Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9](=[O:48])[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24](=[O:33])[NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Br:32])[CH:27]=3)=[CH:20][C:19]=2[NH:34][C:35]2[C:36]3[CH:44]=[CH:43][C:42]([CH:45]([CH3:47])[CH3:46])=[N:41][C:37]=3[N:38]=[CH:39][N:40]=2)[CH:12]=1)(C)(C)C.[F:50][C:51]([F:56])([F:55])[C:52]([OH:54])=[O:53]>>[NH2:7][CH2:8][C:9]([NH:10][C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=1)[O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([Br:32])[CH:27]=2)=[O:33])=[CH:20][C:19]=1[NH:34][C:35]1[C:36]2[CH:44]=[CH:43][C:42]([CH:45]([CH3:47])[CH3:46])=[N:41][C:37]=2[N:38]=[CH:39][N:40]=1)=[O:48].[F:50][C:51]([F:56])([F:55])[C:52]([OH:54])=[O:53]
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4cccc(Br)c4)ccc3Oc3cccc(NC(=O)CNC(=O)OC(C)(C)C)c3)ncnc2n1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4cccc(Br)c4)ccc3Oc3cccc(NC(=O)CN)c3)ncnc2n1

Procedure:
The product of Example 110 (0.04 g, 0.055 mmol) was treated with trifluoroacetic acid as in the procedure for Example 96. The crude product was purified by trituration in dichloromethane to provide the title compound as a trifluoroacetic acid salt (0.046 g, 98%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.33 (d, J=6.99 Hz, 6 H), 3.21-3.32 (m, 1 H), 3.75 (d, J=5.52 Hz, 2 H), 6.81 (d, J=9.19 Hz, 1 H), 7.14 (d, J=8.82 Hz, 1 H), 7.24-7.38 (m, 3 H), 7.45 (s, 1 H), 7.72-7.78 (m, 1 H), 7.81 (d, J=8.46 Hz, 1 H), 8.02 (dd, J=8.82, 2.21 Hz, 1 H), 8.10 (s, 3 H), 8.18 (d, J=1.84 Hz, 1 H), 8.80 (s, 1 H), 8.92 (d, J=8.46 Hz, 1 H), 10.45 (s, 1 H), 11.26 (s, 1 H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=3)=[N:12][N:13]=2)[CH:5]=[C:6](I)[CH:7]=1.[CH:22]1[C:34]2[NH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]=2[CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:31]1[C:32]2[N:33]([C:2]3[CH:3]=[C:4]([C:9]4[O:10][C:11]([C:14]5[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=5)=[N:12][N:13]=4)[CH:5]=[C:6]([N:33]4[C:34]5[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=5[C:27]5[C:32]4=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH:7]=3)[C:34]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27]=2[CH:28]=[CH:29][CH:30]=1
Reactant: COc1cccc(-c2nnc(-c3cc(I)cc(I)c3)o2)c1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(-c2nnc(-c3cc(-n4c5ccccc5c5ccccc54)cc(-n4c5ccccc5c5ccccc54)c3)o2)c1
Reaction time: 5 h

Procedure:
To a solution of 2-(3,5-diiodophenyl)-5-(3-methoxyphenyl)-1,3,4-oxadiazole (1.0 g, 1.98 mmol), carbazole (1.0 g, 5.98 mmol), Cu (4.0 g, 62.95 mmol) in DMF (20.0 ml) was added potassium carbonate (6.0 g, 43.41 mmol) under nitrogen and stirring. Heating was started. The reaction was carried out at 150° C. for 5 h. After cooling, the reaction mixture was filtrated. The solid residues were carefully washed with THF. THF was evaporated from the combined filtration solution. Water (150.0 ml) was added, the brown solid product was obtained by filtration. The crude product was purified by silica gel column chromatography using toluene/ethyl acetate (9.7:0.3) as eluent. After evaporating solvent, the white solid was recrystallized from THF/methanol and finally dried under vacuum. Pure product was obtained as white solid in 0.99 g (86.0%) yield. 1H NMR (399 MHz, CDCl3, δ): 8.47 (d, J=2.4 Hz, 2H), 8.16 (d, J=8.0 Hz, 4 Hz), 8.01 (t, J=1.6 Hz, 1H), 7.69-7.64 (m, 2H), 7.58 (d, J=8.0 Hz, 4H), 7.45 (m, 4H), 7.41 (t, J=8.0 Hz, 1H), 7.34 (m, 4H), 7.08 (m, 1H), 3.87 (s, 3H, OCH3). 13C NMR (100 MHz, CDCl3, δ): 164.72, 164.02, 159.99, 140.90, 140.21, 130.28, 128.58, 127.21, 126.21, 124.88, 123.76, 122.40, 120.57, 120.48, 119.33, 118.29, 111.61, 109.68, 94.23, 55.55. [M]+ calcd for C39H26N4O2, 582.2. found 582.2. Anal. Calcd for C39H26N4O2: C, 80.39; H, 4.50; N, 9.62. Found: C, 80.32; H, 4.41; N, 9.60.
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:13])=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[C:14](#[N:17])[CH:15]=[CH2:16].N12CCN(CC1)CC2>[OH-].[Na+]>[C:1]([C:5]1[CH:12]=[CH:11][CH:10]=[C:7]2[C:6]=1[O:13][CH2:16][C:15]([C:14]#[N:17])=[CH:8]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cccc(C=O)c1O
Reactant: C=CC#N
Agent: C1CN2CCN1CC2
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)c1cccc2c1OCC(C#N)=C2

Procedure:
3-tert-butyl-2-hydroxybenzaldehyde (Aldrich, 4.0 mL, 23.4 mmol), acrylonitrile (7.7 mL, 117 mmol), and 1,4-diazabicyclo[2.2.2]octane (0.66 g, 5.8 mmol) were heated in a microwave Personal Chemistry at 95° C. for 5 hours. Sodium hydroxide (1N, 200 mL) was added and the mixture was extracted twice with ethyl acetate (200 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrate under reduced pressure. The residue was chromatographed on silica gel eluting with 0-to-30% ethyl acetate in hexane to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.31 (s, 9H), 4.85 (d, J=1.36 Hz, 2H), 6.97 (t, J=7.63 Hz, 1H), 7.16 (dd, J=7.63, 1.53 Hz, 1H), 7.29 (dd, J=7.80, 1.70 Hz, 1H), 7.58 (s, 1H). MS (DCI) m/z 231.10 (M+NH4)+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:8][C:9](=[O:19])[C@@H:10]1[CH2:14][CH:13]([OH:15])[CH2:12][N:11]1[C:16](=[O:18])[CH3:17])[CH3:7].C(N(CC)CC)C.Cl>C(Cl)(Cl)Cl>[CH2:6]([O:8][C:9](=[O:19])[C@@H:10]1[CH2:14][CH:13]([O:15][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:12][N:11]1[C:16](=[O:18])[CH3:17])[CH3:7]
Reactant: CCOC(=O)[C@@H]1CC(O)CN1C(C)=O
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)[C@@H]1CC(OS(C)(=O)=O)CN1C(C)=O
Reaction time: 0.5 h
Yield: 72 %

Procedure:
457 g of methanesulfonyl chloride was added dropwise to a solution of 1020 g of N-acetyl-4-hydroxy-L-proline ethyl ester, 435 g of triethylamine and 1.9 L of chloroform at not higher than 15° C. while cooling. After stirring for 30 minutes, 1N hydrochloric acid (0.6 L) was added, and the layers were separated. The organic layer was washed with 5% aqueous sodium bicarbonate (600 g), washed with water (0.6 L), dried over magnesium sulfate, and concentrated under reduced pressure to obtain 802 g of N-acetyl-4-mesyloxy-L-proline ethyl ester as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:15]3([CH2:20][CH2:19][S:18][C:17]([NH:21]C(=O)C4C=CC([N+]([O-])=O)=CC=4)=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([I:33])[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.O.[OH-].[Li+]>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:15]3([CH2:20][CH2:19][S:18][C:17]([NH2:21])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([I:33])[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(NC1=NC2(CCS1)c1cc(I)ccc1Oc1ncc(Br)cc12)c1ccc([N+](=O)[O-])cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: NC1=NC2(CCS1)c1cc(I)ccc1Oc1ncc(Br)cc12

Procedure:
A suspension of N-(3-bromo-7-iodo-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]thiazin]-2′-yl)-4-nitrobenzamide (0.906 g, 1.422 mmol) and lithium hydroxide hydrate (0.179 g, 4.27 mmol) in MeOH (28.4 ml) was heated to reflux for 3 hours. The solvent was removed under reduced pressure to afford 3-bromo-7-iodo-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]thiazin]-2′-amine as a pink solid.
Reaction SMILES: O=[C:2]([CH3:15])[CH2:3][S:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([OH:14])=[O:13].Cl.[Cl:17][C:18]1[CH:19]=[C:20]([NH:24]N)[CH:21]=[CH:22][CH:23]=1>>[Cl:17][C:18]1[CH:19]=[C:20]2[C:21]([C:3]([S:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[CH2:11][C:12]([OH:14])=[O:13])=[C:2]([CH3:15])[NH:24]2)=[CH:22][CH:23]=1
Reactant: NNc1cccc(Cl)c1
Reactant: CC(=O)CSc1ccccc1CC(=O)O
Agent: Cl
Product: Cc1[nH]c2cc(Cl)ccc2c1Sc1ccccc1CC(=O)O

Procedure:
Prepared according to the procedure described in Example 2, Step 1, using the following starting materials: [2-(2-oxo-propylsulfanyl)-phenyl]-acetic acid and 3-chlorophenylhydrazine hydrochloride.
Reaction SMILES: O1CCOCC1.[C:7]([NH:15][C:16]1[C:17]([N+:30]([O-:32])=[O:31])=[CH:18][C:19]2[O:24][C:23]([CH3:26])([CH3:25])[CH:22](Br)[CH:21]([OH:28])[C:20]=2[CH:29]=1)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+]>O>[C:7]([NH:15][C:16]1[C:17]([N+:30]([O-:32])=[O:31])=[CH:18][C:19]2[O:24][C:23]([CH3:26])([CH3:25])[CH:22]3[O:28][CH:21]3[C:20]=2[CH:29]=1)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC1(C)Oc2cc([N+](=O)[O-])c(NC(=O)c3ccccc3)cc2C(O)C1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)Oc2cc([N+](=O)[O-])c(NC(=O)c3ccccc3)cc2C2OC21
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
A mixed solution of a 1,4-dioxane (5 mL) and water (2.5 mL) in which a 6-(benzoylamino)-3-bromo-3,4-dihydro-2,2-dimethyl-7-nitro-2H-1-benzopyran-4-ol (III-1) (223 mg, 0.53 mmol) was dissolved was added with a sodium hydroxide (25.5 mg, 1.2 eq.) and stirred at room temperature for one hour. After the solution was diluted with water, the resulting mixture was extracted with an ethyl acetate and the organic layer was washed with an aqueous saturated sodium chloride solution, the layer was dried over a sodium sulfate anhydride. After the solvent was distilled off, the obtained residue was purified through silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain the intended product (147 mg, 81%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][C:9]3[C:18]([CH3:19])=[CH:17][C:16]([C:20]([OH:22])=[O:21])=[CH:15][C:10]=3[S:11](=[O:14])(=[O:13])[CH2:12][C:6]=2[CH:5]=[C:4]([S:23](Cl)(=[O:25])=[O:24])[CH:3]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.O>C(OCC)(=O)C>[Cl:1][C:2]1[C:7]2[O:8][C:9]3[C:18]([CH3:19])=[CH:17][C:16]([C:20]([OH:22])=[O:21])=[CH:15][C:10]=3[S:11](=[O:14])(=[O:13])[CH2:12][C:6]=2[CH:5]=[C:4]([S:23]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)(=[O:25])=[O:24])[CH:3]=1
Reactant: C1COCCN1
Reactant: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(S(=O)(=O)Cl)cc1CS2(=O)=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(S(=O)(=O)N3CCOCC3)cc1CS2(=O)=O

Procedure:
A mixture of Example 49j (0.2 g, 0.45mm) and morpholine (0.08 mL, 0.9 mmol) in dry ethyl acetate (25 mL) was stirred overnight at room temperature, treated with water and extracted with ethyl acetate. The organic layer was washed with 10% aqueous HCl (50 mL), water, brine, concentrated and purified using flash chromatography (silica gel, methanol/chloroform) to obtain the title compound. Yield: 0.19 g, (86%); 1H NMR (DMSO-d6): δ 2.80 (s, 3H, CH3), 3.0 (t, 4H, 2CH2), 3.7 (s, 4H, 2CH2), 5.5 (s, 2H; CH2), 8.0 (s, 1H, Ar), 8.1 (s, 1H, Ar), 8.2 (s, 2H, Ar). MS: m/e (EI+) 487 (M+).
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[C:9](=[N:10][C:11]([C:15]([F:18])([F:17])[F:16])=[CH:12][CH:13]=2)[N:8]=[C:7]1[CH2:19]O)[CH2:2][CH:3]([CH3:5])[CH3:4].[CH:21]1([N:24]2[C:32]3[CH:31]=[CH:30][N:29]=[CH:28][C:27]=3[NH:26][C:25]2=[O:33])[CH2:23][CH2:22]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C([O-])=O)=NC([O-])=O>C1COCC1>[CH:21]1([N:24]2[C:32]3[CH:31]=[CH:30][N:29]=[CH:28][C:27]=3[N:26]([CH2:19][C:7]3[N:6]([CH2:1][CH2:2][CH:3]([CH3:4])[CH3:5])[C:14]4[C:9]([N:8]=3)=[N:10][C:11]([C:15]([F:16])([F:17])[F:18])=[CH:12][CH:13]=4)[C:25]2=[O:33])[CH2:23][CH2:22]1
Reactant: O=c1[nH]c2cnccc2n1C1CC1
Reactant: CC(C)CCn1c(CO)nc2nc(C(F)(F)F)ccc21
Agent: O=C([O-])N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)CCn1c(Cn2c(=O)n(C3CC3)c3ccncc32)nc2nc(C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.2 %

Procedure:
To a suspension of (1-isopentyl-5-(trifluoromethyl)-1H-imidazo[4,5-b]pyridin-2-yl)methanol 44-3 (1.0 g, 3.5 mmol (73% purity)), 1-cyclopropyl-1H-imidazo[4,5-c]pyridin-2(3H)-one 10-d (731.8 mg, 4.2 mmol) and triphenylphosphine (1.1 g, 4.2 mmol) in 24 ml dry THF was added (E)-diïsopropyl diazene-1,2-dicarboxylate (1.0 ml, 5.2 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was evaporated to dryness and purified by preparative column chromatography to obtain 44 as a white solid (578.0 mg, 37%). m/z=445 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.02 (m, J=6.50 Hz, 8H) 1.13-1.24 (m, 2H) 1.48-1.64 (m, 2H) 1.73 (dquin, J=13.19, 6.49, 6.49, 6.49, 6.49 Hz, 1H) 2.92 (tt, J=6.81, 3.48 Hz, 1H) 4.35-4.52 (m, 2H) 5.41 (s, 2H) 7.13 (d, J=5.27 Hz, 1H) 7.61 (d, J=8.28 Hz, 1H) 7.79 (d, J=8.28 Hz, 1H) 8.34 (d, J=5.27 Hz, 1H) 8.68 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][NH:14]2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.C(N(CC)C(C)C)(C)C.[Cl:29][CH2:30][C:31](Cl)=[O:32]>C1COCC1>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][N:14]2[C:31](=[O:32])[CH2:30][Cl:29])=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCCN2)no1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCCN2C(=O)CCl)no1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (S)-Piperidine-2-carboxylic acid (5-tert-butyl-isoxazol-3-yl) amide; hydrochloride (611 mg; 2.123 mmol) in THF (15 mL) is added N,N-diisopropylethylamine (0.74 mL; 4.246 mmol), followed by alpha-chloroacetyl chloride (0.17 mL; 2.134 mmol). The reaction mixture is stirred at room temperature for 18 hours.
Reaction SMILES: [S:1]1[C:5]([NH:6][S:7]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[N:4][CH:3]=[N:2]1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][C:24]([CH:27]([NH2:29])[CH3:28])=[CH:23][CH:22]=1>>[S:1]1[C:5]([NH:6][S:7]([C:10]2[CH:11]=[CH:12][C:13]([C:14]([NH:29][CH:27]([C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:30])[F:31])=[CH:26][CH:25]=3)[CH3:28])=[O:16])=[CH:17][CH:18]=2)(=[O:8])=[O:9])=[N:4][CH:3]=[N:2]1
Reactant: O=C(O)c1ccc(S(=O)(=O)Nc2ncns2)cc1
Reactant: CC(N)c1ccc(C(F)(F)F)cc1
Product: CC(NC(=O)c1ccc(S(=O)(=O)Nc2ncns2)cc1)c1ccc(C(F)(F)F)cc1

Procedure:
The title compound was prepared from 4-[(1,2,4-thiadiazol-5-ylamino)sulfonyl]benzoic acid (Preparation 29) and 1-[4-(trifluoromethyl)phenyl]ethanamine following the procedure described in Example 309. The reaction mixture was extracted from saturated sodium hydrogen carbonate into DCM and the crude product purified by preparative HPLC.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=1)[CH3:13])[CH:6]=[N:5]2.[C:26]([N:33]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[N:34]1)([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>O1CCOCC1.C(OCC)(=O)C>[C:29]([O:28][C:26]([N:33]1[CH:37]=[C:36]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([N:12]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([C:22]([F:24])([F:23])[F:25])[CH:16]=2)[CH3:13])[CH:6]=[N:5]3)[CH:35]=[N:34]1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CN(Cc1ccc(F)c(C(F)(F)F)c1)c1cnc2cc(Br)ccc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CN(Cc1ccc(F)c(C(F)(F)F)c1)c1cnc2cc(-c3cnn(C(=O)OC(C)(C)C)c3)ccc2n1
Temperature: 108 °C

Procedure:
A mixture of (6-Bromo-quinoxalin-2-yl)-(4-fluoro-3-trifluoromethyl-benzyl)-methyl-amine (0.35 g, 1 eq, 0.84 mmol), 1-Boc-4-pyrazole boronic acid pinacol ester (0.3 g, 1.2 eq, 1.01 mmol), caesium carbonate (1.1 g, 4.0 eq, 3.3 mmol) and potassium iodide (0.014 g, 0.1 eq, 0.84 mmol) in 1,4-dioxane (15 mL) was degassed at RT under vacuum and then placed under an atmosphere of nitrogen. The process was repeated twice and Fu's catalyst (Bis(tri-tert-butylphosphine)palladium(0)) (0.02 g, 0.05 eq, 0.04 mmol) was added at room temperature. The reaction mixture was heated at 108° C. in a microwave reactor for 180 min. After completion of the reaction (confirmed by TLC), the organic mixture was diluted with ethyl acetate (325 mL) and washed with water (100 mL×3) followed by brine (100 mL). The organic solvent was dried and concentrated to give a solid residue.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].Cl[C:6]([CH2:8][S:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:7].S(=O)(=O)(O)O>C1C=CC=CC=1.[Cl-].[Cd+2].[Cl-].[Cd]>[CH3:1][CH2:2][C:6](=[O:7])[CH2:8][S:9][CH2:10][C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)CSCC(=O)Cl
Reactant: CC[Mg]Br
Agent: O=S(=O)(O)O
Agent: [Cd+2]
Agent: [Cd]
Solvent: c1ccccc1
Product: CCC(=O)CSCC(=O)OC
Temperature: 0 °C
Yield: 60.9 %

Procedure:
To a stirred ice-cold ethereal Grignard solution (392 ml) containing 0.56 mole of ethylmagnesium bromide, is added 51.3 g (0.28 mole) of dry powdered cadmium chloride in small portions. Stirring is continued without heating for 5 minutes, followed by refluxing for 30 - 45 minutes until no Gilman test for Grignard reagent is observed. Then, 500 ml of dry benzene is added thereto, and the resulting cadmium reagent is cooled to below 0° C (usually -10° to 0° C). A solution of 91.3 g (0.5 mole) of methyl 2-(chloroformylmethylmercapto)acetate in 500 ml of dry benzene is added with vigorous stirring as rapidly as consistent with control of the exothermic reaction. The reaction mixture is stirred at room temperature for 3 - 5 hours, then decomposed by addition of cold 6N sulfuric acid, and extracted three times with ether. The organic extracts are combined, washed successively with an aqueous sodium bicarbonate solution and an aqueous sodium chloride solution and dried over sodium sulfate. After evaporation of the solvent in vacuo, the residual liquid is distilled under reduced pressure to give 53.7 g (60.9% yield) of methyl 2-(3-methylacetonylmercapto)acetate as an oily material, bp. 137 - 140° C/13 mmHg). IR: νmaxNeat cm-1 : 1740, 1711; νmaxCHCl3 cm-1 : 1737, 1712. NMR: ppm (CDCl3): 1.10 (triplet, 3H, J = 7, CH2CH3), 2.62 (quartet, 2H, J = 7, CH2CH3), 3.28 (singlet, 2H, SCH2COO), 3.43 (singlet, 2H, SCH2CO), 3.73 (singlet, 3H, COOMe). Anal. Calcd. for C7H12O3S (%): C, 47.70; H, 6.86; S, 18.19. Found (%): C, 47.96; H, 6.98; S, 17.90.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[OH:10])=[O:4].[C:11]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH3:11][O:10][C:9]1[CH:8]=[CH:7][S:6][C:5]=1[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)c1sccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1sccc1OC
Temperature: 55 °C
Yield: 108.4 %

Procedure:
To a mixture of 3-hydroxy-thiophene-2-carboxylic acid methyl ester (5 g, 31.6 mmol) and K2CO3 (22.2 g, 161 mmol) in acetone (50 mL) is added CH3I (10.8 mL, 173 mmol,) dropwise at 0° C. The reaction mixture is heated at 55° C. for 4 hours, cooled to room temperature, filtered through diatomaceous earth, and the filtrate is concentrated under vacuum. The residue is diluted with water (100 mL) and extracted with ethyl acetate (2×200 mL). The combined organic layer is washed with brine solution (50 mL), dried over Na2SO4, and evaporated under vacuum to give title compound as a brown solid (5.9 g). ESI/MS m/z 173.1 (M+H)+.
Reaction SMILES: [CH2:1]([N:4]([CH2:12][CH:13]=C)C(=O)OC(C)(C)C)[CH:2]=C.O=[O+][O-].[NH2:18][C@H:19]1[CH2:28][CH2:27][C:26]2[CH:25]=[C:24]([C:29]#[N:30])[CH:23]=[CH:22][C:21]=2[CH2:20]1.C(N(CC)CC)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[N:18]1([C@H:19]2[CH2:28][CH2:27][C:26]3[CH:25]=[C:24]([C:29]#[N:30])[CH:23]=[CH:22][C:21]=3[CH2:20]2)[CH2:13][CH2:12][NH:4][CH2:1][CH2:2]1
Reactant: C=CCN(CC=C)C(=O)OC(C)(C)C
Reactant: N#Cc1ccc2c(c1)CC[C@H](N)C2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=[O+][O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc2c(c1)CC[C@H](N1CCNCC1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl diallylcarbamate (0.63 g, 3.2 mmol) in DCM at −78° C. was bubbled ozone until a blue color persisted. Nitrogen was bubbled through the reaction to remove excess ozone, followed by addition of a DCM solution of (6S)-6-amino-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (0.14 g, 0.80 mmol) and triethylamine (0.22 mL, 1.6 mmol). Then NaB(OAc)3H (0.85 g, 4.0 mmol) was added to the reaction. The mixture was allowed to warm to RT and stir overnight. LC showed formation of the desired product, which was separated by prep-TLC to furnish 87 mg of tert-butyl 4-[(2S)-6-cyano-1,2,3,4-tetrahydronaphthalen-2-yl]piperazine-1-carboxylate. LC-MS (IE, m/z): 173 [M+1]+. The material was further treated with TFA to afford crude (6S)-6-piperazin-1-yl-5,6,7,8-tetrahydronaphthalene-2-carbonitrile.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:6]=1[N+:15]([O-])=O.Cl>C(O)(=O)C.[Fe]>[F:14][C:11]([F:12])([F:13])[C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:5]=1[CH:4]=[CH:3][NH:15]2
Reactant: CN(C)/C=C/c1c([N+](=O)[O-])cccc1C(F)(F)F
Agent: [Fe]
Agent: Cl
Solvent: CC(=O)O
Product: FC(F)(F)c1cccc2[nH]ccc12
Yield: 112.3 %

Procedure:
850 mg of powdered iron are added to a solution of 1.2 g of dimethyl[(E)-2-(2-nitro-6-trifluoromethylphenyl)vinyl]amine in 30 ml of acetic acid. The reaction mixture is refluxed for 16 hours and then poured into a solution of hydrochloric acid (HCl, 2N), and extracted with ethyl acetate. The organic phases are washed with a 10% sodium carbonate solution and then with a saturated NaCl solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure so as to give 959 mg of 4-trifluoromethyl-1H-indole which is used in the next step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[C:11]2[S:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])=[CH:6][CH:5]=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH:11]2[S:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(C=C2SC(=O)NC2=O)cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(CC2SC(=O)NC2=O)cc1
Reaction time: 3 h
Yield: 92.6 %

Procedure:
A solution of the methyl ester 350 (615 mg, 2.32 mmol) in MeOH (120 ml) was hydrogenated over 10% Pd/C (615 mg, Degussa type) for 2 hours at room temperature. Another portion of Pd/C (300 mg) was added and the hydrogenation proceeded for another 3 hrs (monitored by MS). The reaction mixture was filtered through a celite pad, evaporated and the residue was purified by flash chromatography, eluent EtOAc—CH2Cl2 (1:2), to produce the title compound (570 mg, 92% yield). LRMS: 265.3 (calcd.), 266.1 [MH]+ (found).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[C:9]2[CH:10]=[CH:11][N:12]=[CH:13][C:14]=2[CH:15]=[CH:16][CH:17]=1)(=[O:7])=[O:6].[Cl:18][C:19]1[CH:28]=[CH:27][C:22]([CH:23]=[CH:24][CH:25]=O)=[CH:21][CH:20]=1.[Na].C(OCC)(=O)C>CO>[Cl:18][C:19]1[CH:28]=[CH:27][C:22]([CH:23]=[CH:24][CH2:25][NH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]2[C:9]3[CH:10]=[CH:11][N:12]=[CH:13][C:14]=3[CH:15]=[CH:16][CH:17]=2)(=[O:7])=[O:6])=[CH:21][CH:20]=1
Reactant: O=CC=Cc1ccc(Cl)cc1
Reactant: NCCNS(=O)(=O)c1cccc2cnccc12
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=S(=O)(NCCNCC=Cc1ccc(Cl)cc1)c1cccc2cnccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.5 %

Procedure:
2.01 g of N-(2-aminoethyl)-5-isoquinolinesulfonamide was dissolved in 30 ml of methanol, to the solution was added 1.60 g of p-chlorocinnamaldehyde, and the mixture was stirred for one hour at a room temperature. After an addition of 350 mg of sodium tetrahydrideborate in portions with ice cooling, the mixture was stirred for 30 minutes. After an addition of ethyl acetate, the reaction mixture was sequentially washed three times with water, and then twice with a saturated sodium chloride aqueous solution, and dried over magnesium sulfate. The mixture was filtered and evaporated to remove the solvent under a reduced pressure. A residue was purified using a silica gel column (silica gel 80 g, eluant: 5% methanol in chloroform), and resulting crystals were washed with benzene/hexane (1:1), to obtain 2.30 g of the title compound as colorless crystals.