Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[N:6]=[C:5](Cl)[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[C:3]=2[N:2]=1.[CH3:20][O:21][CH2:22][CH2:23][NH2:24]>C(O)C>[CH3:20][O:21][CH2:22][CH2:23][NH:24][C:5]1[C:4]2[N:8]=[CH:9][N:10]([C:3]=2[N:2]=[CH:1][N:6]=1)[C@@H:11]1[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]1[OH:19]
Reactant: COCCN
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Solvent: CCO
Product: COCCNc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 90 °C
Yield: 98 %

Procedure:
547 mg 6-chloropurine riboside, 0.882 mL 2-methoxyethylamine, and 5.0 mL ethyl alcohol are combined and heated to 90° C. in a sealed reaction vessel for about 22 hours. The ligand is then purified by silica gel chromatography using 8:1 methylene chloride:methanol to yield N6-(2-methoxyethyl)-adenosine (0.61 g, 98% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-:3])=[O:2].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][NH2:20]>>[CH3:15][O:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][NH:20][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[CH:13][C:4]=2[N+:1]([O-:3])=[O:2])[N:9]=1
Reactant: COc1ccccc1CN
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Product: COc1ccccc1CNc1ccc2c([N+](=O)[O-])cccc2n1

Procedure:
5-Nitro-2-chloroquinoline (CAS 13067-94-2,3 g, 14 mmol) and 2-methoxy-benzylamine (4.2 g, 31 mmol) were stirred in a sealed tube at 120° C. overnight. The reaction mixture was purified by flash chromatography on silica gel (heptane/ethyl acetate 100:0->30:70 gradient). (2-Methoxy-benzyl)-(5-nitro-quinolin-2-yl)-amine was obtained as a yellow solid (2.2 g, 50%), MS: m/e=310.1 (M+H+).
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].[CH2:7]([CH:9]1[O:11][CH2:10]1)Cl>[Sn](F)F.C1(C)C(C)=CC=CC=1>[CH2:7]([O:5][CH2:4][CH2:3][CH2:2][CH2:1][O:6][CH2:7][CH:9]1[O:11][CH2:10]1)[CH:9]1[O:11][CH2:10]1
Reactant: OCCCCO
Reactant: ClCC1CO1
Agent: F[Sn]F
Solvent: Cc1ccccc1C
Product: C(CCOCC1CO1)COCC1CO1
Temperature: 130 °C
Reaction time: 3 h
Yield: 84.8 %

Procedure:
A reactor equipped with stirrer, reflux condenser, dropping funnel and thermometer is charged with 180.24 g (2.0 mol) of 1,4-butanediol and 6.27 g (0.04 mol) of tin difluoride and the charge is heated to 130° C. Then, with efficient stirring, 388.6 g (4.20 mol) of epichlorohydrin are added over 2 hours at a temperature of 130°-140° C., the reaction being initially exothermic. After 3 hours at this temperature, the reaction mixture is cooled to 50° C. and to the turbid solution are added 350 ml of xylene, followed by the addition of 30 g of Prolit Rapid® (filter aid). After stirring for 15 minutes, the suspension is filtered and the filtrate is freed from solvent on a rotary evaporator. Analysis of the tin content of the residual liquid chlorohydrin ether shows that this ether still contains only about 13% of the total amount of tin catalyst, i.e. 87% of the catalyst can be separated by filtration. The liquid chlorohydrin ether (589 g) is heated to 55° C. and 336 g (4.2 mol) of a 50% aqueous solution of sodium hydroxide are added dropwise at this temperature, with efficient stirring, over 30 minutes. After stirring for 2.5 hours at 50°-60° C. and cooling to room temperature, the suspension is filtered and the filtrate washed with xylene. The organic phase of the two-phase clear filtrate is dried over magnesium sulfate and filtered, and the filtrate is freed from solvent on a rotary evaporator under vacuum (bath temperature 50° C.). Yield: 343 g (85% of theory) of colourless 1,4-butanediol diglycidyl ether for which the following analytical values are obtained: epoxy value: 7.81 eq/kg; total chlorine content: 5.5%; hydrolysable chlorine content: 131 ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:12][CH:13](C(O)=O)[C:14]([OH:16])=[O:15].N1CCCCC1.Cl>N1C=CC=CC=1>[CH3:12][C:13](=[CH:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[C:14]([OH:16])=[O:15]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CC(C(=O)O)C(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: CC(=Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Temperature: 0 °C
Reaction time: 24 h

Procedure:
630 ml of pyridine was added to 76 g of 4-nitrobenzaldehyde (m.p. 105°-106.5° C.), 118 g of methylmalonic acid (prepared by hydrolysis of diethyl methylmalonate) and 85 g of piperidine. The mixture was heated with stirring over a steam bath for 24 hours. After being allowed to cool, the reaction mixture was then added to a mixture of 1,250 ml of concentrated hydrochloric acid and 2.5 kg of ice. The resulting oil content was then extracted with diethyl ether. The oil content was further extracted with a 5% aqueous solution of sodium hydroxide. The aqueous solution was then slightly acidified. The resulting crystal composition was then filtered off and dried. (Yield: 86 g (83%))
Reaction SMILES: [CH3:1][N:2]([CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])[C:3](=[O:23])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[S:13][C:14]3[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=3[C:16](=[O:18])[N:17]=2)[N:7]=1.C(OC(C)C)(C)C>FC(F)(F)C(O)=O>[CH3:1][N:2]([CH2:24][C:25]([OH:27])=[O:26])[C:3](=[O:23])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[S:13][C:14]3[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=3[C:16](=[O:18])[N:17]=2)[N:7]=1
Reactant: CN(CC(=O)OC(C)(C)C)C(=O)CCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Solvent: CC(C)OC(C)C
Solvent: O=C(O)C(F)(F)F
Product: CN(CC(=O)O)C(=O)CCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 89.3 %

Procedure:
tert-Butyl (methyl{3-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propanoyl}amino)acetate (0.32 g, 0.73 mmol) was dissolved in trifluoroacetic acid (1.0 ml), and the mixture was stirred at room temperature for 2.5 hrs. Isopropyl ether was added to the reaction mixture to precipitate crystals, which were collected by filtration and recrystallized from ethanol-hexane to give the titled compound (0.25 g, 83%) as white crystals.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].N1[CH2:17][C@H:15]([OH:16])[CH2:14][C@H:10]1C(O)=O.N[C@H](C(O)=O)CC1C2C(=CC=CC=2)NC=1>>[NH2:1][C@H:2]([C:3]([OH:5])=[O:4])[CH2:6][C:7]1[CH:8]=[CH:17][C:15]([OH:16])=[CH:14][CH:10]=1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Product: N[C@@H](Cc1ccc(O)cc1)C(=O)O

Procedure:
proline (Pro) (pyrrolidin-2-yl), hydroxyproline (4hydroxy-2-pyrrolidinyl), tryptophan (Trp)
Reaction SMILES: O[C:2]1[C:3]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][C:4]=2[N:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:43]>ClC(Cl)C>[Cl:43][C:2]1[C:3]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][C:4]=2[N:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(O)nc(C(F)(F)F)nc2C1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCc2c(Cl)nc(C(F)(F)F)nc2C1
Temperature: 70 °C
Reaction time: 3 h
Yield: 96.3 %

Procedure:
tert-Butyl 4-hydroxy-2-(trifluoromethyl)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (5.12 g, 16.05 mmol) was combined with triphenylphosphine (8.42 g, 32.1 mmol) and stirred in dichloroethane (160 mL) at ambient temperature for 15 minutes, and then carbon tetrachloride (7.41 g, 48.1 mmol) was added. The reaction was stirred at 70° C. for 3 hours, cooled to room temperature, and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (elution gradient from 0% to 3% methanol/DCM) to afford the title compound as a clear oil (5.22 g, 86% yield). MS (ESI) m/e (M−H)−=336.3.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([CH:11]([F:14])[CH2:12]Br)=[C:9]([NH2:15])[N:8]=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([O:23][CH3:24])[C:17]=2[F:25])[N:6]=1)=[O:4].C([SnH](CCCC)CCCC)CCC>COCCOC.N(C(C)(C)C#N)=NC(C)(C)C#N>[CH3:1][O:2][C:3]([C:5]1[C:10]([CH:11]([F:14])[CH3:12])=[C:9]([NH2:15])[N:8]=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([O:23][CH3:24])[C:17]=2[F:25])[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)nc(N)c1C(F)CBr
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: COCCOC
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)nc(N)c1C(C)F
Temperature: 100 °C
Yield: 61 %

Procedure:
6-Amino-5-(2-bromo-1-fluoroethyl)-2-(4-chloro-2-fluoro-3-methoxyphenyl)pyrimidine-4-carboxylic acid methyl ester (324 mg, 0.742 mmol), tri-n-butyltin hydride (0.396 mL, 1.484 mmol), and 2,2′-azobisisobutyronitrile (3.05 mg, 0.019 mmol) were combined in 1,2-dimethoxyethane (2.5 mL) and heated at 100° C. for 15 min in a CEM microwave reactor. The cooled reaction mixture was concentrated under vacuum then purified by flash chromatography on silica gel (dichloromethane/ethyl acetate gradient). A second purification by flash chromatography on silica gel (hexane/ethyl acetate gradient) yielded the title compound (162 mg, 61.0% yield) as a white solid, mp 150-152° C.: 1H NMR (CDCl3) δ 7.64 (dd, 1H), 7.22 (dd, 1H), 6.26 (dq, 1H), 5.73 (br s, 2H), 4.00 (d, 3H), 3.98 (s, 3H), 1.80 (dd, 3H).
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[N:7]=1)[C:3](Cl)=[S:4].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=1[CH3:21].C(=O)([O-])[O-].[K+].[K+].O>C(C(C)=O)C>[CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[N:7]=1)[C:3](=[S:4])[O:20][C:17]1[CH:18]=[CH:19][C:14]([Cl:13])=[C:15]([CH3:21])[CH:16]=1
Reactant: Cc1cccc(N(C)C(=S)Cl)n1
Reactant: Cc1cc(O)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: Cc1cccc(N(C)C(=S)Oc2ccc(Cl)c(C)c2)n1
Temperature: 25 °C
Yield: 34.8 %

Procedure:
A mixture of 2.01 g of N-methyl-N-(6-methyl-2-pyridyl)thiocarbamoylchloride, 1.43 g of 4-chloro-3-methylphenol, and 1.38 g of potassium carbonate in 50 ml of methyl ethyl ketone was refluxed for 48 hours. After the reaction mixture was cooled to room temperature, it was poured into cold water and the product was extracted with benzene. The benzene solution, successively washed with water and brine, was dried over anhydrous magnesium sulfate. The residue obtained by the removal of benzene under reduced pressure was chromatographed through silica gel column using hexane-ethyl acetate (3/1, V/V) as an eluent to give 1.07 g of pure O-4-chloro-3-methylphenyl N-methyl-N-(6-methyl-2-pyridyl)thiocarbamate as solid in the yield of 35%. A part of the solid was recrystallized from benzene-hexane and crystalls having melting point of 134° to 136° C. were obtained.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH:11]3[OH:23])=[CH:9][C:4]=2[O:3][CH2:2]1.Br[CH2:25][C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:12][CH:11]3[O:23][CH2:25][C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc3c(c2)OCO3)C(O)C1
Reactant: BrCc1ccc2ccccc2c1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc3c(c2)OCO3)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 1(g), by alkylating tert-butyl (3RS,4RS)-4-benzo[1,3]dioxol-5-yl-3-hydroxy-piperidine-1-carboxylate with 2-bromomethylnaphthalene there was obtained tert-butyl (3RS,4RS)-4-benzo[1,3 ]dioxol-5-yl-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as white crystals after crystallization from hexane; m.p.: 128-129° C.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:37]([CH3:38])=[CH:36][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([N:25]4[CH2:30][CH2:29][C:28]5[N:31]([CH3:35])[N:32]=[C:33]([CH3:34])[C:27]=5[CH2:26]4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].CN1C2CCNCC=2C(C)=N1.[OH-].[Na+].CN(C=O)C>CO.C1COCC1.C(O)(=O)C>[C:1]([O:5][C@@H:6]([C:12]1[C:37]([CH3:38])=[CH:36][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([N:25]4[CH2:30][CH2:29][C:28]5[N:31]([CH3:35])[N:32]=[C:33]([CH3:34])[C:27]=5[CH2:26]4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:39]1[CH:40]=[CH:41][C:42]([Cl:45])=[CH:43][CH:44]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(N4CCc5c(c(C)nn5C)C4)c3)sc2c1-c1ccc(Cl)cc1
Agent: Cc1nn(C)c2c1CNCC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cc2nc(-c3ccnc(N4CCc5c(c(C)nn5C)C4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 45 °C

Procedure:
A solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-(1,3-dimethyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)pyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate: A mixture of 1,3-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (7.7 mg, 0.012 mmol) and 5M sodium hydroxide (47 μL, 0.24 mmol) in methanol (0.1 mL) and THF (0.5 mL) was heated 45° C. for 2 h. Acetic acid (1 drop) and DMF (0.3 mL) were added and mixture concentrated to ˜0.3 mL, diluted with methanol, filtered and purified by Gilson HPLC (Gemini, 5 to 100% ACN/H2O+0.1% TFA) to give product after lyophilization. LCMS-ESI+: calc'd for C32H34ClN5O3S: 616.2 (M+H+); Found: 616.3 (M+H+); 1H NMR (400 MHz, CD3OD) δ 8.11 (d, J=6.3 Hz, 1H), 7.96 (s, 1H), 7.83 (s, 1H), 7.68 (dd, J=8.5, 1.7 Hz, 1H), 7.67-7.54 (m, 3H), 7.47 (dd, J=6.3, 1.3 Hz, 1H), 5.27 (s, 1H), 4.63 (s, 2H), 4.07 (t, J=5.7 Hz, 2H), 3.72 (s, 3H), 2.93 (t, J=5.5 Hz, 2H), 2.64 (s, 3H), 2.24 (s, 3H), 0.97 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]23[CH2:16][CH2:15][CH2:14][CH:13]2[CH2:12][NH:11][CH2:10][CH2:9]3)[CH:5]=[CH:6][CH:7]=1.[CH2:17](I)[CH:18]=[CH2:19].C(=O)(O)[O-].[Na+]>>[OH:1][C:2]1[CH:3]=[C:4]([C:8]23[CH2:16][CH2:15][CH2:14][CH:13]2[CH2:12][N:11]([CH2:19][CH:18]=[CH2:17])[CH2:10][CH2:9]3)[CH:5]=[CH:6][CH:7]=1
Reactant: C=CCI
Reactant: Oc1cccc(C23CCCC2CNCC3)c1
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCN1CCC2(c3cccc(O)c3)CCCC2C1

Procedure:
Following the procedure set forth in Example 36, 4a-(3-hydroxyphenyl)-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindine was reacted with allyl iodide in the presence of sodium bicarbonate to provide 4a-(3-hydroxyphenyl)-2-(2-propenyl)-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindine. M.P. 106°-108° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[C:18]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:21])[CH:19]=[CH2:20].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.C(#N)CC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5](/[CH:20]=[CH:19]/[C:18]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:6][CH:7]=1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: Nc1ccc(Br)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)/C=C/c1ccc(N)nc1
Temperature: 100 °C
Reaction time: 20 h
Yield: 99.7 %

Procedure:
To a solution of 2-amino-5-bromopyridine (300 mg, 1.73 mmol) in DMF (1.5 mL) and proprionitrile (3.5 mL) under Argon were added DIPEA (613 μL, 3.71 mmol), tert-butyl acrylate (1.02 mL, 7.06 mmol), tri(o-tolyl)phosphine (106 mg, 0.35 mmol) and palladium acetate (39 mg, 0.17 mmol). The mixture was stirred at 100° C. for 20 h, then allowed to come back to room temperature, filtered through Celite pad and rinsed with EtOAc. The residue obtained after concentration was purified by flash chromatography (eluent: 95/5 DCM/MeOH) to give the title compound as an orange solid (380 mg, quantitative).
Reaction SMILES: [Na].Br[C:3]1[CH:7]=[CH:6][S:5][CH:4]=1.Cl.[CH2:9]([OH:13])[CH2:10][CH2:11][OH:12]>[Cu]I.[Cu]=O>[S:5]1[CH:6]=[CH:7][C:3]([O:12][CH2:11][CH2:10][CH2:9][OH:13])=[CH:4]1
Reactant: Brc1ccsc1
Reactant: OCCCO
Agent: O=[Cu]
Agent: [Cu]I
Agent: Cl
Product: OCCCOc1ccsc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
68 mg of sodium was added to 10 ml of 1,3-propandiol, and the mixture was stirred at room temperature for 1 hour. The reaction solution was warmed to 70° C., and to this solution were added, 126 μl of 3-bromothiophene, 13 mg of copper(I) iodide and 16 mg of copper(II) oxide. The mixture was heated at 150° C. with stirring for 20 hours, and then poured into the ice-cold water. The resulting solution was neutralized with diluted hydrochloric acid, and extracted with ethyl ether. The extract was worked up in a customary manner, and the product was purified by medium-pressure liquid chromatography [silica gel column, hexane ethyl acetate=20/1→5/1] to give 49 mg of the captioned compound as a white crystal.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH2:6]([NH:12][C:13]([N:15]1[C:19]([CH3:20])=[CH:18][C:17]([O:21][C:22]2[C:27]([Cl:28])=[CH:26][C:25]([C:29]([F:32])([F:31])[F:30])=[CH:24][C:23]=2[Cl:33])=[N:16]1)=[O:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]>C(O)(=O)C>[CH2:6]([NH:12][C:13]([N:15]1[C:19]([CH3:20])=[C:18]([Cl:4])[C:17]([O:21][C:22]2[C:27]([Cl:28])=[CH:26][C:25]([C:29]([F:32])([F:30])[F:31])=[CH:24][C:23]=2[Cl:33])=[N:16]1)=[O:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCCCCCNC(=O)n1nc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C
Solvent: CC(=O)O
Product: CCCCCCNC(=O)n1nc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)c(Cl)c1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.6 %

Procedure:
Sulfuryl chloride (0.16 g, 1.2 mmol) was added to a solution of N-hexyl-3-(2,6-dichloro-4-trifluoromethylphenyloxy)-5-methylpyrazole-1-carboxamide (0.44 g, 1.0 mmol) in acetic acid (5 ml), and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was poured into ice water and extracted with ethyl acetate (10 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant. The solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane 1/10), to give a white solid of N-hexyl-4-chloro-3-(2,6-dichloro-4-trifluoromethylphenyloxy)-5-methylpyrazole-1-carboxamide (0.40 g, yield: 84.8%). mp: 86-88° C.; 1H-NMR (CDCl3, TMS, ppm): δ 0.88 (t, J=6.8 Hz, 3H), 1.26 (m, 6H), 1.40-1.60 (m, 2H), 2.62 (s, 3H), 3.15-3.35 (m, 2H), 6.50-6.70 (m, 1H), 7.67 (s, 2H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][C:13]([C:15]([F:18])([F:17])[F:16])=[N:12][C:11]=2[C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[CH:6][CH:5]=1.[CH3:29][Si:30]([CH2:33][CH2:34][O:35][CH2:36]Cl)([CH3:32])[CH3:31].[NH4+].[Cl-]>CN(C)C=O.CCCCCC>[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([CH2:36][O:35][CH2:34][CH2:33][Si:30]([CH3:32])([CH3:31])[CH3:29])[C:13]([C:15]([F:18])([F:16])[F:17])=[N:12][C:11]=2[C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:21][CH:20]=2)=[CH:6][CH:5]=1
Reactant: CS(=O)(=O)c1ccc(-c2nc(C(F)(F)F)[nH]c2-c2ccc(F)cc2)cc1
Reactant: C[Si](C)(C)CCOCCl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: C[Si](C)(C)CCOCn1c(C(F)(F)F)nc(-c2ccc(S(C)(=O)=O)cc2)c1-c1ccc(F)cc1
Temperature: 25 °C

Procedure:
A mixture of hexane-washed sodium hydride (NaH) (110 mg of 60%, 2.8 mmol) in dimethylformamide (DMF) (15 ml) was stirred under a nitrogen atmosphere at 25° C. and a solution of 5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2-trifluoromethyl-1H-imidazole (Example 1) (970 mg, 2.5 mmol) in DMF (5 ml) was added over 15 minutes. This mixture was stirred an additional 30 minutes. Trimethylsilylethoxymethyl chloride (450 mg, 3 mmol) was added and the reaction mixture was stirred for 16 hours at 25° C. The reaction mixture was poured into 2% aqueous NH4Cl (150 ml) and extracted with ethyl acetate. After drying (Na2SO4) and solvent removal, the protected sulfone imidazole (1.1 g, 95%) was essentially pure and was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][NH:10][C:11]([C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([C:20]([NH:22][CH2:23][C:24]3[C:25]([NH:37][CH:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)=[C:26]4[CH:34]=[N:33][N:32]([CH2:35][CH3:36])[C:27]4=[N:28][C:29]=3[CH2:30][CH3:31])=[O:21])[CH:14]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[F:8].[CH:44]([C:46]1[CH:47]=[C:48](B(O)O)[CH:49]=[CH:50][CH:51]=1)=[O:45].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C(Cl)Cl.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>[CH2:35]([N:32]1[C:27]2=[N:28][C:29]([CH2:30][CH3:31])=[C:24]([CH2:23][NH:22][C:20]([C:15]3[CH:16]=[C:17]([CH3:19])[CH:18]=[C:13]([C:11]([NH:10][CH2:9][C:4]4[CH:3]=[C:2]([C:50]5[CH:49]=[CH:48][CH:47]=[C:46]([CH:44]=[O:45])[CH:51]=5)[C:7]([F:8])=[CH:6][CH:5]=4)=[O:12])[CH:14]=3)=[O:21])[C:25]([NH:37][CH:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[C:26]2[CH:34]=[N:33]1)[CH3:36]
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)NCc2ccc(F)c(Br)c2)c1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)NCc2ccc(F)c(-c3cccc(C=O)c3)c2)c1
Yield: 67.1 %

Procedure:
N-[(3-Bromo-4-fluorophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-5-methyl-1,3-benzenedicarboxamide (0.849 g, 1.303 mmol), (3-formylphenyl)boronic acid (0.195 g, 1.303 mmol), potassium carbonate (0.540 g, 3.91 mmol), and Pd(Ph3P)4 (0.075 g, 0.065 mmol) were divided into 3 portions and added to three 2-5 mL Biotage microwave vials in 1,4-dioxane (3 mL) and water (1 mL). The vials were capped and the mixtures were microwaved at normal power in the Emrys Optimizer at 100° C. for 15 min. The combined crude product was partitioned between EtOAc (75 mL) and water (20 mL). The phases were separated, and the organic phase was washed with water (2×20 mL), brine (20 mL), dried over anhydrous Na2SO4 filtered and evaporated to give the crude material. It was taken up in DCM and absorbed on Isolute® Sorbent and purified by Combiflash using an 80 g silica column eluted with 0-10% DCM/MeOH. The product fractions were combined and concentrated to give (N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(6-fluoro-3′-formyl-3-biphenylyl)methyl]-5-methyl-1,3-benzenedicarboxamide (596.6 mg, 0.874 mmol, 67.0% yield)) as a beige solid. LC-MS m/z 677.4 (M+H)+, 1.01 min (ret time); mp 107-110° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([C:10]2[C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:13]=3[N:12]([CH:19]([CH3:21])[CH3:20])[CH:11]=2)=[O:9])[CH:5]=[CH:4][N:3]=1.[C:22]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](O)=[O:32])=[CH:26][C:25]=1[C:34]([F:37])([F:36])[F:35])#[N:23]>>[C:22]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]([NH:1][C:2]2[CH:7]=[C:6]([C:8]([C:10]3[C:14]4[CH:15]=[N:16][CH:17]=[CH:18][C:13]=4[N:12]([CH:19]([CH3:21])[CH3:20])[CH:11]=3)=[O:9])[CH:5]=[CH:4][N:3]=2)=[O:32])=[CH:26][C:25]=1[C:34]([F:35])([F:37])[F:36])#[N:23]
Reactant: CC(C)n1cc(C(=O)c2ccnc(N)c2)c2cnccc21
Reactant: N#Cc1ccc(CC(=O)O)cc1C(F)(F)F
Product: CC(C)n1cc(C(=O)c2ccnc(NC(=O)Cc3ccc(C#N)c(C(F)(F)F)c3)c2)c2cnccc21
Reaction time: 16 h

Procedure:
Prepared according to Method M (Example 206) at 60° C. for 16 hours followed by 70° C. for a further 16 hours using (2-aminopyridin-4-yl)-(1-isopropyl-1H-pyrrolo[3,2-c]pyridin-3-yl)methanone (Preparation 20) and [4-cyano-3-(trifluoromethyl)phenyl]acetic acid (Preparation 95). Purified using silica gel column chromatography eluting with 5-7% MeOH in DCM.