Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][P:20](=[O:27])([O:24]CC)[O:21]CC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[Si](C)(C)C.O>ClCCl.CO.C(#N)C>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][P:20](=[O:21])([OH:27])[OH:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOP(=O)(CCCCCCCCCCCOCc1ccccc1)OCC
Agent: C[Si](C)(C)Br
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: O=P(O)(O)CCCCCCCCCCCOCc1ccccc1
Reaction time: 8 h
Yield: 94 %

Procedure:
Diethyl 11-(benzyloxy)undecylphosphonate (1.00 g, 2.51 mmol) was dissolved in dry dichloromethane (20 mL). Bromotrimethylsilane (1.1 mL, 8.28 mmol) was added via syringe. The reaction was capped with a greased glass stopper and allowed to stir overnight. The volatiles were removed under reduced pressure to yield a yellow oil. This was dissolved in 5:1 methanol:water (20 mL) and allowed to stir 4 hours more. After concentration of the organic, the viscous yellow oil was dissolved in hot acetonitrile and a white crystalline solid was obtained (806 mg, 94% yield). 1H NMR (400.14 MHz, DMSO) δ 7.40-7.20 (m, 5H), 4.43 (2H), 3.39 (t, J=6.49 Hz, 2H), 1.60-1.33 (m, 6H), 1.33-1.15 (m, 14H). 13C{1H} NMR (100.62 MHz, DMSO) δ 138.7, 128.2 (2C), 127.4 (2C), 127.3, 71.79, 69.59, 30.09 (d, J=15.9 Hz), 29.21, 29.04, 29.01, 28.89, 28.87, 28.73, 27.53 (d, J=136.6 Hz), 25.72, 22.72 (d, J=4.6 Hz). 31P{1H} NMR (161.97 MHz, DMSO): δ 27.71. Analysis calculated (found) %: C 63.14 (62.87), H 9.13 (9.13). MS (ESI, m/z): 341 (M−, 100%). Exact mass calculated (found) for [M−H]−, m/z): 341.188722 (341.189600).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH:8]=[C:7]([O:16][CH3:17])[C:4]=1[CH:5]=O.[C:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)(=[O:20])[CH3:19]>>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH:8]=[C:7]([O:16][CH3:17])[C:4]=1/[CH:5]=[CH:19]/[C:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)=[O:20]
Reactant: COc1cc(-c2cccs2)cc(OC)c1C=O
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Product: COc1cc(-c2cccs2)cc(OC)c1/C=C/C(=O)c1ccc(C(=O)O)cc1
Yield: 79 %

Procedure:
The title compound was prepared by condensing 2,6-dimethoxy-4-thiophen-2-yl-benzaldehyde (Ex-37A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, 79% yield, m.p. 256–258° C. 1H-NMR (300 MHz, d6-DMSO): 8.11 (d, 1H, J=15.9 Hz), 8.10 (m, 4H), 8.05 (d, 1H, J=15.9 Hz), 7.73 (d, 1H, J=3.6 Hz), 7.61 (d, 1H, J=5.3 Hz), 7.16 (dd, 1H, J=5.3 and 3.6 Hz), 6.95 (s, 2H), 3.98 (s, 6H). MS m/z=394 ([M]+, 100%). HRMS (EI) Calcd. for C22H18O5S: 394.0875. Found: 394.0877.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[CH3:27][C:28]1[C:38]([N:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[CH:37][CH:36]=[CH:35][C:29]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:42]2[CH2:41][CH2:40][N:39]([C:38]3[C:28]([CH3:27])=[C:29]([CH:35]=[CH:36][CH:37]=3)[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:44][CH2:43]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: CCOC(=O)c1cccc(N2CCNCC2)c1C
Product: CCOC(=O)c1cccc(N2CCN(CCCCC3(C(=O)NCC(F)(F)F)c4ccccc4-c4ccccc43)CC2)c1C

Procedure:
The procedure of step (b) of Example 1 was repeated, except that the compound prepared in step (a) of Example 87 was used instead of 3,3-diphenylpropyl bromide and the compound prepared in step (a) of Example 53 was used instead of ethyl 3-piperazin-1-yl-benzoate. Thus, ethyl 3-[4-[4-[9-(2,2,2-trifluoroethylcarbamoyl)-9H-fluoren-9-yl]butyl]piperazin-1-yl]-2-methylbenzoate was obtained.
Reaction SMILES: CN(C)CCCN=C=NCC.O.[C:13]([NH:20][C@H:21]([C:26]([OH:28])=O)[CH2:22][CH:23]([CH3:25])[CH3:24])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].OC1C2N=NNC=2C=CC=1.[CH2:39]([O:46][C:47]([N:49]1[CH2:55][CH:54]([OH:56])[CH:53]([NH2:57])[CH2:52][CH2:51][CH:50]1[CH3:58])=[O:48])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>CN(C=O)C.CCOC(C)=O>[CH2:39]([O:46][C:47]([N:49]1[CH2:55][C@H:54]([OH:56])[C@@H:53]([NH:57][C:26](=[O:28])[C@@H:21]([NH:20][C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:22][CH:23]([CH3:24])[CH3:25])[CH2:52][CH2:51][C@H:50]1[CH3:58])=[O:48])[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC1CCC(N)C(O)CN1C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H]1CC[C@@H](C)N(C(=O)OCc2ccccc2)C[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (0.164 g, 0.22 mmol) was added to a solution of Boc-Leucine-hydrate (0.190 g, 0.76 mmol), diisopropyletbylamine (0.164 g, 0.22 ml, 1.27 mmol), hydroxybenztriazole (0.114 g, 0.83 mmol), and racemic (2R,5S,6S)-5-Amino-6-hydroxy-2-methyl-azepane-1-carboxylic acid benzyl ester (0.27 g, 0.57 mmol) in DMF (3.2 ml). The reaction was stirred overnight at RT, then was diluted with EtOAc (100 ml), washed with H2O (3×50 ml), brine (50 ml), dried with magnesium sulfate, filtered, concentrated in vacuo by rotary evaporation, and chromatographed (silica gel, 50% EtOAc/hexanes) to yield the title compound (0.218 g, 72%): 1H NMR: 7.40–7.29 (m, 5H), 6.75 (1H, bd), 5.12 (2H, AB), 5.0 (1H, bs), 4.15–3.72 (m, 2H), 3.06 (1H, d), 1.60–1.30 (m, 2H), 1.60–1.30 (m, 5H), 1.12 (3H, d), 0.97–0.87(6H, dd); Electrospray mass spec: M+H+=492.0.
Reaction SMILES: [O:1]([CH2:8][C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:13]1[C:17](=[O:18])[CH2:16][CH2:15][C:14]1=[O:19].C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C>[O:1]([CH2:8][C:9]([O:11][N:13]1[C:17](=[O:18])[CH2:16][CH2:15][C:14]1=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)COc1ccccc1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: O=C(COc1ccccc1)ON1C(=O)CCC1=O
Reaction time: 1 h
Yield: 60.2 %

Procedure:
A suspension of phenoxyacetic acid (15.2 g, 100 mmol) and N-hydroxysuccinimide (11.5 g, 100 mmol) in ethyl acetate (300 ml) was cooled in an ice bath, treated with N,N'-dicyclohexylcarbodiimide (20.6 g, 100 mmol) and stirred for 1 hour at 0° and then overnight at room temperature. The precipitate which formed was filtered; the filtrate was evaporated to dryness; and the residue was crystallized from ethyl acetate to yield 15.0 g of N-(phenoxyacetyloxy)succinimide.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([I:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15]CC)=O.[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1>C(OCC)(=O)C>[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH:24][C:13]([C:3]2[CH:4]=[N:5][C:6]3[C:11]([C:2]=2[OH:1])=[CH:10][CH:9]=[CH:8][C:7]=3[I:12])=[O:15])=[CH:21][CH:20]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cnc2c(I)cccc2c1O
Solvent: CCOC(C)=O
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2c(I)cccc2c1O
Temperature: 25 °C

Procedure:
A portion of the resulting ethyl 4-hydroxy-8-iodo-3-quinolinecarboxylate (4.01 g) and 4-chlorobenzylamine (20.00 mL) are heated at 180° C. for 1.5 h. The reaction is cooled to room temperature. Ethyl acetate is added, followed by hexanes, and the solid is filtered, washed with hexanes, and dried to give N-(4-chlorobenzyl)-4-hydroxy-8-iodo-3-quinolinecarboxamide (3.98 g).
Reaction SMILES: CO[C:3](=[O:22])[C:4]([CH3:21])([CH3:20])[NH:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([C:15]([F:18])([F:17])[F:16])[CH:9]=1.Cl>CC(C)=O>[F:18][C:15]([F:16])([F:17])[C:10]1[CH:9]=[C:8]([N:7]2[C:3](=[O:22])[C:4]([CH3:20])([CH3:21])[NH:5][C:6]2=[O:19])[CH:13]=[CH:12][C:11]=1[Cl:14]
Reactant: COC(=O)C(C)(C)NC(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: CC(C)=O
Product: CC1(C)NC(=O)N(c2ccc(Cl)c(C(F)(F)F)c2)C1=O

Procedure:
A solution of 8.00 g. of N-[(3-trifluoromethyl-4-chloro-phenyl)-carbamoyl]-2-methylalanine methyl ester in 20 ml. of 6-N aqueous hydrochloric acid and 20 ml. of acetone are warmed on a steam bath for 2 hours and the mixture is then concentrated. The product which was precipitated is first recystallized from methylene chloride and then from methylene chloride/petroleum ether. After drying under greatly reduced pressure at 50° for 20 hours, 3-(3-trifluoromethyl-4-chloro-phenyl)-5,5-dimethylhydantoin of melting point 152°-153° is obtained.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:13][N:14]([CH3:25])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][C:22]([OH:24])=O.Cl.[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[F:50])[CH:42]2[CH:38]([CH2:39][NH:40][CH2:41]2)[C:37](=[O:43])[CH2:36][CH2:35]1.C(N(CC)CC)C>ClCCl>[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[F:50])[CH:42]2[CH:38]([CH2:39][NH:40][CH:41]2[C:22](=[O:24])[CH2:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]([CH3:13])[CH3:25])[C:37](=[O:43])[CH2:36][CH2:35]1
Reactant: CN(C)c1ccccc1CC(=O)O
Reactant: O=C1CCC(c2ccccc2F)(c2ccccc2F)C2CNCC12
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)c1ccccc1CC(=O)C1NCC2C(=O)CCC(c3ccccc3F)(c3ccccc3F)C21
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
N,N-Carbonyldiimidazole (0.44 g) is added to a solution of (2-dimethylaminophenyl)acetic acid (0.49 g) in dry dichloromethane (20 cc) cooled to +4° C. The mixture is stirred for 1 hour at 25° C. and a solution of 7,7-bis-(2-fluorophenyl)-4-perhydroisoindolone hydrochloride (1 g) and triethylamine (0.76 cc) in dry dichloromethane (25 cc) is then added dropwise. The reaction mixture is stirred for 20 hours at 25° C. and washed with water (2×100 cc) and with saturated sodium chloride solution (100 cc). The organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.063 mm, diameter 2 cm, height 23 cm), eluting under a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (50/50) and collecting 10 cc fractions. Fractions 14 to 36 are combined and concentrated to dryness under reduced pressure (2.7 kPa) to give (3aRS,7aRS)-7,7-bis-(2-fluorophenyl)-2-(2-dimethylaminophenyl)acetyl-4-perhydroisoindolone (1 g), from which the hydrochloride is prepared by dissolving in ethyl acetate (2 cc) and adding a 3N solution of hydrochloric acid in isopropyl ether. The precipitate is drained, washed with isopropyl ether and dried. (3aRS,7aRS)-7,7-bis-(2-fluorophenyl)-2-(2-dimethylaminophenyl)acetyl-4-perhydroisoindolone hydrochloride (0.87 g) is obtained in the form of a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:9])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[H-].[Na+].[Br-].[Li+].I[CH3:15]>C1COCC1.C(Cl)Cl>[Br:1][C:2]1[C:3](=[O:9])[N:4]([CH3:15])[C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: Cc1ccc(Br)c(O)n1
Reactant: CI
Agent: [Br-]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1ccc(Br)c(=O)n1C
Yield: 55.6 %

Procedure:
3-Bromo-6-methylpyridine-2-ol (2 g, 10.6 mmol) was taken up in THF and stirred. Sodium hydride (60% in oil 510 mg, 12.7 mmol) was added portion wise then stirred 30 minutes. Lithium bromide (1.85 g, 21.2 mmol) was added and stirred for 1 hour. Then iodomethane (1.32 mL, 21.2 mmol) was added and the reaction mixture was stirred overnight. The reaction mixture was diluted with DCM and washed with 1N NaOH. The DCM layer was dried over magnesium sulfate, filtered and dried in vacuo to afford 1.19 g product carried on to next step as is. LRMS (ESI) m/z 202/204 [(M+H)]+, calc'd for C7H8BrNO: 202.05.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH3:5])[CH2:2]1.[Na].P(=O)(O)(O)O.[CH:12]([O:15][CH2:16][CH:17]([OH:20])[CH2:18][CH3:19])([CH3:14])[CH3:13]>C(O)(C)C>[CH:12]([O:15][CH2:16][CH:17]([O:20][CH2:2][CH:3]([OH:1])[CH2:4][CH3:5])[CH2:18][CH3:19])([CH3:14])[CH3:13]
Reactant: CCC1CO1
Reactant: CCC(O)COC(C)C
Agent: O=P(O)(O)O
Agent: [Na]
Solvent: CC(C)O
Product: CCC(O)COC(CC)COC(C)C

Procedure:
Into a 1 L separable flask equipped with a stirrer and a condenser, 180 g of isopropanol and 216 g of epoxybutane were introduced. After filling with nitrogen, 1.6 g of sodium was added and refluxed for 16 hours. After addition of 5 g of phosphoric acid to the mixture, 1-isopropoxy-2-butanol (boiling point: 100° C./120 mmHg) and 1-(1-isopropoxy-2-butoxy)-2-butanol (boiling point: 105° C./50 mmHg) were obtained by fractional distillation under reduced pressure. 1-isopropoxy-2-butanol thus obtained is a model compound in the case where one molecule of 1,2-epoxybutane reacted with a hydroxyl group of EVOH and 1-(1-isopropoxy-2-butoxy)-2-butanol is a model compound in the case where two or more molecules of 1,2-epoxybutane reacted with a hydroxyl group of EVOH.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]=2[C:4]2[CH:24]=[CH:25][CH:26]=[CH:27][C:3]1=2.[OH:28][C@@:29]([CH3:41])([C:33]([NH:35][CH2:36][C:37]([F:40])([F:39])[F:38])=[O:34])[C:30](O)=[O:31]>>[CH2:13]([O:12][CH2:11][CH2:10][N:7]1[C:8](=[O:9])[C@@H:2]([NH:1][C:30](=[O:31])[C@:29]([OH:28])([CH3:41])[C:33]([NH:35][CH2:36][C:37]([F:38])([F:39])[F:40])=[O:34])[C:3]2[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=2[C:5]2[CH:23]=[CH:22][CH:21]=[CH:20][C:6]1=2)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Reactant: C[C@@](O)(C(=O)O)C(=O)NCC(F)(F)F
Product: C[C@](O)(C(=O)NCC(F)(F)F)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21

Procedure:
Using (S)-7-amino-5-(2-benzyloxy-ethyl)-5H,7H-dibenzo[b,d]azepin-6-one and (S)-2-hydroxy-2-methyl-N-(2,2,2-trifluoro-ethyl)-malonamic acid, the title compound was prepared in the same manner as described for example 1c. Colorless, amorphous solid (91%). MS: m/e=556(M+H+).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:5]([NH:16][CH2:17][CH3:18])=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH3:15])=[CH:9][CH:8]=2.ClCC1C(NCC)=NC2C(C=1)=CC(OC)=CC=2.[CH3:36][O:37][C:38]1[CH:39]=[C:40]2[C:45](=[CH:46][C:47]=1[O:48][CH3:49])[C:44]([CH2:50][O:51][CH3:52])=[N:43][C:42]([OH:53])=[CH:41]2.[Li+].[OH-]>C1COCC1.C(Cl)Cl>[CH2:17]([NH:16][C:5]1[C:4]([CH2:3][C:41]2[C:40]3[C:45](=[CH:46][C:47]([O:48][CH3:49])=[C:38]([O:37][CH3:36])[CH:39]=3)[C:44]([CH2:50][O:51][CH3:52])=[N:43][C:42]=2[OH:53])=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH3:15])[CH:11]=2)[N:6]=1)[CH3:18]
Reactant: COCc1nc(O)cc2cc(OC)c(OC)cc12
Reactant: CCNc1nc2ccc(OC)cc2cc1CCl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCNc1nc2ccc(OC)cc2cc1Cc1c(O)nc(COC)c2cc(OC)c(OC)cc12
Temperature: 160 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 3-(chloromethyl)-N-ethyl-6-methoxyquinolin-2-amine hydrochloride SLA 28166 (84 mg, 0.29 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 6,7-dimethoxy-1-(methoxymethyl)isoquinolin-3-ol SMA 44012 (73 mg, 0.29 mmol) followed by a 2 N aq. LiOH solution (0.29 mL, 0.58 mmol) and the mixture was stirred at 160° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (150 mL), washed with brine (20 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent EtOAc:MeOH=100:0 to 95:5) followed by a new purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 95:5) provided 4-((2-(ethylamino)-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxy-1-(methoxymethyl)isoquinolin-3-ol. This free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (0.28 mL) and the mixture was stirred for 5 min at room temperature and concentrated at 40° C. under vacuum to afford 4-((2-(ethylamino)-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxy-1-(methoxymethyl)isoquinolin-3-ol dihydrochloride 67 as a yellow solid (9 mg, 6% yield).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:24](C1C=CC=CC=1)(C1C=CC=CC=1)[O:25][SiH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:9][CH2:10][N:11]1[CH2:14][CH:13]([C:15](=[O:23])[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH2:12]1)(C)(C)C.F[C:45](F)(F)[C:46](O)=O>ClCCl>[NH2:7][C@H:8]([CH2:24][O:25][Si:26]([C:27]([CH3:28])([CH3:30])[CH3:29])([C:46]1[CH:45]=[CH:10][CH:9]=[CH:8][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:9][CH2:10][N:11]1[CH2:14][CH:13]([C:15]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)=[O:23])[CH2:12]1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@@H](CCN1CC(C(=O)c2ccc(F)cc2)C1)C(O[SiH2]C(C)(C)C)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CC(C)(C)[Si](OC[C@@H](N)CCN1CC(C(=O)c2ccc(F)cc2)C1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of {(S)-1-(tert-butyl-diphenyl-silanyloxymethyl)-3-[3-(4-fluoro-benzoyl)-azetidin-1-yl]-propyl}-carbamic acid tert-butyl ester. (0.188 g, 0.321 mmol) in dichloromethane (5 ml) is treated with trifluoroacetic acid, and stirred at ambient temperature for 0.5 hour. The reaction mixture is diluted with dichloromethane and washed with water and saturated aqueous NaHCO3. The organic phase is dried over MgSO4 and evaporated to afford {1-[(S)-3-Amino-4-(tert-butyl-diphenyl-silanyloxy)-butyl]-azetidin-3-yl)-(4-fluoro-phenyl)-methanone. [MH]+ 505.2.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]4[N:17]([S:20]([C:23]5[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=5)(=[O:22])=[O:21])[CH:18]=[CH:19][C:12]=34)[CH:7]=[C:6]([NH2:30])[C:5]=2[CH:4]=[N:3]1.N1C=CC=CC=1.[CH3:37][C:38]1[S:39][CH:40]=[C:41]([C:43](Cl)=[O:44])[N:42]=1>C(Cl)Cl>[CH3:37][C:38]1[S:39][CH:40]=[C:41]([C:43]([NH:30][C:6]2[CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]4[N:17]([S:20]([C:23]5[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=5)(=[O:22])=[O:21])[CH:18]=[CH:19][C:12]=34)[CH:9]=[C:10]3[C:5]=2[CH:4]=[N:3][N:2]3[CH3:1])=[O:44])[N:42]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4cc(N)c5cnn(C)c5c4)ccnc32)cc1
Reactant: Cc1nc(C(=O)Cl)cs1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4cc(NC(=O)c5csc(C)n5)c5cnn(C)c5c4)ccnc32)cc1
Temperature: 25 °C

Procedure:
1-Methyl-6-{1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-indazol-4-amine (75 mg) and pyridine (0.029 ml) were added to DCM (5 ml) under stirring at RT under nitrogen. 2-Methyl-1,3-thiazole-4-carbonyl chloride (38 mg) was added into the reaction mixture. The reaction mixture was partitioned between water (20 ml) and DCM (20 ml).
Reaction SMILES: C([N:3]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[CH2:4][C:5]([OH:7])=[O:6])C.O.[OH-].[Li+].Cl>C1COCC1.O>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([NH:3][CH2:4][C:5]([OH:7])=[O:6])=[CH:13][CH:12]=1
Reactant: CCN(CC(=O)O)c1ccc(OC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(NCC(=O)O)cc1
Reaction time: 15 h
Yield: 50.7 %

Procedure:
To a solution of 19.59 g (108 mmol) of ethyl N-(4-methoxyphenyl)glycine in 100 mL of THF under N2 was added 5.44 g (130 mmol) of lithium hydroxide monohydrate in 25 mL water. After 15 hours, the mixture was reduced to 1/2 the original volume in vacuo and then acidified with concentrated hydrochloric acid to ph 3 and a precipitate formed. The solid was collected and washed with 100 mL water, then dried in vacuo to give 9.92 g (51%) of the desired compound as a off-white solid. 1H NMR (CDCl3): δ6.68 (d, J=8.8, 2H); 6.49 (d, J=8.8, 2H); 3.73 (s, 2H); 3.64 (s, 3H); 2.49 (br s, 2H).
Reaction SMILES: [O:1]=[C:2]1[CH:11]2[CH2:12][CH2:13]O[C:10]2=[C:9]2[C:4]([C:5]([O:15][CH3:16])=[CH:6][CH:7]=[CH:8]2)=[N:3]1.[CH3:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21]>C1(O)C=CC=CC=1.O>[CH3:17][C:18]1[CH:19]=[C:20]([N:21]2[C:10]3[C:9]4[CH:8]=[CH:7][CH:6]=[C:5]([O:15][CH3:16])[C:4]=4[NH:3][C:2](=[O:1])[C:11]=3[CH2:12][CH2:13]2)[CH:22]=[CH:23][CH:24]=1
Reactant: COc1cccc2c1=NC(=O)C1CCOC=21
Reactant: Cc1cccc(N)c1
Solvent: O
Solvent: Oc1ccccc1
Product: COc1cccc2c3c(c(=O)[nH]c12)CCN3c1cccc(C)c1
Temperature: 190 °C
Yield: 75.1 %

Procedure:
4-Oxo-6-methoxy-2,3-dihydrofuro[3,2-c]quinoline (217 mg, 1.0 mmol) was dissolved in 7 ml of phenol in a pressure tube and 3-methylaniline (268 μl, 2.5 mmol) was added under nitrogen. The reaction mixture was heated at 190° C. for 15 hours. The reaction mixture was diluted with 20 ml of salt water and the aqueous layer was extracted with methylene chloride (15 ml×3). After washing with water (15 ml×3), the organic layer was dried by anhydrous magnesium sulfate and filtered, and concentrated under reduced pressure. The residue was purified with ethyl acetate as eluent by silica gel chromatography to obtain 230 mg of desired compound as solid in 76% of yield.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[N:4]=1.Br[CH2:15][C:16]1[CH:35]=[CH:34][C:19]2/[C:20](=[C:30](/[CH3:33])\[C:31]#[N:32])/[C:21]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:22]=3[O:23][CH2:24][C:18]=2[CH:17]=1>>[F:29][C:26]1[CH:27]=[CH:28][C:21]2=[C:22]([CH:25]=1)[O:23][CH2:24][C:18]1[CH:17]=[C:16]([CH2:15][N:7]3[C:6]4[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=4[N:4]=[C:3]3[C:2]([F:1])([F:12])[F:13])[CH:35]=[CH:34][C:19]=1/[C:20]/2=[C:30](/[CH3:33])\[C:31]#[N:32]
Reactant: FC(F)(F)c1nc2ccccc2[nH]1
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Product: C/C(C#N)=C1/c2ccc(Cn3c(C(F)(F)F)nc4ccccc43)cc2COc2cc(F)ccc21
Yield: 88.9 %

Procedure:
Using 2-(trifluoromethyl)-1H-benzo[d]imidazole (62 mg, 0.335 mmol) and (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (120 mg, 0.335 mmol) obtained in Reference Example 1, and in the same manner as in Reference Example 1A, the title compound (138 mg, 88%) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8](C(OC(C)(C)C)=O)[CH2:9]2)=[CH:4][C:3]=1[F:19].[ClH:20].O1CCOCC1>C(OCC)(=O)C.C(OCC)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][CH2:9]2)=[CH:4][C:3]=1[F:19].[ClH:20]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(F)c(Br)cc2C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: C1COCCO1
Product: Fc1cc2c(cc1Br)CNCC2

Procedure:
tert-Butyl 7-bromo-6-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.272 g, 1.0 mmol) in ethyl acetate (1 mL) was treated with 4.0 M of hydrogen chloride in 1,4-dioxane (1.0 mL, 4.0 mmol) at r.t. for 2 h. The mixture was diluted with ethyl ether, and centrifugalized. The solvents were decanted. The residue was dried in-vacuo to afford the desired product as HCl salt which was directly used in next step reaction without further purification.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]1[N:9]=[N:10][C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=12.C(N(CC)CC)C.[CH3:31][N:32]([CH3:36])[C:33](Cl)=[O:34]>>[CH3:31][N:32]([CH3:36])[C:33]([N:6]1[CH2:5][CH2:4][N:3]([C:8]2[C:13]3[CH:14]=[N:15][CH:16]=[CH:17][C:12]=3[C:11]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[N:10][N:9]=2)[C@H:2]([CH3:1])[CH2:7]1)=[O:34]
Reactant: C[C@@H]1CNCCN1c1nnc(-c2ccccc2)c2ccncc12
Reactant: CN(C)C(=O)Cl
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(C(=O)N(C)C)CCN1c1nnc(-c2ccccc2)c2ccncc12

Procedure:
Using methods described in Example 18, and starting with (R)-4-(2-methylpiperazin-1-yl)-1-phenylpyrido[4,3-d]pyridazine 16 (125 mg, 409 μmol), triethylamine (86 μl, 614 μmol) and N,N-dimethylcarbamoyl chloride (41 μl, 450 μmol) afforded (R)—N,N,3-trimethyl-4-(1-phenylpyrido[4,3-d]pyridazin-4-yl)piperazine-1-carboxamide 39. MS 376.2 (calc'd) 377.2 (M+H, found).