Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:11]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[O:12])[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.Cl.[CH3:19][N:20]([CH3:25])[CH2:21][C:22]([Cl:24])=[O:23]>N1C=CC=CC=1>[ClH:24].[CH3:19][N:20]([CH3:25])[CH2:21][C:22]([NH:1][C:2]1[N:3]=[C:4]([C:11]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[O:12])[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1)=[O:23]
Reactant: CN(C)CC(=O)Cl
Reactant: Nc1nc(C(=O)c2cccs2)c2sccc2n1
Agent: Cl
Solvent: c1ccncc1
Product: CN(C)CC(=O)Nc1nc(C(=O)c2cccs2)c2sccc2n1
Temperature: 25 °C
Yield: 14.7 %

Procedure:
A solution of 2-aminothieno[3,2-d]pyrimidin-4-yl 2-thienylmethanone (0.15 g, 0.57 mmol) in anhydrous pyridine (6 mL) under argon at 0° C. was treated with N,N-dimethylglycinyl chloride hydrochloride (0.11 g, 0.69 mmol), warmed to room temperature, refluxed for 16 h, cooled, concentrated in vacuo and partitioned between 3-M HCl (25 mL) and EtOAc (25 mL). The aqueous phase was washed with EtOAc (25 mL), filtered through celite, basified to pH 12 with 10% aqueous sodium hydroxide and the resulting precipitate filtered and dried in vacuo to give a brown solid which was purified by chromatography [SiO2; EtOAc-MeOH (100:0 to 85:15)]. The resulting yellow solid was dissolved in CH2Cl2 (5 mL), treated with 1-M HCl in ether (0.25 mL) and the resulting precipitate filtered and dried in vacuo to give the title compound (32 mg, 11%) as a yellow solid.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[C:17]([C:26]([O:28][CH2:29][CH2:30][CH3:31])=[O:27])=[CH:18][C:19]4[C:24]([CH:25]=3)=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:32][CH3:33].C(=O)([O-])[O-].[K+].[K+].[NH:40]1[CH:44]=[CH:43][N:42]=[CH:41]1.O>CN(C)C=O>[N:40]1([CH2:2][CH2:3][O:4][C:5]2[CH:14]=[C:13]3[C:8]([C:9]([O:15][C:16]4[C:17]([C:26]([O:28][CH2:29][CH2:30][CH3:31])=[O:27])=[CH:18][C:19]5[C:24]([CH:25]=4)=[CH:23][CH:22]=[CH:21][CH:20]=5)=[CH:10][CH:11]=[N:12]3)=[CH:7][C:6]=2[O:32][CH3:33])[CH:44]=[CH:43][N:42]=[CH:41]1
Reactant: CCCOC(=O)c1cc2ccccc2cc1Oc1ccnc2cc(OCCCl)c(OC)cc12
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOC(=O)c1cc2ccccc2cc1Oc1ccnc2cc(OCCn3ccnc3)c(OC)cc12
Temperature: 60 °C
Reaction time: 8 h
Yield: 71.3 %

Procedure:
Propyl 3-[7-(2-chloro-ethoxy)-6-methoxy-quinolin-4-yloxy]-naphthalene-2-carboxylate (compound 322) (138 mg) was dissolved in N,N-dimethylformamide (2 ml) to prepare a solution. Potassium carbonate (274 mg) and imidazole (101 mg) were added to the solution, and the mixture was stirred at 60° C. overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was pufified by thin layer chromatography using chloroform-methanol to give the title compound (105 mg, yield 70%).
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:7]=[C:8]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][N:9]2[C:10](=[O:13])[C:11]=1[Br:12])(=O)C.Cl.O1CCOCC1.[OH-].[NH4+]>O>[Br:12][C:11]1[C:10](=[O:13])[N:9]2[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:8]2=[N:7][C:6]=1[CH2:5][OH:4]
Reactant: CC(=O)OCc1nc2ccc(F)cn2c(=O)c1Br
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=c1c(Br)c(CO)nc2ccc(F)cn12
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A heterogeneous mixture of (3-bromo-7-fluoro-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)methyl acetate (7.7539 g, 24.61 mmol), HCl (6.972 mL, 83.67 mmol), and 1,4-dioxane (70.31 mL) was heated under stirring at 70° C. After 4 h, the mixture was cooled to rt and the mixture was concd under reduced pressure. The residue was diluted with water (100 mL) and treated with 28% ammonium hydroxide (10 mL) until pH neutral. The precipitate was filtered, washed with water (300 mL), and dried under high vacuum overnight to give 3-bromo-7-fluoro-2-(hydroxyl-methyl)-4H-pyrido[1,2-a]pyrimidin-4-one as a brown solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.97 (1 H, ddd, J=4.9, 2.8, 0.7 Hz), 8.17 (1 H, ddd, J=9.8, 7.1, 2.8 Hz), 7.88 (1 H, ddd, J=9.8, 5.4, 0.7 Hz), 5.35 (1 H, br. s.), 4.60 (2 H, s); Mass Spectrum (ESI) m/e=273.0 [M+1 (79Br)] and 274.9 [M+1 (81Br)].
Reaction SMILES: C[O:2][C:3](=O)/[C:4](/[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)=[N:5]/[OH:6].[CH3:22][NH2:23]>CO>[OH:6]/[N:5]=[C:4](\[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)/[C:3]([NH:23][CH3:22])=[O:2]
Reactant: COC(=O)/C(=N/O)c1ccccc1Oc1ccc(C)cc1
Reactant: CN
Solvent: CO
Product: CNC(=O)/C(=N/O)c1ccccc1Oc1ccc(C)cc1
Yield: 100 %

Procedure:
E-α-hydroxyimino-2-(4-methylphenoxy)phenylacetic acid methyl ester (1.00 g, 0.0035 mole) was dissolved in methanol (7 ml) and 40% methylamine solution in methanol (0.54 g, 0,007 mole) was added to the mixture, which was refluxed for 70 minutes. A 40% methylamine solution in methanol (1.36 g, 0.0175 mole) was further added to the mixture, which was refluxed for 3 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give E-2-hydroxyimino-N-methyl-2-[2-(4methylphenoxy)phenyl]acetamide (1.00 g, yield: 100.0 %) as an amorphous.
Reaction SMILES: C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[CH2:16]([N:18]1[C:24]2[CH:25]=[CH:26][C:27]([NH2:29])=[CH:28][C:23]=2[O:22][CH2:21][CH2:20][CH2:19]1)[CH3:17].Cl[C:31]1[N:36]=[C:35]([NH:37][C:38]2[CH:43]=[CH:42][C:41]([N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)=[CH:40][C:39]=2[O:50][CH3:51])[C:34]([Cl:52])=[CH:33][N:32]=1.C(=O)([O-])[O-]>C(O)(C)C>[Cl:52][C:34]1[C:35]([NH:37][C:38]2[CH:43]=[CH:42][C:41]([N:44]3[CH2:45][CH2:46][O:47][CH2:48][CH2:49]3)=[CH:40][C:39]=2[O:50][CH3:51])=[N:36][C:31]([NH:29][C:27]2[CH:26]=[CH:25][C:24]3[N:18]([CH2:16][CH3:17])[CH2:19][CH2:20][CH2:21][O:22][C:23]=3[CH:28]=2)=[N:32][CH:33]=1
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: CCN1CCCOc2cc(N)ccc21
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Product: CCN1CCCOc2cc(Nc3ncc(Cl)c(Nc4ccc(N5CCOCC5)cc4OC)n3)ccc21
Yield: 102.3 %

Procedure:
10-Camphorsulfonic acid (1.0E2 mg, 0.44 mmol) was added to 9-Ethyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-3-ylamine (65 mg, 0.34 mmol) and (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine (102 mg, 0.287 mmol) in Isopropyl alcohol (3 mL). The mixture was irradiated in a CEM microwave (130° C., 30 min). The mixture was conc. and purified by, conc., neutralized with MP-Carbonate (2.69 mmol/g loading; 0.50 g, 1.345 mmol), filtered and conc. to give 5-Chloro-N*2*-(9-ethyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-3-yl)-N*4*-(2-methoxy-4-morpholin-4-yl-phenyl)-pyrimidine-2,4-diamine as lavender solids (150 mg, 100%). MP:=185-188° C., LCMS: 511 (M+H); 1H-NMR (DMSO): 9.00 (s, 1H), 8.01 (s, 2H), 7.60 (d, 1H, J=7.8 Hz), 7.10 (d, 1H, J=8.8 Hz), 7.06 (s, 1H), 6.70 (s, 1H), 6.60 (d, 1H, J=8.6 Hz), 6.51 (d, 1H, J=8.7 Hz), 3.96 (t, 2H, J=5.3 Hz), 3.80 (s, 3H), 3.76 (t, 4H, J=4.5 Hz), 3.14 (t, 4H, J=4.5 Hz), 3.12 (m, 4H), 1.87 (m, 2H), 1.10 (t, 3H, J=6.9 Hz).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][C:4]1[O:5][C:6]([CH2:9][O:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](SC)=[CH:16][N+:17]([O-:19])=[O:18])=[CH:7][CH:8]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][S:30][CH2:31][CH2:32][NH2:33])[CH:24]=1>>[CH3:22][N:2]([CH2:3][C:4]1[O:5][C:6]([CH2:9][O:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([NH:33][CH2:32][CH2:31][S:30][CH2:29][C:25]2[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=2)=[CH:16][N+:17]([O-:19])=[O:18])=[CH:7][CH:8]=1)[CH3:1]
Reactant: NCCSCc1cccnc1
Reactant: CSC(=C[N+](=O)[O-])NCCCOCc1ccc(CN(C)C)o1
Product: CN(C)Cc1ccc(COCCCNC(=C[N+](=O)[O-])NCCSCc2cccnc2)o1

Procedure:
A mixture of N,N-dimethyl-5-[[3-[(1-methylthio-2-nitroethenyl)amino]propoxy]methyl]-2-furanmethanamine (0.7 g) and 2-[(3-pyridinylmethyl)thio]ethanamine (0.36 g) was heated at 98°-100° for 3 hr. The oily residue was chromatographed (silica/methanol-0.88 ammonia 79:1) and the appropriate eluate evaporated to dryness to give the title compound as a hemihydrate as an oil (0.52 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:23])=[N:8][C:9](Cl)=[C:10]([N+:19]([O-:21])=[O:20])[C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])=[O:5])[CH3:2].CO.[CH2:26]([NH2:28])[CH3:27]>C(N(CC)CC)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:23])=[N:8][C:9]([NH:28][CH2:26][CH3:27])=[C:10]([N+:19]([O-:21])=[O:20])[C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)nc(Cl)c([N+](=O)[O-])c1NCCCN(C)C
Reactant: CCN
Solvent: CCN(CC)CC
Solvent: CO
Product: CCNc1nc(C)c(C(=O)OCC)c(NCCCN(C)C)c1[N+](=O)[O-]

Procedure:
34.5 g. of 6-chloro-4-[[3-(dimethylamino)propyl]amino]-2-methyl-5-nitropyridine-3-carboxylic acid ethyl ester (0.1 Mol.) are dissolved in 200 ml. of methanol. A mixture of 15 g. of triethylamine and 6 g. of ethylamine are added and the solution is refluxed for one hour with stirring. The solvent is distilled off in vacuo and the residue treated with about 100 ml. of water. The aqueous phase is extracted three times with 100 ml. portions of ether, the ether layers are combined, dried over calcium chloride and the solvent distilled off. The resulting yellow oil is recrystallized from ether/ligroin, yield 31 g. (88%), m.p. < 20°.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][C:5]([N+:9]([O-])=O)=[C:6]([NH2:8])[CH:7]=1.[CH3:19]OC(OC)OC.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+]>CN(C=O)C.C(O)(=O)C>[Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][C:5]2[N:9]=[CH:19][NH:8][C:6]=2[CH:7]=1
Reactant: Nc1cc(Cl)c(Oc2ccccc2)cc1[N+](=O)[O-]
Reactant: COC(OC)OC
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Clc1cc2[nH]cnc2cc1Oc1ccccc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
To a solution of 5-chloro-2-nitro-4-phenoxyphenylamine (0.810 g, 3.06 mmol) in DMF (12 mL) was added trimethylorthoformate (12 mL) followed by sodium dithionite (2.66 g, 15.3 mmol), and glacial acetic acid (1.5 mL). The reaction mixture was heated in a sealed tube at 100° C. for 14 h. Additional sodium dithionite (0.5 g) and acetic acid (1 mL) were added and heating was continued at 120° C. for an additional 3 h. The reaction flask was cooled in ice, added cautiously to half-saturated sodium bicarbonate solution (300 mL) and extracted with EtOAc. Combined organic layers were washed with 5% NaHCO3, brine, dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) (hexanes:EtOAc, 0% to 5% over 20 minutes) to yield the titled compound as a yellow amorphous solid (0.57 g, 76%) as a mixture of tautomers. MS (ESI/CI): mass calcd. for C13H9ClN2O, 244; m/z found, 245 [M+H]+. 1H NMR (500 MHz, CDCl3): 9.55 (s, 1H), 8.06 (s, 1H), 8.0-7.2 (m, 2H), 7.32 (t, J=7.9 Hz, 2H), 7.09 (t, J=7.3 Hz, 1H), 6.96 (d, J=8.3 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[S:13][C:12]3=[N:14][N:15]=[C:16]([C@H:17]([NH:19]C(=O)OCC4C=CC=CC=4)[CH3:18])[N:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.Br>C(O)(=O)C.O>[NH2:19][C@@H:17]([C:16]1[N:11]2[C:12]([S:13][C:9]([NH:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)=[N:10]2)=[N:14][N:15]=1)[CH3:18]
Reactant: C[C@@H](NC(=O)OCc1ccccc1)c1nnc2sc(Nc3cccc(Cl)c3)nn12
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: C[C@@H](N)c1nnc2sc(Nc3cccc(Cl)c3)nn12
Temperature: 90 °C
Yield: 70.1 %

Procedure:
(Step 8-iii) To a slurry of (R)-benzyl 1-(6-(3-chlorophenylamino)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-yl)ethylcarbamate (0.39 g, 0.92 mmol) in acetic acid (20 mL) was added 48% hydrobromic acid in water (10 mL). The mixture was heated to 90° C. for 2 hours. After cooling to room temperature, the resulting solution was concentrated to ⅓ the original volume, poured on ice and the pH adjusted to 8 with 2N sodium hydroxide. The resulting precipitate was filtered, washed with water, and dried overnight in vacuo to provide (R)-3-(1-aminoethyl)-N-(3-chlorophenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-amine (0.19 g): ESMS MH+=294.
Reaction SMILES: C(O[C@@H:5]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C@H:6]1OC(=O)C)(=O)C.[C:17]([O:20][C:21]1([C:37](=[O:39])[CH3:38])[CH2:30][C:29]2[C:28](=[O:31])[CH:27]=[CH:26][C:25](=[O:32])[C:24]=2[C:23]2([O:36][CH2:35][CH2:34][O:33]2)[CH2:22]1)(=[O:19])[CH3:18]>C1(C)C(C)=CC=CC=1>[C:17]([O:20][C:21]1([C:37](=[O:39])[CH3:38])[CH2:30][C:29]2[C:28](=[O:31])[C:27]3[C:26](=[CH:6][C:7]4[C:8]([CH:5]=3)=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:25](=[O:32])[C:24]=2[C:23]2([O:36][CH2:35][CH2:34][O:33]2)[CH2:22]1)(=[O:19])[CH3:18]
Reactant: CC(=O)O[C@@H]1c2ccccc2[C@H]1OC(C)=O
Reactant: CC(=O)OC1(C(C)=O)CC2=C(C(=O)C=CC2=O)C2(C1)OCCO2
Solvent: Cc1ccccc1C
Product: CC(=O)OC1(C(C)=O)CC2=C(C(=O)c3cc4ccccc4cc3C2=O)C2(C1)OCCO2
Yield: 56.6 %

Procedure:
A mixture of 165 mg (0.75 mmol) of trans-1,2-diacetoxy-1,2-dihydrobenzocyclobutene and 160 mg (0.50 mmol) of rac-3-acetoxy-3-acetyl-1,1-ethylenedioxy-1,2,3,4,5,8-hexahydro-5,8-dioxonaphthalene [prepared as described in Example 7(A)] in 15 ml of xylene was stirred and heated under reflux under an atmosphere of nitrogen for 16 hours. The solution was evaporated to dryness and the yellow residue was stirred with 5 ml of diethyl ether and filtered to give 119 mg (57%) of rac-3-acetoxy-3-acetyl-1,1-ethylenedioxy-1,2,3,4,5,12-hexahydro-5,12-dioxonaphthacene in the form of a bright yellow solid of melting point 232°-236° C.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1.Cl.[NH2:20][OH:21].C([O-])(=O)C.[Na+]>C(O)C>[OH:21][N:20]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1
Reactant: O=C(O)Cc1ccc(CC2CCCCC2=O)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(O)Cc1ccc(CC2CCCCC2=NO)cc1
Yield: 103.1 %

Procedure:
A solution of 0.64 g of 4-(2-oxocyclohexan-1-ylmethyl)phenylacetic acid, 0.19 g of hydroxylamine hydrochloride, and 0.45 g of anhydrous sodium acetate in 10 ml of 80% ethanol was heated under reflux for 2 hours. The solvent was removed by distillation, water and ethyl acetate were added to the residue, the mixture was acidified by addition of diluted hydrochloric acid, the ethyl acetate layer separated and the water layer was then extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate, the solvent removed by distillation to give 0.7 g of the desired compound, which by recrystallization from ethyl acetate afforded colorless crystals, m.p. 180°-184° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[CH:46][CH:45]=[CH:44][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:13][CH:12]=1.[Cl:48][C:49]1[CH:54]=[CH:53][C:52]([CH2:55][CH2:56][NH:57][C:58](=[O:60])[CH3:59])=[C:51]([OH:61])[CH:50]=1>>[C:58]([NH:57][CH2:56][CH2:55][C:52]1[CH:53]=[CH:54][C:49]([Cl:48])=[CH:50][C:51]=1[O:61][CH2:32][CH2:31][O:30][CH:18]1[CH:17]([C:14]2[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][C:4]3[CH:44]=[CH:45][CH:46]=[CH:47][C:3]=3[O:2][CH3:1])=[CH:16][CH:15]=2)[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:19]1)(=[O:60])[CH3:59]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: CC(=O)NCCc1ccc(Cl)cc1O
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2cc(Cl)ccc2CCNC(C)=O)cc1

Procedure:
Analogously to Method G, 0.458 g of tert-butyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-[2-(toluene-4-sulphonyloxy)ethoxy]piperidine-1-carboxylate (Example 14b) and 0.30 g of N-[2-(4-chloro-2-hydroxyphenyl)ethyl]acetamide are reacted. The title compound is obtained as a yellow oil. Rf=0.70 (EtOAc); Rt=5.75.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH2:20][O:21][C:22]3[CH:27]=[C:26]([CH:28]([CH3:30])[CH3:29])[CH:25]=[CH:24][C:23]=3[CH3:31])=[C:18]([CH3:32])[N:17]=[C:16](Cl)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:34]([C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42][CH3:43])[C:37]=1B(O)O)[CH3:35].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH2:34]([C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42][CH3:43])[C:37]=1[C:16]1[N:15]=[C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]2)[C:19]([CH2:20][O:21][C:22]2[CH:27]=[C:26]([CH:28]([CH3:30])[CH3:29])[CH:25]=[CH:24][C:23]=2[CH3:31])=[C:18]([CH3:32])[N:17]=1)[CH3:35]
Reactant: CCc1cccc(CC)c1B(O)O
Reactant: Cc1ccc(C(C)C)cc1OCc1c(C)nc(Cl)nc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCc1cccc(CC)c1-c1nc(C)c(COc2cc(C(C)C)ccc2C)c(N2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 90 °C
Reaction time: 40 h

Procedure:
A mixture of 4-[2-chloro-5-(5-isopropyl-2-methyl-phenoxymethyl)-6-methyl-pyrimidin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (700 mg, 1.47 mmol), 2,6-diethylphenylboronic acid (394 mg, 2.21 mmol), 2 M aqueous sodium carbonate (2.21 mL, 4.42 mmol) and toluene (5 mL) is degassed with argon bubbling for 15 min. Pd(PPh3)4 (87 mg, 5 mol %) is added and the resulting yellow-colored mixture is heated at 90° C. under nitrogen with magnetic stirring for 40 h. The reaction mixture is partitioned between EtOAc (50 mL) and water (15 mL), the organic layer is separated, washed with water (15 mL), bring (15 mL), dried over sodium sulfate, filtered and evaporated at reduced pressure to obtain a yellow liquid. Chromatography on a 30 g silica gel cartridge (10-30% EtOAc/Hexanes) affords the title compound as a colorless oil (along with recovered 4-[2-chloro-5-(5-isopropyl-2-methyl-phenoxymethyl)-6-methyl-pyrimidin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester). LC/MS (Method 3), M+H=573.2, Rt=3.18 min.; 1H NMR (CDCl3) δ=7.26 (d, 1H), 7.12 (d, 3H), 6.83 (m, 2H), 4.99 (s, 2H), 3.51 (m, 4H), 2.90 (m, 6H), 2.55, (s, 3H), 2.42 (q, 4H) 2.24 (s, 3H), 1.28 (d, 6H), 1.10 (t, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([OH:12])=[CH:7][CH:8]=2)[N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:20][CH2:21][O:22][CH3:23]>CN1C(=O)CCC1>[CH3:23][O:22][CH2:21][CH2:20][O:12][C:6]1[CH:5]=[C:4]2[C:9]([CH:10]=[CH:11][C:2]([CH3:1])=[N:3]2)=[CH:8][CH:7]=1
Reactant: COCCBr
Reactant: Cc1ccc2ccc(O)cc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COCCOc1ccc2ccc(C)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.5 %

Procedure:
To a stirred mixture of 2-methylquinolin-7-ol (300 mg, 1.88 mmol), Cs2CO3 (1.84 g, 5.65 mmol) and NMP (10 mL) was added 1-bromo-2-methoxyethane (0.786 g, 5.65 mmol). The reaction mixture was stirred at ambient temperature overnight. The reaction was partitioned between ether and water. The aqueous layer was extracted with ether. The combined organic layers were washed with water and brine, dried and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (2:1 to 1:2 hexanes/EtOAc) to give 7-(2-methoxyethoxy)-2-methylquinoline (235 mg, 57%).
Reaction SMILES: C[C@]1(O)[C@@H]2C(=[C:12]([OH:30])[C@:13]3([OH:29])[C:20](=[O:21])[C:19](C(N)=O)=[C:18]([OH:25])[C@@H:17](N(C)C)[C@@H]3C2)C(=O)C2C(O)=CC=CC1=2.CC1(C)S[C@@H]2[C@H](NC([C@H](N)C3C=CC=CC=3)=O)C(=[O:41])N2[C@H]1C(O)=O>>[O:30]=[CH:12][C@@H:13]([C@@H:20]([C@H:19]([C@H:18]([CH3:17])[OH:25])[OH:41])[OH:21])[OH:29]
Reactant: CN(C)[C@@H]1C(O)=C(C(N)=O)C(=O)[C@@]2(O)C(O)=C3C(=O)c4c(O)cccc4[C@@](C)(O)[C@H]3C[C@@H]12
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Product: C[C@H](O)[C@H](O)[C@@H](O)[C@@H](O)C=O

Procedure:
The plasmid pBRsacH3 (Example 1) was used for cloning the rMET1 antibody (Example 9). In this case, the kappa and heavy chains were engineered with human ceruloplasmin and human neutrophil defensin signal sequences, respectively (Example 9). This plasmid was electroporated into E. coli strain DH10B rha+ to generate clone rMET1.LS.1, which was cultured under 10 μg/mL tetracycline selection. The plasmid was also electroporated into E. coli strain ECL339 rha− to generate clone rMET1.ECL.1 which was cultured under 100 μg/mL ampicillin selection.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:12][C:13]3[CH:17]=[CH:16][NH:15][N:14]=3)[N:3]=2)=[CH:21][CH:20]=1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Reactant: Oc1ccc(Cl)cc1
Product: Clc1ccc(Oc2nc(Nc3cc[nH]n3)cc3ccccc23)cc1

Procedure:
Similar procedure as described in example 10 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 4-chloro-phenol to give [1-(4-chloro-phenoxy)-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 337(MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:39][C:40]1[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=1)[CH2:10][N:11]([CH2:14][CH:15]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24]C2C=CC=CC=2)=[CH:19][CH:18]=1)[CH2:12][CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+](=[CH2:49])=[N-]>C(OCC)C>[C:35]([O:34][C:32]([NH:31][C@@H:15]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=1)[CH2:14][N:11]([CH2:10][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:39][C:40]1[CH:45]=[CH:44][C:43]([O:46][CH3:49])=[CH:42][CH:41]=1)[CH2:12][CH3:13])=[O:33])([CH3:37])([CH3:36])[CH3:38]
Reactant: CCN(CC(Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C)C[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: CCN(CC(Cc1ccc(OC)cc1)NC(=O)OC(C)(C)C)C[C@H](Cc1ccc(OC)cc1)NC(=O)OC(C)(C)C
Reaction time: 48 h
Yield: 77 %

Procedure:
The product from Example 19A (21 mg, 38 μmol) was treated with diazomethane in diethyl ether (˜0.4 M, 1 mL) at ambient temperature. After stirring for 2 days, the solvent was removed under reduced pressure. The residue was dissolved in fresh diazomethane solution and stirred at ambient temperature for an additional 2 days. This process was repeated until TLC (CHCl3:methanol, 19:1) indicated the reaction was complete. The residue was purified by column chromatography on silica gel (CH2Cl2:methanol, 99:1) to provide the title compound as a colorless amorphous solid (17 mg, 77%). 1H NMR (CDCl3) δ 7.09 (d, J=8.9 Hz, 4H), 6.82 (d, J=8.5 Hz, 4H), 4.70 (br s, 1.3H), 4.53 (br s, 0.7H), 3.83-3.78 (m, 2H), 3.78 (s, 6H), 2.85-2.68 (m, 4H), 2.60-2.27 (m, 6H), 1.41 (s, 12H), 1.38 (s, 6H), 0.94-0.84 (m, 3H); MS (APCl+) m/z 572 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[N+:9]([C:12]1[CH:24]=[C:16]2[C:17](O[C:20](=O)[N:21](C)[C:15]2=[CH:14][CH:13]=1)=O)([O-:11])=[O:10].B>O1CCCC1>[CH3:20][N:21]1[C:15]2[CH:14]=[CH:13][C:12]([N+:9]([O-:11])=[O:10])=[CH:24][C:16]=2[CH2:17][N:1]2[CH2:8][CH2:7][CH2:6][CH:2]2[C:3]1=[O:5]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: Cn1c(=O)oc(=O)c2cc([N+](=O)[O-])ccc21
Agent: B
Solvent: C1CCOC1
Product: CN1C(=O)C2CCCN2Cc2cc([N+](=O)[O-])ccc21

Procedure:
This compound is obtained when 1,2,3,11a-tetrahydro- 10-methyl-7-nitro-11H-pyrrolo[2,1-c] [1,4]benzodiazepin-5,11- (10H]-dione (prepared from proline and 5-nitro-N-methylisatoic anhydride by the procedure of Example 1) is treated with 1 M borane in tetrahydrofuran by the procedure of Example 1.