Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.[CH3:13][Si](C=[N+]=[N-])(C)C>CO.ClCCl>[CH3:13][O:11][C:10]([C:7]1[CH:8]=[C:9]2[C:4]([CH:3]=[CH:2][NH:1]2)=[CH:5][CH:6]=1)=[O:12]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccc2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of indole-6-carboxylic acid (39.5 g, 245 mmol) in methanol (200 mL) and dichloromethane (750 mL) was added 2 M (trimethylsilyl)diazomethane in hexanes (160 mL, 320 mmol) dropwise over 1 hour. The reaction was stirred at room temperature overnight. The following day the reaction was concentrated to a thick brown crude oil that was diluted with ethyl acetate (500 mL) and washed with saturated aqueous sodium bicarbonate (2×200 mL), saturated aqueous sodium chloride (2×200 mL) and dried over sodium sulfate. The mixture was then filtered and the filtrate concentrated under reduced pressure to form a suspension. The suspension was filtered to provide 43 g of the desired compound as an off-white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([N:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])[CH2:6][CH2:5]2.[C:19]([O:23][CH3:24])(=[O:22])[CH:20]=[CH2:21].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:24][O:23][C:19](=[O:22])/[CH:20]=[CH:21]/[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([N:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])[CH2:6][CH2:5]2
Reactant: C=CC(=O)OC
Reactant: CCCN(CCC)C1CCc2cc(Br)ccc2C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCN(CCC)C1CCc2cc(/C=C/C(=O)OC)ccc2C1
Yield: 28.5 %

Procedure:
3.1 g (0.01 mol) of 6-bromo-2-(N,N-dipropylamino)-1,2,3,4-tetrahydronaphthalene are dissolved in 50 ml of dimethylformamide. There are added in succession to that solution 0.94 g (0.011 mol) of methyl acrylate, 22.4 mg (0.1 mmol) of palladium acetate, 121 mg (0.4 mmol) of tri-ortho-tolylphosphine and 1.6 ml (0.011 mol) of triethylamine. The mixture is heated at 125°-130° C. for 3 h 30 min. with stirring, cooled, poured into 700 ml of water, extracted with ethyl acetate and washed with a solution of LiCl. After acid to base change, 0.9 g of the expected product is obtained.
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH:4]([S:6]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:36]=[CH:35][C:18]([NH:19][C:20]3[N:25]=[C:24]([C:26]4[N:30]([CH:31]([CH3:33])[CH3:32])[C:29]([CH3:34])=[N:28][CH:27]=4)[CH:23]=[CH:22][N:21]=3)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)(=[O:8])=[O:7])=[CH2:5]>CO>[CH3:1][O:2][CH2:5][CH2:4][S:6]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:36]=[CH:35][C:18]([NH:19][C:20]3[N:25]=[C:24]([C:26]4[N:30]([CH:31]([CH3:32])[CH3:33])[C:29]([CH3:34])=[N:28][CH:27]=4)[CH:23]=[CH:22][N:21]=3)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)(=[O:7])=[O:8]
Reactant: C=CS(=O)(=O)N1CCN(c2ccc(Nc3nccc(-c4cnc(C)n4C(C)C)n3)cc2)CC1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCCS(=O)(=O)N1CCN(c2ccc(Nc3nccc(-c4cnc(C)n4C(C)C)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Sodium methoxide (40 mg 0.74 mmol) was added to 2-{4-[4-(vinylsulphonyl)piperazin-1-yl]anilino}-4-(1-isopropyl-2-methyl-1H-imidazol-5-yl)pyrimidine (Example 29; 300 mg 0.64 mmol) in MeOH (4 ml). After stirring at room temperature for 5 hours, the reaction was evaporated. After chromatography on silica gel using MeOH:DCM:EtOAc (5:47.5:47.5) and trituration with ether, the title compound was obtained as a yellow solid. NMR: 1.41 (d, 6H), 2.47 (s, 3H), 3.13 (m, 4H), 3.26 (4H alongside exchangeables), 3.37 (t, 2H), 3.67 (t, 2H), 5.69 (septuplet, 1H), 6.93 (d, 2H), 6.96 (d, 1H), 7.39 (s, 1H), 7.49 (d, 2H), 8.32 (d, 1H), 9.18 (s, 1H); m/z 500.
Reaction SMILES: [CH2:1](O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(O)C=CC=CC=1.[CH2:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[OH:29])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1>>[CH2:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[OH:29])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1.[CH2:1]([C:35]1[CH:36]=[C:31]([Cl:30])[CH:32]=[CH:33][C:34]=1[OH:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: Oc1ccc(Cl)cc1
Agent: Oc1ccccc1Cc1ccccc1
Solvent: Oc1ccccc1
Product: Oc1ccc(Cl)cc1Cc1ccccc1
Temperature: 200 °C
Yield: 25.4 %

Procedure:
A German patent, Ger.Offen 2,547,0310 (1977), disclosed the preparation of o-benzyl-toluenes by the reaction of o-methylbenzyl halides with substituted benzenes in the presence of Al-silicate. The 2-CH3C6H4CH2Cl was stirred with toluene and Al-silicate (25% Al2O3) at 110° C. to give 81% 2-methylbenzyltoluene. According to a Japanese patent, Jpn. Kokai Tokkyo Koho JP 59,186,937 (1984), o-benzylphenol was prepared by the liquid phase reaction of benzyl alcohol with phenol in the presence of γ-Al2O3. For example 7.5 g γ-Al2O3 was added to a mixture of 32.5 g benzyl alcohol and 47 g phenol at 190° C. under stirring to give a product containing 49.9% o-benzylphenol. A German patent, Ger. Offen DE 3,700,917 (1988), disclosed the preparation of p-substituted o-benzylphenols by benzylation of p-substituted phenols with benzylalcohol in the presence of Na—Y type zeolite. A mixture of 0.5 mole 4-ClC6H4OH, 0.1 mole C6H5CH2OH and 0.6 g of Na—Y type zeolite was heated at 200° C. for 3 hrs to give 25.4% 2-benzyl-4-chlorophenol.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21](=O)[CH3:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:24][S:25]([NH:28][NH2:29])(=[O:27])=[O:26]>>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18](/[C:21](=[N:29]/[NH:28][S:25]([CH3:24])(=[O:27])=[O:26])/[CH3:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)NN
Reactant: CC(=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Product: C/C(=N\NS(C)(=O)=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1

Procedure:
The title compound was prepared in analogy to the synthesis of example 52 from 1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone and methanesulfono-hydrazide. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.45 (s, 1H), 8.89 (m, 1H), 8.36 (d, 1H), 7.82 (m, 2H), 7.85 (dd, 1H), 7.53 (dd, 1H), 6.21 (s, 2H), 3.20 (s, 3H), 2.35 (s, 3H)). LCMS (method B): [MH]+=446, tR=1.37 min.
Reaction SMILES: [CH3:1][NH:2][S:3]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]([C:22]#[CH:23])[CH:9]=1)(=[O:5])=[O:4].CC(C)([O-])C.[K+].O.CCCCCCC>CN1CCCC1=O>[CH3:1][NH:2][S:3]([CH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:11](=[CH:12][CH:13]=1)[N:14]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:23]=[CH:22]2)(=[O:4])=[O:5]
Reactant: C#Cc1cc(CCS(=O)(=O)NC)ccc1NCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCCCC
Solvent: CN1CCCC1=O
Solvent: O
Product: CNS(=O)(=O)CCc1ccc2c(ccn2Cc2ccccc2)c1
Temperature: 82.5 °C
Reaction time: 0.5 h

Procedure:
2-(4-benzylamino-3-ethynyl-phenyl)-ethanesulfonic acid methylamide (100 g) was dissolved in N-methylpyrrolidone (1500 ml) at 25° C. Potassium tert-butoxide (67 g) was added and the reaction mass was heated to 80-85° C. for 120-150 minutes. The reaction mass was cooled gradually to 25° C., water (3500 ml) was added and stirred for 30 minutes. The solution was extracted with ethyl acetate (4000 ml). The organic layer was dried over sodium sulfate and distilled under vacuum to obtain a residue. The residue was treated with heptane (500 ml) to obtain a solid which was filtered, washed with heptane and dried at 50-55° C. under vacuum to obtain the title compound. (Yield: 76 g, HPLC Purity: 98%)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[C:10]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[CH:9]=2)[CH:5]=[C:4]([C:24]([F:27])([F:26])[F:25])[N:3]=1.[Br:28][C:29]1[N:30]=[CH:31][NH:32][CH:33]=1>>[Br:28][C:29]1[N:30]=[CH:31][N:32]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:16])([F:17])[F:15])=[C:10]([O:18][CH2:19][C:20]([F:21])([F:22])[F:23])[CH:9]=3)[CH:5]=[C:4]([C:24]([F:27])([F:25])[F:26])[N:3]=2)[CH:33]=1
Reactant: FC(F)(F)COc1cc(-c2cc(C(F)(F)F)nc(Cl)n2)ccc1C(F)(F)F
Reactant: Brc1c[nH]cn1
Product: FC(F)(F)COc1cc(-c2cc(C(F)(F)F)nc(-n3cnc(Br)c3)n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 2-chloro-4-[3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-6-trifluoromethyl-pyrimidine (example A.39) (0.85 g, 2.0 mmol) and commercially available 4-bromo-imidazole (0.44 g, 3.0 mmol) according to the general procedure IVa. Obtained as a light yellow solid (0.83 g, 78%). MS (ISP) 535.0 [(M+H)+]; mp 159° C.
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13]([F:15])[C:12]2[C:11]3[C:6](=[CH:7][C:8]([F:17])=[CH:9][C:10]=3[F:16])[CH:5]([C:18]([O:20][CH3:21])=[O:19])[C:4]=2[CH:3]=1.[H-].[Na+].[Cl:24]N1C(=O)CCC1=O.[K+].[Br-]>C1COCC1.CCCCCC.O>[Cl:24][C:5]1([C:18]([O:20][CH3:21])=[O:19])[C:4]2[CH:3]=[C:2]([F:1])[CH:14]=[C:13]([F:15])[C:12]=2[C:11]2[C:6]1=[CH:7][C:8]([F:17])=[CH:9][C:10]=2[F:16]
Reactant: COC(=O)C1c2cc(F)cc(F)c2-c2c(F)cc(F)cc21
Reactant: O=C1CCC(=O)N1Cl
Agent: [Br-]
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: COC(=O)C1(Cl)c2cc(F)cc(F)c2-c2c(F)cc(F)cc21
Temperature: 25 °C
Reaction time: 21 h

Procedure:
A solution of methyl 2,4,5,7-tetrafluorofluorene-9-carboxylate (1.49 g, 5.03 mmol) in dry THF (15 mL) was added over 14 min to a stirred, room temperature suspension of unwashed sodium hydride (1.25 eq, 6.29 mmol, 250 mg of a 60% oil dispersion) in THF (15 mL). The mixture was then cooled in an ice water bath and after 9 min a solution of N-chlorosuccinimide (1.2 eq, 6.04 mmol, 810 mg) was added over 14 min. After slowly warming to room temperature, the mixture was stirred for 21 h before it was poured into 100 ml of water and extracted with ethyl acetate. The extracts were washed with aqueous sodium carbonate, aqueous sodium bisulfate, and brine, dried (MgSO4), and concentrated to leave 1.4 g of crude material. Chromatography on silica gel using 20% ethyl acetate in hexane provided 970 mg (58%) of nearly pure material: 1H NMR (CDCl3) δ7.20 (dd, 2H), 7.0-6.6 (m, 2H), 3.75 (s, 3H); IR (KBr) 1730, 1600, 1580, 1410, 1105 cm-1 ; MS m/z 330 (M+), 271 (base peak).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].N#N.[H-].[Na+].Cl[C:11]1[N:16]=[C:15]([Cl:17])[CH:14]=[C:13]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:12]=1>CN(C=O)C>[CH2:1]([O:5][C:11]1[N:16]=[C:15]([Cl:17])[CH:14]=[C:13]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:12]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Clc1cc(N2CCOCC2)nc(Cl)n1
Reactant: CCCCO
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCOc1nc(Cl)cc(N2CCOCC2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.3 %

Procedure:
To a solution of n-butanol (0.633 g, 8.54 mmol) in anhydrous DMF (50 mL) at 0° C. under the N2, NaH (0.307 g, 12.8 mmol) was added quickly. The obtained suspension was stirred for 0.5 h at 0° C. 2,4-Dichloro-6-(morpholin-4-yl)pyrimidine (2 g, 8.54 mmol) was added to the suspension. After the suspension was warmed to room temperature and stirred for 12 h, the reaction mixture was quenched with ice/brine and extracted with 200 mL EtOAc. The extract was washed with brine, and dried over Na2SO4. The solvent was removed under reduced pressure. The crude residue was purified using flash chromatography (silica; EtOAc/Hexane: ⅙) to yield 1.4 g of 2-n-butoxy-4-chloro-6-(morpholin-4-yl)pyrimidine (white solid, 60%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=[O:20])=[CH:15][CH:14]=2)=[CH:11][CH:10]=[N:9]1.[C:22]1([CH3:31])[CH:27]=[CH:26][C:25]([CH2:28]C#N)=[CH:24][CH:23]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]3=[N:19][O:20][C:31]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[C:15]3[CH:14]=2)=[CH:11][CH:10]=[N:9]1
Reactant: Cc1ccc(CC#N)cc1
Reactant: O=[N+]([O-])c1ccc(-c2ccnn2-c2ccccc2F)cc1
Product: Cc1ccc(-c2onc3ccc(-c4ccnn4-c4ccccc4F)cc23)cc1

Procedure:
The title compound, light green solid (92 mg, 71%), MS (ISP) m/z=370.1 [(M+H)−], mp 173° C., was prepared in accordance with the general method of example 1 from 1-(2-fluoro-phenyl)-5-(4-nitro-phenyl)-1H-pyrazole (intermediate B) (100 mg, 353 μmol) and commercially available 2-(p-tolyl)-acetonitrile.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[I:13]I>CO.S([O-])([O-])(=O)=O.[Ag+2]>[OH:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]([I:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: II
Reactant: COC(=O)c1cccc(C)c1O
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: COC(=O)c1cc(I)cc(C)c1O
Reaction time: 3 h

Procedure:
Methyl 2-hydroxy-3-methylbenzoate (0.869 g, 5.23 mmol) in MeOH (5 mL) was added dropwise to a suspension of iodine (1.327 g, 5.23 mmol) and silver sulfate (1.63 g, 5.23 mmol), at room temperature under N2. The resultant brown suspension was stirred for 3 h after which time a colorless suspension was observed. The mixture was filtered through a plug of Celite, washed with MeOH (30 mL) and concentrated in vacuo to afford methyl 2-hydroxy-5-iodo-3-methylbenzoate, as a colorless solid. LCMS calc.=292.1; found=292.7 (M+H)+. 1H NMR (500 MHz, CHCl3): δ 11.0 (s, 1 H); 8.02 (s, 1 H); 7.62 (s, 1 H); 3.97 (s, 3 H); 2.25 (s, 3 H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[CH:4][CH:3]=1.[CH2:11]([OH:14])[CH:12]=[CH2:13]>O1CCCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[CH2:13][CH:12]([CH2:11][OH:14])[O:8][N:7]=2)=[CH:4][CH:3]=1
Reactant: C=CCO
Reactant: ON=Cc1ccc(Br)cc1
Solvent: C1CCOC1
Product: OCC1CC(c2ccc(Br)cc2)=NO1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
4-Bromo-benzaldehyde oxime (162 g, 789.9 mmol) and allyl alcohol (130.5 ml) were added to tetrahydrofuran (1000 ml) and then bleach (5305 ml) was added. The reaction was cooled to 0° C. and stirred for 3 hrs. The precipitate was collected and washed with water (2×300 ml) to give the desired product (137 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH:20]=[CH:21][C:22](Cl)=O.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.[C:53]([OH:58])(=[O:57])[C:54]([OH:56])=[O:55]>C(OCC)(=O)C>[C:53]([OH:58])(=[O:57])[C:54]([OH:56])=[O:55].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])/[CH:20]=[CH:21]/[C:22]1[N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]=1
Reactant: Nc1ccccc1Nc1ccccn1
Reactant: COc1ccc(C=CC(=O)Cl)cc1OC
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc(/C=C/c2nc3ccccc3n2-c2ccccn2)cc1OC

Procedure:
Free base of the titled compound was prepared from N-(2-pyridyl)-o-phenylenediamine and 3,4-dimethoxycinnamoyl chloride (Ramamurthy, B.; Sugumaran, M. Synthesis, 1987, 523) according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base and oxalic acid were dissolved into ethyl acetate. Concentration and recrystallization from ethyl acetate/n-hexane yielded the titled compound.
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CO.O>[Cl:19][C:15]1[CH:14]=[C:13]([S:10]([C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:20])=[O:2])=[CH:5][CH:6]=2)(=[O:11])=[O:12])[CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)c2cccc(Cl)c2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(S(=O)(=O)c2cccc(Cl)c2)cc1
Reaction time: 4 h

Procedure:
A mixture of compound 31a (138 mg, 0.44 mmol) and LiOH (42 mg, 1.77 mmol) in THF/MeOH/H2O (2/2/2 mL) was stirred for 4 h. A 15% citric acid solution (10 mL) was added. The mixture was then extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resultant residue, compound 31b (130 mg) was dried under reduced pressure for 18 h and used without further purification.
Reaction SMILES: [CH3:1][O:2]C1C=CC(C)=CC=1.[C-]#N.[Na+].[CH3:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1>>[CH3:13][O:14][CH:15]([O:2][CH3:1])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1
Reactant: COc1ccc(C)cc1
Reactant: COCc1ccc(OC)cc1
Agent: [C-]#N
Agent: [Na+]
Product: COc1ccc(C(OC)OC)cc1
Yield: 15 %

Procedure:
In the article "Nuclear Cyanation of Methylanisoles" by K. Yoshida, M. Shigi and T. Fueno in J. Org. Chem., 1975, Vol. 40, No. 1, pp. 63-66, the reaction of 4-methoxytoluene (Ic) in a methanolic solution of NaCN or Na acetate is described. In this reaction, 4-(methoxymethyl)-anisole and, in a material (current) yield of 15% (24%) of the theoretical, anisaldehyde-dimethylacetal (IIc) are also formed, in addition to the respective ring-substitution products.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH:16]([C:20](N(OC)C)=[O:21])[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>C(OCC)C.C1COCC1>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH:16]([CH:20]=[O:21])[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CON(C)C(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCCC(C=O)C1
Temperature: -15 °C

Procedure:
To a cooled (−15° C.), stirred suspension of lithium aluminum hydride (4.355 g, 114.743 mmol) in diethyl ether (500 mL) was added dropwise a solution of 3-{[methoxy(methyl)amino]carbonyl}-1-piperidine-carboxylic acid tert-butyl ester (25.000 g, 91.795 mmol) in THF (150 mL) over 30 min. The reaction mixture was quenched with aqueous 1N potassium hydrogen sulfate (300 mL), and extracted with a 1:1 mixture of diethyl ether and ethyl acetate. The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure to give 3-formyl-piperidine-1-carboxylic acid tert-butyl ester, which was used for the next steps without further purification. (22.56 g, yield; quant.)
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[N:3]1.[Cl:7][S:8](O)(=[O:10])=[O:9].N#N.S(Cl)(Cl)=O>O>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([S:8]([Cl:7])(=[O:10])=[O:9])=[N:3]1
Reactant: Cn1cccn1
Reactant: O=S(=O)(O)Cl
Agent: N#N
Solvent: O=S(Cl)Cl
Solvent: O
Product: Cn1ccc(S(=O)(=O)Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The N-methylpyrazole sulfonyl chloride was prepared by adding N-methylpyrazole to chilled (0° C.) chlorosulfonic acid. The reaction mixture was allowed to warm to room temperature and then heated to 100° C. overnight under a stream of N2. The reaction mixture was then cooled to room temperature and chilled to 0° C. To this solution was added thionyl chloride (2.5 eq.) and the reaction was stirred at room temperature for 30 min., then warmed to 70° C. for two hours. The reaction was cooled to room temperature and then chilled in an ice bath. Water and ice were slowly added to the reaction mixture to precipitate a white solid which was collected by filtration. The desired sulfonyl chloride was washed with cold water and hexane.
Reaction SMILES: C([O:4][C:5]1[CH:23]=[CH:22][C:8]([CH2:9][C@H:10]2[CH2:15][CH2:14][C:13]3[CH:16]=[C:17]([CH:20]=[O:21])[CH:18]=[CH:19][C:12]=3[O:11]2)=[CH:7][CH:6]=1)(=O)C>CO.O1CCCC1.[OH-].[Na+]>[CH:20]([C:17]1[CH:18]=[CH:19][C:12]2[O:11][C@@H:10]([CH2:9][C:8]3[CH:22]=[CH:23][C:5]([OH:4])=[CH:6][CH:7]=3)[CH2:15][CH2:14][C:13]=2[CH:16]=1)=[O:21]
Reactant: CC(=O)Oc1ccc(C[C@H]2CCc3cc(C=O)ccc3O2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=Cc1ccc2c(c1)CC[C@H](Cc1ccc(O)cc1)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.8 %

Procedure:
(R)-(-)-2-(4-Acetoxybenzyl)-3,4-dihydro-6-formyl-2H-benzopyran (15.7 g, 51 mmol) was dissolved in a mixture of methanol (200 ml), tetrahydrofuran (200 ml) and 2M NaOH (200 ml) and stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo, diluted with water (100 ml) and acidified with 10% HCl (250 ml). The aqueous solution was extracted with ethyl acetate (2×500 ml) and the combined organics were washed with water (250 ml), brine (250 ml), and dried (MgSO4). The solvent was removed in vacuo and the residue was crystallized from hexanes/ethyl acetate (3:1) to afford 10.1 g of the title compound, mp 134°-135° C.; [α]D -155.2° (c 1.0, MeOH); 1H NMR (300 MHz CDCl3) δ1.6 (m, 1H), 1.9 (m, 1H), 2.8 (m, 3H), 3.0 (dd, 1H), 4.2 (m, 1H), 5.1 (br s, 1H, OH), 6.7 (d, 2H), 6.8 (d, 1H), 7.0 (d, 2H), 7.5 (m, 2H), 9.7 (s, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:10]1[C:11]([C:22]([NH2:24])=[O:23])=[C:12]2[CH2:17][NH:16][CH2:15][CH2:14][N:13]2[C:18]=1[CH:19]1[CH2:21][CH2:20]1)#[N:9].C(N(CC)CC)C.[F:32][C:33]([F:45])([F:44])[C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1>C(#N)C>[C:8]([C:10]1[C:11]([C:22]([NH2:24])=[O:23])=[C:12]2[CH2:17][N:16]([S:40]([C:37]3[CH:36]=[CH:35][C:34]([C:33]([F:32])([F:44])[F:45])=[CH:39][CH:38]=3)(=[O:42])=[O:41])[CH2:15][CH2:14][N:13]2[C:18]=1[CH:19]1[CH2:20][CH2:21]1)#[N:9]
Reactant: N#Cc1c(C(N)=O)c2n(c1C1CC1)CCNC2
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1c(C(N)=O)c2n(c1C1CC1)CCN(S(=O)(=O)c1ccc(C(F)(F)F)cc1)C2
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 42.8 %

Procedure:
A suspension of 7-cyano-6-cyclopropyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxylic acid amide trifluoroacetic acid salt [200 mg, Example 44(b)] in dry acetonitrile (50 mL) was treated with dry triethylamine (0.16 mL), then with 4-(trifluoromethyl)benzenesulfonyl chloride (142 mg). After stirring at 60° C. for 2.5 hours the reaction mixture was allowed to cool to room temperature and evaporated. The residue was treated with ethyl acetate (40 mL) and water (40 ml). The organic phase was separated, dried over sodium sulfate and evaporated. The residue was subjected to column chromatography on silica eluting with a mixture of ethyl acetate and pentane (1:1, v/v) to give 7-Cyano-6-cyclopropyl-2-(4-trifluoromethylbenzenesulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxylic acid amide (109 mg) as a white solid, m.p. 253–256° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[C:11]([NH2:13])[S:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[F:14].[C:15]1([C:21]2[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[F:14][C:3]1[CH:4]=[CH:5][C:6]([C:8]2[N:12]=[C:11]([NH:13][S:27]([C:24]3[CH:23]=[CH:22][C:21]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[CH:26][CH:25]=3)(=[O:29])=[O:28])[S:10][CH:9]=2)=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1cc(-c2csc(N)n2)ccc1F
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Product: Cc1cc(-c2csc(NS(=O)(=O)c3ccc(-c4ccccc4)cc3)n2)ccc1F

Procedure:
The title compound was prepared from 2-amino-4-(4′-fluoro-3′-methyl)phenylthiazole and 4-phenylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (15.8 mg) with purity >90%. MS (pos) m/z 425.2.