Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([CH3:14])([CH3:13])[O:10]2)=[C:5]([NH:15][C:16]2[C:17]([C:26](O)=[O:27])=[CH:18][C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:4]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[O:10][C:9]([CH3:14])([CH3:13])[CH:8]=[CH:7][C:6]2=[C:5]2[C:4]=1[C:26](=[O:27])[C:17]1[CH:18]=[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]3=[CH:25][C:16]=1[NH:15]2
Reactant: COc1cc(Nc2cc3ccccc3cc2C(=O)O)c2c(c1)OC(C)(C)C=C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2c(c3[nH]c4cc5ccccc5cc4c(=O)c13)C=CC(C)(C)O2
Reaction time: 2 h

Procedure:
1.02 mmol of the compound obtained in Step A in 14 ml of dichloromethane is treated with 1 ml of trifluoroacetic acid. After 2 hours at room temperature, the reaction mixture is evaporated. The residue is taken up in a mixture of dichloromethane and a saturated NaHCO3 solution, extracted with dichloromethane, washed with a 10% sodium hydroxide solution and then extracted again with dichloromethane. After conventional treatment, chromatography of the residue over silica gel (dichloromethane/methanol: 98/2) enables isolation of the expected product.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([OH:6])=O.O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[Cl:26][C:27]1[CH:28]=[C:29]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][C:41]([O:52][CH3:53])=[CH:42][C:43]=3[O:45][CH2:46][C@H:47]3[CH2:51][CH2:50][CH2:49][NH:48]3)[N:38]=[CH:37][N:36]=2)[CH:30]=[CH:31][C:32]=1[F:33]>C(Cl)Cl>[Cl:26][C:27]1[CH:28]=[C:29]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][C:41]([O:52][CH3:53])=[CH:42][C:43]=3[O:45][CH2:46][C@H:47]3[CH2:51][CH2:50][CH2:49][N:48]3[C:4](=[O:6])[CH2:3][O:2][CH3:1])[N:38]=[CH:37][N:36]=2)[CH:30]=[CH:31][C:32]=1[F:33]
Reactant: COCC(=O)O
Reactant: COc1cc(OC[C@H]2CCCN2)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COCC(=O)N1CCC[C@@H]1COc1cc(OC)cc2ncnc(Nc3ccc(F)c(Cl)c3)c12
Reaction time: 1 h
Yield: 82.3 %

Procedure:
Methoxyacetic acid (27 mg) and 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (103 mg) were added sequentially, each in one portion, to a stirred mixture of N-(3-chloro-4-fluorophenyl)-7-methoxy-5-[(2R)-pyrrolidin-2-ylmethoxy]-quinazolin-4-amine (100 mg) in DCM (2 ml) at room temperature. The reaction mixture was stirred for 1 hour and then diluted with DCM (10 ml) and washed with saturated aqueous sodium hydrogen carbonate. The organic layer was dried (MgSO4) and concentrated in vacuo to leave a yellow solid, which was triturated with 1:1 ether/hexanes and filtered to give the title compound as a white solid (97 mg, 82%); NMR Spectrum (DMSO-d6) 9.90 (br s, 1H), 8.40 (s, 1H), 8.15 (m, 1H), 7.65 (m, 1H), 7.40 (m, 1H), 6.80 (m, 2H), 4.60 (m, 1H), 4.50 (m, 1H), 4.25 (m, 1H), 4.0 (m, 3H), 3.95 (s, 3H), 3.50 (m, 21), 3.20 (m, 2H), 2.0-1.85 (m, 4H); Mass spectrum MH+ 475.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=1.[OH-].[Na+].[CH3:18][NH:19][CH2:20][CH3:21]>O>[CH3:18][N:19]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=1)[CH2:20][CH3:21]
Reactant: ClCCCCCCOc1ccc(Br)cc1
Reactant: CCNC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCN(C)CCCCCCOc1ccc(Br)cc1
Temperature: 40 °C
Yield: 80 %

Procedure:
A 100 mL flask provided with a stirrer and a reflux condenser was charged in a nitrogen gas atmosphere with 14.6 g (0.05 mol) of the p-(6-chlorohexyloxy)bromobenzene, synthesized at the above-mentioned step 1), 4.0 g (0.10 mol) of sodium hydroxide (available from Wako Pure Chemical Industries Ltd.), 0.8 g (0.012 mol) of n-tetrabutylammonium bromide (available from Kanto Chemical Co., Inc.) and 5.0 g of water. The content was maintained at 40° C. while being stirred. Then 5.9 g (0.10 mol) of methylethylamine (available from Wako Pure Chemical Industries Ltd.) was dropwise added at the same temperature over a period of 2 hours. Thereafter the reaction liquid was maintained at that temperature for 20 hours while being stirred. After completion of the reaction, the phase separation was conducted and the organic phase was subjected to silica-gel column chromatography to give 13.4 g of the target p-(N-methyl-N-ethylaminohexyloxy)bromobenzene (yield: 80%, purity: 94%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([C:16](=[O:18])[NH2:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[C:20]([N:24]1[C:28](=[O:29])[CH:27]=[C:26](Cl)[S:25]1(=[O:32])=[O:31])([CH3:23])([CH3:22])[CH3:21]>>[C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([C:16](=[O:18])[NH2:17])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:26]2[S:25](=[O:31])(=[O:32])[N:24]([C:20]([CH3:22])([CH3:21])[CH3:23])[C:28](=[O:29])[CH:27]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N1C(=O)C=C(Cl)S1(=O)=O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(N)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C2=CC(=O)N(C(C)(C)C)S2(=O)=O)cc1)C(N)=O

Procedure:
This compound was prepared according to the procedure of Example 1.1, Step 4, using (S)-2-phenyl-1-carbamoyl-ethyl-carbamic acid tert-butyl ester and 9-A as the starting materials. LCMS found for C21H29N3O6SNa (M+Na)+: m/z=474.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1/[CH:13]=[CH:14]/[CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([CH:37]=O)=[N:29]1>CO.N1CCCCC1>[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30](/[CH:37]=[C:8]2\[O:9][C:5]3[C:4](/[CH:13]=[CH:14]/[CH:15]4[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:29]1
Reactant: O=Cc1n[nH]c2ccccc12
Reactant: COc1ccc2c(c1/C=C/C1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Solvent: C1CCNCC1
Solvent: CO
Product: COc1ccc2c(c1/C=C/C1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 76.7 %

Procedure:
A solution of tert-butyl (E)-4-[2-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)vinyl]piperidine-1-carboxylate (0.0692 g, 0.185 mmol) in methanol (5 mL) was added with 1H-indazole-3-carboxaldehyde (0.0270 g, 0.185 mmol) and piperidine (7 drops), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl 4-((E)-2-{(Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}vinyl)piperidine-1-carboxylate (0.0712 g, 77%).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=O.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:19])([CH3:16])([CH3:15])[CH3:14].CO>C(Cl)Cl>[CH3:1][O:30][C:29](=[O:31])[CH2:28][CH2:27][CH2:26][CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25][N:20]1[C:18]([O:17][C:13]([CH3:16])([CH3:14])[CH3:15])=[O:19]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CCCC(=O)O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)CCCC1CCCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
1,1′-Carbonyldiimidazole (23.3 g, 143.7 mmol) was added to a solution of 4-(1-tert-butoxycarbonyl)piperidin-2-yl)butanoic acid (2) (26 g, 95.8 mmol) in methylene chloride. The reaction mixture was stirred at room temperature for 1 h. Methanol (19.4 ml, 479 mmol) was then added and the reaction mixture was stirred overnight. The complete reaction was checked by means of TLC. When the reaction was complete, the reaction mixture was washed 3× with sat. NH4Cl solution (aqueous) and 2× with sat. NaCl solution. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to obtain tert-butyl 2-(4-methoxy-4-oxobutyl)piperidine-1-carboxylate (3) (25.67 g, 94%).
Reaction SMILES: [CH:1]1([C@:4]2([OH:12])[CH2:8][CH2:7][NH:6][C@H:5]2[CH:9]([CH3:11])[CH3:10])[CH2:3][CH2:2]1.[F:13][C:14]1[CH:21]=[C:20](F)[CH:19]=[C:18]([F:23])[C:15]=1[C:16]#[N:17].C(=O)([O-])[O-].[Li+].[Li+]>>[CH:1]1([C@:4]2([OH:12])[CH2:8][CH2:7][N:6]([C:20]3[CH:21]=[C:14]([F:13])[C:15]([C:16]#[N:17])=[C:18]([F:23])[CH:19]=3)[C@H:5]2[CH:9]([CH3:10])[CH3:11])[CH2:3][CH2:2]1
Reactant: CC(C)[C@@H]1NCC[C@@]1(O)C1CC1
Reactant: N#Cc1c(F)cc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CC(C)[C@@H]1N(c2cc(F)c(C#N)c(F)c2)CC[C@@]1(O)C1CC1

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3R)-3-cyclopropyl-2-isopropylpyrrolidin-3-ol 0.5 oxalate (215 mg), 2,4,6-trifluorobenzonitrile (157 mg) and lithium carbonate (163 mg), the title compound was obtained as a colorless solid (yield: 115 mg, yield: 38%).
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]1[C:8]([Cl:21])=[CH:9][C:10]2[CH:11]3[CH2:20][CH2:19][CH2:18][CH:12]3[C:13](=[O:17])[NH:14][C:15]=2[CH:16]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.C(OCC)(=O)C>[Cl:21][C:8]1[C:7]([CH2:6][CH2:5][OH:4])=[CH:16][C:15]2[NH:14][C:13](=[O:17])[CH:12]3[CH2:18][CH2:19][CH2:20][CH:11]3[C:10]=2[CH:9]=1
Reactant: CC(=O)OCCc1cc2c(cc1Cl)C1CCCC1C(=O)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C1Nc2cc(CCO)c(Cl)cc2C2CCCC12
Reaction time: 72 h
Yield: 84.7 %

Procedure:
380 mg (1.2 mmol) of 7-acetoxyethyl-8-chloro-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one is dissolved in 30 ml of methanol and mixed with 341 mg (2.5 mmol) of potassium carbonate. After 3 days at room temperature, the batch is diluted with ethyl acetate, washed with water, dried (Na2SO4) and concentrated by evaporation in a vacuum. Column chromatography on silica gel with ethyl acetate-ethanol yields 270 mg of product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([CH3:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:17])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[C:24]([Cl:26])[CH:25]=1.Cl>ClCCl>[ClH:19].[Cl:19][C:20]1[CH:21]=[C:22]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3([CH3:18])[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[C:10]([NH2:17])=[N:9]3)[CH:3]=2)[CH:23]=[C:24]([Cl:26])[CH:25]=1
Reactant: CC1(c2cccc(Br)c2)N=C(N)c2ccccc21
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Agent: Cl
Solvent: ClCCl
Product: CC1(c2cccc(-c3cc(Cl)cc(Cl)c3)c2)N=C(N)c2ccccc21
Reaction time: 1 h
Yield: 61.7 %

Procedure:
The title compound was prepared as described for Example 78 (Scheme #14, N) starting from 1-(3-bromophenyl)-1-methyl-1H-isoindol-3-amine (Example 90) (71.4 mg, 0.237) and (3,5-dichlorophenyl)boronic acid (47.4 mg, 0.249 mmol) with the exception that the hydrochloride was made by dissolving the product in dichloromethane (1 mL) and adding hydrochloric acid (0.71 mL, 1 M in diethyl ether). The solution was stirred for 1 h and was then concentrated to afford 31.0 mg (32% yield) of the title compound: 1H NMR (DMSO-d6) δ 8.23 (d, J=7.78 Hz, 1 H), 7.91-7.87 (m, 1 H), 7.84-7.74 (m, 4 H), 7.71 (d, J=7.78 Hz, 1 H), 7.67-7.62 (m, 2 H), 7.47 (t, J=7.78 Hz, 1 H), 7.43-7.38 (m, 1 H), 2.06 (s, 3 H); MS (ES) m/z 367, 369, 371 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH:8]([CH3:13])[CH2:9][C:10](O)=[O:11])=O)=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].O.[NH2:20][NH2:21]>C(O)(=O)C>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]2[CH:8]([CH3:13])[CH2:9][C:10](=[O:11])[NH:20][N:21]=2)=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17]
Reactant: CC(CC(=O)O)C(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: CC1CC(=O)NN=C1c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
920 g of 3-(4-chloro-3-nitrobenzoyl)-butyric acid are added to a mixture of 6.8 1 of acetic acid and 499 g of hydrazine hydrate, and the mixture is stirred for 2 hours at 95°-100°. It is poured into ice water, and filtration gives 6-(4-chloro-3-nitrophenyl)-5-methyl-2,3,4,5-tetrahydropyridazin-3-one, m.p. 186°-188°.
Reaction SMILES: [F:1][C:2]([F:18])([C:9]([F:17])([F:16])[C:10]([F:15])([F:14])[CH:11]([F:13])[F:12])[CH2:3][CH:4]([C:7]#[N:8])[C:5]#[N:6].[Br:19][CH2:20][CH2:21][CH2:22]Br.C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[Br:19][CH2:20][CH2:21][CH2:22][C:4]([CH2:3][C:2]([F:18])([F:1])[C:9]([F:16])([F:17])[C:10]([F:14])([F:15])[CH:11]([F:13])[F:12])([C:7]#[N:8])[C:5]#[N:6]
Reactant: N#CC(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Reactant: BrCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#CC(C#N)(CCCBr)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.8 %

Procedure:
3.2 g of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile and 8.6 g of 1,3-dibromopropane were dissolved in 20 ml of dimethyl sulfoxide, 3.0 g of potassium carbonate was added, and the mixture was stirred at room temperature for 2 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with methyl tert-butyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 3.2 g of 2-(3-bromopropyl)-2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile (hereinafter, referred to as the present compound (65)).
Reaction SMILES: [CH3:1][N:2]1[C:6]([Sn](CCCC)(CCCC)CCCC)=[CH:5][N:4]=[CH:3]1.[C:20]([N:23]1[C:32]2[C:27](=[CH:28][C:29](Br)=[CH:30][CH:31]=2)[C@H:26]([NH:34][C:35](=[O:40])[O:36][CH:37]([CH3:39])[CH3:38])[CH2:25][C@@H:24]1[CH3:41])(=[O:22])[CH3:21]>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.CCOC(C)=O.CCCCCC>[CH3:39][CH:37]([O:36][C:35](=[O:40])[NH:34][C@H:26]1[C:27]2[C:32](=[CH:31][CH:30]=[C:29]([C:6]3[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=3)[CH:28]=2)[N:23]([C:20](=[O:22])[CH3:21])[C@@H:24]([CH3:41])[CH2:25]1)[CH3:38]
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncn1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(=O)N1c2ccc(-c3cncn3C)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 140 °C
Reaction time: 16 h
Yield: 13 %

Procedure:
A mixture of 1-methyl-5-(tributylstannyl)-1H-imidazole (200 mg, 0.54 mmol), 1-methylethyl [(2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation, see Example 4) (199 mg, 0.54 mmol) and tetrakis(triphenylphosphine)palladium(0) (31 mg, 0.027 mmol) in dry, degassed DMF (5 mL) was stirred at 140° C. under nitrogen for 16 h then was cooled to room temperature and diluted with AcOEt (20 mL). The solution was washed with water (×2) then brine. The organic phase was dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 0 to 6% MeOH in DCM) gave 1-methylethyl[(2S,4R)-1-acetyl-2-methyl-6-(1-methyl-1H-imidazol-5-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (27 mg, 0.073 mmol, 13%) as a colourless solid after trituration with AcOEt/hexane. LCMS (method G): Retention time 0.59 min, [M+H]+=402.1
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH2:12])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.[CH:13]1([C:16](Cl)=[O:17])[CH2:15][CH2:14]1.O>N1C=CC=CC=1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:16]([CH:13]3[CH2:15][CH2:14]3)=[O:17])[N:8]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: Nc1cc2ccc(Br)cc2cn1
Reactant: O=C(Cl)C1CC1
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1cc2ccc(Br)cc2cn1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
To a cold solution (below 0° C.) of 7-bromoisoquinolin-3-amine (20 g, 0.09 mol) in pyridine (150 mL) was added cyclopropanecarbonyl chloride (11.2 g, 0.108 mol) dropwise. The mixture was stirred at room temperature overnight. After water (500 mL) was added, the reaction mixture was stirred for 30 min. Solid was collected by filtration and washed with water to give the desired product (21 g, 80.4%). LCMS (ESI): RT (Min)=1.009, M+H+=290.7, method=A. 1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 9.10 (s, 1H), 8.44 (s, 1H), 8.30 (s, 1H), 7.22 (d, J=8.8 Hz, 1H), 7.67 (d, J=8.8 Hz, 1H), 2.02-2.10 (m, 1H), 0.84-0.79 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.[Li]CCCC.CN([CH:34]=[O:35])C>C1COCC1>[Br:1][C:2]1[N:3]=[C:4]([CH:34]=[O:35])[N:5]([C:7]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=1
Reactant: CN(C)C=O
Reactant: Brc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1nc(Br)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1.25 h
Yield: 57.8 %

Procedure:
To 4-bromo-1-trityl-1H-imidazole (2.00 g, 5.14 mmol) in 30 mL THF at 0° C., was added a solution of BuLi (1.6M in hexanes, 3.85 mL, 6.17 mmol). The mixture was stirred at 0° C. for 1.25 h, then DMF (0.80 mL, 10.3 mmol) was added. The mixture was stirred for 1 h at 0° C. and 1 h at rt, then was quenched with sat. NH4Cl. The mixture was diluted with EtOAc, washed with H2O and brine, dried (Na2SO4), filtered through a 1″ pad of SiO2 and concentrated. The crude product was purified by flash chromatography (0 to 40% EtOAc/hexanes gradient) to afford 1.24 g of Intermediate 175.1 as a colorless solid.
Reaction SMILES: [C:1]1([S:7]([CH:9](Br)[CH3:10])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].[CH3:13][SH:14]>C(#N)C>[C:1]1([S:7]([CH:9]([S:14][CH3:13])[CH3:10])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS
Reactant: CC(Br)S(=O)c1ccccc1
Agent: [Na]
Solvent: CC#N
Product: CSC(C)S(=O)c1ccccc1
Yield: 75.4 %

Procedure:
832 mg of (1-bromoethyl) phenyl sulfoxide was dissolved in 1 ml. of acetonitrile, and with addition of 3.3 ml. of a 20% aqueous solution of sodium salt of methyl mercaptan, the mixture was heated at 40° C. for 10 hours. The product was extracted with 50 ml. of chloroform, and dried with anhydrous sodium sulfate. The solvent was removed at reduced pressure, and the product was separated by column-chromatography (silica gel, chloroform). There was obtained 170 mg of 1-methylthioethyl phenyl sulfoxide in a yield of 75.4%.
Reaction SMILES: FC(F)(F)S([O:6][C:7]1[N:12]=[C:11]2[C:13]3[N:20]([CH3:21])[N:19]=[C:18]([C:22](=[O:27])[N:23]([O:25][CH3:26])[CH3:24])[C:14]=3[CH2:15][CH2:16][CH2:17][C:10]2=[CH:9][N:8]=1)(=O)=O.[Cl:30][C:31]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=1O>C1COCC1>[Cl:30][C:31]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=1[O:6][C:7]1[N:12]=[C:11]2[C:13]3[N:20]([CH3:21])[N:19]=[C:18]([C:22]([N:23]([O:25][CH3:26])[CH3:24])=[O:27])[C:14]=3[CH2:15][CH2:16][CH2:17][C:10]2=[CH:9][N:8]=1
Reactant: CON(C)C(=O)c1nn(C)c2c1CCCc1cnc(OS(=O)(=O)C(F)(F)F)nc1-2
Reactant: Oc1ccc(Cl)cc1Cl
Solvent: C1CCOC1
Product: CON(C)C(=O)c1nn(C)c2c1CCCc1cnc(Oc3ccc(Cl)cc3Cl)nc1-2
Temperature: 60 °C
Reaction time: 48 h
Yield: 2 %

Procedure:
To a solution of 3-[methoxy(methyl)carbamoyl]-1-methyl-1,4,5,6-tetrahydropyrazolo[4′,3′:6,7]cyclohepta[1,2-d]pyrimidin-9-yl trifluoromethanesulfonate (73 mg, 0.17 mmol) in THF (3 mL), 2,4-dichlorophenol was added in a microwave vial flushed with argon. The reaction mixture was stirred at 60° C. for 48 h. The solvent was removed under reduced pressure, the crude was purified by preparative HPLC to give 2 mg (2% yield) of the title compound.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.Br[CH2:12][C:13]1[O:17][N:16]=[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]=1>CCOC(C)=O.CCCCCC>[C:18]1([C:15]2[CH:14]=[C:13]([CH2:12][N:2]3[CH2:3][CH2:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH2:1]3)[O:17][N:16]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: BrCc1cc(-c2ccccc2)no1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: c1ccc(-c2cc(CN3CCc4ccccc4C3)on2)cc1
Yield: 81 %

Procedure:
Prepared from 1,2,3,4-tetrahydroisoquinoline and 5-(bromomethyl)-3-phenylisoxazole under typical conditions. Purification by flash chromatography on silica gel 60, eluting with 25% EtOAc in hexane produced adduct 21A (81% yield). 1H NMR(300 MHz, CDCl3, δ): 7.83-7.80 (m, 2H), 7.48-7.40 (m, 3H), 7.16-7.11 (m, 3H), 7.08-6.99 (m, 1H), 6.57 (s, 1H), 3.91 (s, 2H), 3.76 (s, 2H), 3.00-2.80 (m, 4H). 13C NMR(300 MHz, CDCl3, δ): 170.25, 162.45, 134.04, 133.75, 129.97, 129.12, 128.92, 128.72, 126.81, 126.56, 126.36, 125.78, 101.26, 85.61, 53.20, 50.75, 29.03. MS(CI, NH3) m/e 291 (base, M+H+). HRMS(CI, NH3) m/e Calc'd for (M+H+): 291.1497. Found: 291.1512.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:18]=[CH:17][C:16]=1[OH:28].[CH2:29](Br)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].C(=O)([O-])[O-].[K+].[K+]>[Cu].CN(C=O)C>[CH2:29]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:18]=[CH:17][C:16]=1[OH:28])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCCBr
Reactant: COC(=O)CCCc1ccc(O)c(-c2cc(CCCC(=O)OC)ccc2O)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(CCCC(=O)OC)cc1-c1cc(CCCC(=O)OC)ccc1O
Yield: 91.4 %

Procedure:
To 5 ml of a DMF solution containing 200 mg (0.5181 mmol) of 2,2'-dihydroxy-5,5'-bis (3-methoxycarbonylpropyl) biphenyl and 0.895 ml (5.181 mmol) of octyl bromide, there were added 85.8 mg (0.6217 mmol) of anhydrous potassium carbonate and a small amount of copper powder and the resulting mixture was agitated for 5 hours at room temperature. The reaction mixture was filtered by suction through Celite to remove the solid matter and the filtrate was washed with ethyl acetate. After the solvent in the filtrate was evaporated off under reduced pressure, the evaporated residue was dissolve din chloroform. This solution was washed with dilute hydrochloric acid, dilute aqueous sodium bicarbonate, water and aqueous sodium chloride solution in this sequence and was dried by adding anhydrous sodium sulfate. The residue obtained after the solvent had been evaporated off was purified by silica gel column chromatography (with 15 g of WAKO-gel C-200, eluent: toluene and toluene/ethyl acetate of 100/1) to obtain 236 mg (0.4738 mmol, 91%) of 2-octyloxy-2'-hydroxy-5,5'-bis (3-methoxycarbonylpropyl) biphenyl as an oily product. 1H-NMR (CDCl3) δ (ppm): 0.87 (3H, t, CH3), 1.0-2.2 (16H, m, 8CH2), 2.36 (4H, t, 2CH2), 2.65 (4H, t, 2CH2), 3.66 (6H, s, 2CH3), 4.01 (2H, t, CH2), 6.61 (1H, s, OH), 6.8-7.3 (6H, m, arom-H) MS (FAB): 497 (M-H)-
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([OH:10])[C:4]=2[CH:3]=[CH:2]1.[C:11]([O:15][C:16](=[O:22])[N:17]([CH2:19][CH2:20]O)[CH3:18])([CH3:14])([CH3:13])[CH3:12].N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:11]([O:15][C:16](=[O:22])[N:17]([CH2:19][CH2:20][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[CH:3]=[CH:2][NH:1]2)[CH3:18])([CH3:14])([CH3:13])[CH3:12]
Reactant: Oc1cccc2[nH]ccc12
Reactant: CN(CCO)C(=O)OC(C)(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(CCOc1cccc2[nH]ccc12)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 14 h
Yield: 98.8 %

Procedure:
In 50 mL of tetrahydrofuran, 200 mg (1.51 mmol) of 1H-indole-4-ol and 527 mg (3.00 mmol) of 2-hydroxyethyl-methylcarbamic acid tert-butyl ester were dissolved, and 1.51 mL (3.00 mmol) of a diethyl azodicarboxylate 40% toluene solution and 788 mg (3.00 mmol) of triphenylphosphine were added thereto and the mixture solution was stirred at room temperature for 14 hours. The reaction solution was concentrated, and then partitioned between ethyl acetate and a saturated ammonium chloride aqueous solution. The organic layer was washed with a saturated sodium chloride solution, dried and concentrated, and the obtained residue was purified by a silica gel column (50 g, n-hexane:ethyl acetate=2:1) to obtain 433 mg (99%) of [2-(1H-indol-4-yloxy)ethyl]-methyl-carbamic acid tert-butyl ester as a viscous oily substance.