Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH3:2][CH:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16]C)=[O:15])=[CH:10][CH:9]=2)[N:6]([CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][N:24]([C:27]3[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][N:28]=3)[CH2:23][CH2:22]2)[C:5](=[O:34])[CH2:4]1.CC1N(C2C=CC(C(OC)=O)=CC=2)NC(=O)C1.[OH-].[K+].Cl>C(O)C>[ClH:1].[ClH:1].[CH3:2][CH:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)[N:6]([CH2:18][CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][N:24]([C:27]3[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][N:28]=3)[CH2:25][CH2:26]2)[C:5](=[O:34])[CH2:4]1
Reactant: COC(=O)c1ccc(N2C(C)CC(=O)N2CCCN2CCN(c3cc(C)ccn3)CC2)cc1
Agent: COC(=O)c1ccc(N2NC(=O)CC2C)cc1
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: Cc1ccnc(N2CCN(CCCN3C(=O)CC(C)N3c3ccc(C(=O)O)cc3)CC2)c1
Temperature: 25 °C
Yield: 109.5 %

Procedure:
11 g 5-methyl-1-(4-methoxycarbonylphenyl)-2-{3-[4-(4-methyl-pyrid-2-yl)-piperazin-1-yl]-propyl}-pyrazolin-3-one hydrochloride (see Example No. 48 infra, produced in an analogous manner to Example 2A and B starting from 5-methyl-1-(4-methoxycarbonylphenyl) pyrazolin-3-one) are dissolved in 100 ml 85% ethanol, and the solution is mixed with 5 g potassium hydroxide with stirring at ambient temperature. After completion of the reaction, the reaction mixture is neutralized by the addition of pure hydrochloric acid, and the ethanol is distilled off. The remaining aqueous solution is acidified to a pH of 2 with hydrogen chloride, then the water is distilled off and the residue is dissolved in ethanol. The precipitated mineral salts are removed by suction filtration, and the filtrate is cooled, whereupon the dihydrochloride of the title compound crystallizes out. 6.3 g 5-methyl-1-(4-carboxyphenyl)-2-{3-[4-(4-methyl-pyrid-2-yl)-piperazin-1-yl]-propyl}-pyrazolin-3-one dihydrochloride are obtained, melting point: 205°-225° C.
Reaction SMILES: C(=O)(O)[O-].[Na+].Br[C:7]1[S:8][C:9]2[C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O.C(COC)OC.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.[Cu]I>[C:19]1([C:7]2[S:8][C:9]3[C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)c1cccc2nc(Br)sc12
Reactant: OB(O)c1ccccc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Solvent: O
Solvent: COCCOC
Product: O=C(O)c1cccc2nc(-c3ccccc3)sc12
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 78.3 %

Procedure:
Tetrakis(triphenylphosphine)palladium (144 mg, 0.125 mmol) and a solution of sodium bicarbonate (630 mg, 7.50 mmol) in degassed water (10 ml) were added in turn to a solution of ethyl ester of 2-bromobenzothiazole-7-carboxylic acid (715 mg, 2.50 mmol) and phenyl boronic acid (341 mg, 2.8 mmol) in degassed dimethoxyethane (20 ml) and the mixture was stirred at 50° C. for 10 min. Copper (I) iodide (24 mg, 0.125 mmol) was added to the mixture at room temperature and the mixture was heated under reflux for 4 hrs. Dimethoxyethane was distilled off under reduced pressure and the residue was extracted with ethyl acetate. The organic layer was washed with brine and dried and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=10) to give ethyl ester of 2-phenylbenzothiazole-7-carboxylic acid (500 mg, 70%) as colorless crystals.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].CCN(C(C)C)C(C)C.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=1[C:23]1[S:24][C:25]2[C:26]([NH2:33])=[N:27][CH:28]=[C:29]([F:32])[C:30]=2[N:31]=1>C1COCC1>[CH3:5][O:4][C:2](=[O:3])[NH:33][C:26]1[C:25]2[S:24][C:23]([C:17]3[C:18]([Cl:22])=[CH:19][CH:20]=[CH:21][C:16]=3[Cl:15])=[N:31][C:30]=2[C:29]([F:32])=[CH:28][N:27]=1
Reactant: COC(=O)Cl
Reactant: Nc1ncc(F)c2nc(-c3c(Cl)cccc3Cl)sc12
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Nc1ncc(F)c2nc(-c3c(Cl)cccc3Cl)sc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 20.3 %

Procedure:
To a solution of methyl chloroformate (18 mg, 0.191 mmol) and DIPEA (42 μL, 0.24 mmol) in THF (1.0 mL) was added 2-(2,6-dichlorophenyl)-7-fluorothiazolo[5,4-c]pyridin-4-ylamine (50 mg, 0.159 mmol). The reaction mixture was stirred at room temperature for 2.5 hours, then heated at 50° C. for 2 hours and left standing at room temperature for 18 hours. The crude reaction mixture was partitioned between EtOAc and brine. The aqueous phase was extracted with EtOAc and the combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The resultant residue was purified by column chromatography on silica gel eluting with 0-50% EtOAc in pentane to afford the title compound as a white solid (12 mg, 20%). 1H NMR (400 MHz, DMSO-d6): δ 10.87 (s, 1H), 8.48 (d, J=1.8 Hz, 1H), 7.77-7.65 (m, 3H), 3.73 (s, 3H). LCMS (Method C): RT=4.74 min, m/z: 372 [M+H+].
Reaction SMILES: [C:1]1(=O)[CH2:4][CH2:3][CH2:2]1.C(O)(=O)C.[CH:10]12[CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:14]1[CH2:13][NH:12][CH2:11]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[CH:1]1([N:12]2[CH2:11][CH:10]3[CH:14]([CH:15]3[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:13]2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCC1
Reactant: CCOC(=O)C1C2CNCC21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)C1C2CN(C3CCC3)CC21
Temperature: 0 °C
Reaction time: 16 h
Yield: 66 %

Procedure:
A mixture of cyclobutanone (157 mg, 2.19 mmol) in acetic acid (0.11 mL, 1.56 mmol) was added to a stirred solution of ethyl 3-aza bicyclo[3.1.0]hexane-6-carboxylate (243 mg, 1.56 mmol, obtained in the above step) in dichloromethane, cooled at 0° C. Solid sodium triacetoxy borohydride (727 mg, 3.43 mmol) was added portion wise over a period of 15 minutes. The reaction mixture was gradually warmed to room temperature and stirred for 16 hours. The reaction mixture was cooled to 0° C. and basified with saturated sodium bicarbonate solution (pH: 7.5). The two layers were separated, the organic layer was washed with brine, dried over anhydrous sodium sulfate and the volatiles were removed under reduced pressure to obtain ethyl 3-cyclobutyl-3-aza bicyclo[3.1.0]hexane-6-carboxylate (219 mg).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:19]=[C:18]3[C:13]([CH2:14][CH2:15][C@H:16]([CH2:20][NH:21][CH3:22])[O:17]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.BrC[C:32]([O:34][CH3:35])=[O:33]>CN1C(=O)CCC1>[CH3:35][O:34][C:32](=[O:33])[CH2:22][NH:21][CH2:20][C@H:16]1[CH2:15][CH2:14][C:13]2[C:18](=[CH:19][C:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:9])=[O:8])=[CH:11][CH:12]=2)[O:17]1
Reactant: COC(=O)CBr
Reactant: CNC[C@H]1CCc2ccc(S(=O)(=O)c3ccccc3)cc2O1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: COC(=O)CNC[C@H]1CCc2ccc(S(=O)(=O)c3ccccc3)cc2O1
Temperature: 0 °C

Procedure:
(R)-(7-Benzenesulfonyl-chroman-2-ylmethyl)-methyl-amine (81 mg, 2.6 mmol) and triethylamine (0.2 mL) were added to 0.5 mL NMP and the mixture was cooled to 0° C. with stirring. Methyl 2-bromoacetate (26 uL) was added, and the reaction mixture was stirred for two hours at room temperature, then quenched by addition of water. The mixture was extracted with methylene chloride and the combined organic layers were washed with water and brine, dried (Na2SO4), filtered and contrated under reduced pressure. Purification of the residue by flash chromatography gave 40 mg of (R)-[(7-benzenesulfonyl-chroman-2-ylmethyl)-amino]-acetic acid methyl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:26])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.C(N(C(C)C)C(C)C)C.Cl[C:37](=[O:44])[CH2:38][CH2:39][C:40]([O:42][CH3:43])=[O:41]>C1COCC1.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([NH:26][C:37](=[O:44])[CH2:38][CH2:39][C:40]([O:42][CH3:43])=[O:41])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:18][CH2:19]1)[N:11]=2
Reactant: Nc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reactant: COC(=O)CCC(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCC(=O)Nc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-Fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzenamine (140 mg, 0.387 mmol) was dissolved in THF (3.9 mL) and N-ethyl-N-isopropylpropan-2-amine (270 μl, 1.55 mmol) before methyl 4-chloro-4-oxobutanoate (189 μl, 1.55 mmol) was added at ambient temperature and the reaction mixture was stirred at ambient temperature for 30 min. The reaction mixture was diluted with 100 mL of DCM, added to a separatory funnel, partitioned with water, washed 2 times with 50 mL of sodium bicarbonate (saturated, aqueous), separated, dried over sodium sulfate, and concentrated via rotovap to give methyl 4-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenylamino)-4-oxobutanoate after flash chromatography. MS (ESI) m/z: Calculated: 475.1; Observed: 476.4 (M++1).
Reaction SMILES: [C:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:15][C:16]1[CH:21]=[N:20][C:19]([Br:22])=[CH:18][N:17]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.C(O)(=O)C.ClCCl>[C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:14]=[CH:13][C:10]([CH2:11][NH:15][C:16]2[CH:21]=[N:20][C:19]([Br:22])=[CH:18][N:17]=2)=[CH:9][CH:8]=1
Reactant: Nc1cnc(Br)cn1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Solvent: CC(=O)O
Product: Brc1cnc(NCc2ccc(-c3ccccc3)cc2)cn1
Yield: 38.6 %

Procedure:
4-Phenylbenzaldehyde (0.3 g, 1.65 mmol) and 2-amino-5-bromopyrazine (0.24 g, 1.37 mmol) were treated with Na(OAc)3BH (0.44 g, 2.06 mmol) in dichloroethane (7.0 mls) and acetic acid (0.25 mls) for 18 hours at room temperature. The mixture was diluted with dichloromethane, washed with 1.0 N NaOH, washed with brine, dried over MgSO4, and concentrated. Chromatography (SiO2, EtOAc: Hex, 1:1) gave 0.18 g of N-(biphenyl-4-ylmethyl)-5-bromopyrazin-2-amine.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:13]([CH3:15])[CH3:14])[C:11]=1[OH:12])[CH:7]=O)([CH3:3])[CH3:2].[CH3:16][N:17]1[CH2:23][C:21](=[O:22])[NH:20][C:18]1=[O:19]>>[OH:12][C:11]1[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][C:6]([CH:7]=[C:23]2[N:17]([CH3:16])[C:18](=[O:19])[NH:20][C:21]2=[O:22])=[CH:9][C:10]=1[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)c1cc(C=O)cc(C(C)C)c1O
Reactant: CN1CC(=O)NC1=O
Product: CC(C)c1cc(C=C2C(=O)NC(=O)N2C)cc(C(C)C)c1O
Yield: 11 %

Procedure:
Prepared according to the procedure described in Example 92 using 3,5-diisopropyl-4-hydroxybenzaldehyde (2.7 g, 13 mmoles) and 1-methyl hydantoin (1.4 g, 12 mmoles). Recrystallization from acetonitrile gave the pure product (0.4 g), mp 197°-208° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[Cu][C:15]#[N:16]>CN(C)C=O.O.Cl.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[CH:8]([C:5]1[CH:6]=[CH:7][C:2]([C:15]#[N:16])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1)([CH3:10])[CH3:9]
Reactant: N#C[Cu]
Reactant: CC(C)c1ccc(Br)c([N+](=O)[O-])c1
Agent: Cl[Fe](Cl)Cl
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1ccc(C#N)c([N+](=O)[O-])c1
Yield: 77.5 %

Procedure:
The product of Example 91A (0.581 g, 2.380 mmol) and copper (I) cyanide (0.426 g, 4.760 mmol) in N,N-dimethylformamide (5 mL) under a nitrogen atmosphere were heated in 160° oil bath for 1.5 hour. The reaction was cooled, treated with a solution of iron (III) chloride hexahydrate (2.48 g) in water (3.72 mL) and concentrated hydrochloric acid (0.62 mL), and then heated at 65° for 20 minutes. The cooled reaction mixture was extracted with ethyl ether (2×50 mL). The combined ethereal extracts were washed sequentially with 1N aqueous HCl (25 mL), 3N aqueous sodium hydroxide (25 mL), water (25 mL), and brine (25 mL) then dried over magnesium sulfate, filtered, and concentrated by rotary evaporation. Purification of the residue by silica gel flash chromatography eluting with 20:80 ethyl acetate/hexanes afforded the title compound as a yellow liquid (0.351 g, 1.845 mmol, 58%). 1H NMR (300 MHz, CHLOROFORM-D) □ppm 1.33 (d, J=6.99 Hz, 6 H) 2.82-3.47 (m, 1 H) 7.66 (dd, J=7.91, 1.29 Hz, 1 H) 7.83 (d, J=7.72 Hz, 1 H) 8.18 (d, J=1.47 Hz, 1 H); MS (DCI) m/z 208 (M+NH4)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([N:11]2[CH:15]=[CH:14][CH:13]=[CH:12]2)[CH:5]=1)([O-:3])=[O:2].[Br:16][CH:17](Br)[CH3:18].C([O-])([O-])=O.[K+].[K+].[OH-].[Na+]>CN(C=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:18][CH2:17][Br:16])=[C:6]([N:11]2[CH:15]=[CH:14][CH:13]=[CH:12]2)[CH:5]=1)([O-:3])=[O:2]
Reactant: CC(Br)Br
Reactant: O=[N+]([O-])c1ccc(O)c(-n2cccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCCBr)c(-n2cccc2)c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 45.1 %

Procedure:
4-Nitro-2-(1H-pyrrol-1-yl)phenol (2.3 g, 112.6 mmol) and dibromoethane (29.1 ml, 337.8 mmol) were dissolved in DMF (200 ml) and, after adding K2CO3 (18.68 g), the solution was stirred at 70° C. for 1 h. Thereafter, an aqueous solution of 10% sodium hydroxide was added to the reaction solution to render it basic up to a pH of about 10, followed by three extractions with ethyl acetate. The organic solvent layers were combined and dried with magnesium sulfate, followed by evaporation of the solvent. The resulting residue was purified by being subjected to column chromatography on silica gel using a 3:1 solvent system of n-hexane and ethyl acetate as an eluent. The fractions containing the product were collected and the solvent was evaporated to yield the end product 4-nitro-2-(1H-pyrrol-1-yl)phenoxy-2-bromoethane (15.8 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]2[NH:12][N:13]=[C:14]([CH3:16])[CH:15]=2)[CH:3]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[CH3:9][S:8][C:6]1[N:5]=[C:4]([NH:10][C:11]2[NH:12][N:13]=[C:14]([CH3:16])[CH:15]=2)[CH:3]=[C:2]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:7]=1
Reactant: C1COCCN1
Reactant: CSc1nc(Cl)cc(Nc2cc(C)n[nH]2)n1
Product: CSc1nc(Nc2cc(C)n[nH]2)cc(N2CCOCC2)n1

Procedure:
The above-prepared [6-chloro-2-methylsulfanyl-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine (2.42 g, 9.46 mmol) is heated in morpholine (10 mL) at 130° C. for 15 hours. The solvent is then removed in vacuo and the solid residue is triturated in EtOH and collected by filtration to give [2-methylsulfanyl-6-(morpholin-4-yl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[CH:12]=[CH:11][C:10]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:9]=3[CH:8]([C:18]3[C:19](=[O:25])[NH:20][C:21](=[O:24])[NH:22][CH:23]=3)[C:6]=2[N:7]=1)[CH3:2].C[Si](N([Si](C)(C)C)C(=O)C(F)(F)F)(C)C.[CH2:41]([O:43][C:44]([C:46]1[O:47][C:48]([CH2:51]Br)=[CH:49][CH:50]=1)=[O:45])[CH3:42].CO>ClCCCl.C(#N)C>[CH2:1]([C:3]1[O:4][C:5]2[CH:12]=[CH:11][C:10]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:9]=3[CH:8]([C:18]3[C:19](=[O:25])[NH:20][C:21](=[O:24])[N:22]([CH2:51][C:48]4[O:47][C:46]([C:44]([O:43][CH2:41][CH3:42])=[O:45])=[CH:50][CH:49]=4)[CH:23]=3)[C:6]=2[N:7]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(CBr)o1
Reactant: CCc1nc2c(o1)C=Cc1cc(C)ccc1C2c1c[nH]c(=O)[nH]c1=O
Agent: C[Si](C)(C)N(C(=O)C(F)(F)F)[Si](C)(C)C
Solvent: CC#N
Solvent: CO
Solvent: ClCCCl
Product: CCOC(=O)c1ccc(Cn2cc(C3c4ccc(C)cc4C=Cc4oc(CC)nc43)c(=O)[nH]c2=O)o1
Temperature: 25 °C

Procedure:
To a slurry of the product of step (vii) (1.42 g) in dry 1,2-dichloroethane (15 ml) was added bis(trimethylsilyl)trifluoroacetamide (3.4 ml). The mixture was heated at reflux for 2 hours until the mixture became a homogeneous solution. The solution was allowed to cool to room temperature and a solution of 5-[bromomethyl]-2-furancarboxylic acid ethyl ester (J. Chem. Soc. Perkin Trans. 1, 1981, 1125, Bull. Chem. Soc. Jpn., 1987, 60, 1807) (1.1 g) in dry acetonitrile (15 ml) was added. The solution was then heated at reflux for 14 hours. The reaction mixture was allowed to cool and methanol (15 ml) was added. The solvents were evaporated under reduced pressure and the residue was triturated with diethyl ether. The resultant solid was collected by filtration and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic phase was dried (MgSO4) and the solvent was evaporated under reduced pressure. Purification was by chromatography eluting with ethyl acetate.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:13]([CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:12]2[CH:21]=[CH:22][CH:23]=[CH:24][C:11]=2[N:10]=1.[C:25]([C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=1)#[CH:26].C(N(CC)CC)C>O1CCCC1.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.[Cu]I>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:12]3[CH:21]=[CH:22][CH:23]=[CH:24][C:11]=3[N:10]=2)=[C:2]([C:26]#[C:25][C:27]2[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=2)[CH:7]=1
Reactant: C#Cc1ccc(C#N)cc1
Reactant: Clc1ccc(-c2nc3ccccc3n2CC2CCCCC2)c(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#Cc1ccc(C#Cc2cc(Cl)ccc2-c2nc3ccccc3n2CC2CCCCC2)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 38 %

Procedure:
To a solution of 2-(2-bromo-4-chloro-phenyl)-1-cyclohexylmethyl-1H-benzoimidazole (0.56 g, 1.38 mmol) in dry tetrahydrofuran (8 ml) were added 4-ethynyl-benzonitrile (0.22 mg, 1.7 mmol; CAS Reg. No. 3032-92-6), bis(triphenylphosphine)palladium(ii) dichloride (63 mg, 0.09 mmol), copper(I) iodide (8 mg, 0.04 mmol) and triethyl amine (10 ml) at 25° C. in a sealed tube. The resulting mixture was degassed and back-filled with nitrogen three times. It was then allowed to stir at 80° C. for 16 h. The reaction mixture was filtered through a bed of celite, concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (20-25 ethyl acetate/n-hexane) to afford the desired compound as an off-white powder (38%). MS (Turbo Spray): m/z=450.0 (M+H).
Reaction SMILES: [N:1]1[N:2]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([CH2:18][OH:19])[C:11]=2[OH:20])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C(N(CC)CC)C.[C:28](Cl)(=[O:32])[C:29]([CH3:31])=[CH2:30].C(OCC)C>C1COCC1>[C:28]([O:19][CH2:18][C:12]1[CH:13]=[C:14]([O:16][CH3:17])[CH:15]=[C:10]([N:2]2[N:3]=[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]3=[N:1]2)[C:11]=1[OH:20])(=[O:32])[C:29]([CH3:31])=[CH2:30]
Reactant: COc1cc(CO)c(O)c(-n2nc3ccccc3n2)c1
Reactant: C=C(C)C(=O)Cl
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCc1cc(OC)cc(-n2nc3ccccc3n2)c1O
Temperature: -10 °C
Reaction time: 1 h

Procedure:
In a 250 ml round bottom flask equipped with a magnetic stirrer and nitrogen inlet was dissolved 4.03 g (14.9 mmol) 2-(2H-benzo[d][1,2,3]triazol-2-yl)-6-(hydroxymethyl)-4-methoxyphenol from Example 7 in 50 ml anhydrous THF. Triethylamine (7.4 ml, 53 mmol) was added and the mixture was cooled to −10° C. Methacryloyl chloride (1.99 g, 19.0 mmol) was added dropwise and the mixture was stirred for 1 hr at 0° C. followed by 6 hours at ambient temperature. The mixture was poured into 200 ml diethyl ether and washed with 0.5 N HCl and water. The organic layer was dried with magnesium sulfate, filtered, and concentrated via rotary evaporation to give the desired product as a dark yellow oil which was recrystallized in methanol to give 1.73 g of a light yellow solid (34%). 1H NMR (CDCl3) delta: 11.26 (s, 1H, Ar—OH), 7.92 (d, 2H, Ar—H benzotriazole), 7.91 (s, 1H, Ar—H meta to phenol), 7.49 (d, 2H, Ar—H benzotriazole, 5,6-position), 7.05 (s, 1H, Ar—H meta to phenol), 6.21 (s, 1H, C═C—H trans), 5.61 (s, 1H, C═C—H cis), 5.40 (s, 2H, Ar—CH2), 3.90 (s, 3H, Ar—OCH3), 2.01 (s, 3H, C═C—CH3).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[NH2:18][C:19]1[C:28]2[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=2[CH:22]=[CH:21][CH:20]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][C:3]([C:16]#[N:17])=[C:2]2[NH:18][C:19]1[C:28]2[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=2[CH:22]=[CH:21][CH:20]=1
Reactant: Nc1cccc2c1CCCC2
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2ncc(C#N)c(Nc3cccc4c3CCCC4)c2cc1OC

Procedure:
Using an analogous procedure to that described in Example 150, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 176.7 mg (1.2 mmol) of 1-amino-5,6,7,8-tetrahydronaphthalene and 115.6 mg (1 mmol) of pyridine hydrochloride in 12 mL of 2-ethoxyethanol was refluxed for 2 hr. The work up gave 195.1 mg (54.3%) of the product as a yellow solid, m.p. 248° C. (dec.), mass (electrospray, m/e): M+H 360.1. HRCIMS: calcd 359.163 for C22H16N3O2Cl(M+), obsd 359.1632.
Reaction SMILES: [OH:1][C:2]1([C:8]([O:10][CH3:11])=[O:9])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[Br:21][C:22]1[CH:23]=[N:24][C:25](Cl)=[N:26][CH:27]=1.CCCCCC>CCO>[Br:21][C:22]1[CH:23]=[N:24][C:25]([N:5]2[CH2:4][CH2:3][C:2]([OH:1])([C:8]([O:10][CH3:11])=[O:9])[CH2:7][CH2:6]2)=[N:26][CH:27]=1
Reactant: COC(=O)C1(O)CCNCC1
Reactant: Clc1ncc(Br)cn1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCCC
Product: COC(=O)C1(O)CCN(c2ncc(Br)cn2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 43.9 %

Procedure:
To a solution of methyl 4-hydroxypiperidine-4-carboxylate (0.4 g, 2.52 mmol) in EtOH (10 mL) was added DIPEA (2.2 mL, 12.57 mmol) and the solution stirred at rt for 10 min followed by addition of 5-bromo-2-chloropyrimidine (0.49 g, 2.52 mmol). The mixture was then heated up to 70° C. for 1 h. After completion of reaction (by TLC), solvent was evaporated and the crude residue purified over 100-200 M silica-gel using 10% EtOAc:hexane to obtain the desired product as a yellow solid (0.35 g, 44% yield). 1H NMR (DMSO-d6): δ 1.64 (m, 2H), 1.82 (m, 2H), 3.20 (m, 2H), 3.64 (s, 3H), 4.27 (m, 2H), 5.60 (s, 1H) and 8.44 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:7])[S:5][CH:6]=1.Cl[C:9]1[CH:14]=[C:13]([O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:12]=[CH:11][N:10]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>[CH:16]1([O:15][C:13]2[CH:12]=[CH:11][N:10]=[C:9]([NH:7][C:4]3[S:5][CH:6]=[C:2]([CH3:1])[N:3]=3)[CH:14]=2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: Cc1csc(N)n1
Reactant: Clc1cc(OC2CCCCC2)ccn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1csc(Nc2cc(OC3CCCCC3)ccn2)n1
Yield: 31.3 %

Procedure:
Using the method of Example 3, Step B, 4-methylthiazol-2-amine (3.50 mL, 1.40 mmol), 2-chloro-4-(cyclohexyloxy)pyridine (0.326 g, 1.54 mmol), potassium phosphate (0.327 g, 1.54 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.0321 g, 0.0350 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.0223 g, 0.0385 mmol) were reacted in toluene (4 mL) and water (1.5 mL) to afford N-(4-(cyclohexyloxy)pyridin-2-yl)-4-methylthiazol-2-amine (0.127 g, 30.7% yield) as white solid. 1H NMR (CDCl3) δ 8.12 (d, 1H), 6.43 (d, 1H), 6.35 (bs, 1H), 6.32 (d, 1H), 4.29 (m, 1H), 2.34 (d, 3H), 1.97 (m, 2H), 1.80 (m, 2H), 1.54 (m, 3H), 1.36 (m, 3H); Mass spectrum (apci) m/z=290 (100) (M+H).