Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH3:10][CH:11]1[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]1.C(O)=O.N>O>[CH3:10][CH:11]1[CH2:16][CH2:15][CH2:14][N:13]([CH2:5][C:4]2[CH:3]=[C:2]([OH:1])[CH:9]=[CH:8][CH:7]=2)[CH2:12]1
Reactant: CC1CCCNC1
Reactant: O=Cc1cccc(O)c1
Agent: N
Solvent: O=CO
Solvent: O
Product: CC1CCCN(Cc2cccc(O)c2)C1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
24.4 g (0.2 mol) of 3-hydroxybenzaldehyde are mixed with 40 ml (about 0.4 mol) of 3-methylpiperidine and 20 ml (about 0.52 mol) of 100% formic acid with cooling and then stirred for 2 hours at 120° C. When the reaction mixture has cooled to room temperature, it is poured into water and rendered alkaline with ammonia, and the precipitated solid is filtered off and recrystallised from ethanol.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][NH:4]1.S(O[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]2[O:22][CH2:23][O:24][C:18]=2[CH:17]=1)(=O)(=O)C.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(#N)C>[OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]2[O:22][CH2:23][O:24][C:18]=2[CH:17]=1
Reactant: CS(=O)(=O)OCCc1ccc2c(c1)OCO2
Reactant: OC[C@H]1CCCCN1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: OC[C@H]1CCCCN1CCc1ccc2c(c1)OCO2
Temperature: 90 °C

Procedure:
(R)-2-hydroxymethylpiperidine (288 mg, 2.50 mmol), 3,4-methylenedioxyphenethyl mesylate (732 mg, 3.00 mmol), sodium carbonate (320 mg, 3.00 mmol) and sodium iodide (30 mg, 0.20 mmol) were added to acetonitrile (25 ml), and they were heated under reflux at 90° C. for 10 hours. The solvent was evaporated under reduced pressure. The residue was distributed in ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with water and dried over magnesium sulfate. Then the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography. The product was eluted with dichloromethane as the eluent and then with dichloromethane and methanol (20:1). The appropriate fractions were combined, and the solvent was evaporated under reduced pressure to obtain (R)-2-hydroxymethyl-1-(3,4-methylenedioxyphenethyl)piperidine in the form of a light yellow oil (370 mg, 56%).
Reaction SMILES: [F:1][C:2]1([F:36])[CH2:8][N:7]([C@@H:9]2[CH2:11][C@H:10]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]2[N:18]=[C:19]([NH:22][C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=3[O:32][CH3:33])[N:20]=[CH:21][C:5]=2[N:4]([CH3:34])[C:3]1=[O:35].C([N:39](C(C)C)C(C)C)C.[Cl-].[NH4+]>CN(C)C=O>[F:1][C:2]1([F:36])[CH2:8][N:7]([C@@H:9]2[CH2:11][C@H:10]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]2[N:18]=[C:19]([NH:22][C:23]3[CH:31]=[CH:30][C:26]([C:27]([NH2:39])=[O:29])=[CH:25][C:24]=3[O:32][CH3:33])[N:20]=[CH:21][C:5]=2[N:4]([CH3:34])[C:3]1=[O:35]
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N([C@@H]1C[C@H]1c1ccccc1)CC(F)(F)C(=O)N2C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1cc(C(N)=O)ccc1Nc1ncc2c(n1)N([C@@H]1C[C@H]1c1ccccc1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
To a mixture of 0.074 g (0.15 mmole) of 4-[7,7-difluoro-5-methyl-6-oxo-9-(trans-2-phenyl-cyclopropyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino]-3-methoxy-benzoic acid (I-287), 0.11 mL (0.6 mmole) of ethyldiisopropyl amine and 0.016 g (0.30 mmole) of ammonium chloride in 2.0 mL of dimethylformamide was added 0.071 g (0.17 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The mixture was extracted three times with dichloromethane. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-90:10) gave 0.072 g of 4-[7,7-difluoro-5-methyl-6-oxo-9-(trans-2-phenyl-cyclopropyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino]-3-methoxy-benzamide (I-289) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:14])=[C:4]([CH:11]=[CH:12][CH:13]=1)[C:5](N(OC)C)=[O:6].[CH3:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[Mg]Br>C1COCC1>[Br:1][C:2]1[C:3]([F:14])=[C:4]([C:5]([C:17]2[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:16]=2[CH3:15])=[O:6])[CH:11]=[CH:12][CH:13]=1
Reactant: COc1ccc([Mg]Br)c(C)c1
Reactant: CON(C)C(=O)c1cccc(Br)c1F
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2cccc(Br)c2F)c(C)c1

Procedure:
Prepared according to Method A step B from 3-bromo-2-fluoro-N-methoxy-N-methylbenzamide (8 g, 31 mmol) and 2-methyl-4-methoxyphenyl magnesium bromide ((70 ml, 0.5 M in THF) to give 3.58 g of the title compound.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].Cl.[CH2:17]([O:24][C:25](=[O:31])[C@@H:26]1[CH2:30][CH2:29][CH2:28][NH:27]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[CH2:17]([O:24][C:25](=[O:31])[C@@H:26]1[CH2:30][CH2:29][CH2:28][N:27]1[C:8](=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CCCCCC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Triethylamine (23.1 ml) and hexanoyl chloride (11.4 ml) were added dropwise to a methylene chloride solution (300 ml) of L-proline benzylester hydrochloride (20.00 g) under ice cooling, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was successively washed with 1N hydrochloric acid, saturated sodium hydrogencarbonate, and brine, dried over magnesium sulfate, and concentrated to obtain 26.20 g of N-hexanoyl-L-proline benzyl ester.
Reaction SMILES: [O:1]=[C:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:21]([OH:23])=O)=[CH:3]1.C(Cl)(=O)C([Cl:27])=O>C(Cl)Cl.CN(C)C=O>[O:1]=[C:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:21]([Cl:27])=[O:23])=[CH:3]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 3-oxoandrost-4-ene-17β-carboxylic acid (30 g) in methylene chloride (300 mL) and dimethylformamide (1.82 mL) a solution of oxalyl chloride (9.28 mL) in methylene chloride (30 mL) was added dropwise at 0° C. under nitrogen atmosphere. After stirring at 0° C. for 1 hour the reaction was completed. The volatile compounds were removed under vacuum, the solid was taken up with cyclohexane (200 mL) and evaporated to dryness (twice). The 3-oxo-androst-4-ene-17β-carbonyl chloride (30.33 g) so obtained was dissolved in chloroform (1.5 L), cooled to 0° C. and treated with 1,1,1,3,3,3-hexafluorophenylpropyl amine (46.078 g) and pyridine (38.3 mL). The reaction mixture was heated at reflux for 7 hours. After staying overnight at room temperature the reaction mixture was washed with 1N HCl (2×100 mL), with brine, with water until neutral and dried over sodium sulfate. The solvent was evaporated under vacuum and the brownish solid purified by flash chromatography on silica gel (eluant: n-hexane/ethyl acetate 70/30) to yield 9.2 g of the title compound.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:2]1[O:4][CH2:3]1.[CH3:16][C:17]([NH2:28])([CH3:27])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1>>[OH:4][CH:2]([CH2:1][O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:3][NH:28][C:17]([CH3:27])([CH3:16])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1
Reactant: CCCCCCCCCCOCC1CO1
Reactant: COc1ccc(CC(C)(C)N)cc1
Product: CCCCCCCCCCOCC(O)CNC(C)(C)Cc1ccc(OC)cc1
Yield: 44.5 %

Procedure:
Using the method of Example 5, supra, 1-decyl glycidyl ether (235 mg, 1.0 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (197 mg, 1.1 mmol) were used to prepare 175 mg of the title compound as a clear, colorless oil: GC/EI-MS, m/z (rel. int.) 394 (M+1, 1), 378 (6), 273 (97), 272 (100), 222 (9), 163 (37), 121 (61); 1H-NMR (CDCl3) δ7.49 (2H, d, J=8.5), 6.82 (2H, d, J=8.5 Hz), 3.78 (3H, s), 3.75 (1H, m), 3.45 (4H, m), 2.80 (1H, dd, J=11.7 and 4.0), 2.77 (1H, broad s), 2.64 (4H, m), 1.56 (2H, m), 1.26 (16H, m), 1.06 (3H, s), 1.05 (3H, s), 0.88 (3H, t, J=6.1); 13C-NMR (CDCl3) δ158.1, 131.3, 130.0, 113.4, 73.5, 71.7, 69.1, 55.1, 53.3, 46.4, 44.6, 31.8, 29.6, 29.5, 29.4, 29.3, 26.7, 26.6, 26.1, 22.6, 14.1; FT-IR (film) cm−1 3115 (broad s), 1612, 1512, 1245, 1121, 824.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]([NH:5][C:6]1([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:25][C:24]4[C:23]5=[N:33][N:34]=[C:35]([C:36]6[N:41]=[CH:40][CH:39]=[CH:38][N:37]=6)[N:22]5[CH:21]=[CH:20][C:19]=4[N:18]=3)=[CH:13][CH:12]=2)[CH2:9][CH:8]([OH:10])[CH2:7]1)=[O:4].IC.[C:46]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:43][C:2]([F:42])([F:1])[C:3]([N:5]([C:6]1([C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:26]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)=[CH:25][C:24]4[C:23]5=[N:33][N:34]=[C:35]([C:36]6[N:41]=[CH:40][CH:39]=[CH:38][N:37]=6)[N:22]5[CH:21]=[CH:20][C:19]=4[N:18]=3)=[CH:15][CH:16]=2)[CH2:9][CH:8]([OH:10])[CH2:7]1)[CH3:46])=[O:4]
Reactant: O=C([O-])[O-]
Reactant: O=C(NC1(c2ccc(-c3nc4ccn5c(-c6ncccn6)nnc5c4cc3-c3ccccc3)cc2)CC(O)C1)C(F)(F)F
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN(C(=O)C(F)(F)F)C1(c2ccc(-c3nc4ccn5c(-c6ncccn6)nnc5c4cc3-c3ccccc3)cc2)CC(O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2,2,2-trifluoro-N-(3-hydroxy-1-{4-[9-phenyl-3-(2-pyrimidinyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutyl)acetamide (4-3) (16 mg, 0.043 mmol), iodomethane (0.0034 mL, 0.055 mmol), and K2CO3 (7.6 mg, 0.055 mmol) in DMF (1 mL) was stirred at room temperature for 1 hour. The mixture was quenched with water, extracted with EtOAc, washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure to give 2,2,2-trifluoro-N-(3-hydroxy-1-{-4-[9-phenyl-3-(2-pyrimidinyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutyl)-N-methylacetamide (4-8).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[Cl-:9].[Al+3].[Cl-].[Cl-].ClCl>C(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[Cl:9][C:3]1[CH:4]=[C:5]([CH:7]=[O:8])[S:6][C:2]=1[Cl:1]
Reactant: [Cl-]
Reactant: O=Cc1ccc(Cl)s1
Agent: ClCl
Agent: [Al+3]
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: O=Cc1cc(Cl)c(Cl)s1

Procedure:
To a mechanically stirred solution of 31.8 grams (0.217 mole) 5-chloro-2thiophenecarboxaldehyde in 150 ml of methylene chloride, 65 grams (0.487 mole) of anhydrous aluminum chloride was added in small portions. The mixture exothermed and turned purple. To this mixture 20.6 grams (0.29 mole) of chlorine in 250 ml of carbon tetrachloride was added dropwise. The reaction mass was refluxed for about 15 hours, and an additional 15 grams (0.21 mole) of chlorine in 200 ml of carbon tetrachloride was added. The mixture was refluxed for an additional 7 hours. The reaction was quenched by pouring over one liter of ice water. The aqueous layer was extracted with chloroform. The chloroform solution was washed with water and sodium bicarbonate. After drying with anhydrous sodium sulfate and concentration under vacuum, a yellow-brown oil was obtained. The crude 4,5-dichloro-2-thiophenecarboxaldehyde crystallized on standing and was recrystallized from hexane.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]#[N:12])=[N:4][C:5]([F:10])=[C:6]([F:9])[C:7]=1F.[NH4+:13].[OH-]>CCOC(C)=O>[NH2:13][C:7]1[C:6]([F:9])=[C:5]([F:10])[N:4]=[C:3]([C:11]#[N:12])[C:2]=1[Cl:1]
Reactant: [NH4+]
Reactant: N#Cc1nc(F)c(F)c(F)c1Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Product: N#Cc1nc(F)c(F)c(N)c1Cl
Yield: 88.3 %

Procedure:
A solution of 3-chloro-4,5,6-trifluoropicolinonitrile (200 g) in EtOAc (3 L) was cooled to 10° C. To this was slowly added 14% aq NH4OH (1296 g) keeping the temperature between 18-23° C. The aqueous solution was separated from the organic solution. The organic phase was washed sequentially with a 50/50 solution of aqueous saturated NaCl and water (500 mL) and satd NaC1 solution (250 mL). The organic phase was concentrated under vacuum at 50° C. to about 500 mL volume as the product crystallized out. To this slurry was added heptane (1 L), and the mixture was concentrated under vacuum. The solids were collected by filtration. This solid was washed with pentane and dried under vacuum to give 4-amino-3-chloro-5,6-difluoropicolinonitrile (173.8 g, 90%, 99.6% purity) as a white crystalline solid: mp 190-191.5° C.; 13CNMR (101 MHz, DMSO-d6) δ 150.03 (dd, J=232.4, 12.5 Hz, C6), 144.29 (dd, J=11.4, 6.9 Hz, C4), 133.72 (dd, J=257.9, 30.8 Hz, C5), 122.14 (dd, J=19.6, 4.9 Hz, C2), 119.31 (s, C3), 114.25 (s, CN); 19F NMR (376 MHz, DMSO-d6) δ −91.24 (d, J=24.2 Hz), −154.97 (d, J=24.2 Hz); EIMS m/z 189 ([M]+). Anal. Calcd for C6H2C1F2N3: C, 38.02; H, 1.06; N, 22.17. Found: C. 37.91; H.1.00; 22.02.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([CH3:11])[C:3]=1[Br:12]>C(O)(=O)C.C(O)C.[Fe]>[CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([CH3:11])[C:3]=1[Br:12]
Reactant: Cc1ccc([N+](=O)[O-])c(C)c1Br
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1ccc(N)c(C)c1Br

Procedure:
2,6-Dimethyl-3-nitrobromo benzene (5.7 g, 0.025 mol) was dissolved in acetic acid (60 mL) and ethanol (60 mL). To this was added iron powder (5.6 g, 0.01 mol) in small portions and after the addition, it was refluxed for 2-3 h under nitrogen. An additional 2.8 g of iron powder was added and again refluxed for another 2 h. The mixture was filtered through celite and concentrated in vacuo. The residue was neutralized with sodium carbonate solution and repeatedly extracted (×3) with boiling ethyl acetate (50 mL each). Ethyl acetate was concentrated after drying over sodium sulfate to give a brown solid which was purified by chromatography on silica gel using 4% ethyl acetate in hexane to give a pale yellow solid.
Reaction SMILES: [C:1]1([C:7](=[O:13])[CH2:8][C:9](=[O:12])[CH2:10]C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:14]C1C=CC=CC=1C(=O)C>CCOC(C)=O>[F:14][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[C:7](=[O:13])[CH2:8][C:9](=[O:12])[CH3:10]
Reactant: CC(=O)c1ccccc1F
Reactant: CCC(=O)CC(=O)c1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)CC(=O)c1ccccc1F

Procedure:
The title compound was prepared (as described above for Intermediate 16) from 2.0 g of 2′-fluoroacetophenone and 2.86 mL of EtOAc to yield Intermediate 20: 1H NMR (400 MHz, CDCl3, enol form) δ7.70 (dt, 1H. J=1.79, 7.69), 7.45 (m, 1H), 7.24 (m, 1H), 7.10 (m, 1H), 6.28 (s, 1H), 2.20 (s, 3H).
Reaction SMILES: C(N(CC)CC)C.S(O/[N:19]=[C:20](\[C:27]#[N:28])/[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(C1C=CC(C)=CC=1)(=O)=O.[SH:29][CH2:30][C:31]([O:33][CH3:34])=[O:32]>CO>[NH2:28][C:27]1[C:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[N:19][S:29][C:30]=1[C:31]([O:33][CH3:34])=[O:32]
Reactant: COC(=O)CS
Reactant: Cc1ccc(S(=O)(=O)O/N=C(\C#N)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1snc(-c2ccccc2)c1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.3 %

Procedure:
Triethylamine (5.39 g, 53.3 mmol) was added dropwise to a stirred solution of (Z)—N-(tosyloxy)benzimidoyl cyanide (Preparation 103B, 8 g, 26.6 mmol) and methyl 2-mercaptoacetate (2.86 mL, 32.0 mmol) in MeOH (70 mL) at room temperature. After stirring at room temperature for 3 h, the reaction was cooled and treated with 100 mL ice/water. The resultant solid was filtered and washed with water. The solid was vacuum dried to yield 6 g brown colored solid. Recrystallization from hexane/ethyl acetate yielded the titled compound (3 g) as a beige colored needles. The compound had an LC/MS M+1=235.2.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:12][O:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:15]=1B(O)O>>[Cl:11][C:9]1[N:10]=[C:3]2[CH:2]=[CH:7][CH:6]=[C:5]([C:15]3[CH:16]=[CH:17][C:18]([C:20]([F:23])([F:22])[F:21])=[CH:19][C:14]=3[O:13][CH3:12])[N:4]2[N:8]=1
Reactant: COc1cc(C(F)(F)F)ccc1B(O)O
Reactant: Clc1nc2c(Br)cccn2n1
Product: COc1cc(C(F)(F)F)ccc1-c1cccc2nc(Cl)nn12

Procedure:
2-Chloro-5-(2-methoxy-4-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-2-chloro[1,2,4]triazolo[1,5-a]pyridine (0.5 g, 2.15m mol) and 2-methoxy-4-trifluoromethylbenzeneboronic acid (0.71 g, 3.23 mmol), in a manner analogous to Example 2c. Product was isolated as a foam (0.5 g, 70%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.73 (m, 1H), 7.67 (d, J=7.3 Hz, 1H), 7.61 (d, J=8.1 Hz, 1H), 7.40 (d, J=8.1 Hz, 1H), 7.303 (s, 1H), 7.10 (d, J=7.3 Hz, 1H), 3.87 (s, 3H). MS=328 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[C:7]([F:11])=[CH:6][C:3]=1[CH:4]=O.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:17][C:18]#[N:19]>>[CH3:12][O:13][C:14]1[CH:15]=[C:16](/[C:17](=[CH:4]/[C:3]2[CH:6]=[C:7]([F:11])[C:8]([F:10])=[CH:9][C:2]=2[F:1])/[C:18]#[N:19])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: O=Cc1cc(F)c(F)cc1F
Product: COc1ccc(/C(C#N)=C/c2cc(F)c(F)cc2F)cc1OC
Yield: 25.1 %

Procedure:
2,4,5-Trifluorobenzaldehyde (160 mg) and 3,4-dimethoxybenzyl cyanide (177 mg) were subjected to condensation in accordance with process B of (production process 2), to thereby produce the target product (80 mg, yield: 26%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=S)[NH2:19])=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].IC.C([O-])(=O)C.[NH4+:28]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[NH:28])[NH2:19])=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)NCCCCc1ccc(C(N)=S)cc1
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CI
Product: CC(C)(C)OC(=O)NCCCCc1ccc(C(=N)N)cc1
Reaction time: 8 h
Yield: 29.4 %

Procedure:
[4-(4-Thiocarbamoylphenyl)butyl]carbamic acid tert-butyl ester (58) (500 mg, 1.6 mmol) and iodomethane (4 mL, 64 mmol) were combined in methylene chloride (8 mL). The solution was stirred at reflux for 3 h, and allowed to stand overnight. The volatiles were removed by evaporation, and the residue was dried under vacuum for 3 h. The resulting crystalline solid was dissolved in ethanol (5 mL), and ammonium acetate (1.1 g, 14.4 mmol) was added. The resulting solution was stirred at reflux for 2 h, and the solvent was evaporated. The residue was taken up in a mixture of methanol and concentrated ammonium hydroxide (20 mL, 10:1), and the solvent was then evaporated. To this residue were added water (20 mL) and concentrated ammonium hydroxide (3 mL). The resulting mixture was stirred for 1 h, cooled in an ice bath, and suction filtered to collect a solid. The solid was dried under vacuum overnight to afford the product 59 (137 mg, 29%). 1H NMR (300 MHz, DMSO-d6) δ 1.37 (s, 9H), 1.38 (m, 2H), 1.55 (m, 2H), 2.64 (t, 2H), 2.93 (m, 2H), 6.80 (br s, 1H), 7.35 (d, 2H), 7.70 (d, 2H), 9.62 (br s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=[O:5].Cl[CH2:13][N:14]1[C:18](=[O:19])[CH:17]([CH:20]([CH3:22])[CH3:21])[NH:16][S:15]1(=[O:24])=[O:23].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([O:6][CH2:13][N:14]1[C:18](=[O:19])[CH:17]([CH:20]([CH3:21])[CH3:22])[NH:16][S:15]1(=[O:23])=[O:24])=[O:5]
Reactant: CC(C)C1NS(=O)(=O)N(CCl)C1=O
Reactant: O=C(O)c1c(Cl)cccc1Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)C1NS(=O)(=O)N(COC(=O)c2c(Cl)cccc2Cl)C1=O
Yield: 48.9 %

Procedure:
A mixture of 2,6-dichlorobenzoic acid (0.44 g; 2.3 mmol), 2-chloromethyl-4-isopropyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (0.5 g; 2.2 mmol) and triethylamine (230 mg; 2.3 mmol) in toluene was allowed to reflux for 2.5 hours, and then cooled. The mixture was concentrated in vacuo and the residue was purified by flash silica gel chromatography (25%-30% ethyl acetate in hexane) to afford 0.41 g (49%) of 2-(2,6-dichlorophenylcarbonyloxymethyl)-4-isopropyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula I: Ar=2,6-Cl2 -phenyl; R1 =H; R2 =isopropyl; R3 =H) as a solid, m.p.151°-152° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:13]#[N:14])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[C:15](=O)([O-])[O-].[K+].[K+].COS(=O)(=O)OC>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:13]#[N:14])[C:11]=1[O:12][CH3:15])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Cl)c(O)c(C#N)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)c(OC)c(C#N)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.1 %

Procedure:
Methyl 3-chloro-5-cyano-4-hydroxybenzoate (1.27 g) was dissolved in N,N-dimethylformamide (20 mL), and potassium carbonate (5.00 g) and dimethylsulfuric acid (1.70 mL) were added to the solution, and then the mixture was stirred at room temperature for 18 hours. The reaction solution was filtered and water was added, and then the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (1.03 g) as a colorless crystal.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Al](C)C.[F:12][C:13]1[C:34]([NH:35][S:36]([CH2:39][CH2:40][CH3:41])(=[O:38])=[O:37])=[CH:33][CH:32]=[C:31]([F:42])[C:14]=1[C:15]([NH:17][C:18]1[CH:19]=[C:20]2[C:26]([C:27](OC)=[O:28])=[CH:25][NH:24][C:21]2=[N:22][CH:23]=1)=[O:16]>C1(C)C=CC=CC=1>[F:12][C:13]1[C:34]([NH:35][S:36]([CH2:39][CH2:40][CH3:41])(=[O:37])=[O:38])=[CH:33][CH:32]=[C:31]([F:42])[C:14]=1[C:15]([NH:17][C:18]1[CH:19]=[C:20]2[C:26]([C:27]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:28])=[CH:25][NH:24][C:21]2=[N:22][CH:23]=1)=[O:16]
Reactant: Nc1ccccc1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(C(=O)OC)c3c2)c1F
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(C(=O)Nc4ccccc4)c3c2)c1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 35.6 %

Procedure:
A round bottom flask equipped with a stir bar and nitrogen inlet was charged with aniline (4.2 mg, 0.046 mmol) and dry toluene (0.5 mL) under a nitrogen atmosphere. Trimethyl aluminum (8.0 μL, 0.160 mmol, 7 eq.) was added to this solution, and this mixture was stirred at room temperature for 20 minutes. Methyl 5-(2,6-difluoro-3-(propylsulfonamido)benzamido)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (13.5 mg, 0.023 mmol, see Example 14) was added in one portion, and the reaction mixture warmed to 90° C. for 30 minutes. The reaction mixture was then allowed to cool to room temperature. The mixture was then quenched carefully with 30% aqueous sodium potassium tartrate and extracted with ethyl acetate (2×). The extracts were dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was dissolved in THF (1 mL), and a 1M aqueous LiOH solution (1 mL) was then added. The mixture was stirred at room temperature for 16 hours, diluted with AcOH/water and extracted with EtOAc (2×). The extracts were washed with saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated. The resulting residue was subjected to preparative TLC purification (2×0.5 mm plates, 10% MeOH/DCM) to afford 5-(2,6-difluoro-3-(propylsulfonamido)benzamido)-N-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (4.2 mg, 36%). 1H NMR (400 MHz, DMSO-d6) δ 12.31 (s, 1H), 10.97 (s, 1H), 9.76-9.87 (m 2H), 8.89-8.96 (m, 1H), 8.42-8.55 (m 2H), 7.73-7.80 (m, 2H), 7.51-7.59 (m, 1H), 7.20-7.38 (m, 3H), 7.03-7.11 (m, 1H), 3.06-3.14 (m, 2H), 1.71-1.82 (m, 2H), 0.94-1.04 (m, 3H); m/z (APCI-neg) M−1=512.1; (APCI-pos) M+1=514.0.