Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])=[CH2:3].[CH3:14][C:15](=[O:18])[CH:16]=[CH2:17].C(N(CC)CC)C>O1CCCC1>[CH3:3][C:2]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:17][CH2:16][C:15](=[O:18])[CH3:14])[C:5]1=[O:13])=[CH2:1]
Reactant: C=C(C)n1c(=O)[nH]c2ccccc21
Reactant: C=CC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=C(C)n1c(=O)n(CCC(C)=O)c2ccccc21
Yield: 100 %

Procedure:
A mixture of 34.8 parts of 1,3-dihydro-1-(1-methylethenyl)-2H-benzimidazol-2-one, 28 parts of 3-buten-2-one, 20.2 parts of N,N-diethylethanamine and 270 parts of tetrahydrofuran is stirred and refluxed over week-end. The reaction mixture is evaporated, yielding 48.8 parts (100%) of 1,3-dihydro-1-(1-methylethenyl)-3-(3-oxobutyl)-2H-benzimidazol-2-one as a residue.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[C:6](Cl)[N:7]=[CH:8][CH:9]=2)[S:4][CH:3]=1.[OH-].[NH4+:13]>O1CCOCC1>[Br:1][C:2]1[C:10]2[C:5](=[C:6]([NH2:13])[N:7]=[CH:8][CH:9]=2)[S:4][CH:3]=1
Reactant: Clc1nccc2c(Br)csc12
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Nc1nccc2c(Br)csc12
Temperature: 140 °C
Yield: 14.6 %

Procedure:
To a solution of 3-bromo-7-chlorothieno[2,3-c]pyridine (200 mg, 0.805 mmol) in 1,4-dioxane (2.6 mL) was added 28% ammonium hydroxide (2.2 mL, 22 mmol). The mixture was heated in a microwave at 140° C. for 6 h and then concentrated. The residue was suspended in water (15 mL) and extracted with 5% methanol:dichloromethane (5×10 mL). The combined organic fractions were dried over sodium sulfate, filtered, and concentrated. Purification by ISCO chromatography (0 to 5% methanol:dichloromethane) afforded 27 mg (15%) of the title compound as a light yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.10 (d, J=5.8 Hz, 1 H), 7.58 (s, 1 H), 7.18 (d, J=5.6 Hz, 1 H), 4.87 (br. s., 2 H); MS (ESI): 229.04, 231.00 [M+H]+; HPLC tR=2.19 min (ZQ3, polar—4 min).
Reaction SMILES: [I:1]Cl.[CH3:3][N:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[N:15]([S:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)(=[O:24])=[O:23])[C:16]([Si](C)(C)C)=[CH:17][C:10]=23)[C:6]([C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=2)=[N:5]1>C(#N)C>[I:1][C:16]1[N:15]([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])[C:11]2=[N:12][CH:13]=[CH:14][C:9]([C:7]3[C:6]([C:31]4[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=4)=[N:5][N:4]([CH3:3])[CH:8]=3)=[C:10]2[CH:17]=1
Reactant: Cn1cc(-c2ccnc3c2cc([Si](C)(C)C)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1
Reactant: ClI
Solvent: CC#N
Product: Cn1cc(-c2ccnc3c2cc(I)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1
Temperature: -10 °C
Reaction time: 0.08 h
Yield: 53 %

Procedure:
To a solution of ICl (1M in CH2Cl2, 43.3 mmol) in acetonitrile (250 ml) at −10° C. was added a solution of 4-[1-methyl-3-(4-nitrophenyl)-1H-pyrazol-4-yl]-1-(phenylsulfonyl)-2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridine (8.67 mmol) in acetonitrile (46 ml) followed by stirring at −10° C. for 5 minutes. The reaction was concentrated to approx. ⅓ total volume and then diluted with EtOAc (500 ml). The solution was washed with saturated NaHCO3(aq) (100 ml), saturated Na2S2O3(aq) (100 ml), brine (100 ml), and dried over MgSO4. Filtration and concentration in vacuo yielded a tan solid which was triturated with hot acetonitrile/Et2O, providing the title product as a light tan solid (53%). ESMS [M+H]+: 586.0.
Reaction SMILES: Cl.Cl[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5]1.[F:15][C:16]([F:25])([F:24])[CH2:17][CH2:18][CH:19]([C:22]#[N:23])[C:20]#[N:21].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:9]1([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C:19]([CH2:18][CH2:17][C:16]([F:15])([F:24])[F:25])([C:20]#[N:21])[C:22]#[N:23])[N:5]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: ClCn1ccc(-c2ccccc2)n1
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cn1ccc(-c2ccccc2)n1
Yield: 23.7 %

Procedure:
2.01 g of 1-(chloromethyl)-3-phenyl-1H-pyrazole hydrochloride and 1.42 g of (3,3,3-trifluoropropyl) malononitrile were dissolved in 27 ml of N,N-dimethylformamide. 2.43 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.66 g of [(3-phenyl-1H-pyrazole-1-yl)methyl](3,3,3-trifluoropropyl)malononitrile (referred as the compound of the present invention (10), hereinafter) shown by below formula.
Reaction SMILES: OC(CO)CN(CC(O)CO)CCCN.OC(CO)CN(CC(O)CO)CCCN(CC(O)CO)CCCN.[CH:40]12[CH2:46][CH:43]([CH2:44][CH2:45]1)[CH2:42][CH:41]2[CH2:47][CH2:48][CH:49]([NH:59][CH2:60][CH2:61][CH2:62][N:63]([CH2:78][CH:79]([OH:82])[CH2:80][OH:81])[CH2:64][CH2:65][CH2:66][N:67](CC(O)CO)CC(O)CO)[CH2:50][CH2:51][CH:52]1[CH2:57][CH:56]2[CH2:58][CH:53]1[CH2:54][CH2:55]2>>[CH:40]12[CH2:46][CH:43]([CH2:44][CH2:45]1)[CH2:42][CH:41]2[CH2:47][CH2:48][CH:49]([NH:59][CH2:60][CH2:61][CH2:62][N:63]([CH2:78][CH:79]([OH:82])[CH2:80][OH:81])[CH2:64][CH2:65][CH2:66][NH2:67])[CH2:50][CH2:51][CH:52]1[CH2:57][CH:56]2[CH2:58][CH:53]1[CH2:54][CH2:55]2
Reactant: OCC(O)CN(CCCNC(CCC1CC2CCC1C2)CCC1CC2CCC1C2)CCCN(CC(O)CO)CC(O)CO
Agent: NCCCN(CC(O)CO)CC(O)CO
Agent: NCCCN(CCCN(CC(O)CO)CC(O)CO)CC(O)CO
Product: NCCCN(CCCNC(CCC1CC2CCC1C2)CCC1CC2CCC1C2)CC(O)CO

Procedure:
In a like manner and using analogous quantities, but employing N,N-di-(2,3-dihydroxypropyl)trimethylenediamine and 1,1,5-tri-(2,3-dihydroxypropyl)-1,5,9-triazanonane instead of 3,3'-(2,3-dihydroxypropylimino)bispropylamine there are prepared respectively N-[1,5-di-(2-norbornyl)-3-pentyl]-N'-di-(2,3-dihydroxypropyl)trimethylenediamine, and 1-[1,5-di-(2-norbornyl)-3-pentyl]-5-(2,3-dihydroxypropyl)-9,9-di-(2,3-dihydroxypropyl)-1,5,9-triazanonane.
Reaction SMILES: [OH:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[O:12]([C:11]1[C:2]([OH:1])=[C:3]([CH:8]=[CH:9][CH:10]=1)[C:4]([O:6][CH3:7])=[O:5])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1cccc(O)c1O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(Oc2ccccc2)c1O
Temperature: 25 °C
Reaction time: 96 h
Yield: 11.5 %

Procedure:
To a mixture of methyl 2,3-dihydroxybenzoate (1.50 g, 8.9 mmol), phenylboronic acid (1.08 g, 8.9 mmol) and copper acetate (1.62 g, 8.9 mmol) suspended in dichloromethane (100 ml) was added triethylamine (6.15 ml, 44.5 mmol) and the mixture was stirred at room temperature for 96 h. The solvent was removed and the product chromatographed through a silica column using a gradient of 0-10% methanol in dichloromethane. The product was obtained as a pale yellow oil (0.25 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24]Br)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8].[S:31]1[CH2:35][CH2:34][NH:33][CH2:32]1>CN(C)C=O.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24][N:33]4[CH2:34][CH2:35][S:31][CH2:32]4)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C1CSCN1
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCN1CCSC1
Temperature: 25 °C
Reaction time: 19.5 h
Yield: 37.6 %

Procedure:
A mixture of 250 mg (0.51 mmol) of 4-bromo-but-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy-quinolin-6-yl]-amide, and 80 μL (1.02 mmol) of thiazolidine in 2.25 ml dimethylformamide was stirred at room temperature for 19.5 hr. After the mixture was cooled, the suspension was diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate. The extracts were evaporated to an oil and purified by preparative TLC to yield 95.6 mg (38%) yellow solid: mp 135-138° C.
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([O:12][C:13]1[C:14]([C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=2)=[CH:15][C:16]([CH2:36][CH3:37])=[C:17]([CH:35]=1)[O:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[C:24]([CH2:32][CH2:33][CH3:34])=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](O)=[O:27])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C[N:46](C=O)C.[OH-].[NH4+]>C1COCC1.O.CO>[CH2:5]([O:12][C:13]1[C:14]([C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=2)=[CH:15][C:16]([CH2:36][CH3:37])=[C:17]([CH:35]=1)[O:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[C:24]([CH2:32][CH2:33][CH3:34])=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([NH2:46])=[O:27])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CN(C)C=O
Reactant: CCCc1c(OCCCOc2cc(OCc3ccccc3)c(-c3ccc(F)cc3)cc2CC)cccc1C(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCCc1c(OCCCOc2cc(OCc3ccccc3)c(-c3ccc(F)cc3)cc2CC)cccc1C(N)=O
Reaction time: 1 h
Yield: 290.2 %

Procedure:
Add thionyl chloride (8.22 mL, 113 mmol) dropwise to a solution of 3-[3-[5-benzyloxy-2-ethyl-4-(4-fluorophenyl)phenoxy]propoxy]-2-propyl-benzoic acid (50.0 g, 92 mmol) and DMF (2.5 mL, 32 mmol) in THF (250 mL). Stir for 1 h and then add the reaction to a solution of ammonium hydroxide (102.5 mL, 1.52 mol) at 0-5° C. Add MeOH (250 mL) and water (500 mL) in a dropwise fashion. Concentrate to about one half the volume in vacuo and stir the resulting suspension 30 min at 0-5° C. Filter the suspension on a glass frit and dry the resulting solids under vacuum to provide the title compound (50.3 g, quantitative) as an off-white solid. ES/MS m/z 542 (M+1).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:25]#[CH:26])[CH2:20][CH2:19][C:18]4([O:24][CH2:23][CH2:22][O:21]4)[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.I[C:28]1[C:29]([N+:35]([O-:37])=[O:36])=[C:30](O)[CH:31]=[CH:32][CH:33]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>N1CCCCC1.ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH2:23]1[CH2:22][O:21][C:18]2([CH2:19][CH2:20][C:15]([C:9]3[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[CH:8]=3)([C:25]#[C:26][C:33]3[CH:32]=[CH:31][CH:30]=[C:29]([N+:35]([O-:37])=[O:36])[CH:28]=3)[CH2:16][CH2:17]2)[O:24]1
Reactant: O=[N+]([O-])c1c(O)cccc1I
Reactant: C#CC1(c2ccc(OC)c(OC3CCCC3)c2)CCC2(CC1)OCCO2
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Solvent: ClCCl
Product: COc1ccc(C2(C#Cc3cccc([N+](=O)[O-])c3)CCC3(CC2)OCCO3)cc1OC1CCCC1
Temperature: 70 °C

Procedure:
To a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)-4-ethynylcyclohexane (0.14 g, 0.38 mmol) and 3-iodonitrophenol (0.10 g, 0.38 mmol) in piperidine (2 mL) under an argon atmosphere were added tetrakis(triphenylphosphine)palladium(0) (0.02 g, 4%), copper(I) iodide (0.005 g, 6%) and a small crystal of triphenylphosphine. After heating at 70° C. for 0.33 h, the mixture was diluted with dichloromethane, was washed with 1N hydrochloric acid, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 2:8 ethyl acetate:hexanes, provided 1,1-(ethylenedioxy)-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3-nitrophenylethynyl)cyclohexane as an orange wax. 1H-NMR (400MHz, CDCl3) δ 8.29 (s, 1H), 8.16 (d, J=9.0 Hz, 1H), 7.75 (d, J=7.9 Hz, 1H), 7.50 (t, J=8.0 Hz, 1H), 7.26 (d, J=2 Hz, 1H), 7.14 (dd, J=8.3, 2 Hz, 1H), 6.86 (d, J=8.3 Hz, 1H), 4.82 (m, 1H), 4.01 (s, 4H), 3.85 (s, 3H), 2.18 (m, 4H), 2.07 (m, 2H), 1.93 (m, 4H), 1.85 (m, 4H), 1.6 (m, 2H).
Reaction SMILES: CO.[F:3][C:4]1([F:24])[CH2:8][CH2:7][C@@H:6]([C@@:9]([OH:23])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]([O:12][CH2:13][CH2:14][CH2:15][NH2:16])=[O:11])[CH2:5]1.[CH:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[BH4-].[Na+]>C(OCC)(=O)C>[F:3][C:4]1([F:24])[CH2:8][CH2:7][C@@H:6]([C@@:9]([OH:23])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]([O:12][CH2:13][CH2:14][CH2:15][NH:16][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:11])[CH2:5]1
Reactant: NCCCOC(=O)[C@](O)(c1ccccc1)[C@@H]1CCC(F)(F)C1
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(OCCCNCc1ccccc1)[C@](O)(c1ccccc1)[C@@H]1CCC(F)(F)C1
Reaction time: 0.5 h

Procedure:
To a methanol solution of 87 mg of 3-aminopropyl (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate, 35 mg of benzaldehyde was added at room temperature, stirred for 30 minutes at the same temperature, sodium borohydride was added, and further stirred for 30 minutes. The reaction liquid was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, the resulting residue was purified on silica gel column chromatography (eluent: chloroform/methanol=50/1), to provide the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[CH:10]=[CH:9][C:8]=1[CH2:16][CH2:17][NH:18][S:19]([C:22]1[CH:27]=[C:26]([C:28]#[N:29])[CH:25]=[CH:24][C:23]=1[O:30]C)(=[O:21])=[O:20])[CH3:2].[Cl-].[Li+]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH:13]([CH3:14])[CH3:15])[CH:10]=[CH:9][C:8]=1[CH2:16][CH2:17][NH:18][S:19]([C:22]1[CH:27]=[C:26]([C:28]#[N:29])[CH:25]=[CH:24][C:23]=1[OH:30])(=[O:20])=[O:21])[CH3:2]
Reactant: CCOC(=O)COc1cc(C(C)C)ccc1CCNS(=O)(=O)c1cc(C#N)ccc1OC
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc(C(C)C)ccc1CCNS(=O)(=O)c1cc(C#N)ccc1O
Temperature: 140 °C
Reaction time: 3 h
Yield: 96.9 %

Procedure:
To a solution of 148 mg of ethyl[2-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]acetate in 3 mL of N,N-dimethylformamide was added 41 mg of lithium chloride, and the mixture was stirred at 140° C. for 3 hours. After being cooled to room temperature, the reaction mixture was concentrated under reduced pressure. To the residue was added aqueous 10% citric acid solution to adjust pH4, and the mixture was extracted with 100 mL of ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 139 mg of ethyl[2-[2-(5-cyano-2-hydroxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]acetate.
Reaction SMILES: NC1C=CC(OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=NC=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:33]2[CH2:42][CH2:41][C:40]3[C:35](=[CH:36][CH:37]=[C:38]([O:43][C:44]4[CH:49]=[CH:48][C:47]([N+:50]([O-])=O)=[CH:46][N:45]=4)[CH:39]=3)[O:34]2)[CH:30]=[CH:31][CH:32]=1>[Zn]>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:33]2[CH2:42][CH2:41][C:40]3[C:35](=[CH:36][CH:37]=[C:38]([O:43][C:44]4[N:45]=[CH:46][C:47]([NH2:50])=[CH:48][CH:49]=4)[CH:39]=3)[O:34]2)[CH:30]=[CH:31][CH:32]=1
Reactant: COc1cccc(C2CCc3cc(Oc4ccc([N+](=O)[O-])cn4)ccc3O2)c1
Agent: Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Agent: [Zn]
Product: COc1cccc(C2CCc3cc(Oc4ccc(N)cn4)ccc3O2)c1

Procedure:
6-[2-(3-Methoxyphenyl)chroman-6-yloxy]pyridin-3-ylamine was prepared as described for 5-amino-2-(2-phenylchroman-6-yloxy)pyridine in Example 26 using 300 mg 2-[2-(3-methoxyphenyl)chroman-6-yloxy]-5-nitropyridine (Example 99(d)) and 1.0 g of Zn. H NMR (400 MHz, d6-DMSO) δ: 7.51 (d, 1H, J 3.0 Hz), 7.31 (t, 1H, J 15.8, 7.9 Hz), 7.04 (dd, 1H, J 8.7, 3.0 Hz), 6.99-7.02 (m, 1H), 6.99 (d, 1H, J 2.6 Hz), 6.90 (dd, 1H, J 8.9, 2.6 Hz), 6.79-6.81 (m, 1H), 6.72-6.74 (m, 2H), 6.69 (d, 1H, J 8.9 Hz), 5.06 (dd, 1H, J 9.9, 2.2 Hz), 4.50 (s, 2H), 3.77 (s, 3H), 2.88-2.95 (m, 1H), 2.66-2.71 (m, 1H), 2.12-2.17 (m, 1H), 1.94-2.00 (m, 1H).
Reaction SMILES: CS[S:3][CH3:4].S(Cl)(Cl)(=O)=O.[Br:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[N:18]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:17]=[C:16]2[CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Br:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[N:18]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:17]([S:3][CH3:4])=[C:16]2[CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: CSSC
Reactant: CCOC(=O)CCCc1cn(CC(=O)OCC)c2c(Br)cccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CCCc1c(SC)n(CC(=O)OCC)c2c(Br)cccc12
Temperature: -5 °C
Reaction time: 1.5 h

Procedure:
To a chloroform (0.8 mL) solution of dimethyl disulfide (30 mg), sulfuryl chloride (34 mg) was added at −15° C. and the mixture was stirred at −5° C. for 1.5 hours. To the reaction mixture, a chloroform (0.5 mL) solution of the compound prepared in Example 43, namely, ethyl 4-{7-bromo-1-[2-(ethyloxy)-2-oxoethyl]-1H-indol-3-yl}butanoate (100 mg) was added at −78° C., followed by stirring at room temperature for 3 hours. To the reaction mixture, an aqueous saturated sodium hydrogen carbonate solution was added under ice cooling, followed by extraction with ethyl acetate. The organic layer was washed in turn with an aqueous saturated sodium hydrogen carbonate solution, water and saturated saline, dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=95:5→91:9) to obtain the titled compound having the following physical properties (70 mg).
Reaction SMILES: Br[C:2]1[CH:10]=[N:9][C:8]([Cl:11])=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[CH3:12][O-:13].[Na+].Cl>CO.[Cu]I>[CH3:12][O:13][C:2]1[CH:10]=[N:9][C:8]([Cl:11])=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: Clc1ncc(Br)c2cc[nH]c12
Reactant: C[O-]
Agent: [Cu]I
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1cnc(Cl)c2[nH]ccc12
Temperature: 115 °C

Procedure:
A mixture of 4-bromo-7-chloro-6-azaindole (1 g), CuI (0.65 g) and NaOMe (4 mL, 25% in methanol) in MeOH (16 mL) was heated at 110-120° C. for 16 hours in a sealed tube. After cooling to room temperature, the reaction mixture was neutralized with 1N HCl to pH 7. The aqueous solution was extracted with EtOAc (3×30 mL). Then the combined organic layer was dried over MgSO4, filtered and the filtrate was concentrated in vacuo to afford a residue, which was purified by using silica gel chromatography to give 0.3 g of 4-methoxy-7-chloro-6-azaindole, Precursor 2e. MS m/z: (M+H)+ calcd for C8H8ClN2O: 183.03; found 183.09. HPLC retention time: 1.02 minutes (column B).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.C([O-])([O-])=O.[K+].[K+].F[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1.C([O-])(O)=O.[Na+]>CN(C=O)C>[O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([O:12][C:20]2[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=2)=[CH:8][CH:7]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Oc1ccc(-c2ncco2)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2ccc(-c3ncco3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
To a solution of 4-(2-oxazolyl)phenol (4.1 g, 25.44 mmol) in DMF (98 ml), K2CO3 (3.52 g, 25.44 mmol, 1 equiv.) was added. The reaction was stirred at ambient temperature for 30 min. Then, 4-fluorobenzaldehyde (2.73 mL, 25.44 mmol, 1 equiv., Aldrich # 12,837-6) was added and stirring was continued at 150° C. for 4 hours. After cooling, saturated NaHCO3 was added to the reaction mixture. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Flashmaster chromatography on 50 g of silica gel using a gradient of 100% hexane→50% hexane+50% ethyl acetate gave 6.4 g of 4-[4-(2-oxazolyl)phenoxy]benzaldehyde still containing 20 mol % DMF. Further drying led to the pure product (6.05 g; 90% th.; 148% pract.); 1H NMR (CDCl3) δ 9.95 (s, 1H), 8.09 (d, 2H), 7.89 (d, 2H), 7.72 (d, 1H), 7.24 (d, 1H), 7.16 (d, 2H), 7.13 (d, 2H) ppm.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C@@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]2[N:24]2[CH2:28][CH2:27][C@@H:26]([OH:29])[CH2:25]2)=[CH:11][C:10]=1[O:30][CH3:31])C1C=CC=CC=1>CO.O.[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C@@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]2[N:24]2[CH2:28][CH2:27][C@@H:26]([OH:29])[CH2:25]2)=[CH:11][C:10]=1[O:30][CH3:31]
Reactant: COc1cc(CCO[C@@H]2CCCC[C@H]2N2CC[C@@H](O)C2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: COc1cc(CCO[C@@H]2CCCC[C@H]2N2CC[C@@H](O)C2)ccc1O
Reaction time: 1 h
Yield: 46.5 %

Procedure:
A solution of compound (1R,2R)-1-{2-[2-(4-benzyloxy-3-methoxyphenyl)ethoxy]cyclohexyl}-(3R)-pyrrolidin-3-ol (50.3 g, 100 mmol) in methanol (250 mL) was transferred to a Parr shaker bottle that has previously been charged with Pd/C (10% wt/wt, 4.0 g) as a slurry in water. The bottle was placed on a Parr hydrogenator and evacuated. Hydrogen pressure (60 psi) was then applied and the vessel was shaken for 1 hour. The mixture was filtered through a pad of Celite and the filtrate was concentrated. The residue was dissolved in water (250 mL) and washed successively with ethyl acetate (3×200 mL) and chloroform (10×150 mL). The aqueous solution was saturated with NaCl and washed with dichloromethane (4×200 mL). The combined organic extract was concentrated and 5% aqueous NaHCO3 (200 mL) was added to the residue. The suspension was stirred for 30 minutes and then extracted with ethyl acetate (8×250 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated to afford a yellowish powder. The powder was then triturated with ethyl acetate (3×50 mL) and subjected to high vacuum (oil pump) to afford (3R)-1-[(1R,2R)-2-[2-(4-hydroxy-3-methoxy-phenyl)ethoxy]cyclohexyl]-3-pyrrolidinol (15.6 g, 43% yield) as a white powder; 1H NMR (400 MHz, CDCl3) δ 6.82 (d, 1H, J=8.0), 6.75 (br s, 1H), 6.70 (d, 1H, J=8.0), 4.30-4.20 (m, 1H), 3.87 (s, 3H), 3.78-3.70 (m, 1H), 3.56 (q, 1H), 3.33 (td, 1H, J=7.6, J=3.6), 2.97-2.89 (m, 1H), 2.84-2.75 (m, 3H), 2.65 (dd, 1H, J=10, J=5.2), 2.55-2.38 (m, 2H), 2.09-1.95 (m, 2H), 1.91-1.82 (m, 1H), 1.73-1.58 (m, 3H), 1.41-1.15 (m, 4H); 13C-NMR (100 MHz, CDCl3) δ 23.25, 23.68, 27.59, 29.21, 34.42, 36.70, 48.84, 56.06, 59.93, 63.68, 69.83, 71.29, 79.59, 111.98, 114.60, 121.65, 131.35, 144.23, 146.67; IR: 3436 (O—H stretch), 1591, 1515, 1272, 1098, 1030, 851 cm−1; MS (ESI) 336.2 (M+1)+.
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][N:8]1[CH2:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[C:12]2=[C:20]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[C:21]3[CH:22]=[CH:23][C:24]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][C:26]=3[N:11]2[CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.O>[CH:31]1([C:20]2[C:21]3[CH:22]=[CH:23][C:24]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][C:26]=3[N:11]3[CH2:10][CH2:9][N:8]([CH2:7][C:6]([OH:37])=[O:5])[CH2:15][C:14]4[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=4[C:12]=23)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCN(CC(=O)OC(C)(C)C)Cc1ccccc1-3
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCN(CC(=O)O)Cc1ccccc1-3
Temperature: 45 °C

Procedure:
To a solution of methyl 6-(2-tert-butoxy-2-oxoethyl)-14-cyclohexyl-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-11-carboxylate in a 1:1 mixture DCM/H2O (0.05 M) was added a large excess (>100 eq) of TFA and the solution heated for 4 h at 45° C. The volatiles were then removed in vacuo and the crude product was used in the next step without further purification; MS (ES+) m/z 447 (M+H)+.