Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH:18]2[CH2:22][N:21]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH3:31])[CH:25]=3)[C:20](=[O:32])[NH:19]2)=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[H-].[Na+].I[CH3:37]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:33])[C:5]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][CH:18]2[CH2:22][N:21]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH3:31])[CH:25]=3)[C:20](=[O:32])[N:19]2[CH3:37])=[CH:13][CH:14]=1)([CH3:6])[CH3:7])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCC2CN(Cc3ccc(C)c(C)c3)C(=O)N2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCC2CN(Cc3ccc(C)c(C)c3)C(=O)N2C)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 74.7 %

Procedure:
A solution of 2-(4-{2-[1-(3,4-dimethyl-benzyl)-2-oxo-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid ethyl ester (0.128 g, 0.280 mmol) in DMF (4 mL) was treated with 60% oil suspension of NaH (0.028 g, 0.70 mmol) and stirred at room temperature under N2 for 15 minutes. The reaction was cooled to 0° C. and treated with iodomethane (0.16 g, 1.13 mmol) and then warmed to room temperature and stirred for 1 h. The reaction was quenched with 1 N HCl (3 mL) and worked up extractively with Et2O and water. The organic layer was dried (MgSO4) and the solvent removed in vacuo to afford crude product that was purified by flash chromatography using 5:1 hexanes:acetone to afford 0.098 g (74%) 2-(4-{2-[1-(3,4-dimethyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid ethyl ester. MS (ES+) Calc'd for C27H37N2O5 (M+1) 469. Found m/z 469 (100%). 1H NMR.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH:3]([C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([Cl:23])=[C:18]([Cl:24])[CH:17]=1)/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH:11]([NH2:15])[CH2:10][CH2:9]2.[CH3:27][N:28]=[C:29]=[S:30]>CCOCC>[CH3:27][NH:28][C:29]([NH:15][CH:11]1[C:12]2[C:8](=[CH:7][C:6](/[CH:5]=[CH:4]/[CH:3]([C:16]3[CH:17]=[C:18]([Cl:24])[C:19]([Cl:23])=[C:20]([Cl:22])[CH:21]=3)[C:2]([F:1])([F:25])[F:26])=[CH:14][CH:13]=2)[CH2:9][CH2:10]1)=[S:30]
Reactant: NC1CCc2cc(/C=C/C(c3cc(Cl)c(Cl)c(Cl)c3)C(F)(F)F)ccc21
Reactant: CN=C=S
Solvent: CCOCC
Product: CNC(=S)NC1CCc2cc(/C=C/C(c3cc(Cl)c(Cl)c(Cl)c3)C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (E)-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2,3-dihydro-1H-inden-1-amine (0.1 g, 0.23 mmol) in Et2O (5 mL) was added methylisothiocyanate (0.026 g, 0.35 mmol), and the mixture was stirred for 2 h at 25° C. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography (SiO2, 20% EtOAc in petroleum ether). The title compound was isolated as a liquid (65 mg, 50%): 1H NMR (400 MHz, CDCl3) δ 7.39 (s, 2H), 7.25-7.18 (m, 3H), 6.58 (d, J=16.0 Hz, 1H), 6.30 (dd, J=16.0, 8.4 Hz, 1H), 5.91-5.70 (br, 2H), 4.05 (m, 1H), 3.05-2.80 (m, 6H), 2.70 (m, 1H), 1.81 (m, 1H); ESIMS m/z 492.17 ([M+H]+); IR (thin film) 3211, 1569, 1113, 806 cm−1.
Reaction SMILES: [S:1]([O-:4])([O-:3])=[O:2].[Na+:5].[Na+].[S:7]([O-])([OH:9])=[O:8].[Na+]>>[S:1]([S:7]([O-:9])=[O:8])([O-:4])(=[O:3])=[O:2].[Na+:5].[Na+:5]
Reactant: O=S([O-])[O-]
Reactant: O=S([O-])O
Agent: [Na+]
Product: O=S([O-])S(=O)(=O)[O-]

Procedure:
Further comparative experiments were undertaken in the same manner as above except that the 0.01 mole/liter aqueous solution of sodium sulfite was replaced with an equal volume of a 0.01 mole/liter aqueous solution of sodium hydrogensulfite or a 0.00491 mole/liter aqueous solution of sodium pyrosulfite to give the results almost identical with those shown by the curve VI in FIG. 1. The residual cyanide concentration was 24.4 ppm or 29.8 ppm after 120 minutes of the treatment with sodium hydrogensulfite or after 129 minutes of the treatment with sodium pyrosulfite, respectively.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4](O)=[O:5].[CH2:12]([N:14](CC)CC)C.ClC(OC(Cl)(Cl)Cl)=O.CN>ClCCl.CCO>[NH2:1][C:2]1[N:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([NH:14][CH3:12])=[O:5]
Reactant: Nc1ncc(Br)cc1C(=O)O
Reactant: CCN(CC)CC
Agent: CN
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCO
Product: CNC(=O)c1cc(Br)cnc1N
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a solution of 2-amino-5-bromonicotinic acid (Combi-Blocks, San Diego, USA, 1.355 mmol) and triethylamine (0.378 ml) in dichloromethane (10 ml) cooled with an ice-bath was added a solution of trichloromethyl chloroformate (Acros, Basel, Switzerland, 0.677 mmol) in dichloromethane (10 ml). After 40 min stirring at 0° C., was added a solution 8 M of methylamine in EtOH (1.7 ml). The RM was stirred for 30 min at rt then was diluted with dichloromethane, washed with saturated aqueous NaHCO3, with brine, dried over Na2SO4, filtered and evaporated. The residue was taken in DMF and purified by preparative HPLC. The fractions containing product were basified with NaHCO3, concentrated and extracted with dichloromethane (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered, evaporated and dried under vacuum to give the title compound as a white solid. (HPLC: tR 1.69 min (Method A); M+H=230, 232 MS-ES)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][N:3]=1.BrC1C=CC(S(C)=[O:18])=NC=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:9])=[O:18])=[CH:4][N:3]=1
Reactant: CS(=O)c1ccc(Br)cn1
Reactant: CSc1ccc(Br)nc1
Product: CS(=O)c1ccc(Br)nc1

Procedure:
The title compound was prepared from 2-bromo-5-methylsulfanyl-pyridine following a procedure analogous to that described for 5-bromo-2-methanesulfinyl-pyridine in Example 182. Mass spectrum (ESI+): m/z=220/222 (Br) [M+H]+.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([N:8]2[C:20]3[C:19]4[CH:18]=[C:17]([C:21]5[CH:22]=[N:23][C:24]([CH2:27][OH:28])=[CH:25][CH:26]=5)[CH:16]=[CH:15][C:14]=4[N:13]=[CH:12][C:11]=3[N:10]([CH3:29])[C:9]2=[O:30])[C:5]([CH3:31])=[N:4]1)[CH3:2].[H-].[Na+].I[CH3:35]>CN(C=O)C>[CH2:1]([N:3]1[CH:7]=[C:6]([N:8]2[C:20]3[C:19]4[CH:18]=[C:17]([C:21]5[CH:22]=[N:23][C:24]([CH2:27][O:28][CH3:35])=[CH:25][CH:26]=5)[CH:16]=[CH:15][C:14]=4[N:13]=[CH:12][C:11]=3[N:10]([CH3:29])[C:9]2=[O:30])[C:5]([CH3:31])=[N:4]1)[CH3:2]
Reactant: CCn1cc(-n2c(=O)n(C)c3cnc4ccc(-c5ccc(CO)nc5)cc4c32)c(C)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1cc(-n2c(=O)n(C)c3cnc4ccc(-c5ccc(COC)nc5)cc4c32)c(C)n1
Reaction time: 0.33 h

Procedure:
To a mixture of 1-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-8-(6-hydroxymethyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Example 16.1, 28 mg, 0.068 mmol) in DMF (1 ml) was added NaH 55% (4 mg, 0.092 mmol) and the mixture was stirred for 20 min. Then iodomethane (0.006 ml, 0.096 mmol) was added and the RM was stirred again at rt for 30 min. After that, the RM was quenched with saturated aqueous NaHCO3 (20 ml) and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated. The residue was dissolved in DMA and purified directly by Prep.HPLC (H2O (0.1% TFA)/CH3CN 95:5 to 65:35). The fractions containing products were collected together and basified with NaHCO3 (0.3 g), before being concentrated. The resulting suspension was filtered and the cake was washed with water, before being dried under high vacuum to give the title compound as a white solid. (HPLC: tR 2.30 min (Method A); M+H=429 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.98 (s, 1H), 8.63 (s, 1H), 8.20 (s, 1H), 8.15-8.10 (m, 1H), 7.98-7.93 (m, 1H), 7.92-7.87 (m, 1H), 7.58-7.53 (m, 1H), 7.49-7.44 (m, 1H), 4.54-4.50 (m, 2H), 4.23-4.15 (m, 2H), 3.58 (s, 3H), 3.37 (s, 3H), 1.95 (s, 3H), 1.32 (t, 3H))
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].S(OC)(O[CH3:24])(=O)=O.O>C(C(C)=O)C(C)C>[CH3:24][N:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:11][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:9]1
Reactant: c1ccc(-c2cc(-c3ccccc3)[nH]n2)cc1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: Cn1nc(-c2ccccc2)cc1-c1ccccc1
Temperature: 90 °C

Procedure:
Five parts of 3,5-diphenylpyrazole are dissolved in 25 parts (by volume) of methyl isobutyl ketone. Solid anhydrous sodium hydroxide (1.1 parts) is added and the mixture is heated to 90° C. Dimethyl sulfate (3.43 parts) is added and the mixture is next heated to 112° to 115° C. The reaction mixture is sampled after 1.5 hours, and no unreacted 3,5-diphenylpyrazole is found to be present. The reaction mixture is cooled to 50° C., and 30 parts of water are added. The pH is next adjusted to between 11 and 12 by the addition of aqueous sodium hydroxide. The organic layer is washed twice with 30 parts water. For yield determination the methyl isobutyl ketone is removed in vacuo, producing 4.95 parts (93% crude yield) of an oil which crystallizes on cooling (melting point 52° to 53° C). Analysis of the product shows it to be 85.5% pure as 1-methyl-3,5-diphenylpyrazole.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH:27]([C:40]1[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=1)[CH2:28][N:29]1[C:34]2[CH:35]=[CH:36][NH:37][C:33]=2[C:32](=[O:38])[NH:31][C:30]1=[S:39])(C(C)(C)C)(C)C.C(OCC)(=O)C>C1COCC1>[OH:26][CH:27]([C:40]1[CH:41]=[CH:42][C:43]([O:46][CH3:47])=[CH:44][CH:45]=1)[CH2:28][N:29]1[C:34]2[CH:35]=[CH:36][NH:37][C:33]=2[C:32](=[O:38])[NH:31][C:30]1=[S:39]
Reactant: COc1ccc(C(Cn2c(=S)[nH]c(=O)c3[nH]ccc32)O[Si](C)(C)C(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(C(O)Cn2c(=S)[nH]c(=O)c3[nH]ccc32)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 37.3 %

Procedure:
Tetra-n-butylammonium flouride (1M in THF, 1.27 mL, 1.27 mmol) was added to 1-[2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-methoxyphenyl)ethyl]-2-thioxo-1,2,3,5-tetrahydro-pyrrolo[3,2-d]pyrimidin-4-one (0.065 g, 0.152 mmol) in THF (8 mL). The mixture was stirred at 50° C. overnight. Ethyl acetate was added, and the organic phase was washed with water and brine, dried (MgSO4), filtered and concentrated. This crude material was purified by preparative HPLC to yield the title compound (0.018 g, 37%) as a solid.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][CH:4]([C:14]([OH:16])=O)[CH2:3]1.C(C1NC=CN=1)(C1NC=CN=1)=O.Cl.[F:30][C:31]([F:35])([F:34])[CH2:32][NH2:33].N12CCCN=C1CCCCC2>O1CCCC1>[O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:5][CH:4]([C:14]([NH:33][CH2:32][C:31]([F:35])([F:34])[F:30])=[O:16])[CH2:3]1
Reactant: O=C(O)C1CC(=O)N(Cc2ccccc2)C1
Reactant: NCC(F)(F)F
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(NCC(F)(F)F)C1CC(=O)N(Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 28.3 %

Procedure:
A mixture of 21.9 g (0.100 mole) 5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylic acid in 150 ml tetrahydrofuran, was cooled to 0° C. in an ice bath under nitrogen and 24.32 g (0.150 mole) carbonyl diimidazole was added. The reaction was stirred at 0° C. for 30 minutes, then at room temperature for 30 minutes. A solution of 13.55 g (0.100 mole) of 2,2,2-triflouroethylamine hydrochloride, 15.22 g (0.100 mole) 1,8-diazabicyclo[5.4.0]undec-7-ene and 100 ml tetrahydrofuran was added. The reaction was stirred at room temperature overnight. The solvent was removed at reduced pressure. The residue was taken up in dichloromethane and washed with 3×150 ml saturated sodium bicarbonate. The organic layer was dried over magnesium sulfate and the solvent removed under reduced pressure. The product was purified by column chromatography on silica with ethyl acetate to give 8.50 g of 5-oxo-1-(phenylmethyl)-N-(2,2,2-trifluoroethyl)-3-pyrrolidinecarboxamide, mp 110°-112° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:11][CH2:10][C:9]2[C:8](=[O:12])[C:7](=O)[C:6]3[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=3[C:4]=2[O:3]1.[NH2:19][C:20]1[CH:48]=[CH:47][C:23]([C:24]([O:26][CH2:27][CH2:28][NH:29][C:30]([O:32][CH2:33][CH:34]2[C:46]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[C:40]3[C:35]2=[CH:36][CH:37]=[CH:38][CH:39]=3)=[O:31])=[O:25])=[CH:22][CH:21]=1.C(N(CC)CC)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:18])[CH2:11][CH2:10][C:9]2[C:8](=[O:12])/[C:7](=[N:19]\[C:20]3[CH:21]=[CH:22][C:23]([C:24]([O:26][CH2:27][CH2:28][NH:29][C:30]([O:32][CH2:33][CH:34]4[C:46]5[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=5[C:40]5[C:35]4=[CH:36][CH:37]=[CH:38][CH:39]=5)=[O:31])=[O:25])=[CH:47][CH:48]=3)/[C:6]3[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=3[C:4]=2[O:3]1
Reactant: Nc1ccc(C(=O)OCCNC(=O)OCC2c3ccccc3-c3ccccc32)cc1
Reactant: CC1(C)CCC2=C(O1)c1ccccc1C(=O)C2=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)CCC2=C(O1)c1ccccc1/C(=N/c1ccc(C(=O)OCCNC(=O)OCC3c4ccccc4-c4ccccc43)cc1)C2=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 12.8 %

Procedure:
A solution of 2,2-dimethyl-3,4-dihydro-2H-benzo[h]chromene-5,6-dione (2.975 g, 12.3 mmoles) in 120 ml of methylene chloride is treated with 6.14 ml of a 1.0 M solution of TiCl4 in methylene chloride. The mixture is stirred at room temperature for 5 minutes, then a solution of 2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}ethyl 4-aminobenzoate (5.436 g, 13.5 mmoles) in 60 ml of methylene chloride is introduced followed by triethylamine (10.3 ml, 73.7 mmoles). The mixture is stirred at room temperature for 10 minutes. A second portion of 6.14 ml of a 1.0 M solution of TiCl4 in methylene chloride is added and the mixture is stirred at room temperature for 10 minutes. A third portion of 6.14 ml of a 1.0 M solution of TiCl4 in methylene chloride is added and the mixture is stirred at room temperature for 15 minutes. After stirring with the third aliquot of TiCl4, the mixture is poured onto 300 ml of ice, to form a mixture having a precipitate. The mixture is filtered to remove the precipitate and the organic and aqueous phases are then separated. The aqueous phase is extracted with two portions of 200 ml of methylene chloride. The combined organic extracts are dried with Na2SO4, filtered and concentrated in vacuo, giving a brown oil. Purification on silica gel using a gradient of 0-10% ethyl acetate in methylene chloride provided a brown reddish foam, which is triturated in diethyl ether, yielding 990 mg (13%) of the title compound as a brown solid. M.p.: 163-164° C. 400 MHz 1H NMR (DMSO-d6) δ: 8.13 (d, J=7.3 Hz, 1H), 7.93 (d, J=8.4 Hz, 2H), 7.88 (d, J=7.7 Hz, 2H), 7.82 (d, J=8.1 Hz, 1H), 7.7-7.55 (m, 5H), 7.40 (t, J=7.5 Hz, 2H), 7.30 (t, J=7.5 Hz, 2H), 6.79 (d, J=8.4 Hz, 2H), 4.33 (d, J=7.0 Hz, 2H), 4.3-4.2 (m, 3H), 3.45-3.35 (m, 2H), 2.25 (t, J=6.4 Hz, 2H), 1.79 (t, J=6.4 Hz, 2H), 1.41 (s, 6H). LCMS: 627 [M+H]. Calc. for C39H34N2O6.0.1 water: C, 74.46; H, 5.48; N, 4.46; Found C, 74.48; H, 5.06; N, 4.43.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].C(O)(=O)CC(O)=O.C([K])C.[C:23]([O:26][CH2:27][CH3:28])(=[O:25])[CH3:24].CCCCCC>C(O)C.N1C=CC=CC=1.C(O)(=O)C>[CH2:27]([O:26][C:23](=[O:25])[CH2:24][C:5]1([OH:12])[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[NH:7][C:6]1=[O:11])[CH3:28]
Reactant: O=C1Nc2ccc(F)cc2C1=O
Reactant: CCOC(C)=O
Agent: CC[K]
Agent: O=C(O)CC(=O)O
Solvent: CCO
Solvent: CC(=O)O
Solvent: CCCCCC
Product: CCOC(=O)CC1(O)C(=O)Nc2ccc(F)cc21
Temperature: 10 °C

Procedure:
5-Fluoroisatin 32 (10 mmol, Lancaster, order no. 14553) was dissolved in a mixture of ethanol/pyridine/acetic acid (50 ml, 15:5:2), ethyl potassium malonate 33 (1.87 g, 11 mmol) was added, and the mixture was heated under reflux for 14 hours. The course of the reaction was monitored by TLC (eluent: ethyl acetate/hexane 1:1). The product was worked up by distilling off the solvent mixture under reduced pressure, taking up the residue in ethyl acetate (50 ml) and extracting the mixture by shaking with water (50 ml). After separation of the phases, the aqueous phase was extracted twice with 30 ml portions of ethyl acetate. The combined organic phases were washed with 2 N HCl (50 ml), dried over Na2SO4 and concentrated to 20 ml under reduced pressure. Hexane was added to the solution until the product started to crystallize. To bring the crystallization to completion, the mixture was cooled to 10° C. for 12 hours. The solid was filtered out with suction and dried in vacuo.
Reaction SMILES: C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C.[I:17][C:18]1[CH:19]=[N:20][C:21](=[O:24])[NH:22][CH:23]=1.O[CH2:26][C:27]1[S:28][CH:29]=[CH:30][CH:31]=1>CN(C)C=O>[I:17][C:18]1[CH:19]=[N:20][C:21](=[O:24])[N:22]([CH2:26][C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)[CH:23]=1
Reactant: OCc1cccs1
Reactant: O=c1ncc(I)c[nH]1
Agent: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Solvent: CN(C)C=O
Product: O=c1ncc(I)cn1Cc1cccs1
Temperature: 80 °C

Procedure:
N,N-Dimethylformamide dineopentyl acetal (1.5 ml) was added to a stirred suspension of 5-iodopyrimidin-2-one (777 mg) and 2-hydroxymethyl thiophene (0.62 ml) in dry N,N-dimethylformamide (8 ml) under nitrogen and the mixture was then heated at 80° C. After 13/4 h the reaction mixture was evaporated to a brown solid which was crystallised twice from ethyl acetate to give the title pyrimidinone (540 mg), m.p. 207°-209° C., λmax (EtOH) 232.5 nm (ε 21,820), 341.5 nm (ε 2,420).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([CH3:28])=[CH:7][C:8]([CH3:27])=[C:9]([C:11]2[NH:26][C:14]3[CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18][C:13]=3[N:12]=2)[CH:10]=1)=[O:4].[OH-].[Na+]>CO.O>[C:22]([O:21][C:19]([N:16]1[CH2:17][CH2:18][C:13]2[N:12]=[C:11]([C:9]3[C:8]([CH3:27])=[CH:7][C:6]([CH3:28])=[C:5]([CH:10]=3)[C:3]([OH:4])=[O:2])[NH:26][C:14]=2[CH2:15]1)=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: COC(=O)c1cc(-c2nc3c([nH]2)CN(C(=O)OC(C)(C)C)CC3)c(C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(C)c(-c2nc3c([nH]2)CN(C(=O)OC(C)(C)C)CC3)cc1C(=O)O
Reaction time: 2 h
Yield: 76.9 %

Procedure:
A mixture of tert-butyl 2-(5-(methoxycarbonyl)-2,4-dimethylphenyl)-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate (compound 2.6, 300 mg, 0.70 mmol, 1.00 equiv, 90%) and sodium hydroxide (62 mg, 1.55 mmol, 2.00 equiv) in 15 mL methanol/H2O (2:1) was stiffed for at 40° C. in an oil bath. After 2 h, the reaction mixture was concentrated to about ⅓ of the volume under reduced pressure. The pH value of the remaining mixture was adjusted to 3-4 with hydrogen chloride (aq., 1 M). The resulting solids were collected by filtration and dried in an oven under reduced pressure to yield 0.2 g (69%) of the title compound as a yellow solid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[NH:20][CH:21]=[C:22]([NH:23][C:24](=[O:26])[CH3:25])[C:15]=23)[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.Cl.[Pd]>[N:11]1([C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[NH:20][CH:21]=[C:22]([NH:23][C:24](=[O:26])[CH3:25])[C:15]=23)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(=O)Nc1c[nH]c2nccc(N3CCN(Cc4ccccc4)CC3)c12
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(=O)Nc1c[nH]c2nccc(N3CCNCC3)c12
Yield: 98.9 %

Procedure:
N-(4-(4-Benzylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetamide (0.150 g, 0.429 mmol) was placed in MeOH (3 mL). Pd/C (0.0914 g, 0.0429 mmol) was then added, followed by the addition of 3 drops of concentrated HCl. The reaction was then placed under a H2 balloon for 3 hours. The reaction was then filtered, but the product was insoluble. The solids were slurried with 1:1 MeOH:THF (5×) and filtered. The filtrate was then concentrated to give the crude product N-(4-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetamide (0.110 g, 77.1% yield), which was used without further purification.
Reaction SMILES: C(C(C([O:10][C:11]([C:14]([C:17]([F:20])([F:19])[F:18])([F:16])[F:15])(F)[F:12])=O)(F)F)(F)(F)F.ClC(F)=C(F)F>[Ni].O>[C:17]([C:14]([C:11]([F:12])=[O:10])([F:16])[F:15])([F:20])([F:19])[F:18]
Reactant: O=C(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Agent: [Ni]
Agent: FC(F)=C(F)Cl
Solvent: O
Product: O=C(F)C(F)(F)C(F)(F)F
Temperature: 200 °C
Yield: 90 %

Procedure:
CF3CF2COOCF2CF2CF3 (20 g) obtained in Example 5 and chlorotrifluoroethylene oligomer (120 g) were charged into a 200 ml autoclave made of nickel and equipped with a reflux condenser and heated to 200° C. The reflux condenser was cooled by circulating cooling water, and when the pressure became at least 0.1 MPa, the gas was purged while maintaining the pressure to recover a gaseous sample (15 g). By GC-MS, it was confirmed that CF3CF2COF was the main product. The GC yield was 90%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:17]=[C:16]2[C:12]([N:13]=[C:14]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]([OH:29])([CH3:28])[CH3:27])[CH2:22][CH2:21]3)[N:15]2[CH3:18])=[C:11]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[N:10]=1.[N:36]#[C:37]Br>C(O)C>[NH2:36][C:37]1[N:8]([C:9]2[N:17]=[C:16]3[C:12]([N:13]=[C:14]([CH2:19][N:20]4[CH2:21][CH2:22][CH:23]([C:26]([OH:29])([CH3:28])[CH3:27])[CH2:24][CH2:25]4)[N:15]3[CH3:18])=[C:11]([N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)[N:10]=2)[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Nc3ccccc3N)nc21
Reactant: N#CBr
Solvent: CCO
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-n3c(N)nc4ccccc43)nc21
Temperature: 95 °C
Reaction time: 0.25 h
Yield: 7.8 %

Procedure:
A mixture of 2-(1-((2-(2-aminophenylamino)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol (220 mg, 0.46 mmol) and cyanogen bromide (150 mg, 1.4 mmol) in ethanol (2 mL) was stirred at 95° C. for 15 minutes. The reaction mixture was then loaded onto a Biotage Isolute SPE SCX-2 column. The column was washed with MeOH and the desired product was then eluted with 2 M NH3 in MeOH and further purified by RP-HPLC to give 167 (18.1 mg, 7.8%). LCMS: M+H+=506.3. 1H-NMR (400 MHz, DMSO-d6): δ 8.17 (d, 1H), 7.70 (s, br, 2H), 7.24 (d, 1H), 7.12 (t, 1H), 7.03 (t, 1H), 4.26 (s, br, 4H), 4.10 (s, 1H), 3.84 (s, 3H), 3.80 (m, 4H), 1.73 (m, 2H), 1.27 (m, 3H), 1.03 (s, 6H)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][CH2:10][O:11][CH3:12].[CH3:13][O:14][C:15]1[CH:40]=[CH:39][C:18]([CH2:19][N:20]([C:34]2[S:35][CH:36]=[CH:37][N:38]=2)[S:21]([C:24]2[CH:25]=[CH:26][C:27]3[NH:32][CH2:31][CH2:30][O:29][C:28]=3[CH:33]=2)(=[O:23])=[O:22])=[CH:17][CH:16]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+]>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]>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][N:20]([C:34]2[S:35][CH:36]=[CH:37][N:38]=2)[S:21]([C:24]2[CH:25]=[CH:26][C:27]3[N:32]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=4[O:8][CH2:9][CH2:10][O:11][CH3:12])[CH2:31][CH2:30][O:29][C:28]=3[CH:33]=2)(=[O:23])=[O:22])=[CH:39][CH:40]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3)cc1
Reactant: COCCOc1ccccc1Br
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: COCCOc1ccccc1N1CCOc2cc(S(=O)(=O)N(Cc3ccc(OC)cc3)c3nccs3)ccc21
Temperature: 100 °C
Yield: 44.4 %

Procedure:
A mixture of 1-bromo-2-(2-methoxyethoxyl)benzene (302.0 mg, 1.31 mmol), INTERMEDIate M (500 mg, 1.19 mmol), Pd2(dba)3 (76.0 mg, 0.0837 mmol), Xantphos (69.0 mg, 0.119 mmol) and sodium-tert-butoxide (229.0 mg, 2.39 mmol) in toluene (10 mL) was degassed with nitrogen for 10 minutes. The reaction mixture was subjected for heating at 100° C. for 1 h under microwave. After completion, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×15 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material which was purified by combiflash column chromatography (column size: 12 g; elution: 12% ethyl acetate in hexane) to get N-(4-methoxybenzyl)-4-(2-(2-methoxyethoxyl)phenyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (300 mg, 44.2%) as yellow solid. MS (ESI, positive ion) m/z: 568.03 (M+1).