Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[NH:18][C:17]3=[O:25])[CH2:12][CH2:11]2)[CH3:9])[CH2:3][CH2:2]1.[C:26](O)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[N:29][CH:28]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[OH-].[Na+]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[N:29]1[CH:30]=[CH:31][CH:32]=[C:27]([C:26]([N:1]2[CH2:6][CH2:5][CH:4]([CH2:7][CH:8]([N:10]3[CH2:15][CH2:14][CH:13]([N:16]4[C:20]5[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=5[NH:18][C:17]4=[O:25])[CH2:12][CH2:11]3)[CH3:9])[CH2:3][CH2:2]2)=[O:33])[CH:28]=1
Reactant: O=C(O)c1cccnc1
Reactant: CC(CC1CCNCC1)N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(CC1CCN(C(=O)c2cccnc2)CC1)N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Reaction time: 8 h
Yield: 79.7 %

Procedure:
To 9.7 mg of 1-[1-[2-(piperidin-4-yl)-1-methylethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one which was synthesized by the method of Production Example 6, 1 ml of chloroform, 4.4 mg of nicotinic acid, 8 mg of 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride, 6.4 mg of 1-hydroxybenzotriazole and 0.01 ml of triethylamine were added and stirred for an overnight. To the reaction liquid 1N aqueous sodium hydroxide solution and chloroform were added to separate the reaction liquid. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was purified on silica gel chromatography (chloroform/methanol=11:1) to provide 10.1 mg of the title compound as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[CH:10]=2)=[O:7])=[CH:4][CH:3]=1.FC1C=CC(NC(=O)C2C=CC=C(C(F)(F)F)C=2)=CC=1[N+]([O-])=O>>[Br:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[CH:10]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Nc1cccc([N+](=O)[O-])c1)c1ccc(Br)cc1
Agent: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1cccc(C(F)(F)F)c1
Product: Nc1cccc(NC(=O)c2ccc(Br)cc2)c1
Yield: 80 %

Procedure:
The title compound was prepared according to the procedure of Example 114B substituting the product from Example 117A for the product from Example 114A to provide the title product (1.8 g, 80%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:4]=1[O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][C:16]([N:18]([CH3:20])[CH3:19])=[O:17])[N:10]=[CH:9]2.ClC(Cl)(Cl)C[O:29][C:30](=O)[NH:31][C:32]1[N:33]([C:41]2[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=2)[N:34]=[C:35]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:36]=1.CCN(C(C)C)C(C)C.CO>CN(C=O)C.ClCCl>[C:37]([C:35]1[CH:36]=[C:32]([NH:31][C:30](=[O:29])[NH:1][CH2:2][C:3]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:4]=2[O:5][C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[N:11]([CH2:15][C:16]([N:18]([CH3:20])[CH3:19])=[O:17])[N:10]=[CH:9]3)[N:33]([C:41]2[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=2)[N:34]=1)([CH3:40])([CH3:38])[CH3:39]
Reactant: CN(C)C(=O)Cn1ncc2cc(Oc3ccc(F)cc3CN)ccc21
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)NCc2cc(F)ccc2Oc2ccc3c(cnn3CC(=O)N(C)C)c2)cc1
Temperature: 80 °C
Yield: 36.3 %

Procedure:
To a solution of 2-[5-(2-aminomethyl-4-fluoro-phenoxy)-indazol-1-yl]-N,N-dimethylacetamide (46d) (0.010 g, 0.029 mmol) and (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloroethyl ester (0.013 g, 0.032 mmol) in DMF (1 mL) was added DIEA (0.01 mL, 0.058 mmol). The mixture was heated to 80° C. for 18 hours under N2 atmosphere. The mixture was concentrated under reduced pressure and dissolved in dichloromethane. The solution was washed with 1N HCl, filtered, and concentrated under reduced pressure. The oil was chromatographed eluting with dichloromethane/ether (10:1) and then 5% MeOH in dichloromethane to afford 6.3 mg of pale yellow oil (36% yield). MS (APCI+) m/z 598 (M+1) detected; 1H NMR (400 mHz, DMSO-D6) δ 8.29 (s, 1H), 7.97 (s, 1H), 7.58 (d, 1H), 7.36 (d, 2H), 7.28 (d, 2H), 7.19 (d, 1H), 7.12 (d, 1H), 7.07 (m, 2H), 6.99 (m, 1H), 6.84 (m, 1H), 6.24 (s, 1H), 5.40 (s, 2H), 4.28 (d, 2H), 3.10 (s, 3H), 2.84 (s, 3H), 2.35 (s, 3H), 1.25 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH:6](O)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1.S(=O)(=O)(O)O.C(OCC)(=O)C>O>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:20]2[CH:21]=[CH:22][C:17](=[O:16])[NH:18][CH:19]=2)=[CH:4][CH:3]=1
Reactant: OC(c1ccccc1)c1ccc(Cl)cc1
Reactant: Oc1ccccn1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: O
Product: O=c1ccc(C(c2ccccc2)c2ccc(Cl)cc2)c[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Combine 109.3 g. (0.5 mole) of 4-chlorobenzhydrol with 142.7 g. (1.5 mole) of 2-hydroxypyridine and heat at 150° C. with stirring until molten. Add about 2 ml. of concentrated sulfuric acid and continue heating to 240°-250° C. while removing water from the reaction mixture. Permit the reaction to continue for about 2 hours, then cool the reaction mixture to about 25° C. Treat the resulting solid with ethyl acetate and water and filter to remove the undesired 3-(4-chlorophenyl-phenylmethyl)-2-pyridone. The organic layer is separated and washed with water several times and dried over potassium carbonate and filtered. Concentrate the filtrate to half volume and filter to remove the remaining 3-substituted-2-pyridone. Evaporate the filtrate and dissolve the residue in ethyl ether. Upon standing overnight the 5-(4-chlorophenyl-phenylmethyl)-2-pyridone crystallizes, yield 60 g., m.p. 164°-169° C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Br:9][C:10]1[CH:11]=[C:12]([O:17][C:18]2[C:23]([F:24])=[C:22]([CH3:25])[CH:21]=[CH:20][C:19]=2[Cl:26])[CH:13]=[C:14]([Cl:16])[CH:15]=1>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:9][C:10]1[CH:11]=[C:12]([O:17][C:18]2[C:23]([F:24])=[C:22]([CH2:25][Br:1])[CH:21]=[CH:20][C:19]=2[Cl:26])[CH:13]=[C:14]([Cl:16])[CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2)c1F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1c(CBr)ccc(Cl)c1Oc1cc(Cl)cc(Br)c1
Temperature: 90 °C
Reaction time: 4 h
Yield: 81.8 %

Procedure:
N-bromosuccinimide (1.95 g, 10.94 mmol) was added to a solution of 2-[(3-bromo-5-chlorophenyl)oxy]-1-chloro-3-fluoro-4-methylbenzene (3.20 g, 9.12 mmol) in CCl4 (300 mL) at RT. The solution was heated to 90° C. for 5 min under N2 and AIBN (0.070 g, 0.46 mmol) was added. After 4 h, more AIBN (0.070 g, 0.46 mmol) was added and the solution was heated at 90° C. for an additional 2 h. The solution was cooled to 0° C., filtered through Celite and concentrated. The yellow oil was purified by column chromatography (0% to 30% EtOAc/hexanes gradient) to afford the title compound (3.2 g, 60%) as a clear oil 1H NMR (400 MHz, DMSO-d6): δ ppm 7.58-7.49 (m, 3H), 7.13-7.12 (m, 1H), 7.06-7.05 (m, 1H), 4.73 (s, 2H). In addition, 2.25 g (48%) of the di-brominated material, 12-[(3-bromo-5-chlorophenyl)oxy]-1-chloro-4-(dibromomethyl)-3-fluorobenzene was also obtained as a clear oil. 1H NMR (400 MHz, DMSO-d6): δ ppm 7.72-7.68 (m, 1H), 7.61 (dd, 1H), 7.51 (t, 1H), 7.47 (s, 1H), 7.19-7.18 (m, 1H), 7.11 (t, 1H).
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:4]=[O:5].[CH3:15][Mg]Br.CO.[NH4+].[Cl-]>C1COCC1>[OH:5][CH:4]([C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:2]([CH3:14])[CH3:1])[CH3:15]
Reactant: C[Mg]Br
Reactant: CC(C)[C@H](C=O)NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(C)O
Temperature: 0 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
(R)-tert-butyl 3-methyl-1-oxobutan-2-ylcarbamate (2.5 g, 12.42 mmol) was dissolved in THF (50 mL) and cooled to 0° C. Methyl magnesium bromide (17.0 mL, 51.0 mmol, 3.0 M in diethyl ether) was carefully added via syringe. The reaction was allowed to warm to ambient temperature and left stirring overnight. The cloudy mixture was chilled to 0° C., quenched with methanol (3.0 mL, 74.0 mmol), followed by the addition of 200 mL saturated NH4Cl solution, and extracted twice with 200 mL MTBE. The organic phase was washed with 200 mL brine, dried over Na2SO4, filtered, and concentrated to provide the title compound (2.484 g, 11.43 mmol, 92% yield) as a yellow oil. MS (DCI+) m/z 218.1 (M+H).
Reaction SMILES: [F:1][C:2](=[C:8]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[O:17][C:16]([CH3:24])([CH3:23])[CH:15]=[C:14]2[C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:9][CH3:10])[C:3](OCC)=[O:4].F/C(=C(/C1C=C2C(=CC=1OC)OC(C)(C)C=C2C(C)(C)C)\CC)/C(OCC)=O.[H-].C([Al+]CC(C)C)C(C)C>>[C:25]([C:14]1[C:13]2[C:18](=[CH:19][C:20]([O:21][CH3:22])=[C:11](/[C:8](/[CH2:9][CH3:10])=[C:2](/[F:1])\[CH2:3][OH:4])[CH:12]=2)[O:17][C:16]([CH3:23])([CH3:24])[CH:15]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CCOC(=O)C(F)=C(CC)c1cc2c(cc1OC)OC(C)(C)C=C2C(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: CCOC(=O)/C(F)=C(/CC)c1cc2c(cc1OC)OC(C)(C)C=C2C(C)(C)C
Agent: [H-]
Product: CC/C(=C(\F)CO)c1cc2c(cc1OC)OC(C)(C)C=C2C(C)(C)C

Procedure:
Following General Procedure L, ethyl 2-fluoro-3-(4-tert-butyl-7-methoxy-2,2-dimethyl-2H-chromen-6-yl)-pent-2-enoate (Compound 79, 90 mg, 0.23 mmol) and diisobutylaluminum hydride (1 M in dichloromethane, 0.7 mL, 0.7 mmol) were reacted to give the title compound as yellow solid after purification by flash chromatography (silica gel, 1:4 ethyl acetate/hexane).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][NH2:12].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[CH2:13]([NH:12][CH2:11][CH:2]1[O:1][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCC1COc2ccccc2O1
Reactant: O=Cc1ccccc1
Solvent: ClCCl
Product: c1ccc(CNCC2COc3ccccc3O2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
A mixture of (2,3-dihydro-1,4-benzodioxin-2-yl)methylamine (4.13 g), benzaldehyde (2.65 g) and methylene chloride (25 ml) is stirred for 3 hours at room temperature and the methylene chloride removed via evaporation. A solution of the residue in ethanol (30 ml) is hydrogenated at atmospheric pressure and room temperature in the presence of methanesulphonic acid (2.4 g) and 10% palladium on charcoal (0.4 g). After the calculated quantity of hydrogen is consumed (510 ml), the solution is filtered, the ethanol is removed via evaporation, the residue is made alkaline with saturated aqueous potassium carbonate, and the resulting solution is extracted with ether. Evaporation of the dried ether extract yields an oily residue of N-benzyl-(2,3-dihydro-1,4-benzodioxin-2-yl)methylamine (5.9 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9](=[O:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH:20]1[CH2:22][CH2:21]1>CC(C)=O>[CH:20]1([CH2:19][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=2[C:9](=[O:11])[CH3:10])[CH2:22][CH2:21]1
Reactant: BrCC1CC1
Reactant: CC(=O)c1c(O)cccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)c1c(O)cccc1OCC1CC1
Temperature: 50 °C
Reaction time: 48 h
Yield: 83.2 %

Procedure:
To a stirred solution of 1-(2,6-dihydroxyphenyl)ethanone (50.0 g, 328 mmol) in acetone (1000 mL) was added potassium carbonate (227 g, 1643 mmol) and (bromomethyl)cyclopropane (35.1 mL, 361 mmol). The mixture was stirred at 50° C. for 2 days. The reaction mixture was filtrated on celite, and then the filtrate was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The separated organic phase was washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was suspended in hexane. Then the suspension was stirred at 80° C. for 30 minuets. The solution was filtered and the filtrate was allowed to cool to room temperature. The resulting white solid was collected by filtration, washed with hexane, and dried under reduced pressure to give 1-{2-[(cyclopropylmethyl)oxy]-6-hydroxyphenyl}ethanone as a pale yellow solid (56.3 g, yield; 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([N:21]1[CH2:30][C@H:29]([O:31][CH2:32][CH2:33][C:34]#[N:35])[CH2:28][C@H:22]1[C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20].[CH3:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[C:40]([O:48][C:49]([F:52])([F:51])[F:50])[CH:39]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:44]([C:41]1[CH:42]=[CH:43][C:38]([O:37][CH3:36])=[CH:39][C:40]=1[O:48][C:49]([F:50])([F:51])[F:52])(=[O:46])=[O:45])[C:6](=[O:11])[C:5]2([N:21]1[CH2:30][C@H:29]([O:31][CH2:32][CH2:33][C:34]#[N:35])[CH2:28][C@H:22]1[C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20]
Reactant: COc1ccc(C)cc1C1(N2C[C@H](OCCC#N)C[C@H]2C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC(F)(F)F)c1
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(C)ccc3OC)(N3C[C@H](OCCC#N)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Yield: 66.2 %

Procedure:
With 720 mg of the compound obtained in Step 143-4 and 506 mg of 4-methoxy-2-(trifluoromethoxy)benzene sulfonyl chloride as starting materials, 720 mg of the title compound (amorphous) was obtained by a similar procedure to Example 2.
Reaction SMILES: [Br:1][C:2]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([CH3:11])=[CH:5][C:3]=1[NH2:4].O[CH2:13][CH:14]([CH2:16]O)O.O=[As](O[As](=O)=O)=O.S(=O)(=O)(O)O>O.N>[Br:1][C:2]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([CH3:11])=[C:5]2[C:3]=1[N:4]=[CH:16][CH:14]=[CH:13]2
Reactant: OCC(O)CO
Reactant: Cc1cc(N)c(Br)c(C)c1C
Agent: N
Agent: O=S(=O)(O)O
Agent: O=[As](=O)O[As](=O)=O
Solvent: O
Product: Cc1c(C)c(Br)c2ncccc2c1C
Temperature: 100 °C

Procedure:
2-Bromo-3,4,5-trimethylaniline (10.4 g), glycerol (4 equiv) and arsenic oxide (0.75 equiv) were stirred and heated to 100° C. Concentrated sulfuric acid (60% w/w of the glycerol) was added to the mixture dropwise. After heating at 130° C. for 4 hr, the cooled mixture was diluted with water and neutralised with aqueous ammonia. The solid was filtered off, washed with water and dried in air. Purification by column chromatography over alumina with dichloromethane elution gave 8-bromo-5,6,7-trimethylquinoline as a white solid, mp 180° C. Pmr spectrum (CDCl3 ; δ in ppm): 2.50 (3H,s); 2.61 (3H,s); 2.74 (3H,s); 7.37-8.98 (3H,m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[C:5]([NH:7][C:8]1[CH:9]=[N:10][C:11]([O:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH2:17][CH2:18][C:19]3=[O:24])=[CH:12][CH:13]=1)=[O:6].[BH4-].[Na+].CC(C)=O>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[C:5]([NH:7][C:8]1[CH:9]=[N:10][C:11]([O:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH2:17][CH2:18][CH:19]3[OH:24])=[CH:12][CH:13]=1)=[O:6]
Reactant: O=C(Nc1ccc(Oc2cccc3c2CCC3=O)nc1)c1ccc(Cl)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Oc2cccc3c2CCC3O)nc1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.6 %

Procedure:
After 413 mg of 3,4-dichloro-N1-{6-[(1-oxo-2,3-dihydro-1H-inden-4-yl)oxy]-3-pyridinyl}benzamide was dissolved in a mixed solvent of 4 ml of tetrahydrofuran and 1 ml of water, 23 mg of sodium tetrahydroborate was added and the mixture was stirred at room temperature. After 4 hours, acetone was added to the reaction solution to decompose excess sodium tetrahydroborate. Then, water was added and the solution was extracted with ethyl acetate. The organic (ethyl acetate) layer was washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. To the resulting oily substance, diethyl ether was added and the deposited crystal was isolated by filtration to obtain 289 mg of the titled compound.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][C@@H:18]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:19](O)=[O:20])(=[O:16])=[O:15])=[CH:10][CH:9]=1>C1COCC1>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([S:14]([NH:17][C@@H:18]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:19][OH:20])(=[O:15])=[O:16])=[CH:12][CH:13]=1
Reactant: O=C(O)[C@@H](NS(=O)(=O)c1ccc(Cl)cc1)C1CCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=S(=O)(N[C@H](CO)C1CCCCC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 37.4 %

Procedure:
To a solution of LAH (1.0 M in THF, 1.5 mL, 1.5 mmol) was added dropwise at 0° C. a solution of (αS)-α-[[(4-chlorophenyl)sulfonyl]amino]cyclohexaneacetic acid (0.50 g, 1.507 mmol) in THF (8.0 mL). After the addition was complete, the reaction mixture was allowed to warm to 25° C. After 24 hours, the reaction was quenched by sequential addition of H2O (60 μL), 15% NaOH (60 μL) and H2O (180 μL). The precipitate was filtered and washed with THF. The combined THF solution was evaporated to a clear oil which afforded a white solid after washing with hexane. This white solid was purified by flash chromatography (eluant: 1-1 hexane/ethyl acetate), washed with hexane and pumped on to afford 0.179 g (37%) of the desired product as a white solid, mp 115-118° C. Mass Spectrum (+APCI): 318 ([M+H]+). Anal: Calc'd for C14H20ClNO3S: C, 52.91; H, 6.34; N, 4.41. Found: C, 52.16; H, 6.25; N, 4.40.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:25])[C:8]2[CH:9]=[C:10]3[CH:21]=[C:20]([F:22])[C:19](F)=[C:18]([F:24])[C:11]3=[N:12][C:13]=2[N:14]([CH2:16][CH3:17])[CH:15]=1)=[O:5])[CH3:2].[NH:26]1[CH2:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:25])[C:8]2[CH:9]=[C:10]3[CH:21]=[C:20]([F:22])[C:19]([N:26]4[CH2:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)=[C:18]([F:24])[C:11]3=[N:12][C:13]=2[N:14]([CH2:16][CH3:17])[CH:15]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(CC)c2nc3c(F)c(F)c(F)cc3cc2c1=O
Reactant: C1CNCCNC1
Product: CCOC(=O)c1cn(CC)c2nc3c(F)c(N4CCCNCC4)c(F)cc3cc2c1=O
Yield: 46.1 %

Procedure:
The 7,9-difluoro-3-ethoxycarbonyl-1-ethyl-4-oxo-8-(perhydro-1,4-diazepin-1-yl)-1,4-dihydrobenzo[b][1,8]naphthyridine was prepared under the conditions of Example 5, but starting from 3 g of 3-ethoxycarbonyl-1-ethyl-7,8,9-trifluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine and 2 g of hexahydro-1,4-diazepine. 1.7 g of 3-ethoxycarbonyl-1-ethyl-7,9-difluoro-4-oxo-8-(perhydro-1,4-diazepin-1-yl)-1,4-dihydro-benzo[b][1,8]naphthyridine are obtained in the form of a yellow solid melting at 190° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([Cl:11])[CH:3]=1.C(N(CC)C(C)C)(C)C.CN([C:24]([O:28][N:29]1N=NC2C=CC=C[C:30]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN(C)O>CN(C=O)C.CCOCC>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:29]([O:28][CH3:24])[CH3:30])=[O:7])=[C:4]([Cl:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1Cl
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN(C)O
Agent: F[B-](F)(F)F
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
To a solution of 4-bromo-2-chlorobenzoic acid (2.00 g, 8.50 mmol) in DMF (20 ml) was added N,N-diisopropylethyl amine (3.18 ml, 18.69 mmol) followed by TBTU (3.00 g, 9.34 mmol) followed by dimethylhydroxylamine (829 mg, 8.50 mmol). The reaction mixture was stirred at rt overnight and then diluted with ether and the organic layer was washed with water, 1N HCl, sat. NaHCO3, and brine. The organic layer was then dried (MgSO4), filtered and concentrated in vacuo to give a residue which was purified by flash column chromatography to give 4-bromo-2-chloro-N-methoxy-N-methylbenzamide (2.27 g, 96%) as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ 7.59 (d, J=1.5 Hz, 1H), 7.45 (dd, J=1.5, 8.0 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 3.48 (br s, 3H), 3.38 (br s, 3H).
Reaction SMILES: [CH2:1]([Li])CCC.[CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]=1[C:16]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]=1[C:16](=[CH2:1])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)CCCCCCC(=O)c1ccc2ccccc2c1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C(CCCCCCC(=O)OCC)c1ccc2ccccc2c1
Reaction time: 0.33 h
Yield: 52.9 %

Procedure:
To a solution of methyltriphenylphosphonium bromide (469 mg,1.31 mmol) in THF (6 mL) pre-cooled to 0° C. under nitrogen atmosphere was added dropwise n-butyllithium (1.42M solution in hexanes, 905 μL, 1.28 mmol) and stirred over 20 minutes. To this a THF (4mL) solution of 49g (82 mg, 0.262 mmol) was transferred via cannula. The yellow mixture was stirred over 30 minutes and quenched with a saturated aqueous solution of ammonium chloride, as the yellow color immediately disappeared. The solvent was removed by evaporation in vacuo and the aqueous residue was partitioned between water and ethyl acetate. The aqueous layer was then extracted with ethyl acetate and the combined organic layers were washed with brine, dried (MgSO4) and concentrated. The crude residue was purified by flash chromatography (5% to 8% diethyl ether in hexane) to afford the title compound 168 (43 mg) in 52% yield. 1H NMR: (CDCl3) δ: 7.85-7.78 (m, 4H), 7.58 (dd, J=8.8, 1.9 Hz, 1H), 7.48-7.44 (m, 2H), 5.42 (d, J=1.1 Hz, 1H), 5.16 (d, J=1.4 Hz, 1H), 4.12 (q, J=7.1 Hz, 2H), 2.62 (t, J=6.9 Hz, 2H), 2.28 (d, J=7.4 Hz, 2H), 1.64-1.49 (m, 4H), 1.39-1.33 (m, 4H), 1.25 (t, J=7.1 Hz, 3H). MS (ESI)=311 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH:8](O)[CH3:9])[CH:5]=[CH:4][N:3]=1.C(N(S(F)(F)[F:17])CC)C>ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([CH:8]([F:17])[CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(O)c1ccnc(Cl)n1
Solvent: ClCCl
Product: CC(F)c1ccnc(Cl)n1
Reaction time: 3 h
Yield: 49.2 %

Procedure:
To a solution of 1-(2-chloropyrimidin-4-yl)ethanol (150 mg, 0.950 mmol) in dichloromethane (3 mL) at 0° C. was added diethylaminosulfur trifluoride (183 mg, 1.14 mmol) dropwise and stirred for 3 hr. The solution was diluted with dichloromethane, washed with saturated aqueous NaHCO3, dried with MgSO4, and concentrated to dryness. Purification on silica gel by flash chromatography (0-50% EtOAc/hexanes) afforded 2-chloro-4-(1-fluoroethyl)pyrimidine (75 mg, 0.467 mmol, 49% yield) as a yellow oil. MS ESI: [M+H]+ m/z 161.0. 1H NMR (500 MHz, CDCl3) δ 8.67 (d, J=4.2, 1H), 7.46 (d, J=4.2, 1H), 5.58 (dq, J=6.7, 48, 1H), 1.74-1.57 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:7][CH:6]([CH3:8])[CH2:5][CH:4]([CH2:9][C:10]([O:12]CC)=[O:11])[CH2:3]1.[OH-].[Na+].S(=O)(=O)(O)O>O>[CH3:15][C:2]1([CH3:1])[CH2:7][CH:6]([CH3:8])[CH2:5][CH:4]([CH2:9][C:10]([OH:12])=[O:11])[CH2:3]1
Reactant: CCOC(=O)CC1CC(C)CC(C)(C)C1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1CC(CC(=O)O)CC(C)(C)C1
Yield: 83 %

Procedure:
875 g of ethyl 3,3,5-trimethyl-cyclohexylacetate are treated in 2.2 l of water with 670 g of 30% sodium hydroxide and the mixture is held at reflux temperature for 21/2 hours while stirring. After cooling, the mixture is neutralized, acidified with 420 g of 63% sulphuric acid and extracted with cyclohexane. The cyclohexane extract is washed neutral, evaporated and the 770 g of crude product are distilled. There are obtained 630 g of 3,3,5-trimethyl-cyclohexylacetic acid. (Yield: 82%).