Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][S:7][C:8]2([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3F)[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>CS(C)=O.O>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH:6]2[S:7][C:8]3([CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2=3)=[CH:4][CH:3]=1
Reactant: CN1CCC(SCc2ccc(Cl)cc2)(c2ccccc2F)CC1
Solvent: CS(C)=O
Solvent: O
Product: CN1CCC2(CC1)SC(c1ccc(Cl)cc1)c1ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of sodium methylsulfinylmethide is produced from 0.7 g of (50%) sodium hydride and 15 ml of dimethylsulfoxide as in Example 1c. A solution of 4.2 g of 4-(4-chlorobenzylthio)-4-(2-fluorophenyl)-1-methylpiperidine, free base of a, in 15 ml of dimethylsulfoxide is added to this solution over a three minute span. After total addition, the mixture is stirred at ambient temperature for one hour and then poured onto 70 ml of ice-water. The mixture is diluted with water to 120 ml total volume before being filtered to collect the crude product. The product is washed with water and then dissolved with ether. The ethereal solution is sequentially washed thrice with water and once with a saturated sodium chloride solution and dried to give yellow-white crystals. The crystals are chromatographed with ether through an alumina column to give white crystals, mp 121°-123° C. of 3-(4-chlorophenyl)-1,3-dihydro-1'-methylspiro[benzo(c)thiophene-1,4'-piperidine].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2O)=[N:13][C:14]=1[CH2:15][CH3:16].BrC1N=C(CC)C(NC2C3C=C[S:48]C=3CCC2C)=NC=1CC>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[CH:21]=[CH:22][S:48][C:25]=3[CH2:24][CH2:23][C@H:19]2[CH3:20])=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: CCc1nc(NC2c3ccsc3CCC2C)c(CC)nc1Br
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccsc2CC[C@H]1C

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting 5-bromo-3,6-diethyl-N-(5-methyl-4,5,6,7-tetrahydro-1-benzothien-4-yl)pyrazin-2-amine, ethylene glycol dimethyl ether and tetrakis(triphenylphosphine) palladium and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ) 7.50, 7.35–7.30, 7.10, 6.90, 5.18, 4.60, 2.85, 2.66, 2.49, 2.05, 1.82, 1.29–1.12; HRMS (FAB) calcd for C23H25Cl2N3S+H 446.1224, found 446.1230. Anal. Calcd for C23H25Cl2N3S: C, 61.88; H, 5.64; N, 9.41; Cl, 15.88; S, 7.18. Found: C, 62.04; H, 5.77; N, 9.04.
Reaction SMILES: C([N:4]1[CH:12]=[N:11][C:10]2[C:5]1=[N:6][C:7](N)=[N:8][C:9]=2[Cl:13])(=O)C.[Cl:15][Si](Cl)(C)C.N(OCCC(C)C)=O>[Cl-].C([N+](CC)(CC)CC)C.CCCCCCC>[Cl:15][C:7]1[N:6]=[C:5]2[C:10]([NH:11][CH:12]=[N:4]2)=[C:9]([Cl:13])[N:8]=1
Reactant: C[Si](C)(Cl)Cl
Reactant: CC(=O)n1cnc2c(Cl)nc(N)nc21
Agent: CC(C)CCON=O
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: CCCCCCC
Product: Clc1nc(Cl)c2[nH]cnc2n1
Temperature: 55 °C
Reaction time: 14 h
Yield: 69.5 %

Procedure:
9-Acetyl-2-amino-6-chloropurine (0.50 g, 2.36 mmol), dichlorodimethylsilane (1.01 g, 7.80 mmol), tetraethylammonium chloride (0.025 g, 0.15 mmol) and isoamyl nitrite (0.42 g, 3.54 mmol) were added to heptane (4 ml), and the mixture was heated to 50-60° C. and stirred for 14 hr. After the completion of the reaction, the mixture was filtrated. The obtained crystals were diluted with water (4.0 ml), and the mixture was adjusted to pH 4-5 with a 2M aqueous sodium hydroxide solution. After aging under ice-cooling for 1 hr, the mixture was filtrated, and the obtained crystals were dried under reduced pressure at 80° C. to give a white powder (0.31 g, yield 73.8%) of 2,6-dichloropurine.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[Li]N1C(C)(C)CCCC1(C)C.C([O:30][B:31](OC(C)C)[O:32]C(C)C)(C)C.[C:40](#[N:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.OS(O)(=O)=O>C1COCC1.CCCCCC.C(OCC)(=O)C>[C:40]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[B:31]([OH:32])[OH:30])#[N:47]
Reactant: N#Cc1ccccc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC1(C)CCCC(C)(C)N1
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: N#Cc1ccccc1B(O)O
Temperature: -78 °C
Reaction time: 2 h
Yield: 31.7 %

Procedure:
In a 300 ml nitrogen-substituted flask, 21.6 g (0.153 mol) of 2,2,6,6-tetramethylpiperidine was dissolved in 130 ml of THF. Then, to the resulting solution, 96 ml (0.153 mol) of a 15% solution of n-butyllithium in hexane was added dropwise at −10° C. to prepare lithium 2,2,6,6-tetramethylpiperidide. This solution was cooled to −78° C., and then 67 ml (0.291 mol) of triisopropoxyborane was added dropwise thereto. Next, 15 g (0.146 mol) of benzonitrile was added dropwise, and then the resulting solution was aged for 2 hours at the same temperature. The temperature of the reaction solution was increased to room temperature, and then the solution was hydrolyzed by 230 ml of 2N H2SO4. The solution was charged with 150 ml of ethyl acetate and stirred, and then the acid phase (pH<1) was separated. The aqueous phase was extracted with 100 ml of ethyl acetate. Then, the two organic phases were mixed and washed with 90 ml of saturated brine. The resulting organic phase was then dried with anhydrous magnesium sulfate and concentrated using an evaporator. The concentrated solution was charged with 100 ml of dichloromethane, and then the solution was charged with 50 ml of hexane at 0° C. The precipitated crystals were filtered and dried to obtain 6.8 g of 2-cyanophenylboronic acid crystals. The purity of the 2-cyanophenylboronic acid was 98.5%, in which 0.4 mol % of 1-phenyl-1-(2,2,6,6-tetramethylpiperidin-1-yl)methyl imine was included.
Reaction SMILES: C1C2C(CO[C:16]([N:18](C)[C@H:19]([C:23]([NH:25][C@H:26]([C:30]([N:32]([C@@H:34]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:35]([O:60][CH3:61])[CH2:36][C:37]([N:39]3[CH2:43][CH2:42][CH2:41][C@H:40]3[C@H:44]([O:58][CH3:59])[C@@H:45]([CH3:57])[C:46]([NH:48][CH2:49][CH2:50][C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)=[S:47])=[O:38])[CH3:33])=[O:31])[CH:27]([CH3:29])[CH3:28])=[O:24])[CH:20]([CH3:22])[CH3:21])=O)C3C(=CC=CC=3)C=2C=CC=1>ClCCl.C(NCC)C>[CH3:16][NH:18][C@H:19]([C:23]([NH:25][C@H:26]([C:30]([N:32]([C@@H:34]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:35]([O:60][CH3:61])[CH2:36][C:37]([N:39]1[CH2:43][CH2:42][CH2:41][C@H:40]1[C@H:44]([O:58][CH3:59])[C@@H:45]([CH3:57])[C:46]([NH:48][CH2:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[S:47])=[O:38])[CH3:33])=[O:31])[CH:27]([CH3:29])[CH3:28])=[O:24])[CH:20]([CH3:22])[CH3:21]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=S)NCCc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Solvent: ClCCl
Solvent: CCNCC
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=S)NCCc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC)C(C)C)C(C)C
Yield: 87.7 %

Procedure:
According to general procedure A, from #35 (465 mg, 0.502 mmol, 1 eq.) in dichloromethane (5 mL, 0.1 M) and diethylamine (5 mL) was synthesized the crude desired material, which was purified by silica gel chromatography (Gradient: 0% to 10% methanol in dichloromethane) to give #36 (310 mg, 88%) as a solid. LC-MS: m/z 704.6 [M+H+], retention time=0.74 minutes; HRMS: m/z calculated for C38H66N5O5S: 704.4779. found: 704.477 [M+H+]; 1H NMR (400 MHz, CD3OD), presumed to be a mixture of rotamers, characteristic signals: δ 7.23-7.30 (m, 4H), 7.15-7.22 (m, 1H), [4.68 (d, J=8.6 Hz) and 4.74 (d, J=8.0 Hz), total 1H], 3.39 and 3.40 (2 s, total 3H), 3.12 and 3.22 (2 br s, total 3H), [2.82 (d, J=6.0 Hz) and 2.84 (d, J=6.0 Hz), total 1H], 2.29 and 2.30 (2 s, total 3H), [1.27 (d, J=6.8 Hz) and 1.29 (d, J=6.6 Hz), total 3H], [0.84 (t, J=7.4 Hz) and 0.87 (t, J=7.4 Hz), total 3H].
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[K].[C:8]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][C:12]=1[C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)=[O:22])([CH3:10])=[CH2:9].O>CS(C)=O.C1COCC1>[CH3:20][S:17]([C:14]1[CH:15]=[CH:16][C:11]([C:8]2([CH3:2])[CH2:10][CH2:9]2)=[C:12]([C:21]([N:23]2[CH2:24][CH2:25][N:26]([C:29]3[CH:30]=[CH:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=3)[CH2:27][CH2:28]2)=[O:22])[CH:13]=1)(=[O:19])=[O:18]
Reactant: C=C(C)c1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Reactant: C[S+](C)(C)=O
Agent: [I-]
Agent: [K]
Solvent: O
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC1(c2ccc(S(C)(=O)=O)cc2C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
To a suspension of Trimethylsulfoxonium iodide (21.9 mg, 0.1 mmol) in dry DMSO (300 uL) was added Potassium tert-butoxyde (11.3 mg, 0.101 mmol) portionwise. A solution of (2-Isopropenyl-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone; Example 44 (20 mg, 0.0442 mmol) in dry THF (200 uL) was prepared separately and then added to the above suspension dropwise at room temperature. The reaction mixture was stirred at room temperature for 1 hour and then at 60° C. for 20 hours.The it was cooled down to rt and a solution of Trimethylsulfoxonium iodide (21.9 mg, 0.1 mmol) and Potassium tert-butoxyde (11.3 mg, 0.101 mmol) in dry DMSO (300 uL) was slowly added. Water was added and the solution was extracted 2 times with Ethylacetate. The combined organic phases were washed with water (3 times), dried over Na2SO4 ,filtered and the solvent was removed in vacuo. The residue was chromatographed on SiO2 Eluent: Heptane/EtOAc to provide the title compound (4.2 mg, 20%, white solid; Solid; M+H=467.2)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:10]=2[O:11][CH2:12][C:13]#[N:14])[C:5]([Cl:20])=[CH:4][N:3]=1.[CH3:21][O:22][CH2:23][CH2:24][N:25]1[CH2:31][CH2:30][C:29]2[CH:32]=[C:33]([NH2:36])[CH:34]=[CH:35][C:28]=2[CH2:27][CH2:26]1>>[Cl:20][C:5]1[C:6]([NH:8][C:9]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:10]=2[O:11][CH2:12][C:13]#[N:14])=[N:7][C:2]([NH:36][C:33]2[CH:34]=[CH:35][C:28]3[CH2:27][CH2:26][N:25]([CH2:24][CH2:23][O:22][CH3:21])[CH2:31][CH2:30][C:29]=3[CH:32]=2)=[N:3][CH:4]=1
Reactant: N#CCOc1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: COCCN1CCc2ccc(N)cc2CC1
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4c(F)cccc4OCC#N)n3)cc2CC1

Procedure:
The title compound was prepared from [2-(2,5-dichloropyrimidin-4-ylamino)-3-fluorophenoxy]-acetonitrile and 3-(2-methoxyethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine in an analogous manner to Example 930 to afford a yellow foam (48 mg, 55%). Mp: 68-74° C. LCMS (m/e) 497 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.07 (s, 1H), 7.35 (m, 1H), 7.14 (s, 1H), 7.09-6.94 (m, 3H), 6.90 (m, 1H), 6.51 (s, 1H), 4.71 (s, 2H), 3.58 (m, 2H), 3.38 (s, 3H), 2.87 (m, 2H), 2.80-2.65 (m, 8H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23][CH2:24][O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C>[CH2:26]([O:25][CH2:24][CH2:23][CH2:22][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: BrCCCOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)OB(c2cnn(CCCOCc3ccccc3)c2)OC1(C)C
Temperature: 80 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (5.0 g, 26 mmol), potassium carbonate (4.27 g, 30.9 mmol) and 1-bromo-3-benzyloxypropane (6.20 g, 27.0 mmol) in DMF (20 mL) was stirred at 80° C. overnight, quenched with water (20 mL) and extracted with EtOAc (100 mL). The organic layer was washed with water (2×30 mL), brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ISCO system: EtOAc/Heptane=30-70%) to afford 7.67 g of the title compound as a light-yellow oil (87%). 1H NMR (CDCl3, 400 MHz): δ=7.80 (s, 1H), 7.66 (s, 1H), 7.30-7.36 (m, 5H), 4.48 (s, 2H), 4.28 (t, J=6.8 Hz, 2H), 3.43 (t, J=5.8 Hz, 2H), 2.17 (m, 2H), 1.33 (s, 12H). MS (ES+): m/z=343.36 [MH+]. HPLC: tR=4.20 min (ZQ3: polar—5 min).
Reaction SMILES: [CH3:1][NH:2][S:3]([CH3:6])(=[O:5])=[O:4].C(#N)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]([CH:27]([CH3:29])[CH3:28])[N:20]=[C:19](OS(C3C=CC(C)=CC=3)(=O)=O)[N:18]=2)=[CH:13][CH:12]=1>O>[F:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]([CH:27]([CH3:29])[CH3:28])[N:20]=[C:19]([N:2]([CH3:1])[S:3]([CH3:6])(=[O:5])=[O:4])[N:18]=2)=[CH:15][CH:16]=1
Reactant: CNS(C)(=O)=O
Reactant: COC(=O)c1c(-c2ccc(F)cc2)nc(OS(=O)(=O)c2ccc(C)cc2)nc1C(C)C
Solvent: CC#N
Solvent: O
Product: COC(=O)c1c(-c2ccc(F)cc2)nc(N(C)S(C)(=O)=O)nc1C(C)C
Temperature: 81.5 °C
Yield: 74.8 %

Procedure:
In a 25 mL-volume glass flask equipped with a stirrer, a thermometer and a reflux condenser were placed 196 mg (1.8 mmol.) of N-methylmethanesulfonamide, 198 mg (1.8 mmol.) of sodium t-pentoxide, 7.5 mL of acetonitrile, and 667 mg (1.5 mmol.) of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(p-toluenesulfonyloxy)pyrimidine. The mixture was heated to 81-82° C. for 1.5 hours under refluxing, to carry out reaction. After the reaction was complete, the reaction mixture was cooled to room temperature. To the cooled mixture was added 10 mL of water, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate portion was separated, and dried over anhydrous magnesium sulfate. The dried ethyl acetate portion was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (column: Wako Gel C-200, eluent: hexane/ethyl acetate (2:1, volume ratio)). There was obtained 428 mg of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(N-methyl-N-methanesul-fonylamino)-pyrimidine. The yield was 75% (based on the amount of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(p-toluenesulfonyloxy)pyrimidine).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([CH2:12]Br)[C:9]2[N:14]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[S:16][C:8]=2[C:7]=1[O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:5])[CH3:2].[CH3:28][CH:29]([SH:31])[CH3:30].C(=O)([O-])[O-].[Cs+].[Cs+].C1COCC1>C(OCC)(=O)C.C(O)C>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([CH2:12][S:31][CH:29]([CH3:30])[CH3:28])[C:9]2[N:14]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[S:16][C:8]=2[C:7]=1[O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(CBr)c2nc(C(C)(C)C)sc2c1OC(=O)C(C)(C)C
Reactant: CC(C)S
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1nc(CSC(C)C)c2nc(C(C)(C)C)sc2c1OC(=O)C(C)(C)C

Procedure:
A suspension of the crude 4-bromomethyl-2-tert-butyl-7-(2,2-dimethyl-propionyloxy)-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (above), 2-propanethiol (75 μL, 0.8 mmol), and cesium carbonate (130 mg, 0.4 mmol) in 0.8 mL of a 1:1 mixture of THF:ethanol was stirred for 22 h. The resultant reaction mixture was diluted with ethyl acetate, and washed with water and brine. The organic fractions were dried over anhydrous sodium sulfate and concentrated under reduced pressure to 160 mg of the title compound. MS (ESI+): m/z 452.95 (M+1).
Reaction SMILES: [OH-:1].[Na+].[OH-].[NH4+].[Cl:5][C:6]1[O:10][C:9]([CH:11]=[O:12])=[CH:8][CH:7]=1>O.CO.[N+]([O-])([O-])=O.[Ag+]>[Cl:5][C:6]1[O:10][C:9]([C:11]([OH:1])=[O:12])=[CH:8][CH:7]=1
Reactant: O=Cc1ccc(Cl)o1
Reactant: [OH-]
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(Cl)o1
Yield: 95 %

Procedure:
Aqueous sodium hydroxide (80 mL of 10%) was added to a solution of silver nitrate (8.0 g, 47 mmol) in water (20 mL). This suspension was stirred and slowly treated with 30% aqueous ammonium hydroxide until it became clear. A solution of 5-chlorofuran-2-carboxaldehyde (3.0 g, 23 mmol) (Aldrich Chemical) in methanol (5 mL) was added, and the resulting mixture was stirred at ambient temperature for 30 min. The reaction mixture was filtered, and the filtrate was washed with ether (100 mL). The aqueous filtrate was then made acidic (˜pH 3) by the addition of cold 20% sulfuric acid. The resulting mixture was extracted with ethyl acetate (3×100 mL). The extracts were washed with saturated aqueous sodium chloride solution (100 mL), dried (anhydrous sodium sulfate) and concentrated under vacuum to give 3.2 g (95% yield) of white solid (mp 178-179° C.). This reaction was easily scalable and was run multiple times at >10 g scale.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][C:12]([C:15]([OH:18])([CH3:17])[CH3:16])=[N:13][CH:14]=2)O1.[OH:20][CH2:21][CH2:22][NH:23][C:24]([NH:26][C:27]1[S:28][C:29]2[C:35]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=3)=[CH:34][C:33](OS(C(F)(F)F)(=O)=O)=[CH:32][C:30]=2[N:31]=1)=[O:25].C([O-])([O-])=O.[Cs+].[Cs+]>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]>[OH:20][CH2:21][CH2:22][NH:23][C:24]([NH:26][C:27]1[S:28][C:29]2[C:35]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=3)=[CH:34][C:33]([C:9]3[CH:14]=[N:13][C:12]([C:15]([OH:18])([CH3:16])[CH3:17])=[N:11][CH:10]=3)=[CH:32][C:30]=2[N:31]=1)=[O:25]
Reactant: CC(C)(O)c1ncc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C(NCCO)Nc1nc2cc(OS(=O)(=O)C(F)(F)F)cc(-c3ccccn3)c2s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(O)c1ncc(-c2cc(-c3ccccn3)c3sc(NC(=O)NCCO)nc3c2)cn1
Temperature: 100 °C

Procedure:
To a solution of iii (165 mg, 0.626 mmol) in 1,4-dioxane (12 mL) was added ii (193 mg, 0.417 mmol) and PdCl2(dppf) (34 mg, 0.042 mmol). A solution of Cs2CO3 (410 mg, 1.30 mmol) in H2O (3 mL) was added, the reaction vessel sealed, then evacuated/purged with argon (×3). The mixture was then heated under microwave irradiation at 100° C. for 30 min. LCMS analysis indicated complete conversion. The mixture was diluted with EtOAc (100 mL), washed with H2O, brine, then separated and dried (Na2SO4). The organic fraction was concentrated in vacuo. Purification by chromatography on silica, eluting with 0-10% MeOH/EtOAc followed by additional chromatography on silica, eluting with 0-10% MeOH/DCM afforded Compound 5 (9 mg, 5%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([CH3:18])([CH3:17])[CH2:12][O:13]C(=O)C)[N:10]=2)[CH:7]=1.C([O-])([O-])=O.[K+].[K+]>CO>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([CH3:18])([CH3:17])[CH2:12][OH:13])[N:10]=2)[CH:7]=1
Reactant: CC(=O)OCC(C)(C)c1nc2ccc(I)cn2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(CO)c1nc2ccc(I)cn2n1
Yield: 99.9 %

Procedure:
A solution of acetic acid 2-(6-iodo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-2-methyl-propyl ester (example 40, step 6) (750 mg, 2.09 mmol) and K2CO3 (576 mg, 4.18 mmol, 2 equiv.) in MeOH (8 ml) was stirred at 25° C. for 2 hours. The solvent was evaporated and the resulting crude product was purified by column chromatography. The desired 2-(6-iodo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-2-methyl-propan-1-ol (662 mg, 91% yield) was obtained as a white solid, MS: m/e=318.0 (M+H+).
Reaction SMILES: [C:1]1([NH:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([Br:23])=[C:19]([Br:24])[CH:18]=3)[CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:27]I>CN(C=O)C>[CH3:27][N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]([N:10]1[CH2:11][CH2:12][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[C:19]([Br:24])[CH:18]=2)[CH2:14][CH2:15]1)=[O:9]
Reactant: CI
Reactant: O=C(Nc1ccccc1)N1CCN(Cc2ccc(Br)c(Br)c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)N1CCN(Cc2ccc(Br)c(Br)c2)CC1)c1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of 4-(3,4-dibromo-benzyl)-piperazine-1-carboxylic acid phenylamide (0.02 g) in DMF (0.6 mL) was added NaH (60% dispersion in oil; 3 mg) in one portion. The resulting mixture was allowed to stir for 30 min, then was treated with MeI (0.005 mL), and was stirred at rt for 12 h. The mixture was concentrated and the residue was purified by column chromatography (5% MeOH/DCM), giving the product as a white solid (0.015 g). 1H NMR (400 MHz, CDCl3): 7.54-7.50 (m, 2H), 7.33-7.31 (m, 2H), 7.12-7.05 (m, 4H), 3.34 (s, 2H), 3.22-3.20 (m, 6H), 2.23-2.21 (m, 4H), 1.63 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[C:7](=[O:12])[N:6]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[C:5]2([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])O.FC(F)(F)C(O)=O.C([SiH](CC)CC)C.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[C:7](=[O:12])[N:6]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[C:5]2=[CH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCC1(O)c2cc(C)c(C)cc2C(=O)N1c1cccnc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCC=C1c2cc(C)c(C)cc2C(=O)N1c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.2 %

Procedure:
The product of above-mentioned (10-a) (0.23 g, 0.69 mmol) was added into a mixed solvent of methylene chloride (3.5 ml) and trifluoroacetic acid (1.4 ml), and triethylsilane (0.15 ml, 0.96 mmol) was added dropwise thereto, followed by stirring at 25° C. for 2 hrs. The reaction solution was added into 1N aqueous K2CO3 solution, and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform:acetone=5:1) to give 91 mg of 5,6-dimethyl-3-hexylidene-2-(3-pyridyl)isoindolin-1-one.
Reaction SMILES: [N:1]([CH2:4][Si:5]([CH3:8])([CH3:7])[CH3:6])=[N+:2]=[N-:3].[C:9]([C:15]([O:17][CH3:18])=[O:16])#[C:10][C:11]([O:13][CH3:14])=[O:12]>C1C=CC=CC=1.C(OCC)(=O)C.CCCCCC>[CH3:14][O:13][C:11]([C:10]1[N:3]=[N:2][N:1]([CH2:4][Si:5]([CH3:8])([CH3:7])[CH3:6])[C:9]=1[C:15]([O:17][CH3:18])=[O:16])=[O:12]
Reactant: COC(=O)C#CC(=O)OC
Reactant: C[Si](C)(C)CN=[N+]=[N-]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)c1nnn(C[Si](C)(C)C)c1C(=O)OC

Procedure:
A solution of azidomethyl-trimethyl-silane (5.0 g, 38.69 mmol) and dimethyl acetylenedicarboxylate (4.74 mL, 38.69 mmol) in benzene (200 mL) was refluxed for 2 h. The solvent was removed in vacuo and the resultant crude material was diluted with water (100 mL), and extracted with ethyl acetate (3×100 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and evaporated in vacuo. The product was obtained after purification by flash chromatography (using silica gel and 20% ethyl acetate/hexane) as colorless liquid (10 g, 36.9 mmol, 95.2%).