Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].C(N(CC)CC)C.[CH:12]1([N:22]=[C:23]=[O:24])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][CH2:13]1>C(Cl)Cl>[CH3:2][O:3][NH:4][C:23]([NH:22][CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][CH2:13]1)=[O:24]
Reactant: O=C=NC1CCCc2ccccc21
Reactant: CON
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CONC(=O)NC1CCCc2ccccc21
Temperature: 15 °C
Reaction time: 0.25 h
Yield: 76.6 %

Procedure:
To an ice cold, stirred mixture of 6.7 grams (0.080 mole) of methoxyamine hydrochloride in 80 ml. of methylene chloride is added a solution of 8.1 grams (0.080 mole) of triethylamine in 20 ml. of methylene chloride. The mixture is stirred at 15°C. for 15 minutes, and is then allowed to warm to 15°C. to 25°C. while a solution of 6.94 grams (0.04 mole) of 1,2,3,4-tetrahydro-1-naphthyl isocyanate in 25 ml. of methylene chloride is added dropwise. The mixture is stirred for 30 minutes at room temperature and then filtered. The filtrate is washed with water, dried sodium sulfate, and the solvent evaporated at reduced pressure to give a solid. Recrystallization of the solid from acetone/hexane gives 6.75 grams of the product, melting point 122°C. to 125°C. Recrystallization of the product from acetone/hexane gives the analytical sample, melting point 123.5°C. to 125°C. Analysis Calculated for C12H16N2O2 : C, 65.43; H, 7.32; N, 12.72. Found: C, 65.32; H, 7.33; N, 12.64.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2Cl.[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=2)[CH2:19][CH2:18]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:28][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][N:20]2[CH2:19][CH2:18][N:17]([CH3:16])[CH2:22][CH2:21]2)=[CH:30][CH:29]=1
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Cl
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Product: CC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(CN2CCN(C)CC2)cc1
Yield: 82.1 %

Procedure:
Following general procedure C, 1-(6-bromo-4-chloroquinolin-3-yl)ethanone (5.0 g, 18.0 mmol) was reacted with 4-((4-methylpiperazin-1-yl)methyl)aniline (4.0 g, 19.0 mmol) to afford the desired product (6.7 g, 82%) as a yellow foam: 1H NMR (300 MHz, CDCl3) δ 11.96 (s, 1H), 9.11 (s, 1H), 7.85-7.72 (m, 1H), 7.71-7.57 (m, 2H), 7.40-7.29 (m, 2H), 7.14-7.02 (m, 2H), 3.53 (s, 2H), 2.77 (s, 3H), 2.58-2.44 (br s, 8H), 2.30 (s, 3H).
Reaction SMILES: CC(C)(C)[C@H:3]([NH:8][C:9]([N:11]1[C:19]2[CH2:18][CH2:17][N:16]([CH3:20])[CH2:15][C:14]=2[C:13]([C:21]2[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:22]=2F)=[N:12]1)=[O:10])[C:4](NC)=O.FC1C=C(C2C3CN(C(OC(C)(C)C)=O)CCC=3NN=2)C=CC=1F.[OH:56][CH:57]1CCN[CH2:59][CH2:58]1>>[F:27][C:25]1[CH:26]=[C:21]([C:13]2[C:14]3[CH2:15][N:16]([CH3:20])[CH2:17][CH2:18][C:19]=3[N:11]([C:9]([N:8]3[CH2:59][CH2:58][CH:57]([OH:56])[CH2:4][CH2:3]3)=[O:10])[N:12]=2)[CH:22]=[CH:23][C:24]=1[F:28]
Reactant: OC1CCNCC1
Reactant: CNC(=O)[C@@H](NC(=O)n1nc(-c2cc(F)c(F)cc2F)c2c1CCN(C)C2)C(C)(C)C
Agent: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(F)c(F)c3)c2C1
Product: CN1CCc2c(c(-c3ccc(F)c(F)c3)nn2C(=O)N2CCC(O)CC2)C1

Procedure:
Compound 45 was prepared according to the procedure described for the synthesis of compound 37 by replacing intermediate 19 with intermediate 15, and replacing tert-leucine methyl amide with 4-hydroxypiperidine. 1H NMR (CDCl3) δ 7.46-7.51 (m, 1H), 7.32-7.36 (m, 1H), 7.20 (q, J=8.9 Hz, 1H), 3.96-4.08 (m, 3H), 3.60 (s, 2H), 3.41-3.47 (m, 2H), 3.08 (t, J=5.6 Hz, 2H), 2.78 (t, J=5.8 Hz, 2H), 2.54 (s, 3H), 1.97-2.01 (m, 2H), 1.63-1.72 (m, 2H). LCMS (+ESI) m/z=377 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([C:4]([S:12][CH3:13])=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.C(N(CC)CC)C.P(Cl)(Cl)([Cl:23])=O.O>C(Cl)Cl>[CH3:1][S:2][C:4]([S:12][CH3:13])=[C:5]([Cl:23])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSC(=Cc1ccccc1)S(C)=O
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSC(SC)=C(Cl)c1ccccc1
Temperature: -15 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
1-Methylsulfinyl-1-methylthio-2-phenylethylene (1.154 g) was dissolved in 15 ml of methylene chloride, and 1 ml of triethylamine was added. Under cooling at -15° C., 0.55 ml of phosphorus oxychloride was added. The mixture was stirred at -15° C. for 1 hour and then at room temperature for 2 hours. Water (30 ml) was added, and the reaction mixture was extracted three times with 30 ml of methylene chloride. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was chromatographed on a Florisil column using hexane/benzene as an eluant to afford 1.180 g of 1,1-bis(methylthio)-2-chloro-2-phenylethylene in a yield of 94%.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][CH:17]([CH2:19][O:20][CH3:21])[O:16][C:15]3=[O:22])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.Cl[CH:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl>C(N(C(C)C)C(C)C)C>[CH:24]([O:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH2:18][CH:17]([CH2:19][O:20][CH3:21])[O:16][C:15]3=[O:22])=[CH:12][CH:13]=2)[CH2:4][CH2:3]1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: ClC(c1ccccc1)c1ccccc1
Reactant: COCC1CN(c2ccc([C@H]3CC[C@H](O)CC3)cc2)C(=O)O1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: COCC1CN(c2ccc([C@H]3CC[C@H](OC(c4ccccc4)c4ccccc4)CC3)cc2)C(=O)O1
Reaction time: 7 h

Procedure:
0.5 g of (RS)-3-[4-(trans-4-hydroxy-cyclohexyl)-phenyl]-5-methoxymethyl-oxazolidin-2-one in 5 ml of ethyldiisopropylamine was heated with 0.35 ml of chlorodiphenylmethane to 100° and stirred at this temperature for 7 hours. The reaction mixture was cooled, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic phase was washed neutral with water, dried with magnesium sulfate and concentrated. The residue (0.7 g) was chromatographed on a 30-fold amount of silica gel with methylene chloride/ethyl acetate mixtures. 0.3 g of (RS)-3-[4-(trans-4-benzhydryloxy-cyclohexyl)-phenyl]-5-methoxymethyl-oxazolidin-2-one was obtained as colorless crystals. M.p.: 146°-148°.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=O)[C:9]2=[O:18])=[CH:4][CH:3]=1.[F:19][C:20]([F:29])([F:28])[C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24]>>[Cl:1][C:2]1[S:6][C:5]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[N:24][C:23]3[CH:25]=[CH:26][CH:27]=[C:21]([C:20]([F:19])([F:28])[F:29])[CH:22]=3)[C:9]2=[O:18])=[CH:4][CH:3]=1
Reactant: O=C1C(=O)N(Cc2ccc(Cl)s2)c2ccccc21
Reactant: Nc1cccc(C(F)(F)F)c1
Product: O=C1C(=Nc2cccc(C(F)(F)F)c2)c2ccccc2N1Cc1ccc(Cl)s1
Temperature: 140 °C
Yield: 55.6 %

Procedure:
A mixture of 1-[(5-chloro-2-thienyl)methyl]-2H-indole-2,3-dione (25 mg, 0.09 mmol) (prepared as described below) and 3-trifluoromethylaniline (11.3 μL, 0.09 mmol) was heated neat at 140° C. for 2 h. The crude material was purified by preparative TLC using a mixture of 3:7 ethyl acetate in hexane as the eluent, giving the desired product (23 mg 0.05 mmol, 61%). 1H NMR (400 MHz): 6 (major isomer) 7.57 (t, J=7.7, 1H), 7.53 (t, J=7.8, 1H), 7.33 (t, J 7.8, 1H), 7.28 (s, 1H), 7.19 (d, J=7.6, 2H), 6.94–6.72 (m, 4H) 6.56 (d, =7.7, 1H), 5.02 (s, 2H); ESI-MS m/z found 421 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([CH3:13])=[CH:6][C:5]=1[OH:14])([O-:3])=[O:2].I[CH2:16][CH3:17].C(N(CC)CC)C>O1CCOCC1>[N+:10]([C:8]1[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]([O:14][CH2:16][CH3:17])=[CH:6][C:7]=1[CH3:13])([O-:12])=[O:11]
Reactant: CCI
Reactant: Cc1cc(O)c([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCOc1cc(C)c([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
2.5 g (12.5 mmol) of 2,4-dinitro-5-methylphenol (I. R. Gibbs and P. W. Robertson, J. Chem. Soc. (London) 105, 1885) are dissolved in 12.5 ml of dioxane, added to 1.5 ml (19 mmol) of 2-iodoethane and 3.5 ml (25 mmol) of triethylamine and heated for 24 hours to 80° C. The reaction mixture is then poured over ice. The yellow crystals that precipitate out are isolated by suction. 2.2 g (77% of theoretical) of the ethoxy compound, having a melting point of 92° to 93° C., are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=O)[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:17])[CH:13]=2)[NH:8][CH:7]=1)=[O:5])[CH3:2].O(Cl)[Cl:19].[P+5]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:19])=[CH:13][C:12]([Cl:17])=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c2ccc(Cl)cc2c1=O
Reactant: ClOCl
Agent: [P+5]
Product: CCOC(=O)c1cnc2ccc(Cl)cc2c1Cl
Temperature: 125 °C

Procedure:
Ethyl-6-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylate (19.8 mmol) and phosphorus (V) oxychloride (99.3 mmol) was stirred and heated to 125° C. for 12 hours. The mixture was cooled to ambient temperature and the phosphorus (V) oxychloride was evaporated. The crude product was used without further purification. MS m/z: 271.80 (M+1).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[C:7]([CH3:12])=[N:8][NH:9][C:10]=1[CH3:11])C.[NH:14]1C=C(CC(O)=O)C=[N:15]1.O.NN>C(O)CCC>[CH3:12][C:7]1[C:6]([CH2:5][C:4]([NH:14][NH2:15])=[O:3])=[C:10]([CH3:11])[NH:9][N:8]=1
Reactant: CCOC(=O)Cc1c(C)n[nH]c1C
Reactant: O=C(O)Cc1cn[nH]c1
Agent: NN
Solvent: CCCCO
Solvent: O
Product: Cc1n[nH]c(C)c1CC(=O)NN
Yield: 68 %

Procedure:
As described for example 112a, (3,5-dimethyl-1H-pyrazol-4-yl)-acetic acid ethyl ester (Rainer, Georg. 4-Pyrazoleacetic acid derivatives. U.S. (1979), U.S. Pat. No. 4,146,721) in butanol was reacted with hydrazine hydrate (3 equivalents) and the resulting mixture was heated under reflux for 6 h. Evaporation of all volatiles afforded the title compound as a colourless oil (yield: 68%). MS: m/e=183.3 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[C:5]([CH3:16])[NH:4][C:3]1=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.[OH-].[Na+].O>[CH3:16][CH:5]1[CH:6]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)[CH2:7][CH:2]([CH3:1])[CH2:3][NH:4]1
Reactant: COc1ccc(C2=C(C)NC(=O)C(C)C2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C2CC(C)CNC2C)cc1
Reaction time: 0.5 h
Yield: 38 %

Procedure:
A solution of 6.95 g (30 mmol) of 3,6-dimethyl-5-(4-methoxyphenyl)-3,4-dihydro-2-pyridone in 70 ml of tetrahydrofuran was added dropwise under nitrogen to a suspension of 1.7 g (45 mmol) of lithium aluminium hydride in 50 ml of dry tetrahydrofuran. After the reaction mixture had been refluxed for 90 minutes, it was cooled and 1.7 ml of water in 10 ml of tetrahydrofuran, 3.4 ml of 2N sodium hydroxide and 3.4 ml of water were added dropwise successive while cooling with ice. After refluxing for a short period of time the resulting precipitate was filtered off and rinsed thoroughly with warm tetrahydrofuran; the filtrate was evaporated under reduced pressure. The resulting crude product (6.5 g) was dissolved, without further purification, in 75 ml of absolute ethanol. 0.5 g of platinum oxide were added to this solution and the mixture was hydrogenated at room temperature and atmospheric pressure for 30 minutes. After removing the catalyst by filtration the ethanol was evaporated under reduced pressure. The resulting crude product (6 g) was purified by means of flash chromatography over 100 g of silicagel (Merck, grain size 0.040-0.063 mm) using a mixture of ethyl acetate, methanol and concentrated ammonia (93:6.5:0.5) as an eluent, succeeded by flash chromatography over 100 g of silicagel (Merck, grain size 0.040-0.063 mm) using a mixture of dichloromethane, methanol and concentrated ammonia (93:6.5:0.5) as an eluent. After combining and evaporating the desired fractions, totally 2.5 g (38%) of 2,5-dimethyl-3-(4-methoxyphenyl)piperidine were obtained.
Reaction SMILES: [CH:1]1[CH:6]=[C:5](C(O)=O)[C:4]([C:10]([O:12]O)=O)=CC=1.[S:14]([O-:17])([O-])=[O:15].[Na+].[Na+]>CCOCC>[CH2:10]([S:14]([CH:4]1[CH2:5][CH2:6][CH2:1][C:10]1=[O:12])(=[O:17])=[O:15])[CH2:4][CH2:5][CH3:6]
Reactant: O=S([O-])[O-]
Reactant: O=C(O)c1ccccc1C(=O)OO
Agent: [Na+]
Solvent: CCOCC
Product: CCCCS(=O)(=O)C1CCCC1=O

Procedure:
2-Buthylthiocyclopentanone (88 g) was reacted with a 30% excess solution of mono-perphthalic acid in ether at 0° C. After the reaction was completed, the excess mono-perphthalic acid was treated with sodium sulfite, and the resultant solution was washed, evaporated to remove the solvent, and then distilled, thereby giving 2-butylsulfonylcyclopentanone (78 g).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@H:11]([C:13]([OH:15])=O)[CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:16][CH:17]1[CH2:24][CH2:23][CH2:22][NH:21][C:19](=[O:20])[CH2:18]1>>[C:1]1([CH2:7][C:8]([NH:10][C@H:11]([C:13]([NH:16][CH:17]2[CH2:24][CH2:23][CH2:22][NH:21][C:19](=[O:20])[CH2:18]2)=[O:15])[CH3:12])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H](NC(=O)Cc1ccccc1)C(=O)O
Reactant: NC1CCCNC(=O)C1
Product: C[C@H](NC(=O)Cc1ccccc1)C(=O)NC1CCCNC(=O)C1

Procedure:
Following General Procedure B above using N-(phenylacetyl)-L-alanine (Example A) and 3-amino-ε-caprolactam (Sigma), the title compound was prepared as a solid having a melting point of 200-202° C. The reaction was monitored by tlc on silica gel (Rf=0.30 in 1:9 methanol/dichloromethane).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:37])[C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([NH:15][C:16]3[N:17]=[CH:18][C:19]4[N:25]([CH3:26])[C:24](=[O:27])[C:23]([F:29])([F:28])[CH2:22][N:21]([CH:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)[C:20]=4[N:35]=3)=[CH:9][C:8]=2[F:36])[CH2:2]1.[C:38]1(=O)[CH2:42][CH2:41][CH2:40][CH2:39]1>>[CH:30]1([N:21]2[CH2:22][C:23]([F:28])([F:29])[C:24](=[O:27])[N:25]([CH3:26])[C:19]3[CH:18]=[N:17][C:16]([NH:15][C:10]4[C:11]([O:13][CH3:14])=[CH:12][C:7]([C:6]([NH:5][CH:3]5[CH2:2][N:1]([CH:38]6[CH2:42][CH2:41][CH2:40][CH2:39]6)[CH2:4]5)=[O:37])=[C:8]([F:36])[CH:9]=4)=[N:35][C:20]2=3)[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: O=C1CCCC1
Reactant: COc1cc(C(=O)NC2CNC2)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Product: COc1cc(C(=O)NC2CN(C3CCCC3)C2)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized by following the Reductive Amination Procedure using N-(azetidin-3-yl)-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzamide and cyclopentanone. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.23-1.35 (m, 2H) 1.38-1.78 (m, 11H) 1.96 (br. s., 2H) 2.67 (br. s., 1H) 2.87 (t, J=7.33 Hz, 2H) 3.49 (t, J=7.33 Hz, 2H) 3.91 (s, 3H) 4.08 (t, J=13.77 Hz, 2H) 4.33-4.44 (m, 1H) 4.78-4.88 (m, 1H) 7.19 (d, J=6.57 Hz, 1H) 8.05 (s, 1H) 8.25 (d, J=13.39 Hz, 1H) 8.30 (s, 1H) 8.41 (dd, J=6.82, 3.03 Hz, 1H). [M+H] calculated for C29H36F3N7O3, 588. found 588.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[N:4]([CH2:27][C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([NH2:38])[CH:29]=1)[CH2:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:7]=1[C:16]1[CH:21]=[C:20]([CH:22]([CH3:24])[CH3:23])[CH:19]=[CH:18][C:17]=1[O:25][CH3:26].[CH3:40][S:41](Cl)(=[O:43])=[O:42].C(N(CC)C(C)C)(C)C.O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:39])[N:4]([CH2:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:7]=1[C:16]1[CH:21]=[C:20]([CH:22]([CH3:24])[CH3:23])[CH:19]=[CH:18][C:17]=1[O:25][CH3:26])[CH2:27][C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([NH:38][S:41]([CH3:40])(=[O:43])=[O:42])[CH:29]=1
Reactant: COC(=O)N(Cc1cc(N)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(C(C)C)ccc1OC
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N(Cc1cc(NS(C)(=O)=O)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(C(C)C)ccc1OC
Temperature: 25 °C

Procedure:
To a solution of methyl[3-amino-5-(trifluoromethyl)benzyl]{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate (8 mg, 0.014 mmol) (Example 33) and methanesulfonyl chloride (3.3 μL, 0.043 mmol) in CH2Cl2 (1 mL) was added N,N-diisopropylethylamine (15 μL, 0.086 mmol). The reaction was stirred at room temperature for thirty minutes and then was poured into H2O (10 mL). The mixture was extracted with EtOAc (50 mL), and the organic extracts were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated. Purification by preparative thin layer chromatography with 25% EtOAc/hexanes followed by a preparative thin layer chromatography in 2:2:1 (CH2Cl2:Hex:Et2O) and then a third and final purification by silica gel chromatography with 2% to 25% EtOAc/hexanes afforded methyl{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}[3-[(methylsulfonyl)amino]-5-(trifluoromethyl)benzyl]carbamate. Rf=0.40 (25% EtOAc/hexanes). 1H NMR (C6D6, 500 MHz, 70° C.) δ 7.69 (s, 1H), 7.52 (s, 1H), 7.38-7.25 (m, 3H), 7.08-7.04 (m, 2H), 6.86 (s, 1H), 6.30 (d, J=8.5 Hz, 1H), 4.40 (broad singlet, 2H), 4.04-3.99 (m, 2H), 3.33 (s, 3H), 3.26 (s, 3H), 2.74 (m, 1H), 2.67 (s, 3H), 1.22 (d, J=6.5 Hz, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=[O:4].[Cl-].[Cl-].[Cl-].[Al+3].[C:14](Cl)([CH3:17])([CH3:16])[CH3:15]>C(=S)=S>[C:14]([C:7]1[NH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:9][CH:8]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)Cl
Reactant: COC(=O)c1ccc[nH]1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: COC(=O)c1ccc(C(C)(C)C)[nH]1
Temperature: 50 °C
Reaction time: 1 h
Yield: 58.7 %

Procedure:
A mixture of the methylpyrrole-2-carboxylate (1.0 g, 7.99 mmol) and aluminum trichloride (2.13 g, 16.0 mmol) was dissolved in carbon disulfide (20 mL) and stirred at 50° C. for 1 hour. Tert-butyl chloride (0.740 g, 7.99 mmol) in carbon disulfide (5 mL) was added in one portion and the mixture stirred at room temperature for an additional 20 hours. The reaction mixture was quenched with ice and extracted with dichloromethane. The solvent was removed under vacuum and the resulting solid was washed with cold hexane to afford 0.850 g of the expected methyl 5-tert-butyl-1H-pyrrole-2-carboxylate as a tan solid.
Reaction SMILES: [N:1]1([C:5](=O)[CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=2[O:17][CH3:18])[CH2:4][CH2:3][CH2:2]1.B>C1COCC1>[CH3:18][O:17][C:9]1[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:8]=1[O:7][CH2:6][CH2:5][N:1]1[CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc([N+](=O)[O-])ccc1OCC(=O)N1CCC1
Agent: B
Solvent: C1CCOC1
Product: COc1cc([N+](=O)[O-])ccc1OCCN1CCC1
Temperature: 50 °C
Reaction time: 18 h
Yield: 38 %

Procedure:
This amide was dissolved in THF (15 ml) then borane (5.6 ml, 1M solution in THF) was introduced. The reaction mixture was stirred for 18 hours at 50° C. under argon. Excess borane was quenched by the dropwise addition of MeOH then aq HCl (2M, 200 ul). The solvent was removed in vacuo and the residual oil partitioned between ethyl acetate and a saturated solution of aqueous sodium bicarbonate (20 ml). The aqueous phase was extracted with ethyl acetate (3×50 ml). The combined ethyl acetate layers were washed with brine and dried over MgSO4. The solvent was removed in vacuo to yield 1-[2-(2-methoxy-4-nitro-phenoxy)-ethyl]-azetidine as a pale red oil (53 mg, 38%);
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[CH2:17]([O:24][C:25]1[C:35]([O:36][CH3:37])=[CH:34][C:28](/[CH:29]=[CH:30]/[C:31](O)=O)=[CH:27][C:26]=1[O:38][CH3:39])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][C:25]1[C:35]([O:36][CH3:37])=[CH:34][C:28](/[CH:29]=[CH:30]/[C:31]2[NH:1][C:2]3[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=3[N:8]=2)=[CH:27][C:26]=1[O:38][CH3:39])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: COc1cc(/C=C/C(=O)O)cc(OC)c1OCc1ccccc1
Product: CCCn1c(=O)c2[nH]c(/C=C/c3cc(OC)c(OCc4ccccc4)c(OC)c3)nc2n(CCC)c1=O
Yield: 74.4 %

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 3.30 g (14.5 mmol) of 5,6-diamino-1,3-dipropyluracil and 5.0 g (15.9 mmol) of Compound H. Then, the resultant crude crystals were recrystallized from ethanol/2-propanol to give 5.44 g (yield 74%) of Compound 27 as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][CH:9]2[C:12]([OH:14])=O)=[CH:4][CH:3]=1.[CH2:15]([N:17]1[CH:21]=[C:20]([CH2:22][NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=2)[CH:19]=[N:18]1)[CH3:16]>>[CH2:15]([N:17]1[CH:21]=[C:20]([CH2:22][N:23]([C:24]2[CH:25]=[CH:26][C:27]([CH:30]([CH3:31])[CH3:32])=[CH:28][CH:29]=2)[C:12]([CH:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:11]=3)[CH2:6][CH2:7][CH2:8]2)=[O:14])[CH:19]=[N:18]1)[CH3:16]
Reactant: O=C(O)C1CCCc2ccc(F)cc21
Reactant: CCn1cc(CNc2ccc(C(C)C)cc2)cn1
Product: CCn1cc(CN(C(=O)C2CCCc3ccc(F)cc32)c2ccc(C(C)C)cc2)cn1
Yield: 37.5 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 7-fluoro-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.41 g) and [(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.51 g) as starting materials, N-[(1-ethylpyrazol-4-yl)methyl]-7-fluoro-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.33 g) was obtained.
Reaction SMILES: C([Si]([O:8][CH2:9][C:10]1[CH:14]=[C:13]([CH2:15]B2OCC(C)(C)CO2)[O:12][C:11]=1[CH3:24])(C)C)(C)(C)C.ClC1[N:27]=[N:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:33][O:32][C:29]1[N:28]=[N:27][C:15]([C:13]2[O:12][C:11]([CH3:24])=[C:10]([CH2:9][OH:8])[CH:14]=2)=[CH:31][CH:30]=1
Reactant: Cc1oc(CB2OCC(C)(C)CO2)cc1CO[Si](C)(C)C(C)(C)C
Reactant: COc1ccc(Cl)nn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(-c2cc(CO)c(C)o2)nn1
Reaction time: 8 h
Yield: 86.7 %

Procedure:
A mixture of tert-butyl({5-[(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)methyl]-2-methylfuran-3-yl}methoxy)dimethylsilane (2.4 g), 3-chloro-6-methoxypyridazine (1.5 g), tetrakis(triphenylphosphine)palladium(0) (0.4 g), 2N aqueous sodium carbonate solution (7 mL) and 1,2-dimethoxyethane (20 mL) was stirred overnight with refluxing under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL), 1N tetrabutylammonium fluoride in tetrahydrofuran (10 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (40% ethyl acetate/hexane to 100% ethyl acetate/hexane) to give the title compound (1.3 g, 86%) as a white crystal.