Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=1.N1C=CC=CC=1.S(Cl)([Cl:38])=O>C(Cl)(Cl)Cl>[Cl:38][CH:2]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=1
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCCC(O)CCCCCNc1ccc(C(=O)OCC)cc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCC(Cl)CCCCCNc1ccc(C(=O)OCC)cc1

Procedure:
A solution of 10 g. of ethyl 4-(6-hydroxyhexadecylamino)benzoate and 2.4 ml. of pyridine in 50 ml. of chloroform is treated with 2.0 ml. of thionyl chloride, stirred under reflux for 1 hour, washed with 1 N hydrochloric acid and saturated aqueous sodium bicarbonate, dried over magnesium sulfate, and evaporated. The residue is crystallized from aqueous ethanol to yield the product as a white solid.
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:12]=[C:11]([OH:13])[C:10](=[O:14])[CH:9]=[C:8]2[CH3:15])[CH:2]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30]Cl)=[CH:26][CH:25]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:12]=[C:11]([O:13][CH2:30][C:27]3[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=3)[C:10](=[O:14])[CH:9]=[C:8]2[CH3:15])[CH:2]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Cc1cc(=O)c(O)cn1-c1cccc(-c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(COc2cn(-c3cccc(-c4ccccc4)c3)c(C)cc2=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4.8 g (17.4 mmol) l-biphenyl-3-yl-5-hydroxy-2-methylpyridin-4(1H)-one in 150 ml of DMF was added 4.1 g (26.1 mmol) PMBCl, and 12.0 g (87.0 mmol) K2CO3. The reaction was stirred at rt for 2 h, after which time water was added and a precipitate formed. The solid was collected by filtration and purified by flash chromatography (100 g silica gel, 0-20% MeOH;EtOAc) to afford 1-biphenyl-3-yl-5-[(4-methoxybenzyl)oxy]-2-methylpyridin-4(1H)-one.  H NM δ (ppm)(DMSO-d6): 7.84 (1H, d, J=7.86 Hz), 7.77 (2H, d, J=7.71 Hz), 7.73 (1H, s), 7.64 (1H, t, J=7.84 Hz), 7.53-7.47 (3H, m), 7.46-7.39 (2H, m), 7.38-7.30 (3H, m), 6.93 (2H, d, J=8.32 Hz), 6.23 (1H, s), 4.89 (2H, s), 3.77-3.70 (3H, m), 2.03 (3H, s). LCMS (M+H)+=398.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:24])([CH2:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)[C:10]([F:17])([F:16])[C:11](OCC)=[O:12].[Cl:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.C(OCC)(=O)C.Cl>O>[Cl:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:11](=[O:12])[C:10]([F:16])([F:17])[C:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])([OH:24])[CH2:18][N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)=[CH:28][CH:27]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CCOC(=O)C(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(Cl)cc1)C(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Yield: 24.3 %

Procedure:
A mixture of 100 mg of ethyl 3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butyrate and 370 mg of 4-chloroaniline was subjected to reaction at 150°-160° C. for 5 hours. The reaction mixture was cooled to room temperature. Thereto were added 10 ml of ethyl acetate and 5 ml of water. The resulting solution was adjusted to pH 2.0 with 6N hydrochloric acid. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure. The residue obtained was purified by a column chromatography (eluant: toluene/ethyl acetate=1/1) to obtain 30 mg of N-(4-chlorophenyl)-3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butanamide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[NH:10][CH:11]=[CH:12][N:13]=2)=[C:6]([OH:8])[CH:7]=1.Br[CH2:15][CH2:16]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[N:13]([CH:12]=[CH:11][N:10]=3)[CH2:15][CH2:16][O:8][C:6]=2[CH:7]=1
Reactant: BrCCBr
Reactant: Oc1cc(Br)ccc1-c1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Brc1ccc2c(c1)OCCn1ccnc1-2
Temperature: 90 °C
Yield: 75.4 %

Procedure:
A mixture of 5-bromo-2-(1H-imidazol-2-yl)phenol (0.9 g, 4 mmol), 1,2-dibromoethane (1.3 mL, 15 mmol) and cesium carbonate (4.9 g, 15 mmol) in DMF (20 mL) was heated to 90° C. for 12 h. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with water, brine and dried over MgSO4 and concentrated to give 9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (0.8 g).
Reaction SMILES: [CH2:1]([N:10]([CH2:12][C:13]1[CH:14]=[C:15]([C:19](=O)[CH3:20])[CH:16]=[CH:17][CH:18]=1)[CH3:11])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:22]([Li])CCC.CCCCCC>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([N:10]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([CH3:20])=[CH2:22])[CH:14]=1)[CH3:11])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: [Li]CCCC
Reactant: CC(=O)c1cccc(CN(C)CC=Cc2ccccc2)c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Product: C=C(C)c1cccc(CN(C)CC=Cc2ccccc2)c1
Yield: 50.5 %

Procedure:
The procedure described in Example 2 was repeated, except that Compound 46 (0.42 g; 1.50 mmol), methyl triphenylphosphonium bromide (1.5 eq), and n-butyl lithium in n-hexane (1.68 M: 1.5 eq) were used, to thereby yield 0.21 g of the target compound (yield: 50.5%).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:15][CH3:16])[C:4]1[CH:5]=[CH:6][C:7]2[CH2:13][CH2:12][CH2:11][CH2:10][NH:9][C:8]=2[N:14]=1.C1([O:23][C:24](=O)[NH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][N:27]=2)C=CC=CC=1>CN(C1C=CN=CC=1)C.C1COCC1.C([O-])(O)=O.[Na+]>[C:32]([C:29]1[CH:30]=[CH:31][C:26]([NH:25][C:24]([N:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:7]3[CH:6]=[CH:5][C:4]([CH:3]([O:2][CH3:1])[O:15][CH3:16])=[N:14][C:8]2=3)=[O:23])=[N:27][CH:28]=1)#[N:33]
Reactant: COC(OC)c1ccc2c(n1)NCCCC2
Reactant: N#Cc1ccc(NC(=O)Oc2ccccc2)nc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(OC)c1ccc2c(n1)N(C(=O)Nc1ccc(C#N)cn1)CCCC2

Procedure:
A mixture of 2-(dimethoxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepine (intermediate 237, 35 mg, 0.154 mmol), phenyl(5-cyanopyridin-2-yl)carbamate (intermediate 240, 122 mg, 0.509 mmol) and DMAP (28.3 mg, 0.231 mmol) in THF (1.7 ml) was heated at reflux for 23 h. The reaction mixture was diluted with sat. aq. NaHCO3 and extracted with DCM (3×). The combined organic layers were dried over Na2SO4 and evaporated. The crude material was applied to a 40 g RediSep® silica column and purified by normal phase chromatography, eluting with 99:1 DCM/MeOH. Product-containing fractions were combined and evaporated. The residue was triturated with Et2O and the solid removed by filtration. The filtrate was concentrated and the residue triturated with MeOH to give the title compound as a white solid. (UPLC-MS 6) tR 1.06; ESI-MS 368.1 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][C:7]([CH3:11])=[CH:6][C:5]=2[C:4]2[CH2:12][C:13]3[C:18]([C:3]1=2)=[CH:17][CH:16]=[CH:15][CH:14]=3.C([Li:23])CCC>C1(C)C=CC=CC=1.CCCCC>[CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][C:7]([CH3:11])=[CH:6][C:5]=2[C:4]2[CH2:12][C:13]3[C:18]([C:3]1=2)=[CH:17][CH:16]=[CH:15][C:14]=3[Li:23]
Reactant: Cc1ccc2c(c1)c1c(n2C)-c2ccccc2C1
Reactant: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CCCCC
Product: [Li]c1cccc2c1Cc1c-2n(C)c2ccc(C)cc12
Temperature: 25 °C

Procedure:
Under the nitrogen protection, 1.52 grams (0.0077 mole) of 5,8-dimethyl-5,10-dihydroindeno[1,2-b]indole is dissolved in 15 mL of toluene. To the solution is added 3.9 mL of n-butyllithium solution in pentane (2.0 mole/L). The mixture is refluxed for three hours and then cooled to 25° C. The precipitate is isolated by filtration, washed with hexane, and dried under vacuum, yielding 1.26 grams of 5,8-dimethyl-5,10-dihydroindeno [1,2-b]indolyllithium.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([OH:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2].Cl[CH2:17][C:18]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:17][C:18](=[O:19])[N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(O)ccc2[nH]1
Reactant: CCN(CC)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(OCC(=O)N(CC)CC)ccc2[nH]1
Temperature: 25 °C
Reaction time: 6 h
Yield: 32.7 %

Procedure:
A mixture of 5-hydroxy-1H-indole-2-carboxylic acid ethyl ester (1 g, 5 mmol), 2-chloro-N,N-diethylacetamide (1 mL, 7.5 mmol) and cesium carbonate (5 g, 15 mmol) in dimethylformamide (10 mL) was stirred at room temperature for 6 hours. The reaction was diluted with ethyl acetate (160 mL), washed with water (5×50 mL) and brine, dried and concentrated. The residue was recrystallized from ethyl acetate and hexane to give 0.52 g of 5-diethylcarbamoylmethoxy-1H-indole-2-carboxylic acid ethyl ester as an off-white solid.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:10][C:11](=[O:33])[CH:12]([CH2:28][S:29][C:30](=[O:32])[CH3:31])[CH2:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH:20]C(OC(C)(C)C)=O)[CH:15]=1)[CH3:9]>C(Cl)Cl>[CH2:8]([O:10][C:11](=[O:33])[CH:12]([CH2:28][S:29][C:30](=[O:32])[CH3:31])[CH2:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[CH:15]=1)[CH3:9]
Reactant: CCOC(=O)C(CSC(C)=O)Cc1ccnc(NC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(CSC(C)=O)Cc1ccnc(N)c1
Reaction time: 1 h
Yield: 141.7 %

Procedure:
TFA (0.5 mL) was added to a solution of 2-acetylsulfanylmethyl-3-(2-tert-butoxycarbonylamino-pyridin4-yl)-propionic acid ethyl ester (50 mg, 0.13 mmol) in methylene chloride under argon. The solution was stirred for 60 min and concentrated under reduced pressure to give crude 2-acetylsulfanylmethyl-3-(2-amino-pyridin-4-yl)-propionic acid ethyl ester (52 mg, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=O)=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1.[F:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][C:29]=1[C:35]([F:38])([F:37])[F:36].C[Al](C)C>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([NH:32][C:31]3[CH:33]=[CH:34][C:28]([F:27])=[C:29]([C:35]([F:38])([F:36])[F:37])[CH:30]=3)=[O:21])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1OC
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Agent: C[Al](C)C
Product: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1C(=O)Nc1ccc(F)c(C(F)(F)F)c1
Yield: 22 %

Procedure:
The title compound was prepared according to the procedure described in Example-31, by using methyl 4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (step-2 of Intermediate-15, 0.100 g, 0.26 mmol), 4-floro-3-trifloromethyl aniline (0.070 g, 1.5 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL) to afford 0.030 g of desired product. 1HNMR (DMSO-d6): δ 3.94 (s, 3H), 7.50-7.60 (m, 3H), 7.67-7.72 (m, 2H), 7.77-7.82 (m, 2H), 8.01 (m, 1H), 8.26 (m, 1H), 10.38 (br s, 1H), 12.80 (br s, 1H); MS (m/z): 525.17 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]([N:11]1[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[N:13]=[N:12]1)[CH3:10].S(=O)(=O)(O)O.[CH2:24](O)[CH3:25]>>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[CH:9]([N:11]1[CH:15]=[C:14]([C:16]([O:18][CH2:24][CH3:25])=[O:17])[N:13]=[N:12]1)[CH3:10]
Reactant: CCO
Reactant: CC(c1c(F)cccc1F)n1cc(C(=O)O)nn1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cn(C(C)c2c(F)cccc2F)nn1

Procedure:
6.5 g (35 millimoles) of 1-(2,6-difluorophenyl)ethyl azide and 2.45 g (35 millimoles) of propinecarboxylic acid in 50 ml of toluene are heated for 24 hours to 60°-70° C. The cooled reaction mixture is extracted with 100 ml of 1N sodium hydroxide solution and the extract is acidified with hydrochloric acid to give 1-[1-(2,6-difluorophenyl)ethyl-1H-1,2,3-triazole-4-carboxylic acid with a melting point of 135°-138° C. (dec.). 7.1 g (26.6 millimoles) of 1-[1-(2,6-difluorophenyl)ethyl]-1H-1,2,3-triazole-4-carboxylic acid, 150 ml of ethanol and 1 ml of sulfuric acid are heated for 10 hours to reflux. Working up gives ethyl 1-[1-(2,6-difluorophenyl)ethyl]-1H-1,2,3-triazole-4-carboxylate with a melting point of 118°-121° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][Cl:17])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:18][C:19]1[C:24]([Cl:25])=[CH:23][N:22]=[C:21]2[O:26][CH2:27][O:28][C:20]=12>>[Cl:17][CH2:16][CH2:15][O:14][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:18][C:19]3[C:24]([Cl:25])=[CH:23][N:22]=[C:21]4[O:26][CH2:27][O:28][C:20]=34)=[N:3][CH:4]=[N:5]2)=[CH:10][C:9]=1[O:12][CH3:13]
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCl
Reactant: Nc1c(Cl)cnc2c1OCO2
Product: COc1cc2c(Nc3c(Cl)cnc4c3OCO4)ncnc2cc1OCCCl
Yield: 92 %

Procedure:
Using an analogous procedure to that described in Example 1, 4-chloro-7-(2-chloroethoxy)6-methoxyquinazoline was reacted with 4-amino-5-chloro-2,3-methylenedioxypyridine to give the title compound in 92% yield; NMR Spectrum: (DMSOd6 and CD3CO2D) 4.05 (s, 3H), 4.1 (t, 2H), 4.55 (t, 2H), 6.3 (s, 2H), 7.4 (s, 1H), 7.9 (s, 1H), 8.15 (s, 1H), 8.95 (s, 1H); Mass Spectrum: M+H+ 409 and 411.
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[N:1]1([C:6]2[CH:13]=[CH:12][C:9]([CH2:10][N:28]3[CH2:29][CH2:30][CH:25]([C:21]4[CH:20]=[C:19]([NH:18][C:16](=[O:17])[CH:15]([CH3:14])[CH3:31])[CH:24]=[CH:23][CH:22]=4)[CH2:26][CH2:27]3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=Cc1ccc(-n2ccnc2)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc(-n4ccnc4)cc3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 4-(1H-imidazol-1-yl)benzaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 403.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][CH:8]([CH3:14])[N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1.[NH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]=1[O:31][CH3:32].C(O)C>Cl.O>[CH:15]1([N:7]2[CH:8]([CH3:14])[CH2:9][C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:6]2=3)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: CC1CC(=O)N(C)c2cnc(Cl)nc2N1C1CCCC1
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)C(C)CC(=O)N2C
Yield: 72.9 %

Procedure:
A mixture of 0.059 g (0.0002 mole) of (rac)-2-chloro-9-cyclopentyl-5,8-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-3), 0.033 g (0.0002 mole) of 4-amino-3-methoxy-benzoic acid, 0.5 mL of ethanol, 2 mL of water, and 2 drops of hydrochloric acid was heated to 100 degrees overnight. Upon cooling, a precipitate formed which was collected by filtration to give 0.062 g of (rac)-4-(9-cyclopentyl-5,8-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl amino)-3-methoxy-benzoic acid (I-3) as an off-white solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH3:12])[C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)[CH3:2].CS(C)=O.[OH-].[Na+].Cl[CH2:20][CH2:21][CH2:22][Si:23]([O:28][CH3:29])([O:26][CH3:27])[O:24][CH3:25]>C1(C)C=CC=CC=1>[CH2:11]([N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:20][CH2:21][CH2:22][Si:23]([O:28][CH3:29])([O:26][CH3:27])[O:24][CH3:25])[CH3:12]
Reactant: CO[Si](CCCCl)(OC)OC
Reactant: CCN(CC)c1cccc(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: CCN(CC)c1cccc(OCCC[Si](OC)(OC)OC)c1
Temperature: 88 °C

Procedure:
Using the general procedure described in the preceding Example 1, a reactor was charged with 90.75 g (0.55 mole) m-diethylaminophenol, 112 cc dimethylsulfoxide, 120 cc toluene and 43.28 g of a 50% aqueous sodium hydroxide solution. All of the water present in the reactor was removed by azeotropic distillation. The reaction mixture was allowed to cool to 80° C., at which time 109 g (0.55 mole) of chloropropyl trimethoxysilane were gradually added over a period of 2 hours. The temperature of the reaction mixture increased to 88° C. during the addition. Following completion of the addition, external heating was applied to maintain the temperature of the reaction mixture at 80° C. for 16 hours. The reaction mixture was then allowed to cool and was filtered. The liquid phase was recovered and evaporated under a pressure of 5 mm of mercury to remove the toluene and dimethylsulfoxide. The pressure inside the reactor was reduced to 2 mm and the product, 3(m-diethylaminophenoxy)propyl trimethoxysilane, distilled at a temperature of 185°-187° C. Analysis by vapor phase chromatography demonstrated that the product was 97% pure.
Reaction SMILES: [Br:1][C:2]1[C:13]([F:14])=[CH:12][C:5]2[S:6][C:7](C(O)=O)=[CH:8][C:4]=2[CH:3]=1.C1CCN2C(=NCCC2)CC1>CC(N(C)C)=O>[Br:1][C:2]1[C:13]([F:14])=[CH:12][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1
Reactant: O=C(O)c1cc2cc(Br)c(F)cc2s1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(=O)N(C)C
Product: Fc1cc2sccc2cc1Br
Yield: 54.4 %

Procedure:
Using analogous reaction condition and reagents as described in Example 25 for the preparation of I-25c above, 5-bromo-6-fluorobenzo[b]thiophene-2-carboxylic acid (I-28c: 240 mg 0.875 mmol) in DMA (4 mL) and DBU (0.523 mL, 3.503 mmol) were heated in microwave to afford the crude product. Purification by column chromatography on silica gel (100% hexane) afforded 110 mg of the product (55% yield).
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:5][CH2:4]2)[CH2:2]1.[C-]#N.[K+].[CH3:30][N:31](C)C=O>CO>[C:30]([CH2:2][C:3]1([OH:1])[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]3=[O:25])=[CH:11][C:10]=2[F:26])[CH2:5][CH2:4]1)#[N:31]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)CO4)c(F)c2)C(=O)O1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [K+]
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(O)(CC#N)CC3)c(F)c2)C(=O)O1
Yield: 51 %

Procedure:
The title compound was prepared by reacting (S)—N-{3-[4-(1-oxa-6-aza-spiro[2.5]oct-6-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (18.0 mmol) and potassium cyanide (22.0 mmol) in methanol: dimethylformamide mixture (1:5, 20 ml) at a temperature 25° C. for 14 hours and by purifying the compound by silica gel column chromatography in 51% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:11]1([CH2:14][CH:15]([C:18]2[CH:19]=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=2)[CH2:16][NH2:17])[CH2:13][CH2:12]1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:17][CH2:16][CH:15]([C:18]1[CH:19]=[N:20][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:22][CH:23]=1)[CH2:14][CH:11]1[CH2:12][CH2:13]1)=[O:6]
Reactant: O=C(O)c1ccccc1Cl
Reactant: NCC(CC1CC1)c1ccc(C(F)(F)F)nc1
Product: O=C(NCC(CC1CC1)c1ccc(C(F)(F)F)nc1)c1ccccc1Cl

Procedure:
From 2-chlorobenzoic acid and 3-cyclopropyl-2-(6-trifluoromethyl-pyridin-3-yl)-propylamine. LCMS (MH+): m/z=382.9, tR (minutes, Method C)=1.24
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[N-:13]=[N+:14]=[N-:15].[Na+]>CN(C=O)C.CCOC(C)=O>[N:13]([CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cccc(CBr)c1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(CN=[N+]=[N-])c1
Reaction time: 3 h

Procedure:
To a solution of methyl 3-(bromomethyl)benzoate in DMF (55 ml) under N2 was added sodium azide (10.39 g, 160 mmol) and stirred for 3 h. The solution was diluted with EtOAc, washed (water twice, then brine), dried (MgSO4), filtered, and concentrated to give the title compound. This material was used without further purification. MS (EI+) (m/z)=101.1 [M++1]
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH3:8][N:9]([CH3:34])[CH2:10][CH:11]([OH:33])[CH2:12][CH2:13][O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>C1COCC1>[CH3:34][N:9]([CH3:8])[CH2:10][CH:11]([O:33][C:4](=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7])[CH2:12][CH2:13][O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: O=C1CCC(=O)O1
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCOCCC(O)CN(C)C
Solvent: C1CCOC1
Product: CCCCC/C=C\C/C=C\CCCCCCCCOCCC(CN(C)C)OC(=O)CCC(=O)O

Procedure:
Succinic anhydride (0.60 g, 5.99 mmol, 1.1 equiv) was added in one portion to a dry THF (11 mL) solution of 1-(dimethylamino)-4-((9Z,12Z)-octadeca-9,12-dienyloxy)butan-2-ol (2.0 g, 5.45 mmol, 1.0 equiv) and the resultant was refluxed for 18 hours under argon. The mixture was concentrated and the residue was partitioned between EtOAc (10 mL) and deionized water (20 mL). The layers were separated and the aqueous layer was extracted with two additional portions of EtOAc (25 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated to provide crude 4-(1-(dimethylamino)-4-((9Z,12Z)-octadeca-9,12-dienyloxy)butan-2-yloxy)-4-oxobutanoic acid, a thick, yellow oil, which was used without further purification.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[CH3:11][O:12][CH:13]([O:16][CH3:17])[CH2:14][NH2:15].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:11][O:12][CH:13]([O:16][CH3:17])[CH2:14][NH:15][C:2](=[O:3])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COC(CN)OC
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COC(CNC(=O)Oc1ccccc1)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
Phenyl chloroformate (1.73 g.) was added to a vigorously stirred solution of 2,2-dimethoxyethylamine (1.05 g.) and potassium carbonate (1.39 g.) in water (20 ml.), and the mixture stirred at room temperature for 2 hours. The mixture was extracted with ether, and the ether extract dried and evaporated to dryness to give phenyl N-(2,2-dimethoxyethyl)carbamate (1.5 g.) which was used without further purification.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([CH:16]=O)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:18][NH2:19]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([CH2:16][NH:19][CH3:18])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=CC1(c2ccc3c(c2)OCO3)CCCCC1
Reactant: CN
Product: CNCC1(c2ccc3c(c2)OCO3)CCCCC1
Yield: 88.1 %

Procedure:
The title compound was prepared from 1-(benzo[d][1,3]dioxol-5-yl)cyclohexanecarbaldehyde (232 mg, 1.0 mmol) and methylamine (2.0 M in THF, 3 ml, 6.0 mmol) according to General Procedure H2.The crude product was purified by silica gel column chromatography (SiO2, MeOH/CH2Cl2, MeOH from 0% to 20%) to give 1-(1-(benzo[d][1,3]dioxol-5-yl)cyclohexyl)-N-methylmethanamine (218 mg, 88%). 1H NMR (CDCl3): δ 1.26-1.52 (m 4H), 1.54-1.61 (m, 2H), 1.66-1.73 (m, 2H), 2.03-2.12 (m, 2H), 2.28 (s, 3H), 2.60 (s, 2H), 5.90 (s, 2H), 6.75-6.86 (m, 2H), 6.90 (s, 1H). 13C NMR (CDCl3) δ 22.3, 26.7, 35.2, 37.4, 42.3, 64.8, 101.0, 107.6, 108.2, 120.3, 139.4, 145.6, 148.1.ESI MS m/z 248.