Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[N:3]=1.[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C)C=O>[N:25]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[N:3]=1)=[N+:26]=[N-:27]
Reactant: CS(=O)(=O)c1ccc(-c2ccc(Cl)nc2-c2ccc(F)cc2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-c2ccc(N=[N+]=[N-])nc2-c2ccc(F)cc2)cc1
Yield: 37 %

Procedure:
A solution of 1.00 g (2.76 mMol) of 2-chloro-6-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]pyridine (Example 1) and 539 mg (8.29 mMol) of sodium azide in 15 ml of dimethylformamide was stirred in an oil bath at 100° C. for two days. After cooling, the mixture was partitioned between dichloromethane and water. The aqueous layer was further extracted with dichloromethane, the combined organic extracts were dried over sodium sulfate, filtered, and evaporated. Chromatography of the residue over silica gel using ethyl acetate as eluent gave the title compound (376 mg) as a pale yellow crystalline solid: m.p. 229° C. (DSC). Anal. Calc'd for C18H13N4O2S·1/4 H2O (MW 372.89): C, 57.98; H, 3.51; N, 15.03. Found: C, 58.35; H, 3.82; N, 14.70.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][C:22]2[CH:23]=[C:24]([CH2:28][NH2:29])[CH:25]=[CH:26][CH:27]=2)[CH:17]=[N:18][CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39].N(CCO)CCO>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][C:22]2[CH:23]=[C:24]([CH2:28][NH:29][S:38]([CH3:37])(=[O:40])=[O:39])[CH:25]=[CH:26][CH:27]=2)[CH:17]=[N:18][CH:19]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(CCc2cccc(CN)c2)c1
Reactant: CS(=O)(=O)Cl
Solvent: OCCNCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(CCc2cccc(CNS(C)(=O)=O)c2)c1
Temperature: 0 °C

Procedure:
3-[2-[5-[[1-(tert-Butoxycarbonyl)-(2S)-azetidinyl]methoxy]-3-pyridyl]ethyl]phenylmethylamine and triethylamine (1-2 equiv.) are dissolved in anhydrous CH2Cl2, and with exclusion of moisture and ice cooling a solution of methanesulfonyl chloride (1-1.5 equiv.) in CH2Cl2 is added dropwise. The mixture is stirred in the ice bath until no more starting amine is observed, then diethanolamine (0.2-0.7 equiv.) is added to quench the excess of methanesulfonyl chloride. The reaction mixture is evaporated and the residue chromatographed on silica gel with CH2Cl2/methanol. The product-containing fractions are evaporated, and the residue is dried in vacuo to obtain the sulfonamide.
Reaction SMILES: [CH2:1]1[C:6]2[S:7][C:8]3[N:12]([C:5]=2[CH2:4][CH2:3][NH:2]1)[C:11]1[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=1[N:9]=3.[C:17]1([CH3:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C.C(Br)C1C=CC=CC=1>C(OCC)(=O)C>[C:17]1([CH2:23][N:2]2[CH2:3][CH2:4][C:5]3[N:12]4[C:11]5[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=5[N:9]=[C:8]4[S:7][C:6]=3[CH2:1]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: c1ccc2c(c1)nc1sc3c(n12)CCNC3
Reactant: Cc1ccccc1
Agent: BrCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: c1ccc(CN2CCc3c(sc4nc5ccccc5n34)C2)cc1

Procedure:
1,2,3,4-tetrahydropyrido[4',3':4,5]thiazolo[3,2-a]benzimidazole (1.9 g., 0.008 mole) is dissolved in 100 ml. of boiling toluene. Triethylamine (5 ml.) is added at 80°. Benzyl bromide (1.7 g., 0.01 mole) is dissolved in 5 ml. of toluene and added dropwise to the reaction mixture. After the addition, the reaction mixture is refluxed for two hours. It is filtered and concentrated in vacuo to yield 3.6 g. of oil. Ethyl acetate is added and the product, 1,2,3,4-tetrahydro-2-(phenylmethyl)pyrido[4',3':4,5]thiazolo[3,2-a]benzimidazole crystallizes. This is filtered and recrystallized from ethyl acetate:ethanol (10:1) to yield 1.4 g. of analytical product, m.p. 124°-129°.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH2:11][CH:12]([C:14]1[N:15]=[C:16]2[S:29][CH:28]=[C:27]([CH3:30])[N:17]2[C:18](=[O:26])[C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[CH3:13].C(N(CC)C(C)C)(C)C>C(O)C>[CH3:30][C:27]1[N:17]2[C:18](=[O:26])[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)=[C:14]([CH:12]([NH:11][C:2]3[N:10]=[CH:9][N:8]=[C:7]4[C:3]=3[N:4]=[CH:5][NH:6]4)[CH3:13])[N:15]=[C:16]2[S:29][CH:28]=1
Reactant: Cc1csc2nc(C(C)N)c(-c3ccccn3)c(=O)n12
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1csc2nc(C(C)Nc3ncnc4[nH]cnc34)c(-c3ccccn3)c(=O)n12

Procedure:
A mixture of 6-bromo-9H-purine (9.300 mg, 0.004673 mmol), 7-(1-aminoethyl)-3-methyl-6-pyridin-2-yl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (11 mg, 0.039 mmol), and N,N-diisopropylethylamine (8.152 μL, 0.004680 mmol) in ethanol (0.3 mL) was refluxed under nitrogen overnight. The mixture was concentrated under reduced pressure and the residue was purified on RP-HPLC (eluting with a gradient of methanol/water containing 1% TFA) to provide the product as a TFA salt. LCMS calculated for C19H17N8OS (M+H)+: m/z=405.1. Found: 405.3.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]2[O:11][CH:12]=[CH:13][C:9]=2[C:8]([NH:14][C:15](=[O:17])[CH3:16])=[C:7]([Cl:18])[CH:6]=1)=[O:4].[H][H]>CC(C)=O.[Rh]>[C:15]([NH:14][C:8]1[C:9]2[CH2:13][CH2:12][O:11][C:10]=2[C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][C:7]=1[Cl:18])(=[O:17])[CH3:16]
Reactant: COC(=O)c1cc(Cl)c(NC(C)=O)c2ccoc12
Reactant: [H][H]
Agent: [Rh]
Solvent: CC(C)=O
Product: COC(=O)c1cc(Cl)c(NC(C)=O)c2c1OCC2
Yield: 95.3 %

Procedure:
A solution of methyl-4-acetamido-5-chloro-benzo[b]furan-7-carboxylate (0.5 g) in acetone (300 ml) was stirred for 3 hours in presence of 5% Rh/C (0.5 g) in a hydrogen atmosphere. The catalyst was filtered off and the filtrate was evaporated in vacuo to yield 0.48 g of the title product.
Reaction SMILES: [CH:1]1([C:5]2[C:6]([OH:13])=[C:7]([CH:10]=[CH:11][CH:12]=2)[CH:8]=[O:9])[CH2:4][CH2:3][CH2:2]1.[Br:14]N1C(=O)CCC1=O>C(#N)C>[Br:14][C:11]1[CH:12]=[C:5]([CH:1]2[CH2:2][CH2:3][CH2:4]2)[C:6]([OH:13])=[C:7]([CH:10]=1)[CH:8]=[O:9]
Reactant: O=Cc1cccc(C2CCC2)c1O
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: O=Cc1cc(Br)cc(C2CCC2)c1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-cyclobutyl-2-hydroxybenzaldehyde (2.29 g) was dissolved in acetonitrile (30 mL), and N-bromosuccinimide (5.10 g) was added to the solution at 0° C., and then the mixture was stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure and water was added, and then the 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 and the obtained residue was used for the synthesis of (d).
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2]([CH3:4])[CH3:3].C(OCC)C.CC(O[B:16]1[O:20][C@@H:19]2[CH2:21][C@@H:22]3[CH2:25][C@H:24]([C@:18]2([CH3:28])[O:17]1)[C:23]3([CH3:27])[CH3:26])C.[Na+].[Cl-]>O1CCCC1.S(=O)(=O)(O)O.C(OC(C)C)(C)C>[CH3:3][CH:2]([CH3:4])[CH2:1][B:16]1[O:20][C@@H:19]2[CH2:21][C@@H:22]3[CH2:25][C@H:24]([C@:18]2([CH3:28])[O:17]1)[C:23]3([CH3:27])[CH3:26]
Reactant: CC(C)OB1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Reactant: CC(C)C[Mg]Br
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CC(C)OC(C)C
Product: CC(C)CB1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Temperature: -78 °C
Yield: 62 %

Procedure:
A 2M solution of isobutyl magnesium bromide in diethyl ether (131.5 ml, 0.263 mol) was added dropwise, in 1 hour, to a solution of 2-(1-methylethoxy)-(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborole obtained in Step 1 (62.6 g, 0.263 mol), in anhydrous tetrahydrofuran (330 ml) while stirring at −78° C., under nitrogen. The mixture was then allowed to warm to room temperature, then transferred in a mixture of 2N sulfuric acid (150 ml) and diisopropyl ether (250 ml). After stirring for 10 minutes, a saturated solution of NaCl was added (100 ml) and the layers were separated. The organic phase was washed with brine (100 ml), dried over sodium sulfate and concentrated. The residue was purified by column chromatography (silica gel) eluting with 5% diethyl ether in hexane. The product was obtained as a clear oil (38.45 g, 62% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][N:4]([CH3:7])[N:3]=1.C[Al](C)C.CCCCCC.C([O:20][C:21]([C:23]1[C:28]([Br:29])=[CH:27][CH:26]=[C:25]([CH3:30])[N:24]=1)=O)C>O1CCOCC1>[CH3:7][N:4]1[CH:5]=[CH:6][C:2]([NH:1][C:21]([C:23]2[C:28]([Br:29])=[CH:27][CH:26]=[C:25]([CH3:30])[N:24]=2)=[O:20])=[N:3]1
Reactant: Cn1ccc(N)n1
Reactant: CCOC(=O)c1nc(C)ccc1Br
Agent: C[Al](C)C
Solvent: CCCCCC
Solvent: C1COCCO1
Product: Cc1ccc(Br)c(C(=O)Nc2ccn(C)n2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.8 %

Procedure:
To a solution 3-Amino-1-methyl-pyrazole (1.39 g, 14.3 mmol, 3.5 equiv.) in 25 ml of dry dioxane were added 7.17 ml of a 2M solution of trimethyl aluminium in hexane (14.3 mmol, 3.5 equiv.) and the mixture was stirred for 1 h at r.t. Then 3-Bromo-6-methyl-pyridine-2-carboxylic acid ethyl ester (1.00 g, 4.1 mmol) were added and the reaction was refluxed for 2 h. After allowing the reaction to cool to r.t., the reaction was quenched with water (0.5 ml), stirred for 10 min, dried by addition of magnesium sulfate and filtered over Dicalite which was further washed with methylene chloride. The filtrate was concentrated in vaccuo. The residue (1.66 g, yellow oil) was purified by flash chromatography (heptane/ethyl acetate 2:3) to yield the title compound as a yellow solid (total 0.99 g, 82%), MS (ISP): m/e=295.2, 297.2 (M+H+).
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)(=[O:16])=[O:15])[CH2:11][NH:10]2)=[O:8])[CH2:5][CH2:4]1)#[N:2].Cl.[N:28]1([C:34]2([C:37](O)=[O:38])[CH2:36][CH2:35]2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:24])[F:25])[CH:18]=3)(=[O:16])=[O:15])[CH2:11][N:10]2[C:37]([C:34]2([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH2:35][CH2:36]2)=[O:38])=[O:8])[CH2:4][CH2:5]1)#[N:2]
Reactant: O=C(O)C1(N2CCCCC2)CC1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3cccc(C(F)(F)F)c3)CN2)CC1
Agent: Cl
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3cccc(C(F)(F)F)c3)CN2C(=O)C2(N3CCCCC3)CC2)CC1
Yield: 56 %

Procedure:
The reaction of (2S,4R)-N-(1-cyanocyclopropyl)-4-(3-(trifluoromethyl)phenylsulfonyl)pyrrolidine-2-carboxamide 7E with 1-(piperidin-1-yl)cyclopropanecarboxylic acid hydrochloride 16A carried out according to the general procedure L yielded (2S,4R)-N-(1-cyanocyclopropyl)-1-(1-(piperidin-1-yl)cyclopropanecarbonyl)-4-(3-(trifluoromethyl)phenylsulfonyl)pyrrolidine-2-carboxamide as a light yellow solid (56%). MS ISP (m/e): 539.3 (100) [(M+H)]+.
Reaction SMILES: [C:1](=O)([O:27]C1C=CC=CC=1)[O:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]3[CH:16]=[C:17]([Cl:24])[C:18]([C:20]([F:23])([F:22])[F:21])=[CH:19][C:14]=3[N:13]=[C:12]2[CH2:25][CH3:26])=[CH:7][CH:6]=1.[CH:35]1[C:44]2[C:39](=[C:40]([S:45]([NH2:48])(=[O:47])=[O:46])[CH:41]=[CH:42][CH:43]=2)[CH:38]=[CH:37][N:36]=1>>[Cl:24][C:17]1[C:18]([C:20]([F:23])([F:22])[F:21])=[CH:19][C:14]2[N:13]=[C:12]([CH2:25][CH3:26])[N:11]([C:8]3[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][O:2][C:1](=[O:27])[NH:48][S:45]([C:40]4[CH:41]=[CH:42][CH:43]=[C:44]5[C:39]=4[CH:38]=[CH:37][N:36]=[CH:35]5)(=[O:47])=[O:46])=[CH:10][CH:9]=3)[C:15]=2[CH:16]=1
Reactant: NS(=O)(=O)c1cccc2cnccc12
Reactant: CCc1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCOC(=O)Oc2ccccc2)cc1
Product: CCc1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCOC(=O)NS(=O)(=O)c2cccc3cnccc23)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 243 from 2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl phenyl carbonate and 5-isoquinolinylsulfonamide.
Reaction SMILES: Cl.[F:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[C:5]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH:4]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][C:25]1([OH:31])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O>[F:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:28]2[CH2:29][CH2:30][C:25]([OH:31])([CH2:24][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=3)[CH2:26][CH2:27]2)=[O:9])=[C:5]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH:4]=1
Reactant: OC1(Cc2ccccn2)CCNCC1
Reactant: O=C(O)c1ccc(F)cc1-c1ccncc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1ccc(F)cc1-c1ccncc1)N1CCC(O)(Cc2ccccn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.1 %

Procedure:
A suspension of 4-fluoro-2-(pyridin-4-yl)benzoic acid hydrochloride (0.15 g), 4-(pyridin-2-ylmethyl)piperidin-4-ol (0.17 g), HATU (0.34 g) and triethylamine (0.41 mL) in DMF (2.0 mL) was stirred at room temperature for 2 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.16 g).
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[C:5]2[N:9]([C@@H:12]3[O:32][C@H:31]([CH2:33][O:34]CC4C=CC=CC=4)[C@@H:22]([O:23]CC4C=CC=CC=4)[C@@H:13]3[O:14]CC3C=CC=CC=3)[CH:10]=[N:11][C:4]=2[CH:3]=1.C(O)(=O)C.COC(O)C>[Pd].O>[NH2:1][C:2]1[NH:7][C:6](=[O:8])[C:5]2[N:9]([C@@H:12]3[O:32][C@H:31]([CH2:33][OH:34])[C@@H:22]([OH:23])[C@@H:13]3[OH:14])[CH:10]=[N:11][C:4]=2[CH:3]=1
Reactant: Nc1cc2ncn([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@@H]3OCc3ccccc3)c2c(=O)[nH]1
Agent: [Pd]
Agent: COC(C)O
Solvent: O
Solvent: CC(=O)O
Product: Nc1cc2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@@H]3O)c2c(=O)[nH]1
Yield: 13.9 %

Procedure:
A mixture of 5.9 g of 6-amino-3-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)-3,5-dihydro-4H-imidazo-[4,5-c]pyridin-4-one, one g of 20% palladium on carbon, 5 ml of acetic acid, and 95 ml of methoxyethanol is hydrogenated at 50° C. and ca 3 atmospheres until hydrogen uptake ceases, the mixture is filtered, evaporated in vacuo, and co-evaporated with xylenes to provide a syrup which is dissolved in water and treated with 50 ml of wet IR-45 ion exchange resin. The resin is filtered, washed several times with boiling water and the combined filtrates are evaporated in vacuo to provide 2.5 g of crude product. Recrystallization from ethanol-water provides 0.42 g of 6-amino-3-β-D-arabinofuranosyl-3,5-dihydro-4H-imidazo[4,5-c]pyridin-4-one.
Reaction SMILES: C=C.C(O)(=O)C.[CH2:7]=[CH:8][CH2:9][CH3:10].[F:11][C:12]([F:17])([F:16])[C:13]([OH:15])=[O:14]>C(OCC)(=O)C>[F:11][C:12]([F:17])([F:16])[C:13]([O:15][CH:8]([CH2:9][CH3:10])[CH3:7])=[O:14]
Reactant: O=C(O)C(F)(F)F
Reactant: C=CCC
Agent: C=C
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCC(C)OC(=O)C(F)(F)F

Procedure:
In addition, the esterification of olefins with carboxylic acids and subsequent ester hydrolysis of the alkyl esters formed to the corresponding alcohol with recovery of the acid is known. For instance, U.S. Pat. No. 4,384,148 describes the reaction of ethene with acetic acid to give ethyl acetate in an autoclave. The subsequent hydrolysis of the ethyl acetate removed by distillation with water in a molar ratio of 1:5 in an autoclave affords a mixture comprising ethyl acetate, ethanol and diethyl ether. GB 2 238 539 discloses the two-stage hydration of 1-butene by reaction with trifluoroacetic acid to give 2-butyl trifluoroacetate in the presence of a highly acidic ion exchange resin and subsequent hydrolysis of the ester to give 2-butanol.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]2[O:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15](I)[CH:16]=[C:17]([CH3:18])[C:9]=3[N:8]=2)[N:4]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1.O1C2C=CC=CC=2C[C:29](=O)[NH:28]1.[Cu]C#N>O1CCCC1.C(OCC)(=O)C.[Cu]I>[Br:1][C:2]1[CH:6]=[C:5]([C:7]2[O:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15]([C:29]#[N:28])[CH:16]=[C:17]([CH3:18])[C:9]=3[N:8]=2)[N:4]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1
Reactant: Cc1cc(I)cc2c(=O)oc(-c3cc(Br)nn3-c3ncccc3Cl)nc12
Reactant: O=C1Cc2ccccc2ON1
Agent: N#C[Cu]
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(C#N)cc2c(=O)oc(-c3cc(Br)nn3-c3ncccc3Cl)nc12

Procedure:
To a solution of 2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-iodo-8-methyl-4H-3,1-benzoxazin-4-one (i.e. the benzoxazinone product of Step E) (600 mg, 1.1 mmol) in tetrahydrofuran (15 mL) was added copper(I) iodide (126 mg, 0.66 mmol), tetrakis(triphenyphosphine)palladium(0) (382 mg, 0.33 mmol) and copper(I) cyanide (800 mg, 8.8 mmol) sequentially at room temperature. The reaction mixture was then heated at reflux overnight. The reaction turned black in color, at which point thin layer chromatography on silica gel confirmed completion of the reaction. The reaction mixture was diluted with ethyl acetate (20 mL) and filtered through Celite®, followed by washing three times with 10% sodium bicarbonate solution and once with brine. The organic extract was dried (MgSO4) and concentrated under reduced pressure to afford 440 mg of the title compound as a crude yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)#[CH:2].[CH3:12][OH:13]>O1CCCC1>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:13][CH3:12])=[O:8])=[CH:5][CH:4]=1)#[CH:2]
Reactant: C#Cc1ccc(C(=O)Cl)cc1
Reactant: CO
Solvent: C1CCOC1
Product: C#Cc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
Then, a solution prepared by dissolving 24.7 g (0.15 mole) of 4-ethynylbenzoic acid chloride in 30 ml of tetrahydrofuran was added dropwise into 300 ml of methanol cooled in an ice bath. After the addition was completed, the reaction solution became turbid in 20 minutes. The reaction mixture was kept being stirred for 2 hours in the ice bath and then stirred at the room temperature for further 2 hours. The reaction mixture was filtered and dried and 21 g (the yield: 87%) of methyl 4-ethynylbenzoate was obtained.
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[CH:5]=[C:4]([CH3:19])[CH:3]=1.[F:20][C:21]([F:27])([F:26])[CH:22]=[CH:23][CH2:24]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCOCC1.CCCCC.C(OCC)(=O)C>[CH3:14][N:13]1[C:9]([O:8][C:6]2[CH:5]=[C:4]([CH3:19])[CH:3]=[C:2]([O:1][CH2:24]/[CH:23]=[CH:22]/[C:21]([F:27])([F:26])[F:20])[N:7]=2)=[CH:10][C:11]([C:15]([F:18])([F:17])[F:16])=[N:12]1
Reactant: OCC=CC(F)(F)F
Reactant: Cc1cc(O)nc(Oc2cc(C(F)(F)F)nn2C)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCCCC
Solvent: CCOC(C)=O
Product: Cc1cc(OC/C=C/C(F)(F)F)nc(Oc2cc(C(F)(F)F)nn2C)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.4 %

Procedure:
A mixture of 6-hydroxy-2-(1-methyl-3-trifluoromethylpyrazol-5-yloxy)-4-methylpyridine (0.8 g, 2.93 mmol), 4,4,4-trifluorobut-2-en-1-ol (0.44 g, 3.5 mmol), triphenylphosphine (0.92 g, 3.51 mmol) and diethyl azodicarboxylate (0.61 g, 3.51 mmol) in dry dioxane (3 ml) is stirred for 1.5 h at ambient temperature. The reaction mixture is diluted with pentane/ethyl acetate (by volume ration 1/1) and filtered through a bed of silica gel. The filtrate is washed with water. The organic layer is dried with anhydrous magnesium sulfate, filtered and evaporated in vacuo. Purification by flash chromatography (silica gel: pentane/ethyl acetate 9/1 v/v) yields the title compound (1.11 g, 70% yield) as an colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[Cl:14].[CH3:15][O:16][C:17]([C:19]1(OC)[CH2:23][CH2:22][CH:21](OC)O1)=[O:18]>C(O)(=O)C>[Cl:14][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[N:1]1[CH:21]=[CH:22][CH:23]=[C:19]1[C:17]([O:16][CH3:15])=[O:18])[NH:9][C:8](=[O:12])[C:7](=[O:13])[NH:6]2
Reactant: COC(=O)C1(OC)CCC(OC)O1
Reactant: Nc1cc2[nH]c(=O)c(=O)[nH]c2cc1Cl
Solvent: CC(=O)O
Product: COC(=O)c1cccn1-c1cc2[nH]c(=O)c(=O)[nH]c2cc1Cl
Yield: 43.7 %

Procedure:
10 g (47.25 mmol) of 7-amino-6-chloro-2,3(1H,4H)-quinoxalinedione and 8.9 g (47.25 mmol) of 2-methoxycarbonyl-2,5-dimethoxytetrahydrofuran in 150 ml of acetic acid were refluxed for 2 h. The precipitate was then filtered off with suction to yield 6.6 g (44%) of the product. Melting point>260° C.
Reaction SMILES: C[Mg]I.[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5]1.[Cl:13][C:14]1[N:19]=[C:18](Cl)[C:17]([CH3:21])=[CH:16][N:15]=1.O>ClCCCl>[Cl:13][C:14]1[N:19]=[C:18]([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[NH:4][CH:5]=2)[C:17]([CH3:21])=[CH:16][N:15]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: Cc1cnc(Cl)nc1Cl
Agent: C[Mg]I
Solvent: O
Solvent: ClCCCl
Product: Cc1cnc(Cl)nc1-c1c[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Methylmagnesium iodide (3 M in diethyl ether, 30.7 mL, 92.02 mmol) was added over 20 min to a solution of 1H-indole (7.19 g, 61.35 mmol) in DCE (25 mL) under nitrogen at 0° C. 2,4-Dichloro-5-methylpyrimidine (10 g, 61.35 mmol) in DCE (20 mL) was then added slowly to the reaction mixture over 20 min at 0° C. and the reaction mixture was stirred for an additional 30 min at 0° C. The reaction mixture was then allowed to warm up to RT and stirred at 30 min. The reaction mixture was then cooled to 0° C. and water (50 mL) was slowly added. The resultant yellow solids were collected by vacuum filtration. The solids were then suspended in 10% aqueous citric acid solution (150 mL) and stirred for 10 min, filtered, then washed with water and diethyl ether to give the title product. (8.10 g, 54.2%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:10]([O:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2C1CCCCO1.[ClH:26].O1CCOCC1.C(OCC)C>O1CCOCC1>[ClH:26].[CH3:1][C:2]1[C:10]([O:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2
Reactant: Cc1c(Oc2ccc(C#N)cc2)ccc2c1cnn2C1CCCCO1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: Cc1c(Oc2ccc(C#N)cc2)ccc2[nH]ncc12
Yield: 83 %

Procedure:
Under nitrogen, 4-[(4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)oxy]benzonitrile (338 mg, 1.01 mmol) was dissolved in 1,4-dioxane (6 ml), followed by adding thereto a 4N-hydrochloric acid/1,4-dioxane solution (6 ml), and the resulting mixture was stirred at room temperature for 23 hours. After diethyl ether (30 ml) was added thereto and stirred, the precipitate was collected by filtration, washed with diethyl ether and then dried under reduced pressure to obtain 4-[(4-methyl-1H-indazol-5-yl)oxy]benzonitrile monohydrochloride (239 mg, yield 83%).
Reaction SMILES: C(OC([N:6]1[CH2:11][CH:10]=[C:9]([CH3:12])[CH2:8][CH:7]1[C:13]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)([CH3:15])[CH3:14])=O)C.[OH-].[Na+].C(O)COCCO>O>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:13]([CH:7]2[CH2:8][C:9]([CH3:12])=[CH:10][CH2:11][NH:6]2)([CH3:15])[CH3:14])=[CH:21][CH:20]=1
Reactant: CCOC(=O)N1CC=C(C)CC1C(C)(C)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: CC1=CCNC(C(C)(C)c2ccc(Cl)cc2)C1

Procedure:
A mixture of 1-ethoxycarbonyl-1,2,3,6-tetrahydro-2-[1-(4-chlorophenyl)-1-methylethyl]-4-methylpyridine (14.5 g), sodium hydroxide (15 g) and diethylene glycol (150 ml) was refluxed for 5 hours. After cooling, water was added to the reaction mixture and the resulting mixture was extracted with benzene. The extract was washed with water and dried over potassium carbonate. After removal of benzene, the residue was distilled under reduced pressure to obtain 10.7 g of a colorless viscous mass of 2-[1-(4-chlorophenyl)-1-methylethyl]-1,2,3,6-tetrahydro-4-methylpyridine.