Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([CH2:8][OH:9])=[N:6][CH:7]=1.C(N(CC)CC)C.[C:18]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])([CH3:20])[CH3:19]>CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([CH2:8][O:9][Si:22]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:24])[CH3:23])=[N:6][CH:7]=1
Reactant: Cc1cc(Br)cnc1CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Br)cnc1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.5 %

Procedure:
To a solution of 5-bromo-2-hydroxymethyl-3-methylpyridine (1 g, 5 mmol) in N,N-dimethylformamide (50 mL) was added triethylamine (1.56 mL, 15 mmol) and tert-butylchlorodimethylsilane (1.13 g, 7.5 mmol). The mixture was stirred at room temperature for 4 hours, diluted with water (50 mL) and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to give the title compound as a colorless oil (1.51 g, yield 100%).
Reaction SMILES: F[B-](F)(F)F.C([O+](CC)CC)C.[CH3:13][NH:14][C:15](=O)[CH2:16][CH2:17][C:18]1([CH3:31])[C:23]2[CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=3[C:22]=2[CH2:21][CH2:20][O:19]1>C(Cl)Cl>[CH3:13][NH:14][CH2:15][CH2:16][CH2:17][C:18]1([CH3:31])[C:23]2[CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=3[C:22]=2[CH2:21][CH2:20][O:19]1
Reactant: CNC(=O)CCC1(C)OCCC2=C1Cc1ccccc12
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CNCCCC1(C)OCCC2=C1Cc1ccccc12
Reaction time: 18 h

Procedure:
A solution of triethyloxonium fluoroborate (3.5 g) and the amide of formula X, N,1-dimethyl-1,3,4,9-tetrahydroindeno[2,1-c]pyran-1-propionamide (5.5 g), described in Example 108, in 100 ml of methylene chloride is evaporated at reduced pressure and the residue dissolved in 50 ml of absolute ethanol. Sodium borohydride (1.35 g) is added in portions to the stirred solution at 0° C. When the addition is complete, stirring is continued for 18 hr. at 25° C. The solution is poured into 250 ml of water and extracted with 3 × 30 ml portions of ether. The combined extracts are washed with water, dried (MgSO4) and evaporated yielding the title compound, identical to the product of Example 285.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][NH:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[OH:25][C@H:26]1[CH2:31][CH2:30][C@H:29]([C:32](O)=[O:33])[CH2:28][CH2:27]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][N:14]([C:32]([CH:29]3[CH2:30][CH2:31][CH:26]([OH:25])[CH2:27][CH2:28]3)=[O:33])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: O=C(O)[C@H]1CC[C@H](O)CC1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CNC[C@H]1c1ccc(Cl)cc1
Product: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCC(O)CC2)C[C@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 44 (step c), the title compound [(3S,4R)-4-(4-Chloro-phenyl)-1-(4-hydroxy-cyclohexanecarbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester was prepared from [(3S,4R)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester instead of rac-[(3S,4R)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester using trans-4-hydroxycyclohexanecarboxylic acid instead of 1-methylcyclopropane-1-carboxylic acid and was obtained as an off-white foam. MS m/e: 475.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=[O:10].[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9](=[O:10])[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccc(F)cc1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccc(F)cc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 125 mg of (2-Amino-5-chloro-phenyl)-(4-fluoro-phenyl)-methanone and 116 mg of 4-tert-butyl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 1.21 (s, 9H), 7.09 (t, 2H, J=8.8 Hz), 7.29 (m, 3H), 7.43-7.50 (m, 3H), 7.59 (m, 2H), 7.77 (d, 1H, J=8.8 Hz), 9.72 (s, 1H). MS: m/z 446.0 (M++1).
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:12]([C:14]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:15]=1[C:16](O)=[O:17])[CH3:13]>>[CH2:12]([C:14]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:15]=1[C:16]([NH:11][C@@H:7]1[CH2:8][CH2:9][CH2:10][C@@H:6]1[N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:17])[CH3:13]
Reactant: CCc1cccc(C)c1C(=O)O
Reactant: N[C@@H]1CCC[C@@H]1N1CCCC1
Product: CCc1cccc(C)c1C(=O)N[C@@H]1CCC[C@@H]1N1CCCC1

Procedure:
The title compound, white solid, MS: m/e=301.3 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclopentylamine (intermediate Q) and 2-ethyl-6-methylbenzoic acid (CAS 106976-50-5).
Reaction SMILES: ClC1C=CC(OS([N:10]=C=O)(=O)=O)=CC=1.[O:15]=[C:16]1[C:21]2[CH:22]=[C:23]3[C:28](=[C:29]([CH2:30][CH2:31][CH3:32])[C:20]=2[O:19][C:18]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:17]1)[NH:27][C:26]([C:33]([O:35][CH3:36])=[O:34])=[CH:25][C:24]3=O.Cl>C(#N)C>[NH2:10][C:24]1[C:23]2[C:28](=[C:29]([CH2:30][CH2:31][CH3:32])[C:20]3[O:19][C:18]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:17][C:16](=[O:15])[C:21]=3[CH:22]=2)[N:27]=[C:26]([C:33]([O:35][CH3:36])=[O:34])[CH:25]=1
Reactant: O=C=NS(=O)(=O)Oc1ccc(Cl)cc1
Reactant: CCCc1c2[nH]c(C(=O)OC)cc(=O)c2cc2c(=O)cc(C(=O)OCC)oc12
Agent: Cl
Solvent: CC#N
Product: CCCc1c2nc(C(=O)OC)cc(N)c2cc2c(=O)cc(C(=O)OCC)oc12

Procedure:
4-Chlorophenoxysulphonylisocyanate (0.2 ml, 290 mg) was added to a suspension of ethyl 6,9-dihydro-4,6-dioxo-8-methoxycarbonyl-10-propyl-4H-pyrano[3,2-g] quinoline-2-carboxylate (385 mg, 1 mmol) in acetonitrile (5 ml), and then refluxed for 0.5 h. The solution was allowed to cool, ethanolic hydrogen chloride solution (2 ml) was added, and after 5 minutes the pale yellow solution was poured into aqueous ammonial solution (0.88 specific gravity, 5 ml) at 5° C., to give a thick orange precipitate. Filtration and washing with ethanol (10 ml) gave the title compound, 320 mg (83%) as an orange powder, mp 268°-270° C. (decomposes).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]=[C:7]([C:9](=O)[CH2:10][C:11](=O)[CH:12]([F:14])[F:13])[S:8][C:4]=2[CH:3]=1.Cl.[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([NH:30][NH2:31])=[CH:26][CH:25]=1)(=[O:23])=[O:22]>>[F:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]=[C:7]([C:9]3[N:30]([C:27]4[CH:26]=[CH:25][C:24]([S:21]([CH3:20])(=[O:23])=[O:22])=[CH:29][CH:28]=4)[N:31]=[C:11]([CH:12]([F:14])[F:13])[CH:10]=3)[S:8][C:4]=2[CH:3]=1
Reactant: O=C(CC(=O)C(F)F)c1nc2ccc(F)cc2s1
Reactant: CS(=O)(=O)c1ccc(NN)cc1
Agent: Cl
Product: CS(=O)(=O)c1ccc(-n2nc(C(F)F)cc2-c2nc3ccc(F)cc3s2)cc1
Yield: 65 %

Procedure:
The procedure of Example 9 was repeated using 1-(6-fluorobenzothiazol-2-yl)-4,4-difluorobutane-1,3-dione and 4-methylsulfonylphenylhydrazine hydrochloride as the starting materials to obtain 6-fluoro-2-[1-(4-methylsulfonylphenyl)-3-difluoromethyl-1H-pyrazol-5-yl]benzothiazole (yield, 65%). NMR(DMSO-d6) δ: 3.30 (3H, s), 7.23 (1H, t, J=54.1 Hz), 7.38-7.46 (1H, m), 7.56 (1H, s), 7.83-7.88 (2H, m), 7.94-7.99 (1H, m), 8.05-8.13 (3H, m); mp 204-206° C. (ethanol)
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:24][C:25](Br)=[O:26].[CH2:28]([O:30][C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH2:33][NH2:34])[CH3:29]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][N:8]2[CH2:24][C:25]([NH:34][CH2:33][C:32]2[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=2[O:30][CH2:28][CH3:29])=[O:26])=[CH:21][CH:22]=1
Reactant: O=C(Br)CBr
Reactant: COc1cc2c(cc1OC)C(Cc1ccc(Cl)cc1)NCC2
Reactant: CCOc1ccccc1CN
Product: CCOc1ccccc1CNC(=O)CN1CCc2cc(OC)c(OC)cc2C1Cc1ccc(Cl)cc1

Procedure:
prepared by reaction of 1-(4-Chloro-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-ethoxy-benzylamine
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([C:9](=[N:16][O:17][CH2:18][C:19]2[N:24]=[C:23]([NH2:25])[CH:22]=[CH:21][CH:20]=2)[C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C([O-])(O)=O.[Na+]>[CH2:26]([NH:25][C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:18][O:17][N:16]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([S:2][CH3:1])[CH:4]=2)[C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)[N:24]=1)[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCC=O
Reactant: CSc1cccc(C(=NOCc2cccc(N)n2)c2nnnn2C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCNc1cccc(CON=C(c2cccc(SC)c2)c2nnnn2C)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 69 %

Procedure:
To a stirred solution of 6-{[({[3-(methylsulfanyl)phenyl](1-methyl-1H-tetrazol-5-yl)methylene}amino)oxy]methyl}pyridin-2-amine (134 mg, 0.38 mmol) in dry dichloromethane (5 mL) were added capronaldehyde (52.9 mg, 0.53 mmol) and sodium triacetoxyborohydride (151 mg, 0.68 mmol) at room temperature. After stirring at room temperature for 20 h, the reaction mixture was diluted with dichloromethane (10 mL) and aq. NaHCO3 (10 g/L, 10 mL) was added. After phase separation, the organic layer was washed with water, dried over MgSO4 and concentrated in vacuo. Purification on silica gel afforded N-hexyl-6-{[({[3-(methylsulfanyl)phenyl](1-methyl-1H-tetrazol-5-yl)methylene}amino)oxy]methyl}pyridin-2-amine as a colourless oil [115 mg, yield 69%; HPLC/MS: m/z=440 (M+H); logP(HCOOH)=2.78].
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:14](O)[CH3:15])[CH:11]=2)[CH2:6]1)(=[O:3])[CH3:2].S(Cl)([Cl:19])=O>C(Cl)Cl>[C:1]([NH:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:14]([Cl:19])[CH3:15])[CH:11]=2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)NC1Cc2ccc(C(C)O)cc2C1
Solvent: ClCCl
Product: CC(=O)NC1Cc2ccc(C(C)Cl)cc2C1
Reaction time: 1 h

Procedure:
25 g (0.11 mol) of 1-(2-acetamido-indan-5-yl)-1-ethanol are suspended in 280 ml of methylene chloride, and 15 g (0.12 mol) of thionyl chloride are added. A clear solution is formed. After 1 hour, this solution is neutralised by washing with a saturated solution of sodium bicarbonate. The desired reaction product is obtained after drying and evaporating.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:16]([C:19]2(OC)[C@H:24]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@@H:23]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C@H:22]([O:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C@@H:21]([CH2:49][O:50][CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[O:20]2)=[CH:15][C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[O:11][CH2:10][CH2:9][CH2:8]2.C([SiH](CC)CC)C.B(F)(F)F>C(#N)C.ClCCl>[Br:1][C:2]1[CH:18]=[CH:17][C:16]([CH:19]2[C@H:24]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@@H:23]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C@H:22]([O:41][CH2:42][C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[C@@H:21]([CH2:49][O:50][CH2:51][C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=3)[O:20]2)=[CH:15][C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[O:11][CH2:10][CH2:9][CH2:8]2
Reactant: COC1(c2ccc(Br)c(Cc3ccc4c(c3)CCCO4)c2)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CC#N
Solvent: ClCCl
Product: Brc1ccc(C2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc2c(c1)CCCO2
Reaction time: 2 h
Yield: 69.2 %

Procedure:
To a stirred solution of 6-[2-bromo-5-((3R,4S,5R,6R)-3,4,5-tris-benzyloxy-6-benzyloxymethyl-2-methoxy-tetrahydro-pyran-2-yl)-benzyl]-chroman (900 mg, 1.05 mmol) in acetonitrile:dichloromethane (1:1 mixture, 6 mL) was added triethylsilane (0.34 mL, 2.1 mmol) and boron trifluoride diethyletharate complex (0.19 mL, 1.58 mmol), at 0° C. After stirring for 2 h, the reaction was quenched with saturated aqueous sodium bicarbonate solution. The volatiles were evaporated under reduced pressure; the resulting mixture was extracted with ethyl acetate (2×10 mL). The organic layers were combined and dried over sodium sulfate then concentrated to a residue which was purified by silica gel column chromatography to furnish 6-[2-bromo-5-((3S,4R,5R,6R)-3,4,5-tris-benzyloxy-6-benzyloxymethyl-tetrahydro-pyran-2-yl)-benzyl]-chroman (600 mg).
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:8][CH2:7][O:6][CH2:5]1.[F:9][C:10]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14](F)[C:11]=1[C:12]#[N:13].O>O1CCCC1>[F:9][C:10]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:3][CH:4]2[CH2:8][CH2:7][O:6][CH2:5]2)[C:11]=1[C:12]#[N:13]
Reactant: COc1cc(F)c(C#N)c(F)c1
Reactant: OC1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(F)c(C#N)c(OC2CCOC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.4 %

Procedure:
Sodium hydride (60% in mineral oil, 0.83 g, 21 mmol) was added portionwise to 3-hydroxytetrahydrofuran (1.82 g, 21 mmol) in tetrahydrofuran (40 ml) at 0° C. under a nitrogen atmosphere. The suspension was warmed to room temperature and was stirred for 1 hour. The mixture formed was added over 30 minutes to 2,6-difluoro-4-methoxy-benzonitrile (Mol. Cryst. Liq. Cryst. 1989, 172) (3.5 g, 21 mmol) in tetrahydrofuran (50 ml) and the resulting solution was held at room temperature for 16 hours. Water (75 ml) was added and the aqueous mixture was extracted with ethyl acetate (3×200 ml) The combined organic solutions were dried over magnesium sulphate and evaporated under reduced pressure. The material obtained was dried under vacuum to give the title compound as a brown solid (5.1 g).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH:4]=[O:5].CO.[BH4-].[Na+]>CC(C)=O>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: O=Cc1cc(Cl)ccc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)=O
Product: OCc1cc(Cl)ccc1Br
Reaction time: 0.5 h
Yield: 94.3 %

Procedure:
2-Bromo-5-chlorobenzaldehyde (20.5 g) from Example 72 was dissolved with dry methanol (200 ml), followed by sodium borohydride (1.06 g) at 0° C., and the mixture was stirred for 30 minutes. After addition of acetone, the solvent was removed under reduced pressure, water was added the obtained residue, and then extracted with ether. The organic layer was washed with saturated sodium hydrogencarbonate solution and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, to give the title compound (19.5 g; 94%)
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:14])[CH:4]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:6][CH:7]=1.I[CH3:16]>CC(C)=O>[CH3:16][O:1][C:2]1[C:3](=[O:14])[CH:4]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:6][CH:7]=1
Reactant: O=c1cc(-c2ccccc2)occ1O
Reactant: CI
Solvent: CC(C)=O
Product: COc1coc(-c2ccccc2)cc1=O
Temperature: 60 °C
Yield: 93 %

Procedure:
To a solution of 4-oxo-6-phenyl-4H-pyran-3-yl acetate (100 mg, 0.4 mmol) in MeOH (10.9 mL) is added K2CO3 (180 mg, 1.3 mmol) and the reaction was stirred for 15 min at room temperature. The reaction mixture was concentrated under reduced pressure to provide 5-hydroxy-2-phenyl-4H-pyran-4-one which was used in the subsequent step without further purification. To a solution of crude 5-hydroxy-2-phenyl-4H-pyran-4-one (0.4 mmol) in acetone (10.9 mL) is added iodomethane (0.7 mL, 11.3 mmol) and the reaction mixture was heated at 60° C. for 2 h. After being cooled to room temperature, the reaction was concentrated under reduced pressure and diluted with CHCl3 (10 mL) and water (10 mL). The layers were separated and the organic fraction washed with sat. aq. NaCl, dried (Na2SO4), and concentrated under reduced pressure to provide (93%) of 5-methoxy-2-phenyl-4H-pyran-4-one as tan crystals which were used in the subsequent step without further purification. LC/MS (M+H)+ 203.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:48]=[C:49]([O:53][CH3:54])[C:50]=1[O:51][CH3:52])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]([C:31]3[N:35]([CH2:36][CH2:37][CH2:38][C:39]([O:41]CC)=[O:40])[C:34]4[CH:44]=[CH:45][CH:46]=[CH:47][C:33]=4[N:32]=3)=[O:30])[CH2:25][CH2:24]2)([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:9]1)=[O:7].O.[OH-].[Li+].O1CCCC1.O>O>[CH3:54][O:53][C:49]1[CH:48]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:50]=1[O:51][CH3:52])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]([C:31]3[N:35]([CH2:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])[C:34]4[CH:44]=[CH:45][CH:46]=[CH:47][C:33]=4[N:32]=3)=[O:30])[CH2:25][CH2:24]2)([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:9]1)=[O:7]
Reactant: CCOC(=O)CCCn1c(C(=O)C2CCN(CCC3(c4ccc(Cl)c(Cl)c4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)c4nc5ccccc5n4CCCC(=O)O)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Temperature: 5 °C
Reaction time: 20 h

Procedure:
Combine 1-(3,4,5-trimethoxy-benzoyl)-3-[2-[4-[1-(3-ethoxycarbonyl-propyl)-1 H-benzoimidazole-2-carbonyl]-piperidin-1-yl]-ethyl]-3-(3,4-dichloro-phenyl)-pyrrolidine (0.32 g, 0.41 mmol) and lithium hydroxide hydrate (0.052 g, 1.23 mmol) in 4/1 tetrahydrofuran/water (20 mL). After 20 hours, dilute the reaction mixture with water and evaporate in vacuo to remove most of the tetrahydrofuran. Acidify to pH 2 using 1 M hydrochloric acid solution and cool to 5° C. to obtain a solid. Collect the solid by filtration. Suspend the solid in diethyl ether (150 mL) and stir. After 18 hours, collect the solid by filtration and dry to give the title compound: mp; 125-140° C. Elemental Analysis calculated for C39H44Cl2N4O7·HCl: C 59.43; H 5.75; N 7.11; Found: C 59.55; H 5.81; N 6.94.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][C:20]([F:23])([F:22])[F:21])[N:8]=2)[N:5]=[C:4]([C:24]([O:26]CC)=O)[CH:3]=1.CO.[NH4+:31]>>[CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][C:20]([F:23])([F:22])[F:21])[N:8]=2)[N:5]=[C:4]([C:24]([NH2:31])=[O:26])[CH:3]=1
Reactant: [NH4+]
Reactant: CCOC(=O)c1cc(C)n(-c2cccc(-c3ccccc3OC(F)(F)F)n2)n1
Solvent: CO
Product: Cc1cc(C(N)=O)nn1-c1cccc(-c2ccccc2OC(F)(F)F)n1

Procedure:
A solution of the ester from Step 2 of EXAMPLE 137 (0.025 g, 0.064 mmol) in ammonium-methanol solution (7.0M, 3 mL) (placed in a sealed tube) was stirred at 70° C. for 2 days. After cooling, the reaction was concentrated to give the titled compound as yellow powder (0.02 g).
Reaction SMILES: [CH:1]([C:3]1[C:8]([C:9]([O:11]CC)=O)=[CH:7][CH:6]=[CH:5][N:4]=1)=O.[CH3:14][NH:15][NH2:16]>C(O)C>[CH3:14][N:15]1[C:9](=[O:11])[C:8]2[CH:7]=[CH:6][CH:5]=[N:4][C:3]=2[CH:1]=[N:16]1
Reactant: CNN
Reactant: CCOC(=O)c1cccnc1C=O
Solvent: CCO
Product: Cn1ncc2ncccc2c1=O
Reaction time: 2 h

Procedure:
In ethanol (3 ml) was dissolved ethyl 2-formyl-3-pyridinecarboxylate (519 mg) followed by addition of methylhydrazine (267 mg), and the mixture was refluxed with stirring for 2 hours. This reaction mixtrue was concentrated to dryness and the residue was washed with diethyl ether-acetone and dried. Yellow powder, 391 mg. 1H-NMR (DMSO-d6) δ: 3.75(3H,s), 7.86(1H,dd,J=8.4&4.4Hz), 8.48(1H,s), 8.62(1H,d,J=8.4Hz), 9.14(1H,d,J=4.4Hz).
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([C:6]([NH:8][C:9]2([C:15]([NH:17][CH:18]3[CH2:23][CH2:22][N:21]([C:24]4[CH:29]=[CH:28][C:27](F)=[CH:26][C:25]=4[NH2:31])[CH2:20][CH:19]3[OH:32])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:7])=[CH:4][CH:3]=1.[CH:35]1(C(Cl)=O)[CH2:37][CH2:36]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2([C:15]([NH:17][CH:18]3[CH2:23][CH2:22][N:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[NH:31][CH:35]4[CH2:37][CH2:36]4)[CH2:20][C:19]3=[O:32])=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)=[O:7])=[CH:33][CH:34]=1
Reactant: Nc1cc(F)ccc1N1CCC(NC(=O)C2(NC(=O)c3ccc(F)cc3)CCCCC2)C(O)C1
Reactant: O=C(Cl)C1CC1
Product: O=C(NC1(C(=O)NC2CCN(c3ccccc3NC3CC3)CC2=O)CCCCC1)c1ccc(F)cc1

Procedure:
In accordance with the same procedure as in Example 87, except that 4-[N-[1-[N-(4-fluorobenzoyl)amino]cyclohexanecarbonyl]amino]-1-(4-fluoro-2-aminophenyl)piperidin-3-ol was used instead of 4-[N-[1-[N-(furan-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-1-(4-fluoro-2-aminophenyl)piperidin-3-ol and cyclopropylcarbonyl chloride was used instead of methoxyacetyl chloride in Step 3 thereof, 1.5 g of the titled compound was prepared.
Reaction SMILES: [Zn:1].[Br:2]C(Br)C.[CH3:6][O:7][C:8](=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15]Br>C1COCC1>[Br-:2].[C:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][Zn+:1])([O:7][CH3:6])=[O:17]
Reactant: CC(Br)Br
Reactant: [Zn]
Reactant: COC(=O)c1ccccc1CBr
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1C[Zn+]
Product: [Br-]
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
Under atmosphere of argon, to a solution of zinc powder (1.89 g) in anhydrous THF (15 ml) was added dibromoethane (116 μl) and the mixture was stirred for five minutes at 60° C. To the reaction mixture was added a solution of 2-bromomethylbenzoic acid methyl ester (4.42 g) in anhydrous THF (15 ml) over a period of 30 minutes at 0° C. and the mixture was stirred for 2 hours at the temperature to give a 2-carbomethoxybenzylzinc (II) bromide (benzyl zinc) solution.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][C:6]1([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:26])[CH3:25])=[CH:19][CH:18]=2)[CH:14](O)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]1O)[CH3:2]>C(O)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][C:6]1([C:17]2[CH:18]=[CH:19][C:20]([NH:23][C:24](=[O:26])[CH3:25])=[CH:21][CH:22]=2)[CH2:7][C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14]1)[CH3:2]
Reactant: CCOC(=O)CC1(c2ccc(NC(C)=O)cc2)C(O)c2ccccc2C1O
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)CC1(c2ccc(NC(C)=O)cc2)Cc2ccccc2C1
Temperature: 50 °C
Reaction time: 48 h
Yield: 85.3 %

Procedure:
A stirred solution of [2-(4-acetylamino-phenyl)-1,3-dihydroxy-indan-2-yl]-acetic acid ethyl ester (0.38 g, Reference Example 12) in acetic acid (20 mL), under nitrogen, was treated with palladium black (20 mg), then the flask was evacuated and then hydrogen was introduced into the flask via a balloon. After stirring at 50° C. for 2 days the reaction mixture was filtered through Hi-flow supercel. The filtrate was concentrated then diluted with ethyl acetate (100 mL). This solution was washed with saturated sodium hydrogen carbonate solution (100 mL), then with water (100 mL), then dried over magnesium sulfate and then evaporated to give the title compound (0.296 g) as an amber coloured gum.