Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][N:8]=2)[CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)CC)C.[NH2:47][CH2:48][C:49]1[C:58](=[O:59])[C:57]2[C:52](=[CH:53][C:54]([Cl:60])=[CH:55][CH:56]=2)[N:51]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[C:50]=1[C:67]([N:69]([CH3:71])[CH3:70])=[O:68]>CN(C=O)C>[CH3:70][N:69]([CH3:71])[C:67]([C:50]1[N:51]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[C:52]2[C:57]([C:58](=[O:59])[C:49]=1[CH2:48][NH:47][C:11]([C:10]1[CH:9]=[N:8][C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[CH:15][CH:14]=1)=[O:13])=[CH:56][CH:55]=[C:54]([Cl:60])[CH:53]=2)=[O:68]
Reactant: O=C(O)c1ccc(N2CCOCC2)nc1
Reactant: CN(C)C(=O)c1c(CN)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1c(CNC(=O)c2ccc(N3CCOCC3)nc2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
6-Morpholinonicotinic acid (32.6 mg, 0.142 mmol), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBrOP) (120 mg, 0.374 mmol) and triethylamine (100 mg, 0.137 mL, 0.988 mmol) were combined with DMF (4 mL). The reaction mixture was stirred at room temperature for 10 min. After this time, 3-(aminomethyl)-7-chloro-N,N-dimethyl-4-oxo-1-phenyl-1,4-dihydroquinoline-2-carboxamide (intermediate C) (0.052 g, 0.156 mmol) was added. The reaction mixture was stirred at room temperature for 15 hr. The crude material was purified by flash chromatography (10% ethyl acetate-hexanes ramped to 100% ethyl acetate). MS calcd. for C29H28ClN5O4 [(M+H)+] 546.2, obsd. 546.0.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:8])=[CH:3][C:2]=1[C:15]([O:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[O:16].C1C=C(Cl)C=C(C(OO)=[O:31])C=1>>[N+:1]1([O-:31])[C:2]([C:15]([O:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[O:16])=[CH:3][C:4]([C:7]([O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:8])=[CH:5][CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)COC(=O)c1ccnc(C(=O)OCC(=O)OC)c1
Product: COC(=O)COC(=O)c1cc[n+]([O-])c(C(=O)OCC(=O)OC)c1

Procedure:
From 1 g of di-(methoxycarbonylmethyl) pyridine-2,4-dicarboxylate and 1.1 g of MCPBA.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([OH:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[N+:12]([CH2:15][C:16](=[O:34])[C@@H:17]([NH:26]C(=O)OC(C)(C)C)[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([O-:14])=[O:13]>C(OCC)C.ClCCl>[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([S:7]([OH:10])(=[O:8])=[O:9])=[CH:5][CH:6]=1.[NH2:26][C@@H:17]([CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:16](=[O:34])[CH2:15][N+:12]([O-:14])=[O:13]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)C(=O)C[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: N[C@@H](CCc1ccccc1)C(=O)C[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 70 h
Yield: 97.9 %

Procedure:
A solution comprised of anhydrous p-toluenesulfonic acid (26 mmol) in ethyl ether (10 mL) was added to a suspension comprised of tert-butyl (S)-3-nitro-2-oxo-1-phenethylpropylcarbamate (4.5 g, 14 mmol) in dichloromethane (20 mL) and ethyl ether (150 mL). The mixture was stirred for 70 hours at room temperature and the filtered. The solid collected was washed thoroughly with ethyl ether and dried in vacuo to provide (S)-3-amino-1-nitro-5-phenylpentan-2-one p-toluenesulfonic acid salt (5.4 g, 13.7 mmol) as a white solid. 1H NMR (270 MHz, DMSO-d6): δ 1.92-2.05 (m, 1H), δ 2.15-2.28 (m, 1H), δ 2.29 (s, 3H), δ 2.56-2.76 (m, 2H), δ 4.44 (br.s, 1H), δ 6.97 (d, J=16.1 Hz, 1H), δ 6.29 (d J=16.1 Hz, 1H), δ 7.12 (d, J=8.4 Hz, 2H), δ 7.20-7.35 (m, 5H), δ 7.49 (d, J=8.2 Hz, 1H), δ 8.46 (br.s, 3 NH).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.C1(/C=C\C2C=CC=CC=2)C=CC=CC=1.C1(/C=C/C2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C>[C:1]1([CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C(#Cc1ccccc1)c1ccccc1
Agent: C(=C/c1ccccc1)\c1ccccc1
Agent: C(=C\c1ccccc1)\c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: c1ccc(CCc2ccccc2)cc1
Reaction time: 0.5 h
Yield: 92 %

Procedure:
1.34 g (7.5 mmol) of diphenylacetylene (1), 4.01 mL (225 mmol) of distilled water and stainless steel balls (25 pieces) were placed in the vessel of the planetary ball mill, which was then closed, and agitated by operating the planetary ball mill for 6 hours at 650 rpm (reversed every 30 minutes). After the lapse of 6 hours, 200 mL of ethyl acetate was added to the vessel of the ball mill to provide a solution containing the reaction mixture, which was then filtered with celite. The filtrate was concentrated, thereby providing reaction products. The confirmation by 1H-NMR thereof revealed that a mixture of cis-1,2-diphenylethylene (26), trans-1,2-diphenylethylene (27) and 1,2-diphenylethane (2) was obtained at a mixing ratio of 92/0/8. The yield was 92%. The reaction is expressed by the following scheme.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH:7]=[C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH:12]=[CH:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)[CH2:2]1.[CH2:23]=O.Cl>C(O)=O>[CH3:23][N:1]1[CH2:6][CH2:5][O:4][CH:3]([CH:7]=[C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH:12]=[CH:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)[CH2:2]1
Reactant: C1=Cc2ccccc2C(=CC2CNCCO2)c2ccccc21
Reactant: C=O
Agent: Cl
Solvent: O=CO
Product: CN1CCOC(C=C2c3ccccc3C=Cc3ccccc32)C1
Reaction time: 6.5 h

Procedure:
A mixture of 5-(morpholin-2-yl)methylidene-5H-dibenzo[a,d]cycloheptene (0.35 g), 90% formic acid (0.7 g) and 37% formalin (0.65 ml) was stirred at 95°-100° C. for 6.5 hours. After cooling, 4 N hydrochloric acid was added thereto, and the resulting mixture was evaporated to dryness under reduced pressure, neutralized with ammonia water and extracted with benzene. The benzene extract was washed with water, dried over anhydrous sodium sulfate and evaporated to afford 5-(4-methylmorpholin-2-yl)methylidene-5H-dibenzo[a,d]cycloheptene as oily material. M.P., 237°-238° C. (decomp.) (oxalate).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[S:8][C:9]([CH2:12][NH:13][C:14](=[O:16])[CH3:15])=[CH:10][CH:11]=2)[N:6]=1.C(N(CC)CC)C.[C:24](Cl)(=[O:26])[CH3:25]>C(Cl)(Cl)Cl>[C:24]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[S:8][C:9]([CH2:12][NH:13][C:14](=[O:16])[CH3:15])=[CH:10][CH:11]=2)[N:6]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: CC(=O)NCc1ccc(-c2csc(N)n2)s1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)NCc1ccc(-c2csc(NC(C)=O)n2)s1
Temperature: 25 °C

Procedure:
To a suspension of 5.0 g of 2-amino-4-(5-acetylaminomethyl-2-thienyl]thiazole in 200 ml of chloroform is added 12 ml of triethylamine, and is added dropwise 1.7 g of acetyl chloride with stirring at room temperature. The whole mixture is stirred at room temperature for an hour. After completion of the reaction, the resultant mixture is washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. After the residue is crystallized from ethanol, the crystals are collected by filtration and recrystallized from ethanol to give 2-acetylamino-4-(5-acetylaminomethyl-2-thienyl)thiazole, melting at 251° C. with decomposition.
Reaction SMILES: Br[CH:2]1[C:11]2[C:6](=[N:7][C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:10]=2)[N:5]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:4][CH2:3]1.[CH3:31][OH:32]>C(=O)([O-])[O-].[Ag+2]>[CH3:31][O:32][CH:2]1[C:11]2[C:6](=[N:7][C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:10]=2)[N:5]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(Br)c2nc(-c3ccccc3)c(-c3ccccc3)nc21
Reactant: CO
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Product: COC1CCN(C(=O)OC(C)(C)C)c2nc(-c3ccccc3)c(-c3ccccc3)nc21
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of tert-butyl 8-bromo-2,3-diphenyl-7,8-dihydropyrido[2,3-b]pyrazine-5(6H)-carboxylate (Intermediate H) (200 mg, 0.429 mmol) in dry MeOH (8 ml, 198 mmol) was added silver carbonate (237 mg, 0.858 mmol). The mixture was stirred at RT for 2.5 hours under nitrogen and then filtered through Celite® (filter material) washing through with methanol (25 ml). The filtrate was concentrated in vacuo to afford the title compound;
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH:12]1C=CC=CC=1.C(OCC)C>O>[CH2:12]=[C:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: c1ccccc1
Solvent: CCOCC
Solvent: O
Product: C=C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
1,4-Dioxaspiro[4.5]decan-8-one (21 g, 0.13 mol) in dry benzene (50 mL, 0.6 mol) was added to ethylenetriphenylphosphorane [prepared from dimsyl sodium and methyltriphenylphosphonium bromide (106 g, 0.291 mol) in dimethyl sulfoxide (600 mL, 8 mol)] The mixture was stirred at room temperature overnight and poured into a separating funnel containing ethyl ether (500 mL) and water (500 mL). The organic layer was separated and the aqueous phase was extracted with ethyl ether (2×500 mL). The combined ether layers were washed with water (500 mL) and brine (500 mL), and dried. The solvents were removed under reduced pressure and the residue was purified by flash chromatography to afford the desired product (18.0 g, 85%).
Reaction SMILES: [CH2:1]([C@:3]1([OH:19])[C:15]2[CH:14]=[C:13]3[N:9]([CH2:10][CH2:11][C:12]3=O)[C:8](=[O:17])[C:7]=2[CH2:6][O:5][C:4]1=[O:18])[CH3:2].[C:20]([NH:23][CH:24]1[CH2:33][CH2:32][C:31]2[C:26](=[C:27]([NH2:34])[CH:28]=[CH:29][CH:30]=2)[C:25]1=O)(=[O:22])[CH3:21].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C=CC=CC=1>[C:20]([NH:23][CH:24]1[C:25]2=[C:11]3[CH2:10][N:9]4[C:13](=[CH:14][C:15]5[C@:3]([CH2:1][CH3:2])([OH:19])[C:4](=[O:18])[O:5][CH2:6][C:7]=5[C:8]4=[O:17])[C:12]3=[N:34][C:27]3[CH:28]=[CH:29][CH:30]=[C:31]([C:26]=32)[CH2:32][CH2:33]1)(=[O:22])[CH3:21]
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)CCC1=O
Reactant: CC(=O)NC1CCc2cccc(N)c2C1=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1cccc3c1c2C(NC(C)=O)CC3
Reaction time: 24 h

Procedure:
361 mg of (S)-4-ethyl-4-hydroxy-7,8-dihydro-1H-pyrano-[3,4-f]indolizine-3,6,10(4H)-trione (hereinafter abbreviated as "trione") was added to the solution of 300 mg of the compound prepared in (4) above in 200 ml of toluene. The mixture was heated under reflux using a Deanstark apparatus for 10 minutes. To the mixture was added 1 mg of pyridinium-p-toluenesulfonate (hereinafter abbreviated as "PPTS") and the mixture was refluxed while stirring for a further 24 hours. After cooling, the residue obtained by removing toluene by concentration was suspended into 300 ml of chloroform-methanol (10:1) solvent. Insoluble substances were removed and the residue was powdered with methanol to obtain 336 mg of the title compound. mp: above 240° C. (decomposed)
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:17]=[C:16]([O:18][CH:19]([F:21])[F:20])[N:15]([CH3:22])[N:14]=2)=[CH:9][CH:8]=1>C(Cl)(Cl)(Cl)Cl>[Cl:4][C:17]1[C:13]([C:10]2[CH:9]=[CH:8][C:7]([Cl:6])=[CH:12][CH:11]=2)=[N:14][N:15]([CH3:22])[C:16]=1[O:18][CH:19]([F:21])[F:20]
Reactant: O=S(=O)(Cl)Cl
Reactant: Cn1nc(-c2ccc(Cl)cc2)cc1OC(F)F
Solvent: ClC(Cl)(Cl)Cl
Product: Cn1nc(-c2ccc(Cl)cc2)c(Cl)c1OC(F)F
Temperature: 20 °C
Reaction time: 2 h

Procedure:
74.0 g (0.549 mol) of sulfuryl chloride dissolved in 200 ml of carbon tetrachloride were added slowly dropwise to a solution of 128.9 g (0.5 mol) of 3-(4-chlorophenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole in 500 ml of carbon tetrachloride, the ensuing reaction being exothermic with evolution of gas. After the end of the reaction the mixture was stirred at about 20° C. for a further 2 h. The reaction solution was then washed with about 300 ml each of water, saturated sodium hydrogen carbonate solution and saturated sodium chloride solution, and then dried and concentrated. Yield: 139.3 g; 1H-NMR (270 MHz, in CDCl3): δ [ppm]=7.79 (d, 2H), 7.43 (d, 2H), 6.70 (t, 1H), 3.85 (s, 3H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]1[CH2:13][NH:12][C:11](=[O:14])[N:10]2[C:15]3[N:21]=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=[C:9]12.Cl[C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl.NCC(C1NC2C(C=1)=C(OC)C=CN=2)OC1CCCCO1.CCN(C(C)C)C(C)C>C(Cl)Cl>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]1[CH2:13][NH:12][C:11](=[O:14])[N:10]2[C:15]3[N:21]=[CH:20][CH:19]=[C:18]([O:25][CH3:23])[C:16]=3[CH:17]=[C:9]12
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: O=C1NCC(OC2CCCCO2)c2cc3cccnc3n21
Agent: COc1ccnc2[nH]c(C(CN)OC3CCCCO3)cc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccnc2c1cc1n2C(=O)NCC1OC1CCCCO1
Yield: 63 %

Procedure:
Following the same procedure as for 10a, from triphosgene (20 mg, 0.07 mmol) in CH2Cl2 (3 ml), 9b (58 mg, 0.20 mmol) and DIPEA (34 μl, 0.20 mmol) in CH2Cl2 (3 ml). Reaction time 30 min. at room temperature. The crude mixture was purified by flash column chromatography. Elution with CH2Cl2/MeOH (98/2) gave a diastereomeric mixture (1:1) of 10b (40 g, 63%).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:30][O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[C:27]([OH:29])=O)[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:38][CH:39]1[C:58](=[O:59])[N:41]2[C:42]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])=[C:43]([CH2:46][O:47][C:48](=[O:50])[CH3:49])[CH2:44][S:45][C@H:40]12.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:30][O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[C:27]([NH:38][CH:39]2[C:58](=[O:59])[N:41]3[C:42]([C:51]([O:53][C:54]([CH3:56])([CH3:55])[CH3:57])=[O:52])=[C:43]([CH2:46][O:47][C:48](=[O:50])[CH3:49])[CH2:44][S:45][C@H:40]23)=[O:29])[N:25]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(N)[C@H]2SC1
Reactant: O=C(O)C(=NOC1CCCCO1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClC(Cl)Cl
Product: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(NC(=O)C(=NOC3CCCCO3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 0.362 g of the product of Step C, 0.244 g of tert.-butyl 7-amino-3-acetoxymethyl-ceph-3-eme-4-carboxylate, 0.280 g of dicyclohexylcarbodiimide and 4 ml of dry chloroform was stirred for 2 hours at room temperature and the mixture was vacuum filtered to remove dicyclohexylurea which was rinsed with chloroform. The filtrate was evaporated to dryness under reduced pressure and the residue was dissolved in 1 ml of ether. The solution was chromatographed over silica gel and was eluted with ether. The fractions with an Rf=0.38 were combined and evaporated to dryness under reduced pressure. The residue was taken up in isopropyl ether and effloresced. The mixture was vacuum filtered and the recovered product was rinsed with isopropyl ether to obtain 0.184 g of the syn isomer of tert.-butyl 7-[2-(2-tritylamino-4-thiazolyl)-2-tetrahydropyranyloxyimino-acetamido]-3-acetoxymethyl-ceph-3-eme-4-carboxylate.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:5]([CH2:15][C:16]2([OH:22])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[OH:22][C:16]1([CH2:15][C@H:5]2[CH2:4][CH2:3][C@H:2]([O:1][S:31]([CH3:30])(=[O:33])=[O:32])[CH2:7][N:6]2[C:8]([O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[O:9])[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CC(O)CCC1CC1(O)CCOCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@@H](OS(C)(=O)=O)CC[C@@H]1CC1(O)CCOCC1
Temperature: 25 °C
Yield: 28.1 %

Procedure:
To a stirred solution of tert-butyl 5-hydroxy-2-[(4-hydroxytetrahydro-2H-pyran-4-yl)methyl]piperidine-1-carboxylate (1.92 g, 6.09 mmol, step 2 of Example 2), triethylamine (739 mg, 7.30 mmol) in dichloromethane (27 mL) was added methanesulfonyl chloride (836 mg, 7.30 mmol) at 0° C., and the mixture was allowed to warm to room temperature over 20 h. The mixture was quenched with water (50 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (50 mL×3). The combined organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was chromatographed on a column of silica gel eluting with n-hexane/ethyl acetate (1:5) to give 673 mg (28%) of the title compound as a white crystal. (cis isomer, 634 mg, 26% yield)
Reaction SMILES: [C:1]1([N:7]2[C:11]3[C:12]([C:16]#[N:17])=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:18]([NH:20][C:21]2[N:29]=[CH:28][N:27]=[C:26]3[C:22]=2[N:23]=[CH:24][NH:25]3)[CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=[O:31].[K+].[K+].OO>CS(C)=O.O>[C:1]1([N:7]2[C:11]3[C:12]([C:16]([NH2:17])=[O:31])=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:18]([NH:20][C:21]2[N:29]=[CH:28][N:27]=[C:26]3[C:22]=2[N:23]=[CH:24][NH:25]3)[CH3:19])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2cccc(C#N)c2n1-c1ccccc1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2cccc(C(N)=O)c2n1-c1ccccc1
Reaction time: 2 h
Yield: 121.4 %

Procedure:
3-Phenyl-2-[(S)-1-(9H-purin-6-ylamino)ethyl]-3H-benzoimidazole-4-carbonitrile (70 mg, 0.18 mmol) was dissolved in DMSO (2 mL) and to this solution was added a solution of K2CO3 (10 mg) in water (0.1 mL). H2O2 (0.2 mL, 30% in water) was added dropwise and the resulting solution stirred for 2 h. Very slow hydrolysis occurred as observed by LCMS. The solution was heated at 60° C. over 2 days with additional aliquots of H2O2 (2×0.2 mL). The cooled mixture was poured onto water. The resulting aqueous solution was passed through an SCX cartridge, the cartridge was washed with water and MeOH and the product eluted with 2M NH3 in MeOH. The product fractions were combined and evaporated and the residue purified by chromatography (Si—PCC, 0-10% 2M methanolic NH3 in DCM). The product fractions were concentrated in vacuo to give white solid. This was triturated in ether, filtered and dried in vacuo to give 311 as a white solid (35 mg, 50%). 1H NMR (DMSO-d6, 400 MHz): δ 8.18-8.00 (2H, m), 7.87-7.77 (1H, m), 7.66 (1H, d, J=7.4 Hz), 7.55-7.27 (6H, m), 7.23-7.13 (2H, m), 6.95 (1H, s), 5.38-5.18 (1H, m), 1.46 (3H, d, J=6.7 Hz). LCMS (Method K): RT 1.99 min; m/z 399 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](F)=[N:6][C:5]=1[F:11].[F:13][C:14]([F:24])([F:23])[C:15]1[N:20]=[CH:19][C:18]([CH2:21][NH2:22])=[CH:17][CH:16]=1.O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH:22][CH2:21][C:18]2[CH:19]=[N:20][C:15]([C:14]([F:24])([F:13])[F:23])=[CH:16][CH:17]=2)=[N:6][C:5]=1[F:11]
Reactant: COC(=O)c1ccc(F)nc1F
Reactant: NCc1ccc(C(F)(F)F)nc1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(NCc2ccc(C(F)(F)F)nc2)nc1F
Temperature: -40 °C

Procedure:
To 2,6-difluoro-nicotinic acid methyl ester (60, 1.82 g, 0.0105 mol, prepared as described in Example 22, Scheme 24, Step 2) in N,N-dimethylformamide (20.0 mL), under an atmosphere of nitrogen at −40° C., C-(6-trifluoromethyl-pyridin-3-yl)-methylamine (561, 1.00 g, 5.68 mmol) was added. The reaction was stirred at −40° C., then allowed to warm to room temperature for 2 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 35% to 100% ethyl acetate in hexane to give a white solid (562, 1.40 g, 74.9). MS (ESI) [M+H+]+=330.1.
Reaction SMILES: C(O[CH:4](OCC)[CH:5]=[C:6]([CH3:8])[CH3:7])C.[C:12]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)#[N:13].N1C=CC=C(C)C=1>CC1C=CC(C)=CC=1>[CH3:7][C:6]1([CH3:8])[CH:5]=[CH:4][C:16]2[CH:15]=[C:14]([C:12]#[N:13])[CH:19]=[CH:18][C:17]=2[O:20]1
Reactant: N#Cc1ccc(O)cc1
Reactant: CCOC(C=C(C)C)OCC
Solvent: Cc1ccc(C)cc1
Solvent: Cc1cccnc1
Product: CC1(C)C=Cc2cc(C#N)ccc2O1

Procedure:
A 500-mL, 3-necked, round-bottomed flask topped with a distilling head, internal temperature probe/argon inlet, and an overhead stirrer was sequentially charged with the title A compound, 1,1-diethoxy-3-methyl-2-butene (26.59 g, 168.00 mmol), p-xylene (300 mL), 4-cyanophenol (15.00 g, 125.92 mmol), and 3-picoline (3.0 mL, 2.870 g, 30.83 mmol). The reaction mixture was rapidly stirred. The internal temperature was rapidly brought up to 115° C. and then slowly raised in order to distill off the ethanol formed during the reaction.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=2)[N:4]=1.[CH3:23][NH:24][CH2:25][CH2:26][CH2:27][CH3:28]>>[CH2:25]([N:24]([CH3:23])[C:16](=[O:17])[C:15]1[CH:14]=[CH:13][C:12]([N:5]2[C:6]3[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=3[C:3]([C:2]([F:21])([F:1])[F:22])=[N:4]2)=[CH:20][CH:19]=1)[CH2:26][CH2:27][CH3:28]
Reactant: O=C(O)c1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Reactant: CCCCNC
Product: CCCCN(C)C(=O)c1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1

Procedure:
The title compound was prepared from 4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzoic acid and N-methylbutylamine using a similar procedure to that described for Example 2.
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[C:10]([Cl:23])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([I:24])[CH:8]=2)[N:3]=1.C[O-].[Na+].[C:28](=O)(O)[O-:29].[Na+]>C1(C)C=CC=CC=1>[Cl:23][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([I:24])[CH:8]=2)[N:3]=[C:2]([O:29][CH3:28])[C:11]=1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1
Reactant: O=C([O-])O
Reactant: FC(F)(F)c1ccc(Cc2c(Cl)nc3ccc(I)cc3c2Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1nc2ccc(I)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 92 °C
Reaction time: 13 h

Procedure:
A heterogeneous mixture of 2,4-dichloro-6-iodo-3-(4-(trifluoromethyl)benzyl)quinoline (515 g, 1.068 mol, Intermediate 62: step b) and sodium methoxide (577.1 g, 10.68 mol) in toluene (5.34 L) was heated to 92° C. for 18 h and then 100° C. for 13 h. After cooling to room temperature the slurry was poured over an aqueous solution of sodium bicarbonate (11.54 kg, 7 wt %, 9.615 mol). The biphasic system was mixed and then the layers were separated. The organic layer was dried over MgSO4, filtered, and concentrated to afford the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:12](=O)[CH2:13]Br)=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.[NH2:16][C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1.C(N(CC)CC)C>C(O)C>[NH2:1][C:2]1[S:3][C:4]([C:12]2[N:16]=[C:17]3[N:22]=[CH:21][CH:20]=[CH:19][N:18]3[CH:13]=2)=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1
Reactant: Nc1ncccn1
Reactant: CCOC(=O)c1nc(N)sc1C(=O)CBr
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc(N)sc1-c1cn2cccnc2n1
Yield: 27.5 %

Procedure:
A solution of ethyl 2-amino-5-(2-bromoacetyl)-4-thiazolecarboxylate (5.9 g), 2-aminopyrimidine (5.7 g) and triethylamine (8.4 ml) in ethanol (100 ml) was refluxed for 6 hours. The reaction mixture was evaporated in vacuo. To the residue was added a mixture of water and ethyl acetate, and the resulting mixture was acidified to pH 0.5 with conc. hydrochloric acid. The separated aqueous layer was treated with charcoal and filtered. To the filtrate was added ethyl acetate and the resulting mixture was adjusted to pH 7.0 with 20% aqueous potassium carbonate. The precipitate was collected by filtration, washed successively with water, ethyl acetate and ethanol, and dried over phosphorus pentoxide to give 2-(2-amino-4-ethoxycarbonyl-5-thiazolyl)imidazo[1,2-a]pyrimidine (1.6 g). mp 282° C. (dec.).