Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([CH2:3][CH3:4])[CH3:2].CCN(CC)CC.[CH3:19][NH:20][C:21](=S)[OH:22]>C(#N)C>[CH3:19][NH:20][C:21](=[O:22])[O:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH:1]([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)c1ccccc1O
Reactant: CNC(O)=S
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCC(C)c1ccccc1OC(=O)NC
Reaction time: 30 h

Procedure:
To a solution of 2-Sec. butylphenol (1.5 g, 0.01 mole) 0.2 ml of Et3N was added under stirring. S-methyl ester of N-methylcarbamothioic acid (1.05 g, 0.01 mole) in acetonitrile (10ml) was added dropwise over a period of 4 hrs, keeping reflux temperature. After 30 hr, acetonitrile was evaporated under vacuum. The residue was taken in dichloromethane (25 ml), washed with water and a 5% cold NaOH solution, followed by water and brine and dried over sodium sulphate. After removal of the solvent, the liquid residue obtained was further purified by distillation to give 2-Sec. butylphenyl N-methylcarbamate of the formula VI; IR: 3329 (N--H), 1730 (--COO), 1535, 1490 and 750 (aromatic); PMR (CdCl3, 90 MHz): 0.81 (3H, 1, primary methyl of side chain), 1.18 (3H, d, J=7 Hz, secondary/methyl of side chain), 1.58 (2H, m, methylene protons of side chain), 2.88 (4H, doublet overlapping a multiplet, NH--CH3 and benzylic proton), 4.97 (1H, br s, N H) and 6.95 to 7.25 (4H, m, aromatic).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[CH2:12][S:13]([CH3:15])=[O:14].[OH-].[K+].S(OC)(O[CH3:22])(=O)=O.Cl>O>[CH3:22][N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2](=[O:1])[C:3]([CH2:12][S:13]([CH3:15])=[O:14])=[CH:4]1
Reactant: CS(=O)Cc1cnc2ccccc2c1O
Reactant: COS(=O)(=O)OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cn1cc(CS(C)=O)c(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-hydroxy-3-methylsulphinylmethylquinoline (4.4 g.) and potassium hydroxide (1.68 g.) in water (20 ml.) at 0°-5° was added dimethyl sulphate (2.52 g.). The solution was stirred at room temperature for 30 minutes, then neutralised with 5 N aqueous hydrochloric acid. The resultant sticky solid was triturated with industrial methylated spirit to give a solid product. The product was purified by high pressure liquid chromatography over silica gel, eluting with isopropanol: dichloromethane 95:5 at a flow rate of 200 ml. per minute. This procedure gave the novel 1-methyl-3-methylsulphinylmethyl-4-quinolone, m.p. 94°-96°.
Reaction SMILES: [CH3:1][CH:2]([CH3:11])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[Cl:12][C:13]1[N:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.Cl>C(Cl)Cl>[Cl:12][C:13]1[N:18]=[CH:17][C:16]([S:19]([N:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][CH:2]([CH3:11])[CH3:1])[CH2:6][CH2:7]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: CC(C)CCN1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)CCN1CCN(S(=O)(=O)c2ccc(Cl)nc2)CC1
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a solution of 1-(3-methylbutyl)piperazine (0.41 g, 2.60 mmol; described in: Yamane, T. et al. Chem. Pharm. Bull. 1993, 41, 148-155) in methylene chloride (15 mL) cooled on an ice-bath was 6-chloropyridine-3-sulfonyl chloride (0.50 g, 2.36 mmol; described in: Naegeli, C. et al. Helv. Chim. Actal. 1938, 21, 1746-1750) dissolved in methylene chloride (10 mL) added slowly. The reaction was stirred for 30 min and a 5% HCl(aq) solution (30 mL) was added and the phases were separated. The aqueous layer was alkalyzed with a saturated aqueous NaHCO3 solution until pH 9 and the mixture was extracted with methylene chloride. The organic layers were combined, dried (Na2SO4) and the solvent was removed in vacuo affording 650 mg (83% yield) of the title compound as a white solid: 1H NM (CDCl3, 400 MHz) δ 8.75 (d, J=2 Hz, 1 H), 7.97 (dd, J=8, 2 Hz, 1 H), 7.51 (d, J=8 Hz, 1 H), 3.33-3.05 (m, 4 H), 2.86-2.29 (m, 6 H), 1.66-1.50 (m, 1 H), 1.5-1.28 (m, 2 H), 0.88 (d, J=7 Hz, 6 H); MS (ES) mz 332 (M++1).
Reaction SMILES: [O:1]=[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[C:5]([C:14](Cl)=[O:15])[CH:4]=[CH:3]1.[OH:17][CH:18]1[CH:23]2[CH2:24][CH2:25][N:20]([CH2:21][CH2:22]2)[CH2:19]1>N1C=CC=CC=1>[N:20]12[CH2:25][CH2:24][CH:23]([CH2:22][CH2:21]1)[CH:18]([O:17][C:14]([C:5]1[CH:4]=[CH:3][C:2](=[O:1])[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:6]=1)=[O:15])[CH2:19]2
Reactant: OC1CN2CCC1CC2
Reactant: O=C(Cl)c1ccc(=O)n(-c2ccccc2)c1
Solvent: c1ccncc1
Product: O=C(OC1CN2CCC1CC2)c1ccc(=O)n(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 20 %

Procedure:
After dissolution of the mixed solution of 6-oxo-1-phenyl-1,6-dihydro-pyridine-3-carbonyl chloride obtained in Example 115-1 in 5 mL of pyridine, 231 mg (1.82 mmol) of 3-hydroxyquinuclidine was added thereto. Afterward, the resulting reaction solution was stirred at room temperature for about 3 days. After termination of the reaction was determined by liquid chromatography, the solvent was removed in vacuo. Without an additional purification process, the resulting compound was extracted three times with water and chloroform, and the organic phase was purified using liquid chromatography (chloroform:methanol: ammonia water=10:1:0.1) to obtain a target compound (Actual yield: 65 mg, Percent yield: 20%).
Reaction SMILES: C([C:5]1[N:6]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([C:32]([O:34]C)=[O:33])=[O:31])=[CH:20][CH:19]=2)[C:7]([C:15]#[N:16])=[C:8]([CH:10]([OH:14])[CH:11]([CH3:13])[CH3:12])[N:9]=1)CCC.[OH-:36].[Na+]>>[CH2:15]([NH:16][C:15]([C:7]1[N:6]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([C:32]([OH:34])=[O:33])=[O:31])=[CH:22][CH:23]=2)[CH:5]=[N:9][C:8]=1[CH:10]([OH:14])[CH:11]([CH3:13])[CH3:12])=[O:36])[CH2:7][CH2:8][CH3:10]
Reactant: [OH-]
Reactant: CCCCc1nc(C(O)C(C)C)c(C#N)n1Cc1ccc(-c2ccccc2C(=O)C(=O)OC)cc1
Agent: [Na+]
Product: CCCCNC(=O)c1c(C(O)C(C)C)ncn1Cc1ccc(-c2ccccc2C(=O)C(=O)O)cc1

Procedure:
245 mg of 2-butyl-4-(1-hydroxy-2-methylpropyl)-1-[(2'-methoxalylbiphenyl-4-yl)methyl]imidazole-5-carbonitrile [prepared as described in step (a) above] were subjected to hydrolysis using 6 ml of a 1N aqueous solution of sodium hydroxide in the same manner as described in Example 10(b), to give 187 mg of the title compound as a powder, at softening 144°-146° C.
Reaction SMILES: [O:1]1[C:9]2[CH:8]([OH:10])[CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=[CH:2]1.[C:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](F)=[CH:15][CH:14]=1)#[N:12]>>[C:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([O:10][CH:8]2[CH2:7][NH:6][CH2:5][C:4]3[CH:3]=[CH:2][O:1][C:9]2=3)=[CH:15][CH:14]=1)#[N:12]
Reactant: OC1CNCc2ccoc21
Reactant: N#Cc1ccc(F)c2ccccc12
Product: N#Cc1ccc(OC2CNCc3ccoc32)c2ccccc12

Procedure:
The same method as in Example 1 was conducted using 4,5,6,7-tetrahydrofuro[3,2-c]pyridin-7-ol (Reference Example 33) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 4-cyano-1-fluoronaphthalene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[C:9]([Cl:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CN(C)C=O.[Cl:18]N1C(=O)CCC1=O>O>[NH2:1][C:2]1[C:10]([CH3:11])=[C:9]([Cl:12])[C:8]([Cl:18])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1c(Cl)ccc(C(=O)O)c1N
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(N)c(C(=O)O)cc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 54.6 %

Procedure:
To a mixture of 0.34 g of 2-amino-4-chloro-3-methylbenzoic acid and 10 ml of N,N-dimethylformamide was added 0.26 g of N-chlorosuccinimide at room temperature, and the mixture was stirred at room temperature for 5 hours. After 30 ml of water was poured into the reaction mixture, the mixture was extracted with ethyl acetate three times. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 0.22 g of 2-amino-4,5-dichloro-3-methylbenzoic acid of the formula:
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:3]=1[C:4]([C:6]1[C:15]([OH:16])=[CH:14][C:9]2[C:10]([C:12]#[N:13])=[CH:11][C:8]=2[CH:7]=1)=[O:5].[OH:22]O.[OH-].[Na+].Cl>C(O)C>[Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:3]=1[C:4]([C:6]1[C:15]([OH:16])=[CH:14][C:9]2[C:10]([C:12]([NH2:13])=[O:22])=[CH:11][C:8]=2[CH:7]=1)=[O:5]
Reactant: N#CC1=Cc2cc(C(=O)c3c(Cl)cccc3Cl)c(O)cc21
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(=O)C1=Cc2cc(C(=O)c3c(Cl)cccc3Cl)c(O)cc21
Reaction time: 6 h

Procedure:
2 g of 4-(2,6-dichlorobenzoyl)-5-hydroxybenzocyclobutene-1-carbonitrile are dissolved in 50 ml of ethanol, the whole is cooled to 0° and, while stirring at 0°, 10 g of 30% hydrogen peroxide are added dropwise thereto. 1.0 ml of 30% sodium hydroxide solution is then added slowly dropwise thereto and stirring is carried out for 6 hours at room temperature. The whole is neutralised with 6N hydrochloric acid and extracted thoroughly by shaking with 250 ml of dichloromethane. The organic phase is dried over magnesium sulphate and concentrated to dryness by evaporation. After recrystallisation from ether/hexane, 4-(2,6-dichlorobenzoyl)-5-hydroxybenzocyclobutene-1-carboxamide is obtained having a melting point of 174°-175°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:24](=[NH:25])[N:23]([CH3:26])[C:12]2[N:13]=[C:14]([O:17]CCOCC)[N:15]=[CH:16][C:11]=2[CH:10]=1>Cl>[ClH:1].[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:24](=[NH:25])[N:23]([CH3:26])[C:12]2[N:13]=[C:14]([OH:17])[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CCOCCOc1ncc2cc(-c3c(Cl)cccc3Cl)c(=N)n(C)c2n1
Agent: Cl
Product: Cn1c(=N)c(-c2c(Cl)cccc2Cl)cc2cnc(O)nc21

Procedure:
A solution of 78.0 mg (0.20 mmol) of the ethoxyethyl ether from Example 22 in 1.0 mL of 6N hydrochloric acid was heated at reflux for 5 minutes. The solvent was removed by evaporation under reduced pressure. The remaining solid hydrochloride salt was recrystallized from ethanol-ethyl acetate to afford crystalline 6-(2,6-dichlorophenyl)-2-hydroxy-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-ylideneamine, hydrochloride, mp 255°-260° C.;
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1)[CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[Br:16].Cl[C:27]([O:29][CH3:30])=[O:28].C(N(CC)CC)C>C(Cl)Cl>[F:23][C:20]([F:21])([F:22])[C:18]1[CH:17]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:24])[F:25])[CH:19]=1)[CH2:6][N:7]([CH2:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[Br:16])[C:27](=[O:28])[O:29][CH3:30]
Reactant: COC(=O)Cl
Reactant: Fc1ccc(Br)c(CNCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [3,5-bis(trifluoromethyl)benzyl](2-bromo-5-fluorobenzyl)amine from Step A (0.14 g) in methylene chloride at room temperature, excess methyl chloroformate (0.1 ml) and triethyl amine (0.1 ml) were added. The solution was stirred at room temperature for 2 h and the solvent was removed under reduced pressure. The title compound was obtained by flash column chromatography using EtOAc/hexane (1:9) as the eluant. 1H NMR (CDCl3, 500 MHz) δ 7.80 (s, 1H), 7.68 (s, 1H), 7.60 (s, 1H), 7.48 (m, 1H), 6.88 (m, 2H), 4.60 (m, 4H), 3.81 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14]3)=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CC(C)=O>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]([N:13]3[CH2:17][CH2:16][C:15](=[O:18])[CH2:14]3)=[O:12])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C(N1CCC(O)C1)C1(c2ccc(Cl)cc2)CC1
Solvent: CC(C)=O
Solvent: O
Product: O=C1CCN(C(=O)C2(c3ccc(Cl)cc3)CC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}pyrrolidin-3-ol (2.70 g, 0.0102 mol) in acetone (50 mL, 0.7 mol) was added Jone's oxidant in water (8.00M, 1.90 mL) at 0° C. The solution was stirred at rt for 1 hour and then filtered, concentrated. The residue was dissolved in AcOEt, and the solution was washed with water and brine successively, dried over MgSO4, and concentrated. The crude product was purified using Combiflash eluting with 50% AcOEt in hexanes.
Reaction SMILES: [NH:1]1[C:8](=[O:9])[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[OH-].[Na+].I[CH2:13][CH2:14][CH3:15].Cl>O.CN1CCCC1=O>[OH:9][C:8]1[CH:7]=[C:5]([OH:6])[N:4]=[C:2]([S:3][CH2:13][CH2:14][CH3:15])[N:1]=1
Reactant: O=C1CC(=O)NC(=S)N1
Reactant: CCCI
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCCSc1nc(O)cc(O)n1

Procedure:
Water (670 ml) was added to 2-thiobarbituric acid (200 g). The resulting mixture was stirred and sodium hydroxide (126.3 g) was added in portions. The mixture was stirred for 40 mm. then diluted with water. 1-Methyl-2-pyrrolidinone (400 ml) and 1-iodopropane (140.9 ml) were then added. The resulting slurry was stirred at 20° C. for 22 h. The pH of the mixture was then adjusted to 6.5 by addition of 1M HCl (600 ml) over 30 min, then to pH 2.5 by the addition of 6 M HCl (180 ml) over a further 30 min. The resulting slurry was stirred for 18 h and the product was isolated by filtration and washed successively with water (4×100 ml), ethanol (200 ml) and water (2×200 ml). The product was dried under reduced pressure overnight at 50° C. to yield the title product as a white powder (185 g).
Reaction SMILES: O[CH2:2][C@H:3]([NH:5][C:6]([C:8]1[NH:9][C:10]([C:13]2[CH:18]=[C:17]([O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])[CH:16]=[C:15]([O:30][C@@H:31]([CH3:35])[CH2:32][O:33][CH3:34])[CH:14]=2)=[CH:11][CH:12]=1)=[O:7])[CH3:4].CS(O)(=O)=O.C(N(CC)CC)C.[Cl-].[NH4+]>O1CCCC1>[CH3:34][O:33][CH2:32][C@@H:31]([O:30][C:15]1[CH:14]=[C:13]([C:10]2[NH:9][C:8]([C:6]3[O:7][CH2:4][C@@H:3]([CH3:2])[N:5]=3)=[CH:12][CH:11]=2)[CH:18]=[C:17]([O:19][Si:20]([CH:24]([CH3:25])[CH3:26])([CH:21]([CH3:22])[CH3:23])[CH:27]([CH3:29])[CH3:28])[CH:16]=1)[CH3:35]
Reactant: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C(=O)N[C@H](C)CO)[nH]2)c1
Agent: CS(=O)(=O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C3=N[C@H](C)CO3)[nH]2)c1
Temperature: 50 °C
Reaction time: 24 h
Yield: 64.5 %

Procedure:
N-[(2R)-1-Hydroxypropan-2-yl]-5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-[(tripropan-2-ylsilyl)oxy]phenyl)-1H-pyrrole-2-carboxamide (1.95 g, 3.76 mmol) synthesized in Example (107a) was dissolved in tetrahydrofuran (30 mL), and anhydrous methanesulfonic acid (1.25 g, 7.18 mmol) and triethylamine (2.80 mL, 20.09 mmol) were added, followed by stirring at 50° C. for 1 day under nitrogen atmosphere. To the reaction solution, a saturated aqueous ammonium chloride solution (80 mL) was added, and extraction was carried out with methylene chloride (120 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=50%-80%) to afford the desired compound (1.18 g, yield 64%) as a yellow solid.
Reaction SMILES: Br[C:2]1[C:3]([Cl:19])=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:5]2=[N:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:25]([O:27]CC)=[CH2:26])CCC.O.[F-].[K+]>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:19][C:3]1[C:2]([C:25](=[O:27])[CH3:26])=[CH:7][N:6]=[C:5]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[N:10][C:4]=12
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: C[Si](C)(C)CCOCn1cnc2c(Cl)c(Br)cnc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)c1cnc2c(ncn2COCC[Si](C)(C)C)c1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 26.2 %

Procedure:
6-Bromo-7-chloro-3-{[2-(trimethylsilyl)ethoxy]methyl}-3H-imidazo[4,5-b]pyridine (379 mg, 1.05 mmol) in toluene (6 mL) was stirred with bis(triphenylphosphine)palladium(II) dichloride (106 mg, 0.151 mmol) and tributyl(1-ethoxyvinyl)tin (435 mg, 1.21 mmol) at 120° C. 4 hours. The reaction mixture was allowed to cool to room temperature and stirred with water (20 mL) and potassium fluoride (0.5 g) at room temperature for 1 hour. The reaction mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was stirred with hydrogen chloride-methanol solution (10 wt %, 4 mL) at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1→3/1 (v/v)) to give the title compound as a yellow solid (89.6 mg, yield 26%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[C:9](=[CH:14]\[O:15][CH3:16])/[C:10]([O:12][CH3:13])=[O:11].[C:17](Cl)([Cl:19])=[O:18].O>C1(C)C=CC=CC=1>[Cl:19][C:17]([O:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[C:9](=[CH:14]\[O:15][CH3:16])/[C:10]([O:12][CH3:13])=[O:11])=[O:18]
Reactant: CO/C=C(/C(=O)OC)c1ccccc1CO
Reactant: O=C(Cl)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: CO/C=C(/C(=O)OC)c1ccccc1COC(=O)Cl
Reaction time: 3 h
Yield: 13 %

Procedure:
A solution of (E)-methyl 2-[2-(hydroxymethyl)phenyl]-3-methoxypropenoate (1 g) in toluene (10 ml) was added slowly to a solution of phosgene in toluene (12.5% w/w, 6.5 ml). After stirring for 3 hours, water (70 ml) was added and the resulting mixture was extracted with diethyl ether. The diethyl ether extract was washed with brine, dried over anhydrous sodium sulphate and evaporated under reduced pressure to leave an oil. The oil was purified by chromatography on silica gel, eluting with 30% ethyl acetate/hexane to give (E)-methyl 2-[2-(chloroformyloxy-methyl)phenyl]-3-methoxypropenoate (0.163 g, 13%). 1H NMR (CDCl3): 3.7(s,3H), 3.8(s,3H), 4.5(s,2H), 7.1-7.5(m,4H), 7.6(s,1H) ppm. IR (film): 1631, 1707, 1774 cm−1.
Reaction SMILES: BrBr.CCOCC.[Cl:8][C:9]1[CH:10]=[C:11]([C:14](=O)[CH3:15])[S:12][CH:13]=1.[NH2:17][C:18]([NH2:20])=[S:19]>CCO>[NH2:20][C:18]1[S:19][CH:15]=[C:14]([C:11]2[S:12][CH:13]=[C:9]([Cl:8])[CH:10]=2)[N:17]=1
Reactant: CC(=O)c1cc(Cl)cs1
Reactant: NC(N)=S
Agent: BrBr
Solvent: CCO
Solvent: CCOCC
Product: Nc1nc(-c2cc(Cl)cs2)cs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Bromine was added to an ether solution of 4-chloro-2-acetylthiophene under ice cooling, and the mixture was stirred at room temperature for 2 hours to obtain a brominated compound. Thiourea was added to an EtOH solution of the brominated compound at room temperature, and the mixture was stirred overnight at 80° C. to obtain 2-amino-4-(4-chlorothiophen-2-yl)thiazole.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C[O-].[Na+].[F:13][C:14]([F:28])([F:27])[CH2:15]OS(C1C=CC(C)=CC=1)(=O)=O.C1(C)C=CC=CC=1>CO>[F:13][C:14]([F:28])([F:27])[CH2:15][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(O)c1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: O=Cc1cccc(OCC(F)(F)F)c1
Temperature: 90 °C
Reaction time: 24 h
Yield: 25.7 %

Procedure:
EX-659A) 3-Hydroxybenzaldehyde (12.22 g, 0.10 mol) and 100 mL of anhydrous methanol were combined in a 250 mL round-bottom flask. Sodium methoxide was slowly added as a 25 wt. % solution in methanol (21.61 g, 0.10 by mol), and the methanol was removed under vacuum. Then 2,2,2-trifluoroethyl-p-toluenesulfonate (25.42 g, 0.10 mol) was added, the flask was purged with nitrogen, and 100 mL of N-methyl pyrrolidine was added. The solution was stirred for 24 h at 90° C., quenched with water, and extracted with ether (3×). The combined ether layers were washed with 1 M NaOH (2×), water, and brine, dried over MgSO4, filtered, and evaporated to give 11.72 g of crude product Chromatography over silica gel eluting with 0-10% ethyl acetate in hexane followed by a second chromatography with toluene gave 5.24 g (26%) of the desired 3-(2,2,2-trifluoroethoxy)benzaldehyde product as a pale oil. 1H NMR (C6D6) δ9.61 (s, 1H), 7.14 (d, 1H), 7.06 (s, 1H), 6.97 (t, 1H), 6.75 (m, 1H), 3.75 (m, 2H). 19F NMR (C6D6) δ−74.45 (t, 3F).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.C(N(CC)CC)C.[NH:17]1[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26]([C:30]3[CH:31]=[N:32][N:33]4[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][C:34]=34)[N:25]=2)[CH2:18]1.C(=O)([O-])O.[Na+]>ClCCl>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]([C:30]4[CH:31]=[N:32][N:33]5[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][C:34]=45)[N:25]=3)[CH2:18]2)=[N:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccn2ncc(-c3nccc(N[C@@H]4CCCNC4)n3)c2c1
Reactant: N#Cc1ccc(Cl)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(N2CCC[C@@H](Nc3ccnc(-c4cnn5ccc(C#N)cc45)n3)C2)nc1
Temperature: 50 °C
Reaction time: 20 h
Yield: 69.2 %

Procedure:
6-Chloronicotinonitrile (0.04 g, 0.29 mmol) and triethylamine (0.15 mL, 1.08 mmol) were added to a stirred solution of 3-{4-[(3R)-piperidin-3-ylamino]pyrimidin-2-yl}pyrazolo[1,5-a]pyridine-5-carbonitrile (Preparation 7b, 0.11 g, 0.24 mmol) in dichloromethane (3.3 mL) and the resulting mixture was stirred at 50° C. for 20 hours. The reaction mixture was then cooled to ambient temperature and dichloromethane and 4% aqueous sodium hydrogencarbonate solution were added. The organic layer was separated, washed with water and brine, dried (MgSO4) and evaporated in vacuo. The crude product was purified by flash chromatography (200:1 to 60:1 chloroform/methanol) to give the title compound (0.07 g, 71%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH2:24][CH3:25])[C:12]2[N:13]=[C:14](S(C)(=O)=O)[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:32]=[C:33]([O:37][CH3:38])[C:34]=1[O:35][CH3:36])[NH2:31]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH2:24][CH3:25])[C:12]2[N:13]=[C:14]([NH:31][C:30]3[CH:32]=[C:33]([O:37][CH3:38])[C:34]([O:35][CH3:36])=[C:28]([O:27][CH3:26])[CH:29]=3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: CCn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(S(C)(=O)=O)nc21
Solvent: O
Solvent: CC(=O)O
Product: CCn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(Nc3cc(OC)c(OC)c(OC)c3)nc21
Temperature: 160 °C

Procedure:
A mixture of 0.150 g (0.38 mmol) of 6-(2,6-dichlorophenyl)-8-ethyl-2-methanesulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 68 and 0.500 g (2.70 mmol) of 3,4,5-trimethoxyaniline was heated in a 160° C. oil bath for 5 minutes. The dark solution was cooled and dissolved in 2 mL of warm glacial acetic acid. This solution was diluted to 15 mL volume with water to precipitate a violet solid. The solid was filtered, washed well with water, and dried; wt 0.140 g. Purification was effected by filtration of an ethyl acetate (30 mL) solution through a layer of silica gel and washing the silica gel with ethyl acetate. The filtrate was concentrated to 3 mL volume. The crystals that separated on inducement were filtered and washed with 1 mL of ethyl acetate and 1 mL of ether; wt 0.054 g; mp 275°-278° C.