Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].C[N:15]1[CH2:20][CH2:19]O[CH2:17][CH2:16]1.Cl[C:22]([O:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[O:23].O1C[CH2:32][CH2:31][CH2:30]1>C(Cl)(Cl)Cl>[NH:1]([C:7]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8])[C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:2]([C:4]([N:15]1[CH2:16][CH2:17][CH2:19][C@H:20]1[C:22]([O:24][CH2:25][C:26]1[CH:28]=[CH:32][CH:31]=[CH:30][CH:27]=1)=[O:23])=[O:6])[CH3:3]
Reactant: CC(C)COC(=O)Cl
Reactant: CN1CCOCC1
Reactant: C1CCOC1
Agent: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: ClC(Cl)Cl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 2 h

Procedure:
A mixed anhydride of Boc-Ala-OH was prepared by reacting Boc-Ala-OH (10 g, 52.8 mmoles) with N-methylmorpholine (5.80 mL, 52.8 mmoles) and isobutyl chloroformate (6.8 mL, 52.85 mmoles) for 5 minutes in 50 mL of tetrahydrofuran at -20°. The reaction mixture and additional N-methylmorpholine (5.8 mL) were added to H-Pro-Obzl·HCl dissolved in 50 mL of cold CHCl3. After this mixture was stirred for 1 hour at -20° and 2 hours at 23°, it was filtered and the filtrate evaporated. The residue was dissolved in ethyl acetate and was washed sequentially with 0.2N HCl, 5% NaHCO3, and saturated aqueous NaCl. The solvent was evaporated to yield Boc-AlaPro-OBzl as an oil (14.1 g).
Reaction SMILES: I[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1.C(N(CC)CC)C.[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([SH:30])=[CH:26][CH:25]=1)([O-:23])=[O:22]>C1COCC1.CCOC(C)=O>[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([S:30][CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=2)=[CH:26][CH:25]=1)([O-:23])=[O:22]
Reactant: FC(F)(F)c1ccc(CCI)cc1
Reactant: O=[N+]([O-])c1ccc(S)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(SCCc2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 88.5 %

Procedure:
To a solution of 1-(2-iodo-ethyl)-4-trifluoromethyl-benzene (7.51 g, 25.0 mmol), triethylamine (3.84 mL, 27.5 mmol) in THF (100 mL) was added p-nitrothiophenol (4.85 g, 25.0 mmol). The reaction was stirred at room temperature for two days, diluted with EtOAc, washed with water, saturated NaHCO3, H2O, brine and dried over anhydrous sodium sulfate. The compound was purified on silica gel (hexane-EtOAc) to give 7.24 g of a yellow solid.
Reaction SMILES: [F:1][CH:2]([F:44])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]([CH2:34][CH2:35][CH2:36]O)[CH:21]3[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]3)[N:9]=2)[C:6]2[CH:38]=[CH:39][CH:40]=[C:41]([O:42][CH3:43])[C:5]=2[N:4]=1.C[CH2:46][N:47](CC)[CH2:48]C.CS(Cl)(=O)=O.CNC>C(Cl)Cl>[F:44][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]([CH2:34][CH2:35][CH2:36][N:47]([CH3:48])[CH3:46])[CH:21]3[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]3)[N:9]=2)[C:6]2[CH:38]=[CH:39][CH:40]=[C:41]([O:42][CH3:43])[C:5]=2[N:4]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N(CCCO)C2CCCN(C(=O)OC(C)(C)C)C2)n1
Reactant: CCN(CC)CC
Agent: CNC
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N(CCCN(C)C)C2CCCN(C(=O)OC(C)(C)C)C2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of tert-butyl 3-[[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl](3-hydroxypropyl)-amino]-1-piperidinecarboxylate (420 mg, 0.72 mmol) in CH2Cl2 (12 mL) at 0° C. was added Et3N (0.2 mL, 1.4 mmol) and methanesulfonyl chloride (0.1 mL, 1.08 mmol). The reaction mixture was stirred at 0° C. for 30 min, and a solution of 40% aqueous dimethylamine (5 mL) was then added. The reaction mixture was stirred at room temperature for 2 days and the solvent was removed under vacuum. The residue was diluted with water and stirred for 30 min to give a precipitate, which was collected by filtration, washed with water, and dried. Chromatography on SiO2 eluting first with CH2Cl2/EtOAc (4:1), and then with CH2Cl2/MeOH (95:5) containing 1% aqueous NH3, gave tert-butyl 3-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl][3-(dimethylamino)propyl]amino}-1-piperidinecarboxylate (465 mg; 100%) as a white solid: mp (CH2Cl2/MeOH) 133-136° C.; 1H NMR (DMSO-d6) (rotamers) δ 7.96 and 7.88 (2d, J=8.3 Hz, 1H), 7.77 and 7.68 (2t, JHF=53.0, 52.9 Hz, 1H), 7.40-7.34 (m, 1H), 6.96-6.93 (m, 1H), 4.56-4.88 and 4.30-4.27 (2 m, 1H), 3.98 and 3.97 (2s, 3H), 3.97-3.49 (m, 13H), 2.93-2.88 and 2.77-2.63 (2m, 2H), 2.35-2.27 (m, 2H), 2.15 and 2.13 (2s, 6H), 1.93-1.71 (m, 4H), 1.48-1.16 (m, 1H), 1.40 (s, 9H); Anal. Calcd. for C31H45F2N9O4C, 57.7; H, 7.0; N, 19.5. Found: C, 57.7; H, 7.1; N, 19.7%.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][C:18]2[C:17](=[O:25])[C:16]3[C:7](=[CH:8][C:9]4[C:14]([CH:15]=3)=[CH:13][CH:12]=[CH:11][CH:10]=4)[C:6](=[O:26])[C:5]=2[CH:4]=1.[C:29]([O-:32])(=O)[CH3:30].[K+].[C:34](OC(=O)C)(=[O:36])[CH3:35]>[Pd].C(OCC)(=O)C>[F:1][C:2]([F:27])([F:28])[C:3]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][C:18]2[C:5](=[C:6]([O:26][C:29](=[O:32])[CH3:30])[C:7]3[C:16]([C:17]=2[O:25][C:34](=[O:36])[CH3:35])=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=3)[CH:4]=1
Reactant: CC(=O)[O-]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1c2cc(C(F)(F)F)c(C(F)(F)F)cc2C(=O)c2cc3ccccc3cc21
Agent: [Pd]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CC(=O)Oc1c2cc(C(F)(F)F)c(C(F)(F)F)cc2c(OC(C)=O)c2cc3ccccc3cc12
Yield: 76 %

Procedure:
1.65 mmol of 2,3-bis-(trifluoromethyl)-naphthacene-5,12-dione, 5 ml of ethyl acetate, 4.96 mmol of potassium acetate and 3 ml of acetic anhydride are hydrogenated for 35 minutes at 20°-25° C., with the addition of 0.1 g of Pd/C (5%). The mixture is filtered and the residue is extracted by washing three times with CH2Cl2. The filtrates are evaporated and the residue is recrystallized from CH2Cl2 /pentane. Yield 76% of 2,3-bis-(trifluoromethyl)-5,12-diacetoxynaphthacene; melting point >250°.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:16]([C:18]1[CH:33]=[CH:32][C:21]([C:22]([NH:24][C:25]2[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=2)[NH2:28])=[O:23])=[CH:20][CH:19]=1)#[N:17].Cl>C(O)(C)C.C(OCC)C>[ClH:1].[C:16]([C:18]1[CH:19]=[CH:20][C:21]([C:22]([NH:24][C:25]2[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=2)[NH:28][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[O:23])=[CH:32][CH:33]=1)#[N:17]
Reactant: N#Cc1ccc(C(=O)Nc2cccc(N)c2)cc1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: Cl
Solvent: CC(C)O
Solvent: CCOCC
Product: COc1cc2ncnc(Nc3cccc(NC(=O)c4ccc(C#N)cc4)c3)c2cc1OC
Temperature: 85 °C

Procedure:
4-Chloro-6,7-dimethoxyquinazoline (225 mg) was added to 3-(4-cyanobenzamido)aniline (261 mg) in isopropanol (8 ml). A 1M solution of hydrogen chloride in diethyl ether (1.0 ml) was added and the reaction mixture stirred and heated to 85° C. for 18 hours. After cooling to room temperature the precipitated solid was isolated and washed with isohexane and diethyl ether. The title compound was obtained as a solid (399 mg); NMR: 3.99 (s, 3H), 4.01 (s, 3H), 7.37 (s, 1H), 7.45 (m, 2H), 7.65 (m, 1H), 8.02 (m, 2H), 8.12 (m, 2H), 8.20 (m, 1H), 8.31 (s, 2H), 8.80 (s, 1H), 10.71 (s, 1H), 11.44 (s, 1H); m/s: M+H+ 426.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]([CH2:34][CH3:35])[C:16]2[C:17]([CH3:33])=[C:18]([C:29]([O:31][CH3:32])=[O:30])[CH:19]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[CH:21]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:37][CH2:38][O:39][CH3:40].C([O-])([O-])=O.[Cs+].[Cs+].O>C(#N)C>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]([CH2:34][CH3:35])[C:16]2[C:17]([CH3:33])=[C:18]([C:29]([O:31][CH3:32])=[O:30])[CH:19]=[C:20]([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH2:37][CH2:38][O:39][CH3:40])=[CH:26][CH:27]=3)[CH:21]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(c1cc(-c2ccc(O)cc2)cc(C(=O)OC)c1C)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: CCN(c1cc(-c2ccc(OCCOC)cc2)cc(C(=O)OC)c1C)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a stirred solution of methyl 5-(((trans)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(ethyl)amino)-4′-hydroxy-4-methyl-[1,1′-biphenyl]-3-carboxylate (0.6 g, 1.24 mmol) and 1-bromo-2-methoxyethane (0.519 g, 3.73 mmol) in acetonitrile (6 mL), Cs2CO3 (0.485 g, 1.49 mmol) was added and reaction was stirred at 80° C. for 12 h. On completion, water was added to it and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound was purified by column chromatography to afford the title compound (0.6 g, 76.5% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][NH:10][C:11]([C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([C:20]([NH:22][CH2:23][C:24]3[C:25]([NH:37][CH:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)=[C:26]4[CH:34]=[N:33][N:32]([CH2:35][CH3:36])[C:27]4=[N:28][C:29]=3[CH2:30][CH3:31])=[O:21])[CH:14]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[CH3:8].[CH:44]([C:46]1[CH:47]=[C:48](B(O)O)[CH:49]=[CH:50][CH:51]=1)=[O:45].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C(Cl)Cl.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>[CH2:35]([N:32]1[C:27]2=[N:28][C:29]([CH2:30][CH3:31])=[C:24]([CH2:23][NH:22][C:20]([C:15]3[CH:16]=[C:17]([CH3:19])[CH:18]=[C:13]([C:11]([NH:10][CH2:9][C:4]4[CH:3]=[C:2]([C:50]5[CH:49]=[CH:48][CH:47]=[C:46]([CH:44]=[O:45])[CH:51]=5)[C:7]([CH3:8])=[CH:6][CH:5]=4)=[O:12])[CH:14]=3)=[O:21])[C:25]([NH:37][CH:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[C:26]2[CH:34]=[N:33]1)[CH3:36]
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)NCc2ccc(C)c(Br)c2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)NCc2ccc(C)c(-c3cccc(C=O)c3)c2)c1
Yield: 60.8 %

Procedure:
N-[(3-Bromo-4-methylphenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-5-methyl-1,3-benzenedicarboxamide (840 mg, 1.297 mmol), (3-formylphenyl)boronic acid (194 mg, 1.297 mmol), potassium carbonate (538 mg, 3.89 mmol), and Pd(Ph3P)4 (74.9 mg, 0.065 mmol) were divided into 3 portions and added to three 2-5 mL Biotage microwave vials in 1,4-dioxane (3 mL) and water (1 mL). The vials were capped and the mixture was microwaved at normal power in the Emrys Optimizer at 100° C. for 15 min. The combined crude product was partitioned between EtOAc (75 mL) and water (20 mL). The phases were separated, and the organic washed with water (2×20 mL), brine (20 mL), dried over anhydrous Na2SO4 filtered and evaporated to give the crude residue. The residue was taken up in DCM and absorbed on Isolute® Sorbent and purified by Combiflash using an 80 g silica column eluted with 0-10% DCM/MeOH. The product fractions were combined and concentrated to give (N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-formyl-6-methyl-3-biphenylyl)methyl]-5-methyl-1,3-benzenedicarboxamide (537 mg, 0.789 mmol, 60.8% yield)) as a white solid. LC-MS m/z 673.4 (M+H)+, 0.99 min (ret time); mp 117-120° C.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:3]1.Cl[CH2:33][C:34]1[CH:43]=[C:42]([O:44][CH3:45])[C:41]2[C:36](=[C:37]([O:46][CH3:47])[CH:38]=[CH:39][CH:40]=2)[CH:35]=1>>[CH3:45][O:44][C:42]1[C:41]2[C:36](=[C:37]([O:46][CH3:47])[CH:38]=[CH:39][CH:40]=2)[CH:35]=[C:34]([CH2:33][O:1][CH:2]2[CH:7]([C:8]3[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]4[S:21][CH:22]=[CH:23][CH:24]=4)=[CH:12][CH:13]=3)[CH2:6][CH2:5][N:4]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:3]2)[CH:43]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOCc3cccs3)cc2)C(O)C1
Reactant: COc1cc(CCl)cc2c(OC)cccc12
Product: COc1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3cccs3)cc2)cc2c(OC)cccc12

Procedure:
In an analogous manner to that described in Example 1g), by alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-[4-[3-(thiophen-2-ylmethoxy)-propoxy]-phenyl]-piperidine-1-carboxylate [Example 123 b)] with 2-chloromethyl-4,8-dimethoxy-naphthalene there was obtained tert-butyl (3RS,4RS)-3-(4,8-dimethoxy-naphthalen-2-ylmethoxy)-4-{4-[3-(thiophen-2-ylmethoxy)-propoxy]-phenyl}-piperidine-1-carboxylate as a beige solid; MS: 648 (M+H)+.
Reaction SMILES: [I:1][C:2]1[C:3]([Cl:18])=[C:4]([NH:8][C:9](=[O:17])[C@:10]([OH:16])([CH3:15])[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:6][CH:7]=1.[Cl:19][S:20](O)(=[O:22])=[O:21]>>[Cl:19][S:20]([C:7]1[CH:6]=[CH:5][C:4]([NH:8][C:9](=[O:17])[C@:10]([OH:16])([CH3:15])[C:11]([F:14])([F:13])[F:12])=[C:3]([Cl:18])[C:2]=1[I:1])(=[O:22])=[O:21]
Reactant: O=S(=O)(O)Cl
Reactant: C[C@@](O)(C(=O)Nc1cccc(I)c1Cl)C(F)(F)F
Product: C[C@@](O)(C(=O)Nc1ccc(S(=O)(=O)Cl)c(I)c1Cl)C(F)(F)F
Temperature: 80 °C

Procedure:
(R)-N-[3-Iodo-2-chlorophenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Method 31) (4.92 g) was added in portions to chlorosulphonic acid (18 ml) at 0° C. The reaction mixture was heated to 80° C. for 4 hours, allowed to cool to ambient temperature and poured onto ice-water (200 g). The mixture was extracted into DCM (2×250 ml), the organic phase was washed with brine (300 ml) and dried. Volatile material was removed by evaporation to give the title compound (4.8 g) as a brown gum. NMR (CDCl3) 1.78 (s, 3H), 3.59 (s, 1H), 8.23 (d, 1H), 8.74 (d, 1H), 9.53 (s, 1H); m/z: 490.
Reaction SMILES: C(N1CCN([CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[CH2:13][CH2:12][CH2:11]2)CC1)(=O)C.[OH-:22].[Na+]>C(O)C>[OH:22][CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=2)[CH2:13][CH2:12][CH2:11]1
Reactant: COc1ccc2c(c1)C(N1CCN(C(C)=O)CC1)CCC2
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc2c(c1)C(O)CCC2

Procedure:
1-(4-Acetylpiperazin-1-yl)-7-methoxy-1,2,3,4-tetrahydronaphthalene (0.85 g) was dis solved in ethanol (10 ml). After adding an 8 N aqueous solution (3 ml) of sodium hydroxide, the resultant mixture was heated under reflux for 3 hr. Then the liquid reaction mixture was concentrated under reduced pressure and the residue was purified by NH-silica gel column chromatography (ethyl acetate) to give the title compound (0.6 g) as a pale brown oil. (280-4) 1-[4-(4-Fluorophenylacetyl)piperazin-1-yl]-7-methoxy-1,2,3,4-tetrahydronaphthalene
Reaction SMILES: [C:1]([O:10][CH:11]([CH3:13])[CH3:12])(=[O:9])[CH2:2][C:3]([O:5][CH:6]([CH3:8])[CH3:7])=[O:4].[H-].[Na+].[Na+].[I-].CC1C=CC(S(O[CH2:29][C:30]2([C:33]([F:36])([F:35])[F:34])[CH2:32][CH2:31]2)(=O)=O)=CC=1>CN(C=O)C>[F:34][C:33]([F:36])([F:35])[C:30]1([CH2:29][CH:2]([C:3]([O:5][CH:6]([CH3:7])[CH3:8])=[O:4])[C:1]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])[CH2:32][CH2:31]1
Reactant: Cc1ccc(S(=O)(=O)OCC2(C(F)(F)F)CC2)cc1
Reactant: CC(C)OC(=O)CC(=O)OC(C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)OC(=O)C(CC1(C(F)(F)F)CC1)C(=O)OC(C)C
Temperature: 25 °C
Yield: 57.1 %

Procedure:
A 0° C. solution of diisopropyl malonate (4.10 mL, 21.58 mmol) in DMF (30 mL) was treated with NaH (60% in mineral oil, 1.036 g, 25.9 mmol), warmed to RT, treated with NaI (0.647 g, 4.32 mmol) followed by the drop-wise addition of a solution of (1-(trifluoromethyl)cyclopropyl)methyl 4-methylbenzenesulfonate (2.54 g, 8.63 mmol) in DMF (30 mL) and heated at 80° C. overnight. The mixture was cooled to RT, quenched with satd. NH4Cl, extracted with hexane (3×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MTBE/Hex) to afford diisopropyl 2-((1-(trifluoromethyl)cyclopropyl)methyl)malonate (1.53 g, 57.1%). 1H NMR (400 MHz, DMSO-d6): δ 4.91 (m, 2H), 3.47 (t, J=7.2 Hz, 1H), 2.10 (d, J=7.2 Hz, 2H), 1.17 (dd, J=7.3, 6.3 Hz, 12H), 0.89 (m, 2H), 0.76 (m, 2H).
Reaction SMILES: [N:1]1[C:10]2[CH:9]=[CH:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[CH3:12][NH:13]O.C(=O)(O)[O-:16].[Na+]>CO>[OH:16][CH2:12][NH:13][CH:8]1[CH2:9][C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6][CH2:7]1
Reactant: O=C([O-])O
Reactant: C1=Cc2ncccc2CC1
Reactant: CNO
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: OCNC1CCc2cccnc2C1
Reaction time: 2 h

Procedure:
A solution of 5,6-dihydroquinoline (9.17g, 0.07 mmol) in methanol (10 ml) at 0° was treated portionwise with N-methylhydroxylamine hydrochloride (11.5 g, 0.138 mmol), stirred for 2 h, poured into saturated aqueous sodium bicarbonate (250 ml), and extracted with chloroform (3×150 ml). The extracts were washed with water (50 ml), dried (MgSO4), and evaporated in vacuo. The residual brown liquid was purified by chromatography (alumina; ether) to give the product (6.45 g) as a colourless oil, which was converted into the amine of Example 2.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([O-])([O-])=O.[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C.CCOCC.O>[CH2:18]([O:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:4][C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:2]=1)=[O:5])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1ccc(Cl)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1ccc(Cl)cc1OCc1ccccc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 7.0 g (40.6 mmol) 2-hydroxy-4-chlorobenzoic acid in 150 ml of dry DMF was added 16.8 g (122 mmol) of K2CO3 followed by the dropwise addition of 15.2 g (89.2 mmol) of benzyl bromide. The reaction mixture was warmed to 50° C. and stirred overnight. After 16h, the reaction mixture was diluted with Et2O and H2O and the layers were separated. The aqueous layer was extracted with Et2O (2×) and the combined organic layers were successively washed with 1N HCl (3×100 ml), saturated NaHCO3 solution (2×50 ml) and brine (1×50 ml). The solution was dried over anhydrous MgSO4 and concentrated to give 2-benzyloxy-4-chlorobenzoic acid, benzyl ester as a pale yellow solid which was used without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:11]3[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:10]=3[O:9][N:8]=2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][CH2:25][N:26]1[C:35](=[O:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=[C:27]1[CH3:37]>C(#N)C>[F:16][C:14]1[CH:13]=[CH:12][C:11]2[C:7]([CH:4]3[CH2:3][CH2:2][N:1]([CH2:24][CH2:25][N:26]4[C:35](=[O:36])[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[N:28]=[C:27]4[CH3:37])[CH2:6][CH2:5]3)=[N:8][O:9][C:10]=2[CH:15]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: Cc1nc2ccccc2c(=O)n1CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1nc2ccccc2c(=O)n1CCN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A stirred mixture of 3-(4-piperidinyl)-6-fluorobenzisoxazole (4 g, 18.2 mmol), K2CO3 (3.76 g, 27.2 mmol) and 3-(2-chloroethyl)-2-methyl-3H-4-quinazolinone (6.0 g, 27 mmol) in acetonitrile (300 ml) was heated at reflux for 16 hours. The reaction was complete as judged by TLC. The solids were filtered and the solvent was evaporated. The residue was purified over a flash chromatography column (SiO2, 75 gm, eluted with dichloromethane and MeOH in dichloromethane). The pure product thus obtained weighed 6.5 gm. Recrystallization from ethanol yielded white crystals, 3.94 gm (53%), m.p. 164°-165° C. This material appeared pure by TLC over silica gel plates.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[NH2:11][C:12]1[CH:16]=[C:15]([CH3:17])[NH:14][N:13]=1.C(N(C(C)C)CC)(C)C.[I-].[Na+]>C(O)CCC>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH3:10])[N:3]=[C:2]([NH:11][C:12]2[NH:13][N:14]=[C:15]([CH3:17])[CH:16]=2)[CH:7]=1
Reactant: CSc1nc(Cl)cc(Cl)n1
Reactant: Cc1cc(N)n[nH]1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CSc1nc(Cl)cc(Nc2cc(C)n[nH]2)n1
Temperature: 120 °C
Reaction time: 15 h

Procedure:
To a solution of 4,6-dichloro-2-methylsulfanyl-pyrimidine (5 g, 25.6 mmol) and 3-amino-5-methylpyrazole 2.61 g, 26.9 mmol) in BuOH (60 mL) is added diisopropylethylamine (4.69 mL, 26.9 mmol) followed by sodium iodide (3.84 g, 25.6 mmol). The reaction mixture is stirred for 15 hours at 120° C. The solvent is then removed in vacuo and the residue is purified by flash chromatography (SiO2, hexane/AcOEt gradient) to give [6-chloro-2-methylsulfanyl-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5](C=O)=[C:4]([O:10][CH3:11])[CH:3]=1.[CH:12]([O:17][CH3:18])([O:15][CH3:16])OC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:12]([O:15][CH3:16])[O:17][CH3:18])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: COc1cc(Br)ccc1C=O
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COc1cc(Br)ccc1C(OC)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
4-bromo-2-methoxybenzaldehyde (1 g, 4.67 mmol) was dissolved in MeOH (20 ml) and trimethyl orthoformate (562 μl, 5.139 mmol) and p-toluene sulphonic acid monohydrate (89 mg, 0.467 mmol) were added to the resulting solution. The mixture was stirred overnight at room temperature and then the solvent was removed under vacuo. The residue was taken up with Et2O and washed with 5% Na2CO3 and with water. The organic phase was dried over Na2SO4 and evaporated to give 1.22 g of 4-bromo-1-dimethoxymethyl-2-methoxy-benzene as a colorless oil.
Reaction SMILES: C(NC(C)C)(C)C.CC(C)([O-])C.[K+].C([Li])CCC.[Br:19][C:20]1[CH:29]=[CH:28][C:23]2[S:24][CH:25]=[C:26]([CH3:27])[C:22]=2[CH:21]=1.[C:30](=[O:32])=[O:31]>CCOCC>[Br:19][C:20]1[CH:29]=[CH:28][C:23]2[S:24][C:25]([C:30]([OH:32])=[O:31])=[C:26]([CH3:27])[C:22]=2[CH:21]=1
Reactant: Cc1csc2ccc(Br)cc12
Reactant: O=C=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCOCC
Product: Cc1c(C(=O)O)sc2ccc(Br)cc12
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
A mixture of diisopropylamine (4.44 g.) and potassium t-butoxide (5.02 g.) in dry ether was cooled to -78° C. under an atmosphere of dry nitrogen and n-butyl lithium (28.4 ml. of 1.55M solution in hexane) was added with stirring over 5 minutes. The mixture was stirred at -78° for 30 minutes and then a solution of 5-bromo-3-methylbenzo[b]thiophene (9.10 g.) in dry ether (25 ml.) was added over 5 minutes. The resulting mixture was stirred at -78° C. for 30 minutes and then poured onto a mixture of crushed solid carbon dioxide and ether. When all the carbon dioxide had evaporated the mixture was shaken with water and the ether layer was separated. The aqueous layer was acidified with acetic acid and the solid was filtered off, washed with water and crystallized from acetic acid to give 5-bromo-3-methylbenzo[b]thiophene-2-carboxylic acid (7.30 g.), m.p. >300°.