Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[C:6]([O:26][CH3:27])=[C:7]([CH:13]([N:15]3[C:19]4=[N:20][CH:21]=[N:22][C:23]([NH2:24])=[C:18]4[C:17]([Br:25])=[N:16]3)[CH3:14])[CH:8]=[C:9]([Cl:12])[C:10]=2[CH3:11])[CH2:2]1.[CH2:28]([N:30](CC)CC)[CH3:29].BrCC#N>C(#N)C.CN(C=O)C>[NH2:24][C:23]1[N:22]=[CH:21][N:20]=[C:19]2[N:15]([CH:13]([C:7]3[C:6]([O:26][CH3:27])=[C:5]([CH:3]4[CH2:4][N:1]([CH2:29][C:28]#[N:30])[CH2:2]4)[C:10]([CH3:11])=[C:9]([Cl:12])[CH:8]=3)[CH3:14])[N:16]=[C:17]([Br:25])[C:18]=12
Reactant: CCN(CC)CC
Reactant: COc1c(C(C)n2nc(Br)c3c(N)ncnc32)cc(Cl)c(C)c1C1CNC1
Agent: N#CCBr
Solvent: CC#N
Solvent: CN(C)C=O
Product: COc1c(C(C)n2nc(Br)c3c(N)ncnc32)cc(Cl)c(C)c1C1CN(CC#N)C1
Temperature: 25 °C
Yield: 29.5 %

Procedure:
To a mixture of 1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.2 mmol) and triethylamine (37 μL, 0.27 mmol) in acetonitrile (3 mL) was added bromoacetonitrile (19 μL, 0.27 mmol). The resulting mixture was stirred at room temp. After an hour, the reaction mixture was still cloudy with not all of the material in solution. Several drops of DMF were added which allowed for a clear solution. The mixture was stirred overnight at room temperature and then most of the solvents were evaporated. The resulting residue was purified on silica gel (eluted with 0-10% MeOH in dichloromethane) to give 29 mg (30%) of the desired product. LCMS calculated for C20H22BrClN7O (M+H)+: m/z=490.1; Found: 490.1.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH2:28][NH2:29])[CH:22]=1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][C:15](=[O:17])[NH:29][CH2:28][CH2:27][C:23]2[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: NCCc1cccnc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCC(=O)NCCc2cccnc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and 2-pyridin-3-yl-ethylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C19H22N2O5 [M+H]+: 359.
Reaction SMILES: C([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2)C1C=CC=CC=1.[H-].[Na+].[CH:20]([Si:23](Cl)([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25])([CH3:22])[CH3:21]>C1COCC1>[CH:20]([Si:23]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[N:13]1[C:14]2[CH:15]=[CH:16][CH:17]=[C:9]([OH:8])[C:10]=2[CH:11]=[CH:12]1)([CH3:22])[CH3:21]
Reactant: c1ccc(COc2cccc3[nH]ccc23)cc1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(O)cccc21

Procedure:
4-Benzyloxyindole (1 g) was treated with 60% oily NaH (135 mg) and triisopropylsilyl chloride (1 g) in THF, purified by flash chromatography (9812 ethyl acetate, hexanes), then debenzylated in ethanol (35 mL) using Pearlman's catalyst (0.19 g) and a hydrogen balloon.
Reaction SMILES: C([O:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[N:15]=C(C2C=CC=CC=2)C2C=CC=CC=2)[O:7][CH2:6]1)(=O)C.Cl.O.C([O-])([O-])=O.[K+].[K+]>C1COCC1.C(Cl)Cl>[NH2:15][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:13]=1[CH2:14][CH:5]([OH:4])[CH2:6][O:7]2
Reactant: CC(=O)OC1COc2cccc(N=C(c3ccccc3)c3ccccc3)c2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: Nc1cccc2c1CC(O)CO2
Yield: 64.5 %

Procedure:
A solution of Example 51D (504 mg, 1.36 mmol) in THF (5 mL) was stirred at room temperature, followed by addition of 6N aq HCl (3.4 mL, 6.8 mmol). After 10 min water (20 mL) and CH2Cl2 (10 mL) were added and the layers separated. The aqueous layer was washed with CH2Cl2 (5 mL). The aqueous layer was then neutralized with saturated NaHCO3 solution and extracted with CH2Cl2 (3×20 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The residue was taken up in MeOH (5 mL) and K2CO3 (938 mg, 6.78 mmol) was added. After 20 min CH2Cl2 (50 mL) was added and the mixture was filtered and concentrated in vacuo. The crude product was purified by flash chromatography (50%-100% EtOAc/hexanes) to afford 145 mg (65%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 6.73 (t, J=8.0, 1H), 6.18 (dd, J=7.9, 1.1, 1H), 5.98 (dd, J=8.1, 1.0, 1H), 5.06 (d, J=4.2, 1H), 4.81 (bs, 2H), 4.01-3.92 (m, 2H), 3.63 (dd, J=11.0, 8.1, 1H), 2.64 (dd, J=16.9, 6.2, 1H), 2.23 (dd, J=16.1, 6.7, 1H). MS (ESI+) m/z 166 (M+H).
Reaction SMILES: C([NH:20][C:21]1[NH:22][C:23](=O)[C:24]2[N:25]=[CH:26][N:27](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:28]=2[N:29]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.II.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[NH:71]1[CH:75]=[CH:74][N:73]=[CH:72]1.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[NH2:20][C:21]1[N:29]=[C:28]2[C:24]([NH:25][CH:26]=[N:27]2)=[C:23]([N:71]2[CH:75]=[CH:74][N:73]=[CH:72]2)[N:22]=1
Reactant: O=c1[nH]c(NC(c2ccccc2)(c2ccccc2)c2ccccc2)nc2c1ncn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: c1c[nH]cn1
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(-n2ccnc2)c2[nH]cnc2n1
Temperature: 95 °C
Reaction time: 8 h
Yield: 66.3 %

Procedure:
A mixture of 2-N,9-bistritylguanine (1.90 g, 3 mmol), I2 (3.88 g, 15 mmol), Ph3P (3.99 g, 15 mmol) and imidazole (1.10 g, 15 mmol) was stirred in toluene (150 mL) at 95° C. for 15 min, and DIPEA (2.9 mL, 2.15 g, 16.6 mmol) was added. The mixture was stirred at 95° C. overnight. After removal of volatiles, the residue was boiled with EtOAc (3×) and filtered hot. The combined EtOAc extracts were evaporated to dryness. The residue was dissolved in TFA/H2O (9:1, 60 mL), and the solution was stirred at 0° C. for 4 h. Volatiles were evaporated in vacuo, and the residue was dissolved in 0.1 N NaOH/H2O//CH2Cl2 (100 mL/100 mL). The organic layer was extracted with 0.1 N NaOH/H2O (50 mL×2), and the aqueous phase was combined, washed [CH2Cl2 (2×50 mL)], and neutralized with CO2. Volatiles were evaporated in vacuo, and the residue was washed (H2O, CH2Cl2) to give 2-amino-6-(imidazol-1-yl)purine (0.40 g, 69%): UV (MeOH) max 222, 320 nm (∈ 29 800, 8700), min 207, 280 nm (∈ 16 100, 1500); 1H NMR (500 MHz, DMSO-d6) δ 12.89 (s, 1H), 8.94 (s, 1H), 8.25 (s, 1H), 8.16 (s, 1H), 7.18 (s, 1H), 6.67 (s, 2H); 13C NMR (125 MHz, DMSO-d6) δ 160.7, 157.5, 145.4, 141.9, 137.2, 130.5, 117.7, 115.4; HRMS m/z 201.0753 (M+[C8H7N7]=201.0763).
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([CH3:15])=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.C([Li])CCC.[C:21](=[O:23])=[O:22]>C1COCC1.O>[CH3:15][C:8]1[CH:9]=[CH:10][C:11]2[C:12]3[C:4](=[CH:3][C:2]([CH3:1])=[CH:14][CH:13]=3)[CH:5]([C:21]([OH:23])=[O:22])[C:6]=2[CH:7]=1
Reactant: Cc1ccc2c(c1)Cc1cc(C)ccc1-2
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)C(C(=O)O)c1cc(C)ccc1-2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.9 %

Procedure:
A solution of 2,7-dimethylfluorene (5.0 g, 25.7 mmol) in THF (100 mL) at -78° C. was charged with butyl lithium (16.8 mL, 26.0 mmol). The reaction mixture was stirred for 15 min, then CO2 gaseous (5g, 113.6 mmol) was introduced with cannula over a period of 15 min at -78° C. The reaction mixture Was Warmed up to room temperature and stirred overnight, diluted with water (150 mL). The layers were separated, the water layer was washed with ethyl acetate (5×20 mL), then acidified with conc. HCl. The precipitate formed was collected, washed with water and dried to give 4.4 g of 2,7-dimethyl-9-fluorenecarboxylic acid (72.4%).
Reaction SMILES: O[CH:2]([CH3:6])[C:3](=O)[CH3:4].[CH3:7][C:8]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[C:9]=1[NH2:10].[C:17](#[N:21])[CH2:18][C:19]#[N:20]>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[NH2:20][C:19]1[N:10]([C:9]2[C:11]([CH3:16])=[CH:12][C:13]([CH3:15])=[CH:14][C:8]=2[CH3:7])[C:2]([CH3:6])=[C:3]([CH3:4])[C:18]=1[C:17]#[N:21]
Reactant: Cc1cc(C)c(N)c(C)c1
Reactant: N#CCC#N
Reactant: CC(=O)C(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: Cc1cc(C)c(-n2c(C)c(C)c(C#N)c2N)c(C)c1
Reaction time: 2 h
Yield: 45.3 %

Procedure:
A mixture of 3-hydroxy-2-butanone (100.000 g, 1.135 mol), 2,4,6-trimethylaniline (153.225 g, 1.135 mol) and p-toluenesulfonic acid (0.670 g) in 500 ml of benzene was refluxed using a Dean-Stark trap to remove water. After 2 hours, malononitrile (75.000 g, 1.135 mol) was added and the mixture was refluxed for an additional 10 hours until all of the starting material was consumed. The reaction mixture was cooled and precipitate formed and filtered. The solid was washed with a minimum amount of ethanol. The solid was diluted with 500 ml of benzene and product was dissolved. Some undesired product was insoluble and was filtered off. The filtrate was concentrated to give a tan solid which was recrystallized from ethanol to give 130.260 g of off-white crystals. 1H NMR (CDCl3) δ 1.68(s, 3H), 1.93(s, 6H), 2.05(s, 3H), 2.31(s, 3H), 3.62(brs, 2H), 6.95(s, 2H) ppm.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC([O-])(C)C.[K+].[CH2:30]([O:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]2[CH2:44][CH2:43][CH:42]([CH:45]=O)[CH2:41][CH2:40]2)=[C:35]([F:47])[C:34]=1[F:48])[CH3:31].O>C1COCC1>[CH2:30]([O:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]2[CH2:44][CH2:43][CH:42]([CH:45]=[CH:2][O:3][CH3:4])[CH2:41][CH2:40]2)=[C:35]([F:47])[C:34]=1[F:48])[CH3:31]
Reactant: CCOc1ccc(C2CCC(C=O)CC2)c(F)c1F
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ccc(C2CCC(C=COC)CC2)c(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
In a reactor under nitrogen atmosphere, 25 mL of THF was added to 7.7 g of methoxymethyltriphenylphosphonium chloride, and the mixture was cooled to −20° C., to which 2.5 g of t-BuOK was added, followed by stirring for 1 hour A solution containing 5.0 g of 4-(4-ethoxy-2,3-difluorophenyl)cyclohexane-carboaldehyde dissolved in 50 mL of THF was added dropwise thereto, followed by stirring for 1 hour. The temperature of the reaction mixture was increased to room temperature, and 100 mL of water was added to the reaction mixture, followed by extracting three times with 100 mL of toluene. The resulting organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was concentrated to about 100 mL under reduced pressure, and the concentrated solution was placed in 500 mL of toluene, followed by removing deposited solid matters. The solvent was distilled off from the resulting solution under reduced pressure, and the residue was purified by silica gel column chromatography to provide 4.9 g of 1-ethoxy-2,3-difluoro-4-[4-(2-methoxyvinyl)-cyclohexyl]benzene.
Reaction SMILES: C([Li])CCC.CN(C)CCN(C)C.[CH2:14]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([P:35](Cl)(Cl)=[O:36])=[CH:31][CH:30]=1>CCCCCC.C(OCC)C.C1CCCCC1>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([P:35]2(=[O:36])[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:31][CH:30]=1
Reactant: O=P(Cl)(Cl)c1ccc(Cl)cc1
Reactant: c1ccc(CNc2ccccc2)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCCCC1
Solvent: CCCCCC
Product: O=P1(c2ccc(Cl)cc2)c2ccccc2CN1c1ccccc1
Temperature: 26 °C
Reaction time: 2 h
Yield: 9.8 %

Procedure:
Under a static nitrogen atmosphere at 0° C., a solution of n-butyllithium (4.03 g, 0.063 mol) in hexane was added to a solution of tetramethylethylenediamine (1.86 g, 0.016 mol) in 30 ml. of anhydrous cyclohexane with constant stirring. While maintaining the temperature of the reaction at 0° C., a solution of N-benzylaniline (5.5 g, 0.03 mol) in 30 ml. of anhydrous cyclohexane was added to the reaction mixture to produce a suspension containing a dilithio compound. The suspension was stirred for 2 hours at 26° C. and then cooled to 0° C. A solution of 4-chlorophenylphosphonic dichloride (7.35 g, 0.032 mol) in 30 ml. of anhydrous cyclohexane was rapidly added to the suspension. After stirring for 15 minutes at 0° C., the resulting mixture was stirred for 2 hours at 26° C. The reaction mixture was cooled to 0° C., then quenched with the rapid addition of 6 ml. of acetic acid. After stirring for 15 minutes, the cyclohexane was removed on a rotary evaporator and the resulting residue was partitioned between methylene chloride and water. The layers were separated and the methylene chloride layer was washed with 5% hydrochloric acid, then water, dried with sodium sulfate and concentrated in vacuo to yield a blue oil. The blue oil was separated on a silica gel column using first methylene chloride then a 3:1 mixture of methylene chloride:ethyl acetate as the eluant. Fractions containing the benzazaphosphole were combined and concentrated in vacuo to yield a crude product. The crude product was slurried in anhydrous diethyl ether to yield 1-(4-chlorophenyl)-2-phenyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (1.0 g, 5% yield) as a white crystalline solid having a melting point of 180°-182° C. and the following analysis:
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]2[CH:6]=[C:7]([C:9]([OH:11])=O)[S:8][C:4]=2[CH:3]=1.[ClH:14].Cl.[NH2:16][C@@H:17]1[CH:22]2[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]2)[CH2:18]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[ClH:14].[N:19]12[CH2:24][CH2:23][CH:22]([CH2:21][CH2:20]1)[C@@H:17]([NH:16][C:9]([C:7]1[S:8][C:4]3[CH:3]=[C:2]([Br:1])[CH:13]=[CH:12][C:5]=3[CH:6]=1)=[O:11])[CH2:18]2
Reactant: O=C(O)c1cc2ccc(Br)cc2s1
Reactant: N[C@H]1CN2CCC1CC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2ccc(Br)cc2s1

Procedure:
900.0 mg (3.50 mmol) of 6-bromo-1-benzothiophene-2-carboxylic acid (Example 10A), 697.0 mg (3.50 mmol) of (R)-3-aminoquinuclidine dihydrochloride, 1597.1 mg (4.20 mmol) of HATU, 1628.7 mg (12.60 mmol) of N,N-diisopropylethylamine and 8.0 ml of DMF are reacted by general method C. The reaction mixture is purified by preparative HPLC. The product is dissolved in a 1:1 mixture of 4 M hydrogen chloride in dioxane and 1N hydrochloric acid, and the solution is then concentrated. Recrystallization from methanol/ethanol (1:10) affords 594 mg (42% of theory) of the title compound in the form of yellowish-brown crystals.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH2:7][CH2:8][N:9](C(OC(C)(C)C)=O)[C:10](=[O:11])[C:5]2=[N:4][N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[N:6]2[CH2:7][CH2:8][NH:9][C:10](=[O:11])[C:5]2=[N:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCn2c(Br)nnc2C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCCn2c(Br)nnc21
Reaction time: 0.5 h
Yield: 86.2 %

Procedure:
To a solution of tert-butyl 3-bromo-8-oxo-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate (663 mg, 2.1 mmol) in DCM (21 mL) was added TFA (4.2 mL, 55 mmol). After 30 minutes, the reaction was concentrated and the residue was diluted with EtOAc, sonicated, and filtered to provide the desired product as a white solid (393 mg, 87%). MS (ESI): mass calcd. for C5H5BrN4O, 216.0; m/z found, 217.0 [M+H]+.
Reaction SMILES: [O:1]=[S:2]1(=[O:27])[CH:7]=[CH:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19]NC(=O)C(F)F)[O:16][C:15]3=[O:26])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[F:28][CH:29]([F:48])[C:30](OCCC(C1C=CC=CC=1)C1C=CC=CC=1)=[S:31].C([N:51](CC)CC)C>CO>[O:1]=[S:2]1(=[O:27])[CH:7]=[CH:6][CH:5]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][C:29]([F:48])([F:28])[C:30](=[S:31])[NH2:51])[O:16][C:15]3=[O:26])=[CH:12][CH:13]=2)[CH2:4][CH2:3]1
Reactant: O=C(NC[C@H]1CN(c2ccc(C3C=CS(=O)(=O)CC3)cc2)C(=O)O1)C(F)F
Reactant: FC(F)C(=S)OCCC(c1ccccc1)c1ccccc1
Reactant: CCN(CC)CC
Solvent: CO
Product: NC(=S)C(F)(F)C[C@H]1CN(c2ccc(C3C=CS(=O)(=O)CC3)cc2)C(=O)O1
Yield: 70 %

Procedure:
The crude amine hydrochloride prepared in Step 1 of Example 15 (0.350 g, 0.975 mmol), the product of step 2 immediately above (0.358 g, 1.17 mmol), and triethylamine (0.27 ml, 1.95 mmol) in methanol are stirred at room temperature overnight. The reaction mixture is evaporated to dryness and the residue purified by PTLC (10% methanol/dichloromethane) to give the title compound as white solid (0.29 g, 70%). M.p. 139-40° C.
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]1[CH2:14][N:13]([C:15]([O:17]C(C)(C)C)=O)[C@H:12]([C:22]([OH:24])=O)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([C:27]1[CH:35]=[CH:34][C:30](C(Cl)=O)=[CH:29][CH:28]=1)#[N:26].[N:36]1[S:37][N:38]=[C:39]2[C:44]([NH2:45])=[CH:43][CH:42]=[CH:41][C:40]=12>>[N:36]1[S:37][N:38]=[C:39]2[C:44]([NH:45][C:22]([C@@H:12]3[CH2:11][C:10](=[N:9][O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:14][N:13]3[C:15](=[O:17])[C:30]3[CH:29]=[CH:28][C:27]([C:25]#[N:26])=[CH:35][CH:34]=3)=[O:24])=[CH:43][CH:42]=[CH:41][C:40]=12
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: Nc1cccc2nsnc12
Reactant: CC(C)(C)OC(=O)N1CC(=NOCc2ccccc2)C[C@H]1C(=O)O
Product: N#Cc1ccc(C(=O)N2CC(=NOCc3ccccc3)C[C@H]2C(=O)Nc2cccc3nsnc23)cc1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid, 4-cyanobenzoyl chloride, and 2,1,3-benzothiadiazol-4-amine the title compound was obtained in 55% purity by LC/MS. MS(ESI+): m/z=497.4.
Reaction SMILES: CCCCCC.[C:7]([C:10]1[CH:14]=[CH:13][S:12][CH:11]=1)(=[O:9])[CH3:8].C(OCC)(=[O:17])C>>[S:12]1[CH:13]=[CH:14][C:10]([C:7]([CH:8]=[O:17])=[O:9])=[CH:11]1
Reactant: CC(=O)c1ccsc1
Reactant: CCOC(C)=O
Solvent: CCCCCC
Product: O=CC(=O)c1ccsc1

Procedure:
3-Acetylthiophene (20.0 g., 0.159 mol) and SeO2 (19.4 g., 0.175 mol) were dissolved 100 ml. dioxane and 8 ml. H2O by warming to 35°, then heated at reflux 16 hours. The reaction mixture was cooled, filtered and the filtrate stripped to a sludge (the hydrate of title product in crude form). The latter was distilled at reduced pressure to yield title product contaminated with about 10% starting material, 8.53 g.; tlc (5:3 hexane:ethyl acetate) Rf 0.27 (title product) and 0.59 (3-acetylthiophene). The latter was chromatographed on silica gel with 5:3 hexane:ethyl acetate as eluant. Clean product fractions were combined stripped to a solid, triturated with hexane, filtered and the solids (5.60 g.) sublimed to yield purified title product, 3.20 g.; tlc Rf 0.27 as above; sublimation point 70°/1 mm; ms: parent 141, base 111.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[O:13][CH3:14])=[O:4].[CH3:15][NH:16][CH3:17]>C1(C)C=CC=CC=1>[CH3:14][O:13][C:6]1[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:5]=1[C:3](=[O:4])[CH2:2][N:16]([CH3:17])[CH3:15]
Reactant: COc1ccc(OC)c(C(=O)CBr)c1
Reactant: CNC
Solvent: Cc1ccccc1
Product: COc1ccc(OC)c(C(=O)CN(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-bromo-1-(2,5-dimethoxyphenyl)-ethanone (10.0 g) is added dropwise to a solution of dimethylamine (6.1 g) in toluene (450 ml). The mixture is stirred overnight at room temperature and extracted with a 1-N water solution of hydrochloric acid (3×250 ml). The mixed aqueous phases are alcalinized with a 25% water solution of sodium hydroxide (200 ml) and extracted with dichloromethane (4×250 ml). The mixed organic phases are washed with water (3×200 ml) and dried over magnesium sulphate. The solvent is distilled in vacuo and the residue is dried in vacuo to constant weight to give 1-(2,5-dimethoxyphenyl)-2-dimethylamino-ethanone which is a liquid, b.p. 250°-255°.
Reaction SMILES: ClCC([O:5][C:6]1[CH:14]=[CH:13][C:12]2[N:11]([CH3:15])[C:10]3[C:16](=O)[CH2:17][CH2:18][C:9]=3[C:8]=2[CH:7]=1)=O.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1>[CH3:15][N:11]1[C:12]2[CH:13]=[CH:14][C:6]([OH:5])=[CH:7][C:8]=2[C:9]2[CH2:18][CH2:17][C:16](=[N:27][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:10]1=2
Reactant: NCc1ccccc1
Reactant: Cn1c2c(c3cc(OC(=O)CCl)ccc31)CCC2=O
Solvent: Cc1ccccc1
Product: Cn1c2c(c3cc(O)ccc31)CCC2=NCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 17.5 %

Procedure:
To a stirred suspension of 7-chloroacetyloxy-1,4-dihydro-4-methycyclopent[b]-indol-3(2H)-one (6.0 g) in toluene (50 ml) was added benzylamine (9.2 g) and the mixture was heated at reflux temperature with azeotropic removal of water using a Dean Stark trap. After 4 hours, TLC analysis indicated complete conversion to product. The mixture was allowed to cool to room temperature and filtered, and the solid material was washed with acetonitrile. The filtrate and washings were combined, concentrated and purified by flash chromatography on silica gel (2:1 hexane/acetone as eluent). The crystals which formed in the product-containing fractions were collected via filtration to give 4-methyl-3-phenylmethylimino-1,2,3,4-tetrahydrocyclopent[b]indol-7-ol (1.1 grams) and the filtrate was concentrated to give an oil (3.0 grams) which crystallized upon standing.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([NH:13][C:14](SC)=[C:15]([S:18]([CH3:21])(=[O:20])=[O:19])[C:16]#[N:17])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:26][CH:27]([NH2:32])[C:28]([CH3:31])([CH3:30])[CH3:29]>>[F:1][C:2]([F:24])([F:25])[C:3]1[CH:4]=[C:5]([NH:13][C:14]([NH:32][CH:27]([CH3:26])[C:28]([CH3:31])([CH3:30])[CH3:29])=[C:15]([S:18]([CH3:21])(=[O:20])=[O:19])[C:16]#[N:17])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: CSC(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=C(C#N)S(C)(=O)=O
Reactant: CC(N)C(C)(C)C
Product: CC(NC(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=C(C#N)S(C)(=O)=O)C(C)(C)C
Yield: 57 %

Procedure:
3-(3,5-Bis(trifluoromethyl)phenylamino)-2-methylsulfonyl-3-methylsulfanyl-2-propenenitrile (0.225 g, 0.56 mmol) was stirred in 1,2,2-trimethylpropylamine (1 ml) for 22 h at 100° C. under nitrogen in a sealed flask. The reaction mixture was concentrated and the residue dissolved in DCM, washed twice with 1N aqueous HCl and once with water. The organic phase was dried (sodium sulfate) and concentrated. The residue was crystallised from ethyl acetate/heptane 1:4 to give 146 mg (57%) of the title compound. Mp 184.5-188.5° C. 1H NMR (200 MHz, CDCl3): δ=0.9 (s, 9H), 1.03 (d, 3H), 3.0 (m, 1H), 7.52 (s, 2H), 7.68 (s, 1H); EI SP/MS: 457 (M+).