Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]=[CH:11][C:10]=2[CH:14]=1.[CH2:15]([Li])CCC.IC.O>C1COCC1.C(OCC)(=O)C>[CH3:15][C:12]1[O:13][C:9]2[CH:8]=[CH:7][C:6]([CH:2]3[O:3][CH2:4][CH2:5][O:1]3)=[CH:14][C:10]=2[CH:11]=1
Reactant: c1cc2cc(C3OCCO3)ccc2o1
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc2cc(C3OCCO3)ccc2o1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
5-[1,3]Dioxolan-2-yl-benzofuran (50 mg, 0.26 mmol) was dissolved in THF (2 mL) and the solution was cooled down to −78° C. Butyl lithium (180 uL, 1.1 eq.) was added dropwise. This mixture was stirred 30 min at 25° C. Then the reaction mixture was cooled down to −78° C. and iodomethane (18.1 uL, 1.1 eq.) dissolved in 1 mL THF was added dropwise to the reaction mixture. The temperature was increased slowly to room temperature overnight. Despite some starting material was detected, water and ethyl acetate were added to the mixture and the aqueous layer was extracted 3 times. Combined organic phases was dried over MgSO4, filtrated and evaporated to give 2-methyl-5-[1,3]dioxolan-2-yl-benzofuran (41.2 mg, 70%) sufficiently pure to be used in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:22]=[CH:21][C:20]([C:23]([OH:25])=O)=[C:19]2[C:14]=1[CH:15]=[CH:16][CH:17]=[N:18]2.[CH2:26]([N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[N:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=2)[CH2:30][CH2:29]1)[CH3:27]>C(Cl)Cl.CO>[CH2:26]([N:28]1[CH2:29][CH2:30][N:31]([CH2:34][C:35]2[N:40]=[CH:39][C:38]([NH:41][C:23]([C:20]3[CH:21]=[CH:22][C:13]([C:3]4[C:4]([Cl:12])=[C:5]([O:10][CH3:11])[CH:6]=[C:7]([O:8][CH3:9])[C:2]=4[Cl:1])=[C:14]4[C:19]=3[N:18]=[CH:17][CH:16]=[CH:15]4)=[O:25])=[CH:37][CH:36]=2)[CH2:32][CH2:33]1)[CH3:27]
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)O)c3ncccc23)c1Cl
Reactant: CCN1CCN(Cc2ccc(N)cn2)CC1
Solvent: CO
Solvent: ClCCl
Product: CCN1CCN(Cc2ccc(NC(=O)c3ccc(-c4c(Cl)c(OC)cc(OC)c4Cl)c4cccnc34)cn2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 5-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid (Step 159.1), 6-(4-ethyl-piperazin-1-ylmethyl)-pyridin-3-ylamine (prepared as described in Example 39 but using N-ethyl-piperazine in Step 39.2), and stirring the reaction mixture for 3 h at rt. Title compound: ESI-MS: 580.1 [M+H]+; tR=3.70 min (System 1); TLC: Rf=0.33 (DCM/MeOH, 9:1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[C:14]([OH:19])[CH:13]=[C:12]3Br)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[F:35][C:36]([F:46])([F:45])[CH2:37][N:38]1[CH2:43][CH2:42][CH:41]([NH2:44])[CH2:40][CH2:39]1.C([O-])([O-])=O.[Cs+].[Cs+].CC([O-])(C)C.[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[C:14]([OH:19])[CH:13]=[C:12]3[NH:44][CH:41]2[CH2:42][CH2:43][N:38]([CH2:37][C:36]([F:46])([F:35])[F:45])[CH2:39][CH2:40]2)=[CH:4][CH:3]=1
Reactant: NC1CCN(CC(F)(F)F)CC1
Reactant: Oc1cc(Br)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)ccc2n1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: Oc1cc(NC2CCN(CC(F)(F)F)CC2)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)ccc2n1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 8-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 6-[bis(4-chlorophenyl)methyl]-4-bromoquinolin-2-ol (200 mg, 0.44 mmol, 1.00 equip), 1,4-dioxane (5 mL), 1-(2,2,2-trifluoroethyl)piperidin-4-amine 2,2,2-trifluoroacetate (193 mg, 0.65 mmol, 1.50 equip), Pd2(dba)3 (40 mg, 0.04 mmol, 0.10 equip), dppf (84.5 mg, 0.15 mmol, 0.35 equip), Cs2CO3 (355 mg, 1.09 mmol, 2.50 equip), and KOt-Bu (97.6 mg, 0.87 mmol, 2.00 equip). The resulting solution was stirred overnight at 100° C. The reaction was then quenched by the addition of water (100 mL). The resulting solution was extracted with ethyl acetate (3×50 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were removed by filtration. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1). The resulting residue was recrystallized from ethyl acetate:petroleum ether in the ratio of 1:10 to yield 6-[bis(4-chlorophenyl)methyl]-4-[[1-(2,2,2-trifluoroethyl)piperidin-4-yl]amino]quinolin-2-ol as a white solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-:14].[Na+]>CC(=O)CC>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][I:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [I-]
Reactant: BrCCCCCCc1ccccc1
Agent: [Na+]
Solvent: CCC(C)=O
Product: ICCCCCCc1ccccc1

Procedure:
6-Phenylhexyl iodide [VIa; Ar is C6H5, R is H] was prepared from 16 g. of 6-phenylhexyl bromide (Preparation C11) and 10.95 g. of sodium iodide in 325 ml. of 2-butanone, to give 19.1 g. of product as an oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[N:13]1([CH2:9][C:8]2[CH:11]=[CH:12][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CC(=O)Nc1ccc(C=O)cc1
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ccc(CN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 4-acetamidobenzaldehyde (200 mg), piperidine (0.121 mL), NaBH(OAc)3 (636 mg) and DIPEA (0.617 mL) in DCM (4 mL) was stirred at RT for 4 h. DCM and sat. NaHCO3 were added. The phases were separated, the org. layer was dried (Na2SO4), filtered off and evaporated to dryness to afford 267 mg of white solid. LC-MS (B): tR=0.45 min; [M+H]+: 233.24.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[N:21]=[C:20]([C:22]5[C:23]([O:28]C)=[N:24][CH:25]=[CH:26][CH:27]=5)[CH:19]=[C:18]([CH3:30])[CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.[Si](I)(C)(C)C.CO>CC#N>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]([CH3:30])[CH:19]=[C:20]([C:22]5[C:23](=[O:28])[NH:24][CH:25]=[CH:26][CH:27]=5)[N:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: COc1ncccc1-c1cc(C)cc(NC(=O)C2(c3ccc4c(c3)CCO4)CC2)n1
Agent: C[Si](C)(C)I
Solvent: CC#N
Solvent: CO
Product: Cc1cc(NC(=O)C2(c3ccc4c(c3)CCO4)CC2)nc(-c2ccc[nH]c2=O)c1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 1-(2,3-dihydrobenzofuran-5-yl)-N-(2′-methoxy-4-methyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (69 mg, 0.17 mmol) in CH3CN (2.5 mL) was added TMSI (49 uL, 0.34 mmol) dropwise at 20° C. The reaction was stirred at 50° C. for 30 min. MeOH (1.0 mL) was added and the solution was evaporated to dryness. The residue was re-dissolved in DCM-EtOAc (1:3) before it was washed with NaHSO3 (2×) and brine. The organics were dried over MgSO4 and evaporated to dryness. The crude material was purified by column chromatography (0-10% MeOH-EtOAc) to yield 1-(2,3-dihydrobenzofuran-5-yl)-N-(4-methyl-6-(2-oxo-1,2-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 387.2. found 388.1 (M+1)+. Retention time 1.38 minutes.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1I)[C:8]([O:10][CH3:11])=[O:9])[CH:2]=[CH2:3].C([O-])([O-])=O.[Na+].[Na+].C([O-])=O.[Na+]>CN(C=O)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[Cl-].O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:3][C:2]1[C:14]2[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=2[O:4][CH:1]=1
Reactant: C=CCOc1cc(C(=O)OC)ccc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(C)coc2c1
Temperature: 80 °C
Reaction time: 48 h
Yield: 66.7 %

Procedure:
Methyl 3-(allyloxy)-4-iodobenzoate (2.0 g, 6.28 mmol) is dissolved in DMF (15 ml), treated with Pd(OAc)2 (71 mg, 0.31 mmol), Na2CO3 (1.67 g, 15.7 mmol), sodium formate (427 mg, 6.28 mmol), and n-Bu4NCl.H2O (1.92 g, 6.92 mmol) and stirred at 80° C. for 2 days. The mixture is then filtered, the liquor is diluted with EtOAc (75 ml) and washed with 50% saturated NaCl (4×25 ml) followed by 5% HCl (25 ml). The organic layer is dried (Na2SO4), filtered, and concentrated to a brown oil. The crude material is chromatographed over 50 g slurry-packed silica gel, eluting with 20% EtOAc/hexane. The appropriate fractions are combined and concentrated to afford 797 mg (67%) of methyl 3-methyl-1-benzofuran-6-carboxylate as a pale oil. HRMS (FAB) calcd for C11H10O3+H: 191.0708, found 191.0714 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=O)=[N:6][CH:7]=1.C1C=CC2N(O)N=[N:18][C:16]=2C=1.CCN=C=NCCCN(C)C.Cl.CN>C1COCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:18][CH3:16])=[O:11])=[N:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Br)cn1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)Cc1ccc(Br)cn1
Yield: 27.3 %

Procedure:
To a suspension of 5-bromo-pyridin-2-yl-acetic acid (0.87 g, 4.0 mmol) in THF (12 mL) was added HOBt (0.74 g, 4.8 mmol) and EDCI.HCl (0.85 g, 4.4 mmol) and stirred the resulting reaction mixture for 15-20 min at room temperature followed by drop-wise addition of methyl amine (2.0 M in THF, 4.05 mL, 8.0 mmol). The resulting mixture was then continued to stir for 6-7 h at room temperature. After completion of reaction, water was added and extracted with ethyl acetate. The crude residue was purified over silica (60-120 M) using dichloromethane:methanol (97.5:2.5) to obtain the pale-yellow solid compound (0.25 g, 27%). 1H NMR (DMSO-d6, 400 MHz): δ 2.58 (d, J=4.8 Hz, 3H), 3.57 (s, 2H), 7.33 (d, J=1H), 7.96 (d, J=2.4 Hz & 8.4 Hz, 1H), 8.00 (br s, 1H) and 8.58 (d, J=2.4 Hz, 1H). MS: 229.11 (M+H+).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]([C:16]2[CH:33]=[C:32]3[C:19]([S:20](=[O:36])(=[O:35])[NH:21][C:22]4[C:31]3=[CH:30][C:29]([Cl:34])=[C:28]3[C:23]=4[N:24]=[CH:25][CH:26]=[CH:27]3)=[CH:18][CH:17]=2)=[O:15])[CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[NH:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]([C:16]2[CH:33]=[C:32]3[C:19]([S:20](=[O:35])(=[O:36])[NH:21][C:22]4[C:31]3=[CH:30][C:29]([Cl:34])=[C:28]3[C:23]=4[N:24]=[CH:25][CH:26]=[CH:27]3)=[CH:18][CH:17]=2)=[O:15])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(OC(=O)c2ccc3c(c2)-c2cc(Cl)c4cccnc4c2NS3(=O)=O)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(OC1CCNC1)c1ccc2c(c1)-c1cc(Cl)c3cccnc3c1NS2(=O)=O
Yield: 73.4 %

Procedure:
In a similar fashion using route 55 general procedure 124, 12-chloro-6,6-dioxo-5,6-dihydro-6λ*6*-thia-4,5-diaza-chrysene-9-carboxylic acid 1-tert-butoxycarbonyl-pyrrolidin-3-yl ester (70 mg, 0.13 mmol) and 4M HCl in dioxane (3 ml) gave the title compound (41 mg, 73%) after washing with MeOH.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:16](=[O:31])[N:17](C(OC(C)(C)C)=O)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]([NH:8]C(=O)OC(C)(C)C)=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[N:38]1[CH:43]=[CH:42][CH:41]=[C:40]([NH2:44])[CH:39]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.C1(C=CC(=O)C=CC2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.[Pd]>[NH2:8][C:5]1[C:4]([C:16]([NH:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:31])=[N:3][C:2]([NH:44][C:40]2[CH:39]=[N:38][CH:43]=[CH:42][CH:41]=2)=[CH:7][N:6]=1
Reactant: CC(C)(C)OC(=O)Nc1ncc(Br)nc1C(=O)N(C(=O)OC(C)(C)C)c1ccccc1
Reactant: Nc1cccnc1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: Cc1ccccc1
Product: Nc1ncc(Nc2cccnc2)nc1C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 18.8 %

Procedure:
tert-Butyl N-[5-bromo-3-[tert-butoxycarbonyl(phenyl)carbamoyl]pyrazin-2-yl]carbamate (60 mg, 0.1216 mmol), dicesium carbonate (118.9 mg, 0.3648 mmol), pyridin-3-amine (17.17 mg, 0.1824 mmol), 2-(2-dicyclohexylphosphanylphenyl)-N,N-dimethyl-aniline (14.36 mg, 0.03648 mmol), 1,5-diphenylpenta-1,4-dien-3-one; palladium (11.14 mg, 0.01216 mmol) in toluene (06. mL) heated under microwave conditions at 130° C. for 30 minutes. The reaction mixture was filtered and the filtrate diluted with DCM (2 mL) and TFA (0.5 mL) was added. The resulting solution was stirred at ambient temperature for 30 minutes then concentrated in vacuo. The residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 mM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected and freeze-dried to give the title compound as an yellow solid (7 mg, 19% Yield). 1H NMR (400.0 MHz, DMSO) δ 9.99 (s, 1H), 9.86 (s, 1H), 9.12 (s, 1H), 8.30 (d, J=4.8 Hz, 1H), 8.20 (d, J=3.4 Hz, 2H), 7.75 (dd, J=7.7, 16.7 Hz, 3H), 7.41-7.37 (m, 2H), 7.22 (s, 1H) and 7.14 (t, J=7.4 Hz, 2H) ppm; MS (ES+) 307.
Reaction SMILES: C([O:4][CH:5]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:24]=1)[C:6]([C@H:11]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[CH:12]1[CH2:14][CH2:13]1)([F:10])[C:7]([O-:9])=[O:8])(=O)C.[OH-].[Na+].CO>O1CCCC1>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C@H:11]([CH:12]2[CH2:14][CH2:13]2)[C:6]([F:10])([CH:5]([OH:4])[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:24]=2)[C:7]([OH:9])=[O:8])=[CH:16][CH:17]=1
Reactant: CC(=O)OC(Cc1ccc(F)c(Oc2ccccc2)c1)C(F)(C(=O)[O-])[C@H](c1ccc(Cl)cc1)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C(F)(C(O)Cc1ccc(F)c(Oc2ccccc2)c1)[C@H](c1ccc(Cl)cc1)C1CC1

Procedure:
A mixture of methyl (2R,3S or 2S,3R)-3-(acetyloxy)-2-[(S)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)butanoate (Diastereomer B) (0.80 g, 1.50 mmol), aqueous sodium hydroxide (25 ml), methanol (20 ml) and tetrahydrofuran (5 ml) is refluxed for 1 hour. The organic solvents are removed in vacuo, the mixture is diluted with ethyl acetate and acidified to pH 3 with concentrated hydrochloric acid. The organic layer is separated, dried over anhydrous sodium sulfate and concentrated in vacuo to afford the title compound as a colorless semi solid, which is characterized by 1HNMR and 19FNMR and used without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([C:15]([O:17]CC)=[O:16])=[CH:9]2.O[Li].O.C(O)C>C1COCC1.O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([C:15]([OH:17])=[O:16])=[CH:9]2
Reactant: CCOC(=O)c1cc2cc(OCCOC)ccc2[nH]1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: COCCOc1ccc2[nH]c(C(=O)O)cc2c1
Reaction time: 16 h
Yield: 97.3 %

Procedure:
Ethyl 5-(2-methoxyethoxy)-1H-indole-2-carboxylate (2.0 g, 7.4 mmol) in THF (20 ml) was treated with a solution of LiOH•H2O (0.62 g, 14.8 mmol) in water (10 ml). Ethanol was added until a homogenous solution formed and stirring was continued for 16 h. The reaction mixture was diluted with water (50 ml) and the organic solvents were removed in vacuo. The pH was adjusted to 4 with 1M aqueous HCl and the aqueous solution was extracted with dichloromethane. The combined organic extracts were washed with brine, dried over sodium sulfate, and concentrated in vacuo to provide 5-(2-methoxyethoxy)-1H-indole-2-carboxylic acid (1.7 g, 7.2 mmol) as a white solid. The crude acid was directly used without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH3:9])[CH:3]=1.[CH3:10][NH:11][CH2:12][CH2:13][OH:14]>Cl.O>[CH3:8][C:6]1[CH:7]=[C:2]([N:11]([CH2:12][CH2:13][OH:14])[CH3:10])[CH:3]=[C:4]([CH3:9])[N:5]=1
Reactant: CNCCO
Reactant: Cc1cc(Cl)cc(C)n1
Agent: Cl
Solvent: O
Product: Cc1cc(N(C)CCO)cc(C)n1
Yield: 88.8 %

Procedure:
A solution of 4-chloro-2,6-dimethylpyridine (849 mg, 6 mmol), (J. Het. Chem. 1990, 1841), in 2-(methylamino)ethanol (1.35 g, 18 mmol) and 3M ethereal hydrogen chloride (3 drops) was heated at 140° C. for 1 hour. The reaction mixture was allowed to cool and was diluted with water. The insolubles were removed by filtration and the aqueous filtrate was poured onto a suspension of magnesium sulphate (50 g) in ethyl acetate (100 ml). The insolubles were removed by filtration and the filtrate dried (MgSO4) and the solvent removed by evaporation. The solid residue was triturated with ether, collected by filtration and dried under vacuum at 50° C. to give 2-(N-(2,6-dimethyl-4-pyridyl)-N-methylamino)ethanol (960 mg, 90%). m.p. 139-144° C. 1H NMR Spectrum: (CDCl3) 2.4(s, 6H); 3.0(s, 3H); 3.51(t, 2H); 3.81(t, 2H); 6.26(s, 2H) MS-ESI: 181 [MH]+
Reaction SMILES: CC1C([C:8]2[N:13]=[C:12]([C:14](F)(F)F)[C:11]([C:18]([C:20]3[C:21]([C:33]([F:36])([F:35])[F:34])=[N:22][C:23](C4C(C)=NC=NC=4)=[N:24][CH:25]=3)=[O:19])=[CH:10][N:9]=2)=CN=CN=1.[BH4-].[Na+].C(OC(=O)C)C.OP([O-])(O)=O.[K+]>C(O)C>[CH3:14][C:12]1[C:11]([CH:18]([C:20]2[C:21]([C:33]([F:36])([F:34])[F:35])=[N:22][CH:23]=[N:24][CH:25]=2)[OH:19])=[CH:10][N:9]=[CH:8][N:13]=1
Reactant: Cc1ncncc1-c1ncc(C(=O)c2cnc(-c3cncnc3C)nc2C(F)(F)F)c(C(F)(F)F)n1
Agent: O=P([O-])(O)O
Agent: [BH4-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ncncc1C(O)c1cncnc1C(F)(F)F
Reaction time: 0.17 h
Yield: 114.3 %

Procedure:
To a cooled solution of 300 mg of (4-methylpyrimidin-5-yl)-4-trifluoromethylpyrimidin-5-yl ketone in 4.5 ml of ethanol (EtOH) was added 30 mg of sodium borohydride in 1 ml EtOH dropwise over a period of 20 minutes. After stirring at 0°-5° C. for another 10 minutes, ethylacetate (25 ml) and 15 ml of 10% KH2PO4 (pH=3) were added followed by vigorous stirring. The layers were separated and the aqueous extracted twice with dichloromethane-methanol (10:1). The organic layers were combined, dried (MgSO4) and stripped to yield 183 mg of 1-(4-methylpyrimidin-5-yl)-1-(4-trifluoromethylpyrimidin-5-yl)methanol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:23])[CH:11]=2)[C:6]=1Br.[CH3:26]B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:23])[CH:11]=2)[C:6]=1[CH3:26]
Reactant: COC(=O)Cc1cc(OCc2ccccc2)c2cc(F)ccc2c1Br
Reactant: CB(O)O
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)Cc1cc(OCc2ccccc2)c2cc(F)ccc2c1C
Temperature: 150 °C
Yield: 59.5 %

Procedure:
To a solution of (4-benzyloxy-1-bromo-6-fluoro-naphthalen-2-yl)-acetic acid methyl ester (100 mg, 0.248 mmol, prepared using an analogous procedure to the first step of example 5-1), methylboronic acid (19.3 mg, 0.322 mmol), potassium phosphate (184 mg, 0.868 mmol) and tricyclohexylphosphine (69.4 mg, 0.248 mmol) in toluene (4.0 mL) and water (2 drops) was added palladium acetate (3 mg, 0.0124 mmol) under a nitrogen atmosphere. After being heated under microwave conditions (150° C., 30 minutes), the mixture was cooled to room temperature, then diluted with water (10 mL), and extracted with ethyl acetate (15 mL×2). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (10% ethyl acetate in hexanes) to afford (4-benzyloxy-6-fluoro-1-methyl-naphthalen-2-yl)-acetic acid methyl ester (50 mg, 59.5%) as a light yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[N:18]([S:22]([C:25]1[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=1)(=[O:24])=[O:23])[C:17]1[CH:16]=[N:15][C:14]([C:32](=[O:34])[CH3:33])=[C:13]([CH2:35][O:36][CH3:37])[C:12]2=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-:38].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[N:18]([S:22]([C:25]1[CH:26]=[CH:27][C:28]([CH3:29])=[CH:30][CH:31]=1)(=[O:24])=[O:23])[C:17]1[CH:16]=[N:15][C:14]([C:32](=[O:34])[CH2:33][Br:38])=[C:13]([CH2:35][O:36][CH3:37])[C:12]2=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCc1c(C(C)=O)ncc2c1c1cc(OCc3ccccc3)ccc1n2S(=O)(=O)c1ccc(C)cc1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: COCc1c(C(=O)CBr)ncc2c1c1cc(OCc3ccccc3)ccc1n2S(=O)(=O)c1ccc(C)cc1

Procedure:
2.29 g of 6-benzyloxy-4-methoxymethyl-3-acetyl-9-tosyl-β-carboline is stirred with the double molar amount of phenyltrimethylammonium tribromide in 100 ml of absolute tetrahydrofuran for 4 days at room temperature. The reaction mixture is evaporated to dryness, taken up in methylene chloride, washed with saturated NaCl solution, dried on Sikkon and concentrated by evaporation. The crude product is chromatographed on silica gel (cyclohexane/ethyl acetate=8+2). 1.9 g of 6-benzyloxy-3-bromoacetyl-4-methoxymethyl-9-tosyl-β-carboline is obtained. Melting point 165° C. (decomposition).
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[C:5]([C:8]1[CH:13]=[C:12]([C:14](=[O:16])[CH3:15])[C:11]([OH:17])=[CH:10][C:9]=1[NH:18][CH2:19][CH3:20])(=[O:7])[CH3:6].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([O:17][C:11]1[CH:10]=[C:9]([C:8]([C:5](=[O:7])[CH3:6])=[CH:13][C:12]=1[C:14](=[O:16])[CH3:15])[NH:18][CH2:19][CH3:20])[CH:2]=[CH2:3]
Reactant: CCNc1cc(O)c(C(C)=O)cc1C(C)=O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1cc(NCC)c(C(C)=O)cc1C(C)=O
Yield: 93 %

Procedure:
Allyl bromide (2 g) was added to a stirred solution of 4,6-diacetyl-3-ethylaminophenol (0.016 M) in dimethylformamide (30 ml) containing potassium carbonate (2 g). The mixture was heated at 60°-70° C. for two hours, and was then poured into water (100 ml), stirred, and the precipitated product isolated by filtration. Yield 93%, mp 82°-83° C.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.C([O:13][C:14](=O)[C:15]([C:27]#[N:28])=[CH:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([O:25][CH3:26])[CH:18]=1)C>>[C:27]([C:15]1[C:14](=[O:13])[O:9][C:5]2[C:6]([C:16]=1[C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([O:25][CH3:26])[CH:18]=1)=[CH:7][CH:8]=[C:3]([N:2]([CH3:10])[CH3:1])[CH:4]=2)#[N:28]
Reactant: CCOC(=O)C(C#N)=Cc1cc(OC)cc(OC)c1
Reactant: CN(C)c1cccc(O)c1
Product: COc1cc(OC)cc(-c2c(C#N)c(=O)oc3cc(N(C)C)ccc23)c1
Yield: 0.4 %

Procedure:
The title compound was prepared from 3-dimethylaminophenol and 3-(3,5-dimethoxyphenyl)-2-cyano-acrylic acid ethyl ester by a procedure similar to that described for Example 16 in 0.4% yield. 1H NMR (DMSO-d6): 7.09 (d, J=8.7 Hz, 1H), 6.80 (d, J=7.5 Hz, 1H), 6.73-6.71 (m, 2H), 6.65 (d, J=2.1 Hz, 2H), 3.80 (s, 6H), 3.11 (s, 6H).
Reaction SMILES: [OH-].[K+].Br[CH:4]1[CH:13]([O:14][CH3:15])[C:9]2[S:10][CH:11]=[CH:12][C:8]=2[C:7](=[O:16])[C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]1=2>CO>[CH3:15][O:14][C:13]1[C:9]2[S:10][CH:11]=[CH:12][C:8]=2[C:7](=[O:16])[CH:6]=[C:17]2[CH:18]=[CH:19][CH:20]=[CH:5][C:4]=12
Reactant: COC1c2sccc2C(=O)c2ccccc2C1Br
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1c2ccccc2cc(=O)c2ccsc12

Procedure:
9 g of potassium hydroxide are added to a solution of 17.5 g of 9-bromo-9,10-dihydro-10-methoxy-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-one in 400 cc of methanol, and the solution is boiled at reflux for 6 hours. After cooling to 0°-5°, the precipitated crystalline material is filtered off and recrystallized from methanol. The pure 10-methoxy-4H-benzo[4,5]cyclohepta[1,2-b] thiophen-4-one, having a M.P. of 164°-166°, is obtained in this mannner. Microanalysis agrees with the formula C14H10O2S. The structure was ascertained with the nuclear magnetic resonance and mass spectrograph spectra.