(OC)c1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COc1cc(/C=C/C(=O)O)cc(OC)c1O[Si](C)(C)C(C)(C)C
Reaction time: 1 h
Yield: 86 %

Procedure:
3,5-dimethoxy-4-hydroxy-cinnamic acid (3 g, 13.38 mmol) and imidazole (2.73 g, 40.14 mmol) were charged in a 500 mL round-bottom flask and dissolved in 15 mL of dimethylformamide. Tert-butyldimethylsilyl chloride (4.23 g, 28.09 mmol) was added thereto at 0° C., followed by stirring for 1 hour. The reaction liquid was concentrated by distillation under reduced pressure and dichloromethane (50 mL) was added thereto, followed by washing with water. The organic layer was dried over anhydrous magnesium sulfate, concentrated and dissolved in tetrahydrofuran (59 mL)/methanol (167 mL), and a 0.00035M potassium carbonate aqueous solution (62 mL) was added thereto, followed by stirring for 1 hour. After being concentrated by distillation under reduced pressure, the resulting solid was filtered, washed with water, and dried under vacuum to afford the title compound.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10]Cl.[I-:18].[Na+]>CC(=O)CC>[Cl:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][I:18]
Reactant: [I-]
Reactant: COc1ccc(OCCOCCCl)c(Cl)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: COc1ccc(OCCOCCI)c(Cl)c1

Procedure:
was prepared from 24.7 g. of the corresponding chloride of part (a) by three hours reflux with 13.5 g. of sodium iodide in 200 ml. of 2-butanone. The crude product was used directly in part (c) below.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:16])[CH:8]=[CH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:36](=[C:43]1[S:47][C:46](=[O:48])[NH:45][C:44]1=[O:49])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(OC(N=NC(OCC)=O)=O)C>C1COCC1>[CH:36](=[C:43]1[S:47][C:46](=[O:48])[N:45]([CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:16])[CH:8]=[CH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[C:44]1=[O:49])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: O=C1NC(=O)C(=Cc2ccccc2)S1
Reactant: O=C(C=Cc1cccnc1)NCCCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(C=Cc1cccnc1)NCCCCN1C(=O)SC(=Cc2ccccc2)C1=O

Procedure:
Batch size: 13.5 g (61.3 mmol) N-(4-hydroxybutyl)-3-pyridin-3-yl-acrylamide, 16.1 g (61.3 mmol) triphenylphosphine, 12.6 g (61.3 mmol) 5-benzyliden-thiazolidin-2,4-dione and 9.7 ml (61.3 mmol) azodicarboxylic acid diethyl ester in 250 ml THF.
Reaction SMILES: [NH2:1][C:2]([CH2:10][CH2:11][CH3:12])=[C:3]([Cl:9])[C:4](OCC)=[O:5].[CH:13]([NH2:15])=O.C[O-].[Na+]>CO>[Cl:9][C:3]1[C:4]([OH:5])=[N:15][CH:13]=[N:1][C:2]=1[CH2:10][CH2:11][CH3:12]
Reactant: NC=O
Reactant: CCCC(N)=C(Cl)C(=O)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCc1ncnc(O)c1Cl

Procedure:
58.1 g (0.30 mol) of ethyl 3-amino-2-chloro-2-hexenoate are reacted with 47.7 g (1.1 mol) of formamide and 140 ml of sodium methylate solution in 175 ml of methanol and worked up in analogy to Example 9 (reaction time 6 h). Yield: 42.2 g (81.5%)
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][N:6]1[CH:14]=[N:13][C:12]2[C:7]1=[N:8][C:9]([NH2:15])=[N:10][CH:11]=2.[CH3:16][C:17](OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:18]>CN(C)C1C=CN=CC=1.CN(C)C=O>[C:17]([O:1][CH2:2][CH2:3][O:4][CH2:5][N:6]1[CH:14]=[N:13][C:12]2[C:7]1=[N:8][C:9]([NH2:15])=[N:10][CH:11]=2)(=[O:18])[CH3:16]
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Reactant: Nc1ncc2ncn(COCCO)c2n1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CC(=O)OCCOCn1cnc2cnc(N)nc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 0.82 g (3.92 mM) of 9-(2-hydroxyethoxymethyl)-2-amino-9H-purine, 48 mg (0.392 mM) of a 4-dimethylaminopyridine and 0.75 ml (7.84 mM) of acetic anhyride in 18 ml of dry dimethylformamide was stirred at room temperature for two days. The reaction mixture was evaporated in vacuo and the residue dissolved in ethyl acetate and absorbed on silica gel. The solvent was removed by flash evaporation and the residual powder added to a column prepared for flash chromatography. Elution with 5% methanol in dichloromethane gave 1.0 g of a semicrystalline oil which on recrystallization from benzene-hexane gave analytically pure 9-(2-acetoxyethoxymethyl)-2-amino-9H-purine, mpt. 115°-118° C. An additional crop was obtained from the mother liquor.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[Se](=O)=[O:16]>O1CCOCC1>[Cl:1][C:2]1[C:3]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[O:16])=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[Se]=O
Reactant: Cc1ccc(-c2ncccc2Cl)cc1
Solvent: C1COCCO1
Product: O=Cc1ccc(-c2ncccc2Cl)cc1
Temperature: 25 °C
Yield: 85 %

Procedure:
{circle around (1)} 100 g (0.49 mol) of 3-chloro-2-para-tolylpyridine was dissolved in 1 L of 1,4-dioxane in a reactor. 163.4 g (1.47 mol) of selenium dioxide was added, and the mixture was refluxed for 4˜6 hours. The reaction solution was cooled to 25° C., and floating matter was filtered off with celite. A 10% sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried with magnesium sulfate, and concentrated under reduced pressure, yielding 4-(3-chloropyridin-2-yl)benzaldehyde as represented below in a 85% yield.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[OH-].[Na+].Br[CH2:13][CH:14]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:15][CH3:16]>COCCO>[CH2:15]([CH:14]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[CH3:16]
Reactant: CCCCC(CC)CBr
Reactant: N#Cc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Product: CCCCC(CC)COc1ccc(C#N)cc1
Reaction time: 0.25 h
Yield: 84.3 %

Procedure:
61.4 g (0.5 mol) of 4-hydroxybenzonitrile in 500 ml of methylcellosolve are placed in a 1 l sulfonating flask fitted with stirrer, condenser, dropping funnel and internal thermometer. The batch is heated to 80 C., and then 73.3 g of 30% NaOH (0.55 mol) are run in slowly with vigorous stirring. The mixture is stirred for 15 minutes before commencing the dropwise addition, over 30 minutes, of 116.8 g (0.575 mol) of 3-bromomethylheptane. The reaction is continued at 100 C. for about 12 hours. The thin-layer chromatogram indicates virtually quantitative conversion. Solvent and excess bromide are removed in vacuo and the residue (an oil) is taken up in 500 ml of toluene. The mixture is subjected three times to extraction by shaking with water and the extracts are dried over sodium sulfate and concentrated to dryness. High-vacuum distillation via a 10 cm Vigreux column (127-132 C., 0.15 mm) gives 97.5 g (84% of theory) of 4-(2-ethylhexyloxy)benzonitrile as a coloured oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([CH:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][C:29]=4[Cl:31])[C:24](=[O:32])[O:23]3)=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:33]([F:36])([F:35])[F:34].O>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:15]2[C:16]([CH:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][C:29]=4[Cl:31])[C:24](=[O:32])[O:23]3)=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:33]([F:36])([F:35])[F:34]
Reactant: COCN(c1cc(Cl)cnc1C1OC(=O)c2cccc(Cl)c21)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: O=C1OC(c2ncc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c2c(Cl)cccc21
Temperature: 25 °C
Yield: 57.2 %

Procedure:
A mixture of 4-chloro-N-[5-chloro-2-(7-chloro-3-oxo-1,3-dihydro-isobenzofuran-1-yl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzene-sulfonamide (77 mg, 0.13 mmol) in 4M HCl in dioxane (3 mL) and water (1 mL) was heated at reflux for 3 h. The reaction mixture was then cooled to room temperature, evaporated to dryness and neutralized with saturated aqueous NaHCO3 solution to pH 2-3. The aqueous layer was extracted with EtOAc (2×25 mL), dried (Na2SO4), and concentrated. The obtained residue was purified by flash chromatography on silica gel (50% EtOAc-hexanes) to afford 4-chloro-N-[5-chloro-2-(7-chloro-3-oxo-1,3-dihydro-isobenzofuran-1-yl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide (40 mg) as a white solid in 56% yield. MS m/z: 537 (M+H), 559 (M+Na).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][NH:9][C:10](=[O:32])[CH:11]([OH:31])[CH2:12][CH2:13][S:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:19]=2)(=[O:16])=[O:15])[CH2:3][CH2:2]1.[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C>C(Cl)Cl>[CH3:33][S:34]([O:31][CH:11]([C:10]([NH:9][CH2:8][CH2:7][N:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)=[O:32])[CH2:12][CH2:13][S:14]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:19]=1)(=[O:16])=[O:15])(=[O:36])=[O:35]
Reactant: O=C(NCCN1CCOCC1)C(O)CCS(=O)(=O)Cc1cccc(Oc2ccccc2)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC(CCS(=O)(=O)Cc1cccc(Oc2ccccc2)c1)C(=O)NCCN1CCOCC1
Reaction time: 1 h
Yield: 92.5 %

Procedure:
Part H: A cooled solution of 2.1 g (5 mmol) of N1-(2-morpholinoethyl)-2--hydroxy-4-[(3-phenoxybenzyl)sulfonyl]butanamide from Part G in 55 mL of anhydrous CH2Cl2 was treated with 0.5 mL (0.8 g, 7 mM) of methanesulfonyl chloride, followed by 1.0 mL (0.7 g, 7 mM) of triethylamine. After 1 hour, the reaction was concentrated in vacuo, and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The layers were separated and the aqueous layer was extracted with ethyl acetate (1×). The organic layers were combined and washed with brine, dried (MgSO4) and concentrated to yield 2.5 g of 1-[(2-morpholinoethyl)amino]carbonyl-3-[(3-phenoxybenzyl)sulfonyl]propyl methanesulfonate suitable for the next reaction.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5](=O)[C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(#N)C.[C:40](Cl)(Cl)([Cl:42])[Cl:41]>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)=[C:40]([Cl:42])[Cl:41])[CH3:2]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CCOC(=O)C(=O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CCOC(=O)C(=C(Cl)Cl)c1ccc(C(F)(F)F)cc1

Procedure:
680 mg of oxo-(4-trifluoromethyl-phenyl)-acetic acid ethyl ester and 2.2 g of triphenylphosphine are introduced into 8 ml of acetonitrile. 0.8 ml of carbon tetrachloride is then added and the mixture is heated at reflux for 4 hours. The reaction mixture is concentrated completely and the crude product is purified over silica gel. 3,3-Dichloro-2-(4-trifluoromethyl-phenyl)-acrylic acid ethyl ester is obtained. 1H-NMR (CDCl3) 300 MHz: 1.30 (t, 3H), 4.30 (q, 2H), 7.52 (d, 2H), 7.68 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([Cl:13])[C:3]=1[CH2:4][OH:5].N1C=CN=C1.[Si:19](Cl)([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O.O>[Si:19]([O:5][CH2:4][C:3]1[C:6]([Cl:13])=[CH:7][CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:2]=1[Cl:1])([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)c(CO)c1Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](OCc1c(Cl)ccc([N+](=O)[O-])c1Cl)(c1ccccc1)c1ccccc1
Reaction time: 8 h

Procedure:
To a solution of 2,6-dichloro-3-nitrobenzyl alcohol (5.0 g) in N,N-dimethylformamide (25 ml) were added imidazole (1.69 g) and tert-butyldiphenylsilyl chloride (6.0 ml) at ambient temperature with stirring. After 8 hours, the mixture was diluted with water (25 ml) and was extracted with ethyl acetate twice. The organic layer was washed with water and brine, dried over magnesium sulfate. The solvent was removed in vacuo to give 1-(tert-butyldiphenylsilyloxy-methyl)-2,6-dichloro-3-nitrobenzene (11.5 g) as an oil.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:16]3[C:11](=[C:12]([O:17]C)[CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]2[CH3:19])=[CH:3][CH:2]=1.B(Br)(Br)Br.C(Cl)Cl>>[C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:16]3[C:11](=[C:12]([OH:17])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]2[CH3:19])=[CH:3][CH:2]=1
Reactant: COc1cccc2c1cc(C)n2Cc1ccc(-c2ccccc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc2c(O)cccc2n1Cc1ccc(-c2ccccc2)cc1
Yield: 77.4 %

Procedure:
By the method used in Example 1, Part D, 1.3 g (4.0 mmol) of 1-([1,1-biphenyl]-4-ylmethyl)-4-methoxy-2-methyl-1H-indole was O-demethylated by treating it with 16 mL of 1M BBr3/CH2Cl2 to give 970 mg (77% yield) of crude 1-([1,1′-biphenyl]-4-ylmethyl)-4-hydroxy-2-methyl-1H-indole.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH:5]([C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1)[OH:6])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23][CH2:24][S:25][CH2:26][CH2:27][CH3:28]>C(#N)C>[CH2:1]([N:3]([CH2:22][CH2:23][CH2:24][S:25][CH2:26][CH2:27][CH3:28])[CH2:4][CH:5]([C:7]1[CH:8]=[CH:9][C:10]([C:11]#[N:12])=[CH:13][CH:14]=1)[OH:6])[CH3:2]
Reactant: CCNCC(O)c1ccc(C#N)cc1
Reactant: CCCSCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCSCCCN(CC)CC(O)c1ccc(C#N)cc1

Procedure:
1.5 g of 4-[2-(ethylamino)-1-hydroxyethyl]-benzonitrile, 2.1 g of potassiumcarbonate, 1.7 g of 1-bromo-3-(propylthio)-propane was mixed in 50 ml acetonitrile and refluxed over night. The mixture was filtered and evaporated and the residue was dissolved in 2 M hydrochloric acid. The acidic waterlayer was washed twice with ether, alkalized with 10 M sodiumhydroxide and extracted with three portions of dichloromethane.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([C:13]([N:15]2[CH2:20][CH:19]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][CH:22]=3)[CH2:18][CH:17]([NH2:29])[CH2:16]2)=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]1.[Cl:30][C:31]1[CH:32]=[C:33]([C:37](O)=[O:38])[CH:34]=[N:35][CH:36]=1>>[Cl:30][C:31]1[CH:32]=[C:33]([C:37]([NH:29][CH:17]2[CH2:18][CH:19]([C:21]3[CH:22]=[CH:23][C:24]([CH2:27][CH3:28])=[CH:25][CH:26]=3)[CH2:20][N:15]([C:13]([CH:8]3[CH2:9][CH2:10][CH2:11][CH2:12]3)=[O:14])[CH2:16]2)=[O:38])[CH:34]=[N:35][CH:36]=1
Reactant: CCc1ccc(C2CC(N)CN(C(=O)C3CCCC3)C2)cc1
Reactant: O=C(O)c1cncc(Cl)c1
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(C2CC(NC(=O)c3cncc(Cl)c3)CN(C(=O)C3CCCC3)C2)cc1

Procedure:
65 mg (0.15 mmol) of 1-(cyclopentylcarbonyl)-5-(4-ethylphenyl)piperidine-3-amine trifluoroacetate (Example 8A) and 21 mg (0.13 mmol, 0.9 eq.) of 5-chloropyridine-3-carboxylic acid were reacted according to General Method 1. Yield: 39 mg (62% of theory)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[CH:15][CH:14]=[C:13]([CH3:24])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1.BrC1C=C(C#N)[CH:29]=[N:30]C=1>>[CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:18]3[CH:19]=[N:20][CH:21]=[C:22]([C:29]#[N:30])[CH:23]=3)=[CH:15][CH:14]=[C:13]([CH3:24])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(NC(=O)c2nc(C)ccc2Nc2cccnc2)ccn1
Reactant: N#Cc1cncc(Br)c1
Product: Cc1cc(NC(=O)c2nc(C)ccc2Nc2cncc(C#N)c2)ccn1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (2-methyl-pyridin-4-yl)-amide (example 5) in accordance with the general method of example 20 using 5-Bromo-3-cyanopyridine instead of 3-Bromo-4-methylpyridine to yield the final compound as a light yellow crystalline solid, MS (ISP): m/e=345.0 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].[H-].[Na+].[C:14]1([C:20]2[CH:29]=[CH:28][CH:27]=[C:26]3[C:21]=2[C:22]([NH:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)=[N:23][C:24]([CH:30]=O)=[N:25]3)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[C:14]1([C:20]2[CH:29]=[CH:28][CH:27]=[C:26]3[C:21]=2[C:22]([NH:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)=[N:23][C:24](/[CH:30]=[CH:5]/[C:3]([O:2][CH3:1])=[O:4])=[N:25]3)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: O=Cc1nc(NCc2ccccn2)c2c(-c3ccccc3)cccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1nc(NCc2ccccn2)c2c(-c3ccccc3)cccc2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
A solution of trimethyl phosphonoacetate (0.225 g 1.00 mmol) in THF (20 mL) was added 95% sodium hydride (0.050 g, 2.0 mmol). Upon the completion of addition, the mixture was stirred at 0° C. for 30 min and then 5-phenyl-4-(pyridin-2-ylmethylamino)quinazoline-2-carbaldehyde (Example 212, prepared in a similar manner to the procedure described below, 0.340 g, 1.00 mmol) was added to the reaction mixture. The resulting mixture was stirred at room temperature for 14 h. After this time, the reaction mixture was quenched with saturated aqueous ammonium chloride solution (50 mL) and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The filtrate was concentrated and the resulting residue was subjected to silica gel column chromatography using 5% MeOH in chloroform as the eluent to provide (E)-methyl 3-(5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl)acrylate (0.30 g, 72%) as a brown solid. LCMS Method V: retention time 1.94 min; [M+1]=411.2.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:20]([NH2:28])=[N:21][N:22]3[CH:27]=[CH:26][CH:25]=[N:24][C:23]=23)=[CH:15][CH:14]=1>>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:20]([NH:28][C:9](=[O:11])[CH2:8][C:4]3[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=3)=[N:21][N:22]3[CH:27]=[CH:26][CH:25]=[N:24][C:23]=23)=[CH:15][CH:14]=1
Reactant: O=C(O)Cc1cccnc1
Reactant: Nc1nn2cccnc2c1-c1ccc(Cl)cc1
Agent: Cl
Product: O=C(Cc1cccnc1)Nc1nn2cccnc2c1-c1ccc(Cl)cc1

Procedure:
3-Pyridylacetic acid hydrochloride and the product from Example 99A were processed using method analogous to that described in Example 98 to afford the title compound. 1H NMR (400 MHz, CD3OD) δ ppm 8.85 (dd, J=7.0, 1.8 Hz, 1H), 8.55 (dd, J=4.1, 1.8 Hz, 1H), 8.52-8.55 (m, 1H), 8.46-8.50 (m, 1H), 7.78-7.89 (m, 1H), 7.60-7.64 (m, 2H), 7.37-7.45 (m, 1H), 7.29-7.32 (m, 2H), 7.06 (dd, J=7.0, 4.1 Hz, 1H), 3.81 (s, 2H); MS (ESI) m/z 364 (M+H)+; Anal. calculated for C19H14ClN5O.0.35H2O: C, 61.66; H, 4.00; N, 18.92. Found C, 61.40; H, 3.70; N, 18.77.