Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.[CH3:21][O:22][CH2:23][O:24][C:25]1[CH:30]=[C:29]([O:31][CH2:32][O:33][CH3:34])[CH:28]=[CH:27][C:26]=1B(O)O.[Cl-].[Li+].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[CH3:34][O:33][CH2:32][O:31][C:29]1[CH:30]=[C:25]([O:24][CH2:23][O:22][CH3:21])[CH:26]=[CH:27][C:28]=1[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2
Reactant: COCOc1ccc(B(O)O)c(OCOC)c1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: COCCOC
Solvent: O
Product: COCOc1ccc(-c2[nH]c3cc(C(=O)OC)ccc3c2C2CCCCC2)c(OCOC)c1
Temperature: 90 °C
Reaction time: 22 h
Yield: 86.3 %

Procedure:
To a suspension of methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (14.5 g, 43.2 mmol), obtained in the same manner as in the method described in WO03/010140, and 2,4-bismethoxymethoxyphenylboronic acid (13.6 g, 56.2 mmol) in 1,2-dimethoxyethane (140 ml) and water (70 ml) were added lithium chloride (5.5 g, 129 mmol), sodium carbonate (13.7 g, 129 mmol) and tetrakis(triphenylphosphine)palladium (5.0 g, 4.3 mmol), and the mixture was stirred at 90° C. for 22 hr. The mixture was allowed to cool to room temperature, and filtered through celite. The filtrate was extracted with ethyl acetate and the organic layer was washed successively with saturated aqueous ammonium chloride solution and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane:ethyl acetate=3:1) to give methyl 2-(2,4-bismethoxymethoxyphenyl)-3-cyclohexyl-1H-indole-6-carboxylate (16.9 g, yield 86%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[CH:8]=[CH:7]2.Cl.[O:15]=[C:16]1[NH:25][C:24]2[N:23]=[CH:22][C:21](/[CH:26]=[CH:27]/[C:28](O)=[O:29])=[CH:20][C:19]=2[CH2:18][CH2:17]1>>[CH3:1][N:2]([CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[CH:8]=[CH:7]2)[C:28](=[O:29])[CH:27]=[CH:26][C:21]1[CH:22]=[N:23][C:24]2[NH:25][C:16](=[O:15])[CH2:17][CH2:18][C:19]=2[CH:20]=1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: CNCc1ccc2c(ccn2C)c1
Agent: Cl
Product: CN(Cc1ccc2c(ccn2C)c1)C(=O)C=Cc1cnc2c(c1)CCC(=O)N2
Yield: 65.1 %

Procedure:
According to the procedure of Example 35g, (methyl-(1-methyl-1H-indol-5-ylmethyl)-amine (155 mg, 0.89 mmol) and (E)-3-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)acrylic acid hydrochloride (229 mg, 0.90 mmol), were coupled to give crude product. Purification by column chromatography (silica gel, 5% MeOH/CH2Cl2) gave the title compound (217 mg, 65%) as a red solid and a mixture of amide rotomers: 1H NMR (400 MHz, DMSO-d6) δ 10.63-10.62 (m, 1H), 8.36-8.33 (m, 1H), 8.06 (s, 1H), 7.56-7.51 (m, 1H), 7.43-7.19 (m, 4H), 7.08-7.01 (m, 1H), 6.38 (s, 1H), 4.85-4.67 (m, 2H), 3.76 (s, 3H), 3.06-2.85 (m, 5H), 2.54-2.52 (m, 2H); ESI MS m/z 375 [C22H22N4O2+H]+.
Reaction SMILES: FC(F)(F)C(Cl)C(F)(F)Cl.[Cl:11][C:12]([Cl:20])([Cl:19])[C:13](Cl)([Cl:17])[CH:14]([Cl:16])[Cl:15]>>[Cl:11][C:12]([Cl:20])([Cl:19])[C:13]([Cl:17])=[C:14]([Cl:16])[Cl:15]
Reactant: ClC(Cl)C(Cl)(Cl)C(Cl)(Cl)Cl
Agent: FC(F)(F)C(Cl)C(F)(F)Cl
Product: ClC(Cl)=C(Cl)C(Cl)(Cl)Cl

Procedure:
A method of producing 1,1,1,3,3-pentafluoro-2,-3-dichloropropane which comprises reacting 1,1,1,2,2,3,3-heptachloropropane with an alkali metal hydroxide in the presence of a phase transfer catalyst to form 1,1,1,2,3,3-hexachloropropene; and continuously reacting, at a constant pressure and in the liquid phase, 1,1,1,2,3,3-hexachloropropene with excess hydrogen fluoride in the presence of at least one of an antimony trihalogenide and an antimony pentahalogenide, while selectively removing the 1,1,1,3,3-pentafluoro-2,3-dichlorochloropropane as it is formed.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)=[CH:2]1.[ClH:23]>O1CCOCC1>[ClH:23].[NH:13]1[CH2:14][CH2:15][CH:10]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[CH2:11][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ccccc23)CC1
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc2c(C3CCNCC3)c[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
tert-butyl 4-(1H-indol-3-yl)piperidine-1-carboxylate (0.6 g; 2.0 mmol) was dissolved in 6 mL of a 4M solution of HCl in dioxane. The mixture was stirred at room temperature for 2 hours and was concentrated under reduced pressure to give 0.46 g (97%) of the desired compound as a solid.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:17]=[CH:16][C:6]([O:7][S:8]([C:11]2[N:15]=[CH:14][NH:13][N:12]=2)(=[O:10])=[O:9])=[CH:5][CH:4]=1.[CH3:20][N:21]([CH3:26])[S:22](Cl)(=[O:24])=[O:23].O>C(#N)C>[CH3:20][N:21]([CH3:26])[S:22]([N:13]1[CH:14]=[N:15][C:11]([S:8]([O:7][C:6]2[CH:16]=[CH:17][C:3]([C:2]([F:18])([F:1])[F:19])=[CH:4][CH:5]=2)(=[O:10])=[O:9])=[N:12]1)(=[O:24])=[O:23]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: O=S(=O)(Oc1ccc(C(F)(F)F)cc1)c1nc[nH]n1
Solvent: CC#N
Solvent: O
Product: CN(C)S(=O)(=O)n1cnc(S(=O)(=O)Oc2ccc(C(F)(F)F)cc2)n1
Yield: 86.4 %

Procedure:
1.0 g of 3-(4-trifluoromethylphenoxysulfonyl)-1,2,4-triazole synthesized by a method similar to that employed to prepare the precursor according to Reference Example 3 was dissolved in 10 ml of acetonitrile. Then, 0.57 g of potassium carbonate anhydride was added, and 0.59 g of dimethylsulfamoyl chloride was gradually added at room temperature while stirring the solution. The solution was then refluxed for one hour, and the reactant solution was poured into water and extracted with ethyl acetate. The organic layer was washed with brine and dried with magnesium sulfate, and then the solvent was removed by distillation and the residue was purified by silica gel chromatography. As a result, 1.18 g of the titled compound was obtained.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]3[N:10]([CH2:13][CH2:14][NH:15]C(=O)OC(C)(C)C)[N:11]=[CH:12][C:7]3=[C:6]([C:23]([NH:25][CH2:26][C:27]3[C:28](=[O:35])[NH:29][C:30]([CH3:34])=[CH:31][C:32]=3[CH3:33])=[O:24])[CH:5]=2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:15][CH2:14][CH2:13][N:10]1[C:8]2[N:9]=[C:4]([CH:1]3[CH2:2][CH2:3]3)[CH:5]=[C:6]([C:23]([NH:25][CH2:26][C:27]3[C:28](=[O:35])[NH:29][C:30]([CH3:34])=[CH:31][C:32]=3[CH3:33])=[O:24])[C:7]=2[CH:12]=[N:11]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C3CC3)nc3c2cnn3CCNC(=O)OC(C)(C)C)c(=O)[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(C3CC3)nc3c2cnn3CCN)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1,1-dimethylethyl {2-[6-cyclopropyl-4-({[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]amino}carbonyl)-1H-pyrazolo[3,4-b]pyridin-1-yl]ethyl}carbamate (260 mg, 0.541 mmol) in DCM (15 mL) was added trifluoroacetic acid (3 ml, 38.9 mmol) and the mixture stirred at room temperature for 2 h. The contents were concentrated in vacuo and the crude residue purified by reverse phase HPLC. (mobile phase: 10 to 70% ACN in H2O, 0.1% NH4OH). The final product was collected as 0.170 g (89%). LCMS E-S (M+H)=353.3 1H NMR (400 MHz, DMSO-d6) δ ppm 1.07 (d, J=6.32 Hz, 4H), 2.13 (s, 3H), 2.21 (s, 4H), 3.00 (t, J=6.19 Hz, 2H), 4.29-4.47 (m, 4H), 5.90 (s, 1H) 7.43 (s, 1H), 8.22 (s, 1H), 8.75 (t, 1H).
Reaction SMILES: C[O:2][C:3](=O)[NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][NH:16][C:17]([N:19]2[CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]2=[O:28])=[O:18])=[CH:10][CH:9]=1)(=[O:7])=[O:6].[CH:30]1([NH2:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>O1CCOCC1>[O:28]=[C:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:27][N:19]1[C:17]([NH:16][CH2:15][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([S:5]([NH:4][C:3]([NH:36][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:2])(=[O:6])=[O:7])=[CH:9][CH:10]=1)=[O:18]
Reactant: NC1CCCCC1
Reactant: COC(=O)NS(=O)(=O)c1ccc(CCNC(=O)N2Cc3ccccc3C2=O)cc1
Solvent: C1COCCO1
Product: O=C(NC1CCCCC1)NS(=O)(=O)c1ccc(CCNC(=O)N2Cc3ccccc3C2=O)cc1

Procedure:
4.2 g of N-(4-[2-(1-oxo-isoindoline-2-carboxamido)-ethyl]-benzenesulfonyl)-carbamic acid methyl ester (melting point 215°-217° C., prepared from 4-(2-[1-oxo-isoindoline-2-carboxamido]-ethyl)-benzenesulfonamide and methyl chloroformate) are dissolved in 100 ml of dioxane at 50° C. and 1 g of cyclohexylamine is added. The cyclohexylamine salt of the urethane, which precipitates, dissolves slowly on boiling under reflux for one hour. The mixture is concentrated to 1/3 of its volume and the residual solution is poured onto dilute hydrochloric acid. N-(4-[2-(1-Oxo-isoindoline-2-carboxamido)-ethyl]-benzenesulfonyl)-N'-cyclohexyl-urea, which is obtained in good yield, is filtered off and recrystallized from aqueous acetone. It melts at 214°-216° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][OH:12].O[C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:28])[CH2:21][C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O1CCOCC1.C(=O)(O)[O-].[Na+]>[N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:14]1[CH:15]=[CH:16][C:17]([C:20](=[O:28])[CH2:21][C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[CH:18][CH:19]=1
Reactant: O=C(Cc1ccncc1)c1ccc(O)cc1
Reactant: OCc1ccc2ncccc2n1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(Cc1ccncc1)c1ccc(OCc2ccc3ncccc3n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.8 %

Procedure:
Intermediate 4C, (1,5-naphthyridin-2-yl)methanol (142 mg, 0.887 mmol), Intermediate 4A, 1-(4-hydroxyphenyl)-2-(pyridin-4-yl)ethanone (158 mg, 0.739 mmol), and triphenylphosphine (310 mg, 1.182 mmol) were dissolved in dioxane (6 mL). To this stirred solution was added di-tert-butyl azodicarboxylate (272 mg, 1.182 mmol). The reaction mixture was stirred overnight at ambient temperature under a dry nitrogen atmosphere. The reaction mixture was diluted with aqueous sodium bicarbonate and extracted with CHCl3. The combined organic layers were dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to give a yellow oil. The oil was purified by column chromatography on an Analogix IF-280 (Varian SF25-80 g, 100% DCM to 97:3 DCM/2M NH3 in MeOH). Fractions #10-22 were combined and concentrated under reduced pressure to give 1-(4-((1,5-naphthyridin-2-yl)methoxy)phenyl)-2-(pyridin-4-yl)ethanone as a pale green solid (104.5 mg, 39.8%). 1H NMR (300 MHz, CDCl3) δ 9.00 (dd, J=4.2, 1.6 Hz, 1H), 8.55 (dd, J=4.5, 1.6 Hz, 2H), 8.48-8.43 (m, 1H), 8.39 (ddd, J=8.5, 1.6, 0.9 Hz, 1H), 8.01-7.95 (m, 2H), 7.90-7.86 (m, 1H), 7.68 (dd, J=4.5, 1.5 Hz, 2H), 7.12-7.06 (m, 2H), 5.47 (s, 2H), 4.22 (s, 2H). MS (DCI—NH3) m/z=356 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4].[C:12]([S-:14])#[N:13].[K+]>>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][S:14][C:12]#[N:13])=[CH:6][CH:7]=1
Reactant: N#C[S-]
Reactant: O=C(CCl)c1ccc(Cl)cc1
Agent: [K+]
Product: N#CSCC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
A solution of 945 mg (5 mmol) 2,4′-dichloroacetophenone and 583 mg (6 mmol) potassium rhodanide was heated to reflux for 30 minutes. After a few minutes a precipitation was formed. The solvent was evaporated under reduced pressure and the residue was suspended in tetrahydrofurane, stirred for 1 hour at room temperature, filtered and the filtrate was concentrated in vacuo. The residue was stirred with heptane and little ethanol for 15 minutes. The product was filtered off and dried to yield 953 mg (90%) 1-(4-chloro-phenyl)-2-thiocyanato-ethanone as a light yellow solid. 1H NMR (CDCl3, 250 MHz): δ (ppm)=7.89 (d, 2H), 7.51 (d, 2H), 4.692 (s, 2H).
Reaction SMILES: [C:1]([C:4]1[C:12]2[S:11][CH2:10][CH:9]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[C:8]=2[C:7]([CH3:22])=[C:6]([NH:23][C:24](=[O:30])[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:5]=1[CH3:31])(=[O:3])[CH3:2].C(=O)([O-])[OH:33].[Na+].ClC1C=CC=C(C(OO)=O)C=1.S([O-])(O)=O.[Na+]>ClCCl>[C:1]([C:4]1[C:12]2[S:11](=[O:33])[CH2:10][CH:9]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]([CH3:20])[CH3:21])=[CH:15][CH:14]=3)[C:8]=2[C:7]([CH3:22])=[C:6]([NH:23][C:24](=[O:30])[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:5]=1[CH3:31])(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1SCC2c1ccc(C(C)C)cc1
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)c1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1S(=O)CC2c1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.4 %

Procedure:
To a mixture of N-(7-acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzothien-5-yl)-3,3-dimethylbutanamide (960 mg, 2.19 mmol) obtained in Example 166 and sodium hydrogen carbonate (276 mg, 3.29 mmol) in dichloromethane (20 mL) was added m-chloroperbenzoic acid (530 mg, 3.07 mmol) at 0° C. and the resulting mixture was stirred at room temperature for two hours. To reaction solution was added an aqueous sodium hydrogensulfite solution, the organic layer separated, and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate) to obtain 123 mg (yield: 12%) of the title compound as a low polarity isomer. Melting point: 214-216° C. (hexane-ethyl acetate).
Reaction SMILES: [C:1]1([CH3:48])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14](C(OCC3C=CC=CC=3)=O)[CH2:13][CH:12]([NH:32][C:33]([NH:35][C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH:37]=3)=[O:34])[C:11]2=[O:47])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1>C(O)C.[C].[Pd]>[C:1]1([CH3:48])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[NH:14][CH2:13][CH:12]([NH:32][C:33]([NH:35][C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH:37]=3)=[O:34])[C:11]2=[O:47])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cccc(NC(=O)NC2CN(C(=O)OCc3ccccc3)c3ccc(C)cc3N(CC(=O)c3ccccc3C)C2=O)c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cccc(NC(=O)NC2CNc3ccc(C)cc3N(CC(=O)c3ccccc3C)C2=O)c1
Reaction time: 2 h
Yield: 63 %

Procedure:
1-[1-(2-Toluoylmethyl)-2-oxo-5-benzyloxycarbonyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea (1.00 g) obtained from Step 4 of Example 91 was dissolved in ethanol (20 ml), 10% palladium carbon (200 mg) was added, and under hydrogen atmosphere the mixture was stirred for 2 hours and addtionally stirred for one hour at 50° C. The reaction mixture was filtrated through a pad of Celite, the filtrate was concentrated under reduced pressure, to thereby obtain 500 mg of the titled compound.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([C:9]2[S:13][N:12]=[N:11][C:10]=2[S:14]CCC(OC)=O)[CH:6]=[CH:7][CH:8]=1.C[O-].[Na+]>CO>[F:22][C:2]([F:1])([F:21])[C:3]1[CH:4]=[C:5]([C:9]2[S:13][N:12]=[N:11][C:10]=2[SH:14])[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)CCSc1nnsc1-c1cccc(C(F)(F)F)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: FC(F)(F)c1cccc(-c2snnc2S)c1
Reaction time: 1 h
Yield: 77.9 %

Procedure:
A solution of 11.6 g of 3-[[5-[3-(trifluoromethyl)phenyl]-1,2,3-thiadiazol-4-yl]thio]propanoic acid, methyl ester in 100 ml of dry methanol was treated with 32 ml of 1M methanolic sodium methoxide. After standing one hour, the solvent was removed in vacuo, the residue taken up in dry methanol, filtered and then concentrated. The oil was triturated with ether giving a solid which was collected and dried in vacuo, giving 6.8 g of 5-[3-(trifluoromethyl)phenyl]-1,2,3-thiadiazole-4-thiol, monosodium salt as a yellow powder, mp >200° C..
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd]>[C:29]([C:26]1[CH:25]=[CH:24][C:23]([O:22][CH:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:28][CH:27]=1)#[N:30]
Reactant: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)Oc1ccc(C#N)cc1
Agent: [Pd]
Product: CCOC(=O)C(Cc1ccc(O)cc1)Oc1ccc(C#N)cc1
Yield: 100.5 %

Procedure:
In a similar manner to that described in Reference example 1(d), a reaction was carried out using ethyl 3-(4-benzyloxyphenyl)-2-(4-cyanophenoxy)propionate (376 mg), which is the product of Reference example 41(a), and palladium on carbon (5%, 65 mg) and the reaction mixture was treated to afford the title compound (293 mg) as a colorless oil.
Reaction SMILES: [CH2:1]([SnH:5]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[CH2:14]([O:16][Si:17]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])[C:18]#[CH:19])[CH3:15]>CC(N=NC(C#N)(C)C)(C#N)C>[CH2:21]([O:20][Si:17]([O:23][CH2:24][CH3:25])([O:16][CH2:14][CH3:15])/[CH:18]=[CH:19]/[Sn:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:10][CH2:11][CH2:12][CH3:13])[CH3:22]
Reactant: C#C[Si](OCC)(OCC)OCC
Reactant: CCCC[SnH](CCCC)CCCC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CCCC[Sn](/C=C/[Si](OCC)(OCC)OCC)(CCCC)CCCC
Temperature: 80 °C
Reaction time: 20 h
Yield: 101.4 %

Procedure:
Tributyltin hydride (1.9 mL, 7.2 mmol, 1.0 equiv) and triethoxy(ethynyl)silane (1.5 g, 7.9 mmol, 1.1 equiv) were combined. AIBN (60 mg, 0.36 mmol, 0.05 equiv) was added and the resulting yellow solution was heated to 80° C. Upon reaching 80° C., the reaction exothermed to 104° C. The yellow solution was cooled back to 80° C. and stirred for 20 h. The reaction mixture was cooled to provide the title compound as a pale yellow oil (3.5 g, 99% crude yield): IR (thin film) 2957 (s), 2925 (s), 2873 (m), 2854 (m) cm−1; 1H NMR (400 MHz, CDCl3) δ 7.43 (d, J=24 Hz, 1H), 6.37 (d, J=24 Hz, 1H), 3.83 (q, J=7 Hz, 6H), 1.49 (m, 6H), 1.29 (m, 6H), 1.22 (t, J=7 Hz, 9 H), 0.82-0.92 (m, 15 H).
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.[Na].[O:12]([CH2:19][CH:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28]Cl)[CH2:22][CH2:21]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)(C)C>[O:12]([CH2:19][CH:20]1[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][CH2:28][N:5]2[CH:6]=[N:7][C:8]3[C:4]2=[N:3][CH:2]=[N:1][C:9]=3[NH2:10])[CH2:24][CH2:25]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ClCCCN1CCC(COc2ccccc2)CC1
Reactant: Nc1ncnc2nc[nH]c12
Agent: [Na]
Solvent: CC(C)O
Product: Nc1ncnc2c1ncn2CCCN1CCC(COc2ccccc2)CC1
Yield: 63.9 %

Procedure:
9.45 g (0.07 mole) of adenine are added to a solution of 1.6 g (0.07 mole) of sodium in 250 ml of isopropanol and the reaction mixture heated under reflux for 10 minutes. It is then cooled and 21.4 g (0.08 mole) of 3-(4-phenoxymethylpiperidino)-propyl chloride in 50 ml of isopropanol added thereto. After stirring the reaction mixture under reflux for 6 hours, it is evaporated in a vacuum, the residue is taken up in methylene chloride, the methylene chloride solution is washed with 2N aqueous sodium hydroxide solution and subsequently with water, dried over anhydrous sodium sulfate, evaporated and the residue recrystallized from isopropanol. There are obtained 16.4 g (64% of theory) of 9-[3-(4-phenoxymethylpiperidino)-propyl]-adenine; m.p. 142° - 144° C.
Reaction SMILES: FC1N=C([CH2:8][N:9]2[CH:13]=[CH:12][C:11]([N:14]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]3=[O:24])=[N:10]2)C=CC=1.BrC[C:27]1[C:28]([F:33])=[N:29][CH:30]=[CH:31][CH:32]=1>>[F:33][C:28]1[C:27]([CH2:8][N:9]2[CH:13]=[CH:12][C:11]([N:14]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]3=[O:24])=[N:10]2)=[CH:32][CH:31]=[CH:30][N:29]=1
Reactant: Fc1ncccc1CBr
Reactant: O=C1c2ccccc2C(=O)N1c1ccn(Cc2cccc(F)n2)n1
Product: O=C1c2ccccc2C(=O)N1c1ccn(Cc2cccnc2F)n1
Yield: 62.3 %

Procedure:
Title compound was prepared by a method analogous to that described for Intermediate 45, replacing 2-(chloromethyl)-6-fluoropyridine with Intermediate 13 (200 mg, 1.051 mmol) to yield the title compound (211 mg, 0.655 mmol, 62.3% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm: 8.21 (m, 1H), 8.00 (d, 1H), 7.95-7.88 (m, 4H), 7.78 (m, 1H), 7.38 (m, 1H), 6.41 (d, 1H), 5.46 (s, 2H). [ES+MS] m/z 323 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH:7]=O)=[CH:5][NH:4][N:3]=1.[CH3:9][C:10]([S@:13]([NH2:15])=[O:14])([CH3:12])[CH3:11]>C1COCC1.CCOC(C)=O>[CH3:9][C:10]([S@:13](/[N:15]=[CH:7]/[C:6]1[C:2]([CH3:1])=[N:3][NH:4][CH:5]=1)=[O:14])([CH3:12])[CH3:11]
Reactant: Cc1n[nH]cc1C=O
Reactant: CC(C)(C)[S@](N)=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1n[nH]cc1/C=N/[S@](=O)C(C)(C)C
Temperature: 80 °C
Reaction time: 18 h
Yield: 57.2 %

Procedure:
3-methyl-1H-pyrazole-4-carbaldehyde (2.03 g, 18.44 mmol) was dissolved in THF (30 ml) and (R)-2-methylpropane-2-sulfinamide (2.35, 19.39 mmol) was added followed by Ti(OEt)4 (8.41 mmol, 36.90 mmol). The resulting reaction mixture was stirred at 80° C. for 18 h. LCMS shows mostly product. The reaction mixture was diluted with EtOAc (300 mL), washed with 4% aqueous NaCl (2×150, 2×50 mL). The combined aq. layers were back extracted with EtOAc (100 ml). The combined organic layers were washed with brine (100 ml), dried over Na2SO4, filtered and concentrated. Purified by column chromatography (REDI 80 g, EtOAc/heptane 20-100% over 33 min 100% for 7 min.) to give title compound (2.25 g, 10.55 mmol).
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])[N:7]=[C:6]([N:15]([S:17]([CH3:20])(=[O:19])=[O:18])[CH3:16])[CH:5]=1.[OH-].[Li+].Cl>C1COCC1>[CH3:20][S:17]([N:15]([CH3:16])[C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])[N:7]=1)[C:3]([OH:21])=[O:2])(=[O:18])=[O:19]
Reactant: CCCN(C)c1cc(C(=O)OC)cc(N(C)S(C)(=O)=O)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCN(C)c1cc(C(=O)O)cc(N(C)S(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.6 %

Procedure:
Dissolve 2-(methanesulfonyl-methylamino)-6-(methylpropylamino)-isonicotinic acid methyl ester (796 mg, 2.52 mmoles) in THF (35 mL) and add 1 N lithium hydroxide (12.6 mL). Stir at room temperature for 16 h, acidify with 5 N HCl (2.6 mL), and partition between diethyl ether and water. Wash the diethyl ether layer with saturated aqueous sodium chloride, dry (magnesium sulfate) and concentrate to give the title compound as a yellow solid (650 mg, 85%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](Cl)=[N:8][OH:9].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]#[CH:20].N>>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[O:9][N:8]=[C:7]([C:6]2[CH:5]=[N:4][CH:3]=[C:2]([F:1])[CH:11]=2)[CH:20]=1
Reactant: C#Cc1ccccc1Cl
Reactant: ON=C(Cl)c1cncc(F)c1
Agent: N
Product: Fc1cncc(-c2cc(-c3ccccc3Cl)on2)c1

Procedure:
The titled compound was prepared according to Method CB using the product of product of Example 28B (88 mg, 0.5 mmol) and 1-chloro-2-ethynylbenzene (Apollo, 68 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ 7.43-7.55 (m, 2H), 7.56 (s, 1H), 7.60-7.71 (m, 1H), 7.93-8.05 (m, 1H), 8.21 (ddd, J=9.3, 2.9, 1.7 Hz, 1H), 8.61 (d, J=2.7 Hz, 1H), 9.00 (t, J=1.5 Hz, 1H) ppm; MS (DCI/NH3) m/z 275 (M+H)+, 277 (M+H)+.