Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:61]([CH3:63])C)[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:15][C:16]([C:19]2[CH:20]=[CH:21][C:22]3[C:31]4[C:26](=[C:27]5[CH:35]=[CH:34][C:33]([C:36]6[NH:40][C:39]([C@@H:41]7[CH2:45][CH2:44][CH2:43][N:42]7[C:46](=[O:59])[C@H:47]([NH:54][C:55](=[O:58])[O:56][CH3:57])[C:48]7[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=7)=[N:38][CH:37]=6)=[CH:32][C:28]5=[CH:29][CH:30]=4)[O:25][CH2:24][C:23]=3[CH:60]=2)=[CH:17][N:18]=1)=[O:8])=[O:4].[CH3:64][O:65]C(N[C@@H](C(C)C)C(O)=O)=O>>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([C@H:61]([O:65][CH3:64])[CH3:63])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:15][C:16]([C:19]2[CH:20]=[CH:21][C:22]3[C:31]4[C:26](=[C:27]5[CH:35]=[CH:34][C:33]([C:36]6[NH:40][C:39]([C@@H:41]7[CH2:45][CH2:44][CH2:43][N:42]7[C:46](=[O:59])[C@H:47]([NH:54][C:55](=[O:58])[O:56][CH3:57])[C:48]7[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=7)=[N:38][CH:37]=6)=[CH:32][C:28]5=[CH:29][CH:30]=4)[O:25][CH2:24][C:23]=3[CH:60]=2)=[CH:17][N:18]=1)=[O:8])=[O:4]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3c(c2)COc2c-3ccc3cc(-c4cnc([C@@H]5CCCN5C(=O)[C@H](NC(=O)OC)c5ccccc5)[nH]4)ccc23)[nH]1)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3c(c2)COc2c-3ccc3cc(-c4cnc([C@@H]5CCCN5C(=O)[C@H](NC(=O)OC)c5ccccc5)[nH]4)ccc23)[nH]1)[C@@H](C)OC

Procedure:
This compound was made in an analogous manner to methyl (R)-2-((S)-2-(5-(8-(2-((S)-1-((S)-2-methoxycarbonylamino-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate, substituting (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid for (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid in the first amide coupling. LCMS-ESI+: calculated for C48H50N8O8: 866.96; observed [M+1]+: 867.58.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[N+:4]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10](Cl)=[O:11])([O-:6])=[O:5].C(OCC)(=O)C>O1CCOCC1>[CH3:1][N:2]([CH3:3])[C:10](=[O:11])[C:9]1[CH:13]=[CH:14][CH:15]=[C:7]([N+:4]([O-:6])=[O:5])[CH:8]=1
Reactant: CNC
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Dimethylamine (50% aqueous solution, 3.6 ml) was stirred in an ice bath and a solution of 3-nitrobenzoyl chloride (1.8 g) in 1,4-dioxan (4 ml) was dropwise added thereto. The resulting mixture was stirred vigorously at ambient temperature for 2.5 hours. Ethyl acetate was added and organic layer was washed with water, 1N hydrochloric acid, 1N sodium hydroxide, water and saturated sodium chloride solution successively and dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was recrystallized from benzene-n-hexane to afford N,N-dimethyl-3-nitrobenzamide (1.5 g) as a pale yellow prism.
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH:4]=[O:5])[CH3:2].[C:10](#[N:13])[CH:11]=[CH2:12].C(CCC(C)(CCC)C=O)#N>>[C:10]([CH2:11][CH2:12][C:3]([CH2:1][CH3:2])([CH2:6][CH2:7][CH2:8][CH3:9])[CH:4]=[O:5])#[N:13]
Reactant: CCCCC(C=O)CC
Reactant: C=CC#N
Agent: CCCC(C)(C=O)CCC#N
Product: CCCCC(C=O)(CC)CCC#N
Yield: 78 %

Procedure:
2-(Beta-cyanoethyl)-2-ethylhexanal was prepared from 2-ethylhexanal and acrylonitrile analogous to the procedure described in Example 1 for 2-(beta-cyanoethyl)2-methylpentanal. Yield 81% of the product boiling at 112°-114° C. at 0.5 mm.; nD20 1.4538. This product was converted to γ-ethyl-γ-n-butyl-δ-valerolactone as described in Example 1 for γ-methyl-γ-n-propyl-δ-valerolactone. Yield 78%, product boils at 104°-105° C. at 0.6 mm.; nD20 1.4652 and exhibits a hairy, lactonic, fatty, costus-like odor.
Reaction SMILES: CON(C)[C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:7][CH:6]=1.[F:23][C:24]([F:31])([F:30])[CH:25]([Mg]Br)[CH2:26]C>O1CCCC1>[F:23][C:24]([F:31])([F:30])[CH2:25][CH2:26][C:4]([C:5]1[CH:6]=[N:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)=[O:21]
Reactant: CON(C)C(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Reactant: CCC([Mg]Br)C(F)(F)F
Solvent: C1CCOC1
Product: O=C(CCC(F)(F)F)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Temperature: 0 °C
Yield: 80.5 %

Procedure:
N-Methoxy-N-methyl-6-(4-trifluoromethyl-phenyl)-nicotinamide (2.0 g, 6.45 mmol) is suspended in anhydrous tetrahydrofuran (25.0 mL), and cooled to 0° C. with stirring under nitrogen. 1,1,1-Trifluoro-butyl magnesium bromide (11.3 mL, 1.14M in tetrahydrofuran, 12.9 mmol) is slowly added to the reaction over 1 h. The reaction is allowed to warm slowly to room temperature and monitored by TLC. Upon complete consumption of starting material, the reaction is carefully acidified with 1N hydrochloric acid, extracted with diethyl ether, washed, dried, and concentrated. The 4,4,4-Trifluoro-1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-butan-1-one (1.80 g, 5.19 mmol) 80% yield, is used without further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12]C=C[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:18]1[CH2:22][O:21]C[CH2:19]1.C[Li]>C(OCC)C.O>[CH2:1]([N:8]1[CH2:12][CH:18]([CH3:19])[CH:22]([OH:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1=CCN(Cc2ccccc2)C1
Reactant: C1CCOC1
Agent: O=S(=O)(O)O
Agent: [Li]C
Solvent: O
Solvent: CCOCC
Product: CC1CN(Cc2ccccc2)CC1O
Yield: 75.8 %

Procedure:
To a solution of 15.9 g (0.1 mol) of 1-benzyl-3-pyrroline, 12.0 g (0.12 mol) of 98% sulfuric acid, and 60.0 g of THF in a quartz round flask reactor, 45.6 g (0.20 mol) of (NH4)2S2O8 (ammonium peroxydisulfate produced by Mitsubishi Gas Chemical Industry Co., Ltd.) was added with stirring and allowed to react for 5 days at room temperature with irradiation by 500 W Xe lamps (UXL-500D xenon lamp produced by Ushio). 300 mL (0.30 mol) of 1 mol/L methyllithium (MeLi) in diethyl ether solution (produced by Kanto Chemical Co., Inc.) was continuously added to the reaction mixture and stirred for 5 hours at about 5° C. using an ice-bath. After completion, water was added to destroy excess MeLi at about 5° C. using an ice-bath. Acetone and diethyl ether were evaporated under reduced pressure, and extracted with toluene and water. After the solvent was evaporated under reduced pressure, 14.5 g of 1-benzyl-4-methyl-3-pyrrolidinol (yield 76.0%) was obtained.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[CH2:12][CH2:11][CH2:10]2)(=O)=O.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[Sn](CCCC)(CCCC)CCCC.[Cl-].[Li+].[Cl-].[F-].[NH4+]>CN(C)C=O.C(OCC)(=O)C>[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[CH2:12][CH2:11][CH2:10]2
Reactant: O=C1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: [Cl-]
Agent: [F-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1CCCc2cc(-c3cccs3)ccc21
Temperature: 120 °C
Reaction time: 4 h
Yield: 79.2 %

Procedure:
3,4-Dihydro-6-trifluoromethylsulfonyloxy-1(2H)-naphthalenone (3.96 g, 13.5 mmol) was dissolved in 40 ml of N,N-dimethylformamide in an argon atmosphere, and 6.03 g (16.1 mmol) of 2-thienyltributyltin, 1.71 g (40.4 mmol) of lithium chloride and 0.47 g (0.67 mmol) of bistriphenylphosphinepalladium chloride were added to the solution. The mixture was stirred at 120° C. for 4 hours. The reaction product was cooled to room temperature. Ethyl acetate and a 2M-ammonium fluoride aqueous solution were added thereto, followed by stirring the mixture at room temperature overnight. The precipitate was filtered through Celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica-gel column chromatography (eluent: a mixture of 20% ethyl acetate and hexane) to obtain 2.44 g of the above-mentioned compound (yield 79%). NMR (CDCl3) δ (ppm): 8.04(1H, d, J=8 Hz), 7.57-7.35(4H, m), 7.13-7.11(1H, m), 2.99(2H, t, J=6 Hz), 2.67(2H, t, J=6 Hz), 2.21-2.11 (2H, m) MS (m/e): 228 (M+), 200
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[NH2:10][C:11]1[C:23]2[C:22](=O)[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]=2[CH:14]=[CH:13][CH:12]=1.P([O-])(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O>>[C:4]1([C:1]2[N:10]=[C:11]3[C:23]4=[C:22]([C:21]5[C:16]([C:15]4=[CH:14][CH:13]=[CH:12]3)=[CH:17][CH:18]=[CH:19][CH:20]=5)[CH:2]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Reactant: Nc1cccc2c1C(=O)c1ccccc1-2
Agent: O=P([O-])(Oc1ccccc1)Oc1ccccc1
Product: c1ccc(-c2cc3c4c(cccc4n2)-c2ccccc2-3)cc1
Temperature: 25 °C
Yield: 45 %

Procedure:
In a round-bottomed flask, 9.0 mmol of acetophenone, 3.0 mmol of 1-amino-9-fluorenone (manufactured by Aldrich), and 1.5 mmol of diphenyl phosphate were placed, and the resultant mixture was irradiated with microwave (2,450 MHz) for 10 minutes under argon atmosphere. The reaction solution was cooled to room temperature, concentrated, and then separated and purified by silica gel column chromatography (eluant: dichloromethane and methanol), to give 2-phenylindeno[1,2,3-de]quinoline. The isolation yield was 45%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][CH2:9][C@H:10]2[CH2:15][CH2:14][C@H:13]([CH3:16])[CH2:12][CH2:11]2)=[C:6]([NH:17]C(=O)OC(C)(C)C)[CH:5]=[C:4]([Cl:25])[N:3]=1>Cl.O1CCOCC1>[Cl:1][C:2]1[C:7]([NH:8][CH2:9][C@H:10]2[CH2:11][CH2:12][C@H:13]([CH3:16])[CH2:14][CH2:15]2)=[C:6]([NH2:17])[CH:5]=[C:4]([Cl:25])[N:3]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)nc(Cl)c1NC[C@H]1CC[C@H](C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H]1CC[C@H](CNc2c(N)cc(Cl)nc2Cl)CC1

Procedure:
A solution of tert-butyl (2,6-dichloro-3-(((trans-4-methylcyclohexyl)methyl)amino)pyridin-4-yl)carbamate (150 g, 0.386 mol) in HCl/1,4-dioxane (4 M, 3.0 L) was stirred at 45° C. for 15 h. The mixture was concentrated under reduced pressure to give crude 2,6-dichloro-N3-((trans-4-methylcyclohexyl)methyl)pyridine-3,4-diamine.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:6]([O:7][CH3:8])[C:4]=1[OH:5].[H-].[Na+].Cl[CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>CN(C)C=O.C1(C)C=CC=CC=1>[CH3:8][O:7][C:6]1[C:4]([O:5][CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:3]([CH:11]=[CH:10][CH:9]=1)[CH:2]=[O:1]
Reactant: COc1cccc(C=O)c1O
Reactant: ClCCCN1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1cccc(C=O)c1OCCCN1CCOCC1

Procedure:
o-Vanillin (30.4 g), dissolved in 160 ml of dimethylformamide, is treated with 9.6 g of 50% sodium hydride, then with 130 ml of 2 N N-(3-chloropropyl)morpholine in toluene following the procedure described in Example 1A, yielding 42.9 g of the title compound, boiling point 178°-183° C. at 0.2-0.3 mm of Hg.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]1[C:21]3[O:20][C:19]([CH3:23])([CH3:22])[CH2:18][C:17]=3[CH:16]=[CH:15][CH:14]=1)[CH:6]=[CH:5]2.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=1>>[CH3:22][C:19]1([CH3:23])[CH2:18][C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([NH:12][C:7]3[CH:6]=[CH:5][C:4]4[C:9](=[CH:10][CH:11]=[C:2]([NH:24][C:25]5[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=5)[CH:3]=4)[N:8]=3)[C:21]=2[O:20]1
Reactant: Cc1cccc(N)n1
Reactant: CC1(C)Cc2cccc(Nc3ccc4cc(Br)ccc4n3)c2O1
Product: Cc1cccc(Nc2ccc3nc(Nc4cccc5c4OC(C)(C)C5)ccc3c2)n1

Procedure:
The title compound, yellow foam, MS: m/e=397.2 (M+H+), was prepared in accordance with the general method of example 84 from (6-bromo-quinolin-2-yl)-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yl)-amine and commercially available 2-amino-6-methyl-pyridine.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[C:10]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[CH:9]=2)[CH:5]=[C:4]([C:24]([F:27])([F:26])[F:25])[N:3]=1.[Br:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1>>[Br:28][C:29]1[CH:34]=[C:33]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[C:10]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[CH:9]=3)[CH:5]=[C:4]([C:24]([F:27])([F:26])[F:25])[N:3]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: FC(F)(F)COc1cc(-c2cc(C(F)(F)F)nc(Cl)n2)ccc1C(F)(F)F
Product: FC(F)(F)COc1cc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 2-chloro-4-[3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-6-trifluoromethyl-pyrimidine (example A.39) (0.85 g, 2.0 mmol) and commercially available 3-bromo-benzene-boronic acid (0.44 g, 2.19 mmol) according to the general procedure IVb. Obtained as an off-white solid (0.97 g, 80%). MS (EI) 544.1 [(M)+]; mp 122° C.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:23])[CH2:16][CH:17]([OH:22])[CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:3].[Na+]>C(OCC)(=O)C>[CH3:3][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]\[C@@H:15]([OH:23])[CH2:16][C@@H:17]([OH:22])[CH2:18][C:19]([OH:21])=[O:20])=[C:11]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:1]
Reactant: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)n1c(/C=C\[C@@H](O)C[C@@H](O)CC(=O)O)c(-c2ccc(F)cc2)c2ccccc21
Yield: 87.5 %

Procedure:
7.0 g (16 mmole) of fluvastatin sodium was dissolved in 300 mL ethyl acetate and washed with 300 mL 10% (w/v) aqueous sodium hydrogen sulfate solution (pH 3). The organic phase was dried over anhydrous magnesium sulfate, filtered and the solvent removed under reduced pressure to afford 5.76 g (14.0 mmole) of fluvastatin acid. This material was dissolved in 300 mL anhydrous toluene and stirred at room temperature for 7 days, at which time analytical thin-layer chromatography using 5:1 methylene chloride:acetone eluent indicated approximately 30% conversion of the starting acid to a less polar product. The toluene was removed under reduced pressure and the reaction mixture was fractionated on 400 cc of silica gel using 5:1 methylene chloride: acetone eluent to afford, after combining, concentrating and drying of the appropriate fractions, 2.02 g (5.14 mmol, 32% overall) of fluvastatin lactone as a white foam. The 400 MHz 1H nuclear magnetic resonance (NMR) spectrum and the electrospray mass spectrum (ES-MS) were consistent with the lactone product. 1H NMR (Me2SO-d6) δ 7.7 (d, 1H), 7.4 (br s, 3H), 7.3 (m, 2H), 7.2 (t, 1H), 7.1 (t, 1H), 6.8 (t, 1H), 5.7 (dd, 1H), 5.3 (s, 1H), 5.2 (m, 1H), 4.9 (m, 1H), 4.1 (br s, 1H), 2.7 (dd, 1H), 2.4 (d, 1H), 1.8 (d, 1H), 1.7 (t, 1H), 1.57 (d, 6H). ES-MS: obsvd. m/z 394 ([MH]+).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[S:9]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2=[O:22])(=[O:11])=[O:10].[CH2:23](O)[CH2:24][CH2:25][OH:26]>C1C=CC=CC=1>[CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[S:9]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]12[O:26][CH2:25][CH2:24][CH2:23][O:22]1)(=[O:11])=[O:10]
Reactant: OCCCO
Reactant: COC[C@@H]1CCCN1S(=O)(=O)c1ccc2c(c1)C(=O)C(=O)N2
Solvent: c1ccccc1
Product: COC[C@@H]1CCCN1S(=O)(=O)c1ccc2c(c1)C1(OCCCO1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
A mixture of 5-{[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]sulfonyl}-1H-indole-2,3-dione (13.41 g, 41.3 mmol), 1,3 propanediol (12.1 mL, 165 mmol, 4eq) and p-tolune sulfonic acid (3.14 g, 16.5 mmol, 0.4 mole %) in benzene (800 mL) was heated to reflux under a Dean Stark Trap for 5 hours and stirred overnight at room temperature. The mixture was washed with saturated aqueous NaHCO3 (3×300 mL), water (3×300 mL) and brine (3×300 mL), dried over sodium sulfate, filtered, and concentrated to give 10.7 g of crude product that was flash chromatographed (Biotage KP silica gel, step gradient 60/40-50/50 Pet Ether/EtOAc) to give the title compound as a white solid (7.1 g, 45% yield). Anal: Calc'd for C17H22N2O6S: C, 53.39; H, 5.80; N, 7.32; Found: C, 53.08; H,5.82; N, 6.92; NMR (400 MHz, DMSO-d6): consistent. IR: consistent. MS: (ES−) m/z 381 [M−H]. m.p: 127-128° C.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH:7]([NH:15]C(=O)OC(C)(C)C)[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O>>[NH2:15][CH:7]([C:8]1[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=1)[CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2]
Reactant: CC(=O)NCCC(NC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)NCCC(N)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 0.67 h
Yield: 40 %

Procedure:
tert-Butyl 3-acetamido-1-(4-chlorophenyl)propylcarbamate (Intermediate 26) (142 mg, 0.43 mmol) was added to TFA (2 mL) at 20° C. The resulting solution was stirred at 20° C. for 40 minutes. The reaction mixture was evaporated and purified by ion exchange chromatography using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and pure fractions were evaporated to dryness to afford N-(3-amino-3-(4-chlorophenyl)propyl)acetamide (39.0 mg, 39.6%) as a colourless gum. m/z (ESI+) (M+H)+=227; HPLC tR=1.32 min.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:10][CH2:11][C:12]1[S:13][CH:14]=[CH:15][CH:16]=1>>[S:13]1[CH:14]=[CH:15][CH:16]=[C:12]1[CH2:11][NH:10][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: NCc1cccs1
Reactant: N#Cc1ccccc1F
Product: N#Cc1ccccc1NCc1cccs1

Procedure:
According to a similar manner to that in Reference Example 12, the title compound was synthesized from 2-fluorobenzonitrile and 2-aminomethylthiophene.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([C:15]([O:17]CC)=[O:16])[C:7]([C:10]([O:12]CC)=[O:11])=[N:8][CH:9]=1)[CH:2]=[CH2:3].[OH-].[Na+].Cl>CO.O>[CH2:1]([C:4]1[CH:5]=[C:6]([C:15]([OH:17])=[O:16])[C:7]([C:10]([OH:12])=[O:11])=[N:8][CH:9]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1cnc(C(=O)OCC)c(C(=O)OCC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=CCc1cnc(C(=O)O)c(C(=O)O)c1

Procedure:
To a solution of 6.07 g of diethyl 5-allylpyridine-2,3-dicarboxylate in 20 mL of methanol, stirred under nitrogen, is added slowly a solution of 3.3 g of sodium hydroxide in 13 mL water. After diluting the reaction mixture with 10 mL each of water and methanol, it is heated at reflux for 13/4 hours. The reaction is cooled in an ice bath, acidified to pH 3 with concentrated hydrochloric acid, and concentrated in vacuo to a damp solid. This solid is reevaporated from pyridine to afford the product as a brown solid, mp>250°(dec).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH2:12].[Cl-].[C:14]([O:18][C:19](=[O:22])[CH2:20][Zn+])([CH3:17])([CH3:16])[CH3:15].C(OCC)C>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(P(C(C)(C)C)[C-]1C=CC=C1)(C)C.C1C=CC([C-]2C(C3C=CC=CC=3)=C(C3C=CC=CC=3)C(C3C=CC=CC=3)=C2C2C=CC=CC=2)=CC=1.[Fe+2]>[NH2:12][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH2:20][C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:22])[CH:3]=2)[N:8]=[CH:7][N:6]=1
Reactant: Nc1ncnc2ccc(Br)cc12
Reactant: CC(C)(C)OC(=O)C[Zn+]
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cc1ccc2ncnc(N)c2c1
Temperature: 50 °C

Procedure:
To a solution of 6-bromoquinazolin-4-amine (0.400 g, 1.79 mmol), tris(dibenzylideneacetone)dipalladium (o) (0.163 g, 0.179 mmol) and Q-phos (0.20 g) in 10 mL of THF was added 2-tert-butoxy-2-oxoethylzinc chloride 0.5 m in diethyl ether (10.7 ml, 5.36 mmol). The reaction was heated at 50° C. for 16 hours and was quenched with 50 mL of satd. NH4Cl. The mixture was diluted with 60 mL of EtOAc. The organic phase was separated, washed with brine, dried over Na2SO4 and concentrated in vacuo to give red solid. The residue was purified by a silica gel column chromatography (5% EtOAc/hex to EtOAC) to give red solid tert-butyl 2-(4-aminoquinazolin-6-yl)acetate which was used without further purification. MS (ESI pos. ion) m/z: 260.1 (M+H). Calc'd Exact Mass for C14H12N3O2: 259.1.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10]C(N)=O)=[CH:6][CH:5]=1)[CH2:2][CH3:3].[S:14](=O)(=[O:17])([OH:16])[OH:15]>>[NH2:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][C:6]=1[S:14]([OH:17])(=[O:16])=[O:15]
Reactant: O=S(=O)(O)O
Reactant: CCCc1ccc(NC(N)=O)cc1
Product: CCCc1ccc(N)c(S(=O)(=O)O)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 64.1 %

Procedure:
A solution of 31.4 g of p-n-propylaniline dissolved in 116 ml of acetic acid and 232 ml of water was added dropwise into 200 ml of a mixed solution comprising 130 g of sodium isocyanate and 900 ml of water, and then stirred in an ice-bath for 30 minutes. The crystals precipitated were filtered, washed with water and dried to give 38.88 g of 4-n-propylphenylurea. After the 4-n-propylphenylurea was added in portions into 107.6 ml of 20% fuming sulfuric acid, the reaction was carried out at 60° C. for 2 hours. Under cooling in an ice-bath, about 400 ml of ice was added into the reaction mixture, followed by heating under reflux for 4 hours. The crystals precipitated by cooling were filtered, washed with water and then dried to give 30.09 g of the above title product (yield: 64.1%). Melting point: 30 261.7°-262.3° C.
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.[C:30](O)(=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32]>>[CH:8]1([C:13]([N:15]2[CH2:20][CH:19]([C:21]3[CH:22]=[CH:23][C:24]([CH2:27][CH3:28])=[CH:25][CH:26]=3)[CH2:18][CH:17]([NH:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:16]2)=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: CCc1ccc(C2CC(N)CN(C(=O)C3CCCC3)C2)cc1
Reactant: CC(C)(C)C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(C2CC(NC(=O)C(C)(C)C)CN(C(=O)C3CCCC3)C2)cc1

Procedure:
99 mg (0.20 mmol) of 1-(cyclopentylcarbonyl)-5-(4-ethylphenyl)piperidine-3-amine trifluoroacetate (Example 8A) and 20 mg (0.20 mmol, 1.0 eq.) of pivalic acid were reacted according to General Method 1. Yield: 56 mg (73% of theory)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[Cl:10][C:11]1[C:12]([N:16]=[C:17]=[S:18])=[CH:13][S:14][CH:15]=1>C1COCC1>[NH2:9][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[NH:8][C:17]([NH:16][C:12]1[C:11]([Cl:10])=[CH:15][S:14][CH:13]=1)=[S:18]
Reactant: Nc1ccc(F)cc1N
Reactant: S=C=Nc1cscc1Cl
Solvent: C1CCOC1
Product: Nc1cc(F)ccc1NC(=S)Nc1cscc1Cl
Reaction time: 8 h

Procedure:
4-Fluoro-1,2-phenylendiamine (900 mg) was dissolved in THF (25 ml) and 4-chloro-3-thienylisothiocyanat (example 52c), dissolved in THF (15 ml), was added with stirring. The solution was stirred for about 3 h at room temperature and stood overnight. Then the reaction mixture was concentrated und the residue purified by preparative HPLC. The product containing fractions were combined, the acetonitrile was removed, the aqueous residue made basic and three times extracted with ethyl acetate. The organic layers were combined, dried (MgSO4) and filtered. After removal of the solvent the desired product (625 mg) was obtained.