Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[C:8]([C:18]([OH:21])([CH3:20])[CH3:19])[N:9]2C2CCCCO2)=[C:5]([Cl:22])[N:4]=1>C(Cl)Cl.CO>[Cl:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[C:8]([C:18]([OH:21])([CH3:20])[CH3:19])[NH:9]2)=[C:5]([Cl:22])[N:4]=1
Reactant: CC(C)(O)c1nc2c(Cl)nc(Cl)nc2n1C1CCCCO1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CC(C)(O)c1nc2c(Cl)nc(Cl)nc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.2 %

Procedure:
HCl (5 mL, 5 mmol, 1 M aqueous solution) was added to a solution of 2-[2,6-dichloro-9-(tetrahydro-pyran-2-yl)-9H-purin-8-yl]-propan-2-ol (6.0 g, 20.66 mmol) in a mixture of DCM (15 mL) and methanol (15 mL) and the resulting solution stirred at RT for 1 h, then concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, gradient 0 to 50% methanol in DCM) affording 2-(2,6-Dichloro-9H-purin-8-yl)-propan-2-ol as a dark solid (3.38 g, 66%). LCMS (method A): RT=2.12 min, [M−H]=245/247. 1H NMR (400 MHz, CDCl3): δ 1.50 (6H, s)
Reaction SMILES: [CH3:1][C:2]([CH3:42])([CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[N:25](COCC[Si](C)(C)C)[CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[N:28]=3)=[CH:20][N:19]=2)=[CH:14][C:13]=1[CH3:41])[C:3]([O:5]C(C)(C)C)=[O:4]>FC(F)(F)C(O)=O.O>[CH3:1][C:2]([CH3:42])([CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[NH:28][C:27]([C:29]([F:32])([F:30])[F:31])=[CH:26][N:25]=3)=[CH:20][N:19]=2)=[CH:14][C:13]=1[CH3:41])[C:3]([OH:5])=[O:4]
Reactant: Cc1cc(-c2ccc(-c3nc(C(F)(F)F)cn3COCC[Si](C)(C)C)cn2)ccc1OCC(C)(C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1cc(-c2ccc(-c3ncc(C(F)(F)F)[nH]3)cn2)ccc1OCC(C)(C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
In trifluoroacetic acid (5 mL) and water (0.5 mL) was dissolved tert-butyl 2,2-dimethyl-3-[2-methyl-4-[5-[4-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)-imidazol-2-yl]-2-pyridyl]phenoxy]propanoate (103 mg), and the mixture was stirred at room temperature overnight. The residue obtained by concentrating the reaction mixture under reduced pressure was dissolved in tetrahydrofuran, and 1N aqueous sodium hydroxide solution was added to the mixture to adjust a pH thereof to 7. To the mixture were added 0.1N phosphate buffer, ethyl acetate and water, and the liquids were separated. The organic layer was separated, dried over anhydrous sodium sulfate, and ether was added to the residue obtained by concentrating the solution under reduced pressure to pulverize the precipitates to obtain 2,2-dimethyl-3-[2-methyl-4-[5-[5-(trifluoromethyl)-1H-imidazol-2-yl]-2-pyridyl]phenoxy]propanoic acid (59.1 mg).
Reaction SMILES: Cl[CH:2]1[C:7](=[O:8])[CH2:6][C:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[O:4][C:3]1=[O:25].[SH:26][C:27]1[N:28]([CH3:32])[CH:29]=[CH:30][N:31]=1>>[Cl:24][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][C:5]2([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[O:4][C:3](=[O:25])[C:2]([S:26][C:27]3[N:28]([CH3:32])[CH:29]=[CH:30][N:31]=3)=[C:7]([OH:8])[CH2:6]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cl)C(=O)O2)cc1Cl
Reactant: Cn1ccnc1S
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Sc3nccn3C)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared as described in Example C(70), where 3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3 H)-dione was used in place of 3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione and 2-mercapto-1-methylimidazole was used in place of 6-hydroxy-8-mercaptopurine monohydrate.
Reaction SMILES: N([O-])=O.[Na+].[CH2:5]([O:7][C:8]([C:10]1[C:19](N)=[CH:18][C:17]2[C:12](=[C:13]([O:21][CH3:22])[CH:14]=[CH:15][CH:16]=2)[CH:11]=1)=[O:9])[CH3:6].C([O-])(O)=O.[Na+].[ClH:28]>O>[CH2:5]([O:7][C:8]([C:10]1[C:19]([Cl:28])=[CH:18][C:17]2[C:12](=[C:13]([O:21][CH3:22])[CH:14]=[CH:15][CH:16]=2)[CH:11]=1)=[O:9])[CH3:6]
Reactant: Cl
Reactant: CCOC(=O)c1cc2c(OC)cccc2cc1N
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cc2c(OC)cccc2cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of NaNO2 (884 mg, 12.81 mmol, 1.45 equiv) in water (20 ml) was added dropwise at 0° C. to a solution of 3-amino-8-methoxy-naphthalene-2-carboxylic acid ethyl ester (2.165 g, 8.83 mmol) in 18% aqueous HCl (50 ml). After it was stirred for 30 minutes at 0° C., this mixture was added dropwise at −20° C. to a solution of freshly prepared Cu(I)Cl (2.62 g, 26.50 mmol, 3.0 equiv) in concentrated aqueous HCl (90 ml). After 1 hour at −10° C. and 1 hour at rt, solid NaHCO3 was carefully added to the reaction mixture until pH was >7.0. After dilution with water (200 ml), the aqueous phase was extracted with EtOAc (2 liters in total). The combined organic layers were washed with water (300 ml) and concentrated aqueous NH4Cl solution (100 ml), dried over Na2SO4, filtered and concentrated in vacuo. Purification via flash chromatography (gradient of hexane/EtOAc 10:0 to 9:1) afforded the title compound (1.36 g, 58%, inseparable ˜1:1 mixture of regioisomers A:B) as a slightly yellow oil. 1H NMR (400 MHz, CDCl3): δ=8.76 (s, 1H isomer A/B), 8.31 (s, 1H isomer A/B), 7.85 (s, 1H isomer A/B), 7.50-7.40 (m, 3H isomer A/B), 7.32 (d, J=8.6 Hz, 1H isomer A/B), 6.90 (dd, J=6.6/2.0 Hz, 1H isomer A/B), 6.83 (d, J=7.6 Hz, 1H isomer A/B), 4.44 (q, J=7.1 Hz, 2H), 4.01 (s, 3H isomer A/B), 4.00 (s, 3H isomer A/B), 1.44 (t, J=7.1 Hz, 3H isomer A/B), 1.44 (t, J=7.1 Hz, 3H isomer A/B). MS (ES+): 265 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][CH2:14][O:15][CH3:16])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH2:31][CH2:32][CH2:33]Cl)=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>COCCO>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][CH2:14][O:15][CH3:16])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH2:31][CH2:32][CH2:33][N:39]3[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]3)=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1
Reactant: CN1CCNCC1
Reactant: COCCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCCl)c(OC)cc23)c2c1OCO2
Solvent: COCCO
Product: COCCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCN4CCN(C)CC4)c(OC)cc23)c2c1OCO2
Yield: 67.8 %

Procedure:
This was prepared by the method described in example 13 using N-[5-Chloro-7-(4-methoxybut-1-yn-1-yl)-1,3-benzodioxol-4-yl]-7-(3-chloropropoxy)-6-methoxyquinazolin-4-amine (200 mg, 0.40 mmol) and 1-methylpiperazine (198 mg, 1.98 mmol) in 2-methoxyethanol (4 ml). The crude product was purified by column chromatography on silica using increasing concentrations of methanolic ammonia in dichloromethane as eluent. There was thus obtained the title compound (154 mg, 68%) as a pale brown solid; NMR Spectrum:(DMSOd6) 1.95 (quintet, 2H), 2.14 (s, 3), 2.2-2.6 (m, 8H), 2.47 (t, 2H), 2.72 (t, 2H), 3.31 (s, 3H), 3.53 (t, 2H), 3.92 (s, 3H), 4.18 (s, 2H), 6.14 (s, 2H), 7.08 (s, 1H), 7.16 (s, 1H), 7.82 (s, 1H), 8.32 (s, 1H), 9.50 (s, 1H); Mass Spectrum: M+H+ 568/570.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([NH:11][C:12]([C:14]1[C:15]([CH3:27])=[N:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[N:18][CH:19]=1)=[O:13])[CH:6]=[C:5]2[S:28]([OH:31])(=O)=[O:29].C(Cl)(=O)C([Cl:35])=O>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([NH:11][C:12]([C:14]1[C:15]([CH3:27])=[N:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[N:18][CH:19]=1)=[O:13])[CH:6]=[C:5]2[S:28]([Cl:35])(=[O:31])=[O:29]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1cc(S(=O)(=O)O)c2cc(F)ccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1cc(S(=O)(=O)Cl)c2cc(F)ccc21
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a suspension of 5-fluoro-1-{[2-(3-fluorophenyl)-4-methylpyrimidine-5-carbonyl]amino}-1H-indole-3-sulfonic acid (1.06 g) in DCM (60 mL) at 0° C. is added dry DMF (10 drops). Oxalyl chloride (1.05 mL) is added drop wise and the mixture is stirred at 0° C. for 3 h. The mixture is filtered and the collected solid is washed with ether to afford 5-fluoro-1-{[2-(3-fluorophenyl)-4-methylpyrimidine-5-carbonyl]amino}-1H-indole-3-sulfonyl chloride (0.94 g). MS: 461 (M−H)
Reaction SMILES: N.C([O:5][C@H:6]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([N:15]2[CH:23]=[N:22][C:21]3[C:16]2=[N:17][C:18]([C:39]#[N:40])=[N:19][C:20]=3[NH:24][CH2:25][CH:26]2[C:38]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:32]3[C:27]2=[CH:28][CH:29]=[CH:30][CH:31]=3)[O:8][C@@H:7]1[CH2:41][O:42]C(=O)C)(=O)C>C(O)C.[Pd]>[NH2:40][CH2:39][C:18]1[N:17]=[C:16]2[C:21]([N:22]=[CH:23][N:15]2[C@H:9]2[C@H:10]([OH:11])[C@H:6]([OH:5])[C@@H:7]([CH2:41][OH:42])[O:8]2)=[C:20]([NH:24][CH2:25][CH:26]2[C:38]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:32]3[C:27]2=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:19]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NCC4c5ccccc5-c5ccccc54)nc(C#N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Pd]
Agent: N
Solvent: CCO
Product: NCc1nc(NCC2c3ccccc3-c3ccccc32)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 25 °C
Reaction time: 40 h
Yield: 37.7 %

Procedure:
Ammonia gas was passed through an ice cold solution of (2R,3R,4R,5R)-4-(acetyloxy)-2-[(acetyloxy)methyl]-5-{2-cyano-6-[(9H-fluoren-9-ylmethyl)amino]-9H-purin-9-yl}tetrahydro-3-furanyl acetate (1.2 g, 2 mmol) (Preparation 71) in ethanol (40 ml) until the solution was saturated. 10% Palladium on carbon (120 mg) was added and the reaction mixture was stirred under an atmosphere of hydrogen gas (413.7 kPa, 60 psi) at room temperature for 40 hours. The suspension was filtered through Arbocel (Trade Mark) and the solvent was removed from the filtrate under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:0.88 concentrated aqueous ammonia (96:4:0.4 by volume) increasing in polarity to dichloromethane:methanol:0.88 concentrated aqueous ammonia (94:6:0.5 by volume). The solvent was removed under reduced pressure to give the title compound (358 mg) as a foam.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]([OH:38])=O)=[CH:31][CH:30]=1.[C:39]([O:47][NH:48][CH2:49][CH2:50][C:51]1[CH:56]=[CH:55][C:54]([O:57][CH2:58][C:59]#[CH:60])=[C:53]([O:61][CH3:62])[CH:52]=1)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(N(C(C)C)C(C)C)C>CN(C=O)C.O>[C:39]([O:47][N:48]([CH2:49][CH2:50][C:51]1[CH:56]=[CH:55][C:54]([O:57][CH2:58][C:59]#[CH:60])=[C:53]([O:61][CH3:62])[CH:52]=1)[C:36](=[O:38])[CH2:35][C:32]1[CH:31]=[CH:30][C:29]([Cl:28])=[CH:34][CH:33]=1)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: C#CCOc1ccc(CCNOC(=O)c2ccccc2)cc1OC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C#CCOc1ccc(CCN(OC(=O)c2ccccc2)C(=O)Cc2ccc(Cl)cc2)cc1OC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
BOP (2.0 g, 4.5 mmol) is added to a solution of (4-chloro-phenyl)-acetic acid (0.7 g, 4.1 mmol), N-benzoyloxy-2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethylamine (1.4 g, 4.3 mmol) and N-ethyldiisopropylamine (2.8 ml, 16.4 mmol) in 10 ml DMF. The reaction mixture is stirred at room temperature for 20 hours. The reaction mixture is then poured into water and extracted three times with ethyl acetate. The organic phase is dried over Na2SO4 and concentrated. The crude product is purified by flash chromatography (ethyl acetate:hexane, 1:3) to yield N-benzoyloxy-2-(4-chloro-phenyl)-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-acetamide as an oil.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][CH2:14][CH2:15]2)=[CH:11][C:10]=1[O:18][CH2:19][C:20]1[N:21]=[CH:22][C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N:24][CH:25]=1)=O)(C)(C)C.[ClH:31].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:31].[ClH:31].[ClH:31].[NH2:8][C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][CH2:14][CH2:15]2)=[CH:11][C:10]=1[O:18][CH2:19][C:20]1[N:21]=[CH:22][C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N:24][CH:25]=1
Reactant: CCOC(=O)c1cnc(COc2cc3c(cc2NC(=O)OC(C)(C)C)CCC3)cn1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc(COc2cc3c(cc2N)CCC3)cn1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
690 mg of ethyl 5-[({6-[(tert-butoxycarbonyl)amino]-2,3-dihydro-1H-inden-5-yl}oxy)methyl]pyrazine-2-carboxylate was dissolved in 7.00 mL of ethyl acetate, and 4.17 mL of a 4 M hydrogen chloride/ethyl acetate solution was added thereto, followed by stirring at 50° C. for 3 hours. The reaction liquid was concentrated under reduced pressure, and the obtained residue was solidified by the addition of isopropanol to obtain 712 mg of ethyl 5-{[(6-amino-2,3-dihydro-1H-inden-5-yl)oxy]methyl}pyrazine-2-carboxylate trihydrochloride.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:11](=O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH2:21]>C(O)C>[CH:21](=[N:10]/[NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)\[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=[CH2:11]
Reactant: NNC(=O)c1ccccc1
Reactant: C=CCCCCCCCCC=O
Solvent: CCO
Product: C=CCCCCCCCC/C=N/NC(=O)c1ccccc1
Temperature: 25 °C
Yield: 88.2 %

Procedure:
A mixture of 1a (1.50 g, 11.0 mmol) and 10-undecenal (2.80 g, 16.5 mmol) in ethanol (28 ml) was heated under reflux for 2 h. After cooling to room temperature, the product was concentrated, washed with hexane and dried under vacuum (0.20 mbar) to give 2.78 g (88%) of a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.C([O-])([O-])=O.[Na+].[Na+].[C:16](=O)([O:25]N1C(=O)CCC1=O)[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O.CC#N>[CH2:18]([O:17][C:16]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1)=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: O=C(O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 22.4 %

Procedure:
To a solution of piperidine-4-carboxylic acid (10.0 g, 77.4 mmol) and Na2CO3 (8.21 g, 77.4 mmol) in water (100 mL) was added a solution of benzyl 2,5-dioxopyrrolidin-1-yl carbonate (19.3 g, 77.4 mmol) in MeCN (100 mL). The reaction was stirred at ambient temperature for about 16 h and then concentrated under reduced pressure. The resulting aqueous solution was quenched with NH4Cl and was then extracted with EtOAc (2×100 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 1-(benzyloxycarbonyl)piperidine-4-carboxylic acid as a white solid (4.56 g, 22%): LC/MS (Table 2, Method a) Rt=1.93 min; MS m/z: 262 (M−H)−.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9]C(=O)C(C)(C)C)=[C:5]([CH3:16])[C:4]=1[C:17]([F:20])([F:19])[F:18])#[N:2]>Cl.CCO>[NH2:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([C:17]([F:18])([F:19])[F:20])[C:5]=1[CH3:16]
Reactant: Cc1c(NC(=O)C(C)(C)C)ccc(C#N)c1C(F)(F)F
Agent: Cl
Solvent: CCO
Product: Cc1c(N)ccc(C#N)c1C(F)(F)F
Temperature: 25 °C
Yield: 87.1 %

Procedure:
A solution of the mixed product from 18C (7.53 g, 26.5 mmol) in 120 mL of concentrated HCl/EtOH (1:1) was refluxed for 14 h. After cooling to rt, the solution was concentrated under reduced pressure. The resulting residue was dissolved in EtOAc, washed with saturated aqueous NaHCO3 (2×) and brine (1×), dried (MgSO4), filtered and concentrated. The residue was chromatographed (silica gel), eluting with chloroform/MeOH (98:2) to furnish the title compound (4.62 g, 87%). MS (ES) m/z 201 [M+1]+.
Reaction SMILES: C(S[C:9]1[C:22]2[C:21](=[O:23])[C:20]([C:24]([OH:26])=[O:25])=[CH:19][N:14]3[C@@H:15]([CH3:18])[CH2:16][O:17][C:12]([C:13]=23)=[C:11]([C:27]2[CH:32]=[C:31]([CH3:33])[N:30]=[C:29]([CH3:34])[CH:28]=2)[C:10]=1[F:35])C1C=CC=CC=1>[Ni].C(O)C>[CH3:34][C:29]1[CH:28]=[C:27]([C:11]2[C:10]([F:35])=[CH:9][C:22]3[C:21](=[O:23])[C:20]([C:24]([OH:26])=[O:25])=[CH:19][N:14]4[C@@H:15]([CH3:18])[CH2:16][O:17][C:12]=2[C:13]=34)[CH:32]=[C:31]([CH3:33])[N:30]=1
Reactant: Cc1cc(-c2c(F)c(SCc3ccccc3)c3c(=O)c(C(=O)O)cn4c3c2OC[C@@H]4C)cc(C)n1
Agent: [Ni]
Solvent: CCO
Product: Cc1cc(-c2c(F)cc3c(=O)c(C(=O)O)cn4c3c2OC[C@@H]4C)cc(C)n1

Procedure:
It is further contemplated that (S)-8-(benzylthio)-10-(2,6-dimethyl-4-pyridinyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid can be treated with Raney nickel in ethanol to give (S)-10-(2,6-dimethyl-4-pyridinyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid, the compound of Example 3(c).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([N+:16]([O-:18])=[O:17])[C:14]=1F)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.CN(C=O)C.[CH3:24][S-:25].[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([N+:16]([O-:18])=[O:17])[C:14]=1[S:25][CH3:24])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: O=[N+]([O-])c1c(F)c(Cl)cc2c1[nH]c1cnccc12
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1c(Cl)cc2c([nH]c3cnccc32)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
A 250 ml round-bottom flask with magnetic stirrer was charged with 6-chloro-7-fluoro-8-nitro-β-carboline (Intermediate 5, 3.959 g, 14.9 mmol) and 100 ml anhydrous DMF. The resulting orange mixture was cooled to 0° C. (ice and water bath) and sodium thiomethoxide (1.809 g, 25.8 mmol) in powder form was added slowly thereto. The reaction mixture was stirred for 1 hr at 0° C., warmed to RT, and added slowly to a stirring mixture of 4:1 H2O/saturated aqueous sodium bicarbonate (500 ml). The precipitated solid was collected via suction filtration and air-dried to afford 4.017 g of 6-chloro-7-methylsulfanyl-8-nitro-9H-β-carboline as an orange powder. The crude material was used directly in subsequent steps.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]([OH:13])=O)=[CH:4][NH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[CH3:14][N:15](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:16].F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CNC>CN(C=O)C>[Cl:1][C:2]1[C:3]([C:11]([N:15]([CH3:16])[CH3:14])=[O:13])=[CH:4][NH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1[nH]cc(C(=O)O)c1Cl
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1[nH]cc(C(=O)N(C)C)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.5 %

Procedure:
To a solution of 4-chloro-5-[(methyloxy)carbonyl]-1H-pyrrole-3-carboxylic acid (0.075 g, 0.368 mmol) in DMF (1 ml) was added HATU (0.168 g, 0.442 mmol), DIPEA (0.097 ml, 0.553 mmol) and dimethyl amine (2M in THF) (0.276 ml, 0.553 mmol) and the reaction stirred at RT for 1 h. Purification was accomplished by HPLC to afford methyl 3-chloro-4-[(dimethylamino)carbonyl]-1H-pyrrole-2-carboxylate (0.042 g, 49% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.40 (br. s., 1H) 7.23 (d, 1H) 3.80 (s, 3H) 2.93 (s, 6H). MS: m/z 231.0 (M+1).
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1)[C:2]#[CH:3].[Cl:9][C:10]1[CH:15]=[CH:14][C:13](/[C:16](/[C:33]2[CH:38]=[CH:37][C:36](I)=[CH:35][CH:34]=2)=[CH:17]/[CH2:18][O:19][C:20]2[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[C:22]([CH3:32])[CH:21]=2)=[CH:12][CH:11]=1>O1CCCC1.C(N(CC)CC)C.C1C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[Cl:9][C:10]1[CH:11]=[CH:12][C:13](/[C:16](/[C:33]2[CH:34]=[CH:35][C:36]([C:3]#[C:2][CH2:1][N:4]3[CH2:8][CH2:7][CH2:6][CH2:5]3)=[CH:37][CH:38]=2)=[CH:17]/[CH2:18][O:19][C:20]2[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[C:22]([CH3:32])[CH:21]=2)=[CH:14][CH:15]=1
Reactant: COC(=O)COc1ccc(OC/C=C(/c2ccc(Cl)cc2)c2ccc(I)cc2)cc1C
Reactant: C#CCN1CCCC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(/c2ccc(Cl)cc2)c2ccc(C#CCN3CCCC3)cc2)cc1C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
N-Propargylpyrrolidine (300 mg, 2.75 mmol) was added under nitrogen atmosphere to a degassed solution of methyl (Z)-[4-[3-(4-chlorophenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]acetate (500 mg, 0.91 mmol) in a mixture of tetrahydrofuran (8 mL) and triethylamine (8 mL) The solution was cooled, tetrakis(triphenylphosphine)palladium (96 mg, 0.083 mmol) and copper(I) iodide (27.6 mg, 0.145 mmol) were added. The reaction mixture was stirred at ambient temperature for 72 h, diluted with benzene (100 mL) and the resulting mixture was washed with water (2×50 mL). The organic solution was dried with anhydrous potassium carbonate and subsequently evaporated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, benzene-chloroform/ether 2:1) yielding methyl (E)-[4-[3-(4-chlorophenyl)-3-[4-[3-(pyrrolidin-1-yl)propynyl]phenyl]allyloxy]-2-methylphenoxy]-acetate.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][CH:5]=1)=[O:3].[N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[CH2:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O.[O-]CC.[Na+]>C(O)C>[N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[CH2:22][O:23][C:24]1[CH:25]=[C:26]([CH:27]=[CH:1][C:2]([C:4]2[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][CH:5]=2)=[O:3])[CH:29]=[CH:30][CH:31]=1
Reactant: CC(=O)c1ccc(C#N)cc1
Reactant: O=Cc1cccc(OCc2ccc3ccccc3n2)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1ccc(C(=O)C=Cc2cccc(OCc3ccc4ccccc4n3)c2)cc1

Procedure:
4-Cyano acetophenone (0.01 mol) in ethanol (100 ml) is added dropwise to a 0° C. mixture of 3-(2-quinolinylmethyloxy)benzaldehyde (0.01 mol) and sodium ethoxide (0.001 mol) in ethanol (200 ml). The reaction mixture is allowed to thaw to ambient temperature and after several hours it is evaporated and partitioned between ethyl acetate and water. The ethyl acetate fraction is dried and evaporated to give 4-(3-(3-(2-quinolinylmethyloxy)phenyl)-1-oxo-2-propen-1-yl)-benzonitrile.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1([CH3:24])[CH2:15][C:14]2[NH:13][CH:12]=[C:11]([CH2:16][CH2:17][CH2:18][N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[C:10]=2[CH2:9][CH2:8]1.CN(C)[CH:27]=[O:28]>>[CH2:20]([N:19]([CH2:22][CH3:23])[CH2:18][CH2:17][CH2:16][C:11]1[C:10]2[CH2:9][CH2:8][C:7]([CH3:6])([CH3:24])[CH2:15][C:14]=2[NH:13][C:12]=1[CH:27]=[O:28])[CH3:21]
Reactant: CCN(CC)CCCc1c[nH]c2c1CCC(C)(C)C2
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCN(CC)CCCc1c(C=O)[nH]c2c1CCC(C)(C)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Phosphorus oxychloride (0.35 mL, 3.74 mmol) was added dropwise to cooled dimethylformamide (0.8 mL, 10.3 mmol). After stirring at room temperature for 30 minutes, the mixture was cooled to −5° C. and a solution of [3-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-propyl]-diethyl-amine (0.9 g, 3.4 mmol) in dimethylformamide (2 mL) was added dropwise. The mixture was stirred at room temperature for 3 hours. The reaction was quenched with ice, followed by 10 N potassium to adjust the pH to 10–11. After stirring at room temperature for 1 hour, the reaction was extracted with ethyl acetate and the extract was washed with brine, dried and concentrated to give 0.55 g of 3-(3-diethylamino-propyl)-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde. 1H-NMR (360 MHz, dimethylsulfoxide-d6) δ 11.23 (br, s, 1H, NH), 9.41 (s, 1H, CHO), 2.61 (t, 2H, CH2), 2.30–2.43 (m, 10 H, 5×CH2), 1.58 (m, 2H, CH2), 1.45 (t, 2H, CH2), 0.93 (s, 6H, 2×CH3), 0.89 (t, 6H, CH3). MS m/z 290 [M+].