Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:19]O>>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([O:7][CH3:19])=[O:6]
Reactant: CO
Reactant: O=C(O)c1cc(O)cc([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(O)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a clean, dry 100 mL round bottom flask is added 3-hydroxy-5-nitrobenzoic acid (1 g, 5.5 mmole, 1 eq) followed by 10 mL methanol and 2 mL of concentrated sulfuric acid. The exothermic reaction mixture reached 60° C. prior to cooling to room temperature. The reaction mixture was stirred for 18 h prior to partitioning between ethyl acetate and water. After extraction, the organic layer was dried over magnesium sulfate, filtered and evaporated. A white solid product was obtained (1 g, 100%). Calc'd for C8H7NO5; m/z (M+H+)=198; found 198.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([F:23])=[C:18](B(O)O)[CH:19]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Cl:12][C:10]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([C:16]2[CH:15]=[C:14]([Cl:13])[CH:19]=[CH:18][C:17]=2[F:23])[CH:11]=1
Reactant: Clc1cc(Cl)c2cccnc2n1
Reactant: OB(O)c1cc(Cl)ccc1F
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(Cl)cc1-c1cc(Cl)c2cccnc2n1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A solution of 9.95 g (50.0 mmol) 2,4-dichloro-[1,8]naphthyridine, 8.72 g (50.0 mmol) 5-chloro-2-fluorophenylboronic acid and 5.04 g (60.0 mmol) sodium bicarbonate in 100 ml DMF and 50 ml water was heated to 80° C. under nitrogen. 701 mg (1.0 mmol) bis-(triphenylphosphine)-palladium(II)-chloride were added and the mixture was stirred for 16 hrs at 80° C. Water was added to the reaction mixture and the precipitate was filtered off, dried in vacuum and recrystallized from 2-propanol: 4-chloro-2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridine as slightly yellow crystals; HPLC-MS: 2.49 min, [M+H] 293.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].Br[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1.[OH-].[Na+]>CN(C)C=O.[Cu].C(OCC)(=O)C>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([O:12][C:20]3[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=Cc1ccc(Br)cc1
Reactant: Oc1ccc(-n2ccnc2)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2ccc(-n3ccnc3)cc2)cc1
Temperature: 90 °C

Procedure:
A suspension of 40.04 g (0.25 mole) of 4-(1H-imidazol-1-yl)phenol, 15.2 g (0.11 mole) of anhydrous potassium carbonate, 1 g of copper-I-bromide, and 0.5 g of activated copper powder in 100 ml of anhydrous dimethyl formamide was heated to 90° C. Over the course of 7 hours 47.03g (0.25 mole) of 4-bromobenzaldehyde were added in small portions to the suspension while the mixture was heated to 140° to 145° C. After the addition of the aldehyde was completed, the mixture was allowed to cool. Then 1500 ml of ice-cooled ethyl acetate were added to the reaction mixture. The resulting mixture was shaken with 500 ml of 1N aqueous sodium hydroxide solution. After separation of undissolved ingredients, the organic layer was shaken with 1N aqueous sodium hydroxide solution and washed with a saturated aqueous sodium chloride solution. After drying over magnesium sulfate, the drying agent was separated and the resulting filtrate evaporated at 45° C. and 2.6×103 to 6×103Pa. After column chromatography with ethyl acetate, 37.37 g (56.6% of the theoretical yield) of the aldehyde were obtained in the form of yellow brown crystals melting at 120° to 121° C.
Reaction SMILES: [C:1]1([C:7]2([CH2:13][NH:14][C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])=[O:16])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[C:31]([N:10]1[CH2:9][CH2:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([CH2:13][NH:14][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[O:16])[CH2:12][CH2:11]1)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccccc1C(=O)NCC1(c2ccccc2)CCNCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccccc1C(=O)NCC1(c2ccccc2)CCN(C(=O)c2ccccc2)CC1

Procedure:
A solution of 0.083 g (0.255 mmol) of 4-phenyl-4-(3-(2-methoxyphenyl)-3-oxo-2-azaprop-1-yl)piperidine (Example 2), 0.083 mL (1 mmol) of pyridine and 0.12 mL (1 mmol) of benzoyl chloride in 2 mL of methylene chloride was mixed for 18 hr. The reaction was diluted with methylene chloride and washed with saturated NaHCO3. The organic fraction was dried over MgSO4 and the filtrate was concentrated. The residue was purified by chromatography (silica, ethyl acetate) to give the title compound.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1.[CH3:27][O:28][C:29](=[O:41])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH2:37][O:38][CH3:39])[C:31]=1[CH3:40]>C(Cl)(Cl)(Cl)Cl>[CH3:27][O:28][C:29](=[O:41])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH2:37][O:38][CH3:39])[C:31]=1[CH2:40][Br:1]
Reactant: COCOc1cccc(C(=O)OC)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Solvent: ClC(Cl)(Cl)Cl
Product: COCOc1cccc(C(=O)OC)c1CBr
Reaction time: 3.5 h
Yield: 99.9 %

Procedure:
In a 25 ml round-bottom flask, N-bromo succinimide (236 mg, 1.3 mmol) and azobis(cyclohexanecarbonitrile) (33 mg, 0.14 mmol) were added to a solution of 3-methoxymethoxy-2-methyl-benzoic acid methyl ester (265 mg, 1.26 mmol) in carbon tetrachloride (6.5 ml). The reaction was heated to reflux with stirring for 3.5 hours. The volatiles were removed in vacuo and the residue purified by silica gel chromatography using a mixture of hexanes/ethyl acetate (9:1) as eluent, which afforded 364 mg (100%) of 2-bromomethyl-3-methoxymethoxy-benzoic acid methyl ester as a solid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2([C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[NH:8]1[CH2:13][CH2:12][C:11]2([C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)[CH2:10][CH2:9]1
Reactant: c1ccc(CN2CCC3(CCCc4ccccc43)CC2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: c1ccc2c(c1)CCCC21CCNCC1
Reaction time: 24 h

Procedure:
A suspension of 1′-benzyl-3,4-dihydro-2H-spiro[naphthalene-1,4′-piperidine] 17a (1.7 g, 5.8 mmol), 10% Pd/C (1 g), and ammonium formate (4.8 g, 76 mmol) in MeOH (50 ml) was stirred under N2 for 24 hours. The mixture was filtered through Celite, and the filtrate was concentrated. The filtrate was dissolved in CH2Cl2, washed with diluted NaOH, and the aqueous phase was re-extracted with CH2Cl2. The combined organic phase was dried (Na2SO4) and concentrated to give 3,4-dihydro-2H-spiro[naphthalene-1,4′-piperidine] 17b. LC-MS: m/e=202.1 (M+H). Rt=1.61 min. 1H-NMR (500 MHz, CDCl3): 9.74 (s, 2H), 7.58 (d, J=7.9, 1H), 7.22 (t, J=7.8, 1H), 7.14 (t, J=7.9, 1H), 7.08 (d, J=8.0, 1H), 3.47 (d, J=12.4, 2H), 3.22-3.18 (m, 2H), 2.88 (t, J=4.9, 2H), 2.81 (t, J=6.2, H), 2.60 (td, 2H), 1.93-1.89 (m, 2H), 1.83-1.77 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[N:14]1([C:19]2[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=2)[CH2:22][NH2:23])[CH:18]=[CH:17][CH:16]=[CH:15]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:23][CH2:22][C:21]3[CH:24]=[CH:25][CH:26]=[C:19]([N:14]4[CH:18]=[CH:17][CH:16]=[CH:15]4)[CH:20]=3)[CH:3]=2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: NCc1cccc(-n2cccc2)c1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: O=c1[nH]nc(Cl)c2cc(NCc3cccc(-n4cccc4)c3)ccc12
Yield: 23.1 %

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (160 mg, 0.617 mmol), 3-(1H-pyrol-1-yl)benzylamine (100 mg, 0.581 mmol), Pd2(dba)3 (58 mg, 0.063 mmol), rac-BINAP (116 mg, 0.186 mmol) and NaOtBu (160 mg, 1.665 mmol) in DMA (5 mL) was heated at 85° C. for 1.5 h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO3, brine and dried (Na2SO4). Chromatography on silica (EtOAc/hexanes) afforded 4-chloro-6-(3-pyrrol-1-yl-benzylamino)-2H-phthalazin-1-one (47 mg) as an off white solid, 1H (400 MHz, d6-DMSO) δ: 4.49 (d, 2H), 6.26 (t, 2H), 6.87 (s, 1H), 7.19 (dd, 1H), 7.25 (d, 1H), 7.33 (t, 2H), 7.42 (t, 1H), 7.47 (m, 1H), 7.61 (s, 1H), 7.67 (t, 1H), 7.94 (d, 1H), 12.35 (s, 1H) ppm; m/z (M+1) 350.90.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][N:3]=1.BrC1C=NC(Cl)=NC=1.[F:23][C:24]1([F:70])[CH2:29][CH2:28][CH:27]([C:30]2[C:39]3[CH:38]([O:40]CC4C=CC(OC)=CC=4)[CH2:37][C:36]([CH3:51])([CH3:50])[CH2:35][C:34]=3[N:33]=[C:32]([CH:52]3[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]3)[C:31]=2[CH:58]([F:69])[C:59]2[CH:64]=[CH:63][C:62]([C:65]([F:68])([F:67])[F:66])=[CH:61][CH:60]=2)[CH2:26][CH2:25]1>>[F:70][C:24]1([F:23])[CH2:29][CH2:28][CH:27]([C:30]2[C:39]3[CH:38]([OH:40])[CH2:37][C:36]([CH3:50])([CH3:51])[CH2:35][C:34]=3[N:33]=[C:32]([CH:52]3[CH2:57][CH2:56][N:55]([C:2]4[N:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][N:3]=4)[CH2:54][CH2:53]3)[C:31]=2[CH:58]([F:69])[C:59]2[CH:64]=[CH:63][C:62]([C:65]([F:67])([F:68])[F:66])=[CH:61][CH:60]=2)[CH2:26][CH2:25]1
Reactant: FC(F)(F)CCCc1cnc(Cl)nc1
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCNCC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Agent: Clc1ncc(Br)cn1
Product: CC1(C)Cc2nc(C3CCN(c4ncc(CCCC(F)(F)F)cn4)CC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2C(O)C1

Procedure:
Reactions similar to those of the first step of Example 2 and Example 38 were performed except for using 2-chloro-5-(4,4,4-trifluorobutyl) pyrimidine, which was prepared by a method similar to that of Reference Example 26, instead of 5-bromo-2-chloropyrimidine, and from 70 mg (0.10 mmol) of (−)-4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(piperidin-4-yl)-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 10, 45 mg of the title compound was obtained as a white solid (yield: 61%).
Reaction SMILES: [CH3:1][C:2]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C:9]2[C:4](=[C:5]([Cl:13])[C:6]([Cl:12])=[C:7]([OH:11])[CH:8]=2)[C:3]1=[O:14].C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][C:29]([O:31]CC)=[O:30].[OH-].[K+].Cl>CN(C)C=O.O.CO>[O:14]=[C:3]1[C:4]2[C:9](=[CH:8][C:7]([O:11][CH2:28][C:29]([OH:31])=[O:30])=[C:6]([Cl:12])[C:5]=2[Cl:13])[CH2:10][C:2]1([CH3:1])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)CBr
Reactant: CC1(c2ccccc2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: CC1(c2ccccc2)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O

Procedure:
A stirred mixture of 2-methyl-2-phenyl-5-hydroxy-6,7-dichloro-1-indanone (2.05 g., 0.0067 mole), potassium carbonate (1.85 g., 0.0134 mole) and ethyl bromoacetate (2.23 g., 0.0134 mole) in dimethylformamide (30 ml.) is warmed at 55°-60° C. for 3 hours, then treated with potassium hydroxide (0.97 g., 0.0147 mole) dissolved in a minimum amount of water in methanol (30 ml.) and heated on a steam bath for 21/2 hours. The reaction mixture is poured into water (500 ml.), acidified with 6 N hydrochloric acid and the precipitate collected after trituration with ether-petroleum ether and dried to give 1.31 g. of (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy)acetic acid which melts at 168°-169° C. on crystallization from acetic acid:water, 1:1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13](=[S:15])[NH2:14])=[CH:9]2)([O-:3])=[O:2].Br[CH2:17][CH:18](OCC)OCC.C(O)C.CN(C)C(=O)C>O>[N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]1[S:15][CH:17]=[CH:18][N:14]=1)=[CH:9]2)([O-:3])=[O:2]
Reactant: CCOC(CBr)OCC
Reactant: NC(=S)c1cc2cccc([N+](=O)[O-])c2[nH]1
Solvent: CC(=O)N(C)C
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1cccc2cc(-c3nccs3)[nH]c12
Temperature: 100 °C
Reaction time: 4 h
Yield: 96.8 %

Procedure:
A mixture of 7-nitro-1H-indole-2-carbothioamide (2.06 g), 2-bromo-1,1-diethoxyethane (3.67 g), ethanol (10 mL) and N,N-dimethylacetamide (10 mL) was stirred at 100° C. for 4 hr. To the reaction mixture was added water, and the resulting crystals were filtrated, washed with water and hexane, and dried to give the title compound (2.21 g, yield 97%) as yellow crystals. melting point 130-131° C.
Reaction SMILES: [Br:1]Br.[OH:3][CH:4]1[C:9]([CH3:11])([CH3:10])[O:8][C:7]2[CH:12]=[CH:13][S:14][C:6]=2[CH:5]1[N:15]1[CH2:19][CH2:18][CH2:17][C:16]1=[O:20]>ClCCl>[Br:1][C:13]1[S:14][C:6]2[CH:5]([N:15]3[CH2:19][CH2:18][CH2:17][C:16]3=[O:20])[CH:4]([OH:3])[C:9]([CH3:10])([CH3:11])[O:8][C:7]=2[CH:12]=1
Reactant: CC1(C)Oc2ccsc2C(N2CCCC2=O)C1O
Reactant: BrBr
Solvent: ClCCl
Product: CC1(C)Oc2cc(Br)sc2C(N2CCCC2=O)C1O

Procedure:
A solution of bromine (0.20 mL, 3.92 mmol) in dichloromethane (5 mL) was slowly added to a solution of 5,6-dihydro-6-hydroxy-5,5-dimethyl-7-(2-oxopyrrolidin-1-yl)-7H-thieno[3,2-b]pyran (1.0 g, 3.74 mmol) at -5° C. The resultant mixture was stirred at rt for 2 h. The resulting precipitate was collected by filtration and purified by medium pressure chromatography using 5% methanol in dichloromethane as the eluant to give the product as a colorless solid, 0.28 g (22%): mp 162°-165° C.; IR(KBr): 3287, 1666 and 1570 cm-1 ; MS: m/z 346 (MH+); 1H NMR (CDCl3): δ 1.30 (s, 3H), 1.47 (s, 3H), 2.06 (m, 2H), 7.50 (m, 2H), 3.23 (bs, 1H, exchanges with D2O), 3.34 (m, 2H), 3.76 (d, J=9.1 Hz, 1H) 5.16 (d, J=9.1 Hz, 1H) and 6.56 (s, 1H). Anal. Calcd. for C13H16BrNO3S: C, 45.10; H, 4.66; N, 4.05. Found: C, 45.10; H, 4.40; N, 3.97.
Reaction SMILES: [C:1]([NH:10][NH2:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].Cl[C:13](OC(Cl)(Cl)Cl)=[O:14]>O1CCOCC1>[OH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]1[O:9][C:13](=[O:14])[NH:11][N:10]=1
Reactant: NNC(=O)c1ccccc1O
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: O=c1[nH]nc(-c2ccccc2O)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
To a solution of 10 g of salicylhydrazide in 100 ml of p-dioxane was added dropwise 13.1 g of trichloromethyl chloroformate while maintaining the temperature at 20°-30° C. with external cooling. After stirring at 25° C. for 0.5 hours, the suspension was refluxed for 4 hours then cooled to 25° C. and poured into excess ice-water. The mixture was filtered and the residue was recrystallized from acetonitrile to yield 9.0 g of the subject compound; m.p. 198°-200° C.
Reaction SMILES: O.[OH-].[Li+].[CH:4]1[C:9](=[O:10])[C:8]([OH:11])=[CH:7][O:6][C:5]=1[CH2:12][OH:13].S(OCC)(O[CH2:18][CH3:19])(=O)=O.Cl>O>[CH3:18][CH2:19][O:13][CH2:12][C:5]1[O:6][CH:7]=[C:8]([OH:11])[C:9](=[O:10])[CH:4]=1
Reactant: O=c1cc(CO)occ1O
Reactant: CCOS(=O)(=O)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CCOCc1cc(=O)c(O)co1
Reaction time: 0.33 h

Procedure:
60 ml of water was put in a 100 ml-Erlenmeyer flask, and 10.07 g (0.24 mol) of lithium hydroxide monohydrate and then 11.37 g (0.08 mol) of kojic acid were added thereto and dissolved with stirring. While the temperature of the resulting solution was kept at 40 to 45° C., 14.80 g (0.096 mol) of diethyl sulfate was dropwise added thereto over a period of 20 minutes. Afterwards, the whole was stirred for a further 30 minutes at the same temperature and then overnight at room temperature. The pH of the reaction mixture was adjusted to 6.0 by 1N hydrochloric acid. Water was removed from the reaction mixture using an evaporator by distillation under reduced pressure, and the remaining reddish brown viscous liquid was extracted three times each with 70 ml of a hot benzene. The resulting extract was dewatered by adding anhydrous magnesium sulfate thereto, and then filtered. Benzene was removed from the resulting filtrate using an evaporator by distillation under reduced pressure. The remaining yellowish brown viscous liquid was cooled to solidify (Crude yield: 3.67 g (27%), m.p. 68 to 70° C.). The yellowish brown solid was recrystallized three times from di-isopropyl ether using active carbons to obtain a pure white crystal of 2-ethoxymethyl-5-hydroxy-γ-pyrone.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([N:13]2[C:17]([CH3:18])=[C:16]([CH3:19])[N:15]=[N:14]2)[CH2:9]1)C1C=CC=CC=1.[ClH:20]>CO.[Pd]>[ClH:20].[CH3:19][C:16]1[N:15]=[N:14][N:13]([CH:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)[C:17]=1[CH3:18]
Reactant: Cc1nnn(C2CCN(Cc3ccccc3)C2)c1C
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Cc1nnn(C2CCNC2)c1C

Procedure:
10% Pd/C (0.5 g) was added to a solution of 0.86 g of N-benzyl-3-(4 , 5-dimethyl-1,2,3-triazol-1-yl) pyrrolidine in 50 ml of methanol, and 2 ml of 1N hydrochloric acid. The suspension was then hydrogenated at 50 psi pressure overnight. The Pd/C was removed by filtration through celite and the supernatant was evaporated to dryness and crystallized from methanol-ether to yield 0.5 g of the desired product. 1H NMR (D2O) δ: 5.75-5.6 (m, 1H), 4.14-3.9 (m, 2H), 3.8-3.6 (m, 2H), 2.86-2.4 (m, 8H, two singlets at 2.49 and 2.4).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[O:11][CH2:12][CH:13]([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]>CCOC(C)=O.[Pd]>[Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[O:11][CH2:12][CH:13]([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]
Reactant: CCOC(COc1ccc([N+](=O)[O-])cc1Cl)OCC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(COc1ccc(N)cc1Cl)OCC
Reaction time: 2 h

Procedure:
30 g (0.104 mol) of 2-chloro-1-(2,2-diethoxy-ethoxy)-4-nitrobenzene was added to a suspension of 1.50 g Pd/C (10%) in 500 mL EtOAc and the mixture was hydrogenated for 2 hours at 20 psi. The catalyst was filtered off and the filtrate evaporated down i. vac.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH2:9][C:8]2[CH:10]=[CH:11][CH:12]=[C:13]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:7]=2[O:6]1)=[N+]=[N-]>[Pd]>[CH:14]1([C:13]2[C:7]3[O:6][CH:5]([CH2:4][NH2:1])[CH2:9][C:8]=3[CH:10]=[CH:11][CH:12]=2)[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: [N-]=[N+]=NCC1Cc2cccc(C3CCCC3)c2O1
Agent: [Pd]
Product: NCC1Cc2cccc(C3CCCC3)c2O1
Yield: 58 %

Procedure:
Treatment of (±)-(7-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methanol (4.08 g, 18.7 mmol) with p-toluenesulfonyl chloride (3.92 g, 21.9 mmol) in anhydrous pyridine (76 mL) generally according to the procedure described for Intermediate 10 gave (±)-(7-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a tan oil. Treatment of the tosylate with sodium azide (4.39 g, 67.57 mmol) generally according to the procedure described for Intermediate 98 afforded 4.1 g of (±)-2-(azidomethyl)-7-cyclopentyl-2,3-dihydro-1-benzofuran as a yellow oil. Treatment of the azide with palladium on carbon (0.41 g, 10 wt. %) generally according to the procedure described for Example 1 afforded 2.5 g (58%) of (±)-(7-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methylamine as a white solid, hydrochloride salt. mp 174° C.; Anal. calcd. for C14H900N2HCl: C, 66.26; H, 7.94; N, 5.52. Found C, 66.13; H, 7.71; N, 5.5.
Reaction SMILES: [OH:1][C:2]1[C:10]2[NH:9][C:8]([CH2:11][O:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]Br)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>CN(C)C=O>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH2:11][C:8]2[N:7]([CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH:32]3[CH2:33][CH2:34][N:29]([C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])[CH2:30][CH2:31]3)[C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([O:1][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH:32]4[CH2:33][CH2:34][N:29]([C:27]([O:26][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:28])[CH2:30][CH2:31]4)[C:10]=3[N:9]=2)=[CH:14][CH:15]=1
Reactant: Oc1cccc2nc(COc3ccc(Cl)cc3)[nH]c12
Reactant: CC(C)(C)OC(=O)N1CCC(CCCCCBr)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CCCCCOc2cccc3c2nc(COc2ccc(Cl)cc2)n3CCCCCC2CCN(C(=O)OC(C)(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-hydroxy-2-(4-chlorophenoxymethyl)benzimidazole (500 mg, 1.82 mmol) in dry N,N-dimethylformamide (8 ml) was treated with sodium hydride (60% in mineral oil, 162 mg, 4.0 mmol, 2.2 eq). The resulting mixture was stirred at room temperature under a stream of nitrogen for about one hour. To this reaction mixture 5-[1-(t-butoxycarbonyl)piperidin-4-yl)pentyl bromide (4.0 mmol, 2.2 eq) was added and the resulting mixture was stirred for three hours at 70° C. The reaction was quenched by the addition of 10 ml of water. The aqueous fraction was extracted with ethyl acetate (3×10 ml). The organic fractions were combined and washed with water (2×10 ml), and then brine (1×10 ml), and then dried over magnesium sulfate. The solvents were removed in vacuo to yield a light brownish crude material. The desired title product was further purified by flash chromatography. There is some substitution at the 7-position of the benzimidazole present, although the 4-substituted is the major isomer.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[CH3:10][C:11]1[CH:15]=[C:14]([CH3:16])[N:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH:23]([OH:28])[C:24]([F:27])([F:26])[F:25])[N:12]=1.[H-].[Na+]>C1COCC1>[Cl:8][C:6]1[CH:5]=[C:4]([O:28][CH:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:13]2[C:14]([CH3:16])=[CH:15][C:11]([CH3:10])=[N:12]2)[C:24]([F:25])([F:27])[F:26])[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: Cc1cc(C)n(-c2ccccc2C(O)C(F)(F)F)n1
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C)n(-c2ccccc2C(Oc2cc(Cl)nc(N)n2)C(F)(F)F)n1
Temperature: 42.5 °C
Reaction time: 6 h
Yield: 108.9 %

Procedure:
2-Amino-4,6-dichloro pyrimidine (0.074 g, 0.45 mmol), 1-[2-(3,5-dimethyl-pyrazol-1-yl)-phenyl]-2,2,2-trifluoro-ethanol (0.120 g, 0.45 mmol), NaH (0.022 g, 0.59 mmol) were added to anhydrous THF (10 ml) under nitrogen atmosphere. The reaction was stirred at 40-45° C. for 6 h, and then cooled to room temperature, and quenched with water (0.2 ml). The reaction mixture was concentrated to give crude 4-chloro-6-{1-[2-(3,5-dimethyl-pyrazol-1-yl)-phenyl]-2,2,2-trifluoro-ethoxy]-pyrimidin-2-ylamine (0.195 g, >90% pure by LCMS) which was directly used in the following step.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(C(C)C)C(C)C.CC(C)(C)C(Cl)=O.[CH2:32]([O:34][C:35](=[O:45])[CH2:36][NH:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH3:33]>C(Cl)Cl>[CH2:32]([O:34][C:35](=[O:45])[CH2:36][N:37]([C:13](=[O:15])[C@@H:9]([NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH:10]([CH3:11])[CH3:12])[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH3:33]
Reactant: CCOC(=O)CNCc1ccccc1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CN(Cc1ccccc1)C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
To a solution of N-Boc-valine (2.18 g, 10 mmol) and DIEA (4.4 mL, 25.3 mmol) in CH2Cl2 (20 mL) at -20° C. was added trimethylacetyl chloride (1.2 mL, 9.7 mmol). After stirring for 30 min, compound 701 (2.18 g, 10 mmol) was added and the reaction allowed to warm to rt and stir for 5 hr. The reaction was concentrated in vacuo and the residue taken up into EtOAc and H2O. The layers were separated and the organic phase washed with sat. aq. NaHCO3, sat. aq. KHSO4, brine, dried over MgSO4, filtered and concentrated in vacuo to provide 3.45 g of compound 702. ##STR81##