Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[C:11]([C:18]([OH:20])=O)[CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[S:21]1[CH:25]=[CH:24][N:23]=[C:22]1[NH2:26].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>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[C:11]([C:18]([NH:26][C:22]4[S:21][CH:25]=[CH:24][N:23]=4)=[O:20])[CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1nccs1
Reactant: O=C(O)c1cccc2ccc(-c3ccnc(Cl)c3)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nccs1)c1cccc2ccc(-c3ccnc(Cl)c3)nc12
Temperature: 50 °C
Reaction time: 10 h
Yield: 79.1 %

Procedure:
A mixture of 2-(2-chloropyridin-4-yl)quinoline-8-carboxylic acid (285 mg, 1.0 mmol), thiazol-2-amine (100 mg, 1.0 mmol), HATU (760 mg, 2.0 mmol) and DIPEA (258 mg, 2.0 mmol) in DMF (10 mL) was stirred at 50° C. for 10 hours. The mixture was cooled to room temperature and water (20 mL) was added. The mixture was extracted with ethyl acetate (3×25 mL), and the organic layer was dried over anhydrous Na2SO4, concentrated in vacuo and purified by chromatography on silica gel (5% Methanol in CH2Cl2) to give 2-(2-chloropyridin-4-yl)-N-(thiazol-2-yl)quinoline-8-carboxamide (290 mg, 79% yield).
Reaction SMILES: [Si:1]([O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]2([OH:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][C:17]2=[O:25])=[CH:11][C:10]=1[CH3:27])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:28]1([CH3:37])[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1.N1C=CC=CC=1>ClCCl.ClCCl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:4]([Si:1]([CH3:3])([CH3:2])[O:8][C:9]1[C:10]([CH3:27])=[CH:11][C:12]([C:16]2([OH:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([C:30]3[CH:29]=[C:28]([CH3:37])[CH:33]=[CH:32][CH:31]=3)[C:17]2=[O:25])=[CH:13][C:14]=1[CH3:15])([CH3:6])([CH3:5])[CH3:7]
Reactant: Cc1cc(C2(O)C(=O)Nc3ccccc32)cc(C)c1O[Si](C)(C)C(C)(C)C
Reactant: Cc1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1cccc(N2C(=O)C(O)(c3cc(C)c(O[Si](C)(C)C(C)(C)C)c(C)c3)c3ccccc32)c1
Temperature: 32 °C
Yield: 123.5 %

Procedure:
Using a method similar to Preparation 38, with 3-[4-(tert-Butyl-dimethylsilanyloxy)-3,5-dimethyl-phenyl]-3-hydroxy-1,3-dihydro-indol-2-one (11.51 g, 30 mmol), m-tolylboronic acid (8.16 g, 60 mmol), copper (II) acetate (5.45 g, 30 mmol), pyridine (4.9 ml, 60 mmol) and powdered 4A sieves (15 g) in dichloromethane (100 mL) and heat at 32° C. for 1 day stirring mechanically. Add more m-tolylboronic acid (4.08 g, 30 mmol), copper (II) acetate (2.73 g, 15 mmol), pyridine (5.0 ml, 62 mmol) and powdered 4A sieves (15 g) and continue heating for 1 day. Dilute with dichloromethane/ethyl acetate and filter slowly through a pad of Celite and silica gel. Use three such pads to filter the entire reaction washing liberally with ethyl acetate. After the filtration is complete stir the pads in additional ethyl acetate and refilter. Evaporate the organics in vacuo to obtain 17.55 g of a yellow oil. Purify by preparative HPLC (5% ethyl acetate/hexanes for 5 minutes and then use gradient up to 25% ethyl acetate/hexanes) to obtain 9.05 g (64%) of a yellow gum. MS (ES): m/z=474 (M+1); 1H NMR (DMSO-d6); δ7.47 (t, 1H), 7.30-7.23 (m, 5H), 7.09 (t, 1H), 6.77 (d, 1H), 6.72 (s, 1H), 2.39 (s, 3H), 2.14 (s, 6H), 0.99 (s, 9H), 0.17 (s, 6H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[N-:13]=[N+:14]=[N-:15].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]1[NH:15][N:14]=[N:13][N:6]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccccc1C(F)(F)F
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: FC(F)(F)c1ccccc1-c1nnn[nH]1
Temperature: 110 °C

Procedure:
A vigorously stirred suspension of 2-(trifluoromethyl)benzonitrile (2-A) (6.34 g, 37 mmol), sodium azide (4.81 g, 74 mmol) and triethylamine hydrochloride (10.19 g, 74 mmol) in toluene (70 mL) was heated at 110° C. for 48 h. The mixture was cooled and extracted twice with water. The combined extracts were washed with hexane and brought to pH about 1 with concentrated HCl. The precipitate which formed was filtered, washed with water and dried to give 5-[2-(trifluoromethyl)phenyl]-1H-tetrazole (2-B).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:20]I.N1C=CN=C1.[Br:27][C:28]1[CH:29]=[C:30]([CH:35]=[C:36]([CH2:39]O)[C:37]=1[CH3:38])[C:31]([O:33][CH3:34])=[O:32]>ClCCl>[Br:27][C:28]1[CH:29]=[C:30]([CH:35]=[C:36]([CH2:39][I:20])[C:37]=1[CH3:38])[C:31]([O:33][CH3:34])=[O:32]
Reactant: II
Reactant: COC(=O)c1cc(Br)c(C)c(CO)c1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cc(Br)c(C)c(CI)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a dichloromethane (0.05 M) solution of triphenylphosphine (1.1 eq) was added iodine (1.1 eq.). The resulting orange-yellow suspension was stirred at RT for 30 min before imidazole (1.2 eq.) and finally methyl 3-bromo-5-(hydroxymethyl)-4-methylbenzoate (1 eq.) from the previous step were added. The now pale yellow solution was stirred at RT for another 30 min. The volatiles were removed in vacuo and the residue was triturated with a 1:1 (v/v) mixture of hexanes and ether. The insolubles were then removed via filtration through a pad of silica gel. Concentration of the filtrate in vacuo afforded the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:22][CH:21]=3)[S:17][C:13]=2[N:12]2[C:30]([CH3:33])=[N:31][N:32]=[C:11]2[CH2:10][N:9]=1.C(=O)([O-])[OH:35].[Na+].C(Cl)(Cl)Cl.[Cl:43][C:44]1[CH:45]=[C:46]([CH:50]=[CH:51][C:52]=1[Cl:53])[C:47](Cl)=[O:48]>Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:14]1[CH:15]=[C:16]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:22][CH:21]=2)[S:17][C:13]=1[N:12]1[C:30]([CH3:33])=[N:31][N:32]=[C:11]1[CH2:10][NH:9][C:47](=[O:48])[C:46]1[CH:50]=[CH:51][C:52]([Cl:53])=[C:44]([Cl:43])[CH:45]=1)=[O:35]
Reactant: Cc1nnc2n1-c1sc(CCc3ccc(CC(C)C)cc3)cc1C(c1ccccc1Cl)=NC2
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1nnc(CNC(=O)c2ccc(Cl)c(Cl)c2)n1-c1sc(CCc2ccc(CC(C)C)cc2)cc1C(=O)c1ccccc1Cl
Temperature: 60 °C
Reaction time: 5 h

Procedure:
4-(2-Chlorophenyl)-2-(2-(4-isobutylphenyl)ethyl)-9-methyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepine described in Example 1 of Japanese Patent Publication No. 55510/1993 was dissolved in a 5% aqueous hydrochloric acid solution, and the solution was stirred at 60° C. for 5 hours. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture to make the mixture alkaline. Chloroform and 3,4-dichlorobenzoyl chloride were added, and the mixture was stirred under ice-cooling for 1 hour. The organic layer was washed with an aqueous citric acid solution, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated, and the residue was purified to give N-(4-(3-(2-chlorobenzoyl)-5-(2-(4-isobutylphenyl)ethyl)thiophen-2-yl)-5-methyl[1,2,4]triazol-3-ylmethyl)-3,4-dichlorobenzamide.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.O>C1C=CC=CC=1>[NH:13]([C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Clc1ccc2c(Cl)ncnc2c1
Reactant: Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Solvent: O
Product: Clc1ccc2c(Nc3ccccc3)ncnc2c1
Yield: 82.7 %

Procedure:
8.0 g of 4,7-dichloroquinazoline were dissolved in 250 ml of benzene, and then 4.0 g of aniline and 4.8 g of triethylamine were added to the solution. The resulting mixture was heated to reflux for 5 hours, with stirring. After completion of the reaction, 200 ml of water were added to the reaction mixture. The mixture was shaken and the benzene phase was separated and dried over anhydrous sodium sulphate. The benzene was distilled off and the resulting crystals were recrystallized from ethyl acetate to give 8.5 g (yield 83%) of the desired Compound No. 5 in the form of colourless granules having a melting point of 215°-217° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14].[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:23]=[C:22]1[S:30](Cl)(=[O:32])=[O:31]>N1C=CC=CC=1>[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:23]=[C:22]1[S:30]([NH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14])(=[O:32])=[O:31]
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Reactant: COC(=O)c1ccccc1CSc1ccc(C)cc1N
Solvent: c1ccncc1
Product: COC(=O)c1ccccc1CSc1ccc(C)cc1NS(=O)(=O)c1cc2ccccc2o1
Yield: 74.3 %

Procedure:
Following General Procedure B, the title compound (688 mg, 75%) was prepared from methyl 2-(((2-amino-4-methylphenyl)thio)methyl)benzoate (567 mg, 1.98 mmol) and benzofuran-2-sulfonyl chloride (854 mg, 3.96 mmol) in pyridine (10 ml).
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH2:14][C:15](O)=[S:16])=[N:10][N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:18]1[CH2:28][CH2:27][N:26]2[C:21](=NC[CH2:24][CH2:25]2)[CH2:20][CH2:19]1.ClC(OCC(C)C)=O.C(NC1CCCCC1)C>O1CCCC1>[CH2:25]([N:26]([CH:21]1[CH2:20][CH2:19][CH2:18][CH2:28][CH2:27]1)[C:15](=[S:16])[CH2:14][CH2:13][CH2:12][C:11]1[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=[N:9][N:10]=1)[CH3:24]
Reactant: C1CCC2=NCCCN2CC1
Reactant: OC(=S)CCCc1nnnn1-c1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: CCNC1CCCCC1
Solvent: C1CCOC1
Product: CCN(C(=S)CCCc1nnnn1-c1ccccc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43 %

Procedure:
4-(1-Phenyl-1,2,3,4-tetrazol-5-yl)thio-butyric acid (45 mmol) is dissolved in tetrahydrofuran (50 ml) and thereto is added DBU (50 mmole). To the mixture is added dropwise with stirring isobutyl chloroformate (50 mmole) under ice-cooling. The mixture is stirred at room temperature for 30 minutes. To the mixture is added dropwise N-ethylcyclohexylamine (54 mmole) and the mixture is further stirred at room temperature for 2 hours. After distilling off the solvent under reduced pressure, the residue is extracted with chloroform. The chloroform layer is washed with 5% aqueous hydrochloric acid, an aqueous saturated sodium hydrogen carbonate solution and an aqueous saturated sodium chloride solution and dried over anhydrous sodium sulfate. Chloroform is distilled off and the resulting residue is subjected to column chromatogrophy (Wakogel C-200, eluting solvent, chloroform) to isolate N-ethyl-N-cyclohexyl-4-(1-phenyl-1,2,3,4-tetrazol-5-yl)thio-butyramide (yield: 43%), colorless liquid, nD18 =1.5590.
Reaction SMILES: [O:1]([C:8]1[N:13]=[C:12]([CH2:14][OH:15])[CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:16][C:17]1[CH:22]=[CH:21][C:20](O)=[CH:19][CH:18]=1.[H-].[Na+]>C(OCC)(=O)C.C(N(CC)CC)C.CS(Cl)(=O)=O.CN(C)C=O>[I:16][C:17]1[CH:22]=[CH:21][C:20]([O:15][CH2:14][C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[N:13]=2)=[CH:19][CH:18]=1
Reactant: OCc1cccc(Oc2ccccc2)n1
Reactant: Oc1ccc(I)cc1
Agent: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Ic1ccc(OCc2cccc(Oc3ccccc3)n2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (6-phenoxypyridin-2-yl)methanol (100 mg) in ethyl acetate (4 ml), triethylamine (0.103 ml) and methanesulfonyl chloride (0.062 ml) were added under ice-cooling, the reaction solution was stirred at the same temperature for 1 hour. The reaction solution was diluted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to afford a crude product as a brown oil. To a solution of 4-iodophenol in dimethylformamide (1 ml), 24 mg of sodium hydride was added under ice-cooling, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was cooled to 0° C., a solution of the crude product in dimethylformamide (1 ml) was added, and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was diluted with a saturated saline solution, extracted with diethyl ether, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: ethyl acetate/hexane (0:100-20:80)) to afford the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[S:9][C:8]([SH:11])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(O[K])(C)(C)C.[NH2:18][C:19]1[N:27]=[CH:26][N:25]=[C:24]2[C:20]=1[N:21]=[C:22](Br)[N:23]2[CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][N:33]([C:36](=[O:47])[C@@H:37]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH3:38])[CH2:32][CH2:31]1>CN(C=O)C>[NH2:18][C:19]1[N:27]=[CH:26][N:25]=[C:24]2[C:20]=1[N:21]=[C:22]([S:11][C:8]1[S:9][C:10]3[C:2]([Cl:1])=[CH:3][CH:4]=[CH:5][C:6]=3[N:7]=1)[N:23]2[CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][N:33]([C:36](=[O:47])[C@@H:37]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:44])([CH3:43])[CH3:45])[CH3:38])[CH2:32][CH2:31]1
Reactant: Sc1nc2cccc(Cl)c2s1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC(CCn2c(Br)nc3c(N)ncnc32)CC1
Agent: CC(C)(C)O[K]
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC(CCn2c(Sc3nc4cccc(Cl)c4s3)nc3c(N)ncnc32)CC1
Temperature: 130 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 7-Chloro-2-mercaptobenzothiazole (0.020 g, 0.097 mmol) in DMF (2.0 mL) was added (CH3)3COK (0.011 g, 0.97 mmol) at room temperature and stirring continued for 30 min. To the above reaction mixture tert-butyl ((1S)-2-{4-[2-(6-amino-8-bromo-9H-purin-9-yl)ethyl]piperidin-1-yl}-1-methyl-2-oxoethyl)carbamate (0.040 g, 0.081 mmol) in (1 mL) of DMF was added at room temperature. The reaction mixture was heated to 130° C. for 6 h, at the end of this period solvent was evaporated and crude was purified by preparative HPLC [X-Terra prep-RP18 10 um, 19×250 mm (waters), Mobile phase: solvent A: Water HPLC grade containing 0.01% TFA, and solvent B: acetonitrile containing 0.01% TFA, general eluting gradient—solvent B 15% to 80 over 15 to 25 minutes run time]. After lyophilization of HPLC fractions to afford title product. 1H NMR δ (CD3OD), 8.35 (s, 1H), 7.85-7.82 (m, 1H), 7.50-7.40 (m, 2H), 4.40 (t, J=7.2 Hz, 2H), 4.00-3.90 (m, 2H), 1.80-1.70 (m, 4H), 1.21-1.15 (m, 6H), 1.15 (s, 9H), 1.10 (s, 3H); LC-MS [M+H]+ 617.1
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:10]2[N:11]([C:15]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH:25]4[CH2:30][CH2:29][CH:28]([C:31](O)=[O:32])[CH2:27][CH2:26]4)[N:19]=3)=[CH:16][N:17]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:4])=[O:3].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[NH:70]1[CH2:75][CH2:74][CH:73]([OH:76])[CH2:72][CH2:71]1>CN(C=O)C.O>[OH:76][CH:73]1[CH2:74][CH2:75][N:70]([C:31]([CH:28]2[CH2:29][CH2:30][CH:25]([NH:24][C:20]3[N:19]=[C:18]([C:15]4[N:11]5[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:7][CH2:6][CH2:5][S:2]([CH3:1])(=[O:3])=[O:4])[C:10]5=[N:17][CH:16]=4)[CH:23]=[CH:22][N:21]=3)[CH2:26][CH2:27]2)=[O:32])[CH2:71][CH2:72]1
Reactant: OC1CCNCC1
Reactant: CS(=O)(=O)CCCOc1cccn2c(-c3ccnc(NC4CCC(C(=O)O)CC4)n3)cnc12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)CCCOc1cccn2c(-c3ccnc(NC4CCC(C(=O)N5CCC(O)CC5)CC4)n3)cnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.1 %

Procedure:
A solution of 4-{4-[8-(3-methanesulfonyl-propoxy)-imidazo[1,2-a]pyridine-3-yl]-pyrimidin-2-ylamino}-cyclohexanecarboxylic acid (0.09 g) in DMF (3 mL) was treated with BOP (0.126 g), and the mixture stirred at RT for 15 min DIEA (0.1 mL) and piperidin-4-ol (29 mg) were added, and the mixture stirred at RT overnight. The reaction mixture was then diluted with water and stirred at RT for 30 min, permitting the product to precipitate. The resulting solid was filtered, washed with water, dried, and titurated with EtOAc. The product was filtered, dried at 50° C. under vacuum overnight to provide (4-hydroxy-piperidin-1-yl)-(4-{4-[8-(3-methanesulfonyl-propoxy)-imidazo[1,2-a]pyridin-3-yl]-pyrimidin-2-ylamino}-cyclohexyl)-methanone (compound 5, 71 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30](F)=[CH:29][CH:28]=[CH:27][C:26]=4F)[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.C(S([C:39]1[CH:40]=[CH:41][C:42](OC)=[C:43]([NH2:45])[CH:44]=1)(=O)=O)C>>[CH2:2]1[C:39]2[C:40](=[CH:41][CH:42]=[C:43]([NH:45][C:2]3[N:7]=[C:6]([C:8]4[C:9]([C:17]5[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]6[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=6)[CH:20]=[CH:21][CH:22]=5)=[N:10][N:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=45)[CH:5]=[CH:4][N:3]=3)[CH:44]=2)[CH2:5][CH2:4][NH:3]1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Reactant: CCS(=O)(=O)c1ccc(OC)c(N)c1
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CNCC4)n2)c1)c1ccccc1

Procedure:
The title compound was prepared by a procedure similar to Example 27, Step D using N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide and [5-(ethylsulfonyl)-2-(methyloxy)phenyl]amine: MS (APCI): 641 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@H:14]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:15][C@@:9]1([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:10](=[O:25])[CH:11]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].O.CO.C(OCC)(=O)C>[CH2:1]([N:8]1[C@@H:13]2[C@H:14]([S:16]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)(=[O:17])=[O:18])[CH2:15][C@@:9]1([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:10](=[O:25])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C=C[C@H]2[C@H](S(=O)(=O)c3ccccc3)C[C@]1(c1ccccc1)N2Cc1ccccc1
Agent: [Pd]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C1CC[C@H]2[C@H](S(=O)(=O)c3ccccc3)C[C@]1(c1ccccc1)N2Cc1ccccc1
Reaction time: 1 h
Yield: 97.8 %

Procedure:
10% Palladium on carbon (1 g) was added as a slurry in water (2 ml) to a solution of (1R*,5S*,6R*)-8-benzyl-1-phenyl-6-phenylsulphonyl-8-azabicyclo[3.2.1]oct-3-ene-2-one (Description 6; 11 g, 25.6 mmol) in methanol (50 ml) and ethyl acetate (50 ml). The mixture was hydrogenated at 30 psi for one hour. The reaction mixture was filtered through a pad of Celite™. The filter cake was washed with dichloromethane (1L) and the combined filtrates concentrated in vacuo to give the title compound (10.8 g, 98%).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:7][CH2:6][CH:5]([N:8]([C@H:16]2[CH2:20][CH2:19][NH:18][CH2:17]2)[C:9](=[O:15])[C:10]([CH3:14])([CH3:13])[CH2:11][F:12])[CH2:4][CH2:3]1.[C:22]([N:26]1[CH2:30][C@@H:29]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[C@H:28]([C:38](O)=[O:39])[CH2:27]1)([CH3:25])([CH3:24])[CH3:23]>>[ClH:37].[C:22]([N:26]1[CH2:30][C@@H:29]([C:31]2[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=2)[C@H:28]([C:38]([N:18]2[CH2:19][CH2:20][C@H:16]([N:8]([CH:5]3[CH2:6][CH2:7][C:2]([CH3:21])([CH3:1])[CH2:3][CH2:4]3)[C:9](=[O:15])[C:10]([CH3:13])([CH3:14])[CH2:11][F:12])[CH2:17]2)=[O:39])[CH2:27]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)N1C[C@@H](C(=O)O)[C@H](c2ccc(Cl)cc2)C1
Reactant: CC1(C)CCC(N(C(=O)C(C)(C)CF)[C@H]2CCNC2)CC1
Product: CC1(C)CCC(N(C(=O)C(C)(C)CF)[C@H]2CCN(C(=O)[C@@H]3CN(C(C)(C)C)C[C@H]3c3ccc(Cl)cc3)C2)CC1
Product: Cl

Procedure:
The title compound was prepared according to the procedure described in Step F, G of Example A1, using N-(4,4-dimethylcyclohexyl)-3-fluoro-2,2-dimethyl-N-[(3S)-pyrrolidine-3-yl]propaneamide (100 mg, 0.47 mmol) prepared in Step B and (3S,4R)-1-t-butyl-4-(4-chlorophenyl)pyrrolidine-3-carboxylic acid prepared in Preparation Example A9-2 (230 mg, 89%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][CH2:10][CH3:11])[CH:3]=1.[F:12][CH:13]([F:23])[O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[CH:22])=[CH:17][CH:16]=1>>[CH2:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:22]#[C:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][CH:13]([F:23])[F:12])=[CH:16][CH:17]=2)[CH:3]=1)[CH2:9][CH2:10][CH3:11]
Reactant: C#Cc1ccc(OC(F)F)cc1
Reactant: CCCCc1cccc(Br)c1
Product: CCCCc1cccc(C#Cc2ccc(OC(F)F)cc2)c1

Procedure:
Using essentially the same procedure described in Example 1, step a, and employing 1-bromo-3-butylbenzene and 1-(difluoromethoxy)-4-ethynylbenzene, the phenylethynylbenzene product was obtained. This product was purified on silica gel (Biotage) using hexanes/EtOAc 50/1 as the eluting solvents to give 1-butyl-3-{[4-(difluoromethoxy)phenyl]ethynyl}benzene as a colorless oil (0.56 g, 28% yield), MS m/e M+ 300; 1H NMR (400 MHz, DMSO-d6) 0.82 (t, J=7.19 Hz, 3H), 1.25 (m, 2H), 1.55 (m, 2H), 2.56 (t, J=7.56 Hz, 2H), 7.2 (m, 3H), 7.35-7.45 (m, 4H), 7.58 (d, J=8.79 Hz, 2H).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:14]=1)=O.[C:15]([NH2:18])(=[S:17])[CH3:16]>O1CCOCC1>[O:13]1[C:8]2[CH:7]=[CH:6][C:5]([C:3]3[N:18]=[C:15]([CH3:16])[S:17][CH:2]=3)=[CH:14][C:9]=2[CH2:10][CH2:11][CH2:12]1
Reactant: CC(N)=S
Reactant: O=C(CCl)c1ccc2c(c1)CCCO2
Solvent: C1COCCO1
Product: Cc1nc(-c2ccc3c(c2)CCCO3)cs1
Yield: 87.5 %

Procedure:
A solution of 2-chloro-1-(3,4-dihydro-2H-1-benzopyran-6-yl)ethan-1-one (9b) (270 mg, 1.28 mmol) and thioacetamide (106 mg, 1.41 mmol) in dioxane (10 mL) was refluxed for 20 hours, then the reaction mixture was concentrated in vacuo. The residue was diluted with dichloromethane (20 mL), washed with water (10 mL), brine (10 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 80/20) to afford the desired thiazole (13a) as a yellow oil (260 mg, 1.12 mmol, 88%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].CN(C)C=O.[F:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[C:20]([CH:25]=[CH:26][C:27]1[O:28][C:29]([N+:32]([O-:34])=[O:33])=[CH:30][CH:31]=1)[N:19]=[C:18]2Cl>O>[F:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[C:20]([CH:25]=[CH:26][C:27]1[O:28][C:29]([N+:32]([O-:34])=[O:33])=[CH:30][CH:31]=1)[N:19]=[C:18]2[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8]
Reactant: O=[N+]([O-])c1ccc(C=Cc2nc(Cl)c3cc(F)ccc3n2)o1
Reactant: Nc1ccccc1O
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(C=Cc2nc(Nc3ccccc3O)c3cc(F)ccc3n2)o1
Reaction time: 8 h
Yield: 95.6 %

Procedure:
An Erlenmeyer flask equipped with magnetic stirrer and oil bath for heating is charged with 5.0 g (0.046 mole) of o-aminophenol and 100 ml of dimethylformamide. The charge is stirred to dissolve o-aminophenol and 6.0 g (0.02 mole) of 6-fluoro-2-[2-(5-nitro-2-furyl)vinyl]-4-chloroquinazoline (IV) added. The reaction mixture is reacted at 80° to 90° C. for 2 hours to form an organic precipitate; 100 ml of water is added to the warm mixture which is then allowed to cool and placed overnight in a refrigerator to crystallize. The solids are collected, washed with methanol and dried to obtain 7.5 g of brown-tan solid. A solution of the product in 100 ml of dimethylformamide is treated with activated carbon and filtered. A first portion of 75 ml of methanol is added to the warm filtrate then an additional 25 ml portion. Cooling and scratching gives 5.5 g of orange crystals of the purified product.