Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8](OCC)=[O:9])=[C:4]([NH:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH:21]([CH3:23])[CH3:22])[N:15]=2)[CH:3]=1.[NH3:24]>CO>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:24])=[O:9])=[C:4]([NH:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH:21]([CH3:23])[CH3:22])[N:15]=2)[CH:3]=1
Reactant: CCOC(=O)c1nnc(Cl)cc1Nc1cc(C)cc(C(C)C)n1
Reactant: N
Solvent: CO
Product: Cc1cc(Nc2cc(Cl)nnc2C(N)=O)nc(C(C)C)c1
Temperature: 45 °C
Yield: 100 %

Procedure:
To a solution of ethyl 6-chloro-4-(6-isopropyl-4-methylpyridin-2-ylamino)pyridazine-3-carboxylate (115 mg, 343 μmol) in methanol (1 mL) was added ammonia in methanol (7 N, 4.91 mL, 34.3 mmol) and then the mixture heated at 45° C. for 20 h. The mixture was concentrated in vacuo to give 6-chloro-4-(6-isopropyl-4-methylpyridin-2-ylamino)pyridazine-3-carboxamide (105 mg, 343 μmol, 100%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.91 (s, 1H), 9.25 (s, 1H), 8.85 (s, 1H), 8.21 (s, 1H), 6.87 (s, 1H), 6.77 (s, 1H), 3.01 (m, 1H), 2.31 (s, 3H), 1.28 (d, J=6.6 Hz, 6H); MS (EI/CI) m/z: 305.9 [M+H].
Reaction SMILES: [CH2:1]([C:5](=[CH2:9])[C:6]([OH:8])=O)[CH2:2][CH2:3][CH3:4].CCN(C(C)C)C(C)C.C(Cl)(=O)C(C)(C)C.[CH2:26]([C@H:33]1[CH2:37][O:36][C:35](=[O:38])[NH:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([Li])CCC>C1COCC1>[CH2:26]([CH:33]1[CH2:37][O:36][C:35](=[O:38])[N:34]1[C:6](=[O:8])[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH2:9])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: C=C(CCCC)C(=O)O
Agent: CC(C)(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C=C(CCCC)C(=O)N1C(=O)OCC1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
2-n-butyl acrylic acid (9.90 g, 77.2 mmol, and 1 equiv.) is dissolved in dry THF (260 mL) and cooled to −78° C. under nitrogen. Hunig's base (17.5 mL, 100.4 mmol, 1.3 equiv.) and pivaloyl chloride (9.5 mL, 77.2 mmol, 1 equiv.) are added at such a rate that the temperature remains below −60° C. The mixture is stirred at −78° C. for 30 minutes, warmed to rt for 2 hours, and finally cooled back to −78° C. In a separate flask, (S)-(−)-4-benzyl-2-oxazolidinone (13.49 g, 77.24 mmol) is dissolved in dry THF (150 mL) and cooled to −78° C. under nitrogen. n-butyllithium (2.5 M solution in hexanes, 30.9 mL, 77.2 mmol, 1 equiv.) is added slowly at −78° C., and the mixture is stirred for 30 minutes at rt. The resulting anion is slowly transferred via a cannula into the original reaction vessel. The mixture is allowed to warm to rt and is stirred overnight at rt. The reaction is quenched with 1 M KHCO3, and the solvents are removed under reduced pressure. The residue is partitioned between EtOAc and water. The organic layer is washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give a yellow oil which is purified by FC (hexane:EtOAc=4:1) to yield the title compound A-3 as a white solid.
Reaction SMILES: S([O-])(O)(=O)=O.[K+].CN(C)[C:9]1[CH2:13][O:12][C:11](=[O:14])[CH:10]=1.[Cl:16][C:17]1[N:22]=[CH:21][C:20]([CH2:23][NH:24][CH2:25][CH:26]([F:28])[F:27])=[CH:19][CH:18]=1>C(#N)CCC>[Cl:16][C:17]1[N:22]=[CH:21][C:20]([CH2:23][N:24]([CH2:25][CH:26]([F:28])[F:27])[C:9]2[CH2:13][O:12][C:11](=[O:14])[CH:10]=2)=[CH:19][CH:18]=1
Reactant: CN(C)C1=CC(=O)OC1
Reactant: FC(F)CNCc1ccc(Cl)nc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCCC#N
Product: O=C1C=C(N(Cc2ccc(Cl)nc2)CC(F)F)CO1
Temperature: 25 °C
Yield: 85.9 %

Procedure:
3.9 g of potassium hydrogen sulphate are added at room temperature to a suspension of 4.1 g of 4-(dimethylamino)furan-2(5H)-one and 5 g of N-[(6-chloropyridin-3-yl)methyl]-2,2-difluoroethylamine in 50 ml of butyronitrile. The mixture is refluxed for 8 h. Thereafter, cooling at room temperature and washing twice with 50 ml of water are effected. The solvent is removed in vacuo. 6 g of 4-[[(6-chloropyridin-3-yl)methyl](2,2-difluoroethyl)amino]furan-2(5H)-one are obtained with a purity of 92% (82% yield).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:24]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[C:16]([NH2:25])[C:15]=2[N:14]=[C:13]1[CH2:26][CH2:27][CH2:28][CH3:29].[CH3:30][N:31]([CH3:46])[C:32]1[CH:41]=[CH:40][CH:39]=[C:38]2[C:33]=1[CH:34]=[CH:35][CH:36]=[C:37]2[S:42](Cl)(=[O:44])=[O:43].C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.O>[NH2:25][C:16]1[C:15]2[N:14]=[C:13]([CH2:26][CH2:27][CH2:28][CH3:29])[N:12]([CH2:11][CH2:10][CH2:9][NH:8][S:42]([C:37]3[C:38]4[C:33](=[C:32]([N:31]([CH3:46])[CH3:30])[CH:41]=[CH:40][CH:39]=4)[CH:34]=[CH:35][CH:36]=3)(=[O:44])=[O:43])[C:24]=2[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:17]=1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCN
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Solvent: O
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCNS(=O)(=O)c1cccc2c(N(C)C)cccc12
Yield: 65.8 %

Procedure:
Under a nitrogen atmosphere triethylamine (765 mg, 7.56 mmol) was added to a solution of 1-(3-aminopropyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (1.5 g, 5.04 mmol) in 1-methyl-2-pyrrolidinone (75 mL). A solution of 5-dimethylamino-1-naphthalenesulfonyl chloride (1.5 g, 5.55 mmol) in 1-methyl-2-pyrrolidinone was added. The reaction was monitored by HPLC. The reaction mixture was combined with water (500 mL) and the pH was adjusted to 10 with solid potassium carbonate. The resulting yellow precipitate was isolated by filtration, rinsed with water and then purified by column chromatography (silica gel eluting with 1-5% methanol in chloroform). The purified material was recrystallized from acetonitrile to provide 1.76 g of N-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]-5-(dimethylamino)naphthalene-1-sulfonamide as a solid, m.p. 216.5-217.5° C. Analysis: Calculated for C29H34N6O2S: % C, 65.64; % H, 6.46; % N, 15.84; Found: % C, 65.52; % H, 6.44; % N, 15.90.
Reaction SMILES: [F:1][CH:2]([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=2)[NH2:15])=[CH:6][CH:5]=1.N1C=CC=CC=1.[CH2:26]([S:28](Cl)(=[O:30])=[O:29])[CH3:27].O>C(Cl)Cl>[F:1][CH:2]([F:19])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]#[C:11][C:12]2[CH:13]=[C:14]([NH:15][S:28]([CH2:26][CH3:27])(=[O:30])=[O:29])[CH:16]=[CH:17][CH:18]=2)=[CH:8][CH:9]=1
Reactant: CCS(=O)(=O)Cl
Reactant: Nc1cccc(C#Cc2ccc(OC(F)F)cc2)c1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1cccc(C#Cc2ccc(OC(F)F)cc2)c1
Reaction time: 5 h
Yield: 91.4 %

Procedure:
A cold (0° C.) solution of 3-{[4-(difluoromethoxy)phenyl]ethynyl}aniline (0.5 g, 1.93 mmol) and pyridine (0.31 mL, 3.80 mmol) in CH2Cl2 was treated dropwise with ethylsulfonyl chloride (0.27 mL, 2.89 mmol). The mixture was stirred for 5 hours, poured into water and extracted with EtOAc/ethyl ether 1/1. The organic extracts were combined, dried over MgSO4 and concentrated in vacuo. Purification of the resultant residue on silica gel (Biotage) using hexanes/EtOAc (3/1) as the eluting solvent gave N-(3-{[4-(difluoromethoxy)phenyl]ethynyl}phenyl)ethanesulfonamide as a yellow oil (0.62 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[N:22][C:23]([NH:26][C:27]4[CH:28]=[N:29][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:32]=4)=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1.CO>[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]4[CH:28]=[N:29][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:32]=4)=[N:22][CH:21]=3)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(-c3ccc(Nc4ccc(C(F)(F)F)nc4)nc3)cc2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc(Nc2ccc(-c3ccc(C4CCNCC4)cc3)cn2)cn1
Reaction time: 18 h

Procedure:
4-{4-[6-(6-Trifluoromethyl-pyridin-3-ylamino)-pyridin-3-yl]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester (1.02 g, 2.0 mmol) was slurried in 1,4-dioxane/MeOH (5:1, 6 mL) and was treated with HCl (4M in 1,4-dioxane, 2 mL). After 18 hours, added more HCl (4M, 1,4-dioxane, 3 mL) and stirred 2 days. The solvents were removed via rotary evaporation and the crude was dried under vacuum to obtain the hydrochloride salt of the title compound as a sticky yellow solid which was used in the next step without further purification: MS (M+H)+ 399.4.
Reaction SMILES: C([O:8][C:9]1[C:13]([CH2:14][CH2:15][C:16]2[N:17]=[CH:18][S:19][CH:20]=2)=[CH:12][N:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:10]=1)C1C=CC=CC=1.C(#N)C.I[Si](C)(C)C>O>[C:21]1([N:11]2[CH:12]=[C:13]([CH2:14][CH2:15][C:16]3[N:17]=[CH:18][S:19][CH:20]=3)[C:9]([OH:8])=[N:10]2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: c1ccc(COc2nn(-c3ccccc3)cc2CCc2cscn2)cc1
Agent: C[Si](C)(C)I
Solvent: O
Solvent: CC#N
Product: Oc1nn(-c2ccccc2)cc1CCc1cscn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 51.6 %

Procedure:
To a mixture of 4-[2-(3-benzyloxy-1-phenyl-1H-pyrazol-4-yl)ethyl]-1,3-thiazole (1.24 g) and acetonitrile (50 mL) was added iodotrimethylsilane (2.04 g) at room temperature. After stirring the reaction mixture at room temperature for 15 hrs., water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (1:2, v/v) to give 1-phenyl-4-[2-(1,3-thiazol-4-yl)ethyl]-1H-pyrazol-3-ol as colorless crystals (0.48 g, yield 52%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 152-153° C.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:13][CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)=O>>[CH2:1]([N:8]1[CH2:13][CH2:14][CH:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCNCc1ccccc1
Reactant: O=C(CCCl)c1ccc(Cl)cc1
Product: Clc1ccc(C2CCN(Cc3ccccc3)CCN2)cc1

Procedure:
This compound was prepared by the method of preparation 2 starting from N-benzylethylenediamine but using commercially available 3-chloro-1-(4-chlorophenyl)propan-1-one. LRMS: APCl+ m/z 300 [MH+].
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH2:15])[N:13]=[CH:14][C:9]=3[C:8]3[CH:16]=[CH:17][N:18]=[CH:19][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:21]1[N:22]=[N:23][C:24]([N:27]2[CH2:32][CH:31]=[CH:30][CH2:29][CH2:28]2)=[CH:25][CH:26]=1>>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:21]4[N:22]=[N:23][C:24]([N:27]5[CH2:28][CH:29]=[CH:30][CH2:31][CH2:32]5)=[CH:25][CH:26]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:16]=[CH:17][N:18]=[CH:19][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1ncc2c3ccncc3n(C3CCCC3)c2n1
Reactant: Clc1ccc(N2CC=CCC2)nn1
Product: C1=CCN(c2ccc(Nc3ncc4c5ccncc5n(C5CCCC5)c4n3)nn2)CC1
Yield: 20 %

Procedure:
Compound 409 was prepared from compound 4 and compound 410 using chemistry similar to that described in example 1. The yield is 20%. 1H NMR (500 MHz, CD3OD) δ ppm 9.68 (1 H, d, J=1.5 Hz), 9.36 (1 H, s), 9.36 (1 H, d, J=0.5 Hz), 8.69 (3 H, t, J=2.2 Hz), 8.60-8.72 (1 H, m), 8.22 (1 H, d, J=10.5 Hz), 8.08 (1 H, dd, J=10.0, 1.0 Hz), 6.02-6.09 (1 H, m, J=8.1, 4.1, 4.1, 2.0 Hz), 5.89 (1 H, dddd, J=8.4, 3.4, 3.3, 1.5 Hz), 5.50 (2 H, t, J=8.8 Hz), 4.17 (3 H, qd, J=2.7, 2.6 Hz), 3.87 (3 H, t, J=5.7 Hz), 2.47-2.60 (3 H, m), 2.37-2.43 (2 H, m, J=6.1, 6.1, 3.5, 2.2 Hz), 2.15-2.35 (7 H, m), 1.87-1.99 (3 H, m); LCMS-ESI (POS), M/Z, M+1: Found 413.2, Calculated 413.2.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:11]=[C:10]([I:12])[CH:9]=[C:8]2[C:4]=1[C:5](=[O:14])[C:6](=[O:13])[NH:7]2.[H-].[Na+].[CH3:19][Si:20]([CH3:27])([CH3:26])[CH2:21][CH2:22][O:23][CH2:24]Cl.O>CN(C)C=O>[CH3:19][Si:20]([CH3:27])([CH3:26])[CH2:21][CH2:22][O:23][CH2:24][N:7]1[C:8]2[C:4](=[C:3]([C:2]([F:15])([F:1])[F:16])[CH:11]=[C:10]([I:12])[CH:9]=2)[C:5](=[O:14])[C:6]1=[O:13]
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=C1Nc2cc(I)cc(C(F)(F)F)c2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCN1C(=O)C(=O)c2c1cc(I)cc2C(F)(F)F
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
A solution of 4-trifluoromethyl-6-iodo-1H-indole-2,3-dione (12.0 g, 35.2 mmol) in N,N-dimethylformamide (120 mL) was cooled to 0° C. under nitrogen, and thereto was added 55% sodium hydride (1.70 g, 39.0 mmol) and the mixture was stirred for 30 minutes. Then, to the reaction solution was added dropwise 2-(trimethylsilyl)-ethoxymethyl chloride (7.00 mL, 39.6 mmol), and the mixture was stirred at room temperature for 5 minutes. To the reaction solution was added water, and the mixture was extracted with ethyl acetate-toluene (1:1) twice, washed with water twice, and then dried over magnesium sulfate, and filtered. The filtrate was evaporated and purified by silica gel column chromatography (hexane/ethyl acetate=5/1) to give the titled compound (13.7 g, 83%).
Reaction SMILES: NC1C=CC(C2N=C(N3CCOCC3)C3=CC(CN(C)C)=CN3N=2)=CC=1.[OH:27][CH2:28][C:29]1[CH:30]=[C:31]([C:35]2[N:40]=[C:39]([N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)[C:38]3=[CH:47][C:48]([C:50]([N:52]([CH3:54])[CH3:53])=O)=[CH:49][N:37]3[N:36]=2)[CH:32]=[CH:33][CH:34]=1>>[CH3:54][N:52]([CH2:50][C:48]1[CH:47]=[C:38]2[N:37]([CH:49]=1)[N:36]=[C:35]([C:31]1[CH:30]=[C:29]([CH2:28][OH:27])[CH:34]=[CH:33][CH:32]=1)[N:40]=[C:39]2[N:41]1[CH2:42][CH2:43][O:44][CH2:45][CH2:46]1)[CH3:53]
Reactant: CN(C)C(=O)c1cc2c(N3CCOCC3)nc(-c3cccc(CO)c3)nn2c1
Agent: CN(C)Cc1cc2c(N3CCOCC3)nc(-c3ccc(N)cc3)nn2c1
Product: CN(C)Cc1cc2c(N3CCOCC3)nc(-c3cccc(CO)c3)nn2c1

Procedure:
Compound I-24 was prepared by the method which was identical with that for preparing compound 13a, wherein compound 18 (70 mg, 0.184 mmol) was used as the starting material. White solid (100%). m.p. 163-165° C. 1H NMR (300 MHz, DMSO-d6): δ 8.20 (s, 1H), 8.11 (dt, J=2.4, 6.0 Hz, 1H), 7.99 (d, J=1.3 Hz, 1H), 7.45-7.41 (m, 2H), 7.15 (d, J=1.3 Hz, 1H), 5.27 (t, J=5.8 Hz, 1H), 4.57 (d, J=5.8 Hz, 2H), 4.07 (t, J=4.6 Hz, 4H), 3.95 (s, 2H), 3.80 (t, J=4.6 Hz, 4H), 2.44 (s, 6H). MS (EI) m/e (%): 367 (M+, 16).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]#[N:12].[Li+].[BH4-]>C1COCC1>[OH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]#[N:12]
Reactant: COC(=O)c1ccccc1CC#N
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CCc1ccccc1CO
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-cyanomethylbenzoic acid methyl ester (1.75 g, 10 mmol) in THF (15 mL) is added LiBH4 (660 mg, 30 mmol) and the mixture is stirred at RT for 3 h. The mixture is quenched with MeOH then water is added. The mixture is extracted with EtOAc and the organic phase is washed with 1N HCl and brine then is dried over magnesium sulfate. The solvent is removed under reduced pressure to give the title compound which is used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[Cl-].[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][C:34]=1[CH2:35][Zn+]>C(C1C=CC=C(C(C)C)C=1N1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C1=[Pd-3](Cl)(Cl)C1C(Cl)=CC=CN=1)(C)C>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:35][C:34]5[CH:37]=[C:38]([O:41][CH3:42])[CH:39]=[CH:40][C:33]=5[O:32][CH3:31])[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Br)ccc21
Reactant: COc1ccc(OC)c(C[Zn+])c1
Agent: CC(C)c1cccc(C(C)C)c1-n1ccn(-c2c(C(C)C)cccc2C(C)C)c1=[Pd-3](Cl)(Cl)c1ncccc1Cl
Agent: [Cl-]
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Cc3cc(OC)ccc3OC)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2,5-dimethoxy-benzylzinc chloride following a procedure analogous to that described in Step 6 of Intermediate 1; [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]-(3-chloropyridyl)-palladium(II) dichloride (Pd-PEPPSI-IPr) is used as catalyst. LC (method 3): tR=0.94 min; Mass spectrum (ESI+): m/z=565 [M+Na]+.
Reaction SMILES: O[C@H]1[C@H](OC2C=CC(C)=C(C)C=2)CCNCC1.[OH:18][C@H:19]1[C@H:25]([O:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=2)[CH2:24][CH2:23][N:22](C)[CH2:21][CH2:20]1.Cl.O[C@H]1[C@H](OC2C=CC(C(F)(F)F)=CC=2)CCN(C)CC1>>[OH:18][C@H:19]1[C@H:25]([O:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1
Reactant: CN1CC[C@@H](O)[C@H](Oc2ccc(Cl)c(Cl)c2)CC1
Agent: CN1CC[C@@H](O)[C@H](Oc2ccc(C(F)(F)F)cc2)CC1
Agent: Cc1ccc(O[C@@H]2CCNCC[C@H]2O)cc1C
Agent: Cl
Product: O[C@@H]1CCNCC[C@H]1Oc1ccc(Cl)c(Cl)c1

Procedure:
Analogously to Example 20, the 1-methyl derivatives corresponding to the compounds indicated below are obtained using, in each case, 0.04 mol of the indicated compounds, i.e. trans-3-hydroxy-4-(m-chlorophenoxy)-1-methyl-piperidine is obtained from 9.12 g of trans-3-hydroxy-4-(m-chorophenoxy)-piperidine (Example 21), trans-3-hydroxy-4-phenylthio-1-methyl-piperidine is obtained from 8.36 g of trans-3-hydroxy-4-phenylthio-piperidine (Example 13), trans-3-hydroxy-4-(5,6,7,8-tetrahydro-1-naphthyloxy)-1-methyl-piperidine is obtained from 9.88 g of trans-3-hydroxy-4-(5,6,7,8-tetrahydro-1-naphthyloxy)-piperidine (Example 33), trans-3-hydroxy-4-(p-fluorophenoxy)-1-methyl-piperidine is obtained from 8.44 g of trans-3-hydroxy-4-(p-fluorophenoxy)-piperidine (Example 31), trans-3-acetoxy-4-(3,4-dimethyl-phenoxy)-1-methyl-piperidine is obtained from 10.60 g of trans-3-acetoxy-4-(3,4-dimethylphenoxy)-piperidine (Example 9), trans-3-hydroxy-4-(p-trifluoromethylphenoxy)-1-methyl-piperidine is obtained from 10.44 g of trans-3-hydroxy-4-(p-trifluoromethyl-phenoxy)-piperidine (Example 36), trans-4-hydroxy-5-(3,4-dimethyl-phenoxy)-1-methyl-hexahydro-1 H-azepine and its hydrochloride are obtained from 9.40 g of trans-4-hydroxy-5-(3,4-dimethyl-phenoxy)-hexahydro-1H-azepine (Example 40), trans-4-hydroxy-5-(3,4-dichloro-phenoxy)-1-methyl-hexahydro-1H-azepine and its hydrochloride are obtained from 11.04 g of trans-4-hydroxy-5-(3,4-dichloro-phenoxy)-hexahydro-1H-azepine (Example 40) and trans-4-hydroxy-5-(p-trifluoromethyl-phenoxy)-1-methyl-hexahydro-1H-azepine and its hydrochloride are obtained from 11.0 g of trans-4-hydroxy-(p-trifluoromethyl-phenoxy)-hexahydro-1H-azepine (Example 40).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])#[N:2].Br[CH2:11][CH2:12][CH2:13][Cl:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(Cl)(Cl)Cl>[Cl:14][CH2:13][CH2:12][CH2:11][O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: ClCCCBr
Reactant: N#Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: N#Cc1ccccc1OCCCCl
Yield: 97.5 %

Procedure:
A mixture of 2-cyanophenol (50.0 g, 0.42 mole), 1-bromo-3-chloropropane (67.7 g, 0.43 mole), and potassium carbonate (58.0 g, 0.42 mole) was heated overnight at gentle reflux in 500 ml of acetone. The reaction mixture was stripped to dryness and the residue was dissolved in chloroform. The chloroform layer was extracted several times with 5% sodium hydroxide. The chloroform layer was dried (anhydrous sodium sulfate), filtered, and the solvent was removed, to give a brown oil (80.09 g). A ten gram portion of this oil was subjected to flash chromatography on silica gel with 10% ethyl acetate-hexanes and 20% ethyl acetate-hexanes used for elution. Fractions were combined and solvent removed in vacuo. The clear oil obtained was dried 18 hrs in vacuo at room temperature and 8 hrs at 80° C. in vacuo. This furnished 5.24 g (50.0% yield--based on aliquot taken) of clear oil. 1H HMR (CDCl3); δ 2.1-2.5 (q, 2, --CH2), 3.8 (t, 2, --ClCH2), 4.2 (t, 2, --OCH2), 6.9 (m, 2, aromatic protons ortho and para to ether), 7.5 (m, 2, aromatic protons ortho and para to CN group).
Reaction SMILES: [CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[C:27]([CH2:31]I)([F:30])([F:29])[F:28].[F-].[Cs+].O>CS(C)=O>[CH2:1]([C@@:4]1([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:31][C:27]([F:30])([F:29])[F:28])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: FC(F)(F)CI
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(O)cc2)C(=O)O1
Agent: [Cs+]
Agent: [F-]
Solvent: CS(C)=O
Solvent: O
Product: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(OCC(F)(F)F)cc2)C(=O)O1
Temperature: 120 °C
Yield: 58 %

Procedure:
A mixture of (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-hydroxyphenyl)ethyl)-1,3-oxazinan-2-one (700 mg, 1.97 mmol), CF3CH2I (621 mg, 2.96 mmol) and CsF (360 mg, 2.37 mmol) in DMSO (10 mL) was heated under 120° C. overnight. The mixture was poured into water and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by preparative TLC to give (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1,3-oxazinan-2-one (500 mg, 58%).
Reaction SMILES: Cl[C:2]1[C:14]2[C:13]3[CH:12]=[C:11]([F:15])[CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[C:5]([C:16]#[N:17])=[CH:4][N:3]=1.[F:18][C:19]1[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[C:20]=1[NH2:21].CC(C)([O-])C.[Na+].COCCOC>C(OCC)(=O)C.O>[F:15][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[C:5]([C:16]#[N:17])=[CH:4][N:3]=[C:2]([NH:21][C:20]4[C:19]([F:18])=[CH:25][C:24]([F:26])=[CH:23][C:22]=4[F:27])[C:14]=3[C:13]=2[CH:12]=1
Reactant: Nc1c(F)cc(F)cc1F
Reactant: N#Cc1cnc(Cl)c2c1[nH]c1ccc(F)cc12
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1cnc(Nc2c(F)cc(F)cc2F)c2c1[nH]c1ccc(F)cc12
Temperature: 85 °C
Reaction time: 20 h

Procedure:
1-Chloro-8-fluoro-5H-pyrido[4,3-b]indole-4-carbonitrile (150 mg, 0.611 mmol), 2,4,6-trifluoroaniline (269 mg, 1.83 mmol), and sodium tert-butoxide (188 mg, 1.95 mmol) were placed in a reaction vessel which was placed under an argon atmosphere. DME (3.0 ml) was added. The vessel was sealed and the reaction was heated to 85° C. and stirred for 20 hrs. The resulting solution was cooled to ambient temperature, diluted with ethyl acetate and water. The aqueous layer was extracted with ethyl acetate three times. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by reverse phase HPLC. Desired fractions were combined, diluted with ethyl acetate, and washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the title compound. LRMS (APCI) calc'd for (C18H8F4N4) [M+H]+, 357.1. found 357.0.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([SH:15])[CH:12]=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].[Cl:18][C:19]1[CH:24]=[C:23]([N+]([O-])=O)[CH:22]=[CH:21][N:20]=1>>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([S:15][C:23]2[CH:22]=[CH:21][N:20]=[C:19]([Cl:18])[CH:24]=2)[CH:12]=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(S)c1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)[Si](C)(C)Oc1cccc(Sc2ccnc(Cl)c2)c1
Yield: 64.4 %

Procedure:
Using the method of Example 3, Step A, 3-(tert-butyldimethylsilyloxy)benzenethiol (1.52 g, 6.31 mmol), 60% sodium hydride in mineral oil (252 mg, 6.31 mmol), and 2-chloro-4-nitropyridine (1.00 g, 6.31 mmol) were reacted to provide 4-(3-(tert-butyldimethylsilyloxy)phenylthio)-2-chloropyridine (1.43 g, 64% yield) as an oil. 1H NMR (CDCl3) δ 8.11 (d, 1H), 7.34 (t, 1H), 7.16 (d, 1H) 7.02 (s, 1H), 6.97 (d, 1H), 6.90 (s, 1H), 6.87 (d, 1H).