Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([CH3:13])[CH3:12])=[N:9][N:10]=2)[N:7]=1.[C:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])#[N:15].[H-].[Na+]>CN(C=O)C>[C:14]([CH:16]([C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([CH3:13])[CH3:12])=[N:9][N:10]=2)[N:7]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18])#[N:15]
Reactant: CCOC(=O)CC#N
Reactant: CC(C)c1nnc2ccc(Cl)nn12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C#N)c1ccc2nnc(C(C)C)n2n1
Temperature: 0 °C
Reaction time: 14 h
Yield: 16.7 %

Procedure:
6-Chloro-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine (5.00 g, 25.4 mmol, Preparation #G.1) and ethyl 2-cyanoacetate (3.16 g, 28.0 mmol) were added to DMF (50 mL) then the solution was cooled to about 0° C. Sodium hydride (60% in oil, 1.22 g, 30.5 mmol) was added then the mixture was stirred for about 5 min at ambient temperature and at about 60° C. for about 14 h. The mixture was cooled to ambient temperature then concentrated under reduced pressure. The residue was stirred with EtOAc (100 mL) and 2N HCl (50 mL) for about 10 min and the insoluble material was collected by filtration and dried to give the title compound (1.16 g, 17%): LC/MS (Table 1, Method g) Rt=1.53 min; MS m/z: 273.9 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([C:11](O)=[O:12])[S:8][C:7]=2[CH:14]=1.C(Cl)(C([Cl:21])=O)=O>C(Cl)Cl.CN(C=O)C>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([C:11]([Cl:21])=[O:12])[S:8][C:7]=2[CH:14]=1
Reactant: O=C(O)c1cc2ccc(C(F)(F)F)cc2s1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc2ccc(C(F)(F)F)cc2s1
Reaction time: 20 h

Procedure:
To a mixture of 6-(trifluoromethyl)benzo[b]thiophene-2-carboxylic acid 4a (65 mg, 0.26 mmol) in CH2Cl2 (2.5 mL) was added (COCl)2 (0.026 mL, 0.30 mmol), followed by DMF (1 drop) at room temperature. The reaction was kept at room temperature for 20 h. The resulting solution was concentrated to give compound 4b.
Reaction SMILES: [CH3:1][CH:2]([OH:6])[CH:3]([OH:5])[CH3:4].CCN(CC)CC.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C(Cl)Cl>[CH3:14][S:15]([O:5][CH:3]([CH:2]([O:6][S:15]([CH3:14])(=[O:17])=[O:16])[CH3:1])[CH3:4])(=[O:17])=[O:16]
Reactant: CC(O)C(C)O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(OS(C)(=O)=O)C(C)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
To a solution of butane 2,3-diol (15 g, 0.166 mol) and Et3N (57.7 mL, 0.415 mol) in CH2Cl2 (150 mL) at 0° C. was slowly added a solution of CH3SO2Cl (32.1 mL, 0.415 mol) in CH2Cl2 (75 mL). The mixture was stirred at 0° C. for 2 h and diluted with CH2Cl2. The mixture was washed with water, 1 N HCl, 5% aqueous NaHCO3 and brine. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to afford butane-2,3-diyl dimethanesulfonate (40 g, 98%) as a light yellow oil. 1HNMR (CDCl3): δ 4.9 (m, 2H, CH), 3.05 (s, 6H, CH3), 1.4 (m, 6H, CH3).
Reaction SMILES: [CH3:1][C:2](=[O:6])[C:3](=[O:5])[CH3:4].CN(C1C=CC=CN=1)C.C(N(CC)CC)C.[C:23](OC(=O)C)(=[O:25])[CH3:24]>CCOCC>[C:23]([O:5][C:3](=[CH2:4])[C:2](=[O:6])[CH3:1])(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)C(C)=O
Agent: CN(C)c1ccccn1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=C(OC(C)=O)C(C)=O
Reaction time: 3 h
Yield: 56 %

Procedure:
To a solution of 19.6 g. (228 mol) of 2,3-butanedione in 200 ml. of ether was added 3.34 g. (27 mmole) of dimethylamino pyridine, and 23 g. (228 mmole) of triethylamine. The solution was cooled to 0° and 23.24 g. (228 mmol) of acetic anhydride was added dropwise with vigorous stirring. The clear yellow solution was allowed to warm to 25° and was stirred 3 hours. The reaction mixture was transferred to a separatory funnel, washed with water (3×) and dried over MgSO4. Filtration and evaporation in vacuo afforded 17.6 g. of crude 3-acetoxy-3-buten-2-one (assayed by 1H-NMR with internal standard as 91% pure, 56% yield): 1H-NMR (CDCl3) delta 2.06 (s, 3), 2.25 (s, 3), 5.42, 5.49, 5.79, 5.82 (AB, 2).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](I)=[CH:6][CH:5]=1.[C:12]([Si:14]([CH3:17])([CH3:16])[CH3:15])#[CH:13].C(N(CC)CC)C.O>O1CCCC1.[Cu]I>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:13]#[C:12][Si:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)c1ccc(I)cc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)c1ccccc1C#C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
20.60 g (78.61 mmol) of 4-Iodobenzoic acid methyl ester and 9.26 g (94.33 mmol) of ethynyl trimethylsilane were dissolved in 200 ml of tetrahydrofuran, and thereto 23.86 g (235.83 mmol) of triethylamine, 1.65 g (2.36 mmol) of dichloro(bistriphenylphosphine)palladium(II) and 0.45 g (2.36 mmol) of copper(I) iodide were added. The mixture was stirred at room temperature for 8 hours. At the end of reaction, added water and extracted with ethylacetate. The extract was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and separated by column chromatography to obtain trimethylsilylethynylbenzoic acid methyl ester 18.30 g (Yield 100%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH:6]([C@@H:19]1[O:24][CH2:23][C@@H:22]([OH:25])[CH2:21][CH2:20]1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(Cl)Cl>[CH:6]([C@@H:19]1[O:24][CH2:23][C@@H:22]([O:25][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:21][CH2:20]1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O[C@H]1CC[C@H](C(c2ccccc2)c2ccccc2)OC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@H]1CC[C@H](C(c2ccccc2)c2ccccc2)OC1
Yield: 78.7 %

Procedure:
Methanesulfonyl chloride (0.33 g, 2.87 mmol) was reacted with trans-2-diphenylmethyl-tetrahydropyran-5-ol 11 (0.38 g, 1.43 mmol) in the presence of triethylamine (0.22 g, 2.15 mmol) in methylene chloride (10 ml) to give trans-2-diphenylmethyl-tetrahydropyran-5-yl methanesulfonate 13 (0.39 g, 77.8%) as an oil (Procedure A).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[N:11][CH:12]=[C:13]([CH:17]=1)[C:14]([OH:16])=O.[O-:18][N+:19]1[C:24]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:22]=[C:21]([C@H:29]([NH2:31])[CH3:30])[CH:20]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[N:11][CH:12]=[C:13]([CH:17]=1)[C:14]([NH:31][C@@H:29]([C:21]1[CH:20]=[N+:19]([O-:18])[C:24]([C:25]([F:26])([F:27])[F:28])=[CH:23][CH:22]=1)[CH3:30])=[O:16]
Reactant: C[C@@H](N)c1ccc(C(F)(F)F)[n+]([O-])c1
Reactant: O=C(O)c1cncc(-c2ccc(F)cc2F)c1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: C[C@@H](NC(=O)c1cncc(-c2ccc(F)cc2F)c1)c1ccc(C(F)(F)F)[n+]([O-])c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5-(2,4-difluorophenyl)nicotinic acid (40.0 mg, 0.15 mmol) in DMF (0.7 mL) were added hydrochloride salt of (1R)-1-[1-oxido-6-(trifluoromethyl)pyridin-3-yl]ethanamine (49.3 mg, 0.18 mmol), EDC (33.9 mg, 0.18 mmol), HOBT (22.6 mg, 0.15 mmol) and triethylamine (0.10 mL, 0.74 mmol). The mixture was stirred at ambient temperature for 18 h. Purification by reverse chromatography (C-18, 95% water/acetonitrile→25% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title product, which was converted to hydrochloride salt using 2.0 M HCl in ether (47 mg). HRMS 424.1086. 1H NMR (400 MHz, CD3OD): δ 9.22 (s, 1H); 9.15 (s, 1H); 9.00 (s, 1H); 8.52 (s, 1H); 7.92 (d, J=8.4 Hz, 1H); 7.83-7.73 (m, 1H); 7.70 (d, J=8.4 Hz, 1H); 7.31-7.21 (m, 2H); 5.33-5.25 (m, 1H); 1.67 (d, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[C:5](=[C:6]([CH3:11])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:12]([OH:14])=[O:13]>C(O)C.O.[Pd]>[CH3:1][C@@H:2]1[C:10]2[C:5](=[C:6]([CH3:11])[CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]1[C:12]([OH:14])=[O:13]
Reactant: Cc1cccc2c1C=C(C(=O)O)C2C
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: Cc1cccc2c1C[C@H](C(=O)O)[C@@H]2C

Procedure:
1,4-Dimethyl-indene-2-carboxylic acid (35.5 g) is hydrogenated in ethanol-water (700 ml-70 ml) over 10% palladium on carbon at ambient temperature. After filtration ethanol is evaporated. Water is added and the precipitated cis-2,3-dihydro-1,4-dimethyl-1H-indene-2-carboxylic acid is filrated. Yield 33.3 g, 93% M.p. 132°-135° C.
Reaction SMILES: [CH2:1]([N:3]1[CH2:9][CH2:8][C:7]2[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:6]=2[CH2:5][CH2:4]1)[CH3:2].Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]([CH3:31])([CH3:30])[CH2:24][NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[C:19]([Cl:32])=[CH:18][N:17]=1>>[Cl:32][C:19]1[C:20]([NH:22][C:23]([CH3:31])([CH3:30])[CH2:24][NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[N:21][C:16]([NH:14][C:11]2[CH:12]=[CH:13][C:6]3[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:9][CH2:8][C:7]=3[CH:10]=2)=[N:17][CH:18]=1
Reactant: CC(C)(CNS(C)(=O)=O)Nc1nc(Cl)ncc1Cl
Reactant: CCN1CCc2ccc(N)cc2CC1
Product: CCN1CCc2ccc(Nc3ncc(Cl)c(NC(C)(C)CNS(C)(=O)=O)n3)cc2CC1

Procedure:
N-{2-[5-Chloro-2-(3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-2-methyl-propyl}-methanesulfonamide was prepared from 3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and N-[2-(2,5-dichloro-pyrimidin-4-ylamino)-2-methyl-propyl]-methanesulfonamide in an analogous manner to Example 306. Product isolated as a white foam (22 mg, 10%). LCMS (m/e) 467 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 7.93 (s, 1H), 7.26-7.18 (m, 2H), 7.05 (d, 1H, J=7.9 Hz), 6.93 (s 1H), 5.95-5.80 (m, 1H), 5.13 (s, 1H), 3.47 (d, 2H, J=5.8 Hz), 2.97-2.88 (m, 4H), 2.78 (s, 3H), 2.72-2.58 (m, 4H), 2.59 (q, 2H, J=7.1 Hz), 1.50 (s, 6H), 1.12 (t, 3H, J=7.1 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:15]([CH3:18])=[N:16][N:17]=3)[C:9]=2[CH:8]=[C:7]1[C:19]1[CH:23]=[CH:22][N:21]([CH2:24][CH2:25][C:26]([O:28]C)=[O:27])[N:20]=1.[OH-].[Na+].O.Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:15]([CH3:18])=[N:16][N:17]=3)[C:9]=2[CH:8]=[C:7]1[C:19]1[CH:23]=[CH:22][N:21]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])[N:20]=1
Reactant: COC(=O)CCn1ccc(-c2cc3c(ccc4nnc(C)n43)n2Cc2cccc(Cl)c2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nnc2ccc3c(cc(-c4ccn(CCC(=O)O)n4)n3Cc3cccc(Cl)c3)n12
Reaction time: 0.42 h

Procedure:
6-(3-Chlorobenzyl)-1-methyl-7-(1H-pyrazol-5-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (25 mg, 0.069 mmol, from Example 103, Step 5) in acetonitrile (0.90 mL) was treated with methyl acrylate (19 μL, 0.21 mmol, Aldrich) and 1,8-diazabicyclo[5.4.0]undec-7-ene (10. μL, 0.069 mmol, Aldrich) and stirred for 70 minutes. Purification via preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) followed by evaporation of eluent afforded methyl 3-(3-(6-(3-chlorobenzyl)-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-7-yl)-1H-pyrazol-1-yl)propanoate. The ester intermediate was dissolved in THF (0.45 mL) and was treated with 1.0 M NaOH in water (0.45 mL, 0.45 mmol). After 25 minutes, the reaction was acidified to pH 3-4 by the addition of 1 N HCl. Water was added (3 mL), and the precipitated product was isolated by filtration and air dried. Yield: (21 mg, 70%).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:8])[O:4][C:5](=[O:7])[CH:6]=1.[Br:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[F:18])[CH:13]=O.[CH3:19][C:20]1([CH3:28])[CH2:25][CH2:24][C:23](=O)[CH2:22][C:21]1=[O:27]>C(O)C>[Br:9][C:10]1[CH:11]=[C:12]([CH:13]2[C:22]3[C:21](=[O:27])[C:20]([CH3:28])([CH3:19])[CH2:25][CH2:24][C:23]=3[NH:1][C:2]3[N:3]([CH3:8])[O:4][C:5](=[O:7])[C:6]2=3)[CH:15]=[CH:16][C:17]=1[F:18]
Reactant: CC1(C)CCC(=O)CC1=O
Reactant: Cn1oc(=O)cc1N
Reactant: O=Cc1ccc(F)c(Br)c1
Solvent: CCO
Product: Cn1oc(=O)c2c1NC1=C(C(=O)C(C)(C)CC1)C2c1ccc(F)c(Br)c1
Temperature: 25 °C
Yield: 30.9 %

Procedure:
The product from Example 45A (0.11 g, 1 mmol), 3-bromo-4-fluoro-benzaldehyde(0.2 g, 1 mmol), and 4,4-dimethyl-1,3-cyclohexanedione (0.11 g, 1 mmol) in ethyl alcohol (3 mL) were heated at 80° C. for 2 days in a sealed tube. The reaction mixture was allowed to cool to ambient temperature and evaporated under reduced pressure. The residue was chromatographed eluting with 5% ethanol/dichloromethane to yield 0.130 g of the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 0.92 (s, 3H), 1.0 (s, 3H), 1.82 (t, 2H), 2.65 (m, 2H), 3.22 (s, 3H), 4.67 (s, 1H), 7.21 (m, 2H), 7.43 (dd, 1H), 10.39 (s, 1H); MS (ESI−) m/z 419,421 (M−H)−; Anal. Calcd for C19H18BrFN2O3: C, 54.15; H, 4.27; N, 6.65.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][N:13]1[C:17]2[CH:18]=[C:19]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH:20]=[C:21]([C:22]([O:24]C)=[O:23])[C:16]=2[N:15]=[C:14]1[C:32]([F:35])([F:34])[F:33].[OH-].[Li+]>C1COCC1>[CH3:1][C:2]1[C:7]([C:8]([F:9])([F:11])[F:10])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][N:13]1[C:17]2[CH:18]=[C:19]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH:20]=[C:21]([C:22]([OH:24])=[O:23])[C:16]=2[N:15]=[C:14]1[C:32]([F:34])([F:33])[F:35]
Reactant: COC(=O)c1cc(N2CCOCC2)cc2c1nc(C(F)(F)F)n2Cc1cccc(C(F)(F)F)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(Cn2c(C(F)(F)F)nc3c(C(=O)O)cc(N4CCOCC4)cc32)cccc1C(F)(F)F
Temperature: 50 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
A mixture of methyl 1-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-2-(trifluoromethyl)-1H-benzimidazole-4-carboxylate, prepared as described in Example 46 (510 mg, 1.017 mmol) and 2 M lithium hydroxide (6 mL, 12.00 mmol) in THF (12 mL) was stirred at 50° C. for 2 h. The reaction was cooled to room temperature. The organic solvent was removed under reduced pressure and the aqueous was diluted with water and acidified by the addition of 1 N HCl. The precipitate formed was collected by filtration. The solid was washed with ether and turned into a gummy residue. The residue was washed with MeOH until all the material was transferred into the collection flask. The organics were evaporated and a white solid formed upon standing. The precipitate was collected by filtration, washed with water and dried to give the desired product (438 mg, 0.881 mmol, 87% yield) as a white powder. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.68 (d, J=2.02 Hz, 1H), 7.61 (d, J=8.08 Hz, 1H), 7.23 (t, J=7.83 Hz, 1H), 7.08 (d, J=2.02 Hz, 1H), 6.27 (d, J=7.58 Hz, 1H), 5.74 (s, 2H), 3.63-3.82 (m, 4H), 3.05-3.21 (m, 4H), 2.52 (br. s., 3H). MS(ES+) m/e 488 [M+H]+.
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[O:8]([C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CCN(C(C)C)C(C)C.[NH2:31][C:32]1[S:33][CH:34]=[CH:35][N:36]=1>O1CCCC1>[O:8]([C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH:17][S:2]([NH:5][C:6]([NH:31][C:32]1[S:33][CH:34]=[CH:35][N:36]=1)=[O:7])(=[O:4])=[O:3])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Nc1nccs1
Reactant: Nc1ccccc1Oc1ccccc1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nccs1)NS(=O)(=O)Nc1ccccc1Oc1ccccc1
Temperature: 0 °C
Yield: 66.6 %

Procedure:
To a solution of chlorosulfonyl isocyanate (0.22 ml, 2.5 mmol) in tetrahydrofuran (25 ml) were added 2-phenoxyaniline (0.37 g, 2.0 mmol) and DIEA (0.89 ml, 5.0 mmol) at −78° C. The solution was stirred and slowly allowed to warmed up to 0° C. To this reaction mixture, was added 2-amino thiazole (0.20 g, 2.0 mmol) and continued stirring at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure and the crude product was purified by column chromatography (ethylacetate:hexanes, from 50:50 to 90:10 as eluent system) to afford the title compound (0.52 g, 66%).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([O:24][CH2:25][CH:26]=[C:27]([Cl:29])[Cl:28])[CH:21]=[C:20]([Cl:30])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=O)[CH2:16][O:17][CH3:18])=[CH:11][CH:10]=1.Cl.[CH3:32][O:33][NH2:34].C([O-])(=O)C.[Na+].O>CO>[CH3:32][O:33][N:34]=[C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][CH2:5][O:4][C:3]2[C:2]([Cl:1])=[CH:23][C:22]([O:24][CH2:25][CH:26]=[C:27]([Cl:29])[Cl:28])=[CH:21][C:20]=2[Cl:30])=[CH:10][CH:11]=1)[CH2:16][O:17][CH3:18]
Reactant: CON
Reactant: COCC(=O)c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COCC(=NOC)c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1

Procedure:
296 mg of 1-(4-{3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propoxy}-phenyl)-2-methoxy-ethanone, 56 mg of O-methylhydroxylamine hydrochloride and 55 mg of sodium acetate are stirred in 4 ml of methanol at room temperature for 24 hours. The reaction mixture is poured into water and extracted with ethyl acetate. After concentration of the organic phases and purification over silica gel, the title compound is obtained in the form of an E/Z mixture. 1H-NMR (CDCl3) 300 MHz: 2.30 (m, 2H), 3.32+3.46 (s+s, 3H), 3.93+3.99 (s+s, 3H), 4.18 (t, 2H), 4.29 (m, 2H), 4.53-4.61 (m, 4H), 6.11 (t, 1H), 6.83 (s, 2H), 6.91 (d, 2H), 7.62 (d, 2H)
Reaction SMILES: [C:1]1([CH2:7][C:8](O)=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:13])=O>>[C:1]1([CH2:7][C:8]([Cl:13])=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: OC(=S)Cc1ccccc1
Product: S=C(Cl)Cc1ccccc1
Temperature: 40 °C
Reaction time: 3 h
Yield: 91.8 %

Procedure:
A quantity of 762 g (4.536 mol) of 2-phenylthioacetic acid is stirred at room temperature for 3 hours with thionyl chloride (375 ml, 5.14 mol), then stirred at 40° C. for 3 hours. Rotary evaporation followed by bulb-to-bulb distillation gives 777 g (4.166 mol, 92%) of 2-phenylthioacetyl chloride.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29](Br)=[CH:28][N:27]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:29]3[CH:30]=[CH:31][C:26]([NH2:25])=[N:27][CH:28]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: Nc1ccc(Br)cn1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: Nc1ccc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cn1

Procedure:
The title compound was prepared from 7-difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (340 mg, 1 mmol) and commercially available 2-amino-5-bromopyridine (157 mg, 1 mmol) according to general procedure II. Obtained as a dark red solid (13 mg, 3%). MS (ISP) 430.3 [(M+H)+]; mp 216° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]3=[CH:5][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH:37]([CH3:39])[CH3:38])=[C:32]([C:40]([F:43])([F:42])[F:41])[CH:31]=1>CC(N(C)C)=O>[CH:37]([O:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][O:1][C:2]2[CH:10]=[CH:9][C:8]3[N:7]4[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]4=[CH:5][C:4]=3[CH:3]=2)=[CH:31][C:32]=1[C:40]([F:41])([F:42])[F:43])([CH3:39])[CH3:38]
Reactant: CC(C)(C)OC(=O)CC1CCn2c1cc1cc(O)ccc12
Reactant: CC(C)Oc1ccc(CCl)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CC(C)Oc1ccc(COc2ccc3c(c2)cc2n3CCC2CC(=O)OC(C)(C)C)cc1C(F)(F)F
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a mixture of tert-butyl 2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (1.86 mmol) and cesium carbonate (2.8 mmol) in DMA (7.45 mL) was added 4-(chloromethyl)-1-isopropoxy-2-(trifluoromethyl)benzene (1.96 mmol). The reaction was stirred at 80° C. for 16 h. The mixture was filtered through Celite®. The solvent was removed under vacuum. The residue was purified by silica gel column chromatography to give the title compound as a solid. LCMS m/z=504.2 [M+H]+; 1H NMR (400 MHz, DMSO-db) δ ppm 1.28 (d, J=5.94 Hz, 6H), 1.44 (s, 9H), 2.14-2.25 (m, 1H), 2.51-2.58 (m, 1H), 2.59-2.67 (m, 1H), 2.71-2.81 (m, 1H), 3.57 (m, 1H), 3.91-3.99 (m, 1H), 4.06-4.13 (m, 1H), 4.72-4.83 (m, 1H), 5.05 (s, 2H), 5.99 (s, 1H), 6.75 (dd, J=8.72, 2.40 Hz, 1H), 7.07 (d, J=2.40 Hz, 1H), 7.18 (d, J=8.72 Hz, 1H), 7.28 (d, J=9.22 Hz, 1H), 7.62-7.68 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:14]([O-])=[O:15])[CH:6]=[C:7]([CH:13]=1)[C:8](OCC)=[O:9].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.CCOCC>[OH:9][CH2:8][C:7]1[CH:13]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]([CH2:14][OH:15])[CH:6]=1
Reactant: CCOC(=O)c1cc(OC)cc(C(=O)[O-])c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc(CO)cc(CO)c1
Reaction time: 1 h

Procedure:
To a solution of 5.00 g (22.32 mmoles) of methyl,methyl 5-methoxyisophthalate in 100 ml dry THF is added dropwise, maintaining a gentle reflux, 67 ml (66.96 mmoles) of a 1M solution of lithium aluminum hydride in Et2O. After addition the reaction mixture is stirred for 1 hour and is then quenched with saturated NH4Cl. The reaction mixture is then extracted with Et2O (3 times). The Et2O layers are combined, washed with brine, dried with MgSO4, filtered and concentrated down in vacuo to yield 1,3-di-(hydroxymethyl)-5-methoxybenzene which is used directly in the next step.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]([NH2:16])=[NH:15])=[N:6]1.[C:21](/[C:23](/[N:26]([C:28]([O:30][CH3:31])=[O:29])[CH3:27])=[CH:24]\[O-])#[N:22].[Na+].C(N(CC)CC)C>C1(C)C=CC=CC=1>[NH2:22][C:21]1[C:23]([N:26]([CH3:27])[C:28](=[O:29])[O:30][CH3:31])=[CH:24][N:16]=[C:14]([C:7]2[C:8]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[N:5]([CH2:4][C:3]3[CH:17]=[CH:18][CH:19]=[CH:20][C:2]=3[F:1])[N:6]=2)[N:15]=1
Reactant: N=C(N)c1nn(Cc2ccccc2F)c2ncccc12
Reactant: COC(=O)N(C)/C(C#N)=C/[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)N(C)c1cnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Temperature: 25 °C

Procedure:
Under argon, 0.80 g (2.61 mmol) of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamidine from Example 6A, 0.51 g (2.86 mmol) of sodium (E)-2-cyano-2-[(methoxycarbonyl)(methyl)amino]ethenolate from Example 10A and 0.53 g (0.73 ml, 5.23 mmol) of triethylamine are added to 50 ml of toluene. The mixture is heated under reflux for 9 hours. It is then cooled to RT again and is mixed and extracted with dichloromethane and water. The organic phase is dried over magnesium sulphate, filtered and concentrated in vacuo in a rotary evaporator. The residue is mixed with 5 ml of diethyl ether and crystallizes therewith. The crystals are filtered off with suction, dried and purified by preparative RP-HPLC.
Reaction SMILES: NC1C2C=CN(C(OCC3C=CC=CC=3)=O)C=2C=CN=1.C(Cl)(=O)CC.[NH:26]1[C:34]2[CH:33]=[CH:32][N:31]=[C:30]([NH:35][C:36]([CH:38]3C[CH2:39]3)=[O:37])[C:29]=2[CH:28]=[CH:27]1>>[NH:26]1[C:34]2[CH:33]=[CH:32][N:31]=[C:30]([NH:35][C:36](=[O:37])[CH2:38][CH3:39])[C:29]=2[CH:28]=[CH:27]1
Reactant: O=C(Nc1nccc2[nH]ccc12)C1CC1
Agent: CCC(=O)Cl
Agent: Nc1nccc2c1ccn2C(=O)OCc1ccccc1
Product: CCC(=O)Nc1nccc2[nH]ccc12

Procedure:
This was prepared by treating benzyl 4-amino-1H-pyrrolo[3,2-c]pyridine-1-carboxylate with propionyl chloride following a procedure similar to the one described herein. for intermediate 28.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH2:4][OH:5].[CH3:11][N:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]1>>[F:10][C:7]1[CH:8]=[CH:9][C:2]([C:15]2([OH:18])[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]2)=[C:3]([CH2:4][OH:5])[CH:6]=1
Reactant: CN1CCC(=O)CC1
Reactant: OCc1cc(F)ccc1Br
Product: CN1CCC(O)(c2ccc(F)cc2CO)CC1

Procedure:
Reaction of 2-bromo-5-fluorobenzyl alcohol and 1-methyl-4-piperidone by the method described in Example 16a provides 4-(5-fluoro-α-hydroxy-2-tolyl)-4-hydroxy-1-methylpiperidine.