Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([O-:21])=[O:20])=[CH:15][CH:14]=1.[Na+].O>COCCOC.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.[I-].[Na+]>[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH2:2][CH2:3][CH2:4][O:5][CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][O:7]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: BrCCCOC1CCCCO1
Reactant: Cc1ccc(S(=O)[O-])cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [I-]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(S(=O)(=O)CCCOC2CCCCO2)cc1
Reaction time: 24 h
Yield: 75.6 %

Procedure:
32 g (144 mmol) of 3-bromo-1-tetrahydropyranyloxypropane (1a) are dissolved in 200 ml of 1,2-dimethoxyethane, 26.9 g (151 mmol) of anhydrous sodium 4-methylphenyl-sulfinate, 4.5 g (14 mmol) of tetrabutylammoniumbromide and 1.05 g (7 mmol) of sodium iodide are added and the mixture is heated to boiling for 24 hours. After cooling, 500 ml of water are added, the mixture is extracted with three times 300 ml of dichloromethane each time, the combined dichloromethane extracts are washed with water and dried with magnesium sulfate. After filtering off the drying agent and distilling off the solvent in vacuo a yellowish brown oil is obtained which is purified by column chromatography (silica gel; dichloromethane or dichloromethane/ethyl acetate mixtures). 32.5 g (76%) of a colorless oil are isolated, which partly crystallizes on prolonged standing (m.p.<30° C.)
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[H-].[Na+].[CH2:7](Cl)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[CH2:7]([O:2][CH2:1][CH2:3][NH2:4])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NCCO
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: NCCOCc1ccccc1
Yield: 90.8 %

Procedure:
To a solution of ethanolamine (5 g, 81.8 mmol) in 100 mL of dried THF was added 60% NaH (3.27 g, 81.8mmol) at room temperature. The mixture was heated to reflux for 30min, then benzyl chloride (9.32 g, 73.6 mmol) was added. The resulting mixture was refluxed for 3 hours. The mixture was concentrated, the residue was diluted with 1 N aq. HCl, extracted with dichloromethane. The aqueous layer was adjusted to pH>14 with 10% aq. NaOH, extracted with dichloromethane. The organic was dried over MgSO4, concentrated to give desired product (10.11 g, 82%). 1H NMR (CDCl3): δ 7.34 (m, 5H), 4.54 (s, 2H), 3.54 (t, 2H), 2.93 (t, 2H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[C@H:6]([NH:8][C:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([C:20]3[C:28]4[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=4)[N:22]([CH3:30])[N:21]=3)[N:18]=2)[N:13](COCC[Si](C)(C)C)[CH:12]=1)=[O:10])[CH3:7].FC(F)(F)C(O)=O.C(N)CN>ClCCl>[O:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[C@H:6]([NH:8][C:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([C:20]3[C:28]4[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=4)[N:22]([CH3:30])[N:21]=3)[N:18]=2)[NH:13][CH:12]=1)=[O:10])[CH3:7]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)[C@@H]1CCCO1
Solvent: ClCCl
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)[C@@H]1CCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.2 %

Procedure:
In a round-bottomed flask, 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)—(S)-1-(tetrahydro-furan-2-yl)-ethyl]-amide (152 mg, 0.28 mmol) was dissolved in dichloromethane (1.4 ml) and trifluoroacetic acid (0.87 ml, 11.3 mmol) was added. The reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was dissolved in dichloromethane (1.4 ml) and ethylenediamine (1.2 ml, 17.8 mmol) was added. The yellow solution was stirred at room temperature for 1 h then quenched with water and diluted with ethyl acetate. The resulting suspension was filtered, washed with hot water and ethyl acetate and dried under high vacuum to provide 46 mg (40%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)—(S)-1-(tetrahydro-furan-2-yl)-ethyl]-amide as an off-white powder. MS: (M+Na)+=431; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.09 (br. s., 1H), 9.13 (s, 1H), 8.64 (dd, J=8.7, 5.3 Hz, 1H), 8.44 (s, 1H), 8.22 (d, J=9.4 Hz, 1H), 7.67 (d, J=8.3 Hz, 1H), 7.10 (t, J=8.1 Hz, 1H), 4.32 (br. s., 1H), 4.15 (s, 3H), 3.96 (d, J=3.0 Hz, 1H), 3.52-3.68 (m, 2H), 1.86-2.00 (m, 1H), 1.52-1.84 (m, 3H), 1.33 (d, J=6.8 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][C:10]2=[O:13])=[CH:5][CH:4]=1.Br[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[N:19][CH:18]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[F:15][C:2]([F:1])([F:14])[C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[N:19][CH:18]=3)[C:10]2=[O:13])=[CH:5][CH:4]=1
Reactant: O=C1NCCc2ccc(C(F)(F)F)cc21
Reactant: Brc1cncc2ccccc12
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C1c2cc(C(F)(F)F)ccc2CCN1c1cncc2ccccc12
Yield: 10.5 %

Procedure:
Using analogous reaction conditions as described in Example 1, 7-trifluoromethyl-3,4-dihydro-2H-isoquinolin-1-one (I-16c: 150 mg, 0.698 mmol) was reacted with 4-bromo-isoquinoline (145 mg, 0.698 mmol), 1,4-dioxane (10 mL), copper iodide (13.29 mg, 0.0698 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (29.74 mg, 0.209 mmol) and potassium phosphate (369.94 mg, 1.745 mmol) to afford the crude product. Purification by column chromatography on silica gel (1.5% methanol in DCM) afforded 25 mg of the product (10.50% yield).
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([CH2:11][C:12]([C:14]2[CH:19]=C[CH:17]=[CH:16][CH:15]=2)=[O:13])[CH:6]=[CH:7][C:8]=1OC.CO[N:22](C)C(=O)C1C=CC=NC=1.C([Mg]Cl)C1C=CC=CC=1>>[C:5]1([CH2:11][C:12]([C:14]2[CH:19]=[N:22][CH:17]=[CH:16][CH:15]=2)=[O:13])[CH:6]=[CH:7][CH:8]=[CH:3][CH:4]=1
Reactant: CON(C)C(=O)c1cccnc1
Reactant: COc1ccc(CC(=O)c2ccccc2)cc1OC
Agent: Cl[Mg]Cc1ccccc1
Product: O=C(Cc1ccccc1)c1cccnc1
Reaction time: 3 h
Yield: 19 %

Procedure:
Followed the procedure described in Step 2 of Intermediate 7 with N-methoxy-N-methylnicotinamide and benzylmagnesium chloride, where the mixture was stirred for 3 hours. Purification was achieved by column chromatography (PE:EtOAc=5:1) to give Intermediate 31 (110 mg, yield 19%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH:11]=1)[N:8]=[C:7]([CH:20]([OH:25])[CH2:21][CH:22]([CH3:24])[CH3:23])[CH:6]=[CH:5]2.[H-].[Na+].[CH3:28][O:29][CH2:30]Cl.[NH4+].[Cl-]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH:11]=1)[N:8]=[C:7]([CH:20]([O:25][CH2:28][O:29][CH3:30])[CH2:21][CH:22]([CH3:23])[CH3:24])[CH:6]=[CH:5]2
Reactant: CCOP(=O)(OCC)c1cc(Br)cc2ccc(C(O)CC(C)C)nc12
Reactant: COCCl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)c1cc(Br)cc2ccc(C(CC(C)C)OCOC)nc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 70.3 %

Procedure:
To a solution of diethyl 6-bromo-2-(1-hydroxy-3-methylbutyl)-8-quinolylphosphonate (219 mg, 0.51 mmol) (Example 19, step 3) in THF (2 mL) at 0° C. was added NaH (40 mg, 1.02 mmol, 60% in oil). To the resulting green suspension was added chloromethyl methyl ether (82 mg, 1.02 mmol). The mixture was stirred at r.t. for 1.5 h, Aqueous NH4Cl was added and the mixture was extracted with EtOAc. The organic extracts were washed with brine, dried (anhyd. MgSO4) and concentrated in vacuo. The residue was purified by chromatography on silica gel to give 170 mg (70%) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH:8]=[CH:7]2)([O-])=O.[H][H]>CO.O=[Pt]=O>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH:8]=[CH:7]2
Reactant: O=c1ccc2cc([N+](=O)[O-])ccc2[nH]1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CO
Product: Nc1ccc2[nH]c(=O)ccc2c1

Procedure:
In a Parr catalytic hydrogenation apparatus 6-nitrocarbostyril, 5.3 g (0.028 mole), in 150 mL of methanol and 0.5 g PtO2 were shaken in a hydrogen atmosphere. The resulting yellow solid was extracted with refluxing methanol to yield 6-aminocarbostyril, 3.5 g, as yellow crystals; m.p. 315°-317° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH2:18]OC)[NH:5][C:6]=1[C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[CH3:17])[C:10]([O:12]C)=[O:11].[N:21]1([CH2:25]CC2NC(C3C=C(C=CC=3C)C(OC)=O)=CN=2)[CH2:24][CH2:23][CH2:22]1.COCC1NC(C2C=C(C=CC=2C)C(OC)=O)=CN=1>>[N:21]1([CH2:25][CH2:18][C:4]2[NH:5][C:6]([C:7]3[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=3[CH3:17])[C:10]([OH:12])=[O:11])=[C:2]([Cl:1])[N:3]=2)[CH2:24][CH2:23][CH2:22]1
Reactant: COCc1nc(Cl)c(-c2cc(C(=O)OC)ccc2C)[nH]1
Reactant: COC(=O)c1ccc(C)c(-c2cnc(CCN3CCC3)[nH]2)c1
Agent: COCc1ncc(-c2cc(C(=O)OC)ccc2C)[nH]1
Product: Cc1ccc(C(=O)O)cc1-c1[nH]c(CCN2CCC2)nc1Cl

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compounds 27.4 and 27.5, except methyl 3-(2-(2-(azetidin-1-yl)ethyl)-1H-imidazol-5-yl)-4-methylbenzoate (compound 157.2) was used in place of methyl 3-(2-(methoxymethyl)-1H-imidazol-5-yl)-4-methylbenzoate (compound 27.3).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[S:18][C:17]3[C:12](=[N:13][CH:14]=[CH:15][C:16]=3[O:19][C:20]3[CH:32]=[CH:31][C:23]4[C:24]([C:28]([OH:30])=O)=[C:25]([CH3:27])[O:26][C:22]=4[CH:21]=3)[CH:11]=2)=[O:9])[CH2:4]1.C(Cl)(=O)C(Cl)=O.[NH2:39][CH2:40][CH:41]1[CH2:43][CH2:42]1>>[CH:41]1([CH2:40][NH:39][C:28]([C:24]2[C:23]3[CH:31]=[CH:32][C:20]([O:19][C:16]4[CH:15]=[CH:14][N:13]=[C:12]5[CH:11]=[C:10]([C:8]([N:5]6[CH2:6][CH2:7][CH:3]([O:2][CH3:1])[CH2:4]6)=[O:9])[S:18][C:17]=45)=[CH:21][C:22]=3[O:26][C:25]=2[CH3:27])=[O:30])[CH2:43][CH2:42]1
Reactant: COC1CCN(C(=O)c2cc3nccc(Oc4ccc5c(C(=O)O)c(C)oc5c4)c3s2)C1
Reactant: NCC1CC1
Agent: O=C(Cl)C(=O)Cl
Product: COC1CCN(C(=O)c2cc3nccc(Oc4ccc5c(C(=O)NCC6CC6)c(C)oc5c4)c3s2)C1

Procedure:
This material was prepared from 6-[2-(3-methoxypyrrolidine-1-carbonyl)-thieno[3,2-b]pyridin-7-yloxy]-2-methyl-benzofuran-3-carboxylic acid 89e by treatment with oxalyl chloride and (aminomethyl)cyclopropane in a manner as previously described for example 16d. 1H NMR (DMSO-d6) δ8.55 (1H, d, J=5.1 Hz), 8.20 (1H, s), 8.05 (1H, s), 7.80 (1H, d, J=8.6 Hz), 7.64 (1H, s), 7.22 (1H, d, J=8.3 Hz), 6.69 (1H, d, J=5.3 Hz), 4.10-3.80 (3H, m), 3.70-3.50 (2H, m), 3.26 (3H, d, J=12.6 Hz), 3.15 (2H, m), 2.63 (3H, s), 2.20-1.95 (2H, m), 1.08 (1H, m), 0.45 (2H, d, J=7.1 Hz), 0.25 (2H, d, J=4.3 Hz).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][O:12][C:13]2[C:21]([C:22]3[C:23]4[CH:32]=[N:31][N:30](COCC[Si](C)(C)C)[C:24]=4[C:25](=[O:29])[N:26]([CH3:28])[CH:27]=3)=[CH:20][CH:19]=[C:18]3[C:14]=2[CH:15]=[N:16][N:17]3[CH3:41])[CH2:10][CH2:9]1.[OH-].[NH4+].O>C(Cl)Cl.CO>[CH:8]1([CH2:11][O:12][C:13]2[C:21]([C:22]3[C:23]4[CH:32]=[N:31][NH:30][C:24]=4[C:25](=[O:29])[N:26]([CH3:28])[CH:27]=3)=[CH:20][CH:19]=[C:18]3[C:14]=2[CH:15]=[N:16][N:17]3[CH3:41])[CH2:10][CH2:9]1
Reactant: Cn1cc(-c2ccc3c(cnn3C)c2OCC2CC2)c2cnn(COCC[Si](C)(C)C)c2c1=O
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cn1cc(-c2ccc3c(cnn3C)c2OCC2CC2)c2cn[nH]c2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.3 %

Procedure:
Trifluoroacetic acid (0.564 mL) was added dropwise to a solution of 4-[4-(cyclopropylmethoxy)-1-methyl-1H-indazol-5-yl]-6-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one (0.0549 g, 0.114 mmol) in methylene chloride (0.564 mL) and the resultant reaction mixture was stirred at RT for 30 min. The reaction mixture was concentrated in vacuo to yield a crude residue. The crude residue was dissolved in methanol (1.00 mL), followed by dropwise addition of 15.0 M solution of ammonium hydroxide in water (0.250 mL, 3.76 mmol). The resultant reaction mixture was stirred at RT for 30 min. The reaction mixture was purified via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (26.8 mg, 67%). 1H NMR (500 MHz, DMSO-d6) δ 14.00 (br s, 1H), 8.23 (s, 1H), 7.72 (s, 1H), 7.38 (d, J=8.5 Hz, 1H), 7.33 (d, J=8.5 Hz, 1H), 7.28 (s, 1H), 4.05 (d, J=6.8 Hz, 2H), 4.03 (s, 3H), 3.58 (s, 3H), 1.23-0.81 (m, 1H), 0.51-0.26 (m, 2H), 0.25-0.01 (m, 2H); LCMS calculated for C19H20N5O2 (M+H)+: m/z=350.2. found: 350.1.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][C:6](=[O:8])[O:5][C:3]1=[O:4].[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CCl>[C:10]1([NH:9][C:6]([CH2:7][C:2](=[CH2:1])[C:3]([OH:5])=[O:4])=[O:8])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccccc1
Reactant: C=C1CC(=O)OC1=O
Agent: CCl
Product: C=C(CC(=O)Nc1ccccc1)C(=O)O

Procedure:
A solution of 2-methylenesuccinic anhydride (500 mg, 4.46 mmol) and aniline (0.4 mL, 4.46 mmol) in CH3Cl were shaken overnight. A precipitate formed, which was filtered off, washed with hexanes, and dried under vacuum to afford 2-[(N-phenylcarbamoyl)methyl]prop-2-enoic acid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[N:14][N:15]3[CH:20]=[CH:19][C:18]([N:21]4[C@@H:25]([CH:26]([CH3:28])[CH3:27])[CH2:24][N:23]([CH2:29][CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)[C:22]4=[O:36])=[N:17][C:16]=23)=[CH:8][CH:7]=1.C=O.[BH3-][C:40]#N.[Na+].C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:55].Cl.Cl>CC#N.ClCCl.O1CCOCC1>[ClH:55].[ClH:55].[NH:3]1[CH:4]=[CH:5][N:1]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[N:14][N:15]3[CH:20]=[CH:19][C:18]([N:21]4[C@@H:25]([CH:26]([CH3:28])[CH3:27])[CH2:24][N:23]([CH2:29][CH:30]5[CH2:35][CH2:34][N:33]([CH3:40])[CH2:32][CH2:31]5)[C:22]4=[O:36])=[N:17][C:16]=23)=[CH:8][CH:7]=1
Reactant: CC(C)[C@H]1CN(CC2CCNCC2)C(=O)N1c1ccn2ncc(-c3ccc(-c4ncc[nH]4)cc3)c2n1
Reactant: [BH3-]C#N
Agent: C=O
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: ClCCl
Solvent: CC#N
Solvent: C1COCCO1
Product: CC(C)[C@H]1CN(CC2CCN(C)CC2)C(=O)N1c1ccn2ncc(-c3ccc(-c4ncc[nH]4)cc3)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (S)-3-(3-(4-(1H-imidazol-2-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-isopropyl-1-(piperidin-4-ylmethyl)imidazolidin-2-one (Example 21; 2.1 mg, 0.0043 mmol) and formaldehyde (37% aqueous solution, 0.003 mL, 0.04 mmol) in MeCN (0.5 mL) was added NaBH3CN (0.8 mg, 0.42 mmol), and the reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was diluted with dichloromethane, washed with saturated aqueous NaHCO3 solution and brine, dried and concentrated. The residue was purified by column chromatography (dichloromethane:7N ammonia in MeOH, 10:1) to give the free base, which was converted to dihydrochloride salt by treatment with 4N HCl in dioxane. LCMS (APCI+) m/z 499.8 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([OH:12])=[CH:7][CH:6]=2.Br[CH:14]([CH2:26][O:27][CH3:28])[C:15]([NH:17][C:18]([CH3:25])([CH3:24])[C:19]#[C:20][CH2:21][O:22][CH3:23])=[O:16]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH:14]([CH2:26][O:27][CH3:28])[C:15]([NH:17][C:18]([CH3:25])([CH3:24])[C:19]#[C:20][CH2:21][O:22][CH3:23])=[O:16])=[CH:7][CH:6]=2
Reactant: Oc1ccc2ncc(Br)cc2c1
Reactant: COCC#CC(C)(C)NC(=O)C(Br)COC
Product: COCC#CC(C)(C)NC(=O)C(COC)Oc1ccc2ncc(Br)cc2c1

Procedure:
In a similar procedure to Example 6 Stage 2, 3-bromo-6-hydroxyquinoline was reacted with 2-bromo-N-(1-methoxy-4-methylpent-2-yn-4-yl) 3-methoxypropionamide to give 2-(3-bromo-6-quinolinyloxy)-N-(1-methoxy-4-methylpent-2-yn-4-yl) 3-methoxypropionamide as a gum. 1H NMR (CDCl3) δ: 1.58(3H, s); 1.59(3H, s); 1.77(3H, s0; 3.44(3H, s); 3.87–3.95(2H, m); 4.73(1H, m); 6.52(1H, s); 7.08(1H, m); 7.48(1H, dd); 8.02(1H, d); 8.21(1H, m); 8.79(1H, m).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:25])[C:7]3[C:8](=[CH:11][S:12][C:13]=3[N:14]3C(=O)C4C(=CC=CC=4)C3=O)[C:9]=2[CH:10]=1.CC1C2C(=O)C3C(=CSC=3N3C(=O)C4C(=CC=CC=4)C3=O)C=2C=CC=1.O.NN>C(O)C>[NH2:14][C:13]1[S:12][CH:11]=[C:8]2[C:9]3[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=3[C:6](=[O:25])[C:7]=12
Reactant: Cc1ccc2c(c1)-c1csc(N3C(=O)c4ccccc4C3=O)c1C2=O
Agent: Cc1cccc2c1C(=O)c1c-2csc1N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1ccc2c(c1)-c1csc(N)c1C2=O
Temperature: 25 °C

Procedure:
To a mixture of 2-(5-methyl-8-oxo-8H-2-thia-cyclopenta[a]inden-1-yl)-isoindole-1,3-dione and 2-(7-methyl-8-oxo-8H-2-thia-cyclopenta[a]inden-1-yl)-isoindole-1,3-dione (0.45 mmol, Example 2 & 3, Part E) in absolute ethanol (5 mL) was added hydrazine hydrate (0.5 mmol). The suspension was heated to reflux for one hour, cooled to room temperature, concentrated in vacuo, and the residue dissolved in methylene chloride. The solution was chilled to 5° C. for one hour, during which time the phthaloyl hydrazide precipitated. The precipitate was removed by filtration, the filtrate concentrated in vacuo, and the residue purified by column chromatography on silica gel, eluting with a 4:1 mixture of petroleum ether and ethyl acetate. Fractions containing the individual products were pooled, evaporated, and each product was isolated after recrystallization from petroleum ether.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH:10]=[CH:9]2.[CH3:17][NH2:18]>CO>[CH3:17][NH:18][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH:10]=[CH:9]2
Reactant: CN
Reactant: O=c1ccc2cc(OCCCCl)ccc2[nH]1
Solvent: CO
Product: CNCCCOc1ccc2[nH]c(=O)ccc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
6-(3-Chloropropoxy)carbostyril (20 g) is added into a 40% solution of methylamine in methanol (200 ml), and the mixture is heated with stirring at 100° C. overnight in a sealed tube. The mixture is concentrated under reduced pressure to remove the solvent, and the precipitated crystals are washed with a mixture of chloroform-diethyl ether, purified by silica gel column chromatography (solvent; methylene chloride:methanol:aqueous ammonia=50:10:1), and recrystallized from chloroform-diethyl ether to give 6-(3-methylaminopropoxy)carbostyril (15.4 g).
Reaction SMILES: [C:1]([NH:6][C:7]1[CH:14]=[CH:13][C:12]2[O:15][CH2:16][O:17][C:11]=2[C:8]=1[CH:9]=O)(OCC)=[O:2].C([O-])(=O)C.[NH4+:22].[Cl-].[NH4+]>C(O)(=O)C.O>[CH2:16]1[O:15][C:12]2[C:11](=[C:8]3[C:7](=[CH:14][CH:13]=2)[NH:6][C:1](=[O:2])[N:22]=[CH:9]3)[O:17]1
Reactant: [NH4+]
Reactant: CCOC(=O)Nc1ccc2c(c1C=O)OCO2
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: O
Solvent: CC(=O)O
Product: O=c1ncc2c3c(ccc2[nH]1)OCO3
Temperature: 90 °C
Reaction time: 15 h
Yield: 6.2 %

Procedure:
2-Carboethoxyamino-5,6-methylenedioxybenzaldehyde (5.0 g, 21.1 mmoles) was added to a suspension of ammonium acetate (1.63 g, 21.1 mmoles) and ammonium chloride (1.13 g, 21.1 mmoles) in 50 ml of acetic acid. The temperature was slowly raised to 90° C. and held there for 15 hours. The mixture was diluted with one volume of water and then extracted with ethyl acetate, after adjusting the pH to 9 with concentrated ammonium hydroxide. The ethyl acetate layers were evaporated to dryness and the residue was recrystallized first from 10% NH4OH then from methanol to give 250 mg of 5,6-methylenedioxy-2(1H)-quinazolinone (6%), mp >300° C., M+ 190. PG,10
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:17]2[CH2:21][C@H:20]([CH2:22][N:23]3[CH:27]=[C:26]([Cl:28])[N:25]=[N:24]3)[O:19][C:18]2=[O:29])[CH:5]=[CH:6][C:7]=1B1OC(C)(C)C(C)(C)O1.Br[C:31]1[CH:32]=[CH:33][C:34]([C:37]2[N:38]=[N:39][N:40]([CH3:42])[N:41]=2)=[N:35][CH:36]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([N:17]2[CH2:21][C@H:20]([CH2:22][N:23]3[CH:27]=[C:26]([Cl:28])[N:25]=[N:24]3)[O:19][C:18]2=[O:29])[CH:5]=[CH:6][C:7]=1[C:31]1[CH:36]=[N:35][C:34]([C:37]2[N:38]=[N:39][N:40]([CH3:42])[N:41]=2)=[CH:33][CH:32]=1
Reactant: CC1(C)OB(c2ccc(N3C[C@H](Cn4cc(Cl)nn4)OC3=O)cc2F)OC1(C)C
Reactant: Cn1nnc(-c2ccc(Br)cn2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1nnc(-c2ccc(-c3ccc(N4C[C@H](Cn5cc(Cl)nn5)OC4=O)cc3F)cn2)n1
Temperature: 70 °C

Procedure:
A mixture of (5R)-3-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5-(4-chloro-1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (300 mg, 0.71 mmol), 5-bromo-2-(2-methyl-2H-tetrazol-5-yl)pyridine (170 mg, 0.71 mmol), and sodium carbonate (226 mg, 2.13 mmol) in N,N-dimethylformamide:water (5 mL, 10:1) was degassed, flushed with nitrogen, and treated with tetrakis(triphenylphosphine)palladium (0) (82 mg, 10 mol %). The reaction mixture was heated at 70° C. for 3 hours, cooled to room temperature, and evaporated to dryness under reduced pressure. The involatile residue was purified by chromatography on silica gel [elution with dichloromethane:N,N-dimethylformamide (25:1 to 20:1)]. The product fraction was concentrated to a small volume (˜3 mL) and treated with dichloromethane (5 mL) and hexanes (15 mL) to precipitate the product as a colorless amorphous solid (229 mg, 71%).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[C:14](=O)[NH:13][CH2:12][CH2:11]3)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH2:14][NH:13][CH2:12][CH2:11]3)=[CH:19][CH:20]=1
Reactant: O=C1NCCc2cc(OCc3ccc(F)cc3)ccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Fc1ccc(COc2ccc3c(c2)CCNC3)cc1
Yield: 98.1 %

Procedure:
As described for example 43, the title compound (1.86 g, 98%) was prepared from a mixture of 6-(4-fluoro-benzyloxy)-3,4-dihydro-2H-isoquinolin-1-one (2 g, 7.37 mmol) and lithium aluminum hydride (0.559 g, 14.74 mmol) in tetrahydrofuran. MS: m/e=258.0 (M+H+)
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:9]1([CH3:32])[CH:14]=[CH:13][CH:12]=[C:11]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH:23]([C:29]([CH3:31])=O)[C:24](OCC)=[O:25])[CH2:17][CH2:16]2)[CH:10]=1.[OH-].[Na+]>O>[C:9]1([CH3:32])[CH:14]=[CH:13][CH:12]=[C:11]([N:15]2[CH2:16][CH2:17][N:18]([CH2:21][CH2:22][C:23]3[C:24](=[O:25])[N:4]4[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]4=[N:8][C:29]=3[CH3:31])[CH2:19][CH2:20]2)[CH:10]=1
Reactant: Cc1cccnc1N
Reactant: CCOC(=O)C(CCN1CCN(c2cccc(C)c2)CC1)C(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cccc(N2CCN(CCc3c(C)nc4c(C)cccn4c3=O)CC2)c1
Yield: 15.1 %

Procedure:
A mixture of 0.19 g of 3-methyl-2-aminopyridine, 1 g of ethyl 2-[2-(4-m-tolyl-1-piperazinyl)ethyl]acetoacetate and 1.17 g of polyphosphoric acid was heated at 120° - 130°C for 2 hours. After completion of the reaction, water was added to the reaction mixture. The resulting mixture was made basic by addition of an aqueous sodium hydroxide solution and then extracted with ethyl acetate. After evaporation of the solvent from the extract, the remaining residue was washed with isopropyl alcohol and recrystallized from isopropyl alcohol to give 0.1 g of the desired compound as pale yellow needles, m.p. 106° - 106.5°C.