Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH3:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[F:12][C:13]([F:23])([F:22])[C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1>C(COC)OC>[O:3]=[C:4]([CH3:11])[CH:5]([CH2:18][C:17]1[CH:16]=[CH:15][C:14]([C:13]([F:12])([F:22])[F:23])=[CH:21][CH:20]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)CC(C)=O
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(C)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% dispersion in mineral oil, 1.5 g, 38.4 mmol) was added in portions over 2 minutes to an ice-cooled, stirring solution of ethyl 3-oxobutanoate (5 g, 38.4 mmol) in dry dimethoxyethane (65 mL). After 30 minutes, a solution of 4-(trifluoromethyl)benzyl bromide (9.2 g, 38.4 mmol) in dry dimethoxyethane (10 mL) was added dropwise over 2 minutes. The flask was removed from the cooling bath. After 2 hours, water (10 mL) was added. The mixture was partitioned between half-saturated aqueous sodium chloride solution (50 mL) and ethyl acetate (150 mL). The layers were separated. The organic layer was dried with magnesium sulfate and the dried solution was filtered. The filtrate was concentrated and the residue was purified by flash-column chromatography on silica gel eluting with hexanes-ethyl acetate to provide the title compound as a colorless liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:21])=[CH:5][C:6]2[CH2:12][CH2:11][N:10]([CH:13]([CH2:17][O:18][CH3:19])[CH2:14][O:15][CH3:16])[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:23]1[N:28]=[C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36]([CH:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])[C:26]([Cl:42])=[CH:25][N:24]=1>>[Cl:42][C:26]1[C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36]([CH:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])=[N:28][C:23]([NH:21][C:4]2[C:3]([O:2][CH3:1])=[CH:20][C:7]3[CH2:8][CH2:9][N:10]([CH:13]([CH2:14][O:15][CH3:16])[CH2:17][O:18][CH3:19])[CH2:11][CH2:12][C:6]=3[CH:5]=2)=[N:24][CH:25]=1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COCC(COC)N1CCc2cc(N)c(OC)cc2CC1
Product: COCC(COC)N1CCc2cc(Nc3ncc(Cl)c(Nc4ccccc4S(=O)(=O)C(C)C)n3)c(OC)cc2CC1

Procedure:
The title compound was prepared from 8-Methoxy-3-(2-methoxy-1-methoxymethyl-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and (2,5-Dichloro-pyrimidin-4-yl)-[2-(propane-2-sulfonyl)-phenyl]-amine in an analogous manner to Example 61e. Product isolated as an off-white solid (0.022 g, 31%). MP: 52-76° C. 1HNMR (400 MHz, CDCl3, δ, ppm): 9.50 (s, 1H), 8.56 (d, 1H, J=8.6 Hz), 8.15 (s, 1H), 7.96 (s, 1H), 7.92 (d, 1H, J=8.1 Hz), 7.63-7.57 (m, 1H), 7.48 (s, 1H), 7.28-7.22 (m, 1H), 6.65 (s, 1H), 3.87 (s, 3H), 3.57-3.51 (m, 2H), 3.47-3.42 (m, 2H), 3.33 (s, 6H), 3.31-3.20 (m, 1H), 3.06-2.99 (m, 1H), 2.88-2.68 (m, 8H), 1.32 (d, 6H, J=6.8 Hz). MS: 604.51 (MH)+.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH2:5][NH:6][NH2:7])[CH3:2].[CH3:11][N:12]=[C:13]=[S:14]>C(O)C>[CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH2:5][N:6]([C:13]([NH:12][CH3:11])=[S:14])[NH2:7])[CH3:2]
Reactant: CCOC(CNN)OCC
Reactant: CN=C=S
Solvent: CCO
Product: CCOC(CN(N)C(=S)NC)OCC

Procedure:
A mixture of 4 g of hydrazino-acetaldehyd diethylacetal in 40 ml of ethanol is stirred with 1.97 g of methylisothiocyanate for ca. 4 hours at room temperature, the solvent is evaporated off and 2-(2,2-diethoxy-ethyl)-4-methyl-thiosemicarbazide is obtained in crystalline form.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[Cl:24])[CH2:10][CH:9]1[CH3:25])=O)(C)(C)C.C=O.C(=O)([O-])[O-].[K+].[K+]>C(O)=O>[Cl:24][C:16]1[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:15]=1[O:14][CH:11]1[CH2:12][CH2:13][N:8]([CH3:6])[CH:9]([CH3:25])[CH2:10]1
Reactant: CC1CC(Oc2ccc([N+](=O)[O-])cc2Cl)CCN1C(=O)OC(C)(C)C
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=CO
Product: CC1CC(Oc2ccc([N+](=O)[O-])cc2Cl)CCN1C
Temperature: 100 °C
Reaction time: 2 h
Yield: 90.6 %

Procedure:
To a suspension of 4-(1-t-butoxycarbonyl-2-methylpiperidin-4-yloxy)-3-chloronitrobenzene (1.15 g) obtained in reference example 85 in 90% formic acid (3.10 g) was added 37% formaldehyde (2.50 g), and the resulting mixture was stirred at 100° C. for 2 hours. After cooling to room temperature, the reaction mixture was neutralized with an aqueous potassium carbonate solution and extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue obtained was purified by chromatography on a silica gel column using a mixed solvent of dichloromethane and methanol (9:1) as the eluent to afford the title compound (0.80 g, yield: 90%) as a yellow oil.
Reaction SMILES: Br[C:2]([CH2:11][C:12](Cl)([Cl:14])[Cl:13])([CH:8]([CH3:10])[CH3:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(C(=CC(Cl)(Cl)Cl)C(OCC)=O)(C)C.[H][H]>C(Cl)(Cl)Cl.C(OCC)C.C(O)C.[Pd]>[Cl:13][C:12]([Cl:14])=[CH:11][CH:2]([CH:8]([CH3:10])[CH3:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: [H][H]
Reactant: CCOC(=O)C(Br)(CC(Cl)(Cl)Cl)C(C)C
Agent: [Pd]
Agent: CCOC(=O)C(=CC(Cl)(Cl)Cl)C(C)C
Solvent: CCOCC
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(C=C(Cl)Cl)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.3 %

Procedure:
In 20 g of chloroform were dissolved 6.0 g of the ethyl α-bromo-α-(2,2,2-trichloroethyl)isovalerate and, after the addition of 3.5 g of 1,5-diazabicyclo[5,4,0]undecene-5(DBU), the solution was stirred at room temperature for 2 hours. The reaction mixture was then diluted with diethyl ether, washed with water and dilute aqueous hydrogen chloride and dried over anhydrous magnesium sulfate. The low-boiling fraction was removed by distillation, whereupon 4.6 g of oily product were obtained. Based on its NMR spectrum and GC-mass spectrum, this product was identified to be ethyl α-isopropyl-β-trichloromethylacrylate containing a certain amount of ethyl α-bromo-α-(2,2-dichlorovinyl) isovalerate. In 50 ml of ethanol were dissolved 4.6 g of the oily product obtained above and, following the addition of 0.4 g of 5% palladium-on-carbon, the solution was stirred in an atmosphere of hydrogen gas at 55° C. for 6 hours. Thereafter, the reaction mixture was filtered to remove the catalyst and the ethanol was distilled off. By the above procedure there were obtained 3.9 g of ethyl α-(2,2-dichlorovinyl)isovalerate as an oil. Then, 3.9 g of this ethyl α-(2,2-dichlorovinyl)isovalerate were dissolved in 20 ml of ethanol and a solution of 2.0 g of sodium hydroxide in 10 ml of water was added to the above ethanol solution. The mixture was stirred at room temperature for 10 hours, at the end of which time the ethanol was distilled off. The residue was neutralized with aqueous hydrogen chloride and extracted with diethyl ether. The ethereal solution yielded 2.9 g of α-(2,2-dichlorovinyl)isovaleric acid having the following NMR spectrum [yield: 84% based on ethyl α-bromo-α-(2,2,2-trichloroethyl)isovalerate].
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[CH2:22]([OH:35])/[CH:23]=[CH:24]/[C:25]#[C:26][CH2:27][C:28]#[C:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>ClCCl>[CH:22](=[O:35])/[CH:23]=[CH:24]/[C:25]#[C:26][CH2:27][C:28]#[C:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCC#CCC#C/C=C/CO
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCCCCC#CCC#C/C=C/C=O
Reaction time: 3 h
Yield: 55.6 %

Procedure:
Pyridinium dichromate (60 g) was stirred with dichloromethane (250 mL) at 0° and treated over a period of 5 min with a solution of (E)-2-tridecen-4,7-diyn-1-ol (20 g) dissolved in dichloromethane. The cooling bath was then removed and the reaction mixture was stirred for a further 3 hours (slight exotherm; maximum temperature 33°-35°). Ether (250 mL) was then added and the solids were filtered off (through paper) and washed with more ether. The combined filtrates were concentrated and the residue was treated with hexane and filtered through celite. The filtrate was then washed with water (5×250 mL), dried (MgSO4) and concentrated to a small volume (100 ml). This solution was purified by liquid chromatography (two columns, 4:1 parts by volume hexane-ethyl acetate) to give the pure (E)-2-tridecen-4,7-diyn-1-al (11 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([OH:11])[CH:3]=1.[CH3:12]CCCCC.C[Si](C=[N+]=[N-])(C)C>C1C=CC=CC=1.CO>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:12])=[O:7])=[C:4]([OH:11])[CH:3]=1
Reactant: O=C(O)c1ccc(F)cc1O
Reactant: CCCCCC
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)c1ccc(F)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
A solution of 4-fluoro-2-hydroxybenzoic acid (9.8 g, 62.3 mmol) in benzene (100 mL) and MeOH (20 mL) was cooled in an ice bath and a 2 M hexane solution of (trimethyl-silyl)diazomethane (50 mL) was added dropwise. The reaction was stirred overnight at ambient temperature, diluted with benzene (348 mL) and MeOH (39 mL), and treated with more of the (trimethylsilyl)diazomethane solution (15 mL). The mixture was concentrated in vacuo to dryness to give the title compound (10.4 g, 98%) as a solid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][C:34]=1[CH2:35][CH2:36][S:37]([N:40]1[CH2:45][CH2:44][C:43](=[O:46])[CH2:42][CH2:41]1)(=[O:39])=[O:38])[C:29]([OH:31])=O.[CH2:47]([O:50][CH2:51][CH2:52][NH:53][CH3:54])[CH:48]=[CH2:49].C(N(C(C)C)CC)(C)C.Cl>CN(C=O)C.O>[CH2:47]([O:50][CH2:51][CH2:52][N:53]([CH3:54])[C:29](=[O:31])[C:28]1[CH:32]=[CH:33][C:34]([CH2:35][CH2:36][S:37]([N:40]2[CH2:45][CH2:44][C:43](=[O:46])[CH2:42][CH2:41]2)(=[O:39])=[O:38])=[C:26]([CH3:25])[CH:27]=1)[CH:48]=[CH2:49]
Reactant: Cc1cc(C(=O)O)ccc1CCS(=O)(=O)N1CCC(=O)CC1
Reactant: C=CCOCCNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOCCN(C)C(=O)c1ccc(CCS(=O)(=O)N2CCC(=O)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 116.8 %

Procedure:
HATU (91 mg, 0.239 mmol) was added to a solution of 3-methyl-4-[2-(4-oxo-piperidine-1-sulfonyl)-ethyl]-benzoic acid (50 mg, 0.154 mmol), (2-allyloxy-ethyl)-methyl-amine (36 mg, 0.312 mmol) and diisopropylethylamine (0.065 ml, 0.384 mmol) in DMF (0.5 ml), and the mixture was stirred at room temperature overnight. Water (12 ml) and 1 N hydrochloric acid (1.5 ml) were added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was sequentially washed with 0.1 N hydrochloric acid, water and saturated brine, and then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give N-(2-allyloxy-ethyl)-3,N-dimethyl-4-[2-(4-oxo-piperidine-1-sulfonyl)-ethyl]-benzamide (76 mg, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@@H:6]2[N:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:10]([CH2:11][C:12]=1OS(C(F)(F)F)(=O)=O)[CH2:9][N:8]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:7]2)=[O:4].[Cl:36][C:37]1[C:42]([F:43])=[CH:41][CH:40]=[C:39]([F:44])[C:38]=1[C:45]1[CH:49]=[C:48]([CH2:50][O:51][C:52]2[CH:57]=[CH:56][C:55](B3OC(C)(C)C(C)(C)O3)=[CH:54][N:53]=2)[O:47][N:46]=1.N#N>COCCOC.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O.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>[CH3:1][O:2][C:3]([C:5]1[C@@H:6]2[N:21]([C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[C@H:10]([CH2:11][C:12]=1[C:55]1[CH:54]=[N:53][C:52]([O:51][CH2:50][C:48]3[O:47][N:46]=[C:45]([C:38]4[C:39]([F:44])=[CH:40][CH:41]=[C:42]([F:43])[C:37]=4[Cl:36])[CH:49]=3)=[CH:57][CH:56]=1)[CH2:9][N:8]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:7]2)=[O:4]
Reactant: CC1(C)OB(c2ccc(OCc3cc(-c4c(F)ccc(F)c4Cl)no3)nc2)OC1(C)C
Reactant: COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]1N2C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COC(=O)C1=C(c2ccc(OCc3cc(-c4c(F)ccc(F)c4Cl)no3)nc2)C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]1N2C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
(rac.)-(1R*,5S*)-7-Trifluoromethanesulfonyloxy-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid 3,9-di-tert-butyl ester 6-methyl ester (WO 2006/021402, 4.72 g, 8.90 mmol) and 2-[3-(2-chloro-3,6-difluoro-phenyl)-isoxazol-5-ylmethoxy]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (5.77 g crude, about 13.4 mmol) were dissolved in a mixture of DME (59.3 mL) and aq. 2M Na2CO3 (44.5 mL). The mixture was degassed with N2, and Pd(PPh3)4 (514 mg, 0.445 mmol) was added. The mixture was heated rapidly to 80° C., and was stirred at this temperature for 1 h. The mixture was diluted with EtOAc (100 mL), and washed with water (100 mL). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc 100%→EtOAc/MeOH 95:5) yielded the title compound (4.56 g, 73%). LC-MS: tR=1.15 min, ES+: 703.25.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[CH:7][CH:6]=1>CN(C=O)C>[Br:1][C:14]1[S:13][C:12]([NH:11][C:8]2[CH:7]=[CH:6][C:5]([O:4][CH3:3])=[CH:10][CH:9]=2)=[N:16][CH:15]=1
Reactant: COc1ccc(Nc2nccs2)cc1
Reactant: BrBr
Solvent: CN(C)C=O
Product: COc1ccc(Nc2ncc(Br)s2)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A 1 M solution of Br2 in DMF (12.9 mL, 13.2 mmol) is added dropwise to a solution of (4-methoxy-phenyl)-thiazol-2-yl-amine (2.72 g, 13.2 mmol) in DMF (40 mL), under an argon atmosphere. During the addition, the internal temperature of the reaction mixture is kept below 26° C. The mixture is stirred for 20 min at 25° C. and concentrated in vacuo. Purification of the crude product by silica gel (250 g) column chromatography (CH2Cl2/MeOH, 99/1) affords the title compound: ES-MS: 287.0 [M+H]+; single peak at tR=7.99 min (System 1); Rf=0.47 (CH2Cl2/MeOH, 98/2).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[N:13]=2)[N:8]=[CH:7][C:6]=1[F:17].[C:19](=O)([O-])[O-].[K+].[K+].C=O.O>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C1CCCCC1.C(OCC)(=O)C>[F:17][C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:5]=1[C:4](=[CH2:19])[C:3]([O:2][CH3:1])=[O:18])=[N:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2
Reactant: O=C([O-])[O-]
Reactant: COC(=O)Cc1c(F)cnc2ccc(OC)nc12
Agent: C=O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: C1CCCCC1
Solvent: O
Solvent: CCOC(C)=O
Product: C=C(C(=O)OC)c1c(F)cnc2ccc(OC)nc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 65.8 %

Procedure:
A mixture of methyl[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]acetate (35.79 g, 143 mmol), benzyltriethylammonium chloride (51.5 g), potassium carbonate (30.4 g) and paraformaldehyde (30.4 g) in cyclohexane (1 litre) was stirred at 80° C. under argon overnight, cooled and shaken with water and ethyl acetate. After separation, the aqueous was re-extracted with ethyl acetate and the combined organic phases dried and evaporated. Chromatography, eluting with 15% ethyl acetate/hexane, provided the product (24.66 g, 66%).
Reaction SMILES: I[C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH2:12][C:13]([F:16])([F:15])[F:14])[CH:7]=[N:6][C:5]=2[N:4]([CH3:17])[CH:3]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20](B(O)O)[CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:17][N:4]1[C:5]2[N:6]=[CH:7][N:8]([CH2:12][C:13]([F:16])([F:15])[F:14])[C:9](=[O:11])[C:10]=2[C:2]([C:20]2[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=2)=[CH:3]1
Reactant: Cn1cc(I)c2c(=O)n(CC(F)(F)F)cnc21
Reactant: OB(O)c1cccnc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: Cn1cc(-c2cccnc2)c2c(=O)n(CC(F)(F)F)cnc21
Temperature: 70 °C
Yield: 90.8 %

Procedure:
A mixture of 5-iodo-7-methyl-3-(2,2,2-trifluoroethyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (358 mg, 1.00 mmol), pyridin-3-ylboronic acid (148 mg, 1.20 mmol), sodium carbonate (319 mg, 3.01 mmol) and PdCl2(dppf)-CH2Cl2 adduct (82 mg, 0.100 mmol) in 1,4-dioxane (8 ml) and water (1.5 ml) was degassed. The resulting mixture was heated at 70° C. for 16 h. The reaction mixture was cooled down and partitioned between saturated sodium bicarbonate (35 mL) and DCM (35 mL). The organic phase was separated and concentrated in vacuo. The remaining residue was purified by flash chromatography (0-100% ethyl acetate/cyclohexane) to afford the title compound (280 mg, 90%). LCMS RT=0.647 min, M+H+=309.1
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][OH:21])[C:13](=[O:22])[NH:12][C:11]=2[N:10]=[C:9]1[O:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:34])([F:33])[F:32])[CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:36][CH3:37].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][OH:21])[C:13](=[O:22])[N:12]([CH2:36][CH3:37])[C:11]=2[N:10]=[C:9]1[O:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:33])([F:32])[F:34])[CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCI
Reactant: O=c1[nH]c2nc(Oc3cccc(OC(F)(F)F)c3)n(Cc3ccccc3)c2c(=O)n1CCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1c(=O)n(CCCO)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccccc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 48.8 %

Procedure:
To a solution of 7-benzyl-1-(3-hydroxypropyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (1.2 g, 2.52 mmol, example 59) in DMF (5 mL) was added iodoethane (0.7 g, 4.49 mmol), followed by potassium carbonate (0.7 g, 5.07 mmol). The reaction was stirred at 80° C. for 2 h; then it was cooled and partitioned between ethyl acetate and water. The phases were separated and the organic phase was washed with brine. The organic layer was dried over sodium sulfate, filtered and concentrated to give 7-benzyl-3-ethyl-1-(3-hydroxypropyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (0.62 g, 49.2% yield) as yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH:7]=[CH:8][N:9]=[C:10]([CH:30]=3)[C@@H:11]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:12][CH2:13][CH2:14][C@@H:15]([CH3:21])[C:16](=[O:20])[NH:17][C:18]=2[CH:19]=1.[I:31]Cl>CO.C(Cl)Cl>[NH2:1][C:2]1[C:3]([I:31])=[CH:4][C:5]2[C:6]3[CH:7]=[CH:8][N:9]=[C:10]([CH:30]=3)[C@@H:11]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:28])[CH3:27])[CH2:12][CH2:13][CH2:14][C@@H:15]([CH3:21])[C:16](=[O:20])[NH:17][C:18]=2[CH:19]=1
Reactant: ClI
Reactant: C[C@@H]1CCC[C@H](NC(=O)OC(C)(C)C)c2cc(ccn2)-c2ccc(N)cc2NC1=O
Solvent: ClCCl
Solvent: CO
Product: C[C@@H]1CCC[C@H](NC(=O)OC(C)(C)C)c2cc(ccn2)-c2cc(I)c(N)cc2NC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
To cooled (0° C.) solution of 86A (0.87 g, 2.119 mmol) in MeOH (21.19 ml) was added a solution of iodine monochloride (0.516 g, 3.18 mmol) in DCM (5.0 mL). The reaction was stirred at rt for 1 h and then it was concentrated. The residue was redissolved in EtOAc, washed with sat. NaHCO3, brine, dried over Na2SO4, filtered, and concentrated. Purification by normal phase chromatography afforded 86B (0.9 g, 79% yield) as a brown solid. MS (ESI) m/z: 537.1 (M+H)+.
Reaction SMILES: [Li+].[OH-].[Cl:3][C:4]([Cl:15])([Cl:14])[CH:5]=[CH:6][C:7]([O:9]CCCC)=[O:8].Cl>O.C1COCC1>[Cl:3][C:4]([Cl:15])([Cl:14])[CH:5]=[CH:6][C:7]([OH:9])=[O:8]
Reactant: CCCCOC(=O)C=CC(Cl)(Cl)Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C=CC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
17.82 g of LiOH in 20 ml of water are added to a solution containing 3 g of butyl 4,4,4-trichloro-but-2-enoate (0.0128 moles) in 300 ml of THF. The mixture is stirred for 1 hour at room temperature. It is then brought to neutral pH with the addition of HCl 1N, extracted with ethyl acetate and anhydrified on Na2SO4. The solid obtained after evaporation of the solvent at reduced pressure and washing with petroleum ether weighs 2.1 g (87% yield).
Reaction SMILES: Cl[C:2]1[N:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:3]=1[C:4]([NH:6][C:7](=[NH:23])[CH2:8][O:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=1)=[O:5].CC([O-])(C)C.[K+]>>[Cl:28][C:25]1[CH:26]=[N:27][C:2]2[N:23]=[C:7]([CH2:8][O:9][CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=3)[NH:6][C:4](=[O:5])[C:3]=2[CH:24]=1
Reactant: N=C(COCCc1cccc(OC(F)(F)F)c1)NC(=O)c1cc(Cl)cnc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: O=c1[nH]c(COCCc2cccc(OC(F)(F)F)c2)nc2ncc(Cl)cc12

Procedure:
In analogy to the procedure described in example 78.4, 2,5-dichloro-N-{1-imino-2-[2-(3-trifluoromethoxy-phenyl)-ethoxy]-ethyl}-nicotinamide was treated with KOtBu to obtain 6-chloro-2-[2-(3-trifluoromethoxy-phenyl)-ethoxymethyl]-3H-pyrido[2,3-d]pyrimidin-4-one as colorless crystals. MS: m/e=400.1 [M+H+].
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][N:4]=1.[CH2:14]([S:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](O)=O)[CH:15]=[CH2:16].CCN=C=NCCCN(C)C>C1(C)C(C)=CC=CC=1>[CH2:14]([S:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]1[N:2]([CH3:1])[C:3]2=[N:4][CH:5]=[C:6]([C:10]([F:11])([F:12])[F:13])[CH:7]=[C:8]2[N:9]=1)[CH:15]=[CH2:16]
Reactant: CNc1ncc(C(F)(F)F)cc1N
Reactant: C=CCSc1ccccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: Cc1ccccc1C
Product: C=CCSc1ccccc1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 145 °C
Yield: 47.3 %

Procedure:
A mixture of N2-methyl-5-trifluoromethylpyridin-2,3-diamine (0.96 g), 2-allylsulfanylbenzoic acid (1.46 g), WSC (1.06 g), and xylene (10 ml) was stirred with heating at 145° C. for 3 hours. After the mixture was evaporated to remove xylene, acetic acid (10 ml) was added thereto, and stirred with heating at 120° C. for further 1 hour. To the reaction mixture cooled to room temperature, 5 mol/l of aqueous sodium hydroxide solution was added to neutralize, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 0.83 g of 2-(2-allylsulfanylphenyl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 10).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][C:8]([N:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]3=[O:18])=[CH:7][N:6]2[C:19]=1[CH3:20])[CH3:2].[Cl:21][C:22]1[S:26][CH:25]=[C:24]([CH2:27]O)[CH:23]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[Cl:21][C:22]1[S:26][CH:25]=[C:24]([CH2:27][O:17][C:14]2[CH:15]=[CH:16][N:11]([C:8]3[CH:9]=[CH:10][C:5]4[N:6]([C:19]([CH3:20])=[C:3]([CH2:1][CH3:2])[N:4]=4)[CH:7]=3)[C:12](=[O:18])[CH:13]=2)[CH:23]=1
Reactant: OCc1csc(Cl)c1
Reactant: CCc1nc2ccc(-n3ccc(O)cc3=O)cn2c1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCc1nc2ccc(-n3ccc(OCc4csc(Cl)c4)cc3=O)cn2c1C
Temperature: 60 °C
Reaction time: 5 h
Yield: 26.9 %

Procedure:
To a solution of 1-(2-ethyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (150 mg), (5-chlorothiophen-3-yl)methanol (165 mg) and tributylphosphine (340 mg) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (424 mg), and the mixture was stirred at 60° C. for 5 h. The reaction mixture was cooled to room temperature, concentrated in vacuo, and diluted with DCM. The mixture was washed with water and brine successively, dried over Na2SO4, concentrated in vacuo and purified by column chromatography (MeOH/DCM) to afford the title compound (60 mg) as a white solid.