Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1COCC1.[C:6](#[N:8])[CH3:7].C([Li])CCC.[CH3:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][N:24]=1)[C:18]([O:20]C)=O>CC(O)=O>[CH3:14][C:15]1[CH:16]=[C:17]([C:18](=[O:20])[CH2:7][C:6]#[N:8])[CH:22]=[CH:23][N:24]=1
Reactant: CC#N
Reactant: COC(=O)c1ccnc(C)c1
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)CC#N)ccn1
Temperature: -78 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a 50 ml flask was added 8 ml of THF, acetonitrile (156 μl, 2.98 mmole), the mixture was cooled to −78° C. and then n-butyllithium (1191 μl, 2.98 mmole, 2.5 m in hexanes) was added. The reaction was stirred for 30 minutes at which time methyl 2-methylisonicotinate 16.1.B (150 mg, 0.99 mmoles) was added as a 2 ml THF solution. After 2 hour at −78° C., 500 μL of AcOH was added and the reaction was warmed to room temperature. The solvent was removed and the crude was purified on a silica gel column (eluting with 2% MeOH in DCM) to give 3-(2-methylpyridin-4-yl)-3-oxopropanenitrile 16.1.C as a light orange solid (170 mg 100% yield).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:5]=[C:6](/[CH:9]=[CH:10]/[C:11]2[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[CH:13][C:12]=2[CH3:20])[S:7][CH:8]=1)[CH3:3].O.O.[Sn](Cl)Cl.C(O)C>[OH-].[Na+]>[CH3:20][C:12]1[CH:13]=[CH:14][C:15]([NH2:17])=[CH:16][C:11]=1/[CH:10]=[CH:9]/[C:6]1[S:7][CH:8]=[C:4]([CH:2]([CH3:3])[CH3:1])[N:5]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1/C=C/c1nc(C(C)C)cs1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(N)cc1/C=C/c1nc(C(C)C)cs1
Yield: 111.6 %

Procedure:
A solution of 1.2 g of (E)-4-(1-methylethyl)-2-[2-(2-methyl-5-nitrophenyl)ethenyl]thiazole, 3.2 g of tin(II) chloride dihydrate and 50 ml of ethyl alcohol was heated to reflux for 2 hr. The reaction mixture was cooled in an ice bath and then diluted with 50 ml of 3N sodium hydroxide. This mixture was extracted with ethyl acetate, dried (MgSO4) and condensed in vacuo to yield 1.2 g of (E)-4-methyl-3-[2-[4-(1-methylethyl)-2-thiazolyl]ethenyl]benzenamine; m.p. 60°-61° C. from hexane.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[OH-].[NH4+:13]>O>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[NH2:13]
Reactant: [NH4+]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: [OH-]
Solvent: O
Product: Nc1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
A stirred solution of 3,4-difluoronitrobenzene (2.00 g, 12.57 mmol) in ammonium hydroxide (20 ml, 28% in water) was heated at 150° C. in a sealed flask for 3.5 hrs. The mixture was cooled to room temperature, and the resulting suspension was diluted in water, shaken for 15 min, the solid was isolated by filtration, rinsed with water, air-dried, and dried under high vacuum to afford title compound 337 (1.76 g, 90% yield) as a yellow crystalline solid. MS (m/z): 157.0 (M+H)+ and 179.0 (M+Na)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH2:19]([O:21][C:22]([CH:24]1[CH2:28][CH2:27][NH:26][CH2:25]1)=[O:23])[CH3:20]>C1COCC1>[CH2:19]([O:21][C:22]([CH:24]1[CH2:28][CH2:27][N:26]([C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:25]1)=[O:23])[CH3:20]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CCOC(=O)C1CCNC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C1CCN(C(=O)c2ccc(OC)cc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83 %

Procedure:
4-Methoxy-benzoyl chloride (185 mL, 1.36 mol) and triethylamine (259 mL, 1.86 mol) were added to a stirred solution of pyrrolidine-3-carboxylic acid ethyl ester (177.5 g, 1.24 mol) (see Preparation 1) in THF (2500 mL) at 10° C. The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched with 10% citric acid aqueous solution (2000 mL) then ethyl acetate (2000 mL) was added. The organic layer was washed with saturated aqueous NaHCO3 (2000 mL) and water (2000 mL), dried over magnesium sulphate then concentrated under reduced pressure to afford the title compound as a brown oil (285.3 g, 83%).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]2([OH:14])[CH2:12][CH:11]3[NH:13][CH:8]([CH2:9][CH2:10]3)[CH2:7]2)[C:3]2[CH:15]=[CH:16][CH:17]=[CH:18][C:2]1=2.[CH3:19][O:20][C:21]1[C:26]2[O:27][C@H:28]([CH2:31]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:29][O:30][C:25]=2[CH:24]=[CH:23][CH:22]=1>>[S:1]1[C:2]2[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=2[C:4]([C:6]2([OH:14])[CH2:7][CH:8]3[N:13]([CH2:31][C@@H:28]4[O:27][C:26]5[C:21]([O:20][CH3:19])=[CH:22][CH:23]=[CH:24][C:25]=5[O:30][CH2:29]4)[CH:11]([CH2:10][CH2:9]3)[CH2:12]2)=[CH:5]1
Reactant: COc1cccc2c1O[C@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Reactant: OC1(c2csc3ccccc23)CC2CCC(C1)N2
Product: COc1cccc2c1O[C@@H](CN1C3CCC1CC(O)(c1csc4ccccc14)C3)CO2
Yield: 33 %

Procedure:
The title compound was prepared by the same procedure described in Example 1, Step 4 using 3-benzo[b]thiophen-3-yl-8-aza-bicyclo[3.2.1]octan-3-ol in place of 3-naphthalen-2-yl-8-aza-bicyclo[3.2.1]octan-3-ol, and (S)-toluene-4-sulfonic acid 8-methoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl ester in place of (S)-toluene-4-sulfonic acid 8-ethoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl ester. Yield: 33%, white solid.
Reaction SMILES: CC([S@]([NH:7][C@@H:8]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[CH2:9][CH:10]([CH3:12])[CH3:11])=O)(C)C.CO.[ClH:31]>CCOCC>[ClH:31].[CH3:11][CH:10]([CH3:12])[CH2:9][C@H:8]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[NH2:7]
Reactant: CC(C)C[C@@H](N[S@](=O)C(C)(C)C)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CC(C)C[C@@H](N)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 89 %

Procedure:
A round bottom flask was charged with (R)-2-methyl-N—((R)-3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butyl)propane-2-sulfinamide (47.5 g, 115.5 mmol) and methanol (300 mL). The mixture was cooled to 0° C. and 2.0N HCl in ether (150 mL) was added. The reaction was stirred for 20 minutes. The reaction was then concentrated under reduced pressure. Trituration with ether provided (R)-3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butan-1-amine hydrochloride (35.3 g, 89%), as a white solid. 1H NMR (400 MHz, CD3OD, δ): 0.95 (d, 3 H) 0.99 (d, J=6.44 Hz, 3 H) 1.38-1.51 (m, 1 H) 1.78-1.91 (m, 1 H) 1.92-2.03 (m, 1 H) 4.40 (dd, J=10.15, 5.66 Hz, 1 H) 7.56-7.63 (m, 2 H) 7.74-7.88 (m, 6 H). MS (M+1): 291.2. [α]D =−11.9, c=1.8 (MeOH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[NH:23][N:24]=[C:25]([O:26][CH2:27][CH2:28]O)[C:18]=23)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[NH:30]1[CH2:36][C:34](=[O:35])[NH:33][C:31]1=[O:32].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[NH:23][N:24]=[C:25]([O:26][CH2:27][CH2:28][N:33]4[C:34](=[O:35])[CH2:36][NH:30][C:31]4=[O:32])[C:18]=23)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: OCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: O=C1CNC(=O)N1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C1CNC(=O)N1CCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 25.3 %

Procedure:
2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}-1H-pyrazolo[3,4-d]pyrimidin-3-yl)oxy]ethanol (prepared as described in Example 4/50 mg, 0.12 mmol), hydantoin (36 mg, 0.36 mmol) and triphenylphosphine (94 mg) were dissolved in a 1:1 mixture of THF and DMF (1.2 ml). Ditertbutyl azodicarboxylate (69 mg, 0.3 mmol) was added at 0° C. and mixture was stirred at room temperature for 3 hours. After evaporation, the crude mixture was purified by preparative HPLC (column beta-basic, Hypercil 5 μm, 21×100 mm) eluting with a mixture of water and acetonitrile containing 2g/l of ammonium carbonate (gradient) to give the title compound (15 mg, 25%); NMR Spectrum: 3.88 (t, 2H), 3.96 (s, 2H), 4.37 (t, 2H), 5.29 (s, 2H), 7.24 (d, 1H), 7.36-7.38 (m, 1H), 7.58 (d, 1H), 7.78 (dd, 1H), 7.88 (t, 1H), 8.09 (s, 1H), 8.17 (s, 1H), 8.21 (s, 1H), 8.34 (s, 1H), 8.59 (d, 1H); Mass Spectrum: 495 (MH+).
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:8][CH2:7][S:6](=[O:10])(=[O:9])[NH:5]1)([CH3:3])[CH3:2].Br[C:12]1[CH:17]=[CH:16][C:15]([C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:26]3[C:31]([CH3:32])=[CH:30][C:29]([CH3:33])=[CH:28][N:27]=3)[CH2:22][CH2:21]2)=[O:19])=[C:14]([S:34]([CH3:37])(=[O:36])=[O:35])[CH:13]=1>>[CH3:32][C:31]1[C:26]([N:23]2[CH2:24][CH2:25][N:20]([C:18]([C:15]3[CH:16]=[CH:17][C:12]([N:5]4[C@H:4]([CH:1]([CH3:3])[CH3:2])[CH2:8][CH2:7][S:6]4(=[O:10])=[O:9])=[CH:13][C:14]=3[S:34]([CH3:37])(=[O:36])=[O:35])=[O:19])[CH2:21][CH2:22]2)=[N:27][CH:28]=[C:29]([CH3:33])[CH:30]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Reactant: CC(C)[C@@H]1CCS(=O)(=O)N1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4[C@H](C(C)C)CCS4(=O)=O)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 26.6 %

Procedure:
Using (S)-3-isopropylisothiazolidine 1,1-dioxide (240 mg) described in Preparation Example 6 and (4-bromo-2-methanesulfonylphenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (452 mg) described in Preparation Example 112 and by the reaction and treatment in the same manner as in Example 4, the title compound (142 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][O:13][C:12]([CH3:16])([CH3:15])[N:11]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:5]=[C:6]([CH2:8]O)[CH:7]=1.[Cl:24]C1N=C(Cl)N=C(Cl)N=1>CS(C)=O.CCOC(C)=O>[Cl:24][CH2:8][C:6]1[CH:5]=[C:4]([C@H:10]2[CH2:14][O:13][C:12]([CH3:16])([CH3:15])[N:11]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H](c2cc(F)cc(CO)c2)COC1(C)C
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1[C@@H](c2cc(F)cc(CCl)c2)COC1(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 157.1 %

Procedure:
To a solution of (S)-tert-butyl 4-(3-fluoro-5-(hydroxymethyl)phenyl)-2,2-dimethyloxazolidine-3-carboxylate (330 mg, 1.014 mmol) in anhydrous DMSO (2. 028 mL) was added 2,4,6-trichloro-1,3,5-triazine (112 mg, 0.609 mmol) portionwise. The mixture was stirred at room temperature for 30 min. The mixture was diluted with EtOAc, and separated. The organic phase was washed with H2O (5×30 mL), dried over anhydrous Na2SO4, filtered off and concentrated under reduced pressure. The residue was purified with flash chromatography eluting with 0-100% EtOAc/heptane to provide (S)-tert-butyl 4-(3-(chloromethyl)-5-fluorophenyl)-2,2-dimethyloxazolidine-3-carboxylate (329 mg, 94%). LCMS (m/z): 288.1 (MH+-56), 1.12 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])/[C:4](/[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)=[N:5]/[OH:6].[H-].[Na+].[CH3:24]OS(OC)(=O)=O.Cl>O1CCCC1.O>[CH3:1][O:2][C:3](=[O:21])/[C:4](/[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=1)=[N:5]/[O:6][CH3:24]
Reactant: COS(=O)(=O)OC
Reactant: COC(=O)/C(=N/O)c1ccccc1Oc1ccc(C)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CO/N=C(/C(=O)OC)c1ccccc1Oc1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 81.5 %

Procedure:
E-α-hydroxyimino-2-(4-methylphenoxy)phenylacetic acid methyl ester (0.71 g, 0.0025 mole) was dissolved in dried tetrahydrofuran (10 ml), followed by the addition of 60% sodium hydride (0.13 g, 0.033 mole). Then, the mixture was stirred at room temperature for 20 minutes and to this was added dropwise a solution of dimethylsulfate (0.44 g, 0.0035 mole) dissolved in dried THF (2.5 ml) under ice cooling, followed by stirring for 1.75 hours under ice cooling. After completion of the reaction, water was added to the reaction mixture which was adjusted to pH 1 with conc. hydrochloric acid. The mixture was extracted twice with methylene chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to obtain E-α-methoxyimino-2-(4-methylphenoxy)phenylacetic acid methyl ester (0.61 g, yield: 81.3%) as a colorless oil.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[CH3:10]N(C=O)C.[H-].[Na+].CI>CCOC(C)=O>[CH3:10][N:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: CN(C)C=O
Reactant: c1cnc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCOC(C)=O
Product: Cn1ccc2cccnc21
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a solution of 1H-pyrrolo[2,3-b]pyridine (1.00 g, 8.46 mmol) and DMF (10 mL) is added 60% NaH (0.41 g, 10.16 mmol). After 30 min, MeI (0.63 mL, 10.16 mmol) is added and the solution stirred for 1 h. The solution is diluted with EtOAc (60 mL), washed with water (2×50 mL), brine (50 mL), dried aver MgSO4, filtered and concentrated to furnish the title compound (1.10 g, 0.83 mmol, 99%). 1H NMR (CDCl3), δ 3.90 (s, 3H), 6.45 (d, J=3.5 Hz, 1H), 7.05 (dd, J=8.1, 4.6 Hz, 1H), 7.17 (d, J=3.5 Hz, 1H), 7.90 (d, J=7.7, 1.8 Hz, 1H), 8.40 (dd, J=4.8, 1.3 Hz, 1H). LC/MS (m/z): calcd. for C8H8N2 (M+H)+: 133.2. found.
Reaction SMILES: C([O:9][C:10]([C:12]1[NH:13][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:24](=[O:25])[NH:23][CH2:22][CH2:21][C:20]=1[C:19]=23)=[O:11])CCCCCCC.[OH-].[Li+].CO>O>[O:25]=[C:24]1[C:18]2[C:19]3[C:20](=[C:12]([C:10]([OH:11])=[O:9])[NH:13][C:14]=3[CH:15]=[CH:16][CH:17]=2)[CH2:21][CH2:22][NH:23]1
Reactant: CCCCCCCCOC(=O)c1[nH]c2cccc3c2c1CCNC3=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1[nH]c2cccc3c2c1CCNC3=O

Procedure:
6-Oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indole-2-carboxylic acid octyl ester (Example FFF) (350 mg, 1.02 mmol) and lithium hydroxide (122 mg, 5.11 mmol) were dissolved in 10 mL 2:1 methanol:water and stirred at room temperature for 24 h. The reaction mixture was diluted with water then washed twice with dichloromethane. The aqueous solution was acidified to ca. pH 2 with conc. HCl. The white precipitate was collected by filtration, washed with water, and dried in vacuo to yield 6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indole-2-carboxylic acid, 235 mg (99%) as a white solid: m.p. 298-299° C. (dec); 1H NMR (300 MHz, d6-DMSO) δ3.17 (m, 2H), 3.41 (m, 2H), 7.35 (t, J=7.8 Hz, 1H), 7.59 (d, J=8.1 Hz, 1H), 7.73 (d, J=7.5 Hz, 1H), 8.14 (br t, 1H), 11.77 (br s, 1H), 13.14 (br s, 1H). MS (electrospray, MH+): 231. Anal. (C12H10N2O3.1.0 H2O)C, H, N.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[C:4]([CH:19]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:20]([O:22]C)=[O:21])[C:3]=1[CH3:29].[C:30]([Cu])#[N:31].CN1C(=O)CCC1>CCO>[C:25]([O:24][CH:19]([C:4]1[C:3]([CH3:29])=[C:2]([C:30]#[N:31])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[C:20]([OH:22])=[O:21])([CH3:26])([CH3:28])[CH3:27]
Reactant: N#C[Cu]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)c(Br)c2ccccc2c1-c1ccc(Cl)cc1
Solvent: CCO
Solvent: CN1CCCC1=O
Product: Cc1c(C(OC(C)(C)C)C(=O)O)c(-c2ccc(Cl)cc2)c2ccccc2c1C#N
Temperature: 200 °C
Reaction time: 1 h
Yield: 57.7 %

Procedure:
A suspension of methyl 2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate (10.5 mg, 22.1 μmol), CuCN (9.8 mg, 0.11 mmol), and NMP (500 μL) was heated to 200° C. in a microwave. The reaction was cooled to 23° C., treated with EtOH (2.5 mL), filtered through a 0.45 micron filter, and directly purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H2O+0.1% TFA). The product-containing fractions were combined and treated with LiOH monohydrate until the pH was distinctly basic. The mixture was concentrated with warming to remove most of the water and all of the CH3CN. The solution was treated with EtOH (absolute, 500 μL) and THF (1.0 mL). The suspension was stirred at 23° C. for 1 h. It was filtered through a 0.45 micron filter, and directly purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H2O+0.1% TFA). The product-containing fractions were combined and lyophilized, giving the title compound (parent form) (5.2 mg, 55% over 2 steps).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:7]([CH2:13][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])=[O:15])[C:8](=[O:12])[O:9]2)=[CH:4][C:3]=1[CH2:34][C:35]#[N:36]>C1COCC1.[Co]>[NH2:36][CH2:35][CH2:34][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[Cl:1])[O:9][C:8](=[O:12])[C:7]([CH2:13][C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[C:24]([F:26])([F:27])[F:25])=[O:15])=[C:6]2[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: N#CCc1cc2c(-c3ccccc3)c(CC(=O)Nc3ccc(Cl)cc3C(F)(F)F)c(=O)oc2cc1Cl
Agent: [Co]
Solvent: C1CCOC1
Product: NCCc1cc2c(-c3ccccc3)c(CC(=O)Nc3ccc(Cl)cc3C(F)(F)F)c(=O)oc2cc1Cl
Temperature: 25 °C
Reaction time: 7 h
Yield: 26.8 %

Procedure:
A solution of 2-[7-chloro-6-(cyanomethyl)-2-oxo-4-phenyl-2H-chromen-3-yl]-N-(4-chloro-2-trifluoromethylphenyl)acetamide (100 mg) in THF (5 ml) was combined with Raney-cobalt (100 mg), and stirred under hydrogen atmosphere (4.5 atm) at room temperature for 7 hours. After the catalyst was filtered off, the filtrate was concentrated under reduced pressure to obtain the residue, which was recrystallized from ethyl acetate to obtain the title compound (27 mg, yield: 27%). Melting point: 165-167° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([F:29])=[C:15]([NH:17][S:18]([C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:16]=2)=O)[CH:5]=[CH:4][N:3]=1.C1C(=O)N(Br)C(=O)C1.[O:38]1[CH2:43][CH2:42][CH:41]([C:44](=[S:46])[NH2:45])[CH2:40][CH2:39]1.O>CC(N(C)C)=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:46][C:44]([CH:41]3[CH2:42][CH2:43][O:38][CH2:39][CH2:40]3)=[N:45][C:9]=2[C:11]2[CH:12]=[CH:13][C:14]([F:29])=[C:15]([NH:17][S:18]([C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Cc1ccnc(Cl)n1)c1ccc(F)c(NS(=O)(=O)c2cc(F)ccc2F)c1
Reactant: NC(=S)C1CCOCC1
Agent: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=S(=O)(Nc1cc(-c2nc(C3CCOCC3)sc2-c2ccnc(Cl)n2)ccc1F)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.7 %

Procedure:
To a solution of N-{5-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (0.910 g, 2.06 mmol) (prepared in a manner analogous to Intermediate 35) in DMA (8.24 mL) was added NBS (0.385 g, 2.16 mmol). The reaction stirred 30 min at rt and then tetrahydro-2H-pyran-4-carbothioamide (0.389 g, 2.68 mmol) was added. The reaction stirred 16 h at rt. The reaction mixture was poured into water (150 mL), causing precipitation of a solid. The solid was collected by vacuum filtration, redissolved in EtOAc (50 mL), and concentrated onto silica gel. Purification by chromatography (20 to 100% EtOAc:hexanes) afforded the title compound (690 mg, 1.21 mmol, 58.5% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.86 (s, 1H), 8.58 (d, J=5.3 Hz, 1H), 7.45-7.69 (m, 4H), 7.42 (dd, J=7.5, 2.0 Hz, 1H), 7.32 (dd, J=10.1, 8.8 Hz, 1H), 7.14 (d, J=5.3 Hz, 1H), 3.95 (dd, J=11.7, 2.0 Hz, 2H), 3.40-3.56 (m, 2H), 3.25-3.41 (m, 1H), 2.02 (dd, J=12.9, 1.6 Hz, 2H), 1.65-1.86 (m, 2H). MS (ESI): 567.09 [M+H]+.
Reaction SMILES: [NH2:1][C:2](=[N:15][OH:16])[C:3]1[CH:12]=[CH:11][C:6](C(OC)=O)=[CH:5][C:4]=1OC.[OH:17][CH2:18][CH2:19][N:20]([CH2:22]C1C=C(C=CC=1)C#N)[CH3:21]>>[OH:16][NH:15][C:2](=[NH:1])[C:3]1[CH:4]=[CH:5][CH:6]=[C:11]([CH2:21][N:20]([CH2:19][CH2:18][OH:17])[CH3:22])[CH:12]=1
Reactant: CN(CCO)Cc1cccc(C#N)c1
Reactant: COC(=O)c1ccc(C(N)=NO)c(OC)c1
Product: CN(CCO)Cc1cccc(C(=N)NO)c1
Yield: 99 %

Procedure:
The title compound was obtained following procedure and work up described for Intermediate 47 step 2 but starting from 3-{[(2-Hydroxy-ethyl)-methyl-amino]-methyl}-benzonitrile obtained in step 1 (4.9 g, 26.28 mmol) to give the title compound as white gummy solid (5.7 g, 99%). 1H NMR (DMSO-d6, 400 MHz) δ 9.58 (s, 1H), 7.60 (s, 1H), 7.51-7.54 (m, 1H), 7.28-7.31 (m, 2H), 5.76-7.83 (s, 2H), 4.38 (bs, 1H), 3.48-3.51 (m, 4H), 2.40-2.43 (m, 2H), 2.13 (m, 3H). LC/MS (Method A): 224.1 (M+H)+. HPLC (Method B): Rt 0.7 min, (Purity 91.1%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)=[CH:5][C:4]=1[O:21][CH:22](C)[CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[CH3:33]O>O1CCCC1.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:19][CH:20]=2)=[CH:5][C:4]=1[O:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]1([CH3:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH2:27]1
Reactant: CO
Reactant: COC(=O)c1ccc(C=Cc2ccc(OC)c(OC(C)CCCc3ccccc3)c2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CCc2ccc(OC)c(OCCCCC3(C)C=CC=CC3)c2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of (1.18 g, 2.74 mmol, 1.0 eq) methyl 4-[2-[4-methoxy-3-(1-methyl-4-phenylbutoxy)phenyl]ethenyl]benzoate and 0.600 g of 10% Pd/C in 30 ml methanol and 30 ml tetrahydrofuran was placed on a Parr hydrogenation apparatus and shaken under 20 psi H2 at room temperature for 1.5 hours. The reaction mixture was filtered through celite, concentrated in vacuo, and flash chromatographed on a silica gel column eluting with 20% ether-hexane to afford 1.00 g, 84%, of a clear oil. Elemental Analysis Calc'd for C28H32O4 : Calc'd: C, 77.75; H, 7.46. Found: C, 77.55; H, 7.55.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][N:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]1.Cl>O1CCCC1.CCCCCC>[CH3:11][N:12]1[CH2:17][CH2:16][C:15]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])([OH:18])[CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccccc1Br
Reactant: CN1CCC(=O)CC1
Agent: Cl
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN1CCC(O)(c2ccccc2[N+](=O)[O-])CC1
Temperature: -100 °C
Reaction time: 8 h
Yield: 39.6 %

Procedure:
To a solution of 19.3 g of 2-bromonitrobenzene in 480 ml of anhydrous tetrahydrofuran cooled to -100° C., 79 ml of 1,6M solution of n-Buli in hexane are dropped under N2. After two hours 10.9 g of 1-methyl-4-piperidone are added and the resulting mixture is stirred eight hours at -100° C. Then 1N hydrochloric acid is added at 0° C. to acidify to pH 2 and the solution is extracted with hexane. The aqueous phase is brought to pH 10 and extracted with ethyl ether. Evaporation of the extracts gives 8.95 g of 1-methyl-4(2-nitrophenyl)-4-hydroxypiperidine, m.p. 166°-167°.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:12]2[C:7](=[CH:8][C:9]([Cl:14])=[C:10]([Cl:13])[CH:11]=2)[CH2:6][C@@H:5]([C:15]([O:17]C)=O)[CH2:4]1.[NH3:19]>CO>[ClH:13].[NH2:2][C@@H:3]1[C:12]2[C:7](=[CH:8][C:9]([Cl:14])=[C:10]([Cl:13])[CH:11]=2)[CH2:6][C@@H:5]([C:15]([NH2:19])=[O:17])[CH2:4]1
Reactant: N
Reactant: COC(=O)[C@@H]1Cc2cc(Cl)c(Cl)cc2[C@@H](N)C1
Agent: Cl
Solvent: CO
Product: NC(=O)[C@@H]1Cc2cc(Cl)c(Cl)cc2[C@@H](N)C1

Procedure:
Into a solution of 3.6 g of methyl trans-4-amino-6,7-dichloro-1,2,3,4-tetrahydro-2-naphthoate hydrochloride in 50 ml of methanol and 15 ml of 28% aqueous ammonia, ammonia gas is blown at 30°-40° C. for 8 hours. The solvent is distilled off and water is added. The precipitated crystals are separated by filtration and dissolved in methanol and to the solution is added methanolic hydrochloric acid. Crystals are deposited, separated by suction filtration and recrystallized from methanol to give 1.6 g of trans-4-amino-6,7-dichloro-1,2,3,4-tetrahydro-2-naphthalene carboxamide hydrochloride having a m.p. of above 280° C.