Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[N:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[CH2:20]([NH2:25])[CH2:21][CH:22]([CH3:24])[CH3:23].[BH4-].[Na+]>CO>[F:1][C:2]1[CH:17]=[C:16]([CH2:18][NH:25][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[N:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1
Reactant: CC(C)CCN
Reactant: NC(=O)c1cnc(Oc2ccc(C=O)cc2F)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CCNCc1ccc(Oc2cnc(C(N)=O)cn2)c(F)c1
Reaction time: 8 h
Yield: 44.2 %

Procedure:
Place 5-(2-fluoro-4-formylphenoxy)pyrazine-2-carboxamide (Example 737, Part E) (0.400 g, 1.53 mmol), isoamylamine (0.147 g, 1.68 mmol) and 3 Å molecular sieves in a vial. Add methanol (7.7 mL), cap and stir overnight. Add NaBH4 (0.058 g, 1.53 mmol) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 0% to 15% (2.0 M NH3 in methanol) in 80% (ethyl acetate in hexanes) to give the title compound (0.225 g, 50%): TOF MS ES+ 333.2 (M+H)+, HRMS calcd for C17H22N4O2F 333.1727 (M+H)+, found 333.1714, time 0.55 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=10.1 min, 100% purity.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]=1[CH3:25].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]=2[CH3:25])=[CH:6][N:7]=1
Reactant: Oc1ccc(Cl)nc1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])ccc1Oc1ccc(Cl)nc1
Temperature: 50 °C

Procedure:
To a suspension of 6-chloropyridin-3-ol (3.37 g, 26.0 mmol) and K2CO3 (7.19 g, 52.0 mmol) in DMF (200 mL) was added 1-fluoro-2-methyl-4-nitrobenzene (4.44 g, 28.6 mmol). After heating to 50° C. for 16 hours, the reaction mixture was cooled to room temperature and poured into water and extracted with ethyl acetate (2×). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to provide the product as yellow oil.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>N1C=CC=CC=1>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2]
Reactant: C1COCCN1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCOCC3)c(F)c21
Yield: 52.2 %

Procedure:
A mixture of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.43 g), morpholine (1.4 g), and pyridine (3 ml) was refluxed for 6 hours. After the mixture evaporated to dryness, the residue was acidified with aqueous acetic acid and extracted with dichloromethane. The organic layer was washed with water, dried, and evaporated. The solid was recrystallized from a mixture of DMF and ethanol and gave 1-ethyl-6,8-difluoro-1,4-dihydro-7-(4-morpholinyl)-4-oxoquinoline-3-carboxylic acid (0.28 g), mp 268°-271° C. (decomp.).
Reaction SMILES: C[Si](C)(C)[NH:3][Si](C)(C)C.[Li]CCCC.[F:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1.Cl>CCOCC>[F:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]([NH2:3])=[NH:21])=[CH:18][CH:17]=1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: N#Cc1ccc(F)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: N=C(N)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To an ice-cold solution of hexamethyldisilazane (7 ml) in Et2O (40 ml) was added n-BuLi (1.6M in hexanes, 20.6 ml), followed by a solution of 4-fluorobenzonitrile (2 g) in Et2O (10 ml). After stirring at 0° C. for 10 min, the mixture was allowed to warm to RT and was stirred at RT for 20 h. The mixture was acidified to pH 1 by adding a 1M HCl solution and was washed with CHCl3. The aqueous layer was then basified to pH 14 by adding Na2CO3 and NaOH and was extracted twice with CHCl3. The org. layers were dried (Na2SO4) and evaporated off to afford the desired compound (1.59 g).
Reaction SMILES: [CH:1]([O:3][CH2:4][CH3:5])=[CH2:2].N1C=CC=CC=1.[F:12][C:13]([F:18])([F:17])[C:14](Cl)=[O:15]>C(Cl)Cl>[CH2:1]([O:3][CH:4]=[CH:5][C:14](=[O:15])[C:13]([F:18])([F:17])[F:12])[CH3:2]
Reactant: O=C(Cl)C(F)(F)F
Reactant: C=COCC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC=CC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
In 150 ml of methylene chloride, 21 ml (0.22 mol) of ethyl vinyl ether and 26.1 g (0.33 mol) of pyridine were dissolved, and 43.8 g (0.33 mol) of trifluoroacetyl chloride was blown into this solution over a period of 30 minutes at room temperature. The mixture was further stirred at room temperature for 2.5 hours. Then, the reaction solution was extracted by an addition of 100 ml of methylene chloride and 100 ml of ice water.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]([F:34])[CH:25]=2)=[N:4][C:5]([C:8]2[CH2:13][CH2:12][C:11](=[O:14])[N:10](CC3C=CC(OC)=CC=3)[CH:9]=2)=[CH:6][N:7]=1>CO.[Pd]>[NH2:1][C:2]1[C:3]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]([F:34])[CH:25]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[NH:10][CH2:9]2)=[CH:6][N:7]=1
Reactant: COC(=O)c1ccc(-c2nc(C3=CN(Cc4ccc(OC)cc4)C(=O)CC3)cnc2N)cc1F
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(-c2nc(C3CCC(=O)NC3)cnc2N)cc1F
Reaction time: 8 h

Procedure:
Methyl 4-(3-amino-6-(1-(4-methoxybenzyl)-6-oxo-1,4,5,6-tetrahydropyridin-3-yl)pyrazin-2-yl)-2-fluorobenzoate (361 mg, 0.781 mmol) was dissolved in MeOH (Volume: 7 mL) and then Pd—C (400 mg, 3.76 mmol) was added. The mixture was evacuated and purged with hydrogen thrice and finally, the mixture was agitated under 1 atm of hydrogen overnight. The next morning, desired product along with over-reduced amino-pyrazine was obtained. The mixture was filter over celite and the filtrate concentrated in vacuo and the residue dissolved in DCM and agitated under air for 1 day and then concentrated and purified by flash chromatography (0-50% DCM/EtOAc) to afford 144 mg the desired product as a yellow solid. LCMS (m/z): (MH+), 465.1, 0.81 min.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:24]=[CH:23][C:18]([CH:19]=[CH:20][CH:21]=O)=[CH:17][C:16]=1[O:25][CH2:26][CH2:27][CH3:28].[O:29]1[CH2:33][C:32](=[O:34])[NH:31][C:30]1=[O:35]>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:24]=[CH:23][C:18]([CH2:19][CH2:20][CH2:21][CH:33]2[O:29][C:30](=[O:35])[NH:31][C:32]2=[O:34])=[CH:17][C:16]=1[O:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCOc1cc(C=CC=O)ccc1OCc1nc(-c2ccccc2)oc1C
Reactant: O=C1COC(=O)N1
Product: CCCOc1cc(CCCC2OC(=O)NC2=O)ccc1OCc1nc(-c2ccccc2)oc1C

Procedure:
In substantially the same manner as in Working Example 11, 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-propoxycinnamaldehyde was condensed with 2,4-oxazolidinedione. The condensate was subjected to catalytic hydrogenation to yield 5-[3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-propoxyphenyl]propyl]-2,4-oxazolidinedione, which was recrystallized from ethyl acetate-ether to give colorless needles, m.p.119-120° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1I)[C:5]([O:7][CH3:8])=[O:6].C([O-])([O-])=O.[K+].[K+].CC1(C)COB([C:26]2[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=2)OC1>O1CCOCC1.O.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>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:26]1[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: Cn1nccc1B1OCC(C)(C)CO1
Reactant: COC(=O)c1ccc(I)c(Br)c1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2ccnn2C)c(Br)c1
Temperature: 80 °C

Procedure:
To a solution of methyl 3-bromo-4-iodobenzoate (409 mg, 1.2 mmol) in dioxane/H2O (4:1, 10 mL) was added K2CO3 (497 mg, 3.6 mmol), tetrakistriphenylphosphine Pd(0) (69 mg, 0.06 mmol) and 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole (349 mg, 3.6 mmol). The reaction mixture was heated to 80° C. in a sealed tube for 12 h and was then partitioned between 6N NaOH and DCM. The pH of the aqueous phase was adjusted to ˜3 with 3M HCl and washed several times with DCM. The combined organic fractions were dried (Na2SO4), concentrated under vacuum and used directly without further purification (307 mg, 87%): LC-MS (ES) m/z=296 (M+H)+.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:7]=C[C:9]=1[N:10]1[C:14]2=[N:15][CH:16]=[CH:17][C:18]([I:19])=[C:13]2[C:12]([C:20]([F:23])([F:22])[F:21])=[N:11]1)[C:5]#[N:6].IC.[H-].[Na+].C(OCC)(=O)C.[CH3:34][N:35]([CH:37]=O)[CH3:36]>O>[CH3:34][N:35]([CH3:36])[C:37]1[CH:7]=[C:4]([CH:3]=[CH:2][C:9]=1[N:10]1[C:14]2=[N:15][CH:16]=[CH:17][C:18]([I:19])=[C:13]2[C:12]([C:20]([F:23])([F:21])[F:22])=[N:11]1)[C:5]#[N:6]
Reactant: CN(C)C=O
Reactant: N#Cc1ccc(-n2nc(C(F)(F)F)c3c(I)ccnc32)c(N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CI
Product: CN(C)c1cc(C#N)ccc1-n1nc(C(F)(F)F)c2c(I)ccnc21
Reaction time: 1 h

Procedure:
Compound (158a) (0.100 g) and iodomethane (0.18 mL) were dissolved in DMF (6.0 mL), and sodium hydride (0.038 g, a 55% dispersion in paraffin liquid) was added to the resulting solution under ice cooling, followed by stirring for 1 hr. The reaction solution was distributed between ethyl acetate and water, and the organic layer was washed with saturated saline. The organic layer after the washing was dried over anhydrous sodium sulfate, and then the solvent was distilled away to obtain 3-(dimethylamino)-4-{4-iodo-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzonitrile, which was used in the subsequent reaction without being purified. This 3-(dimethylamino)-4-{4-iodo-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzonitrile was dissolved in DMSO (3.0 mL), and a hydrogen peroxide solution (30 wt %) (0.060 mL) and a 4 mol % aqueous sodium hydroxide solution (0.15 mL) were added to the resulting solution, followed by stirring at room temperature for 20 min. Water was added to the reaction solution, and the precipitate was collected by filtration and dried under reduced pressure to obtain 3-(dimethylamino)-4-{4-iodo-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide. Lastly, according to Example 99(2), compound (159) (0.025 g, the third stage yield: 17%) was prepared using 3-(dimethylamino)-4-{4-iodo-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide instead of compound (99a).
Reaction SMILES: [OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([O:49][CH3:50])=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][C@@H:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44].C(=O)([O-])[O-].[K+].[K+].[CH2:57](Br)[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1>>[CH2:57]([O:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([O:49][CH3:50])=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][C@@H:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44])[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1
Reactant: COC(=O)c1c(C)cc2c(c1O)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)C(=O)C=C(N[C@H]1O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]1OC)C4=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1c(C)cc2c(c1OCc1ccccc1)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)C(=O)C=C(N[C@H]1O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]1OC)C4=O
Yield: 45.7 %

Procedure:
Following General Procedure: Method A using (6R,6aS,14aR)-methyl 1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (35 mg, 0.050 mmol), potassium carbonate (21 mg, 0.15 mmol) and benzyl bromide (18 μL, 0.15 mmol), the product was purified by preparative TLC (silica gel, 95:5 dichloromethane/methanol) to afford (6R,6aS,14aR)-methyl 1-(benzyloxy)-6,8,14a-trihydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (18 mg, 45%) as a brown solid: 1H NMR (500 MHz, CDCl3) δ 14.17 (s, 1H), 7.82 (s, 1H), 7.46-7.44 (m, 2H), 7.40-7.38 (m, 1H), 7.34-7.32 (m, 2H), 6.85 (s, 1H), 6.81 (d, J=8.6 Hz, 1H), 5.86 (s, 1H), 5.07 (br s, 1H), 4.98-4.94 (m, 1H), 4.93 (d, J=11.3 Hz, 1H), 4.82 (d, J=11.3 Hz, 1H), 4.68 (d, J=8.8 Hz, 1H), 4.54 (d, J=10.5 Hz, 1H), 3.82 (s, 3H), 3.74-3.72 (m, 2H), 3.65-3.62 (m, 1H), 3.60 (s, 3H), 3.54 (s, 3H), 3.51-3.38 (m, 1H), 3.39 (s, 3H), 3.36-3.32 (m, 1H), 3.13 (t, J=9.0 Hz, 1H), 2.48 (d, J=4.1 Hz, 1H), 2.19 (s, 3H), 1.36 (d, J=6.2 Hz, 3H); MS (ESI+) m/z 788 (M+H); HPLC 95.4% (AUC), tR 14.56 min.
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].C(N(CC)CC)C.CS(ON=C(C#N)C(OCC)=O)(=O)=O.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(OCC)(=O)C>[C:1]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:4])[CH3:2]
Reactant: Nc1ccccc1
Reactant: CC(=O)O
Agent: CCOC(=O)C(C#N)=NOS(C)(=O)=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccccc1
Reaction time: 0.67 h
Yield: 88.9 %

Procedure:
Acetic acid (0.3 g) and triethylamine (0.7 ml) are dissolved in ethyl acetate (10 ml), and thereto is added ethyl 2-methanesulfonyloxyimino-2-cyanoacetate (1.1 g) and the mixture is stirred for 40 minutes. To the solution is added aniline (0.5 g) and the mixture is stirred for 2 hours. The reaction mixture is washed well with 1 N aqueous sodium hydrogen carbonate, water and 1 N hydrochloric acid in order and then dried over anhydrous magnesium sulfate. After drying, the solvent is distilled off to give flasks of acetanilide (0.6 g), melting poit: 95°-105° C. The product recrystallized from water has a melting point of 104°-108° C.
Reaction SMILES: [Br:1][CH:2]=[C:3]1[CH2:11][CH2:10][CH2:9][C@@:8]2([CH3:12])[CH:4]1[CH2:5][CH2:6][C@@H:7]2[C@H:13]([CH3:17])[CH2:14][C:15]#N.ClCCl.S([O-])([O-])(=O)=[O:22].[Na+].[Na+].Cl>C(OCC)(=O)C.CO.C1(C)C=CC=CC=1>[Br:1][CH:2]=[C:3]1[CH2:11][CH2:10][CH2:9][C@@:8]2([CH3:12])[CH:4]1[CH2:5][CH2:6][C@@H:7]2[C@H:13]([CH3:17])[CH2:14][CH2:15][OH:22]
Reactant: O=S(=O)([O-])[O-]
Reactant: C[C@H](CC#N)[C@H]1CCC2C(=CBr)CCC[C@@]21C
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C[C@H](CCO)[C@H]1CCC2C(=CBr)CCC[C@@]21C
Temperature: -70 °C
Reaction time: 1 h

Procedure:
A 84 mg amount of (3R)-3-[(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl]butyronitrile was taken in a 25 ml eggplant-shaped flask, then 5 ml of dried dichloromethane was then added to dissolve the same. The solution was cooled by a -70° C. bath, then 660 μl of a 1.5 M [(CH3)2CHCH2 ]2AlH/toluene solution was added dropwise. The solution was stirred at the same temperature for 1 hour, then 0.5 ml of a saturated aqueous solution of sodium sulfate, 0.3 ml of methanol, 0.5 ml of 2 N hydrochloric acid, and 15 ml of ethyl acetate were added and the solution stirred for 30 minutes. The reaction solution was filtered by Celite, then was washed by a saturated solution of ammonium chloride and saturated saline, then was dried over anhydrous magnesium sulfate and the desiccant filtered out. The solvent was distilled off under reduced pressure to obtain (3R)-3-[(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl]butanol in an amount of 85 mg.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:16]O>>[CH3:16][O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([F:11])[CH:10]=[C:2]([NH2:1])[CH:3]=1
Reactant: Nc1cc(F)cc(C(=O)O)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(N)cc(F)c1
Temperature: 25 °C

Procedure:
To a stirred solution of 3-amino-5-fluoro-benzoic acid (25 g, 161 mmol) in methanol (300 mL) was added thionyl chloride (30 mL, 403 mmol) dropwise at 0° C. Then the mixture solution was refluxed for 12 hours before cooling to room temperature. Then the reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (500 mL), washed with saturated aqueous sodium bicarbonate solution (3×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford 3-amino-5-fluoro-benzoic acid methyl ester (27.5 g, quant.) as a pale-white solid: LC/MS m/e calcd for C8H8FNO2 (M+H)+: 170.16, observed: 169.9.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[C:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17][C:18](=O)[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)([CH3:10])([CH3:9])[CH3:8]>C1C=CC=CC=1>[C:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]=[C:18]([Cl:2])[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: Cc1ccc(C(=O)Nc2ccccc2C(C)(C)C)cc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: Cc1ccc(C(Cl)=Nc2ccccc2C(C)(C)C)cc1
Yield: 95.9 %

Procedure:
Phosphorus pentachloride (6.88 g, 33 mmol) was dissolved in 50 mL of benzene. Under a gentle argon purge, N-(2-tert-butylphenyl)-4-methylbenzamide (Amide II) (8.02 g, 30 mmol) was added slowly with stiffing at room temperature. The yellow solution was refluxed for 2 hours. Benzene was removed in vacuo, yielding a yellow solid (8.22 g, 96%). 1H NMR (400 MHz, C6D6): 8.17 (d, 2H), 7.38 (d, 1H), 7.11 (t, 1H), 7.06 (t, 1H), 6.90 (d, 2H), 6.85 (d, 1H), 1.98 (s, 3H), 1.42 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH2:4][C:5](=[O:7])[N:6]=1.[CH:8]([C:10]1[CH:28]=[CH:27][C:13]([O:14][C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=2[C:23]([F:26])([F:25])[F:24])=[C:12]([O:29][CH3:30])[CH:11]=1)=O>>[NH2:1][C:2]1[S:3][C:4](=[CH:8][C:10]2[CH:28]=[CH:27][C:13]([O:14][C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=3[C:23]([F:24])([F:25])[F:26])=[C:12]([O:29][CH3:30])[CH:11]=2)[C:5](=[O:7])[N:6]=1
Reactant: NC1=NC(=O)CS1
Reactant: COc1cc(C=O)ccc1Oc1ccc(C#N)cc1C(F)(F)F
Product: COc1cc(C=C2SC(N)=NC2=O)ccc1Oc1ccc(C#N)cc1C(F)(F)F

Procedure:
4-[4-(2-Amino-4-oxo-4H-thiazol-5-ylidenemethyl)-2-methoxy-phenoxy]-3-trifluoromethyl-benzonitrile was prepared using 2-amino-thiazol-4-one and 4-(4-Formyl-2-methoxy-phenoxy)-3-trifluoromethyl-benzonitrile according to General Procedure B. 1H NMR (400 Hz, DMSO-d6) δ 8.96 (bs, NH), 8.74 (bs, NH), 8.32 (d, 1H), 7.99 (dd, 1H), 7.65 (d, 1H), 7.47 (d, 1H), 7.36 (d, 1H), 7.24 (d, 1H), 6.89 (d, 1H), 3.88 (s, 3H); LC/MS (m/z) [M+1]+420.0 (C19H13F3N3O3S, 420.38).
Reaction SMILES: [C:1]([CH:3]([NH:13][C:14](=O)[CH:15]([CH3:17])[CH3:16])[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)#[N:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:39]>C(#N)C>[Cl:39][C:1]1[N:2]=[C:14]([CH:15]([CH3:17])[CH3:16])[NH:13][C:3]=1[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)C(=O)NC(C#N)COCc1ccccc1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CC(C)c1nc(Cl)c(COCc2ccccc2)[nH]1
Reaction time: 0.17 h
Yield: 41.3 %

Procedure:
A solution of N-{1-cyano-2-[(phenylmethyl)oxy]ethyl}-2-methylpropanamide (1.60 g, 6.5 mmol), triphenylphosphine (4.2 g, 16.0 mmol), and carbon tetrachloride (1.6 mL, 16.6 mmol) in acetonitrile (65 mL) was heated at 45° C. for 4.5 h. The reaction was concentrated and the residue was stirred in CH2Cl2 (70 mL) and 0.5 N NaOH (60 mL) for 10 min. The organic layer was isolated, dried (Na2SO4), filtered, concentrated and the residue was purified by silica gel flash column chromatography (5-50% EtOAc:hexanes) to give the title compound (0.710 g, 41%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 10.69 (br. s., 1H), 7.28-7.36 (m, 5H), 4.51 (s, 2H), 4.48 (s, 2 H), 2.92 (sept, 1H), 1.24 (d, 6H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)(=[O:23])=[O:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:31]>ClCCl.FC(F)(F)C(O)=O.C(OC(=O)C)C.O1CCOCC1>[ClH:31].[F:30][C:27]1[CH:26]=[CH:25][C:24]([S:21]([C:18]2[CH:19]=[CH:20][C:15]([NH:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:16][CH:17]=2)(=[O:23])=[O:22])=[CH:29][CH:28]=1.[ClH:31]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(S(=O)(=O)c3ccc(F)cc3)cc2)CC1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=S(=O)(c1ccc(F)cc1)c1ccc(NC2CCNCC2)cc1
Temperature: 25 °C

Procedure:
4-[4-(4-Fluoro-benzenesulfonyl)-phenylamino]-piperidine-1-carboxylic acid tert-butyl ester (640 mg; 1.47 mmol, prepared in accordance with Example 31) is dissolved in a 1 to 1 mixture of dichloromethane and trifluoroacetic acid (2 mL) and the resulting solution is stirred at room temperature until complete conversion is observed (about 90 minutes). After concentration under reduced pressure, the residue obtained is co-evaporated with dichloromethane (2×10 mL). The crude residue is then diluted in ethylacetate (2 mL) and a 4N solution of hydrochloric acid in dioxane (3 mL) is added under stiffing. The solid formed is filtered and dried under high vacuum to afford the desired product as hydrochloride (546 mg; 1.47 mmol).
Reaction SMILES: C1(S([CH2:10][C:11]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[NH:13][N:12]=2)(=O)=O)C=CC=CC=1.[CH3:23][O:24][C:25]1[N:30]=[CH:29][C:28](/[CH:31]=[CH:32]\[C:33]#[N:34])=[CH:27][CH:26]=1>>[F:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:14]1[N:15]=[C:11]2[CH:10]=[C:31]([C:28]3[CH:29]=[N:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=3)[CH:32]=[C:33]([NH2:34])[N:12]2[N:13]=1
Reactant: O=S(=O)(Cc1n[nH]c(-c2ccccc2F)n1)c1ccccc1
Reactant: COc1ccc(/C=C\C#N)cn1
Product: COc1ccc(-c2cc(N)n3nc(-c4ccccc4F)nc3c2)cn1

Procedure:
The title compound, MS m/e (%):336(M+H+,100), was prepared in accordance with the general method of example 1 from 3-benzenesulfonylmethyl-5-(2-fluoro-phenyl)-1H-[1,2,4]triazole and (E)/(Z)-3-(6-methoxy-pyridin-3-yl)-acrylonitrile.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:13]([CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])[C:12]2[CH:22]=[CH:23][C:24]([N+:26]([O-:28])=[O:27])=[CH:25][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O.ClCCl>[CH2:1]([S:8][C:9]1[N:13]([CH2:14][C:15]([OH:17])=[O:16])[C:12]2[CH:22]=[CH:23][C:24]([N+:26]([O-:28])=[O:27])=[CH:25][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)Cn1c(SCc2ccccc2)nc2cc([N+](=O)[O-])ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)Cn1c(SCc2ccccc2)nc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.6 %

Procedure:
tert-Butyl (2-benzylsulfanyl-5-nitro-benzoimidazol-1-yl)-acetate (Precursor 5-NO2-C-02b, 20 mg, 0.05 mmol) is dissolved in TFA/dichloromethane (1:1, 0.5 ml) and stirred for 2 h at rt. The solvents are evaporated under a stream of air and Et2O (1 ml) is added to the crude mixture. The solid obtained is filtered, rinsed twice with Et2O and dried under high vacuum yielding the title compound (10.4 mg) in 60% as a slightly yellow solid: tR=6.30 min (LC-1), ESI-MS (pos.): m/z 344.23 [M+H]+, ESI-MS (neg.): m/z 342.34 [M−H]+; 1H-NMR (DMSO-d6): δ (ppm) 4.66 (s, 2H, SCH2), 5.07 (s, 2H, CH2CO2), 7.23-7.33 (m, 3Harom), 7.46 (dd, 2Harom), 7.74 (d, 1Harom), 8.13 (dd, 1 Harom), 8.44 (d, 1Harom).