Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])(=O)C.[Na+].[Cl:6][C:7]1[N:16]=[C:15](Cl)[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:18])[CH:13]=2)[N:8]=1.[NH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[C:28]([C:33]([OH:35])=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:23][CH:22]=1>C1COCC1>[Cl:6][C:7]1[N:16]=[C:15]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[C:28]([C:33]([OH:35])=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:23][CH:22]=2)[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:18])[CH:13]=2)[N:8]=1
Reactant: NCc1ccc(-c2ccccc2C(=O)O)cc1
Reactant: Clc1ccc2nc(Cl)nc(Cl)c2c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1-c1ccc(CNc2nc(Cl)nc3ccc(Cl)cc23)cc1

Procedure:
A mixture of sodium acetate (0.56 g), 2,4,6-trichloroquinazoline (0.40 g) and 4'-aminomethyl (1,1'-biphenyl)-2-carboxylic acid (0.43 g) was stirred at room temperature in 10 mL of THF for 5 days. All solvents were removed by evaporation and the resulting residue was partitioned between ethyl acetate and brine. The ethyl acetate fraction was dried over anhydrous magnesium sulfate, filtered and evaporated. The crude material was purified using silica gel chromatography to yield 0.15 g (21%) of an off white solid (m.p.=210°-240° C.): 1H NMR (DMSO-d6, 400 MHz) δ9.45 (t, J=6.2 Hz, 1H), 8.52 (d, J=2.3 Hz, 1H), 7.83 (dd, J=2.3, 8.9 Hz, 1H), 7.66 (m, 2H), 7.49 (m, 1H), 7.35 (m, 7H), 4.77 (d, J=5.2 Hz); negative FAB MS m/e 422(M-H). Anal. calcd for C 22 H15Cl2N3O2 : C, 62.28; H, 3.56; N, 9.90. Found: C, 62.44; H, 3.52; N, 9.95.
Reaction SMILES: [I-].[Li+].CC1C=C(C)N=C(C)C=1.C[O:13][C:14]1[CH:15]=[C:16]([CH2:22][CH2:23][NH:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[CH:17]=[CH:18][C:19]=1[O:20]C>>[OH:13][C:14]1[CH:15]=[C:16]([CH2:22][CH2:23][NH:24][C:25](=[O:30])[C:26]([CH3:28])([CH3:27])[CH3:29])[CH:17]=[CH:18][C:19]=1[OH:20]
Reactant: COc1ccc(CCNC(=O)C(C)(C)C)cc1OC
Agent: [I-]
Agent: [Li+]
Solvent: Cc1cc(C)nc(C)c1
Product: CC(C)(C)C(=O)NCCc1ccc(O)c(O)c1
Temperature: 25 °C

Procedure:
Suspend 0.86 g. of lithium iodide in 10.0 ml. of S-collidine and add 0.53 g. of N-[β-(3,4-dimethoxyphenyl)-ethyl] 2,2-dimethylpropionamide (see Example 5, step A). Reflux the mixture for 3 hours with vigorous stirring, then cool to room temperature. Extract the two liquid phases with ethyl acetate and water and proceed as described in Example 8 to obtain the product of this example.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([NH:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:14]([CH:16]=1)[NH2:15].OOS([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]2[N:17]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:2]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:16]=3)=[N:15][C:14]=2[CH:16]=1
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NC1CCOCC1
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(-c2nc3cc(-c4nc5ccccc5o4)ccc3n2C2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 120.2 %

Procedure:
5-(Benzoxazol-2-yl)-2-(tetrahydropyran-4-yl)aminoaniline (see Working Example 20-2) (0.15 g, 0.484 mmol) was dissolved in DMF (3 mL) and water (0.1 mL), phenyl aldehyde (0.06 g, 0.561 mmol) was added followed by oxone (0.19 g, 0.310 mmol), and this was stirred at room temperature for 2.5 hours. Aqueous potassium carbonate solution (0.09 g/15 mL) was added to the reaction solution. This was extracted with chloroform, washed with water, and after drying over magnesium sulfate, this was concentrated and purified by silica gel column chromatography. The crystals obtained were washed with hexane and a small amount of ethyl acetate, and dried to yield the title compound (115 mg, 59.9% yield) as white crystals.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]#[N:12])=[CH:8][C:7]=2[CH:13]=1)=O.[CH2:14]([C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][C:18]=1[C:24]([F:27])([F:26])[F:25])[CH2:15][CH3:16].[BH4-].[Na+]>>[CH2:14]([C:17]1[CH:23]=[CH:22][C:20]([NH:21][CH2:1][C:3]2[CH:4]=[CH:5][C:6]3[O:10][C:9]([C:11]#[N:12])=[CH:8][C:7]=3[CH:13]=2)=[CH:19][C:18]=1[C:24]([F:25])([F:26])[F:27])[CH2:15][CH3:16]
Reactant: CCCc1ccc(N)cc1C(F)(F)F
Reactant: N#Cc1cc2cc(C=O)ccc2o1
Agent: [BH4-]
Agent: [Na+]
Product: CCCc1ccc(NCc2ccc3oc(C#N)cc3c2)cc1C(F)(F)F
Temperature: 37.5 °C
Reaction time: 0.08 h
Yield: 69.2 %

Procedure:
5-Formylbenzofuran-2-carbonitrile (168 mg, 0.98 mmol) was added to 2 mL of TFE and stirred at 35-40° C. After 5 min, the solution became clear, 4-propyl-3-(trifluoromethyl)aniline (199 mg, 0.982 mmol) was added, and a yellow precipitate formed. The mixture was vigorously stirred at the same temperature for 0.5 hr, NaBH4 (44.6 mg, 1.18 mmol) was added and the reaction was stirred at this temperature for another 0.5 hr. The mixture was then filtered, and the residue was washed with TFE (2 mL). The solvent was concentrated under reduced pressure and the crude product was purified by silica gel flash chromatography, 100% Heptane-10% Ethyl Acetate/90% Heptane, to give 5-(((4-propyl-3 (trifluoromethyl)phenyl)amino)-methyl)benzofuran-2-carbonitrile (243 mg). LCMS retention time=1.76 minutes (LC method 3); MS (m+1)=358.8. 1H NMR (400 MHz, DMSO-d6) δ 0.88 (t, J=7.3 Hz, 3H), 1.48 (sxt, J=7.5 Hz, 2H), 2.47 (br. s., 2H) 4.41 (d, J=6.0 Hz, 2H), 6.64 (t, J=6.1 Hz, 1H), 6.74 (dd, J=8.4, 2.4 Hz, 1H), 6.86 (d, J=2.5 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 7.59 (dd, J=8.7, 1.7 Hz, 1H), 7.71 (d, J=8.7 Hz, 1H), 7.78 (d, J=1.0 Hz, 1H), 8.09 (d, J=0.9 Hz, 1H).
Reaction SMILES: [C:1]([Si:5]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[O:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][N:12]1C(=O)C2C(=CC=CC=2)C1=O)([CH3:4])([CH3:3])[CH3:2].CNN>ClCCl>[C:1]([Si:5]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[O:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][NH2:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](OCCCCON1C(=O)c2ccccc2C1=O)(c1ccccc1)c1ccccc1
Agent: CNN
Solvent: ClCCl
Product: CC(C)(C)[Si](OCCCCON)(c1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 89.6 %

Procedure:
A solution of 2-[4-(tert-butyl-diphenyl-silanyloxy)-butoxy]-isoindole-1,3-dione (11.1 g, 23.4 mmol) in dichloromethane (100 ml) was treated with methylhydrazine. The reaction mixture was stirred overnight and was filtered. The filtrate was concentrated and purified by column chromatography [hexane/ethyl acetate (3.5/1)] to afford O-[4-(tert-butyl-diphenyl-silanyloxy)-butyl]-hydroxylamine (7.2 g, 90% yield) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.62-7.66(4H, m), 7.33-7.42 (6H, m), 3.64-3.68(4H), 1.54-1.70 (4H, m), 1.02 (9H, s); MS (APCI+)=344.2.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([C:7]1[C:15]2[CH:14]=[CH:13][C:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][C:10]=2[N:9]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[N:8]=1)=[O:6].[H-].[Na+].O.Cl>CN(C)C=O>[N:4]1([C:5]([C:7]2[C:15]3[CH:14]=[CH:13][C:12]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:11][C:10]=3[N:9]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[N:8]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: C[Si](C)(C)CCOCn1nc(C(=O)NCCCl)c2c1CC(c1ccccc1)(c1ccccc1)C=C2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1nc(C(=O)N2CC2)c2c1CC(c1ccccc1)(c1ccccc1)C=C2
Temperature: 5 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
A solution of 0.2 g of 6,6-diphenyl-1 (2-trimethylsilanylethoxymethyl)-6,7-dihydro-1H-indazole-3-carboxylic acid (2-chloroethyl)amide in 7 cm3 of dimethylformamide is added dropwise to a suspension of 0.023 g of sodium hydride (at 60% in oil) in 3 cm3 of dimethylformamide cooled to a temperature in the region of 5° C. The reaction mixture is stirred for two hours at a temperature in the region of 20° C. The solution obtained is poured into a mixture of 30 cm3 of water and 0.3 cm3 of aqueous 1N hydrochloric acid solution while maintaining the temperature in the region of 5° C., and the mixture is extracted with three times 30 cm3 of ethyl acetate. The combined organic phases are washed with three times 30 cm3 of water and 30 cm3 of saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (13 kPa). After flash chromatography on a column of silica [eluent: cyclohexane/ethyl acetate (70/30 by volume)], 0.078 g of aziridin-1-yl(6,6-diphenyl-1-(2-trimethylsilanylethoxymethyl)-6,7-dihydro-1H-indazol-3-yl)methanone is thus obtained in the form of a resin, the characteristics of which are as follows:
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[C:30]([C:34]#[N:35])=[CH:31][CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[C:30]([C:34]#[N:35])=[CH:31][CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cccc(C#N)c2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2cccc(C#N)c2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-7-cyano-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][C:13]([F:16])([F:15])[F:14])[CH:10]=2)[O:5][C:4]([CH3:18])([CH3:17])[C@H:3]1[OH:19].[CH2:20]([O:22][C:23]1[C:27](OCC)=[N:26][S:25](=[O:32])(=[O:31])[N:24]=1)[CH3:21].[K+].[Br-]>C(#N)C>[CH2:20]([O:22][C:23]1[C:27]([NH:1][C@@H:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:12][C:13]([F:16])([F:14])[F:15])[CH:10]=3)[O:5][C:4]([CH3:17])([CH3:18])[C@H:3]2[OH:19])=[N:26][S:25](=[O:32])(=[O:31])[N:24]=1)[CH3:21]
Reactant: CC1(C)Oc2ccc(OC(F)(F)F)cc2[C@@H](N)[C@@H]1O
Reactant: CCOC1=NS(=O)(=O)N=C1OCC
Agent: [Br-]
Agent: [K+]
Solvent: CC#N
Product: CCOC1=NS(=O)(=O)N=C1N[C@@H]1c2cc(OC(F)(F)F)ccc2OC(C)(C)[C@H]1O

Procedure:
(3S, 4R)-4-Amino-2,2-dimethyl-6-(trifluoromethoxy)-chroman-3-ol [prepared by the method of Quagliato et al. Biorg. and Med. Chem. Let. 1991, 1, 39; (1.00 g, 3.61 mmol)] and the thiadiazole derivative (0.78 g, 3.79 mmol) obtained in Step 1 were stirred together in acetonitrile (15 mL) at 90° C. for 18 hours. The mixture was cooled and concentrated, and the residue was purified by column chromatography (1:1:05 hexane/ethyl acetate/dichloromethane) to give after trituration with hexanes 1.10 g (71%) of product as a white solid: mp 192°-194° C.; 1H NMR (DMSO-D6): δ 9.55 (d, 1H), 7.29 (d, 1H), 7.19 (d, 1H), 6.87 (d, 1H), 5.89 (d, 1H), 4.73 (t, 1H), 4.51 (q, 2H), 3.78 (m, 1H), 1.41 (t, 3 H), 1.38 (s, 3H), 1.15 (s, 3H); IR (KBr): 2500-3250, 1620, 1490 cm-1 ; MS (m/z) 438 (MH+, 100%), 261 (20).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:12][C@H:13]1[CH2:17][CH2:16][N:15]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:14]1=[O:24].C(N(C(C)C)C(C)C)C.[Cl:34][C:35]1[C:36](Cl)=[N:37][CH:38]=[C:39]([CH:44]=1)[C:40]([O:42][CH3:43])=[O:41]>CN(C=O)C.CCOC(C)=O>[Cl:34][C:35]1[C:36]([N:21]2[CH2:22][CH2:23][CH:18]([N:15]3[CH2:16][CH2:17][C@H:13]([NH:12][C:3]4[CH:4]=[CH:5][C:6]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:7][C:2]=4[F:1])[C:14]3=[O:24])[CH2:19][CH2:20]2)=[N:37][CH:38]=[C:39]([CH:44]=1)[C:40]([O:42][CH3:43])=[O:41]
Reactant: CS(=O)(=O)c1ccc(N[C@H]2CCN(C3CCNCC3)C2=O)c(F)c1
Reactant: COC(=O)c1cnc(Cl)c(Cl)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc(N2CCC(N3CC[C@H](Nc4ccc(S(C)(=O)=O)cc4F)C3=O)CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.6 %

Procedure:
To a solution of (S)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)-1-(piperidin-4-yl)pyrrolidin-2-one (Preparation E; 1.0 g, 2.8 mmol) in DMF (30 mL) was added N-ethyl-N-isopropylpropan-2-amine (1.1 g, 8.4 mmol) and methyl 5,6-dichloronicotinate (1.7 g, 8.4 mmol) and the reaction was stirred overnight at ambient temperature. The reaction was diluted with EtOAc (250 mL) and washed with water (100 mL), and brine (50 mL), and the combined organic phases were dried over MgSO4, filtered and concentrated under vacuum. The crude material was purified on silica using a gradient of 1:9 to 1:4 EtOAc:DCM as eluent to yield a solid, which was further precipitated from using isopropanol to give (S)-methyl 5-chloro-6-(4-(3-(2-fluoro-4-(methylsulfonyl)phenylamino)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinate (0.70 g, 47% yield).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[C:7]=2[C:15]2[C:16]3[NH:23][CH:22]=[C:21]([C:24](O)=[O:25])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[C:27]([O:31][C:32]([N:34]1[CH2:38][CH2:37][C@@H:36]([NH2:39])[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32]([N:34]1[CH2:38][CH2:37][C@@H:36]([NH:39][C:24]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:7]4[C:8]5[O:12][CH2:11][O:10][C:9]=5[CH:13]=[CH:14][C:6]=4[O:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)[C:16]=3[NH:23][CH:22]=2)=[O:25])[CH2:35]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Reactant: O=C(O)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-cyclopropylmethoxy-1,3-benzodioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A67) and (R)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester the title compound is obtained as colorless solid.
Reaction SMILES: C([O:3][C:4](=[O:18])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH:14]([F:17])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)C.[OH-].[Na+]>C(O)C>[F:17][CH:14]1[CH2:13][CH2:12][N:11]([C:8]2[CH:9]=[CH:10][C:5]([C:4]([OH:18])=[O:3])=[CH:6][CH:7]=2)[CH2:16][CH2:15]1
Reactant: CCOC(=O)c1ccc(N2CCC(F)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(N2CCC(F)CC2)cc1

Procedure:
A mixture of 4-(4-fluoro-piperidin-1-yl)benzoic acid ethyl ester (0.7 g, 2.7 mmoles) in ethanol (50 ml) and a solution of 2N sodium hydroxide (20 ml) was stirred at room temperature for 24 hours. The ethanol was then evaporated, the solution diluted with water (20 ml) and neutralized with 2N HCl. The acid separated as a white solid which was washed with water and dried under vacuum (0.52 g, 82%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]=2[N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[O:9])[CH2:4][CH2:3]1.N1C=CC=CC=1.[O:37]1[CH:41]=[CH:40][CH:39]=[C:38]1[C:42](Cl)=[O:43].Cl>C(Cl)(Cl)Cl>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]=2[N:25]2[CH2:26][CH2:27][N:28]([C:42]([C:38]3[O:37][CH:41]=[CH:40][CH:39]=3)=[O:43])[CH2:29][CH2:30]2)=[O:9])[CH2:6][CH2:7]1
Reactant: CN1CCN(C(=O)c2c(N3CCNCC3)n(-c3ccccc3)c3ccccc23)CC1
Reactant: O=C(Cl)c1ccco1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CN1CCN(C(=O)c2c(N3CCN(C(=O)c4ccco4)CC3)n(-c3ccccc3)c3ccccc23)CC1
Temperature: -20 °C
Reaction time: 4 h

Procedure:
To a mixture of 16.1 g (0.04 mol) of 1-phenyl-2-(1-piperazinyl)-indole 3-carboxylic acid 4-methyl piperazide (Example 7), 5 ml of pyridine and 40 ml of chloroform, that had been cooled to -20° C., a solution of 6.5 g (0.05 mol) of furan-2-yl carboxylic acid chloride in 80 ml of chloroform was added. The mixture was allowed to stand for 4 hours at room temperature, then 200 ml of chloroform were added and the mixture was washed four times with water. The solvent was eliminated in vacuo, the crystallized residue was digested with ether, suction-filtered and washed with ether. Yield: 19 g (95% of the theoretical yield), m.p. 180°-181° C.; the hydrochloride decomposed above 300° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[CH:22]=[CH:21][C:16]2[N:17]=[CH:18][N:19]([CH3:20])[C:15]=2[CH:14]=1)[C:7]#[N:8].CI.[CH2:25](Cl)Cl>C1COCC1>[F:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[N:12]([CH3:25])[C:13]1[CH:22]=[CH:21][C:16]2[N:17]=[CH:18][N:19]([CH3:20])[C:15]=2[CH:14]=1)[C:7]#[N:8]
Reactant: ClCCl
Reactant: Cn1cnc2ccc(Nc3ccc(C#N)cc3F)cc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CN(c1ccc2ncn(C)c2c1)c1ccc(C#N)cc1F
Reaction time: 0.5 h

Procedure:
NaH (7.14 mmol) was added to a solution of 3-fluoro-4-[(3-methylbenzimidazol-5-yl)amino]benzonitrile (2.38 mmol) in THF (10 mL) at 0° C. The mixture was stirred for 30 min. MeI (4.76 mmol) was added and the mixture was stirred at room temperature during 3 h. The mixture was diluted (DCM), washed (H2O) and concentrated. The residue was purified by prep HPLC to yield the desired product (Compound C).
Reaction SMILES: Br[CH:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25])[C:3]([C:5]1[S:18][C:8]2[C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[O:11][CH2:12][CH2:13][C:7]=2[CH:6]=1)=O.[NH2:26][C:27]([NH2:29])=[S:28]>CC(C)=O>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:2]1[S:28][C:27]([NH2:29])=[N:26][C:3]=1[C:5]1[S:18][C:8]2[C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[O:11][CH2:12][CH2:13][C:7]=2[CH:6]=1
Reactant: NC(N)=S
Reactant: O=C(c1cc2c(s1)-c1ccccc1OCC2)C(Br)c1ccccc1Cl
Solvent: CC(C)=O
Product: Nc1nc(-c2cc3c(s2)-c2ccccc2OCC3)c(-c2ccccc2Cl)s1
Temperature: 25 °C

Procedure:
A solution of crude 2-bromo-2-(2-chlorophenyl)-1-(4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-2-yl)ethanone (0.21 mmol) in 2 mL acetone was treated with thiourea (48 mg) and the resultant suspension was heated at 80° C. overnight. The reaction mixture was cooled to room temperature and concentrated. The crude residue was purified by reverse phase HPLC to give 280 as a colorless solid. 1H NMR (400 MHz, DMSO-d6) δ 7.65 (m, 1H), 7.55-7.53 (m, 2H), 7.47-7.43 (m, 2H), 7.29 (br s, 2H), 7.14 (m, 1H), 7.02 (m, 1H), 6.45 (s, 1H), 4.17 (t, 2H), 2.95 (t, 2H). MS: (ESI+) 411.1
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:9])[CH2:7][CH3:8].C[Si](Cl)(C)C.[CH2:15](O)[CH2:16][OH:17]>>[CH2:7]([C:6]1([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[O:17][CH2:16][CH2:15][O:9]1)[CH3:8]
Reactant: OCCO
Reactant: CCC(=O)c1cccs1
Agent: C[Si](C)(C)Cl
Product: CCC1(c2cccs2)OCCO1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
30 g (214.3 mmol) of 1-2-thienyl-1-propanone are dissolved in 120 mL of ethylene glycol. 93 g (856 mmol) of trimethylsilyl chloride are then added. The reaction medium is stirred at room temperature for 24 hours. After treatment with water, the medium is extracted with ethyl acetate and the organic phases are then combined, dried and concentrated under reduced pressure. The residue obtained is purified by chromatography on a column of silica (eluent: 90 heptane/10 ethyl acetate). A yellow oil is obtained (m=15 g; Y=38%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]([C@H:7]1[CH2:10][C@H:9]([O:11]CC2C=CC=CC=2)[CH2:8]1)([CH3:6])[CH3:5]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:19])[C:4]([C@H:7]1[CH2:8][C@H:9]([OH:11])[CH2:10]1)([CH3:6])[CH3:5]
Reactant: COC(=O)C(C)(C)[C@H]1C[C@H](OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(C)(C)[C@H]1C[C@H](O)C1
Temperature: 40 °C
Yield: 120.6 %

Procedure:
A solution of trans-2-(3-benzyloxy-cyclobutyl)-2-methyl-propionic acid methyl ester (70 mg, 0.26 mmol) as 0.05 M solution in MeOH is pumped through the H-Cube™ flow hydrogenator fitted with 10 mol % Pd/C catalyst cartridge heated to 40° C. at 10 bar. The flow rate is set at 1 mL/min. The solvent is removed under reduced pressure to give trans-2-(3-hydroxy-cyclobutyl)-2-methyl-propionic acid methyl ester (54 mg, quant.); TLC (hexane/AcOEt, 1:1) Rf 0.45, 1H NMR (400 MHz, chloroform-d) δ ppm 1.12 (s, 6H), 1.92-2.03 (m, 2H), 2.18-2.24 (m, 2H), 2.63-2.71 (m, 1H), 3.65 (s, 3H), 4.25-4.31 (m, 1H).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[N:11]([CH:12]([CH3:14])[CH3:13])[C:10]([CH2:15][O:16][CH3:17])=[N:9][CH:8]=1)=O.C(=O)(O)O.[C:23]1([NH:29][C:30]([NH2:32])=[NH:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C[O-].[Na+]>CC(N(C)C)=O>[NH:29]([C:30]1[N:32]=[C:5]([C:7]2[N:11]([CH:12]([CH3:14])[CH3:13])[C:10]([CH2:15][O:16][CH3:17])=[N:9][CH:8]=2)[CH:4]=[CH:3][N:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: N=C(N)Nc1ccccc1
Reactant: COCc1ncc(C(=O)C=CN(C)C)n1C(C)C
Agent: C[O-]
Agent: O=C(O)O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COCc1ncc(-c2ccnc(Nc3ccccc3)n2)n1C(C)C
Temperature: 110 °C

Procedure:
5-(3-Dimethylaminoprop-2-en-1-oyl)-1-isopropyl-2-methoxymethylimidazole (Method 50; 1.26 g, 5 mmol), phenylguanidine hydrogen carbonate (1.09 g, 5.5 mmol) and sodium methoxide (594 mg, 11 mmol) were suspended in anhydrous DMA (10 ml) and the mixture heated at 110° C. for 3 hours. The volatiles were evaporated in vacuo the residues was suspended in water (50 ml). The solution was extracted DCM (3×50 ml). The combined extracts were washed with water (50 ml) and then brine (50 ml), dried and the volatiles removed by evaporation. The residue was purified by flash silica chromatography eluting with DCM:MeOH (100:0 increasing in polarity to 97:3) to give the title compound as brown oil. NMR: 1.43 (d, 6H), 3.30 (s, 3H), 4.56 (s, 2H), 5.54 (m, 1H), 6.96 (t, 1H), 7.05 (d, 1H), 7.24 (t,2H), 7.44 (s, 1H), 7.65 (d, 2H), 8.41 (d, 1H), 9.42 (s, 1H); m/z 324.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])([OH:12])[C:9]([OH:11])=[O:10].C1N=CN(C(N2C=NC=C2)=O)C=1.[Br-:32].O[C@@H:34]1[CH:39]2[CH2:40][CH2:41][N+:36]([CH2:42][C:43](=[O:50])[NH:44][C:45]3[CH:49]=[CH:48][O:47][N:46]=3)([CH2:37][CH2:38]2)[CH2:35]1>CN(C=O)C>[Br-:32].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])([OH:12])[C:9]([O:11][C@@H:38]1[CH:39]2[CH2:40][CH2:41][N+:36]([CH2:42][C:43](=[O:50])[NH:44][C:45]3[CH:49]=[CH:48][O:47][N:46]=3)([CH2:35][CH2:34]2)[CH2:37]1)=[O:10]
Reactant: O=C(O)C(O)(c1ccccc1Cl)c1ccccc1Cl
Reactant: O=C(C[N+]12CCC(CC1)[C@@H](O)C2)Nc1ccon1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Br-]
Solvent: CN(C)C=O
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C(O)(c1ccccc1Cl)c1ccccc1Cl)C2)Nc1ccon1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a stirred solution of bis-(2-chloro-phenyl)-hydroxy-acetic acid (0.17 g, 0.572 mmol) in dry DMF (3 ml) under an inert atmosphere of Argon is added CDI (0.097 g, 0.6 mmol). After 1 hour, (R)-3-hydroxy-1-(isoxazol-3-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octane bromide (Intermediate A) (0.2 g, 0.602 mmol) is added and the reaction mixture is heated to 40° C. overnight. Purification using C-18 reverse phase column chromatography (eluent: water-acetonitrile) affords a solid which is triturated with diethyl ether to yield the titled compound as a crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[CH2:12]([O:18][C@H:19]([CH3:23])[C:20](Cl)=[O:21])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:20](=[O:21])[C@H:19]([O:18][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:23])[C:5]([OH:7])=[O:6]
Reactant: CCCCCCO[C@H](C)C(=O)Cl
Reactant: O=C(O)c1ccc(O)c(Cl)c1
Product: CCCCCCO[C@H](C)C(=O)Oc1ccc(C(=O)O)cc1Cl

Procedure:
Using 3-chloro-4-hydroxybenzoic acid 1/2 hydrate (3.76 g, 20.7 mmol) and (R)-2-n-hexyloxypropanoyl chloride (3.98 g, 20.7 mmol), the reaction was carried out in the same manner as described in Example 4, (1), to give the title compound as a pale yellow oil; yield: 2.60 g.