Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=2)=[C:9]([Cl:30])[CH:8]=1.[CH3:31][C:32]1[C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36][N:35]=[C:34]([O:47][CH2:48][C:49]2([C:52]([O:54][CH3:55])=[O:53])[CH2:51][CH2:50]2)[CH:33]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.C(OCC)(=O)C>[Cl:30][C:9]1[CH:8]=[C:7]([C:37]2[C:32]([CH3:31])=[CH:33][C:34]([O:47][CH2:48][C:49]3([C:52]([O:54][CH3:55])=[O:53])[CH2:50][CH2:51]3)=[N:35][CH:36]=2)[CH:12]=[CH:11][C:10]=1[C:13]1[N:14]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=1
Reactant: COC(=O)C1(COc2cc(C)c(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: C[Si](C)(C)CCOCn1cc(C(F)(F)F)nc1-c1ccc(Br)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C1(COc2cc(C)c(-c3ccc(-c4nc(C(F)(F)F)cn4COCC[Si](C)(C)C)c(Cl)c3)cn2)CC1
Temperature: 65 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
N,N-dimethylformamide (11 mL) was added to 2-(4-bromo-2-chlorophenyl)-4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole (220 mg), methyl 1-({[4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxy}-methyl)cyclopropanecarboxylate (201 mg), and palladium chloride (dppf) methylene chloride complex (39 mg), and after adding 2N aqueous sodium carbonate solution (0.72 mL) to the mixture, the atmosphere was replaced with nitrogen and the mixture was stirred at 65° C. for 2 hours. To the reaction mixture were added ethyl acetate and water to extract the objective compound, and the organic layer was washed with a saturated brine, and dried over anhydrous sodium sulfate. After concentrating the mixture under reduced pressure, the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=95:5 to 80:20) to obtain methyl 1-{[(5-{3-chloro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]methyl}cyclopropanecarboxylate (237 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[N:10]([N:14]=[C:15]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([CH:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)=[CH:20][CH:19]=4)[N:16]=3)[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.Cl[CH2:31][C:32]([N:34]([CH3:36])[CH3:35])=[O:33]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[N:10]([N:14]=[C:15]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([CH:24]5[CH2:29][CH2:28][N:27]([CH2:31][C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH2:26][CH2:25]5)=[CH:20][CH:19]=4)[N:16]=3)[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CN(C)C(=O)CCl
Reactant: Fc1ccc(-c2cccn3nc(Nc4ccc(C5CCNCC5)cc4)nc23)cc1
Product: CN(C)C(=O)CN1CCC(c2ccc(Nc3nc4c(-c5ccc(F)cc5)cccn4n3)cc2)CC1

Procedure:
2-(4-{4-[8-(4-Fluoro-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-piperidin-1-yl)-N,N-dimethyl-acetamide was prepared from [8-(4-fluoro-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-yl]-(4-piperidin-4-yl-phenyl)-amine (0.092 g, 0.240 mmol) and 2-chloro-N,N-dimethyl-acetamide (0.037 mL, 0.360 mmol) in a manner analogous to Example 313 to give product (0.035 g, 31%). MP=209-212° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.64 (s, 1H), 8.79 (d, 1H), 8.22 (m, 2H), 7.82 (d, 1H), 7.60 (d, 2H), 7.35 (m, 2H), 7.12 (m, 3H), 3.13 (s, 2H), 3.05 (s, 3H), 2.92 (m, 2H), 2.82 (s, 3H), 2.40 (m, 1H), 2.12 (m, 2H), 1.64-1.70 (br m, 4H). MS=473 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([OH:8])[C:3]=1[C:9]1[CH:17]=[CH:16][C:12]2[O:13][CH2:14][O:15][C:11]=2[CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:25][CH2:26][O:27][C:28](=[O:30])[CH3:29].O>CN(C)C=O>[C:28]([O:27][CH2:26][CH2:25][O:8][C:4]1[C:3]([C:9]2[CH:17]=[CH:16][C:12]3[O:13][CH2:14][O:15][C:11]=3[CH:10]=2)=[C:2]([NH2:1])[N:6]([CH3:7])[N:5]=1)(=[O:30])[CH3:29]
Reactant: Cn1nc(O)c(-c2ccc3c(c2)OCO3)c1N
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCCOc1nn(C)c(N)c1-c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.7 %

Procedure:
5-amino-4-(1,3-benzodioxol-5-yl)-1-methyl-1H-pyrazol-3-ol (Preparation 16) (11.39 g) was dissolved in dimethylformamide (40 mm), caesium carbonate (15.9 g) was added followed by 2-bromoethylacetate (8.16 g). The mixture was stirred at room temperature for 16 hours. The mixture was treated with water (750 ml) and extracted with ethyl acetate (2×250 ml). The organic fractions were combined washed with water (3×350 ml), brine (250 ml), dried over magnesium sulfate, filtered and evaporated. The crude product was purified on. silica (300 g) eluting with ethyl acetate:hexane (3:1) to yield the title compound as a white solid (5.57 g).
Reaction SMILES: [CH:1]([Si:4]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[N:5]1[C:9]2=[N:10][C:11]([S:14]([Cl:17])(=[O:16])=[O:15])=[CH:12][CH:13]=[C:8]2[CH:7]=[CH:6]1)([CH3:3])[CH3:2].C1C(=O)N([Br:31])C(=O)C1>C(Cl)Cl>[Br:31][C:7]1[C:8]2[C:9](=[N:10][C:11]([S:14]([Cl:17])(=[O:16])=[O:15])=[CH:12][CH:13]=2)[N:5]([Si:4]([CH:1]([CH3:3])[CH3:2])([CH:18]([CH3:20])[CH3:19])[CH:21]([CH3:23])[CH3:22])[CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2ccc(S(=O)(=O)Cl)nc21
Solvent: ClCCl
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(Br)c2ccc(S(=O)(=O)Cl)nc21
Reaction time: 4 h
Yield: 83.7 %

Procedure:
A 100-mL recovery flask was charged with 1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine-6-sulfonyl chloride (2.11 g, 5.66 mmol) and DCM (28 ml) to give a clear solution. n-Bromosuccinimide (1.108 g, 6.22 mmol) was added in one portion. The resulting mixture was stirred in the dark for 4 h, then an additional portion of n-bromosuccinimide (1.108 g, 6.22 mmol) was added. The mixture was stirred overnight. In the morning, silica gel was added, and the mixture was concentrated. The impregnated silica gel was loaded onto a column, and the column was eluted onto a silica gel column with 0 to 15% EtOAc/Heptane to give 3-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine-6-sulfonyl chloride (2.14 g, 4.74 mmol, 84% yield) as a light-yellow solid. 1H NMR (400 MHz, CDCl3) δ=8.08 (d, J=8.3 Hz, 1 H), 7.95 (d, J=8.3 Hz, 1 H), 7.63 (s, 1 H), 1.88 (spt, J=7.5 Hz, 4 H), 1.15 (d, J=7.5 Hz, 18 H).
Reaction SMILES: [CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[F:27][C:28]([F:35])([F:34])[C:29]1[CH:33]=[CH:32][NH:31][N:30]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>CCOC(C)=O.[Cu]I>[CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([N:31]3[CH:32]=[CH:33][C:29]([C:28]([F:35])([F:34])[F:27])=[N:30]3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: FC(F)(F)c1cc[nH]n1
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-n3ccc(C(F)(F)F)n3)cc2)C(=O)O1
Temperature: 130 °C
Yield: 42.7 %

Procedure:
(R)-6-Allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (20 mg, 0.048 mmol), 3-(trifluoromethyl)-1H-pyrazole (20 mg, 3 equiv.), CuI (1.4 mg, 15% mol), (1R,2R)-(−)-1,2-transcyclohexanediamine (2 mg, 30% mol), K3PO4 (20 mg, 2 equiv.) were mixed with dry toluene (2 mL) and heated in Microwave Oven for 1 h at 130° C. LC-MS found product peak. The mixture was diluted with EtOAc (8 mL), washed by water (2 mL), brine (3 mL) and dried over Na2SO4. After filtration and concentration, the residue was purified chromatography on a 4-g silica gel cartridge eluted with a gradient from 5 to 55% EtOAc in gexanes to afford (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)ethyl)-1,3-oxazinan-2-one (9.7 mg, 43%) product. LC-MS Method 1 tR=2.05, min, m/z=474; 1H NMR (CDCl3) 7.86 (s, 1H), 7.43 (d, 2H), 7.26 (t, 2H), 7.01 (dd, 2H), 6.69 (d, 1H), 5.76-5.64 (m, 2H), 5.05 (dd, 2H), 2.95 (m, 1H), 2.65-2.51 (m, 2H), 1.54 (d, 3H).
Reaction SMILES: [Na].[NH2:2][CH:3]([CH2:6][CH3:7])[CH2:4][OH:5].NO.Cl[CH2:11][C:12](OCC)=[O:13].[O:17]1CC[CH2:19][CH2:18]1>>[CH3:18][N:2]1[CH:3]([CH2:6][CH3:7])[CH2:4][O:5][CH2:11][C:12]1=[O:13].[CH2:6]([CH:3]1[CH2:4][O:5][CH2:19][C:18](=[O:17])[NH:2]1)[CH3:7]
Reactant: C1CCOC1
Reactant: CCC(N)CO
Reactant: CCOC(=O)CCl
Agent: NO
Agent: [Na]
Product: CCC1COCC(=O)N1
Product: CCC1COCC(=O)N1C

Procedure:
A solution of the crude intermediate 4-methyl-5-ethyl-tetrahydro-1,4-oxazine-3-one was prepared in a manner similar to that described in Example I by reacting the sodium salt of 2-amino-butan-1-ol (from 240 g of the amino alcohol and 62 grams of sodium) in 2500 ml of tetrahydrofuran with 338 g of ethyl chloroacetate following alcohol and 62 grams of sodium) in 2500 ml evaporation of the reaction solvent, the crude product was taken up in chloroform and washed with water. After drying the organic solution and removal of the solvent, recrystallization of the crude product from isopropyl ether/ethyl acetate yielded 151 grams of 5-ethyl-tetrahydro-1,4-oxazin-3-one, m.p. 70°-73°. Absence of carbonyl absorption bands in the infrared in the lactone region and the presence of a strong band at 6.10μ confirmed lactam rather than lactone cyclisation. Other major IR bands: 3.42, 3.52, 6.7, 6.8, 7.0, 7.2, 7.5, 7.8, 8.0, 8.7, 8.9, 8.98, 9.2, 9.5, 10.1, 10.5, 10.9, 11.8, 12.4 and 13.8μ NMR(CDCl3, δ): 2.95, singlet, NCH3 ; 3.2, multiplet, N-CH(CH2CH3); 1.75, quintet, CH2 (CH3); 0.93 triplet, CH3 (CH2); 3.78 and 3.84, AB pair, CH2O; 4.07 singlet, CH2CO.
Reaction SMILES: [O:1]1[CH2:5]CCC1.ClC(OC(Cl)(Cl)Cl)=O.[CH2:14]([O:16][C:17]([CH2:19][NH:20][CH2:21][C:22]1[O:26][CH:25]=[CH:24][CH:23]=1)=[O:18])[CH3:15].[NH:27]1[CH:31]=[CH:30][N:29]=[N:28]1>O>[CH2:14]([O:16][C:17]([CH2:19][N:20]([CH2:21][C:22]1[O:26][CH:25]=[CH:24][CH:23]=1)[C:5]([N:27]1[CH:31]=[CH:30][N:29]=[N:28]1)=[O:1])=[O:18])[CH3:15]
Reactant: CCOC(=O)CNCc1ccco1
Reactant: c1c[nH]nn1
Reactant: C1CCOC1
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: O
Product: CCOC(=O)CN(Cc1ccco1)C(=O)n1ccnn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into a solution of 100 ml of dry tetrahydrofuran containing 10 g (0.05 mol) of trichloromethyl chloroformate, 30 ml of a dry tetrahydrofuran solution containing 13 g (0.071 mol) of N-(1-ethoxycarbonylmethyl)-N-furfurylamine was added dropwise while cooling the former at 0° to 5° C. After stirring the mixture for 30 min at room temperature, 200 ml of dry tetrahydrofuran solution containing 9.8 g (0.121 mol) of triazole was added at 10° to 15° C. to the mixture. Then the mixture was gradually heated to boiling and reacted for about one hour while refluxing. After the reaction was over, the reaction mixture was cooled to a room temperature and poured into water. The mixture was extracted with ethyl acetate, and the extract was treated by the usual procedures of washing with water, separating, dehydrating and concentrating. The thus obtained concentrate was subjected to silica gel chromatography to obtain 13 g (0.0468 mol) of an oily substance. The thus obtained Compound No. 4 gave the following physical constants:
Reaction SMILES: [NH2:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([S:18]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])(=[O:20])=[O:19])[C:15](Br)=[CH:16][C:7]=3[CH2:6][CH2:5][C:4]=2[N:3]=1>CO.[Pd]>[NH2:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([S:18]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])(=[O:19])=[O:20])[CH:15]=[CH:16][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCN(CC)S(=O)(=O)c1cc2c(cc1Br)CCc1nc(N)[nH]c(=O)c1-2
Agent: [Pd]
Solvent: CO
Product: CCN(CC)S(=O)(=O)c1ccc2ccc3nc(N)[nH]c(=O)c3c2c1
Reaction time: 3 h

Procedure:
3-Amino-8-bromo-N,N-diethyl-5,6-dihydrobenzo[f]quinazolin-1(2H)-one-9-sulfonamide (0.43 g,1 mmole) was suspended in methanol(200 ml). 10% Palladium on carbon(0.60 g) was added to the suspension and the mixture was shaken under a hydrogen atmosphere at 23 psi for 3 hours. Methanol (750 ml) was added, and the mixture refluxed until the solid dissolved. The hot solution was filtered through celite. The celite and catalyst were washed by heating under reflux in methanol (500 ml) and the suspension filtered through fresh celite. Methanol was removed from the combined filtrates and the solid heated under reflux with pivalic anhydride (8 ml, Aldrich) under nitrogen for 30 minutes. The reaction mixture was evaporated to dryness, the residue applied to a silica column, and eluted with methanol/methylene chloride(1:199). The main fractions represented the title compounds;
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][C:8]([NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14])=[O:9].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH2:31](I)[CH3:32]>CC(C)=O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][C:8]([NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([O:15][CH2:31][CH3:32])=[O:14])=[O:9]
Reactant: CCI
Reactant: O=C(C=Cc1cccs1)Nc1ccccc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccccc1NC(=O)C=Cc1cccs1
Temperature: 60 °C
Reaction time: 1 h
Yield: 65.4 %

Procedure:
To a suspension of 2-[3-(2-thienyl)acrylamido]benzoic acid (273 mg, 1 mmol) in acetone (2 ml) were added potassium carbonate (194 mg, 1.4 mmol) and dry dimethylformamide (1 ml). To the resulting solution, ethyl iodide (218 mg, 1.4 mmol) and dry dimethylformamide (2 ml) were added and the mixture was stirred at 60° C. for 1 hour. The reaction mixture was poured into ice water. The precipitated solid was collected by suction, and recrystallized from methanol to give pale yellow crystals of the desired compound (197 mg, yield, 65%). m.p., 120°-122° C.
Reaction SMILES: [C:1]1([C:7]2[CH:19]=[CH:18][C:10]([C:11]([CH:13]=[CH:14][C:15]([OH:17])=[O:16])=[S:12])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(OC)(O[CH3:24])(=O)=O.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]1([C:7]2[CH:19]=[CH:18][C:10]([C:11]([CH:13]=[CH:14][C:15]([O:17][CH3:24])=[O:16])=[S:12])=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COS(=O)(=O)OC
Reactant: O=C(O)C=CC(=S)c1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C=CC(=S)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.8 %

Procedure:
To a solution of 8.53 g of 3-(4-phenylthiobenzoyl)acrylic acid in 50 ml of dimethylformamide were added 4.54 g of dimethyl sulfate and 2.50 g of potassium carbonate, and the resulting mixture was stirred at room temperature for 3 hours. To the reaction solution was added water, and the mixture was extracted from diethyl ether. The organic layer was washed, in turn, with water, a saturated aqueous solution of sodium hydrogen-carbonate and water, and dried over magnesim sulfate. The diethyl ether was removed from the solution by evaporation, and the residue was recrystallized from a mixture of hexane and dichloromethane to give 6.80 g of methyl 3-(4-phenylthiobenzoyl)acrylate.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][N:10]=2)=[CH:5][C:3]=1[NH2:4].[C:16]([O:20][C:21]([NH:23][C:24]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=S)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(N(C(C)C)CC)(C)C.[I-].C[N+]1C=CC=CC=1Cl>ClCCl>[C:30]([O:29][C:27]([NH:26][C:24]([NH:23][C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])=[N:4][C:3]1[CH:5]=[C:6]([C:9]2[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][N:10]=2)[CH:7]=[CH:8][C:2]=1[CH3:1])=[O:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: Cc1ccnc(-c2ccc(C)c(N)c2)c1
Reactant: CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccnc(-c2ccc(C)c(N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c2)c1
Reaction time: 2 h
Yield: 83.2 %

Procedure:
To a suspension of 2-methyl-5-(4-methylpyridin-2-yl)aniline (285 mg), N,N′-bis(tert-butoxycarbonyl)thiourea (475 mg) and diisopropylethylamine (0.577 ml) in dichloromethane (15 ml) was added 1-methyl-2-chloropyridinium iodide (478 mg), and the mixture was stirred for 2 hours. The mixture was diluted with dichloromethane, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. To the residue was added 2-propanol, and the mixture was stirred. The precipitate was collected by filtration and dried to give N,N′-bis(tert-butoxycarbonyl)-N″-(2-methyl-5-(4-methylpyridin-2-yl)phenyl)guanidine (527 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:24])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[CH:20]=[C:19]([CH3:21])[N:18]=[C:17]1[CH2:22]O.[C:25]1(=[O:35])[NH:29][C:28](=[O:30])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:24])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[CH:20]=[C:19]([CH3:21])[N:18]=[C:17]1[CH2:22][N:29]1[C:25](=[O:35])[C:26]2=[CH:34][CH:33]=[CH:32][CH:31]=[C:27]2[C:28]1=[O:30]
Reactant: Cc1cn(-c2ccc(Cl)cc2C(=O)c2ccccc2Cl)c(CO)n1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1cn(-c2ccc(Cl)cc2C(=O)c2ccccc2Cl)c(CN2C(=O)c3ccccc3C2=O)n1

Procedure:
In the manner given in Example 17, 2',5-dichloro-[2-(hydroxymethyl)-4-methylimidazol-1-yl]benzophenone is treated with phthalimide and triphenylphosphine and finally with diethyl azocarboxylate to give 2',5-dichloro-2-[4-methyl-2-(phthalimidomethyl)imidazol-1-yl]benzophenone.
Reaction SMILES: [Br:1]Br.[OH:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=1>O>[Br:1][C:12]1[C:4]([OH:3])=[N:5][CH:6]=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9]
Reactant: BrBr
Reactant: O=C(O)c1ccc(O)nc1
Solvent: O
Product: O=C(O)c1cnc(O)c(Br)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
Bromine (3.6 mL, 70.5 mmol) was added dropwise to a suspension of 6-Hydroxy-nicotinic acid (7 g, 50.32 mmol) in water (70 mL) at 00° C. and the mixture was stirred at room temperature for 4 hours. The precipitated solid was filtered, washed with cold water and dried to get the title compound as off white solid in 82% yield, 9 g.
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[CH:19]([C:21]1[C:22]([CH3:32])=[N:23][N:24]([CH3:31])[C:25]=1[S:26][CH2:27][C:28](O)=[O:29])=[O:20].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>O.CN(C)C=O.C(N(CC)CC)C>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:28](=[O:29])[CH2:27][S:26][C:25]2[N:24]([CH3:31])[N:23]=[C:22]([CH3:32])[C:21]=2[CH:19]=[O:20])[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Reactant: Cc1nn(C)c(SCC(=O)O)c1C=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nn(C)c(SCC(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)c1C=O
Temperature: 25 °C
Yield: 64 %

Procedure:
A mixture of 1-(2-tert-butylphenyl)piperazine dihydrochloride obtained in Reference Example 1 (1.0 g), [(4-formyl-1,3-dimethyl-1H-pyrazol-5-yl)sulfanyl]acetic acid obtained in Reference Example 3 (736 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (786 mg), 1-hydroxy-1H-benzotriazole monohydrate (628 mg), triethylamine (1.39 mL), and N,N-dimethylformamide (50 mL) was stirred at room temperature for over-night. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 80:20-30:70 hexane/ethyl acetate) to provide 5-({2-[4-(2-tert-butylphenyl)piperazin-1-yl]-2-oxoethyl}sulfanyl)-1,3-dimethyl-1H-pyrazole-4-carbaldehyde (900 mg, 64%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][CH:4]([C:13]2[CH:14]=[C:15]([NH2:19])[CH:16]=[CH:17][CH:18]=2)[CH2:3]1.N1C=CC=CC=1.[CH2:27]([S:29](Cl)(=[O:31])=[O:30])[CH3:28]>ClCCl>[CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][CH:4]([C:13]2[CH:14]=[C:15]([NH:19][S:29]([CH2:27][CH3:28])(=[O:31])=[O:30])[CH:16]=[CH:17][CH:18]=2)[CH2:3]1
Reactant: Cc1ccc2c(c1)C(C)(C)CC(c1cccc(N)c1)N2
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1cccc(C2CC(C)(C)c3cc(C)ccc3N2)c1
Yield: 37.4 %

Procedure:
To a stirred mixture of 3-(4,4,6-trimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (150 mg, 0.56 mmol) in dichloromethane (3 mL) was added pyridine (79 mg, 1.01 mmol) in dichloromethane (2 mL) and ethanesulfonyl chloride (108 mg, 0.84 mmol) under nitrogen. The resultant mixture was stirred for 18 h. The reaction mixture was diluted with dichloromethane, washed with water (twice), saturated brine, and dried over Magnesium sulfate. Magnesium sulfate was removed by filtration, and after evaporation, the residue was purified on chromatography column (silica gel, petroleum ether: ethyl acetate=10:1) to afford 75 mg of ethanesulfonic acid [3-(4,4,6-trimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-amide yellow solid (Yield: 37%). MS (ESI+APCI) M+1=359.2.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[N:9][C:8]2[N:4]([N:5]=[C:6]3[CH2:14][N:13]([C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][CH:24]4[CH2:28][CH2:27][NH:26][CH2:25]4)=[O:16])[CH2:12][C:7]3=2)[C:3]=1[CH3:29].C=O.[BH4-].[Na+].[C:34](O)(C(F)(F)F)=O>C1COCC1.CC(=O)OCC>[Cl:1][C:2]1[C:10]([CH3:11])=[N:9][C:8]2[N:4]([N:5]=[C:6]3[CH2:14][N:13]([C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][CH:24]4[CH2:28][CH2:27][N:26]([CH3:34])[CH2:25]4)=[O:16])[CH2:12][C:7]3=2)[C:3]=1[CH3:29]
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1OC1CCNC1)C3
Reactant: O=C(O)C(F)(F)F
Agent: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1OC1CCN(C)C1)C3
Temperature: 25 °C
Reaction time: 18 h
Yield: 48 %

Procedure:
A mixture of Example 68 (150 mg; 0.36 mmol; 1 eq.), formaldehyde (0.27 mL; 3.64 mmol; 10 eq.) and NaBH4 (69 mg; 1.82 mmol; 5 eq.) in THF (12 mL) was cooled to 0° C. and TFA (1 mL) was added. The reaction mixture was stirred at room temperature for 18 hours then diluted with EA. The organic phase was washed with 0.1M NaOH (2×), dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (DCM/MeOH/TEA) afforded the title compound (75 mg, 48%) as white foam. 1H NMR (DMSO-d6) δ 7.47-7.38 (m, 1H), 7.33-7.25 (m, 1H), 7.09-6.99 (m, 2H), 4.99-4.89 (m, 1H), 4.82 (m, 2H), 4.65-4.42 (m, 2H), 2.88-2.75 (m, 4H), 2.62 (s, 1.5H), 2.60-2.52 (m, 2.5H), 2.37-2.20 (m, 2H), 2.19 (s, 1.5H), 2.18 (s, 1.5H), 1.80-1.66 (m, 1H), 1.46-1.31 (m, 1H). HPLC (max plot) 95.6%, Rt 2.63 min. UPLC/MS: (MS+) 426.5 ([M+H]+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH3:14])[C:11]([O:13][C:7]2([CH3:10])[CH2:8][CH2:9][CH2:4][CH2:5][CH2:6]2)=[O:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(C(=O)O)c1ccc([N+](=O)[O-])cc1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C(=O)OC1(C)CCCCC1)c1ccc([N+](=O)[O-])cc1
Temperature: 80 °C
Yield: 48 %

Procedure:
A stirred mixture of 97.5 g of 2-(p-nitrophenyl)-propionic acid [J. Med. Chem. Vol. 26, pages 222-226 (1983)], 40 ml of thionyl chloride and 500 ml of dry toluene was heated at 80° C. for 5 hours. The mixture was then allowed to cool and the solvent was evaporated under reduced pressure. The residual oil was dissolved in 400 ml of dry toluene, and 100 g of 1-methylcyclohexanol were added to the solution. The stirred mixture was heated at 80° C. for 1 hour and then at ambient temperature overnight. The solution was washed with 5% NaHCO3 solution, then water, dried over MgSO4 and finally evaporated to dryness. The crude mixture was purified over a column of 600 g of silica using CHCl3 as the eluant 34.95 g (24% yield) of 1-methyl-cyclohexyl 2-(p-nitrophenyl)-propionate as a golden yellow liquid.