Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:9]([CH2:16][C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=3[C:19]#[N:20])[C:10](=[O:15])[C:11](Br)=[CH:12][N:13]=2)[CH2:3]1.C([SnH](CCCC)CCCC)CCC.CC(N=NC(C#N)(C)C)(C#N)C>C1(C)C=CC=CC=1.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>[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:9]([CH2:16][C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=3[C:19]#[N:20])[C:10](=[O:15])[CH:11]=[CH:12][N:13]=2)[CH2:3]1
Reactant: N#Cc1ccccc1Cn1c(N2CCC[C@@H](N)C2)ncc(Br)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: N#Cc1ccccc1Cn1c(N2CCC[C@@H](N)C2)nccc1=O
Temperature: 108 °C
Reaction time: 24 h
Yield: 79.7 %

Procedure:
2-[2-(3-(R)-Amino-piperidin-1-yl)-5-bromo-6-oxo-6H-pyrimidin-1-ylmethyl]-benzonitrile (Example 1) (80 mg, 0.21 mmol) and tributyltin hydride (83 μL, 0.31 mmol) were stirred in dry toluene (5 mL) under nitrogen. Tetrakis(triphenylphosphine)palladium(0) (36 mg, 0.013 mmol) and a catalytic amount of AIBN were added, and the reaction stirred at 108° C. for 24 h. Concentration in vacuo and purification by Prep HPLC gave 51.8 mg (59%) of the title compound as the TFA salt. 1H NMR (400 MHz, CDCl3): δ 8.40 (br s, 3H), 7.71 (d, 1H, J=6.4 Hz), 7.63 (d, 1H, 7.6 Hz), 7.57 (t, 1H, J=7.6 Hz), 7.40 (t, 1H, J=7.6 Hz), 7.33 (d, 1H, J=7.6 Hz), 6.25 (d, 1H, J=6.4 Hz), 5.36 (AB q, 2H, J=113.2, 15.2 Hz), 3.47-3.59 (m, 3H), 3.21-3.28 (m, 2H), 1.95-2.05 (m, 2H), 1.80-1.91 (m, 1H), 1.60-1.71 (m, 1H). MS (ES) [m+H] calc'd for C17H19N5O, 310; found 310.
Reaction SMILES: [CH:1](=[C:8]1/[C:9](=[O:18])[NH:10][C:11]2[C:16]/1=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(N(CC)CC)C>ClCCl>[CH2:23]([O:22][C:20]([N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)/[C:8](=[CH:1]/[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)/[C:9]1=[O:18])=[O:21])[CH3:24]
Reactant: CCOC(=O)Cl
Reactant: O=C1Nc2cc(Cl)ccc2/C1=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1C(=O)/C(=C\c2ccccc2)c2ccc(Cl)cc21
Yield: 104 %

Procedure:
In a manner similar to the method described in example 4b, E/Z-3-benzylidene-6-chloro-1,3-dihydro-indol-2-one (1.5 g, 5.87 mmol) was reacted with ethyl chloroformate (0.83 mL, 8.8 mmol) and triethylamine (1.64 mL, 12 mmol) in dichloromethane to give E/Z-3-benzylidene-6-chloro-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester as a yellow solid (Yield 2.0 g, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH:9]([NH:17]S(C(C)(C)C)=O)[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[C:7]([O:24][CH3:25])[N:6]=[CH:5][N:4]=1.[ClH:26].O1CCOCC1>CO>[ClH:26].[NH2:17][CH:9]([C:8]1[C:3]([O:2][CH3:1])=[N:4][CH:5]=[N:6][C:7]=1[O:24][CH3:25])[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)CCCC(NS(=O)C(C)(C)C)c1c(OC)ncnc1OC
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)CCCC(N)c1c(OC)ncnc1OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A cooled (0° C.) slightly yellow solution of methyl 5-(4,6-dimethoxypyrimidin-5-yl)-5-(1,1-dimethylethylsulfinamido)pentanoate (178 mg; 0.47 mmol) in MeOH (4 ml) was treated dropwise with a solution of 4 M HCl in 1,4-dioxane (0.24 ml; 0.96 mmol). The resulting yellow mixture was further stirred at 0° C., under nitrogen, for 10 min., and then at rt for 5 h. The reaction mixture was then concentrated to dryness under reduced pressure and the yellow oily residue was further dried under HV to give methyl 5-amino-5-(4,6-dimethoxypyrimidin-5-yl)pentanoate HCl salt as a yellow solid. LC-MS (conditions A): tR=0.41 min.; [M+H]+: 270.10 g/mol.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH2:15][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: BrCCc1ccccc1
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(CCc3ccccc3)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (2-bromoethyl)benzene and isolated as light-yellow gum (7.3 mg, 46%). MS (m/e): 387.4 (MH+).
Reaction SMILES: C(O[C@@:5]([CH3:21])([C:19]#[CH:20])[CH2:6][CH2:7][C:8]1[C:9](=[O:18])[C:10]([CH3:17])=[C:11]([CH3:16])[C:12](=[O:15])[C:13]=1[CH3:14])(=O)C.C(O)(=O)C>C(Cl)Cl.[Zn]>[C:19]([C@:5]1([CH3:21])[CH2:6][CH2:7][C:8]2[C:13]([CH3:14])=[C:12]([OH:15])[C:11]([CH3:16])=[C:10]([CH3:17])[C:9]=2[O:18]1)#[CH:20]
Reactant: C#C[C@@](C)(CCC1=C(C)C(=O)C(C)=C(C)C1=O)OC(C)=O
Agent: [Zn]
Solvent: CC(=O)O
Solvent: ClCCl
Product: C#C[C@]1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Temperature: 4 °C
Reaction time: 0.83 h
Yield: 25 %

Procedure:
A solution of 285 mg (0.99 mmol) of (R)-2-[3-(acetyloxy) -3-methyl-4-pentynyl]-3,5,6-trimethyl-2,5-cyclohexadiene-1,4-dione in 4 mL of CH2Cl2 was stirred with 250 mg of Zn dust, and 250 mg of glacial acetic acid. The reaction mixture was stirred at 4° C. under argon for 50 min., then filtered. It was worked up with CH2Cl2 as described above. The crude hydroquinone acetate was taken into 6 mL of CH2Cl2 and treated with 20 mg of AgClO4 ·H2O as described above to give 124 mg of crude product after workup, and purification by flash chromatography. Crystallization of this material from toluene-hexane (1:1) at -15° C. gave 57 mg of (S)-2-ethynyl-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol: [α]D25 +20.20°, (c 1.3, CHCl3).
Reaction SMILES: Cl.[CH:2]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]3)=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25])([CH3:4])[CH3:3].[CH3:32][N:33]([CH3:38])[S:34](Cl)(=[O:36])=[O:35]>>[CH3:32][N:33]([CH3:38])[S:34]([N:29]1[CH2:28][CH2:27][N:26]([C:24]([C:6]2[N:5]([CH:2]([CH3:3])[CH3:4])[C:13]3[C:8]([CH:7]=2)=[CH:9][C:10]([O:14][CH:15]2[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]2)=[CH:11][CH:12]=3)=[O:25])[CH2:31][CH2:30]1)(=[O:36])=[O:35]
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCNCC2)n3C(C)C)CC1
Reactant: CN(C)S(=O)(=O)Cl
Agent: Cl
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCN(S(=O)(=O)N(C)C)CC2)n3C(C)C)CC1

Procedure:
The title compound was prepared in analogy to example 51, from [1-isopropyl-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-piperazin-1-yl-methanone hydrochloride and dimethylsulfamoyl chloride. Light-yellow foam. MS (m/z): 520.2 (M+H)+.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH2:17]([O:24][C:25]1[CH:26]=[CH:27][C:28]([O:39][CH3:40])=[C:29]([C:31]([C:33]2[S:34][C:35]([CH3:38])=[CH:36][N:37]=2)=O)[CH:30]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>C1COCC1.O>[CH2:17]([O:24][C:25]1[CH:26]=[CH:27][C:28]([O:39][CH3:40])=[C:29](/[C:31](/[C:33]2[S:34][C:35]([CH3:38])=[CH:36][N:37]=2)=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:30]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COc1ccc(OCc2ccccc2)cc1C(=O)c1ncc(C)s1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\c1ncc(C)s1)c1cc(OCc2ccccc2)ccc1OC
Temperature: -78 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
To a suspension of NaH (60%, 884 mg, 22.1 mmol) in dry THF (120 mL) was added ethyl 2-(diethoxyphosphoryl)acetate (4.96 g, 22.1 mmol) at −78° C. After being stirred at −78° C. for 1 hour, a solution of (5-(benzyloxy)-2-methoxyphenyl)(5-methylthiazol-2-yl)methanone (2.50 g, 7.37 mmol) in THF (30 mL) was added drop wise over 30 min. The mixture was stirred at −78° C. for 30 min and then warmed to room temperature with stirring overnight. The mixture was cooled to 0° C. and treated with water (50 mL), pH value was adjusted to 6 with HCl (0.5N). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with petroleum ether/EtOAc (3:1) to afford (Z)-ethyl 3-(5-(benzyloxy)-2-methoxyphenyl)-3-(5-methylthiazol-2-yl)acrylate (1.75 g, 58.0%) as yellow gel.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH:10]2[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].C(C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C.[F:32][C:33]([F:45])([F:44])[C:34](OS(C(F)(F)F)(=O)=O)=[O:35]>C(Cl)(Cl)(Cl)Cl>[CH2:1]([CH:4]1[CH2:5][CH2:6][CH:7]([CH:10]2[CH2:15][CH2:14][C:13]([O:16][C:34](=[O:35])[C:33]([F:45])([F:44])[F:32])=[CH:12][CH2:11]2)[CH2:8][CH2:9]1)[CH2:2][CH3:3]
Reactant: CCCC1CCC(C2CCC(=O)CC2)CC1
Reactant: O=C(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Solvent: ClC(Cl)(Cl)Cl
Product: CCCC1CCC(C2CC=C(OC(=O)C(F)(F)F)CC2)CC1
Temperature: 25 °C
Yield: 22.8 %

Procedure:
To 50 ml of carbon tetrachloride were added 3.9 g (18 mmol) of 4-(4-propylcyclohexyl)cyclohexanone and 3.8 g (19 mmol) of 2,6-di-t-butyl-4-methylpyridine, and the mixture was stirred at room temperature. To this mixture was added dropwise 2 ml of solution of 4.5 g (18 mmol) of trifluoroacetyltriflate in carbon tetrachloride. Subsequently, 25 ml of carbon tetrachloride was added thereto and the mixture was stirred at room temperature for 1 hour. The reaction solution was filtered off and then the filtrate was concentrated under a reduced pressure. After the residue was purified by column chromatography on silica gel (eluent: heptane/toluene=3/1), the solvent was distilled off, and the residue was subjected twice to recrystallization by using heptane to give 1.3 g (4.1 mmol) of trifluoroacetic acid 4-(4-propylcyclohexyl)-1-cyclohexenyl ester. Yield of this compound based on 4-(4-propylcyclohexyl)cyclohexanone was 23%.
Reaction SMILES: OC(C(F)(F)F)=O.[CH3:8][N:9]([C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)[CH2:10][CH2:11]OS(C1C=CC(C)=CC=1)(=O)=O.C(N(CC)CC)C.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>C1(C)C=CC=CC=1>[CH3:8][N:9]([CH2:10][CH2:11][N:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1)[C:23]1[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=1
Reactant: C1COCCN1
Reactant: Cc1ccc(S(=O)(=O)OCCN(C)c2ccc([N+](=O)[O-])cc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CN(CCN1CCOCC1)c1ccc([N+](=O)[O-])cc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of toluene-4-sulfonic acid 2-[methyl-(4-nitro-phenyl)-amino]-ethyl ester TFA salt (74 mg, 0.21 mmol) in toluene (1 mL) is added triethylamine (50 μL) and morpholine (55 μL, 0.63 mmol). The mixture is shaken in 70° C. block shaker overnight. The reaction mixture is concentrated and purified by reverse phase high performance liquid chromatography to give methyl-(2-morpholin-4-yl-ethyl)-(4-nitro-phenyl)-amine as a di-TFA salt (80 mg, 77%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:17]=[CH:18][C:19]4[N:20]([C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][N:24]=4)[N:21]=3)[CH2:12][CH2:11]2)[CH3:9])=[CH:4][CH:3]=1.[CH3:29][N:30](C)CCN(C)C>CN(C=O)C.[C-]#N.[Zn+2].[C-]#N.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].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[F:26][C:25]([F:28])([F:27])[C:22]1[N:20]2[N:21]=[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C@@H:8]([C:5]4[CH:6]=[CH:7][C:2]([C:29]#[N:30])=[CH:3][CH:4]=4)[CH3:9])[CH2:11][CH2:12]3)[CH:17]=[CH:18][C:19]2=[N:24][N:23]=1
Reactant: C[C@H](c1ccc(Br)cc1)N1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Reactant: CN(C)CCN(C)C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: C[C@H](c1ccc(C#N)cc1)N1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Temperature: 160 °C
Yield: 380.5 %

Procedure:
6-[4-[(1R)-1-(4-Bromophenyl)ethyl]piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (obtained as described in Example 306) (250 mg, 0.55 mmol), zinc cyanide (38.7 mg, 0.33 mmol), tris(dibenzylideneacetone)dipalladium(0) (5.0 mg, 5.49 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (6.3 mg, 10.98 μmol) and N,N,N′,N′-tetramethylethylenediamine (0.017 mL, 0.11 mmol) were suspended in DMF (2.5 mL) and sealed into a microwave tube. The reaction was heated to 160° C. for 5 minutes in a microwave reactor and cooled to ambient temperature. The resulting mixture was applied to an SCX column and eluted with methanol followed by 2M ammonia in methanol. Fractions containing product were combined and evaporated then purified by preparative HPLC (Waters XTerra C18 column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 4-[(1R)-1-[4-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]ethyl]benzonitrile (168 mg, 76%) as a colourless solid.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1[N:8]=[C:7]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1.Cl>O.[Pd]>[CH3:1][N:2]([CH3:18])[C:3]1[NH:8][CH:7]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][N:4]=1
Reactant: CN(C)c1nccc(-c2ccc(C(=O)O)cc2)n1
Agent: [Pd]
Agent: Cl
Solvent: O
Product: CN(C)C1=NCCC(c2ccc(C(=O)O)cc2)N1
Reaction time: 2.5 h
Yield: 93 %

Procedure:
To a solution of 4-(2-dimethylamino-pyrimidin-4-yl)-benzoic acid (275 mg, 1.13 mmol reference example 92aab) in H2O (13 ml) was added conc HCl (212 μL, 2.54 mmol) followed by 10% palladium on carbon (366 mg). The resulting mixture was stirred under H2 for 2.5 hrs. The mixture was filtered through a celite pad to remove the catalyst, using CH2Cl2 as a wash. The filtrate was concentrated under reduced pressure to give 260 mg of product as the HCl salt. MS (ion spray) m/z 248 (M+H)+.
Reaction SMILES: B(Br)(Br)Br.[CH3:5][O:6][C:7]([C:9]1[S:13][C:12]2[CH:14]=[C:15]([O:18]C)[CH:16]=[CH:17][C:11]=2[C:10]=1[CH3:20])=[O:8].CO>C(Cl)Cl>[CH3:5][O:6][C:7]([C:9]1[S:13][C:12]2[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:11]=2[C:10]=1[CH3:20])=[O:8]
Reactant: COC(=O)c1sc2cc(OC)ccc2c1C
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1sc2cc(O)ccc2c1C
Reaction time: 0.25 h
Yield: 81 %

Procedure:
Boron tribromide (5.0 ml.) was added dropwise to a stirred solution of 6-methoxy-3-methylbenzo[b]thiophene-2-carboxylic acid methyl ester (4.70 g.) in dry methylene chloride (200 ml.) at -78° C. and the resulting suspension was stirred at -78° for 15 minutes followed by 24 hours at room temperature. The mixture was then treated cautiously with methanol and the solution was washed with sodium bicarbonate solution. The organic layer was dried (Na2SO4) and evaporated to give a solid which was chromatographed on silica gel. Elution with chloroform first gave a trace of impurity followed by pure product. The product-containing fractions were evaporated to give a solid which was crystallized from ethyl acetate/petrol (b.p. 60°-80°) to give 6-hydroxy-3-methylbenzo[b]thiophene-2-carboxylic acid methyl ester (3.58 g.), m.p. 174°-176°.
Reaction SMILES: CC1N=C(N2C(=O)N(CC3C=CC(C(F)(F)F)=CC=3)N=C2)SC=1C(O)=O.[CH3:27][C:28]1[N:29]=[C:30]([N:36]2[C:40](=[O:41])[N:39]([CH2:42][C:43]3[O:44][C:45]([C:48]([F:51])([F:50])[F:49])=[CH:46][CH:47]=3)[N:38]=[CH:37]2)[S:31][C:32]=1[C:33]([OH:35])=O.[N:52]1[CH:57]=[CH:56][CH:55]=[C:54]([CH2:58][NH2:59])[CH:53]=1>>[CH3:27][C:28]1[N:29]=[C:30]([N:36]2[C:40](=[O:41])[N:39]([CH2:42][C:43]3[O:44][C:45]([C:48]([F:49])([F:51])[F:50])=[CH:46][CH:47]=3)[N:38]=[CH:37]2)[S:31][C:32]=1[C:33]([NH:59][CH2:58][C:54]1[CH:53]=[N:52][CH:57]=[CH:56][CH:55]=1)=[O:35]
Reactant: Cc1nc(-n2cnn(Cc3ccc(C(F)(F)F)o3)c2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: Cc1nc(-n2cnn(Cc3ccc(C(F)(F)F)cc3)c2=O)sc1C(=O)O
Product: Cc1nc(-n2cnn(Cc3ccc(C(F)(F)F)o3)c2=O)sc1C(=O)NCc1cccnc1
Yield: 57 %

Procedure:
Following the procedure as described in Example 21, making variations as required to replace 4-methyl-2-(5-oxo-1-(4-(trifluoromethyl)benzyl)-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylic acid with 4-methyl-2-(5-oxo-1-((5-(trifluoromethyl)furan-2-yl)methyl)-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylic acid to react with pyridin-3-ylmethanamine, the title compound was obtained as a white solid in 57% yield: mp 124-125° C. (ethyl acetate/hexane); 1H NMR (300 MHz, CDCl3) δ 8.63 (s, 2H), 8.28 (s, 1H), 7.82-7.75 (m, 1H), 7.36 (s, 1H), 6.77-6.72 (m, 1H), 6.52 (t, J=5.5 Hz, 1H), 6.47-6.42 (m, 1H), 5.04 (s, 2H), 4.66-4.60 (m, 2H), 2.64 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 161.6, 115.4, 150.9, 150.8, 149.7, 149.3, 149.2, 135.7, 131.4, 123.7, 121.8, 120.5, 116.9, 112.6, 112.5, 110.4, 42.1, 41.6, 17.2; MS (ES+) m/z 465.3 (M+1).
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]#[C:12][CH2:13][CH2:14]O)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1.C(N(CC)CC)C.[B-](F)(F)(F)[F:30].CCN([S+](F)F)CC.C([O-])(O)=O.[Na+]>ClCCl>[F:1][C:2]1[C:10]([C:11]#[C:12][CH2:13][CH2:14][F:30])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1
Reactant: F[B-](F)(F)F
Reactant: OCCC#Cc1ccc2c(cnn2C2CCCCO2)c1F
Agent: CCN(CC)[S+](F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: FCCC#Cc1ccc2c(cnn2C2CCCCO2)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.9 %

Procedure:
To a solution of 4-(4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-3-yn-1-ol (3.4 g, 11.8 mmol; Intermediate 33, Step 1) in dry dichloromethane (100 mL), was added triethylamine.3HF (7.6 g, 47.2 mmol). XtalFluor-E (8.0 g, 34.9 mmol) was then added. The resulting solution was stirred at room temperature for 30 minutes. Upon completion, the reaction solution was neutralized by slow addition of saturated NaHCO3 (30 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (0˜20% EtOAc in petroleum ether), and then re-crystallized from petroleum ether to afford the title compound (1.3 g). 1H NMR (300 MHz, DMSO-d6): δ 8.27 (s, 1H), 7.58 (d, 1H), 7.44 (dd, 1H), 5.89 (dd, 1H), 4.60 (dt, 2H), 3.91-3.85 (m, 1H), 3.80-3.69 (m, 1H), 2.93 (dt, 2H), 2.46-2.28 (m, 1H), 2.06-1.95 (m, 2H), 1.78-1.67 (m, 1H), 1.60-1.52 (m, 2H); LCMS: 291 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]#[N:17])=[C:11]([O:18][CH3:19])[N:10]=1)([CH3:4])([CH3:3])[CH3:2]>CC(O)=O.C(O)C.[Ni]>[C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([CH2:16][NH2:17])=[C:11]([O:18][CH3:19])[N:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1nc(CNC(=O)OC(C)(C)C)cc(C)c1C#N
Agent: [Ni]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1nc(CNC(=O)OC(C)(C)C)cc(C)c1CN
Yield: 87.9 %

Procedure:
A clear solution of tert-butyl((5-cyano-6-methoxy-4-methylpyridin-2-yl)methyl)carbamate (0.65 g, 2.344 mmol) in HOAc (5 mL) and Ethanol (20 mL) was treated on an H-Cube apparatus (50 psi, 40° C., 1 mL/min., Raney Nickel cartridge) for 18 hr overnight. LCMS showed that the reaction was complete. The reaction was evaporated to dryness under vacuum. Purified by silica gel chromatography (Analogix, SF25-60 g, 0 to 10% (5% NH4OH/MeOH) in CH2Cl2). The pure fractions were combined and evaporated to dryness under vacuum to give the product tert-butyl((5-(aminomethyl)-6-methoxy-4-methylpyridin-2-yl)methyl)carbamate (0.58 g, 2.061 mmol, 88% yield) as a clear thick oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Cl)=[CH:32][CH:31]=1>O1CCCC1>[CH2:1]([O:3][C:4](=[O:18])[C:5]1([CH2:34][C:33]2[CH:36]=[CH:37][C:30]([Cl:29])=[CH:31][CH:32]=2)[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10]1)[CH3:2]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: ClCc1ccc(Cl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(Cc2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C

Procedure:
A solution of ethyl-N-boc-isonipecotate (51.4 g, 0.2 mole) in tetrahydrofuran (1 L) at -78° C. was treated with a solution of lithium bis (trimethylsilyl)amide in tetrahydrofuran (220 mL of a 1M solution). The solution was stirred at -60° for 15 minutes at which time 4-chlorobenzyl chloride (33.8 g, 0.22 moles) was added and the reaction warmed to room temperature over 1.5 hours. The reaction was concentrated at reduced pressure to one quarter volume and then poured into saturated aqueous sodium bicarbonate (1 L) and extracted with ethyl acetate (2×800 mL). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated at reduced pressure. The residue was chromatographed on silica gel with 30% ethyl acetate/hexane as eluent to give 61.3 g.
Reaction SMILES: [NH2:1][CH2:2][P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1>>[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[N:1][CH2:2][P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6])=[CH:15][CH:14]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CCOP(=O)(CN)OCC
Product: CCOP(=O)(CN=Cc1ccc(OC)cc1)OCC
Yield: 100 %

Procedure:
Starting from 16.7 g. (0.1 mol) diethyl aminomethylphosphonate and 13.6 g. (0.1 mol) p-methoxybenzaldehyde and following the procedure described in Example 1, 28.5 g. (yield: 100%) of the desired product are obtained in the form of a yellow oil.
Reaction SMILES: S(=O)(=O)(O)O.Cl.C([CH:9]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=1)[C:10](=[O:17])[CH2:11][N:12]1[CH:16]=[N:15][CH:14]=[N:13]1)#N.C(=O)=O>O>[F:26][C:24]([F:25])([F:27])[C:20]1[CH:19]=[C:18]([CH2:9][C:10](=[O:17])[CH2:11][N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)[CH:23]=[CH:22][CH:21]=1
Reactant: N#CC(C(=O)Cn1cncn1)c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: O=C=O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(Cc1cccc(C(F)(F)F)c1)Cn1cncn1
Temperature: 100 °C
Yield: 60.6 %

Procedure:
320 ml of concentrated sulphuric acid and 94 ml of water were added to 266.3 g of 1-cyano-1-(3-trifluoromethylphenyl)-3-(1,2,4-triazol-l-yl)-propanone hydrochloride, and the mixture was heated at 100° C. for 1.5 hours. After the vigorous evolution of CO2 had ended, the mixture was allowed to cool, and 940 ml of water were added. After a short time at from 0° to 20° C., the sulphate of the desired end product crystallized out. This was suspended in water, and the suspension was adjusted to a pH value of 7-8 with sodium bicarbonate solution. The resulting crystalline precipitate was filtered off under suction, dissolved in chloroform, dried over sodium sulphate and concentrated. 131.3 g (72% of theory) of 1-(3-trifluoromethylphenyl)-3-(1,2,4-triazol-l-yl)-propanone of melting point 85° to 87° C. were obtained. ##STR8##