Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH3:11][C:12]1[CH:16]=[C:15]([CH3:17])[NH:14][C:13]=1[CH:18]=O>N1CCCCC1.C(O)C>[CH3:18][C:13]1[NH:14][C:15]([CH:17]=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:10])=[CH:16][C:12]=1[CH3:11]
Reactant: Cc1cc(C)c(C=O)[nH]1
Reactant: O=C1Cc2ccccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C=C2C(=O)Nc3ccccc32)[nH]c1C
Temperature: 90 °C
Reaction time: 3 h
Yield: 57 %

Procedure:
A reaction mixture of 134.0 mg of oxindole, 147.8 mg of the 3,5-dimethylpyrrole-2-carboxaldehyde, and 3 drops of piperidine in 2 mL of ethanol was stirred at 90° C. for 3 h. After cooling, the precipitate was filtered, washed with cold ethanol, and dried to yield 136.7 mg (57%) of the title compound as a yellow solid.
Reaction SMILES: [C:1]([O-])(=O)C.[Na+].P(Cl)(Cl)(Cl)=O.[C:11]([O:14][C@@:15]1([C:35]#[CH:36])[CH2:20][CH2:19][C@H:18]2[C@H:21]3[C@H:31]([CH2:32][CH2:33][C@:16]12[CH3:17])[C@:29]1([CH3:30])[C:24](=[CH:25][C:26](=[O:34])[CH2:27][CH2:28]1)[CH2:23][CH2:22]3)(=[O:13])[CH3:12]>C(Cl)(Cl)Cl.COCOC>[C:11]([O:14][C@@:15]1([C:35]#[CH:36])[CH2:20][CH2:19][C@H:18]2[C@H:21]3[C@H:31]([CH2:32][CH2:33][C@:16]12[CH3:17])[C@:29]1([CH3:30])[C:24](=[CH:25][C:26](=[O:34])[CH2:27][CH2:28]1)[C:23](=[CH2:1])[CH2:22]3)(=[O:13])[CH3:12]
Reactant: C#C[C@]1(OC(C)=O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: COCOC
Solvent: ClC(Cl)Cl
Product: C#C[C@]1(OC(C)=O)CC[C@H]2[C@@H]3CC(=C)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Yield: 60.9 %

Procedure:
A suspension of 1.0 g of sodium acetate in 30 ml of chloroform and 30 ml of methylal is combined with 1.9 ml of phosphorus oxychloride and refluxed for 1 hour. The reaction mixture is combined with 1.0 g of 17β-acetoxy-17α-ethynyl-4-androsten-3-one and, under reflux, 1.9 ml of phosphorus oxychloride is added dropwise within 2 hours. The mixture is refluxed for 1 hour, cooled, and rendered alkaline by the dropwise addition of saturated soda solution. The organic phase is separated and concentrated under vacuum. For working-up purposes, the crude product is mixed with a small amount of methylene chloride and water, as well as 5 g of soda. After steam distillation, the product is vacuum-filtered, the residue washed neutral with water, and purified on 105 g of silica gel with a hexane/ethyl acetate gradient (0-50% ethyl acetate). In this way, 630 mg of 17β-acetoxy-17α-ethynyl-6-methylene-4-androsten-3-one is isolated, mp 158°-160° C.
Reaction SMILES: [CH2:1]([N:3](C(OC(C)(C)C)=O)[CH2:4][CH2:5][CH2:6][N:7](C(OC(C)(C)C)=O)[CH2:8]/[CH:9]=[CH:10]/[CH2:11][N:12](C(OC(C)(C)C)=O)[CH2:13][CH2:14][CH2:15][N:16](C)[C:17](OC(C)(C)C)=O)[CH3:2].[ClH:46]>C(OCC)C>[ClH:46].[ClH:46].[ClH:46].[ClH:46].[CH2:1]([NH:3][CH2:4][CH2:5][CH2:6][NH:7][CH2:8]/[CH:9]=[CH:10]/[CH2:11][NH:12][CH2:13][CH2:14][CH2:15][NH:16][CH3:17])[CH3:2]
Reactant: CCN(CCCN(C/C=C/CN(CCCN(C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Product: CCNCCCNC/C=C/CNCCCNC
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 0.32 g (0.498 mmol) of (E)-1-ethyl-14-methyl-1,5,10,14-tetra-BOC-1,5,10,14-tetraazatetradec-7-ene and 6 ml of 3N methanolic hydrochloric acid is stirred for 15 h at room temperature, and then 10 ml of diethyl ether are added. Working up analogously to Example 1 yields the title compound, m.p. >260° C. 1H-NMR (D2O): δ1.28(t,3H); 2.03-2.17(m,4H); 2.74(s,3H); 3.07-3.19(m,10H); 3.77(d,4H); 6.04-6.07(m,2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][C:14]2[CH:15]=[C:16]([Cl:20])[CH:17]=[N:18][CH:19]=2)=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Br:21][C:22]1[CH:23]=[CH:24][C:25]([O:32][CH3:33])=[C:26]([S:28](Cl)(=[O:30])=[O:29])[CH:27]=1>ClCCl>[CH3:33][O:32][C:25]1[CH:24]=[CH:23][C:22]([Br:21])=[CH:27][C:26]=1[S:28]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][C:14]2[CH:15]=[C:16]([Cl:20])[CH:17]=[N:18][CH:19]=2)=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:30])=[O:29]
Reactant: COc1ccc(Br)cc1S(=O)(=O)Cl
Reactant: CCOC(=O)c1cc(N)ccc1Oc1cncc(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)c1cc(NS(=O)(=O)c2cc(Br)ccc2OC)ccc1Oc1cncc(Cl)c1

Procedure:
Alternatively, poly(4-vinylpyridine) (250 mg, 60 mesh) can be washed with dichloromethane (2×7 mL) and diluted into dichloromethane (2 mL). The aniline produced in Example 1 (29.2 mg, 0.1 mmol) can be added followed by 5-bromo-2-methoxybenzenesulfonyl chloride (59 mg, 0.25 mmol). The reaction vessel is then agitated for ten hours and ArgoPore-NH2 (0.50 g, 1.11 mmol/gram loading) is added along with dichloromethane (6 mL). The reaction vessel is agitated for three hours and the solvent is collected. The resin is washed with dichloromethane (2×6 mL) and the dichloromethane is combined and evaporated to yield the title compound.
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:21]=[CH:20][C:19]2[C:18]3[C:13](=[CH:14][C:15]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:16][CH:17]=3)[CH2:12][C:11]=2[CH:10]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1C[O:33][CH2:32]C1>C(OCC)=O>[CH:32]([CH:12]1[C:11]2[CH:10]=[C:9]([NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH:21]=[CH:20][C:19]=2[C:18]2[C:13]1=[CH:14][C:15]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:16][CH:17]=2)=[O:33]
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)Cc1cc(NC(=O)OC(C)(C)C)ccc1-2
Reactant: C1CCOC1
Solvent: CCOC=O
Product: CC(C)(C)OC(=O)Nc1ccc2c(c1)C(C=O)c1cc(NC(=O)OC(C)(C)C)ccc1-2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Purified 2,7-di(Boc-amino)fluorene (5 g, 12.5 mmol) (prepared from step A, above), was dissolved in ethyl formate (50 mL) and anhydrous THF (60 mL) with gentle heating. (Note: ethyl formate was stored over K2CO3 to remove formic acid.) The solution was cooled in an ice bath and sodium hydride 60% in mineral oil was added portion-wise (5.5 eq, 69 mmol, 2.75 g). The reaction was slowly warmed to room temperature and then heated to 50° C. after fitting with a reflux condenser. After two hours, the reaction was cooled in an ice bath and quenched by the slow addition of deionized water (50 mL). The aqueous layer was adjusted to pH 5 with glacial acetic acid and extracted with ethyl acetate (2×400 mL). The combined organic layers were dried with Na2SO4, filtered and evaporated under reduced pressure. The crude product (dark brown solid) was purified by flash chromatography: silica gel 60 Å step-wise gradient elution 1-5% methanol in chloroform. Yield (4.8 g, ˜90%) of a yellow to brown solid, depending on purity. 1H-NMR (d6-DMSO): δ (ppm) 11.0 (s, 0.9H, enol); 9.3 (2 s, 1.9H, NH urethane); 7.2-8.3 (m, Ar, C10 H enol); 6.5 (2 s, 0.1H, NH urethane); 4.1 (m, 0.3H, CH); 1.5 (s, 18H, Boc).
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[N:6]([C:14]([CH3:19])([CH3:18])[C:15]([O-:17])=O)=[N:7][C:8]([CH3:13])([CH3:12])[C:9]([O-:11])=O.C[O-].[Na+].O>CO>[N:7]([C:8]([CH3:12])([CH3:13])[C:9]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:11])=[N:6][C:14]([CH3:19])([CH3:18])[C:15]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:17]
Reactant: CC(C)(N=NC(C)(C)C(=O)[O-])C(=O)[O-]
Reactant: CCCCN
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCNC(=O)C(C)(C)N=NC(C)(C)C(=O)NCCCC
Temperature: 10 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
34.9 Grams of n-butylamine is mixed with 50 g of 2,2'-azobis (2-methyl propionate), and 10 g of 28% sodium methoxide solution in methanol is dropwise added thereto with stirring, followed by conducting a reaction at room temperature with stirring for 6 hours and keeping standing overnight. 100 Milliliter of water is added to the reaction solution and cooled to 10° C. to precipitate crystals. The crystals are recovered by filtration and dried to give 58.0 g (yield 85.5%) of 2,2'-azobis [N-butyl-2-methyl propionamide] as pale yellow crystal. The solubility is shown in Table 1.
Reaction SMILES: [Cl:1][CH:2]=[CH:3][NH:4][C:5](=[O:14])[C:6]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:7]=1[F:13].S(=O)(=O)(O)O.[CH3:20][N:21]([CH3:37])[C:22](=[O:36])[S:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:26][CH:25]=1.O>ClCCl>[CH3:20][N:21]([CH3:37])[C:22](=[O:36])[S:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:31]=[CH:32][C:33]([CH:3]([NH:4][C:5](=[O:14])[C:6]3[C:7]([F:13])=[CH:8][CH:9]=[CH:10][C:11]=3[F:12])[CH2:2][Cl:1])=[CH:34][CH:35]=2)=[CH:26][CH:25]=1
Reactant: CN(C)C(=O)Sc1ccc(-c2ccccc2)cc1
Reactant: O=C(NC=CCl)c1c(F)cccc1F
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Product: CN(C)C(=O)Sc1ccc(-c2ccc(C(CCl)NC(=O)c3c(F)cccc3F)cc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 82.3 %

Procedure:
A solution of 1 g (4.59 mmol) N-(chloroethenyl)-2,6-difluorobenzamide in 2 mL of dichloromethane was added to 4 mL of concentrated sulfuric acid at 0° C. A portion of 1 g (3.89 mmol) of S-[1,1'-biphenyl]-4-yl dimethylcarbamothioate was added to the mixture and the mixture was stirred at 0° C. for 2 h. The mixture was stored in the refrigerator overnight. The mixture was poured into water (100 mL) and the mixture was filtered. The solid was washed with water (100 mL) and was dried overnight in vacuo at 70° C. to give the crude product 1.52 g (84% yield) as solid.
Reaction SMILES: C(OC(COC1C=CC(F)=CC=1)CCCNS(C)(=O)=O)(=O)C.C(OC(COC1C=CC(F)=CC=1)/C=C/CNS(C)(=O)=O)(=O)C.C([O:48][CH:49]([CH2:68][O:69][C:70]1[CH:75]=[CH:74][C:73]([F:76])=[CH:72][CH:71]=1)/[CH:50]=[CH:51]/[CH2:52][N:53]([CH2:58][C:59]#[C:60][CH2:61][CH2:62][CH2:63][C:64]([O:66]C)=[O:65])[S:54]([CH3:57])(=[O:56])=[O:55])(=O)C>>[OH:48][CH:49]([CH2:68][O:69][C:70]1[CH:71]=[CH:72][C:73]([F:76])=[CH:74][CH:75]=1)/[CH:50]=[CH:51]/[CH2:52][N:53]([CH2:58][C:59]#[C:60][CH2:61][CH2:62][CH2:63][C:64]([OH:66])=[O:65])[S:54]([CH3:57])(=[O:56])=[O:55]
Reactant: COC(=O)CCCC#CCN(C/C=C/C(COc1ccc(F)cc1)OC(C)=O)S(C)(=O)=O
Agent: CC(=O)OC(/C=C/CNS(C)(=O)=O)COc1ccc(F)cc1
Agent: CC(=O)OC(CCCNS(C)(=O)=O)COc1ccc(F)cc1
Product: CS(=O)(=O)N(CC#CCCCC(=O)O)C/C=C/C(O)COc1ccc(F)cc1

Procedure:
This compound is prepared by the procedure described in Example 2, Step I, except that the N-[4 -acetoxy-5-(4-fluorophenoxy)pentyl]methanesulfonamide is replaced by an equimolar amount of N-[4-acetoxy-5-(4 -fluorophenoxy)trans-2-pentenyl]methanesulfonamide (Example 6, Step G). This product is thus methyl 7-{N-[4-acetoxy-5-(4-fluorophenoxy)trans-2-pentenyl] -methanesulfonamido}hept-5-ynoate. The subsequent hydrolysis is carried out as described in Example 2, Step J and affords 7-{N-[4-hydroxy-5-(4-fluorophenoxy)trans-2 -pentenyl]methanesulfonamido}hept-5-ynoic acid. The hydrogenation is carried out by the procedure described in Example 3 and affords the subject compound.
Reaction SMILES: Cl[C:2]1[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:19]1([CH2:25][CH2:26][CH2:27][CH2:28][NH2:29])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC#N>[CH:15]([N:4]1[C:3](=[O:18])[C:2]([NH:29][CH2:28][CH2:27][CH2:26][CH2:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:5]1(=[O:14])=[O:13])([CH3:17])[CH3:16]
Reactant: CC(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: NCCCCc1ccccc1
Solvent: CC#N
Product: CC(C)N1C(=O)C(NCCCCc2ccccc2)=C(c2ccccc2)S1(=O)=O
Yield: 83.8 %

Procedure:
A solution of 4-chloro-2-isopropyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.150 g, 0.521 mmol), TEA (0.079 g, 0.782 mmol) and 4-phenylbutylamine (0.117 g, 0.782 mmol) in MeCN (3 mL) was heated in a microwave reactor at 120° C. for 5 mins. The reaction mixture was evaporated and the residue was purified by silica gel column chromatography (Horizons Biotage) using a 75:25 mixture of heptane and EtOAc as eluant, to give the title compound (0.174 g, 84%); 1H NMR (500 MHz, CDCl3): δ 7.52-7.48 (m, 2H), 7.45-7.41 (m, 3H), 7.30-7.26 (m, 2H), 7.22-7.17 (m, 1H), 7.10-7.06 (m, 2H), 5.28-5.23 (m, 1H), 4.45-4.38 (m, 1H), 2.89-2.84 (m, 2H), 2.49-2.44 (m, 2H), 1.59 (d, 6H), 1.43-1.38 (m, 4H); 13C NMR (125 MHz, CDCl3): δ 158.8, 141.8, 135.6, 131.8, 129.8, 128.8, 128.6, 128.5, 126.2, 125.3, 106.8, 47.7, 44.2, 35.4, 29.2, 28.3, 20.4; Mass Spectrum: M−H+ 399.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH2:47])=[CH:45][C:44]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1.Cl[C:55]1[C:64]2[C:59](=[CH:60][CH:61]=[C:62]([Cl:66])[C:63]=2[F:65])[N:58]=[C:57]([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][N:68]=2)[C:56]=1[CH3:73].C1(C)C=CC=CC=1.CC(C)([O-])C.[Na+]>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:66][C:62]1[C:63]([F:65])=[C:64]2[C:59](=[CH:60][CH:61]=1)[N:58]=[C:57]([C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][N:68]=1)[C:56]([CH3:73])=[C:55]2[NH:47][C:46]1[C:41]([N:38]2[CH2:39][CH2:40][O:35][CH2:36][CH2:37]2)=[N:42][CH:43]=[C:44]([N:48]2[CH2:49][CH2:50][O:51][CH2:52][CH2:53]2)[CH:45]=1
Reactant: Cc1c(-c2ccccn2)nc2ccc(Cl)c(F)c2c1Cl
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1c(-c2ccccn2)nc2ccc(Cl)c(F)c2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Temperature: 120 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.018 g, 0.038 mmol), 2,5-dimorpholinopyridin-3-amine (0.074 g, 0.281 mmol), 4,6-dichloro-5-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (0.072 g, 0.234 mmol) and Pd2dba3 (8.59 mg, 9.38 μmol) in toluene (2.3 mL, 0.23 mmol) was added sodium t-butoxide (0.056 g, 0.59 mmol). The reaction mixture was heated to 120° C. and stirred for 45 min. The reaction was cooled to rt and diluted with water (25 mL). The mixture was extracted with EtOAc (2×10 mL) and DCM (1×10 mL). The organic layers were combined and dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (0 to 100% EtOAc/DCM) to give the desired product 6-chloro-N-(2,5-di-4-morpholinyl-3-pyridinyl)-5-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinamine. 1H NMR (400 MHz, CDCl3) δ ppm 8.70 (1H, dd, J=4.7, 1.2 Hz), 7.90 (3H, m), 7.57-7.73 (3H, m), 7.39 (1H, m), 6.41 (1H, s), 3.94 (4H, br. s.), 3.80 (4H, br m), 3.22 (4H, br. s.), 3.06 (4H, br m), 2.26 (3H, s). Mass Spectrum (ESI) m/e=535.3 (M+1).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:12](=[C:13](Cl)[CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][C:7]([CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([C:16]([NH:18][C@H:19]([CH2:23][OH:24])[CH:20]([CH3:22])[CH3:21])=[O:17])[CH2:6][C:5]2=1.ClC1C=C(Cl)C=CC=1NN>>[OH:24][CH2:23][C@@H:19]([NH:18][C:16]([C:7]1([CH2:25][CH2:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:6][C:5]2[C:4]3[C:12](=[CH:13][CH:14]=[CH:2][CH:3]=3)[NH:11][C:10]=2[CH2:9][CH2:8]1)=[O:17])[CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)[C@@H](CO)NC(=O)C1(CCCc2ccccc2)CCc2[nH]c3c(Cl)cc(Cl)cc3c2C1
Agent: NNc1ccc(Cl)cc1Cl
Product: CC(C)[C@@H](CO)NC(=O)C1(CCCc2ccccc2)CCc2[nH]c3ccccc3c2C1

Procedure:
25 mg of 6,8-dichloro-2,3,4,9-tetrahydro-N-[(1S)-1-(hydroxymethyl)-2-methylpropyl]-3-(3-phenylpropyl)-1H-carbazole-3-carboxamide 278 is produced analogously with use of 2,4-dichlorophenylhydrazine.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].CO[C:12](=[NH:20])[CH:13]([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]>>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:12](=[NH:20])[CH:13]([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]
Reactant: CCOC(OCC)C(=N)OC
Reactant: NCc1ccccc1Br
Product: CCOC(OCC)C(=N)NCc1ccccc1Br

Procedure:
Starting from 2-bromobenzylamine (20.00 g; commercial) and 2,2-diethoxy-ethanimidic acid methyl ester (24.46 g; 85% pure) and proceeding in analogy to Procedure A, the title compound was obtained as a yellow oil (39.31 g).
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3]1[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[C:4]=1[NH:5][C:6]2=O.P(Cl)(Cl)([Cl:22])=O>CN(C)C=O>[Cl:22][C:6]1[C:7]2[C:2](=[CH:1][CH:10]=[CH:9][CH:8]=2)[C:3]2[C:18]3[C:13]([C:12](=[O:19])[C:4]=2[N:5]=1)=[CH:14][CH:15]=[CH:16][CH:17]=3
Reactant: O=C1c2ccccc2-c2c1[nH]c(=O)c1ccccc21
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: O=C1c2ccccc2-c2c1nc(Cl)c1ccccc21
Yield: 78.7 %

Procedure:
A mixture of 6H-indeno[2,1-c]isoquinoline-5,7-dion obtained in reference example 16 (26.6 g, 108 mmol) and phosphorous oxychloride (300 ml) was refluxed with heat in the presence of 1 ml of N,N-dimethylformamide for 2 hours. The reaction mixture was distilled to dryness. To the residue was added ice water to obtain a crystal precipitated by filtration. The crystal obtained was washed with water and recrystallized from toluene to give 22.5 g (yield 78.7%) of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][C@H:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])=[CH:5][C:4]=1[F:20])#[CH:2].C(NC(C)C)(C)C.I[C:29]1[N:37]=[CH:36][N:35]=[C:34]2[C:30]=1[NH:31][CH:32]=[N:33]2>CN(C=O)C.[Cu](I)I.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>[F:20][C:4]1[CH:5]=[C:6]([N:9]2[CH2:13][CH:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])[CH:7]=[CH:8][C:3]=1[C:1]#[C:2][C:29]1[N:37]=[CH:36][N:35]=[C:34]2[C:30]=1[NH:31][CH:32]=[N:33]2
Reactant: Ic1ncnc2nc[nH]c12
Reactant: C#Cc1ccc(N2C[C@H](CNC(C)=O)OC2=O)cc1F
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CC(=O)NCC1CN(c2ccc(C#Cc3ncnc4nc[nH]c34)c(F)c2)C(=O)O1
Temperature: 60 °C

Procedure:
To a suspension of Example 3B (100 mg) and diisopropylamine (0.25 mL) in degassed DMF (1 mL) was added sequentially 6-iodopurine (89 mg), copper iodide (3.5 mg) and tetrakis(triphenylphosphine)palladium (21 mg). The mixture was heated to 60° C. for 4 hours. Next, the reaction mixture was cooled to room temperature and concentrated. The resultant material was dissolved in dichloromethane (4 mL), then filtered. The precipitate was washed with water (10 mL), then cold acetone (3 mL) to provide the desired solid. MS (ESI(+)) m/e 395 (M+H)+; 1H NMR (300 MHz, DMSO) δ 8.91 (s, 1H), 8.69 (s, 1H), 8.25 (t, J=5.7 Hz, 1H), 7.89 (m, 1H), 7.82 (t, J=9 Hz, 1H), 7.7 (dd, J=2.1, 12.3 Hz, 1H), 7.5 (dd, J=2.1, 9 Hz, 1H), 4.78 (m, 1H), 4.19 (t, J=9 Hz, 1H), 3.8 (dd, J=6.3, 9.6 Hz, 1H), 3.44 (t, J=5.7 Hz, 2H), 1.84 (s, 3H).
Reaction SMILES: [C:1]([OH:16])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].S(Cl)(Cl)=O.CN(C)C=O.[CH2:26](O)[C:27]#[CH:28].N1C=CC=CC=1>O.CCOCC>[C:1]([O:16][CH2:28][C:27]#[CH:26])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCC(=O)O
Reactant: C#CCO
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C#CCOC(=O)CCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3.00 g. (13.5 mmoles) of tetradecanoic acid in 40 ml. of dry ether at 0° is added 1.42 ml. (19.74 mmoles) of thionyl chloride and 0.2 ml (2.63 mmoles) of dimethylformamide. The solution is allowed to warm to room temperature and then is stirred for 21/2 hours. The solvent is removed from the top layer of the now biphasic mixture by evaporation and the residue is taken up in 30 ml. of ether. To this solution at 0° under nitrogen is added 1.15 ml. (19.75 mmoles) of propargyl alcohol and 2.1 ml. (2.0 mmoles) of pyridine. The reaction mixture is allowed to warm to room temperature and stirred for one day, ether and water are then added, the organic phase separated, the aqueous phase extracted with ether, and the combined organic phases washed with 3N sulfuric acid, 10% aqueous sodium carbonate, water, saturated aqueous copper sulfate, water and brine. The reaction mixture is dried over calcium sulfate and concentrated to yield propargyl tetradecanoate, boiling at 125° at 0.25 mm.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[C:25]3[C:20](=[C:21]([F:29])[C:22]([F:28])=[C:23]([F:27])[C:24]=3[F:26])[NH:19][CH:18]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>[Pd].C(O)C.O1CCCC1>[F:26][C:24]1[C:23]([F:27])=[C:22]([F:28])[C:21]([F:29])=[C:20]2[C:25]=1[C:17]([CH:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1)=[CH:18][NH:19]2
Reactant: O=C(OCc1ccccc1)N1CCC(c2c[nH]c3c(F)c(F)c(F)c(F)c23)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Fc1c(F)c(F)c2c(C3CCNCC3)c[nH]c2c1F
Reaction time: 3 h
Yield: 90 %

Procedure:
To a solution of N-benzyloxycarbonyl-4-(4,5,6,7-tetrafluoroindol-3-yl)piperidine (20.0 g, 49.21 mmol) [prepared as described in Step 1 above] in argon deoxygenated 80% ethanol/tetrahydrofuran (800 ml) was added 10% Pd-C (5 g), and the resulting mixture was stirred under a hydrogen atmosphere (1 atm) for 3 h. The mixture was degassed under argon, filtered through Celite, and concentrated in vacuo. The solid residue was recrystallized from methylene chloride/hexane to afford 4-(4,5,6,7-tetrafluoroindol-3-yl)piperidine (90%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([C:25]([O:27][CH3:28])=[O:26])=[C:9]([CH3:24])[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)=[N:11]2)=[CH:6][C:5]=1[S:29]([CH:32]([CH3:34])[CH3:33])(=[O:31])=[O:30])[CH3:2].[Br:35]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:35][CH2:24][C:9]1[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=2)=[N:11][C:12]2[C:7]([C:8]=1[C:25]([O:27][CH3:28])=[O:26])=[CH:6][C:5]([S:29]([CH:32]([CH3:33])[CH3:34])(=[O:31])=[O:30])=[C:4]([O:3][CH2:1][CH3:2])[CH:13]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOc1cc2nc(-c3cccc(C(F)(F)F)c3)c(C)c(C(=O)OC)c2cc1S(=O)(=O)C(C)C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOc1cc2nc(-c3cccc(C(F)(F)F)c3)c(CBr)c(C(=O)OC)c2cc1S(=O)(=O)C(C)C
Temperature: 100 °C

Procedure:
A suspension of methyl 7-(ethyloxy)-3-methyl-6-[(1-methylethyl)sulfonyl]-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (9.5 g, 19.17 mmol), N-bromosuccinimide (4.09 g, 23.01 mmol), and benzoyl peroxide (0.464 g, 1.917 mmol) in carbon tetrachloride (100 mL) was heated to reflux (100° C.) overnight. The reaction mixture was concentrated in vacuo to give methyl 3-(bromomethyl)-7-(ethyloxy)-6-[(1-methylethyl)sulfonyl]-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate. This material was used without further purification. MS (m/z) 576.0 (M+H+).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].[I-].[Na+].[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[C:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29]Cl)[CH2:24][CH2:23]2)=[CH:17][CH:16]=1>O1CCCC1>[C:3]([CH:2]([CH2:29][CH2:28][N:25]1[CH2:24][CH2:23][C:22](=[C:21]([C:18]2[CH:17]=[CH:16][C:15]([F:14])=[CH:20][CH:19]=2)[C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)[C:1]([O:7][CH2:8][CH3:9])=[O:6])(=[O:4])[CH3:5]
Reactant: Fc1ccc(C(=C2CCN(CCCl)CC2)c2ccc(F)cc2)cc1
Reactant: CCOC(=O)CC(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CCN1CCC(=C(c2ccc(F)cc2)c2ccc(F)cc2)CC1)C(C)=O
Temperature: 20 °C

Procedure:
0.182 mol of ethyl acetoacetate is added at 0° C. to a suspension containing 0.182 mol of sodium hydride in 800 ml c.f tetrahydrofuran. The reaction medium is maintained for one hour at 20° C. and 0.182 mol of sodium iodide is then added. The mixture is cooled to 0° C. and 0.182 mol of 4-[bis(4-fluorophenyl)methylene]-1-(chloroethyl)piperidine is added. The mixture is brought to reflux for 12 hours and then concentrated under vacuum. The residue is taken up in water and the product is extracted with dichloromethane. The oil obtained is purified by chromatography on a column of 70-230 mesh silica, eluting with a mixture of dichloromethane and methanol (99:1 V/V).