Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[C:5]#[N:6].[CH3:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>>[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([C:2]2[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=2)[C:5]#[N:6])[CH2:17][CH2:16]1
Reactant: CN1CCNCC1
Reactant: N#Cc1cc(F)cc(C(F)(F)F)c1
Product: CN1CCN(c2cc(C#N)cc(C(F)(F)F)c2)CC1

Procedure:
The title compound is prepared using an analogous method as described in Example 1.1, utilising 3-fluoro-5-(trifluoromethyl)-benzonitrile (Lancaster Synthesis GmbH) and 1-methylpiperazine (Fluka, Buchs, Switzerland).
Reaction SMILES: CO[C:3]([C:5]1([CH2:11][CH:12]=O)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[CH3:14][C@H:15]1[CH2:19][CH2:18][CH2:17][N:16]1[CH:20]1[CH2:24][CH2:23][C@H:22]([C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)[CH2:21]1>>[CH3:14][C@H:15]1[CH2:19][CH2:18][CH2:17][N:16]1[CH:20]1[CH2:24][CH2:23][C@H:22]([C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:12][CH2:11][C:5]4([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]4)[C:3]3=[O:4])=[CH:27][CH:26]=2)[CH2:21]1
Reactant: C[C@H]1CCCN1C1CC[C@H](c2ccc(N)cc2)C1
Reactant: COC(=O)C1(CC=O)CCCCC1
Product: C[C@H]1CCCN1C1CC[C@H](c2ccc(N3CCC4(CCCCC4)C3=O)cc2)C1

Procedure:
The title compound was synthesized in the manner essentially the same as the Example 1 by condensing 1-(2-oxo-ethyl)-cyclohexanecarboxylic acid methyl ester (Intermediate 6) with 4-[(S)-3-((S)-2-methyl-pyrrolidin-1-yl)-cyclopentyl]-phenylamine (Intermediate 14), and subsequently cyclization.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:19](=[O:20])[C:18]3[C:17]([OH:21])=[C:16]4[C:11]([CH:12]=[CH:13][CH:14]=[N:15]4)=[C:10]([O:22][CH3:23])[C:9]=3[CH:8]2O)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.[CH3:34][O:35][C:36](=[O:40])[CH2:37][CH2:38][SH:39]>C(Cl)Cl>[CH3:34][O:35][C:36](=[O:40])[CH2:37][CH2:38][S:39][CH:8]1[C:9]2[C:10]([O:22][CH3:23])=[C:11]3[C:16](=[C:17]([OH:21])[C:18]=2[C:19](=[O:20])[N:7]1[CH2:6][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:26][CH:25]=1)[N:15]=[CH:14][CH:13]=[CH:12]3
Reactant: COc1c2c(c(O)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2O
Reactant: COC(=O)CCS
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CCSC1c2c(c(O)c3ncccc3c2OC)C(=O)N1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 20 (215 mg, 0.422 mmol) in CH2Cl2 (4.2 mL) and TFA (98 μL, 1.26 mmol) was added methyl-3-mercaptopropionate (56 μL, 0.506 mmol). The solution was stirred at ambient temperature for 5 hours when LCMS analysis indicated complete conversion of the starting materials to the products. The solution was dried under reduced pressure and azeotroped with CH2Cl2 three times to provide the product 23 as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 2.30-2.38 (m, 4H), 3.63 (s, 3H), 4.04 (s, 3H),4.42 (d, 1H, J=15 Hz), 5.33 (d, 1H, J=15 Hz), 5.49 (s, 1H), 7.05 (t, 2H, J=9 Hz), 7.38 (dd, 2H, J=5, 8 Hz), 7.59 (dd, 1H, J=4,9 Hz), 8.53 (d, 1H, J=8 Hz), 8.91-9.01 (m, 1H); 19F NMR (282.6 MHz, CDCl3) δ 62.6; EI MS (m/z) 457.3 [MH+], 479.2 [M+Na].
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[CH2:14][CH2:15][C:16]2=[O:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:55]([Si:59]([CH2:72][O:73][C:74]1([CH2:77]O)[CH2:76][CH2:75]1)([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)([CH3:58])([CH3:57])[CH3:56]>O1CCCC1>[Si:59]([CH2:72][O:73][C:74]1([CH2:77][O:1][C:2]2[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[CH:4][C:3]=2[C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH2:14][CH2:15][C:16]3=[O:21])[CH2:76][CH2:75]1)([C:55]([CH3:58])([CH3:56])[CH3:57])([C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1)[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1
Reactant: CC(C)(C)[Si](COC1(CO)CC1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(O)c1OC
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(OC[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CC2)c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirring solution of 4-(2-hydroxy-3,4-dimethoxy-phenyl)-indan-1-one (Compound 303) (5 g, 17.60 mmol) in tetrahydrofuran (50 mL), were added triphenylphosphine (9.2 g, 35.21 mmol) and diisopropylazodicarboxylate (7.11 g, 35.21 mmol) and {1-[(tert-Butyl-diphenyl-silanyl)-methoxy]-cyclopropyl}-methanol (7.18 g, 21.12 mmol) and the resultant reaction mixture was stirred at RT for 2 h. The reaction mixture was quenched with water and extracted with ethyl acetate (3×). The combined ethyl acetate layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification by column chromatography (silica gel, 0-10% ethyl acetate in pet ether) afforded 4-(2-((1-((tert-butyldiphenylsilyl)methoxy)cyclopropyl)methoxy)-3,4-dimethoxyphenyl)-2,3-dihydro-1H-inden-1-one as a liquid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:19])[CH:12]=[CH:13][C:14]=1[C:15]([CH3:18])([CH3:17])[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][C:14]=1[C:15]([CH3:16])([CH3:18])[CH3:17])[O:19][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)c1ccc(O)cc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)COc1ccc(C(C)(C)C)c(OCc2ccccc2)c1
Yield: 85.2 %

Procedure:
3-(Benzyloxy)-4-tert-butylphenol (4.9 g, 19.2 mmol), potassium carbonate (8.0 g, 57.6 mmol) and ethyl bromoacetate (2.6 ml, 23.0 mmol) were treated in the same procedure described in Example 13(d). The crude residue was applied to a silica gel chromatography column and eluted with a volume mixture of hexane and ethyl acetate (29/1 to 19/1) to furnish 5.6 g (85% yield) of the title compound as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:10])=[N:4][C:5]([CH3:9])=[CH:6][C:7]=1[CH3:8].[H-].[Na+].Cl[C:14]1[N:19]=[C:18]([CH3:20])[N:17]=[C:16]([NH:21][CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[C:15]=1[N+:27]([O-:29])=[O:28]>C1COCC1>[CH2:23]([CH:22]([NH:21][C:16]1[C:15]([N+:27]([O-:29])=[O:28])=[C:14]([O:1][C:2]2[C:3]([CH3:10])=[N:4][C:5]([CH3:9])=[CH:6][C:7]=2[CH3:8])[N:19]=[C:18]([CH3:20])[N:17]=1)[CH2:25][CH3:26])[CH3:24]
Reactant: CCC(CC)Nc1nc(C)nc(Cl)c1[N+](=O)[O-]
Reactant: Cc1cc(C)c(O)c(C)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(CC)Nc1nc(C)nc(Oc2c(C)cc(C)nc2C)c1[N+](=O)[O-]
Temperature: -78 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
A solution of 3-hydroxy-2,4,6-trimethylpyridine (41 mg, 0.3 mmol) in 1 ml of dry THF was treated with 60% sodium hydride in oil (13 mg, 0.3 mmol) at rt. The reaction mixture was cooled to −78° C. and a solution of (6-chloro-2-methyl-5-nitro-pyrimidin-4-yl)-(1-ethyl-propyl)-amine (78 mg, 0.3 mmol) in 1 ml of dry THF was added. The reaction was stirred at −78° C. for 1 hour, quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give 91 mg (84%) of white solid of the title compound, mp 134-135° C. 1H NMR (CDCl3) δ 8.30 (d, 1H), 6.89 (s, 2H), 4.30 (m, 1H), 2.31 (s, 3H), 2.26 (s, 3H), 2.10 (s, 6H), 1.5-1.8 (m, 4H), 0.97 (t, 6H) ppm.
Reaction SMILES: ClC1C=CC2CCNC[C@@H](C)C=2C=1Cl.[CH3:15][N:16]1[CH2:22][C@H:21]([CH3:23])[C:20]2[C:24]([Cl:29])=[C:25]([Cl:28])[CH:26]=[CH:27][C:19]=2[CH2:18][CH2:17]1>>[CH3:15][N:16]1[CH2:22][C@@H:21]([CH3:23])[C:20]2[C:24]([Cl:29])=[C:25]([Cl:28])[CH:26]=[CH:27][C:19]=2[CH2:18][CH2:17]1
Reactant: C[C@H]1CN(C)CCc2ccc(Cl)c(Cl)c21
Agent: C[C@@H]1CNCCc2ccc(Cl)c(Cl)c21
Product: C[C@@H]1CN(C)CCc2ccc(Cl)c(Cl)c21

Procedure:
Compound 10 was prepared from (S)-8,9-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine utilizing a similar procedure as described herein for the preparation of Compound 9. 1H NMR (400 MHz, CDCl3) δ 7.19 (d, J=8 Hz, 1H), 6.89 (d, J=8 Hz, 1H), 3.91-3.88 (m, 1H), 3.28 (ddd, J=15, 12, 2 Hz, 1H), 2.99-2.88 (m, 2H), 2.68 (ddd, J=15, 5, 1 Hz, 1H), 2.36-2.32 (m, 4H), 2.13 (t, J=11 Hz, 1H), 1.27 (d, J=7 Hz, 3H). MS calculated for C12H15Cl2N+H: 243, observed: 243.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:15](=[CH:16][CH:17]=1)[C:8]1[S:9][C:10]([C:12](=[O:14])[CH3:13])=[CH:11][C:7]=1[CH:6]=[CH:5]2.OC1C([O:26][S:27]([C:30]2[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=2)(=[O:29])=[O:28])=C(I)C=CC=1.C(O)C>C(#N)C>[CH3:34][C:33]1[CH:32]=[CH:31][C:30]([S:27]([O:29][CH2:13][C:12]([C:10]2[S:9][C:8]3[C:15]4[C:4]([CH:5]=[CH:6][C:7]=3[CH:11]=2)=[CH:3][C:2]([Br:1])=[CH:17][CH:16]=4)=[O:14])(=[O:28])=[O:26])=[CH:36][CH:35]=1
Reactant: CC(=O)c1cc2ccc3cc(Br)ccc3c2s1
Reactant: Cc1ccc(S(=O)(=O)Oc2c(O)cccc2I)cc1
Solvent: CC#N
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)OCC(=O)c2cc3ccc4cc(Br)ccc4c3s2)cc1
Yield: 81.5 %

Procedure:
To a solution of 1-(7-bromonaphtho[1,2-b]thiophen-2-yl)ethanone (11c) (1.26 g, 4.13 mmol) in 15 ml of acetonitrile at 75° C., hydroxytosyloxyiodobenzene (2.59 g, 6.61 mmol) was added and the mixture was refluxed for 8 hr. The volume of acetonitrile was reduced under vacuum and ethanol was added to it. The orange solid obtained was filtered and washed with ether to obtain the desired compound (11d) (1.6 g, 82%).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2].N1C=CC=CC=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[CH2:1]([N:3]([CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[S:26]([CH3:25])(=[O:28])=[O:27])[CH3:2]
Reactant: CCNCCCCNC(=O)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCN(CCCCNC(=O)OCc1ccccc1)S(C)(=O)=O
Reaction time: 8 h
Yield: 70.3 %

Procedure:
To a mixture of benzyl 4-(ethylamino)butylcarbamate (Step 1, 250 mg, 1.00 mmol) in dichloromethane was added pyridine (145 mg, 1.8 mmol) and then methanesulfonyl chloride (137 mg, 1.20 mmol) at 0° C. The reaction was stirred overnight and diluted with dichloromethane. The phases were separated, and the organic phase was washed with hydrochloride solution (1 N), saturated sodium bicarbonate and saline. The separated organic layer was concentrated and purified by Biotage column chromatography to give benzyl 4-(N-ethylmethylsulfonamido)butylcarbamate (231 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[CH3:18][C:19](OC(C)=O)=O>C1COCC1.N1C=CC=CC=1>[CH2:18]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:17])([C:9]([F:10])([F:11])[F:12])[C:13]([F:14])([F:15])[F:16])=[CH:6][CH:7]=1)[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCNc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 96.5 %

Procedure:
A solution of 1 g (3.86 mmol) of 2-(4-amino-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol in 2 ml of THF and 5 mL of pyridine was treated with 0.44 mL (4.63 mmol) of Ac2O and stirred for 2 hrs at 60° C. The solvent was evaporated and the crude distributed between a diluted aqueous solution of HCl and Et2O. the combined organic phases were dried over Na2SO4 and the solvent evaporated. The residue was dissolved in 5 mL of THF, treated with 7.7 mL of a 1M BH3*THF-solution in THF and refluxed for 2 hrs. The solvent was evaporated and the residue distributed between a diluted aqueous solution of NaOH and Et2O. The aqueous phase was then acidified by addition of an aqueous solution of HCl to a pH of ca. 7 and extracted with Et2O. The combined organic phases were dried over Na2SO4 and the solvent evaporated to give 1.07 g (96%) of crude 2-(4-ethylamino-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol, light yellow solid, MS: 288 (MH+).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13]([NH2:17])[CH2:14][CH:15]=[CH2:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH2:32][C:33](O)=[O:34])[CH:24]=[CH:25][C:26]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:19]>>[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH2:32][C:33]([NH:17][CH:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:14][CH:15]=[CH2:16])=[O:34])[CH:24]=[CH:25][C:26]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:19]
Reactant: C=CCC(N)c1ccccc1N1CCCCC1
Reactant: CCOC(=O)c1ccc(CC(=O)O)cc1OCC
Product: C=CCC(NC(=O)Cc1ccc(C(=O)OCC)c(OCC)c1)c1ccccc1N1CCCCC1

Procedure:
Prepared analogously to Example 19 from 1-(2-piperidino-phenyl)-3-buten-1-yl-amine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:12].C(OC(=O)C)(=O)C.[N+:20]([O-])([OH:22])=[O:21]>C(O)(=O)C>[CH3:1][C:2]1[CH:10]=[C:9]([N+:20]([O-:22])=[O:21])[C:8]([OH:11])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:12]
Reactant: Cc1ccc(O)c2c1CCC2=O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: Cc1cc([N+](=O)[O-])c(O)c2c1CCC2=O

Procedure:
Into a solution of 25.6 g of 4-methyl-7-hydroxy-1-indanone in 250 ml of acetic acid was added 19.4 ml of acetic anhydride and a solution of 15.4 ml of concentrated nitric acid in 50 ml of acetic acid gradually. The reaction mixture was concentrated to drynsss, and the residue was washed with ether to obtain 25.7 g of 4-methyl-6-nitro-7-hydroxy-1-indanone.
Reaction SMILES: [CH2:1]([N:3]1C=CC(=O)C(OCC2C=CC=CC=2)=C1COC)C.[CH3:21][O:22][CH:23]([C:26]1O[C:28]([CH3:41])=[CH:29][C:30](=[O:40])[C:31]=1[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:24][CH3:25].CN>>[CH3:1][N:3]1[C:28]([CH3:41])=[CH:29][C:30](=[O:40])[C:31]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[C:26]1[CH:23]([O:22][CH3:21])[CH2:24][CH3:25]
Reactant: CCn1ccc(=O)c(OCc2ccccc2)c1COC
Reactant: CCC(OC)c1oc(C)cc(=O)c1OCc1ccccc1
Agent: CN
Product: CCC(OC)c1c(OCc2ccccc2)c(=O)cc(C)n1C
Yield: 37.6 %

Procedure:
In an analogous procedure in the preparation of 1-ethyl-2-methoxymethyl-3-benzyloxy-pyridin-4(1H)-one using 2-(1-methoxypropyl)-3-benzyloxy-6-methyl-pyran-4(1 H)-one 4.32 g (15 mmol, 1 eq.) and 3.49 g (45 mmol, 3 eq.) of 40% aqueous methylamine yielded the title compound (1.7 g, 37.6%) after purification by column chromatography on silica gel (eluant: 15% CH3OH/85% CHCl3) as a yellow oil.
Reaction SMILES: [CH2:1]([NH:8][N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N+:14]([O-])=[CH:13][C:12]=2[N:11]=[C:10]1[CH2:23][O:24][CH2:25][CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+:27].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O>C(Cl)Cl>[CH2:1]([NH:8][N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[C:13]([NH2:27])[C:12]=2[N:11]=[C:10]1[CH2:23][O:24][CH2:25][CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: CCOCc1nc2c[n+]([O-])c3ccccc3c2n1NCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCOCc1nc2c(N)nc3ccccc3c2n1NCc1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of N-benzyl-(2-ethoxymethy-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)amine (0.99 g, 2.84 mmol) in 50 mL of CH2Cl2 was treated with 25 mL of concentrated NH4OH solution. To the rapidly stirred solution was added p-toluenesulfonyl chloride (569 mg, 2.98 mmol). After stirring for 30 min, the reaction was treated with CH2Cl2 (50 mL) and H2O (25 mL). The layers were separated and the organic portion was washed 2% Na2CO3 solution, H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated to give a tan solid. Chromatography (SiO2, 2% MeOH/CHCl3 containing 0.5% concentrated NH4OH) followed by crystallization from propyl acetate gave N1-benzyl-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline-1,4-diamine (148 mg) as white needles. mp 152–155° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.61 (dd, J=8.2, 1.2 Hz, 1H), 7.85–7.77 (m, 1H), 7.59–7.52 (m, 1H), 7.42–7.34 (m, 4H), 7.33–7.24 (m, 2H), 6.02 (t, J=6.6 Hz, 1H), 5.39 (s, 2H), 4.43 (s, 2H), 4.40 (d, J=6.7 Hz, 2H), 3.55 (q, J=7.0 Hz, 2H), 1.22 (t, J=7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 151.1, 147.9, 144.9, 135.7, 129.2, 129.1, 128.6, 127.8, 126.7, 122.4, 120.7, 66.7, 65.3, 56.7, 15.0; MS m/z 348 (M+H)+; Anal. Calcd for C2OH21N5O.0.36H2O: C, 68.90; H, 6.11; N, 20.09; Found: C, 68.50; H, 6.07; N, 20.11.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:3]=1[CH2:4][NH:5][C:6]1[C:11](C2C=CC=CC=2)=[C:10]([NH:18][CH3:19])[N:9]=[C:8](N=NC2N=CC=CN=2)[N:7]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].C[N:42](C)C=O>[OH-].[Na+]>[NH2:42][C:11]1[C:6]([NH:5][CH2:4][C:3]2[C:28]([F:32])=[CH:29][CH:30]=[CH:31][C:2]=2[Cl:1])=[N:7][CH:8]=[N:9][C:10]=1[NH:18][CH3:19]
Reactant: CNc1nc(N=Nc2ncccn2)nc(NCc2c(F)cccc2Cl)c1-c1ccccc1
Reactant: CN(C)C=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Product: CNc1ncnc(NCc2c(F)cccc2Cl)c1N
Yield: 79 %

Procedure:
In N,N-dimethylformamide (20 ml) and 2 N NaOH (5 ml) was dissolved 4-(2-chloro-6-fluorobenzyl)amino-6-methylamino-5-phenylazopyrimidine (1.112 g, 3 mmols), and sodium dithionite (3.27 g, 15 mmol; purity 80%) was added portionwise to the solution with stirring at 140°-150° C. The mixture was stirred at the same temperature for 30 minutes, after which it was concentrated to dryness under reduced pressure, and water was added to the residue. The mixture was adjusted to pH 12-13 by addition of 2 N NaOH, and extracted with ethyl acetate (150 ml, 100 ml). The extract was dried over anhydrous sodium sulfate. The ethyl acetate was evaporated under reduced pressure, and the resultant residue was recrystallized from ethyl acetate-petroleum ether to give 5-amino-4-(2-chloro-6-fluorobenzyl)amino-6-methylaminopyrimidine as brown crystals (671 mg, yield 79%), m.p. 210°-213° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([CH:29]([CH3:31])[CH3:30])[CH2:25][CH2:24]2)=[O:22])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([N:13]1[CH2:18][CH2:17][C:16]([F:20])([F:19])[CH2:15][CH2:14]1)=[O:12])=[CH:7]2.[H-].[Na+].Br[CH:35]([CH3:37])[CH3:36]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([CH:29]([CH3:31])[CH3:30])[CH2:25][CH2:24]2)=[O:22])[CH:5]=[C:6]2[C:10]=1[N:9]([CH:35]([CH3:37])[CH3:36])[C:8]([C:11]([N:13]1[CH2:18][CH2:17][C:16]([F:20])([F:19])[CH2:15][CH2:14]1)=[O:12])=[CH:7]2
Reactant: CC(C)N1CCN(C(=O)c2cc(Cl)c3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(=O)c2cc(Cl)c3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3C(C)C)CC1
Yield: 24 %

Procedure:
The title compound was synthesized in analogy to example 51, from [7-chloro-2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone (example 232), sodium hydride and 2-bromopropane in N,N-dimethylformamide, to give the desired product as a colorless foam (24%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:33]([F:36])([F:35])[F:34])[N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]([CH2:21][C:22]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[C:25](=[O:32])[NH:24][N:23]=4)[CH:17]=[CH:18][C:19]=3[F:20])=[O:13])[CH2:8][C:7]=12.[CH3:37][NH2:38].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O1CCCC1>[F:20][C:19]1[CH:18]=[CH:17][C:16]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25](=[O:32])[NH:24][N:23]=2)=[CH:15][C:14]=1[C:12]([N:9]1[CH2:10][CH2:11][N:6]2[C:5]([C:33]([F:36])([F:34])[F:35])=[N:4][C:3]([CH2:2][NH:38][CH3:37])=[C:7]2[CH2:8]1)=[O:13]
Reactant: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCn2c(C(F)(F)F)nc(CCl)c2C1
Reactant: CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: C1CCOC1
Product: CNCc1nc(C(F)(F)F)n2c1CN(C(=O)c1cc(Cc3n[nH]c(=O)c4ccccc34)ccc1F)CC2
Yield: 10.1 %

Procedure:
4-[[3-[1-(Chloromethyl)-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carbonyl]-4-fluoro-phenyl]methyl]-2H-phthalazin-1-one 9a (372 mg, 1.25 mmol) was dissolved in 5 mL of acetonitrile, followed by addition of 0.6 mL of a 2 M solution of methylamine in tetrahydrofuran and potassium carbonate (159 mg, 1.15 mmol). The reaction mixture was heated to reflux for 6 hours. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure and was purified by thin layer chromatography with elution system A to obtain 4-[[4-fluoro-3-[1-(methylaminomethyl)-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carbonyl]phenyl]methyl]-2H-phthalazin-1-one 9 (20 mg, yield 10.1%) as a yellow solid.
Reaction SMILES: I.[CH2:2]([N:6]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[S:8][C:7]1=[NH:15])[CH2:3][CH2:4][CH3:5].C(N(CC)CC)C.[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([O:33][CH3:34])=[C:28]([CH:32]=1)[C:29](Cl)=[O:30]>C(Cl)Cl>[CH2:2]([N:6]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[S:8]/[C:7]/1=[N:15]\[C:29](=[O:30])[C:28]1[CH:32]=[C:24]([Cl:23])[CH:25]=[CH:26][C:27]=1[O:33][CH3:34])[CH2:3][CH2:4][CH3:5]
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Reactant: CCCCn1cc(C(C)(C)C)sc1=N
Agent: I
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCn1cc(C(C)(C)C)s/c1=N\C(=O)c1cc(Cl)ccc1OC
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of Example 6A (1.4 g, ˜4 mmol) and triethylamine (1.4 mL, 10 mmol) in CH2Cl2 (35 mL) at 0° C. was added 5-chloro-2-methoxy-benzoyl chloride (820 mg, 4 mmol), the mixture was allowed to warm to room temperature was stirred for 14 hours. The mixture was washed sequentially with water, brine, dried with anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by chromatography (6:2:2 Hexane-EtOAc-CH2Cl2) to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ: 0.94 (t, J=7 Hz, 3H), 1.30 (m+s, 11H), 1.75 (m, 2H), 3.77 (s, 3H), 4.14 (t, J=7 Hz, 2H), 7.10 (d, J=9 Hz, 1H), 7.31 (s, 1H), 7.43 (d-d, J=9 Hz, 3 Hz, 1H), 7.65 (d, J=3 Hz, 1H); MS (ESI+) m/z 381 (M+H)+.
Reaction SMILES: FC1C=CC=CC=1CC=O.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]=[CH:19][CH:20]([CH:24]([CH3:26])[CH3:25])[C:21]([OH:23])=[O:22].[O:27]([C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37]O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]=[CH:19][CH:20]([CH:24]([CH3:26])[CH3:25])[C:21]([O:23][CH2:37][C:36]1[CH:39]=[CH:40][CH:41]=[C:34]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:35]=1)=[O:22]
Reactant: CC(C)C(C=Cc1ccccc1F)C(=O)O
Reactant: OCc1cccc(Oc2ccccc2)c1
Agent: O=CCc1ccccc1F
Product: CC(C)C(C=Cc1ccccc1F)C(=O)OCc1cccc(Oc2ccccc2)c1

Procedure:
2-Fluorophenylacetaldehyde is converted into ethyl 4-(2-fluorophenyl)-4-isopropyl-3-butanoate and hydrolyzed to the acid using the procedure of Example 9. The acid, 4-(2-fluorophenyl)-2-isopropyl-3-butenoic acid, is reacted, via the acid chloride, with m-phenoxybenzyl alcohol to yield m-phenoxybenzyl 4-(2-fluorophenyl)-2-isopropyl-3-butenoate, MS m/e 404.3 (M+). 2-Fluorophenylacetaldehyde is prepared from o-fluoro-β-methoxystyrene via the dimethylacetal using the procedure of Winterfeldt, Berichte 96(12), 3349 (1963).