Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:8]2[N:13]=[C:12]([C:14]([C:16]3[C:17]([NH2:23])=[N:18][CH:19]=[C:20]([Br:22])[CH:21]=3)=[O:15])[CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:24][C:25]([F:31])([F:30])[CH2:26][C:27](O)=[O:28].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.N=C=N>ClCCl>[NH2:23][C:17]1[N:18]=[CH:19][C:20]([Br:22])=[CH:21][C:16]=1[C:14]([C:12]1[N:13]=[C:8]([N:1]2[CH2:7][CH2:6][CH2:5][N:4]([C:27](=[O:28])[CH2:26][C:25]([F:31])([F:30])[F:24])[CH2:3][CH2:2]2)[CH:9]=[CH:10][CH:11]=1)=[O:15]
Reactant: Nc1ncc(Br)cc1C(=O)c1cccc(N2CCCNCC2)n1
Reactant: O=C(O)CC(F)(F)F
Agent: N=C=N
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Nc1ncc(Br)cc1C(=O)c1cccc(N2CCCN(C(=O)CC(F)(F)F)CC2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.7 %

Procedure:
(6-(1,4-diazepan-1-yl)pyridin-2-yl)(2-amino-5-bromopyridin-3-yl)methanone (650 mg, 1.36 mmol) was added to a stirred suspension of 3,3,3-trifluoropropionic acid (0.13 ml, 1.50 mmol), 1-hydroxybenzotriazole (184 mg, 1.36 mmol), triethylamine (1.33 ml, 9.52 mmol) and PS-carbodiimide (2.08 g, 2.72 mmol) in dichloromethane (20 ml). The resulting mixture was stirred at room temperature for 18 hours. The crude mixture was filtered and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography (ISCO Companion|, 40 g column, 0-50% EtOAc/Petroleum ether) to afford the title compound as an orange solid (355 mg, 54% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:19])[NH:7][N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:10]=1)=[O:4].Br[CH2:21][CH2:22][CH3:23]>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:19])[N:7]([CH2:21][CH2:22][CH3:23])[N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:10]=1)=[O:4]
Reactant: COC(=O)c1cc(-c2ccc(OC)cc2)n[nH]c1=O
Reactant: CCCBr
Product: CCCn1nc(-c2ccc(OC)cc2)cc(C(=O)OC)c1=O
Yield: 78.3 %

Procedure:
Using 4-methoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one and bromopropane as starting materials, the procedures of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 78.3%.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[CH3:20][C:21]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:26])[CH2:22][C:23](O)=[O:24]>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:19])[N:2]([NH:1][C:23](=[O:24])[CH2:22][C:21]([CH3:20])([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:26])[N:11]=2)=[CH:13][CH:14]=1
Reactant: CC(C)(CC(=O)O)c1ccccc1
Reactant: Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O
Product: CC(C)(CC(=O)Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O)c1ccccc1

Procedure:
The product of Example 86A and 3-methyl-3-phenylbutanoic acid were treated as in Example 51 to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.39 (s, 1H), 8.39-8.44 (m, 1H), 7.88-8.02 (m, 2H), 7.70-7.77 (m, 1H), 7.63-7.67 (m, 2H), 7.60-7.63 (m, 2H), 7.42-7.46 (m, 2H), 7.28-7.34 (m, 2H), 7.15-7.21 (m, 1H), 2.62 (s, 2H), 1.47 (s, 6H); MS (APCI+) M/Z 432 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[C:9]([CH3:11])=[CH:10][C:3]=12.C([Li])(CC)C.C1CCCCC1.[C:33](Cl)(=[O:37])[O:34][CH2:35][CH3:36].[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[C:7]([C:33]([O:34][CH2:35][CH3:36])=[O:37])=[CH:6][N:5]=[C:4]2[N:8]([Si:12]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[CH:19]([CH3:21])[CH3:20])[C:9]([CH3:11])=[CH:10][C:3]=12
Reactant: Cc1cc2c(Cl)ccnc2n1[Si](C(C)C)(C(C)C)C(C)C
Reactant: CCOC(=O)Cl
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CCOC(=O)c1cnc2c(cc(C)n2[Si](C(C)C)(C(C)C)C(C)C)c1Cl
Temperature: -78 °C

Procedure:
A solution of 4-chloro-2-methyl-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (525 mg) in tetrahydrofuran (10 ml) was cooled to −78° C. under nitrogen atmosphere, and to the reaction mixture was added 0.99M sec-butyllithium/cyclohexane solution (4.1 ml) dropwise. After the mixture was stirred at −78° C., ethyl chlorocarbonate (389 μl) was added dropwise. The reaction solution was stirred at −78° C. for 30 minutes, saturated aqueous ammonium chloride (20 ml) was added, and the temperature was returned to ambient temperature. The reaction solution was transferred into a separating funnel and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane) to obtain ethyl 4-chloro-2-methyl-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (645 mg) as a colorless viscous liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21]([O:23]CC)=O)[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:27][CH2:28][CH2:29][NH:30][C:31]([NH:33][CH3:34])=[S:32]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21]([NH:27][CH2:28][CH2:29][NH:30][C:31]([NH:33][CH3:34])=[S:32])=[O:23])[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CNC(=S)NCCN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(C)c1=O
Product: CNC(=S)NCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(C)c1=O
Yield: 32.2 %

Procedure:
In a similar manner to that described in example 196, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (10 mg, 0.028 mmol) described in example 92 and N-(2-aminoethyl)-N′-methylthiourea (48 mg, 0.364 mmol), was prepared 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-N-(2-{[(methylamino)carbonothioyl]amino}ethyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide(4 mg, 33% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.55 (br s, 1 H), 8.56 (s, 1 H), 7.40 (s, 1 H), 7.24-7.15 (m, 2 H), 7.05-7.00 (m, 2 H), 6.79 (br s, 1 H), 6.19 (br s, 1 H), 4.14 (s, 2 H), 3.75-3.70 (m, 4 H), 3.56 (s, 3 H), 2.95 (s, 3 H); HRMS m/z calcd for C21H23N5O3FS: 444.1506 Found: 444.1532.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[S:6][C:7]([S:10](Cl)(=[O:12])=[O:11])=[C:8]([CH3:9])[C:4]=2[CH:3]=1.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][C:18]=1[N:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1>>[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][S:10]([C:7]2[S:6][C:5]3[CH:14]=[CH:15][C:2]([Cl:1])=[CH:3][C:4]=3[C:8]=2[CH3:9])(=[O:12])=[O:11])=[CH:19][C:18]=1[N:24]1[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]1
Reactant: Cc1ccc(N)cc1N1CCN(C)CC1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Product: Cc1ccc(NS(=O)(=O)c2sc3ccc(Cl)cc3c2C)cc1N1CCN(C)CC1

Procedure:
The title compound (E142) was prepared from 5-chloro-3-methylbenzo[b]thiophene-2-sulfonyl chloride and 4-methyl-3-(4-methylpiperazin-1-yl)benzenamine according to the method of Example 1 MH+=448/450.
Reaction SMILES: [BH4-].[Na+].[CH:3]1([NH:9][C:10]2[C:15]([C:16]3[CH2:20][C:19]([CH2:25][C:26](OC)=[O:27])([C:21](OC)=[O:22])[O:18][N:17]=3)=[CH:14][N:13]=[C:12]3[N:30]([CH2:33][CH3:34])[N:31]=[CH:32][C:11]=23)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1>O1CCCC1.CO>[CH:3]1([NH:9][C:10]2[C:15]([C:16]3[CH2:20][C:19]([CH2:25][CH2:26][OH:27])([CH2:21][OH:22])[O:18][N:17]=3)=[CH:14][N:13]=[C:12]3[N:30]([CH2:33][CH3:34])[N:31]=[CH:32][C:11]=23)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CCn1ncc2c(NC3CCCCC3)c(C3=NOC(CC(=O)OC)(C(=O)OC)C3)cnc21
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCn1ncc2c(NC3CCCCC3)c(C3=NOC(CO)(CCO)C3)cnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium borohydride (14 mg, 0.00036 mole) was added to methyl 3-[4-(cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridin-5-yl]-5-(2-methoxy-2-oxoethyl)-4,5-dihydroisoxazole-5-carboxylate (80 mg, 0.00018 mole) (example 10) in tetrahydrofuran (5 ml). Methanol (2 drops) was added and the reaction mixture was stirred at room temperature overnight. It was quenched with saturated ammonium chloride solution, diluted with ethyl acetate and extracted with brine. The organic layer was dried over anhydrous sodium sulphate and concentrated in vacuo. The crude product was purified by column chromatography.
Reaction SMILES: [S:1]1[C:5]2[C:6]([C:10](Cl)=[O:11])=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.N1C(C)=CC=CC=1C>C(OCC)(=O)C.O1CCCC1.[Pd]>[S:1]1[C:5]2[C:6]([CH:10]=[O:11])=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: O=C(Cl)c1cccc2nnsc12
Agent: [Pd]
Solvent: Cc1cccc(C)n1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=Cc1cccc2nnsc12

Procedure:
99 g of benzo-1,2,3-thiadiazole-7-carboxylic acid chloride are dissolved in 1.2 l of ethyl acetate, the mixture is treated at 0°-5° C. with a solution of 58.7 g of 2,6-lutidine in 200 ml of tetrahydrofuran as well as 33 g of palladium/charcoal catalyst (5% Pd), and hydrogenated under low pressure (104Pa) with a further addition of a total of 57 g of palladium/charcoal catalyst and 500 ml of tetrahydrofuran in 5 portions. The catalyst is subsequently removed by filtration and washed with tetrahydrofuran, and the filtrate is evaporated. The residue is purified on silica gel (CH2Cl2) and gives the title compound of m.p. 134°-136° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11])=[O:4].[S-:12][C:13]#[N:14].[K+].O>C(O)C>[Cl:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3](=[O:4])[CH2:2][S:12][C:13]#[N:14]
Reactant: O=C(CBr)c1ccccc1Cl
Reactant: N#C[S-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CSCC(=O)c1ccccc1Cl
Temperature: 25 °C
Yield: 75.3 %

Procedure:
A solution of 2-bromo-1-(2-chlorophenyl)ethanone (7.55 g, 32.3 mmol) and potassium thiocyanate (3.14 g, 32.3 mmol) in ethanol (70 ml) was stirred at 80° C. for 2 hours. After cooling to room temperature, water (70 ml) was poured to the reaction mixture, and crystals were collected by filtration and washed with water to give 5.15 g (75.3%) of the desired product as a solid.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]([CH3:13])([CH3:12])[C:8]2=[O:11])=[CH:4][CH:3]=1.[C:14]([Cu])#[N:15].CCOC(C)=O.O>CN1C(=O)CCC1>[CH3:12][C:7]1([CH3:13])[C:8](=[O:11])[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([C:14]#[N:15])[CH:10]=2)[CH2:6]1
Reactant: N#C[Cu]
Reactant: CC1(C)Cc2ccc(Br)cc2C1=O
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC1(C)Cc2ccc(C#N)cc2C1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
A slurry of 6-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-one (U.S. Pat. No. 5,401,758) (24.97 g, 0.104 mol) and CuCN (18.7 g, 0.208 mol) in NMP (160 mL) was heated at 175° C. for 4 h. After cooling to rt, the reaction mixture was poured into EtOAc (300 mL) and water (200 mL) with stirring. After 15 min, the solid was collected and the filter cake was rinsed with EtOAc (150 mL). The resulting two layers were separated and the aqueous portion was extracted with EtOAc (150 mL×3). The combined organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give a dark oil, which was divided into three portions and purified by flash chromatography on silica gel (120 g) eluting with EtOAc/Hexane mixtures to provide the title compound as a near colorless oil after concentration in vacuo (17.8 g, 90% yield). HPLC Ret. time: 2.55 min. LCMS MH+ (m/z) 186.31. 1H NMR: (DMSO-d6, 400 MHz): δ 8.13 (s, 1H), 8.11 (d, 1H), 7.78 (d, 1H), 3.10 (s, 2H), 1.15 (s, 6H).
Reaction SMILES: [O-:1]Cl.[Na+].[Cl:4][C:5]1[N:6]=[C:7]2[N:11]([C:12]=1[CH:13]=[O:14])[CH:10]=[CH:9][S:8]2>O.C(O)(C)(C)C>[Cl:4][C:5]1[N:6]=[C:7]2[N:11]([C:12]=1[C:13]([OH:1])=[O:14])[CH:10]=[CH:9][S:8]2
Reactant: O=Cc1c(Cl)nc2sccn12
Reactant: [O-]Cl
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: O=C(O)c1c(Cl)nc2sccn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of NaOCl (230 mmol) and NaH2PO4 (176 mmol) in water (195 mL) is added dropwise to a solution of 6-chloro-imidazo[2,1-b]thiazole-5-carbaldehyde (26.8 mmol) in tert.-butanol (195 mL) and the mixture is stirred for 8 h at RT. The solvents are partially removed in vacuo and the obtained precipitate is filtered off. The filtrate is made acidic and the obtained precipitate is filtered off to give the desired product as a white solid. LC-MS: tR=0.67 min; [M+H]+=202.9.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:33])=[C:4]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][C@H:13]([NH:17][C:18]([C@H:20]3[CH2:25][CH2:24][CH2:23][N:22]([C:26](OC(C)(C)C)=[O:27])[CH2:21]3)=[O:19])[CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl.[C:35](O)(C(F)(F)F)=O>O1CCOCC1.CO>[C:26]([N:22]1[CH2:23][CH2:24][CH2:25][C@H:20]([C:18]([NH:17][C@H:13]2[CH2:14][CH2:15][CH2:16][N:11]([S:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[CH3:33])(=[O:9])=[O:10])[CH2:12]2)=[O:19])[CH2:21]1)(=[O:27])[CH3:35]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1c(Cl)cccc1S(=O)(=O)N1CCC[C@H](NC(=O)[C@H]2CCCN(C(=O)OC(C)(C)C)C2)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(=O)N1CCC[C@H](C(=O)N[C@H]2CCCN(S(=O)(=O)c3cccc(Cl)c3C)C2)C1

Procedure:
tert-Butyl (3S)-3-[((3S)-1-[(3-chloro-2-methylphenyl)sulfonyl]piperidin-3-ylamino)-carbonyl]-piperidine-1-carboxylate (10.0 mg, 200 μmol) was treated with 4.0 M of hydrogen chloride in 1,4-dioxane (0.5 mL) at rt for 1 h. The volatiles were removed in-vacuo and the residue was dissolved in acetonitrile (0.8 mL) and was treated with diisopropylethylamine (20.0 μL) and acetyl chloride (5.0 μL). The crude reaction mixture was diluted with MeOH (1.3 mL) and was adjusted to a pH of 2 using TFA and was purified by prep-HPLC to give the desired product. LCMS: (M+H)+=442.1/444.1.
Reaction SMILES: CC1C=CC(S(O[CH:12]2[CH2:25][C:24]3[C:15]([CH3:38])([CH:16]4[CH:21]([CH2:22][CH:23]=3)[CH:20]3[CH2:26][CH2:27][CH:28]([CH:29]([CH2:31][CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH3:30])[C:19]3([CH3:37])[CH2:18][CH2:17]4)[CH2:14][CH2:13]2)(=O)=O)=CC=1.[CH2:39]([OH:46])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][OH:45].O1CCOCC1>CCCCCC>[OH:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][O:46][C@H:12]1[CH2:13][CH2:14][C@@:15]2([CH3:38])[C:24](=[CH:23][CH2:22][C@@H:21]3[C@@H:16]2[CH2:17][CH2:18][C@@:19]2([CH3:37])[C@H:20]3[CH2:26][CH2:27][C@@H:28]2[C@H:29]([CH3:30])[CH2:31][CH2:32][CH2:33][CH:34]([CH3:35])[CH3:36])[CH2:25]1
Reactant: OCCCCCCO
Reactant: Cc1ccc(S(=O)(=O)OC2CCC3(C)C(=CCC4C3CCC3(C)C(C(C)CCCC(C)C)CCC43)C2)cc1
Solvent: C1COCCO1
Solvent: CCCCCC
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCO)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 52 %

Procedure:
By use of the procedure described in the literature [Kosower, E. M. and Weinstein, S., J. Am. Chem. Soc., 78 (1956) 4347-4354; Davis, M., J. Chem. Soc., (1962) 178-181] cholesteryl p-toluenesulfonate and 1,6-hexanediol were condensed in boiling dioxane to give cholest-5-en-3β-yl 6-hydroxyhexyl ether in 52% yield as colorless plates (from hexane), m.p. 75.9°-81° C.
Reaction SMILES: Br[CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](=O)[CH3:4].[Cl:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([NH2:17])=[S:16]>C(O)C>[Cl:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]1[S:16][C:2]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[C:3]([CH3:4])[N:17]=1
Reactant: NC(=S)c1ccccc1Cl
Reactant: CC(=O)C(Br)c1ccccc1
Solvent: CCO
Product: Cc1nc(-c2ccccc2Cl)sc1-c1ccccc1
Yield: 79.1 %

Procedure:
1-Bromo-1-phenyl-2-propanone (10.6g, 0.050 mole), o-chlorothiobenzamide (8.8g, 0.051 mole), and ethanol (100 ml) are mixed and, after the initial exothermic reaction has subsided, heated under reflux for two hours. The ethanol is evaporated and the residue is treated with chloroform and aqueous sodium bicarbonate. The chloroform layer is separated and evaporated to leave a yellow oil which solidifies on standing. Recrystallization from acetonitrile yields 11.3g (79%) of 2-(2-chlorophenyl)-4-methyl-5-phenylthiazole, m.p. 63°-65° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C@@H:16]([OH:17])[CH2:15][CH2:14][C@@H:13]3[C@H:9]2[CH2:10][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:12]3)=[CH:4][CH:3]=1.[F:25][C:26]([F:41])([F:40])[C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[C:30](Cl)=[O:31]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:25][C:26]([F:40])([F:41])[C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([C:36]([F:39])([F:37])[F:38])[CH:35]=1)[C:30]([O:17][C@H:16]1[CH2:15][CH2:14][C@@H:13]2[C@@H:9]([CH2:10][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:12]2)[C@@H:8]1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[O:31]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CC[C@H](O)[C@@H](c3ccc(F)cc3)[C@@H]2C1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H]2CC[C@H](OC(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3ccc(F)cc3)[C@@H]2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4.75 g (14.0 mmol) of the intermediate of step B in dry methylene chloride under nitrogen atmosphere at RT was added 4.71 g (17.0 mmol) of 3,5-bis(trifluoromethyl)benzoyl chloride, 2.4 mL (17.3 mmol) TEA and a catalytic amount of DMAP. The resulting mixture was stirred at RT for 2 hr then transferred to a separatory funnel, washed with saturated. aq. NaHCO3 and brine. The combined organic layers dried over magnesium sulfate, filtered and the solvent evaporated under vacuum to afford the crude title compound which was used without further purification. 1H-NMR (CDCl3): δ: 8.63 (1 H, s), 8.19 (2 H, s), 7.25 (2 H, m), 7.00 (2 H, m), 5.22 (1 H, m), 3.59-3.33 (2 H, m), 3.30-3.20 (2 H, m), 2.83 (1 H, t, J=12.7 Hz), 2.62 (1 H, m), 2.43 (1 H, m), 2.20 (1 H, m), 2.02 (1 H, m), 1.90-1.70 (2 H, m), 1.55, 1.47 (9 H, two singlets).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:7]=[C:6]([CH3:17])[C:3]=1[CH:4]=[O:5].C(N(CC)CC)C.[O:25](S(C(F)(F)F)(=O)=O)[S:26]([C:29]([F:32])([F:31])[F:30])(=O)=[O:27]>ClCCl>[F:30][C:29]([F:32])([F:31])[S:26]([O:1][C:2]1[CH:9]=[C:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:7]=[C:6]([CH3:17])[C:3]=1[CH:4]=[O:5])(=[O:27])=[O:25]
Reactant: Cc1cc(OC2CCCCO2)cc(O)c1C=O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(OC2CCCCO2)cc(OS(=O)(=O)C(F)(F)F)c1C=O
Temperature: -78 °C

Procedure:
Into a 50-mL 3-necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, were placed a solution of 2-hydroxy-6-methyl-4-(tetrahydro-2H-pyran-2-yloxy)benzaldehyde (300 mg, 1.27 mmol, 1.00 equiv) in dichloromethane (20 mL) and triethylamine (510 mg, 5.05 mmol, 3.97 equiv). This was followed by the addition of a solution of Tf2O (720 mg, 2.55 mmol, 2.01 equiv) in dichloromethane (5 mL) dropwise with stirring at −78° C. The resulting solution was stirred for 2 h at −78° C., then quenched by the addition of 5 mL of water. The resulting solution was extracted with 3×30 mL of dichloromethane. The organic layers were combined, washed with 3×10 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:10). This resulted in 110 mg (19%) of 2-formyl-3-methyl-5-(tetrahydro-2H-pyran-2-yloxy)phenyl trifluoromethanesulfonate as a yellow oil.
Reaction SMILES: [Zn:1].[Cl-].[Li+].[Br:4]CCBr.Cl[Si](C)(C)C.Br[CH2:14][C:15]1[CH:16]=[C:17]([F:23])[C:18]([F:22])=[C:19]([F:21])[CH:20]=1>C1COCC1>[Br-:4].[F:21][C:19]1[CH:20]=[C:15]([CH:16]=[C:17]([F:23])[C:18]=1[F:22])[CH2:14][Zn+:1]
Reactant: Fc1cc(CBr)cc(F)c1F
Reactant: BrCCBr
Reactant: [Zn]
Agent: C[Si](C)(C)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Fc1cc(C[Zn+])cc(F)c1F
Product: [Br-]
Temperature: 150 °C
Reaction time: 20 h

Procedure:
Zinc powder (2.62 g, 40.00 mmol) and lithium chloride (1.696 g, 40.00 mmol) were added to a dried flask and heated to 150° C. under vacuum for 30 min. The flask was allowed to reach room temperature. THF (20 mL) and 1,2-dibromoethane (0.115 mL, 1.33 mmol) were added. The mixture was heated until boiling occurred and the flask was then allowed to reach room temperature. Chlorotrimethylsilane (0.034 mL, 0.27 mmol) was added and the mixture was again heated until boiling occurred. The flask was cooled with an ice-bath and 5-(bromomethyl)-1,2,3-trifluorobenzene (6 g, 26.67 mmol) dissolved in THF (5 mL) was then added dropwise. The ice-bath was removed and the reaction stirred at room temperature for 20 h. Solids were allowed to settle and the supernatant used in the next transformation.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][CH:17]3[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26](F)[CH:25]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:42][NH2:43]>CCO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][CH:17]3[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:25]=[C:26]3[C:27]([C:30]([NH2:31])=[N:42][NH:43]3)=[CH:28][CH:29]=2)[N:3]=1
Reactant: NN
Reactant: CC1CCC(NC(=O)[C@H]2CCCN(c3cc(-c4ccc(C#N)c(F)c4)nc(N)n3)C2)CC1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCC(NC(=O)[C@H]2CCCN(c3cc(-c4ccc5c(N)n[nH]c5c4)nc(N)n3)C2)CC1
Temperature: 150 °C
Yield: 64.1 %

Procedure:
Into a microwave tube, (3S)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-N-(4-methylcyclohexyl)-3-piperidinecarboxamide (190 mg, 0.435 mmol), 3 mL of EtOH, Hunig's base (0.30 mL, 1.74 mmol), and hydrazine anhydrous (0.082 mL, 2.61 mmol) were added, and the yellow mixture was heated at 150° C. for 180 minutes under microwave conditions. The solution turned black. LCMS showed mainly product. The black solids were filtered and the yellow filtrate was evaporated. The yellow residue was sonicated in EtOAc at 50° C., and the solid was filtered. This material was then sonicated in water at 50° C., and the solid was filtered and washed with water to afford the title compound (125 mg) as a light yellow solid. LC-MS (ES) m/z=449 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.87 (m, 3H), 0.89-1.94 (m, 13H), 2.18-2.44 (m, 1H), 2.78-3.05 (m, 2H), 3.76 (m, 1H), 4.39 (m, 2H), 5.38 (s, 2H), 6.12 (s, 2H), 6.62 (s, 1H), 7.54-7.79 (m, 3H), 7.90-7.99 (m, 1H), 11.51 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:11]=[N:12][C:13]3[CH:14]=[CH:15][CH:16]=[C:17]([C:20](O)=[O:21])[C:18]=3[N:19]=2)[CH:7]=[CH:8][CH:9]=1.[NH2:25][C:26]1[S:27][CH:28]=[CH:29][N:30]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[S:27]1[CH:28]=[CH:29][N:30]=[C:26]1[NH:25][C:20]([C:17]1[C:18]2[N:19]=[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:1])([F:23])[F:24])[CH:5]=3)[CH:11]=[N:12][C:13]=2[CH:14]=[CH:15][CH:16]=1)=[O:21]
Reactant: Nc1nccs1
Reactant: O=C(O)c1cccc2ncc(-c3cccc(OC(F)(F)F)c3)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1nccs1)c1cccc2ncc(-c3cccc(OC(F)(F)F)c3)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
A mixture of 3-(3-(trifluoromethoxy)phenyl)quinoxaline-5-carboxylic acid (100 mg, 0.30 mmol), 2-aminothiazole (30 mg, 0.30 mmol), HATU (171 mg, 0.45 mmol) and DIEA (116 mg, 0.9 mmol) in DMF (10 mL) was stirred at room temperature for 2 h. Water (20 mL) was added, and the resulting precipitate was collected by filtration and dried under vacuum to give N-(thiazol-2-yl)-3-(3-(trifluoromethoxy)phenyl)quinoxaline-5-carboxamide as a solid (115.5 mg, 92% yield). MS (ESI) calcd for C19H11F3N4O2S (m/z): 416.06. found: 417 [M+1].