Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[N:13]1[CH2:17][CH2:16][CH:15]([S:18][CH2:19][CH2:20][NH2:21])[CH2:14]1.C(N(CC)CC)C.ClC(OCC)=O.[O:35]=[C:36]1[CH2:41][S:40][C:39]2[CH:42]=[CH:43][C:44]([C:46](O)=[O:47])=[N:45][C:38]=2[NH:37]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[N:13]1[CH2:17][CH2:16][CH:15]([S:18][CH2:19][CH2:20][NH:21][C:46]([C:44]2[CH:43]=[CH:42][C:39]3[S:40][CH2:41][C:36](=[O:35])[NH:37][C:38]=3[N:45]=2)=[O:47])[CH2:14]1
Reactant: O=C1CSc2ccc(C(=O)O)nc2N1
Reactant: COc1ccc2nccc(N3CCC(SCCN)C3)c2n1
Agent: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2nccc(N3CCC(SCCNC(=O)c4ccc5c(n4)NC(=O)CS5)C3)c2n1
Reaction time: 1 h
Yield: 38.9 %

Procedure:
The hydrochloride salt of [2-({1-[6-(methyloxy)-1,5-naphthyridin-4-yl]-3-pyrrolidinyl}thio)ethyl]amine (from Example 7b) (300 mg, 0.88 mmol) was dissolved in DCM (5 mL) with triethylamine (0.31 mL, 2.2 mmol) and cooled in an ice bath. The cooled solution was treated with ethyl chloroformate (0.15 mL, 1.59 mmol) and triethyl amine (0.79 mL, 5.3 mmol) and stirred for 1 h. 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylic acid (222 mg, 1.06 mmol) was added. After stirring at 25° C. for 12 h, the reaction mixture was diluted with chloroform and poured into saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with chloroform, and the combined organic layers were washed with brine, dried over magnesium sulfate, concentrated and purified by column chromatography (silica, 0-10% MeOH in CDCl3 (1% NH4OH) to afford the title compound as a white solid (170 mg, 39%): LC/MS m/z 497 (M+H)+; 1H NMR (CDCl3, 400 MHz) δ 8.33 (d, J=4.4 Hz, 1H), 8.29 (br, 1H), 8.2 (d, J=9.0 Hz, 1H), 8.02-8.06 (m, 1H), 7.88 (d, J=7.8 Hz, 1H), 7.81 (d, J=7.8 Hz, 1H), 7.09 (d, J=9.0 Hz, 1H), 6.47 (d, J=4.4 Hz, 1H), 4.47-4.49 (m, 1H), 3.95-4.15 (m, 6H), 3.75-3.81 (m, 2H), 3.64-3.70 (m, 2H), 3.13-3.17 (m, 1H), 2.92-2.94 (m, 2H), 2.47-2.52 (m, 1H), 2.11-2.19 (m, 1H).
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[CH2:3][N:4]1[CH:9]=[CH:8][C:7]([C:10]([OH:12])=O)=[CH:6][C:5]1=[O:13].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.O[NH:49][C:50]([C:52]1[C:53]2[CH:54]=[CH:55][N:56]=[CH:57][C:58]=2[CH:59]=[CH:60][CH:61]=1)=[NH:51]>CN(C=O)C>[CH:57]1[C:58]2[C:53](=[C:52]([C:50]3[N:49]=[C:10]([C:7]4[CH:8]=[CH:9][N:4]([CH2:3][CH:2]([CH3:1])[CH3:14])[C:5](=[O:13])[CH:6]=4)[O:12][N:51]=3)[CH:61]=[CH:60][CH:59]=2)[CH:54]=[CH:55][N:56]=1
Reactant: N=C(NO)c1cccc2cnccc12
Reactant: CC(C)Cn1ccc(C(=O)O)cc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)Cn1ccc(-c2nc(-c3cccc4cnccc34)no2)cc1=O
Temperature: 120 °C
Yield: 5.4 %

Procedure:
1-(2-Methylpropyl)-2-oxo-1,2-dihydro-4-pyridinecarboxylic acid (D28; 57 mg, 0.294 mmol) was stirred in DMF (0.5 ml) with HATU (122 mg, 0.321 mmol) and DIPEA (0.14 ml, 0.802 mmol) at room temperature for 30 mins before adding a solution of N-hydroxy-5-isoquinolinecarboximidamide (D1, 50 mg, 0.267 mmol) in DMF (0.5 ml). The resulting mixture was heated to 120° C. for 40 mins in a Biotage Initiator microwave. The solvent was removed under vacuum, and the residue was purified by column chromatography on silica, eluting with 0-4% methanol in dichloromethane. The relevant fractions were combined and concentrated under vacuum to give the title compound as a pale yellow oil (5 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:29]([NH2:30])=[N:28][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1.[Br:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][CH:33]=1>CO.CC#N>[Br:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39]([NH:30][C:29]2[C:9]([C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[CH:10][C:11]3[CH:16]=[N:15][C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)=[N:13][C:12]=3[N:28]=2)=[O:40])=[CH:34][CH:33]=1
Reactant: O=C=Nc1ccc(Br)cc1
Reactant: CN1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(N)nc3n2)CC1
Solvent: CC#N
Solvent: CO
Product: CN1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(NC(=O)Nc4ccc(Br)cc4)nc3n2)CC1
Yield: 67.7 %

Procedure:
6-(2,6-Dichlorophenyl)-N2 -[3-(4-methyl-piperazin-1-yl)-propyl]-pyrido[2,3-d]pyrimidine-2,7-diamine (1.0 g) from Example 36 was reacted with 0.44 g of 4-bromophenyl isocyanate according to the general procedure of Example 37 to give 0.97 g of 1-(4-Bromo-phenyl)-3-{6-(2,6-dichlorophenyl)-2-[3-(4-methylpiperazin-1-yl)-propylamino]-pyrido[2,3-d]pyrimidin-7-yl}-urea, ESMS (20/80 MeOH/CH3CN+0.1% AcOH+DMSO): M+ +H=645; mp 171-175° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5](OS(C(F)(F)F)(=O)=O)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1.[CH3:21][NH:22][CH3:23]>O1CCCC1>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N:22]([CH3:23])[CH3:21])=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1
Reactant: COc1cc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])cc1Cl
Reactant: CNC
Solvent: C1CCOC1
Product: COc1cc(N(C)C)c([N+](=O)[O-])cc1Cl
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of trifluoro-methanesulfonic acid 4-chloro-5-methoxy-2-nitro-phenyl ester (1.0 g) in tetrahydrofuran (2.0 mL) is added dimethylamine (4.0 mL of a 40% aqueous solution) and the mixture is stirred at room temperature for approximately 15 hours. The solution is then concentrated under reduced pressure and the residue is dissolved in ethyl acetate and then washed with water. The aqueous layer is extracted once with ethyl acetate and the combined organic layers are washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent is removed by evaporation under reduced pressure and the residue is triturated with hexanes to provide the desired product as a colorless solid.
Reaction SMILES: I.CS[C:4](=[N:18][CH3:19])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>C(O)C>[CH3:19][NH:18][C:4]([N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)=[N:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: CN=C(Nc1ccccc1N1CCOCC1)SC
Reactant: C1CCNC1
Agent: I
Solvent: CCO
Product: CNC(=Nc1ccccc1N1CCOCC1)N1CCCC1

Procedure:
A mixture of 2-methyl-1-(2-morpholinophenyl)-3-methyl-2-thiopseudourea hydroiodide (3.9 g prepared as described in Example 210), pyrrolidine (1 ml) and ethanol (40 ml) was heated under reflux for two weeks to yield an oil which was purified by chromatography on a neutra alumina column eluted with a 1:1 mixture of dichloromethane and hexane and then a 1:9 mixture of methanol and dichloromethane to give N-methyl-N'-(2-morpholinophenyl)pyrrolidine-1-carboxamidine which was converted into its monofumarate salt (m.p. 168°-171° C.) which was recrystallised from propan-2-ol.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:18]O)[CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[Br-:32].[Li+]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:18][Br:32])[CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(CO)cc1OCc1ccccc1
Reactant: [Br-]
Agent: CS(=O)(=O)Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(CBr)cc1OCc1ccccc1
Temperature: -20 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of (3-benzyloxy-4-nitrophenyl)-methanol (11.0 g, 0.042 mol) in anhydrous THF is added triethylamine (8.7 g, 0.86 mol). The mixture is cooled to −20° C., followed by the addition of methanesulfonyl chloride (5.8 g, 0.051 mol) and then stirred at −20° C. for 45 min. To this mixture is added lithium bromide (37.3 g, 0.43 mol) in anhydrous THF (40 mL) over 40 min. followed by stirring at ambient temperature for 2 h. The suspension is concentrated under reduced pressure and diluted with EtOAc and water. The organic phase is washed with brine, dried over MgSO4, filtered and concentrated to afford 2-benzyloxy-4-bromomethyl-1-nitrobenzene as a yellow solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([O:26][CH3:27])=[CH:5][C:6]([Cl:25])=[C:7]([C:9]2[NH:10][C:11](=[O:24])[N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[N:13]=2)[CH:8]=1.[C:28](Cl)(=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30]>C1COCC1>[Cl:25][C:6]1[C:7]([C:9]2[NH:10][C:11](=[O:24])[N:12]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=3)[N:13]=2)=[CH:8][C:3]([CH2:2][NH:1][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[C:4]([O:26][CH3:27])[CH:5]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: COc1cc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)cc1CN
Solvent: C1CCOC1
Product: COc1cc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)cc1CNC(=O)C(C)(C)C

Procedure:
The title compound was prepared according to the procedure described in Example-108 by using 5-(5-(aminomethyl)-2-chloro-4-methoxyphenyl)-2-(4-(trifluoromethyl)phenyl)-2H-1,2,4-triazol-3(4H)-one (Intermediate-79, 0.200 g), pivaloyl chloride (0.2 mL), TEA (2.0 mL), dry THF (5 mL) to afford 0.015 g of the desired product. 1H NMR (300 MHz, CDCl3): δ 1.15 (s, 9H), 3.91 (s, 3H), 4.22 (m, 2H), 7.26 (s, 1H), 7.42 (s, 1H), 7.87 (m, 2H), 7.99 (m, 1H), 8.15 (m, 2H), 12.57 (s, 1H); MS (m/z): 483.38 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:12]([CH3:17])=[C:13]([CH2:15][OH:16])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.[H-].[Na+].[C:25]1(=[O:32])[O:31][C:29](=[O:30])[CH2:28][CH2:27][CH2:26]1>O1CCCC1>[CH3:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:12]([CH3:17])=[C:13]([CH2:15][O:16][C:25](=[O:32])[CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1cccc(C)c1CNc1cccn2c(C)c(CO)nc12
Reactant: O=C1CCCC(=O)O1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cccc(C)c1CNc1cccn2c(C)c(COC(=O)CCCC(=O)O)nc12
Reaction time: 0.17 h
Yield: 8.3 %

Procedure:
To a solution of 8-(2,6-dimethylbenzylamino)-2-hydroxymethyl-3-methylimidazo[1,2-a]pyridine (0.3 g, 1.0 mmol) in tetrahydrofuran(10 ml) was added sodium hydride (50% in oil) (0.054 g, 1.1 mmol) and the mixture was stirred for 10 min. To the mixture was added glutaric anhydride (0.13 g, 1.1 mmol) and the reaction mixture was refluxed for 20 h. The solvent was evaporated under reduced pressure. The residue was partitioned between dichloromethane and water. The pH was adjusted to 4 with 2M HCl. The organic layer was separated, dried (Na2SO4) and evaporated under reduced pressure. Purification of the residue by column chromatography on silica gel using dichloromethane:methanol (94:6) as eluent gave 0.034 g (8%) of the title compound.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1.CS[C:9]1[N:10]=[N:11][CH:12]=[CH:13][N:14]=1.N1(C2N=NC=CN=2)CCNCC1>>[N:11]1[CH:12]=[CH:13][N:14]=[C:9]([N:1]2[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]2)[N:10]=1
Reactant: OC1CCNC1
Reactant: CSc1nccnn1
Agent: c1cnc(N2CCNCC2)nn1
Product: OC1CCN(c2nccnn2)C1

Procedure:
Intermediate 5d is synthesised from pyrrolidin-3-ol and the precursor 2a according to the procedure described for the synthesis of 5a. Intermediate 5d is isolated in oil form with a 92% yield.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O)=[O:2].Br[C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[C:15]([F:20])[CH:14]=1>C1COCC1.C([O-])([O-])=O.[Na+].[Na+].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:15]1[CH:14]=[C:13]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH2:1][OH:2])[CH:19]=[CH:18][C:16]=1[NH2:17]
Reactant: Nc1ccc(Br)cc1F
Reactant: O=Cc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1ccc(-c2ccccc2CO)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.4 %

Procedure:
Part A: 2-Fluoro-4-((2′-tert-butyldimethylsilyloxymethyl)phenyl)aniline: A solution of 2-formylphenylboronic acid (5 g, 33.3 mmol) and 4-bromo-2-fluoroaniline (4.2 g, 22.2 mmol) in THF (80 mL) and aqueous Na2CO3 solution (2M, 80 mL) was bubbled with nitrogen for 10 minutes. After Pd(PPh3)4 (1.54 g, 1.33 mmol) was added, the resulting mixture was refluxed under nitrogen for 4 hours. The THF layer was separated and filtered through a pad of silica gel. The silica gel was washed with THF. To the combined filtrates containing 2-fluoro-4-(2′-formylphenyl)aniline (65 mL) was portion by portion added NaBH4 (2.2 g, 29.1 mmoL). The resulting mixture was stirred at room temperature for 1 hour, quenched with 1N HCl (10 mL), and washed with 1N HCl (100 mL×3). The combined HCl layers were neutralized with 50% NaOH to pH 12 and extracted with EtOAc (100 mL×3). The EtOAc layers were dried over Na2SO4, concentrated, and purified by column chromatography with a graduate solvent (hexane to EtOAc) to give 2-fluoro-4-(2′-hydroxymethylphenyl)aniline (3.83 g, 97.6%). 1H NMR (CDCl3) δ7.53 (dd, J=6.6 Hz, J=2.2 Hz, 1H), 7.36-7.33 (m, 2H), 7.25 (dd, J=6.6 Hz, J=2.2 Hz, 1H), 7.06 (dd, J=12.1 Hz, J=1.8 Hz, 1H), 6.97 (dd, J=8.0 Hz, J=1.8 Hz, 1H), 6.82 (t, J=8.8 Hz, 1H), 4.63 (s, 2H), 3.79 (bs, 2H); 19F NMR (CDCl3): δ−135.66 (dd, J=12.21 Hz, J=9.2 Hz); CIMS(CI) m/z 218 (M+H, 100%).
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[N:15][CH:16]=2)[N:13]([CH3:17])[C:12](=[O:18])[C:11]([C:19](=[O:26])[CH2:20][CH2:21][C:22]([O:24]C)=[O:23])=[C:10]3[OH:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H].C(OCC)(=O)C>[Pd].C(O)C>[CH:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[N:15][CH:16]=2)[N:13]([CH3:17])[C:12](=[O:18])[C:11]([C:19](=[O:26])[CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[C:10]3[OH:27])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)CCC(=O)c1c(O)c2cc(C3CCCCC3)cnc2n(C)c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cn1c(=O)c(C(=O)CCC(=O)O)c(O)c2cc(C3CCCCC3)cnc21

Procedure:
Methyl 4-(6-cyclohexyl-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl)-4-oxobutanoate. The title compound is prepared by hydrogenation with palladium black in the presence of hydrogen gas in a suitable solvent such as ethyl acetate or ethanol.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.[F:14][C:15]([F:39])([F:38])[CH2:16][NH:17][C:18]([C:20]1([CH2:33][CH2:34][CH2:35][CH2:36]Br)[C:32]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:19]>>[F:14][C:15]([F:38])([F:39])[CH2:16][NH:17][C:18]([C:20]1([CH2:33][CH2:34][CH2:35][CH2:36][N:11]2[CH2:12][CH2:13][N:8]([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=3)[CH2:9][CH2:10]2)[C:32]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:19]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: Cc1cccc(N2CCNCC2)n1
Product: Cc1cccc(N2CCN(CCCCC3(C(=O)NCC(F)(F)F)c4ccccc4-c4ccccc43)CC2)n1

Procedure:
Prepared analogously to Example 2 b from 1-(6-methyl-pyridin-2-yl)-piperazine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.Cl[C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20]>>[CH2:22]([O:21][C:19]([NH:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1)=[O:20])[CH:23]=[CH2:24]
Reactant: C=CCOC(=O)Cl
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Product: C=CCOC(=O)Nc1ccc2[nH]c3c(c2c1)CC(N(C)C)CC3
Yield: 32.1 %

Procedure:
Beginning with 10.0 mg (0.0437 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 5.5 mg (0.0458 mMol) allyl chloroformate, 4.4 mg (33%) of the title compound were recovered.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]([NH:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19](C(OCC)=O)[CH2:18][CH:17]2[O:27][CH3:28])=[O:13])[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.[OH-].[K+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]([NH:14][CH2:15][C@H:16]2[CH2:21][CH2:20][NH:19][CH2:18][C@H:17]2[O:27][CH3:28])=[O:13])[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1
Reactant: CCOC(=O)N1CCC(CNC(=O)c2cc(Cl)cc3c2OCCO3)C(OC)C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CO[C@@H]1CNCC[C@@H]1CNC(=O)c1cc(Cl)cc2c1OCCO2
Yield: 51.8 %

Procedure:
A mixture of ethyl 4-[[[(7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)carbonyl]-amino]methyl]-3-methoxy-1-piperidinecarboxylate (0.051 mol) and potassium hydroxide (0.5 mol) in ethanol (200 ml) was stirred and refluxed for 30 hours and then cooled. The solvent was evaporated. The residue was dissolved in water and the solvent was evaporated again. The residue was partitioned between DCM and water. The organic layer was separated, dried, filtered, and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent : CH2Cl2/(CH3OH/NH3)93/7). The pure fractions were collected and the solvent was evaporated, yielding 9 g of (cis)-7-chloro-2,3-dihydro-N-[(3-methoxy-4-piperidinyl)methyl]-1,4-benzodioxin-5-carboxamide (interm. 3-i). Part of interm. (3-i) was dissolved in 2-propanol and converted into the ethanedioic acid salt (1:1). The precipitate was filtered off and dried, yielding 1.2 g of (cis)-7-chloro-2,3-dihydro-N-[(3-methoxy4-piperidinyl)methyl]-1,4-benzodioxin-5-carboxamide ethanedioate (1:1) (interm. 3-j, mp. 208° C.).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:5]([C:7](Cl)=[O:8])[N:6]=1.C(=S)=S.[Cl-].[Al+3].[Cl-].[Cl-]>C(OCC)(=O)C>[CH3:1][C:2]1[O:3][C:4]2[CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:7](=[O:8])[C:5]=2[N:6]=1
Reactant: Cc1nc(C(=O)Cl)c(CCc2ccccc2)o1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: S=C=S
Product: Cc1nc2c(o1)CCc1ccccc1C2=O

Procedure:
1.0 g. of 2-methyl-5-phenethyl-4-oxazolecarbonyl chloride (obtainable by Step D, above) in 15 ml. of carbon disulfide, 2.5 g. of anhydrous aluminum chloride added, and the mixture refluxed for 1 hour. The mixture is then cooled, poured on to ice, and extracted twice with 10 ml. portions of chloroform. The extracts are combined, dried over anhydrous sodium sulfate and evaporated (under vacuum) to obtain a solid residue, which is recyrstallized from ethyl acetate to obtain the title compound, m.p. 174°-176°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.CCN(CC)CC.[O:25](C(OC(C)(C)C)=O)[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=O>C1COCC1.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[C:26](=[O:25])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cccc(Nc2ccnc(Cl)c2)c1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(c1cccc([N+](=O)[O-])c1)c1ccnc(Cl)c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 96.4 %

Procedure:
To a stirring solution of 2-Chloro-N-(3-nitrophenyl)pyridine-4-amine (2.70 g, 10.82 mmol) in THF (45 mL) was added Et3N (6.32 mL, 45.3 mmol). The mixture was cooled to 0° C., and DMAP (0.0135 g, 0.110 mmol) and BOC2O (2.84 g, 12.99 mmol) were added. The mixture was warmed to rt and stirred for 18 h. The mixture was quenched with ice and diluted with water. Extracted with EtOAc (3×200 mL), washed with brine and water, dried (MgSO4), and concentrated. A dark oil was afforded, which was passed through a pad of silica gel, eluting with 1:1 EtOAc/hexanes. Concentrated and dried under high vacuum to afford tert-Butyl 2-chloropyridin-4-yl(3-nitrophenyl)carbamate (3.65 g, 96.5% yield).
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1>CN(C=O)C>[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][CH:4]([C:5](=[O:6])[CH3:7])[C:3]([O:9][CH2:10][CH3:11])=[O:8])=[CH:15][CH:14]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: Clc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccc(Cl)cc1)C(C)=O
Reaction time: 0.5 h
Yield: 63.8 %

Procedure:
To a suspension of NaH (1.6 g, 40 mmol) in DMF (60 mL) at 0° C. was added ethyl acetoacetate (5.7 g, 44 mmol). The mixture was stirred for 30 minutes and p-chlorobenzyl bromide (8.2 g, 40 mmol) was added. The reaction mixture was stirred at r.t. for 2 hours and then quenched with water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with 10% EtOAc in Hexanes to provide 6.5 g of the title compound as a colorless oil.
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[CH2:9]([O:11][C:12](=[O:38])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]2[C:29]3[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=3)[N:23]([C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)[C:22]=2[CH3:37])[CH:15]=1)[CH3:10].IC>C1COCC1>[CH2:9]([O:11][C:12](=[O:38])[CH:13]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]2[C:29]3[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=3)[N:23]([C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)[C:22]=2[CH3:37])[CH:15]=1)[CH3:1])[CH3:10]
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)Cc1cccc(Sc2c(C)n(-c3cccnc3)c3cc(Cl)ccc23)c1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C(C)c1cccc(Sc2c(C)n(-c3cccnc3)c3cc(Cl)ccc23)c1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A solution of lithium diisopropylamide (10.7 mmol) in THF (10 mL), freshly prepared at −78° C., was added to a solution of ([3-(6-Chloro-2-methyl-1-pyridin-3-yl-1H-indol-3-ylsulfanyl)-phenyl]-acetic acid ethyl ester (0.256 g, 0.586 mmol) in THF (5 mL) at −78° C. The reaction was stirred at −78° C. for 2 hours then iodomethane (0.044 mL, 0.71 mmol) was added and the reaction was allowed to warm to 0° C. After stirring at 0° C. for 30 minutes the reaction was submitted to standard aqueous workup then purified by silica gel chromatography (0-30% EtOAc in hexanes) to yield the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:25]2[CH:26]=[N:27][C:28](C(F)(F)F)=[CH:29][CH:30]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1N=NC(C#C)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.BrC1C=NC=C([C:66]([F:69])([F:68])[F:67])C=1>>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:25]2[CH:26]=[N:27][CH:28]=[C:29]([C:66]([F:69])([F:68])[F:67])[CH:30]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cn1
Reactant: FC(F)(F)c1cncc(Br)c1
Agent: C#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Product: FC(F)(F)c1cncc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)c1

Procedure:
Prepared as described for 3,4-bis(benzyloxy)-6-{[6-(trifluoromethyl)pyridin-3-yl]ethynyl}pyridazine (Intermediate 9) from 3,4-bis(benzyloxy)-6-ethynylpyridazine (Intermediate 5) and 3-bromo-5-trifluoromethylpyridine.