Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9](=[O:37])[C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](=[O:36])[CH:18]([C:24]2[CH:33]=[C:32]3[C:27]([C:28]([CH3:35])([CH3:34])[CH2:29][CH2:30][O:31]3)=[CH:26][CH:25]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:12][CH:11]=1)C1C=CC=CC=1>C([O-])(=O)C.[Pd]>[CH3:34][C:28]1([CH3:35])[C:27]2[C:32](=[CH:33][C:24]([CH:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:17]([O:16][C:13]3[CH:12]=[CH:11][C:10]([C:9]([OH:37])=[O:8])=[CH:15][CH:14]=3)=[O:36])=[CH:25][CH:26]=2)[O:31][CH2:30][CH2:29]1
Reactant: CCCCCC(C(=O)Oc1ccc(C(=O)OCc2ccccc2)cc1)c1ccc2c(c1)OCCC2(C)C
Agent: [Pd]
Agent: CC(=O)[O-]
Product: CCCCCC(C(=O)Oc1ccc(C(=O)O)cc1)c1ccc2c(c1)OCCC2(C)C
Reaction time: 2 h
Yield: 60.1 %

Procedure:
A solution of 4-[2-(4,4-dimethyl-chroman-7-yl)-heptanoyloxy]-benzoic acid benzyl ester (152 mg, 0.3 mmol) in 10 mL of elthyl acetate with 32 mg of 10% palladium on carbon, was subjected to 1 atm. H2. After 2 h, the mixture was filtered through Celite and silica gel, concentrated under vacumn and purified by flash chromatography (gradient elution, 10-50% ethyl acetate/hexane) to afford 74 mg (59%) of 4-[2-(4,4-dimethyl-chroman-7-yl)-heptanoyloxy]-benzoic acid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.[NH2:34][C@@H:35]1[C:47](=[O:48])[N:37]2[C@@H:38]([C:44]([OH:46])=[O:45])[C@@:39]([Cl:43])([CH3:42])[CH2:40][S:41][C@H:36]12>O1CCCC1.O>[C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([NH:34][C@@H:35]1[C:47](=[O:48])[N:37]2[C@@H:38]([C:44]([OH:46])=[O:45])[C@@:39]([Cl:43])([CH3:42])[CH2:40][S:41][C@H:36]12)=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1ccccc1
Reactant: C[C@@]1(Cl)CS[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(C(=O)N[C@@H]1C(=O)N2[C@@H]1SC[C@@](C)(Cl)[C@@H]2C(=O)O)c1ccccc1
Reaction time: 0.17 h
Yield: 89.3 %

Procedure:
To a cooled solution of α-tert.-butoxycarbonylaminophenylacetic acid (1.0 g) and triethylamine (405 mg) in tetrahydrofuran (16 ml), is added isobutylchloroformate (550 mg) at -10°C and the mixture is stirred for 10 minutes. To the solution is added a solution of 7β-amino-3β-chloro-3α-methylcepham-4α-carboxylic acid (870 mg), and triethylamine (405 mg) in a mixture of tetrahydrofuran and water (1:1; 15 ml), and the mixture is stirred for 1 hour at 5°C, and for 1 hour at room temperature. The reaction mixture is evaporated in vacuo to remove tetrahydrofuran, and the resultant solution is diluted with a mixture of water and ethyl acetate (3:1). The aqueous layer is separated, acidified to pH 3 with 10% hydrochloric acid, and extracted with ethyl acetate. The extract solution is washed with water, dried, and evaporated to give 7β-(α-tert.-butoxycarbonylaminophenylacetamido)-3β-chloro-3α-methylcepham-4α-carboxylic acid (1.5 g). Yield: 77%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][C:5]=1[CH3:12].C(=O)(O)[O-].[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:5]=1[CH3:12]
Reactant: COC(=O)c1ccc(CO)cc1C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1ccc(C=O)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
To a 0° C. solution of 4-hydroxymethyl-2-methyl-benzoic acid methyl ester (0.49 g, 2.7 mmol) in methylene chloride (8.0 mL) are added sodium bicarbonate (0.46 g, 5.4 mmol) and Dess-Martin periodinane (0.14 g, 3.3 mmol) sequentially. The mixture is stirred at room temperature for 1.0 h and is quenched with water (2.0 mL). The mixture is partitioned between CH2Cl2 (30 mL) and water (30 mL). The organic phase is washed with brine (30 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to a residue. The residue is purified by flash chromatography to afford the title compound as syrup (0.35 g, 72%). 1HNMR (CDCl3) (ppm): 2.6 (3H, s), 3.85 (3H, s), 7.65-8.0 (3H, m), 10.0 (1H, s).
Reaction SMILES: [H][H].[CH3:3][C:4](=[CH:6][CH2:7][CH2:8][C:9](=[CH:11][CH:12]=[O:13])[CH3:10])[CH3:5]>CO>[CH3:5][C:4](=[CH:6][CH2:7][CH2:8]/[C:9](=[CH:11]/[CH2:12][OH:13])/[CH3:10])[CH3:3].[OH:13][CH2:12]/[CH:11]=[C:9](/[CH3:10])\[CH2:8][CH2:7][CH:6]=[C:4]([CH3:5])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)=CCCC(C)=CC=O
Solvent: CO
Product: CC(C)=CCC/C(C)=C/CO
Product: CC(C)=CCC/C(C)=C\CO

Procedure:
Solid bed catalyst from Example 2 with recycle: 100 ml (41.1 g) of the catalyst were installed in the reactor and activated as per the general prescription. At a hydrogen pressure of 40 bar (24 l/h, s.t.p.), the addition rates were set as follows: citral (2, 60 g/h, purity 98%), methanol +10% TMA (3, 25.5 g/h), return flow (6, 240 g/h). At a reactor temperature of 75° C. and a conversion of 95.61% (reaction time: 713 h), a selectivity for geraniol/nerol of 95.22% was obtained (ratio of Ger/Ner: 1.20). Byproducts: selectivity for citronellol: 1.80%, selectivity for nerol isomers: 1.70%.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[CH2:17][CH2:18][O:19][C:20]1[C:29]2[C:24](=[CH:25][C:26]([Cl:31])=[C:27]([NH2:30])[CH:28]=2)[NH:23][C:22](=[O:32])[C:21]=1[C:33]1[CH:38]=[C:37]([CH3:39])[CH:36]=[C:35]([CH3:40])[CH:34]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:41](Cl)(Cl)=[O:42].[CH2:45]([N:47](CC)CC)[CH3:46].Cl.C(N)C>C(Cl)Cl.C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[CH2:17][CH2:18][O:19][C:20]1[C:29]2[C:24](=[CH:25][C:26]([Cl:31])=[C:27]([NH:30][C:41]([NH:47][CH2:45][CH3:46])=[O:42])[CH:28]=2)[NH:23][C:22](=[O:32])[C:21]=1[C:33]1[CH:38]=[C:37]([CH3:39])[CH:36]=[C:35]([CH3:40])[CH:34]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OCc3ccccc3)c3cc(N)c(Cl)cc3[nH]c2=O)c1
Reactant: O=C(Cl)Cl
Reactant: CCN(CC)CC
Agent: CCN
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCNC(=O)Nc1cc2c(OCCC3CCCCN3C(=O)OCc3ccccc3)c(-c3cc(C)cc(C)c3)c(=O)[nH]c2cc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-{2-[6-amino-7-chloro-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid benzyl ester (prepared essentially as described in Example 6, 158 mg in 4 mL dry methylene chloride) at 0° C. was added phosgene (0.22 mL of a 1.93 M solution in toluene) followed by 0.081 mL of triethylamine and the mixture stirred for 1 hour at 0° C. At this time, 114.5 mg of ethylamine hydrochloride was added followed by additional triethylamine (0.195 mL) and the mixture allowed to warm to room temperature. After 20 hours, the mixture was diluted with ethyl acetate (200 mL) and the reaction quenched by the addition of water. The organic portion was washed sequentially with saturated sodium bicarbonate and brine. The solvent was removed in vacuo to provide the crude title compound (187 mg).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[CH2:10]Br.C(=O)([O-])[O-].[K+].[K+].[C:18]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:23])[CH2:19][C:20]([CH3:22])=[O:21].O>CC(CC)=O>[C:20]([C:19]1([C:18]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:23])[CH2:10][C:4]2[C:3](=[CH:8][CH:7]=[C:6]([F:9])[CH:5]=2)[CH2:2]1)(=[O:21])[CH3:22]
Reactant: CC(=O)CC(=O)OCc1ccccc1
Reactant: Fc1ccc(CBr)c(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CC(=O)C1(C(=O)OCc2ccccc2)Cc2ccc(F)cc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 111.9 %

Procedure:
To 5 g of 1,2-bis-(bromomethyl)-4-fluoro-benzene in 100 ml of methylethylketone were added 14.7 g of potassium carbonate followed by 4.1 g of benzyl acetoacetate. The mixture was stirred for 16 h at ambient temperature. 100 ml of water were added. The phases were separated and the aqueous phase was extracted once with 50 ml of methylethylketone. The combined organic phases were evaporated to give 6.2 g of crude product as an oil. The crude product was crystallized from cold heptane and from cold methanol. Melt.p. 55° C. 1HNMR: δ=2.16 ppm (s, 3H); 3.50 ppm (AB, 2H); 3.53 ppm (AB, 2H); 5.22 (s, 2H); 6.88 ppm (m, 2H); 7.12 ppm (dd, 1H) 7.30-7.42 ppm (m, 5H).
Reaction SMILES: [H-].[Na+].C(S)C.[CH:6]1[C:19]2[C:18]3([CH2:21][N:22]4[CH2:27][CH2:26][C:25]([C:29]5[C:30]([O:35]C)=[N:31][CH:32]=[CH:33][CH:34]=5)([OH:28])[CH2:24][CH2:23]4)[CH2:20][CH:11]([C:12]4[C:17]3=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:10]=2[CH:9]=[CH:8][CH:7]=1>CN(C)C=O.O>[OH:35][C:30]1[C:29]([C:25]2([OH:28])[CH2:24][CH2:23][N:22]([CH2:21][C:18]34[CH2:20][CH:11]([C:12]5[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=53)[C:10]3[C:19]4=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:27][CH2:26]2)=[CH:34][CH:33]=[CH:32][N:31]=1
Reactant: COc1ncccc1C1(O)CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCS
Product: Oc1ncccc1C1(O)CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Temperature: 25 °C
Yield: 82.2 %

Procedure:
To a dimethylformamide solution (3.5 mL) of sodium hydride (60% in mineral oil, 58 mg, 1.46 mmol, 2.5 eq) under nitrogen was added ethanethiol (0.108 mL, 1.46 mmol, 2.5 eq) via gas tight syringe. Once gas evolution had ceased, a solution of 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-(2-methoxy-3-pyridyl)piperidin-4-ol (described in example 32) (240 mg, 0.58 mmol) in dimethylformamide (2.0 mL) was added in a single portion. After the reaction had refluxed for 2 h, it was cooled to room temperature and diluted with water (25 mL). The resulting precipitate was filtered and purified by flash chromatography over silica gel (140 mL, eluent: 15% methanol in methylene chloride) to yield 190 mg (83%) of the title compound as a white solid. TLC analysis (Rf 0.10, 15% methanol in methylene chloride). 1H NMR (CDCl3, 300 MHz) 7.36 (dd, J=2.0, 7.2 Hz, 1H), 7.23 (m, 5H), 6.94 (m,4H), 6.31 (dd, J=6.7, 6.8 Hz, 1H), 5.82 (s, 1H), 4.27 (s, 1H), 3.48 (s, 2H), 2.84 (m, 2H), 2.61 (d, J=1.4 Hz, 1H), 2.00 (m, 2H), 1.89 (m, 2H) MS (CI, CH4) m/z 399 (M+1,100), 427 (M+29,7), 381 (18). The free base was dissolved in methanol/methylene chloride, acidified with ethereal HCl and the hydrochloride salt was precipitated by ether dilution. The salt was filtered, rinsed with fresh diethyl ether, and dried in vacuo (50° C., 75 pascal, 18 h) to yield a white solid, up 195°-199° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:27]=[CH:26][C:12]([CH2:13][O:14][C:15](=[O:25])[CH2:16][NH:17]C(OC(C)(C)C)=O)=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:28]2[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=2[O:35][CH2:36][CH3:37])[N:3]=1.Cl>C(OCC)(=O)C.O1CCOCC1>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:13][O:14][C:15](=[O:25])[CH2:16][NH2:17])=[CH:26][CH:27]=2)[CH:5]=[C:4]([C:28]2[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=2[O:35][CH2:36][CH3:37])[N:3]=1
Reactant: CCOc1ccc(Cl)cc1-c1cc(Nc2ccc(COC(=O)CNC(=O)OC(C)(C)C)cc2)nc(N)n1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOc1ccc(Cl)cc1-c1cc(Nc2ccc(COC(=O)CN)cc2)nc(N)n1
Reaction time: 16 h
Yield: 48 %

Procedure:
A solution of tert-butoxycarbonylamino-acetic acid 4-[2-amino-6-(5-chloro-2-ethoxy-phenyl)-pyrimidin-4-ylamino]-benzyl ester in ethyl acetate (15 ml) was treated with a solution of hydrogen chloride in dioxane (4.0 M, 15 ml). After stirring for 16 hours, the solid was filtered and dried under reduced pressure to provide the hydrochloride salt of the title compound (0.273 g, 48% yield). 1H NMR (DMSO-d6) δ 1.39 (t, 3H, J=6.4 Hz, CH3), 3.89 (d, 2H, J=4.9 Hz, CH2), 4.17 (q, 2H, J=6.2 Hz, CH2), 5.25 (s, 2H, CH2), 6.70 (s, 1H, Ar), 7.28 (d, 1H, J=8.7 Hz, Ar), 7.46 (d, 2H, J=8.4 Hz, Ar), 7.62-7.67 (m, 2H, Ar), 7.88 (d, 2H, J=7.4 Hz, Ar), 8.37 (s, 3H), 11.10 (s, 1H), 12.68 (s, 1H).
Reaction SMILES: [C@@H:1]1([NH:11][C:12]([N:14]([CH3:17])N=O)=[O:13])[O:9][C@H:8]([CH3:10])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].Cl.[Cl:19][CH2:20]CN.C(N(CC)CC)C.C(O)C>O>[Cl:19][CH2:20][CH2:17][NH:14][C:12]([NH:11][C@@H:1]1[O:9][C@H:8]([CH3:10])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3])=[O:13]
Reactant: NCCCl
Reactant: C[C@H]1O[C@@H](NC(=O)N(C)N=O)[C@H](O)[C@@H](O)[C@@H]1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: C[C@H]1O[C@@H](NC(=O)NCCCl)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 234 mg (0.91 mmol) of 1-(6-deoxy-β-D-glucopyranosyl)-3-methyl-3-nitrosourea in 2 ml of water was admixed with a solution of 401 mg (3.5 mmol) of 2-chloroethylamine hydrochloride and 0.5 ml (3.3 mmol) of triethylamine in 3 ml of aqueous 50% ethanol. The admixture was stirred for 2 hours at ambient temperature, and the reaction mixture was passed through a column (10×160 mm) of Amberlite IRA-400 (OH- form), which was then washed with water. The effluent was concentrated to dryness under a reduced pressure, and the crystalline residue so obtained was subjected to chromatography in a column (8×350 mm) of silica gel (8 g) using chloroformmethanol (5:2 by volume) as eluent. Such fractions of the eluate which gave a single spot at Rf 0.50 were combined together and concentrated to dryness by evaporation of the solvent under a reduced pressure. Recrystallization of the residue from acetone gave the titled compound. Yield 98 mg (37.7%). mp. 130°-132° C. [α]D24 -25.5° (c 0.5, water).
Reaction SMILES: [CH2:1]([N:5]([CH2:23][CH2:24][CH2:25][CH3:26])[C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].[CH:27]1([N:33]=[C:34]=[O:35])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH:27]1([NH:33][C:34]([NH:22][S:19]([C:17]2[CH:16]=[CH:15][C:12]3[CH2:13][CH2:14][N:8]([C:6](=[O:7])[N:5]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:1][CH2:2][CH2:3][CH3:4])[CH2:9][CH2:10][C:11]=3[CH:18]=2)(=[O:21])=[O:20])=[O:35])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: O=C=NC1CCCCC1
Reactant: CCCCN(CCCC)C(=O)N1CCc2ccc(S(N)(=O)=O)cc2CC1
Product: CCCCN(CCCC)C(=O)N1CCc2ccc(S(=O)(=O)NC(=O)NC3CCCCC3)cc2CC1

Procedure:
In a manner analogous to that described in Example 1, from 3-dibutylcarbamoyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide and cyclohexylisocyanate, there is obtained 1-cyclohexyl-3-[(3-dibutylcarbamoyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)sulfonyl]urea, m.p. 118°-120° C. The starting material can be prepared by the reaction of 2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide hydrochloride with dibutylcarbamoyl chloride in a manner analogous to that described in Example 1.
Reaction SMILES: [NH2:1][C@@H:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20]([F:23])([F:22])[F:21])[C:3]1=[O:24].C(N(CC)CC)C.[NH:32]1[CH2:37][CH2:36][CH:35]([N:38]2[CH:42]=[CH:41][NH:40][C:39]2=[O:43])[CH2:34][CH2:33]1.[O:44]1CCC[CH2:45]1>CN(C)C=O>[O:43]=[C:39]1[NH:40][CH:41]=[CH:42][N:38]1[CH:35]1[CH2:34][CH2:33][N:32]([C:45]([NH:1][C@@H:2]2[N:8]=[C:7]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[N:4]([CH2:19][C:20]([F:21])([F:23])[F:22])[C:3]2=[O:24])=[O:44])[CH2:37][CH2:36]1
Reactant: N[C@@H]1N=C(c2ccccc2)c2ccccc2N(CC(F)(F)F)C1=O
Reactant: O=c1[nH]ccn1C1CCNCC1
Reactant: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(N[C@@H]1N=C(c2ccccc2)c2ccccc2N(CC(F)(F)F)C1=O)N1CCC(n2cc[nH]c2=O)CC1
Reaction time: 1 h

Procedure:
(3R)-3-Amino-5-phenyl-1-(2,2,2-trifluoroethyl) 1,3-dihydro-2H-1,4-benzodiazepin-2-one (199 mg, 0.598 mmol) (Y.-J. Shi et al., Tetrahedron, 1999, 55, 909-918) and triethylamine (83 uL, 0.598 mmol) in tetrahydrofuran (5 mL) were added to a solution of p-nitrophenylchloroformate (100 mg, 0.598 mmol) in tetrahydrofuran (15 mL) at 0 oC. After 1 h, 1-piperidin-4-yl-1,3-dihydro-2H-imidazol-2-one (100 mg, 0.598 mmol) in tetrahydrofuran (9 mL) and dimethylforamide (1 mL) were added and stirred at 0 oC for 10 min and then warned to room temperature. After 16 h, the reaction was concentrated and the residue dissolved in ethyl acetate, washed with 1 N sodium hydroxide solution (3×), water, brine, and dried over magnesium sulfate. Purification by silica gel chromatography (100% dichloromethane→10% methanol/dichloromethane) gave 70 mg of the titled compound. MS 527.5 (M+1).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:17]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:11][CH:10]=1)C1C=CC=CC=1.C(O)(=O)C>[Pd].C(O)C>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:17]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1cc(OC)ccc1Nc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(OC)ccc1Nc1ccc(O)cc1
Reaction time: 8 h
Yield: 122.6 %

Procedure:
A mixture of 6 g of ethyl 2-(4-benzyloxyphenylamino)-5-methoxybenzoate, 30 ml of acetic acid, 270 ml of ethanol and 500 mg of 10% palladium-on-carbon catalyst was hydrogenated on a Parr apparatus for eight hours. The mixture was filtered, the filtrate stripped of solvent and the residue partitioned between ether and saturated sodium bicarbonate solution. The ether solution was dried over anhydrous magnesium sulfate and the solvent removed to give 5.6 g of ethyl 2-(4-hydroxyphenylamino)-5-methoxybenzoate as a yellow solid, m.p. 134°-136° C. when recrystallized from toluene.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([N:14](C)[C:15](=O)C)[C:8]=2[N:7]=[C:6]1[C:19]1[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=1[F:26].Cl>O>[F:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([NH:14][CH3:15])[C:8]=2[N:7]=[C:6]1[C:19]1[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=1[F:25]
Reactant: CC(=O)N(C)c1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F
Agent: Cl
Solvent: O
Product: CNc1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F
Yield: 77.6 %

Procedure:
To 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-(N-methylacetamido)-benzimidazole (Example 96) (0.50 g, 1.17 mmol) suspended in water (9.0 mL) was added HCl (1.0 mL). After 3 h at reflux, the solution was concentrated to dryness, diluted with ethylacetate, and washed with NaHCO3 (sat. aq) and NaCl (sat. aq). The combined washings were dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash chromatography eluting with 2% methanol in CH2Cl2, yielding 1-(2,6-Difluorobenzyl)-2-(2,6-difluorophenyl)-4-(N-methylamino)-benzimidazole (0.35 g, 78% yield). M.p. 194-195° C. 1H NMR (200 MHz, CD2Cl2): δ 7.52 (m, 1H, H4′), 7.23 (m, 1H, H4″), 7.13 (dd, J=8.3, 8.0 Hz, 1H, H6), 7.07 (m, 2H, H3′,5′), 6.80 (m, 2H, H3″,5″), 6.76 (d, J=8.3 Hz, 1H, H5) 6.36 (d, J=8.0 Hz, 1H, H7), 5.29 (s, 2H, CH2PhF2), 2.96 (s, 3H, NCH3).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4]Br.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[N+:14]([C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1)([O-:16])=[O:15]>CC(C)=O>[Br:1][CH2:2][CH2:3][CH2:4][O:23][C:19]1[CH:18]=[C:17]([N+:14]([O-:16])=[O:15])[CH:22]=[CH:21][CH:20]=1
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1cccc(OCCCBr)c1

Procedure:
43 ml of 1,3-dibromopropane are added to a suspension of 29 g of potassium carbonate and 0.5 g of potassium iodide in 170 ml of acetone and the mixture is refluxed. A solution of 19.4 g of 3-nitrophenol is then added dropwise in the course of 2 hours and the mixture is refluxed for a further 15 hours. The reaction mixture is filtered hot and evaporated. Chromatography of the residue on silica gel with toluene gives 3-(3-bromopropoxy)-nitrobenzene as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[CH:3]=1.C(Cl)(Cl)Cl.[Br:26]N1C(=O)CCC1=O.N(C(C)(CC(C)C)C#N)=NC(C)(CC(C)C)C#N>O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][Br:26])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2nc(-c3ccccc3[N+](=O)[O-])cc(Cl)c2c1
Agent: CC(C)CC(C)(C#N)N=NC(C)(C#N)CC(C)C
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=[N+]([O-])c1ccccc1-c1cc(Cl)c2cc(CBr)ccc2n1
Temperature: 25 °C
Yield: 44.3 %

Procedure:
To 27.6 g (92.4 mmol) of the 4-chloro-6-methyl-2-(2-nitrophenyl)quinoline obtained in Example 1, 110 ml of chloroform was added. After stirring, 15.6 g (87.8 mmol) of N-bromosuccinimide (NBS) was added thereto. Then, 15 ml of chloroform containing 0.78 g of 2,2'-azobis(2,4-dimethylvaleronitrile) was added dropwise thereto, and the thus-prepared mixture was heated under reflux for 1 hour. After cooling to room temperature, the mixture was poured into 220 ml of water and separated out, and the organic layer was washed with 110 ml of water twice. Next, the washed organic layer was evaporated and dried in an evaporator and recrystallized from toluene to obtain 14.7 g of 4-chloro-6-(bromomethyl)-2-(2-nitrophenyl)quinoline.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[N:9]=[CH:10][C:5]2=[C:4]([NH:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:3]=1.[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24](B2OC(C)(C)C(C)(C)O2)=[N:23]1>>[NH:22]1[C:30]2[C:25](=[C:26]([C:2]3[N:7]=[C:6]4[N:8]([CH3:11])[N:9]=[CH:10][C:5]4=[C:4]([NH:12][CH2:13][CH2:14][O:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:3]=3)[CH:27]=[CH:28][CH:29]=2)[CH:24]=[N:23]1
Reactant: Cn1ncc2c(NCCOc3ccccc3)nc(Cl)nc21
Reactant: CC1(C)OB(c2n[nH]c3ccccc23)OC1(C)C
Product: Cn1ncc2c(NCCOc3ccccc3)nc(-c3cccc4[nH]ncc34)nc21

Procedure:
(6-Chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-(2-phenoxy-ethyl)-amine was reacted with indazole boronic acid pinacol ester in General Procedure A. Purification by preparative HPLC yielded 143. NMR (CDCl3) 4.19 (s, 3H, CH3), 4.27 (m, 2H, CH2), 4.36 (m, 2H, CH3), 5.83 (sbr, H, NH), 7.00 (m, 3H, 3×ArH), 7.32 (m, 2H, 2×ArH), 7.55 (m, H, ArH), 7.64 (m, H, ArH), 7.96 (s, H, ArH), 8.45 (d, H, ArH, J=7.23 Hz0, 9.18 (s, H, ArH), 10.16 (sbr, H, NH). MS: (ESI+) MEI+=386.19
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([CH3:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:45])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]2[C:35]([CH2:36][O:37]C3CCCCO3)=[CH:34][N:33]=[N:32]2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:37][CH2:36][C:35]1[N:31]([C:27]2[CH:26]=[C:25]([C:24]3[CH2:23][C:22](=[O:45])[NH:21][C:9]4[CH:10]=[C:11]([CH3:20])[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])=[CH:13][C:8]=4[N:7]=3)[CH:30]=[CH:29][CH:28]=2)[N:32]=[N:33][CH:34]=1
Reactant: Cc1cc(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)c(NC(=O)OC(C)(C)C)cc1N(C)CC(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2c(cc1N(C)CC(C)C)N=C(c1cccc(-n3nncc3CO)c1)CC(=O)N2

Procedure:
The title compound was prepared from (RS)-[5-(isobutyl-methyl-amino)-4-methyl-2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionylamino)-phenyl]-carbamic acid tert-butyl ester (Example M108) (0.33 g, 0.52 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a pale brown solid (188 mg, 79%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH2:7]O)[CH:6]=1.S(Cl)([Cl:11])=O>ClCCl>[ClH:1].[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH2:7][Cl:11])[CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: OCn1cc(Cl)cn1
Solvent: ClCCl
Product: Cl
Product: ClCn1cc(Cl)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.73 g of 4-chloro-1H-pyrazole-1-ylmethanol was dissolved to 20 ml of dichloromethane. 4.4 ml of thionyl chloride was added to the solution, followed by stirring at room temperature for overnight. The reaction mixture was concentrated under reduced pressure to obtain 2.90 g of 4-chloro-1-(chloromethyl)-1H-pyrazole hydrochloride.