Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[S:9]([CH2:12][C:13](=[O:15])[CH3:14])(=[O:11])=[O:10])=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:33]NS(C1C=CC=CC=1)(=O)=O>C1COCC1.O>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[S:9]([CH:12]([F:33])[C:13](=[O:15])[CH3:14])(=[O:10])=[O:11])=[CH:21][CH:20]=1
Reactant: O=S(=O)(NF)c1ccccc1
Reactant: CC(=O)CS(=O)(=O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)C(F)S(=O)(=O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reaction time: 0.5 h

Procedure:
To a stirring solution of the methyl ketone (Example 1, 0.6 g, 1.7 mmol) in dry THF (11 mL) at 0° C., under dry nitrogen was added LiHMDS (1.0 M/THF, 2.2 mL, 1.2 mmol) and the mixture stirred for 30 minutes without warming. After this time, the resulting enolate was lowered to −78° C., whereupon a solution of N-fluorobenzenesulfonamide (0.85 g, 2.7 mmol) in dry THF (5.0 mL) was added via canula. The reaction was then stirred for 30 minutes and then at room temperature for 1 hour, and was then diluted with water and extracted with ethyl acetate. The organic layers were combined, dried on Na2SO4, and filtered to give a mixture that was purified on SiO2 with 15%–20% EtOAcHexane to give (0.075 g, the fluorinated species as a colorless oil. Anal. Calcd for C16H13Cl2F1O3S1: 0.15H2O: Calcd C, 50.85; H, 3.55; Cl, 18.76; F, 5.03; O, 13.33; S, 8.48. Found: C, 50.45; H, 3.51; S, 8.15. 1H NMR (CDCl3, 400 MHz): δ 2.1 (s, 3H), 5.2 (d, 1H, J=49.0 Hz), 5.65 (s, 1H), 7.28–7.5 (m, 4H), 7.5–7.7 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([OH:11])=O)[CH:5]=[N:6][C:7]=1Cl.[Cl:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.Cl.[NH2:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]1[OH:30]>CC(C)CO>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[C:7]([O:11][CH2:9][CH:4]([CH3:5])[CH3:3])=[N:6][CH:5]=[C:4]([CH:3]=2)[C:9]([NH:23][C@@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]2[OH:30])=[O:11])=[CH:15][CH:14]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Agent: Cl
Solvent: CC(C)CO
Product: CC(C)COc1ncc(C(=O)N[C@@H]2CCCC[C@H]2O)cc1-c1ccc(Cl)cc1

Procedure:
The title compound was synthesized in analogy to Example 75, using 5-bromo-6-chloro-3-pyridinecarboxylic acid, 2-methyl-propanol, (4-chloro-phenyl)-boronic acid and (1R,2R)-2-amino-cyclohexanol hydrochloride as starting materials to yield 5-(4-chloro-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-6-isobutoxy-nicotinamide. MS (ISP) 403.4 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.[H-].[Na+].[CH:21]1(Br)[CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH:21]1([N:8]2[C:7]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[C:6]3[C:10]([C:2]([F:1])=[CH:3][CH:4]=[CH:5]3)=[N:9]2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: BrC1CCCC1
Reactant: COc1ccc(-c2n[nH]c3c(F)cccc23)cc1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(-c2c3cccc(F)c3nn2C2CCCC2)cc1
Yield: 5.7 %

Procedure:
Prepared according to Method D step B from 7-fluoro-3-(4-methoxyphenyl)-1H-indazole (0.75 g, 3.1 mmol), sodium hydride (60% in oil, 0.124 g, 3.1 mmol) and cyclopentylbromide (0.36 mL, 3.3 mmol) to give the title compound (0.055 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[C:13](=O)[CH2:12][CH2:11][CH2:10][C:9]2=[O:15])=[CH:5][CH:4]=1.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].CCN(C(C)C)C(C)C.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH:13]=[CH:12][CH2:11][CH2:10][C:9]2=[O:15])=[CH:16][CH:17]=1
Reactant: COc1ccc(CN2C(=O)CCCC2=O)cc1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: CN(C)c1ccncc1
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN2C=CCCC2=O)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
1-(4-methoxybenzyl)piperidine-2,6-dione (8.99 g, 38.5 mmol) was dissolved in Toluene (Volume: 128 ml) and cooled to −78° C. L-Selectride (42.4 ml, 42.4 mmol) was added dropwise and the mixture agitated for 1 h. After 1 h, thick slurry along with precipitate observed. Reaction mixture was briefly pulled outside cooling bath to homogenize the mixture. Then DMAP (0.047 g, 0.385 mmol) was added in one portion and then DIEA (38.4 ml, 220 mmol) was added and then TFAA (6.53 ml, 46.2 mmol) was added. Then the cooling flask was removed and the mixture agitated at room temperature for 2 h and then quenched with water and the product extracted with EtOAc. The combined organic layer was dried (MgSO4), filtered and concentrated in vacuo to afford crude residue which was purified by flash chromatography to afford 7.66 g of the desired product as a yellow syrup. LCMS (m/z): (MH+), 234.2, 0.73 min.
Reaction SMILES: Cl[C:2](=[O:7])[C:3]([O:5][CH3:6])=[O:4].[NH2:8][C:9]1[CH:10]=[C:11]([C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=1.C(=O)([O-])O.[Na+]>ClCCl.O>[C:23]([C:20]1[CH:21]=[CH:22][C:17]([CH2:16][O:15][C:14]2[CH:13]=[CH:12][C:11]([C:27]3[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:35])[F:36])=[CH:29][CH:28]=3)=[CH:10][C:9]=2[NH:8][C:2](=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[CH:18][CH:19]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: COC(=O)C(=O)Cl
Reactant: CC(C)(C)c1ccc(COc2ccc(-c3ccc(OC(F)(F)F)cc3)cc2N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)C(=O)Nc1cc(-c2ccc(OC(F)(F)F)cc2)ccc1OCc1ccc(C(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 90.9 %

Procedure:
A solution of methyl chloroglyoxylate (184 μl, 2.0 mmol) in dichloromethane (1.5 ml) was added dropwise at a slow speed to a mixture of 3-amino-4-[4-(tert-butyl)benzyloxy]-4′-(trifluoromethoxy)biphenyl (415 mg, 1.0 mmol), sodium hydrogencarbonate (168 mg, 2.0 mmol), water (5 ml) and dichloromethane (7 ml), and the mixture was stirred at 0° C. for 2 hours. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (456 mg, 90.9%) as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].Cl[S:6]([N:9]=[C:10]=[O:11])(=[O:8])=[O:7].[CH2:12]([C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17])[CH3:13].C(N(CC)CC)C>ClCCl>[CH2:12]([C:14]1[CH:15]=[C:16]([NH:17][S:6]([N:9]2[CH2:2][CH2:3][O:4][C:10]2=[O:11])(=[O:8])=[O:7])[CH:18]=[CH:19][CH:20]=1)[CH3:13]
Reactant: OCCBr
Reactant: CCc1cccc(N)c1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1cccc(NS(=O)(=O)N2CCOC2=O)c1
Reaction time: 1.5 h
Yield: 80 %

Procedure:
2-Bromoethanol (0.28 mL, 4.00 mmol) was added to a solution of chlorosulfonyl isocyanate (0.35 mL, 4.00 mmol) in dichloromethane (1.8 mL) at 0° C. After stirring for 90 minutes, a solution of 3-ethylaniline (0.55 mL, 4.40 mmol) and triethylamine (1.23 mL, 8.80 mmol) in dichloromethane (3.6 mL) was added. The mixture was stirred for 90 minutes and then quenched with a 2 N aqueous hydrochloric acid solution. The mixed solution was separated, and the aqueous layer was then extracted with ether. The organic layers were combined and washed with water and saturated brine, and then dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was washed with ether (5 mL) to give 2-oxo-oxazolidine-3-sulfonic acid (3-ethylphenyl)amide (LCMS yield 80%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].[C:10]1(=O)[O:15][C:13](=[O:14])[C:12]2[CH2:16][CH2:17][CH2:18][CH2:19][C:11]1=2>C(O)(=O)C>[F:8][C:7]1[CH:6]=[CH:5][C:4]([OH:9])=[CH:3][C:2]=1[N:1]1[C:13](=[O:14])[C:12]2[CH2:16][CH2:17][CH2:18][CH2:19][C:11]=2[C:10]1=[O:15]
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: Nc1cc(O)ccc1F
Solvent: CC(=O)O
Product: O=C1C2=C(CCCC2)C(=O)N1c1cc(O)ccc1F
Yield: 80.3 %

Procedure:
3-Amino-4-fluorophenol (V) (2 g) and 3,4,5,6-tetrahydrophthalic anhydride (2.4 g) were dissolved in acetic acid (50 ml), and the resultant solution was heated under reflux for lhour, followed by extraction with ethyl acetate. The extract was concentrated, and the precipitated crystals were collected by filtration and washed with a small amount of ether to give 3.3 g of N-(2-fluoro-5-hydroxyphenyl)-3,4,5,6-tetrahydrophthalimide (VI). M.P. 164.6° C.
Reaction SMILES: B.[NH2:2][C:3]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:4]=1[C:5]#[N:6].C(O)C.[ClH:17]>C1COCC1>[ClH:17].[NH2:2][C:3]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:4]=1[CH2:5][NH2:6]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1N
Agent: B
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: NCc1cc([N+](=O)[O-])ccc1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Borane in THF (400 ml, 0.40 mol) is added dropwise to 2-amino-5-nitrobenzonitrile (60 g, 0.35 mol) in THF (600 ml) at 0° C. The mixture is allowed to warm to room temperature and is stirred for 16 hours. The resulting mixture is cooled to 0° C. and 200 ml of absolute ethanol/HCl are added. The THF is removed and the product is filtered off and recrystallized from isopropyl ether. Yield: 68.8 g (96%); Rf (1:1 methanol/chloroform): 0.15; IR (KBr): 3416, 2980, 1669, 1601, 1474, 1285 cm−1.
Reaction SMILES: OCCCCCCCCC[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].N1C=CC=CC=1.[C:26]([Cl:43])(=[O:42])CCCCCCCCCCCCCCC.[O:44]1CCC[CH2:45]1>>[Cl:43][C:26]([O:44][CH2:45][O:19][C:17](=[O:18])[C:16]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:42]
Reactant: C1CCOC1
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: O=C(O)CCCCCCCCCCCCCCCO
Solvent: c1ccncc1
Product: O=C(Cl)OCOC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83 %

Procedure:
16-Hydroxyhexadecanoic acid (5.43 g, 19.9 mmol) was dissolved in tetrahydrofuran (190 ml) and pyridine (2.36 g, 29.9 mmol) was added. palmitoyl chloride (5.48 g, 19.9 mmol) was dissolved in tetrahydrofuran (10 ml) and added dropwise at room temperature. After stirring at room temperature for 16 hours, the mixture was filtered and the filtrate evaporated under reduced pressure. The residue was dissolved in chloroform, washed with water (3×50 ml), and the organc phase was dried (MgSO4). After evaporating under reduced pressure, the residue was purified on a silica column, eluted with chloroform with increasing methanol concentration (from 1% to 2% methanol in chloroform) to give 8.41 g (83%) of the title compound. 1H NMR (300 MHz, CDCl3): δ0.85 (t, 3H, CH3), 1.20-1.35 (s, 46H, --CH2 --), 1.55-1.70 (m, 6H, --CH2 --), 2.25 (t, 2H, --CH2 --C(O)--O), 2.45 (t, 2H, --CH2 --COOH), 4.05 (t, 2H, --O--CH2). 13C NMR (75 MHz, CDCl3): δ14.01, 22.57, 24.10, 24.91, 25.82, 28.53, 28.75, 28.94, 29.08, 29.15, 29.25, 29.36, 29.54, 31.81, 34.29, 35.16, 64.27, 76.48, 76.90, 77.10, 77.32, 169.50, 173.91.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]3[N:14]=[CH:15][CH:16]=[C:12]3[N:11]=[C:10]([NH:17][C:18](=[O:29])[C:19]3[CH:24]=[CH:23][C:22]([C:25]([OH:28])([CH3:27])[CH3:26])=[CH:21][CH:20]=3)[CH:9]=2)[CH2:3]1.F[C:31](F)(F)[C:32]([O-])=[O:33].C(Cl)(=O)C.O>N1C=CC=CC=1>[C:32]([NH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]3[N:14]=[CH:15][CH:16]=[C:12]3[N:11]=[C:10]([NH:17][C:18](=[O:29])[C:19]3[CH:24]=[CH:23][C:22]([C:25]([OH:28])([CH3:26])[CH3:27])=[CH:21][CH:20]=3)[CH:9]=2)[CH2:3]1)(=[O:33])[CH3:31]
Reactant: O=C([O-])C(F)(F)F
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(N3CCC[C@@H](N)C3)n3nccc3n2)cc1
Solvent: O
Solvent: c1ccncc1
Solvent: CC(=O)Cl
Product: CC(=O)N[C@@H]1CCCN(c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3ccnn23)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
As crude product mixture of (R)—N-(7-(3-aminopiperidin-1-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (Compound 309 in Example 323) and trifluoroacetate salt (65 mg, 0.165 mmol) was dissolved in pyridine (2 ml). At 0° C. acetyl chloride (0.025 ml, 0.353 mmol) was added and the mixture was stirred for 2 hours at room temperature. Afterwards an additional amount of acetyl chloride (0.009 ml) was added to drive the reaction to completion. Water (2 ml) was then added to quench the reaction. The mixture was concentrated in vacuo, and the crude product was purified by preparatory HPLC (25-60% MeCN/H2O gradient+0.01% TFA). Lyophilization of the collected fractions gave the titled compound (35 mg, 34% yield). 1H NMR (400 MHz, DMSO-d6) δ=10.90 (s, 1H), 8.08 (d, J=2.3 Hz, 1H), 8.03-7.94 (m, 4H), 7.64-7.56 (m, 2H), 7.36 (s, 1H), 6.35 (d, J=2.3 Hz, 1H), 4.26-4.17 (m, 1H), 4.13 (d, J=11.9 Hz, 1H), 3.86 (br. s., 1H), 3.14 (s, 1H), 3.07 (dd, J=9.5, 11.7 Hz, 1H), 1.90 (br. s., 2H), 1.81 (s, 3H), 1.75 (br. s., 1H), 1.59-1.47 (m, 1H), 1.45 (s, 5H); ESI-MS: m/z 437.5 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][CH:3]=1.Cl.[O-:12][Mn](=O)(=O)=O.[K+].[CH3:18][N:19]=[C:20]=[O:21]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9](=[O:12])[S:10][N:19]([CH3:18])[C:20]2=[O:21])=[CH:4][CH:3]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CN=C=O
Reactant: S=C=Nc1ccc(Br)cc1
Agent: Cl
Agent: [K+]
Product: Cn1sc(=O)n(-c2ccc(Br)cc2)c1=O

Procedure:
Reagents: 4-Bromophenyl isothiocyanate (1.4 g, 6.5 mmol), 35% HCl (3.1 ml), KMnO4 (0.5 g), methyl isocyanate (0.38 ml, 6.5 mmol).
Reaction SMILES: Cl.[NH:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:19](=[CH:20][CH:21]=2)[O:18][C:12]2([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH2:11][C:10]3=[O:22])=[N:5][N:4]=[N:3]1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:46][O:47][C:48]1[CH:49]=[C:50]([CH:54]=[C:55]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[N:56]=1)[C:51](O)=[O:52]>O.CN(C=O)C.C(N(CC)CC)C>[CH3:46][O:47][C:48]1[CH:49]=[C:50]([C:51]([N:15]2[CH2:16][CH2:17][C:12]3([CH2:11][C:10](=[O:22])[C:9]4[C:19](=[CH:20][CH:21]=[C:7]([C:6]5[NH:2][N:3]=[N:4][N:5]=5)[CH:8]=4)[O:18]3)[CH2:13][CH2:14]2)=[O:52])[CH:54]=[C:55]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[N:56]=1
Reactant: O=C1CC2(CCNCC2)Oc2ccc(-c3nnn[nH]3)cc21
Reactant: COc1cc(C(=O)O)cc(-c2ccccc2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4nnn[nH]4)ccc2O3)cc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-(Tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one hydrochloride (42 mg), 1-hydroxybenzotriazole monohydrate (20 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (25 mg), triethylamine (21 μL) and water (1 mL) were added in that order to a DMF (3 mL) solution of 2-methoxy-6-phenyl-isonicotinic acid (25 mg), and stirred at room temperature for 2 hours. Water was added to the reaction liquid, the formed precipitate was taken out through filtration, washed with water, and dried to obtain the title compound as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ: 8.41 (1.0H, d, J=2.0 Hz), 8.23 (1.0H, dd, J=8.6, 2.4 Hz), 8.13 (2.0H, d, J=6.8 Hz), 7.57 (1.0H, br s), 7.51-7.44 (3.0H, m), 7.32 (1.0H, d, J=8.6 Hz), 6.78 (1.0H, br s), 4.31-4.27 (1.0H, m), 3.97 (3.0H, s), 3.40-3.20 (3.0H, m), 2.97 (2.0H, s), 2.10-2.05 (1.0H, m), 1.90-1.83 (3.0H, m). MS [M−H]−=495.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[Cl:6][C:7]1[CH:8]=[C:9]([CH2:14][C:15](Br)=O)[CH:10]=[CH:11][C:12]=1[Cl:13]>O1CCOCC1>[Cl:6][C:7]1[CH:8]=[C:9]([C:14]2[N:5]=[C:3]([NH:2][NH2:1])[S:4][CH:15]=2)[CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: O=C(Br)Cc1ccc(Cl)c(Cl)c1
Reactant: NNC(N)=S
Solvent: C1COCCO1
Product: NNc1nc(-c2ccc(Cl)c(Cl)c2)cs1

Procedure:
A solution of a thiosemicarbazide (10 mmol, 0.91 g) and 3,4-dichlorophenylacetyl bromide (10 mmol, 2.68 g) in dioxane (20 mL) was stirred at room temperature for 16 h. The precipitate of hydrobromide salt was filtered and washed with dioxane (3×10 mL), then basified with 2N Na2CO3 (20 mL). The product was filtered, washed with water and dried (2.08 g, 80%). The product was generally satisfactory for further reaction.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:4][CH2:3]1.[CH3:17][Li].[NH4+].[Cl-]>O1CCCC1.CCOCC>[OH:1][C:2]1([CH3:17])[CH2:3][CH2:4][CH:5]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)NCC1CCC(=O)CC1
Reactant: [Li]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(O)CCC(CNC(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 1.2 h

Procedure:
To a vigorous stirring solution of tert-butyl (4-oxocyclohexyl)methylcarbamate (1.7 g) in tetrahydrofuran (40 mL) at −78° C. was dropwise added 1.6 M methyllithium (14.02 mL) in ether. After completion of the addition, the mixture was stirred at −78° C. for 1.2 hours and poured into a cold aqueous NH4Cl solution. The resulting mixture was extracted with dichloromethane (3×100 mL) and the organic layer was dried over Na2SO4, filtered and concentrated. The residue was dissolved in dichloromethane and loaded onto an Analogix purification system, eluted with 0-50% ethyl acetate in dichloromethane to provide the title compound.
Reaction SMILES: [Na].[C:2]([O:8][CH3:9])(=[O:7])[CH2:3][C:4]([CH3:6])=[O:5].[C:10](OCC)(=[O:14])/[CH:11]=[CH:12]/[CH3:13]>CO>[CH3:13][CH:12]1[CH:3]([C:2]([O:8][CH3:9])=[O:7])[C:4](=[O:5])[CH2:6][C:10](=[O:14])[CH2:11]1
Reactant: COC(=O)CC(C)=O
Reactant: C/C=C/C(=O)OCC
Agent: [Na]
Solvent: CO
Product: COC(=O)C1C(=O)CC(=O)CC1C
Reaction time: 0.25 h

Procedure:
To a freshly prepared solution of sodium (17.78 g, 0.77 gram-atom) in methanol (220 mL) is added methyl acetoacetate 89.66 g (0.77 mole) and the mixture is stirred on an ice bath 15 min after the addition. Ethyl crotonate (100 mL of a 96% product≈88.13 g (100%; 0.77 mole) is added dropwise and the mixture is stirred at room temperature for an additional 30 min. After refluxing (2 h), methyl 6-methyl-2,4-dioxo-cyclohexane carboxylate enolate, which separates, is filtered, and the solid residue is dissolved in a minimum amount of cold water. The aqueous solution acidifed with sulfuric acid (500 mL of a 2 M solution), the precipitate extracted with dichloromethane (4×300 mL) and the organic phase dried over sodium sulfate. The residue is evaporated and the residue recrystallized from toluene to give the title compound: yield, 37 g, 40%, mp 122-123° C. The mother liquor from the reaction is evaporated to dryness, dissolved in cold water and extracted with dichloromethane (after acidification with the same 2 M sulfuric acid used previously). After evaporation and recrystallization from toulene, the mp is identical to the original crop. Total yield: 47 g; 51%.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[CH3:32][N:33]([CH3:43])[C:34](=[O:42])[CH2:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:39]5[CH2:38][CH2:37][N:36]([CH2:35][C:34]([N:33]([CH3:43])[CH3:32])=[O:42])[CH2:41][CH2:40]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1
Reactant: CN(C)C(=O)CN1CCNCC1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CN(C)C(=O)CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CC1

Procedure:
2-(4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperazin-1-yl)-N,N-dimethyl-acetamide one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and N,N-dimethyl-2-piperazin-1-yl-acetamide following General Procedure C.
Reaction SMILES: Br[C:2]1[C:3]([CH3:11])=[C:4]([C:7]([F:10])=[CH:8][CH:9]=1)[C:5]#[N:6].ClC1C([CH2:21][CH:22]=[O:23])=CC=C(F)C=1C#N>>[F:10][C:7]1[C:4]([C:5]#[N:6])=[C:3]([CH3:11])[C:2]([CH2:21][CH:22]=[O:23])=[CH:9][CH:8]=1
Reactant: Cc1c(Br)ccc(F)c1C#N
Reactant: N#Cc1c(F)ccc(CC=O)c1Cl
Product: Cc1c(CC=O)ccc(F)c1C#N

Procedure:
6-Fluoro-2-methyl-3-(2-oxoethyl)benzonitrile was prepared in two steps starting from 3-bromo-6-fluoro-2-methylbenzonitrile in an analogous fashion to that described for the synthesis of 2-chloro-6-fluoro-3-(2-oxoethyl)benzonitrile (Steps B and C) above.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:8][S:9][CH3:10])[CH:7]=1.ClC1C=C(C=CC=1)C(OO)=[O:16]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:8][S:9]([CH3:10])=[O:16])[CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCc1cncc(Br)c1
Solvent: ClC(Cl)Cl
Product: CS(=O)Cc1cncc(Br)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 53.4 %

Procedure:
3-Bromo-5-methylsulfanylmethyl-pyridine (6.0 g, 28 mmol) is dissolved in chloroform (200 mL) and the solution is cooled to 0° C. Meta-chloroperoxybenzoic acid (7.2 g, 30 mmol, 72%) is added slowly at 0° C. and the reaction mixture is stirred at 0° C. for 1 hr. Then the solvent is removed and the residue is purified by flash column chromatography to give 3.5 g of 3-bromo-5-methanesulfinylmethyl-pyridine.
Reaction SMILES: C(NCC)C.[CH2:6]([O:8][C:9](=[O:29])[CH:10]([CH2:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:16]=1)[C:11](O)=O)[CH3:7].C=O>C(Cl)Cl>[CH2:6]([O:8][C:9](=[O:29])[C:10]([CH2:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:16]=1)=[CH2:11])[CH3:7]
Reactant: CCOC(=O)C(Cc1ccnc(NC(=O)OC(C)(C)C)c1)C(=O)O
Agent: C=O
Solvent: ClCCl
Solvent: CCNCC
Product: C=C(Cc1ccnc(NC(=O)OC(C)(C)C)c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 5 h
Yield: 71.2 %

Procedure:
A solution of diethylamine (0.26 g, 2.67 mmol) in methylene chloride (4 mL) was added to a mixture of 2-(2-tert-butoxycarbonylamino-pyridin4-ylmethyl)-malonic acid monoethyl ester (0.90 g, 2.66 mmol) and 37% aq. solution of formaldehyde (0.24 g, 3.00 mmol) at 0° C. The mixture was stirred for 5 h at room temperature and the mixture was poured onto ice-water and extracted with methylene chloride. The organic layer was washed with 5% NaHCO3 and dried. The crude product was purified by flash chromatography (1% methanol in CH2Cl2) to yield 2-(2-tert-butoxycarbonylamino-pyridin4-ylmethyl)-acrylic acid ethyl ester (0.58 g, 71%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([CH:12]2[CH2:14][CH2:13]2)=[CH:9][O:10]C)[C:3]=1[CH3:15].S(=O)(=O)(O)O.O.C(=O)(O)[O-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]([CH:12]2[CH2:14][CH2:13]2)[CH:9]=[O:10])[C:3]=1[CH3:15]
Reactant: COC=C(c1nccc(Cl)c1C)C1CC1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(Cl)ccnc1C(C=O)C1CC1
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 67.8 %

Procedure:
To a solution of 4-chloro-2-(1-cyclopropyl-2-methoxyvinyl)-3-methylpyridine (1.7 g, 7.60 mmol) in THF (15 mL) a 2M aqueous solution of sulfuric acid (15.20 mL, 30.4 mmol) was added and the reaction mixture was stirred at 50° C. for a total of 2.5 h. The resulting mixture was poured into water and neutralized with a saturated sodium bicarbonate solution, and thereafter, extracted with chloroform (3×20 mL). The resulting organic layers were washed with saturated salt water (20 mL), dried over sodium sulfate and concentrated under reduced pressure. The resulting yellow solid was purified by silica gel column chromatography (hexane:ethyl acetate) (4:1) to obtain the aldehyde (1.08 g, 67.8%).