Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([CH2:26][CH3:27])=[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[C:10]([CH3:17])=[N:11]2.C[O:30][C:31](=[O:56])[CH2:32][O:33][C:34]1[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]2[C:35]=1[C:36]([CH3:55])=[C:37]([CH2:47][C:48]1[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][CH:49]=1)[C:38]([CH2:45][CH3:46])=[N:39]2.CO.[OH-].[Li+]>C(O)(=O)C.O>[Cl:16][C:13]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:28])=[O:2])=[C:7]2[C:12]=1[N:11]=[C:10]([CH3:17])[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)=[C:8]2[CH2:26][CH3:27].[Cl:44][C:41]1[CH:42]=[CH:43][C:34]([O:33][CH2:32][C:31]([OH:56])=[O:30])=[C:35]2[C:40]=1[N:39]=[C:38]([CH2:45][CH3:46])[C:37]([CH2:47][C:48]1[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][CH:49]=1)=[C:36]2[CH3:55]
Reactant: CCc1c(Cc2ccc(Cl)cc2)c(C)nc2c(Cl)ccc(OCC(=O)OC)c12
Reactant: CCc1nc2c(Cl)ccc(OCC(=O)OC)c2c(C)c1Cc1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CCc1c(Cc2ccc(Cl)cc2)c(C)nc2c(Cl)ccc(OCC(=O)O)c12
Product: CCc1nc2c(Cl)ccc(OCC(=O)O)c2c(C)c1Cc1ccc(Cl)cc1

Procedure:
A solution of [8-chloro-3-(4-chlorobenzyl)-4-ethyl-2-methylquinolin-5-yloxy]acetic acid methyl ester and [8-chloro-3-(4-chlorobenzyl)-2-ethyl-4-methylquinolin-5-yloxy]acetic acid methyl ester (0.26 g), methanol (15 mL), water (1.5 mL) and saturated aqueous lithium hydroxide solution (1.5 mL) was stirred at room temperature for 3 hours. The pH of the solution was adjusted to 4 by the addition of glacial acetic acid and the methanol removed under reduced pressure. The resulting precipitate was collected by filtration and purified by preparative reverse-phase HPLC using a gradient over 30 minutes of acetonitrile in water (40% to 98% of organic modifier) to afford [8-chloro-3-(4-chlorobenzyl)-4-ethyl-2-methylquinolin-5-yloxy]acetic acid as a yellow foam, 0.049 g and [8-chloro-3-(4-chlorobenzyl)-2-ethyl-4-methylquinolin-5-yloxy]acetic acid as a yellow foam, 0.10 g.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:16]=1[S:23]([O:26][NH2:27])(=[O:25])=[O:24]>C(Cl)Cl>[CH3:22][C:17]1[CH:18]=[C:19]([CH3:21])[CH:20]=[C:15]([CH3:14])[C:16]=1[S:23]([O-:26])(=[O:25])=[O:24].[CH2:1]([C:8]1[CH:13]=[CH:12][N:11]([NH3+:27])[CH2:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Cc2ccncc2)cc1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Solvent: ClCCl
Product: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Product: [NH3+]N1C=CC(Cc2ccccc2)=CC1
Yield: 73.9 %

Procedure:
A solution of 4-benzyl pyridine (0.6 g, 3.5 mmol) in methylene chloride (5 ml) is cooled with ice bath. Freshly prepared O-(2,4,6-trimethyl-benzenesulfonyl)hydroxylamine (0.92 g, 4.2 mmol) in methylene chloride (5 ml) is added dropwise with stirring. The ice bath is removed and the mixture stirred for 1 hour, then concentrated in vacuo. The residue is dissolved in methylene chloride and precipitated with hexanes. The hexane layer is decanted. Concentration provides 1.0 g (62%) of the title compound as a viscous oil.
Reaction SMILES: [C@@H:1]12[CH2:28][C@@H:4]([N:5]([C:7]3[N:12]=[C:11]([C:13]4[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=4)[N:10]=[C:9]4[N:20]([CH2:23][C:24]([F:27])([F:26])[F:25])[N:21]=[CH:22][C:8]=34)[CH2:6]1)[CH2:3][O:2]2.C(N(CC)CC)C.ClC(Cl)(O[C:40](=[O:46])[O:41][C:42](Cl)(Cl)Cl)Cl.N(C1C=CC(C2N=C3N(CC(F)(F)F)N=CC3=C(N3C[C@H]4C[C@@H]3CO4)N=2)=CC=1)=[C:49]=[O:50]>ClCCl.C(O)CO>[OH:50][CH2:49][CH2:42][O:41][C:40](=[O:46])[NH:17][C:16]1[CH:15]=[CH:14][C:13]([C:11]2[N:10]=[C:9]3[N:20]([CH2:23][C:24]([F:26])([F:27])[F:25])[N:21]=[CH:22][C:8]3=[C:7]([N:5]3[CH2:6][C@H:1]4[CH2:28][C@@H:4]3[CH2:3][O:2]4)[N:12]=2)=[CH:19][CH:18]=1
Reactant: O=C=Nc1ccc(-c2nc(N3C[C@H]4C[C@@H]3CO4)c3cnn(CC(F)(F)F)c3n2)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc(-c2nc(N3C[C@H]4C[C@@H]3CO4)c3cnn(CC(F)(F)F)c3n2)cc1
Solvent: ClCCl
Solvent: OCCO
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(-c2nc(N3C[C@H]4C[C@@H]3CO4)c3cnn(CC(F)(F)F)c3n2)cc1)OCCO
Reaction time: 8 h

Procedure:
A solution of 4-(4-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)aniline (62 mg, 0.16 mmol) in dichloromethane (2 mL) was treated with triethylamine (130 μL), followed by a solution of triphosgene (24 mg, 0.08 mmol) in dichloromethane (1 mL). After the passage of 5 minutes, the appropriate nucleophile—in the case, ethylene glycol (56 μL)—was added to the (1R,4R)-5-(6-(4-isocyanatophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane (“isocyanate”) mixture. After standing overnight at room temperature, the reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography using a Phenomenex Prodigy 21 mm×250 mm column, running a gradient elution of 5% acetonitrile/95% of 0.1% aqueous trifluoroacetic acid to 95% acetonitrile to provide 2-hydroxyethyl(4-{4-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl}phenyl)carbamate. MS (ES+): 479.2 (M+H)+
Reaction SMILES: [CH3:1][C:2]([CH3:13])([O:4][C:5]([N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:6])[CH3:3].[C:14]1([CH2:20][N:21]2[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:3][C:2]([CH3:13])([O:4][C:5]([N:7]1[CH2:8][CH2:9][N:10]([CH:24]2[CH2:23][CH2:22][N:21]([CH2:20][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:26][CH2:25]2)[CH2:11][CH2:12]1)=[O:6])[CH3:1]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCN(C2CCN(Cc3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 15.0 g ( 0.8054 mol) of 1-(1,1-dimethylethoxycarbonyl)piperazine and 14.26 ml (0.08053 mol) of 1-(phenylmethyl)-4-piperidinone in 250 ml of methanol was adjusted to a pH of between 5 and 6 by dropwise addition of acetic acid and mixed in batches with a total of 4.13 g ( 0.0624 mol) of 95% sodium cyanoborohydride, whilst taking care to maintain a pH of 5 to 6 by further dropwise addition of acetic acid. After stirring for 18 hours at room temperature the mixture was evaporated down in vacuo, the residue was made alkaline with soda and divided between water and ethyl acetate. After working up the ethyl acetate phase in the usual way 21.76 g (75.2% of theory) of a highly viscous colourless oil were obtained, Rf 0.66 (FM1).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:16]2[CH2:15][CH2:14][C:13]3[CH:17]=[CH:18][CH:19]=[C:20](I)[C:12]=3[C:11](=O)[C:10]=2[CH:9]=[CH:8][CH:7]=1)(=O)C.C(OCC1C2CCC3C=CC=CC=3C(=O)C=2C(I)=CC=1)(=O)C.O.O.[NH2:47][NH2:48]>N1C=CC=CC=1.CO>[N:47]1[NH:48][C:9]2[CH:8]=[CH:7][C:6]([CH2:5][OH:4])=[C:16]3[CH2:15][CH2:14][C:13]4[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=4[C:11]=1[C:10]=23
Reactant: CC(=O)OCc1cccc2c1CCc1cccc(I)c1C2=O
Reactant: NN
Agent: CC(=O)OCc1ccc(I)c2c1CCc1ccccc1C2=O
Solvent: O
Solvent: CO
Solvent: c1ccncc1
Product: OCc1ccc2[nH]nc3c2c1CCc1ccccc1-3

Procedure:
2.1 g of the mixture of (6-iodo-5-oxo-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-1-yl)methyl acetate and (4-iodo-5-oxo-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-1-yl)methyl acetate prepared in Example 1-g was dissolved in a mixed solvent of 5 ml of pyridine and 5 ml of methanol, and 5 ml of hydrazine monohydrate was added, followed by heating under reflux for 3 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified and separated by silica gel column chromatography (ethyl acetate:hexane=3:7), to give 330 mg and 130 mg of the title compounds as a colorless powder, respectively.
Reaction SMILES: O[C@@H:2]1[CH2:11][CH2:10][CH2:9][C:8]2[C:7]([C:12]#[N:13])=[CH:6][CH:5]=[CH:4][C:3]1=2.C1C=CC(P([N:28]=[N+:29]=[N-:30])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[N:28]([C@H:2]1[CH2:11][CH2:10][CH2:9][C:8]2[C:7]([C:12]#[N:13])=[CH:6][CH:5]=[CH:4][C:3]1=2)=[N+:29]=[N-:30]
Reactant: N#Cc1cccc2c1CCC[C@H]2O
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1cccc2c1CCC[C@@H]2N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 4 h
Yield: 72.6 %

Procedure:
A stirring solution of (R)-5-hydroxy-5,6,7,8-tetrahydronaphthalene-1-carbonitrile INT-2 (3.00 g, 17.32 mmol) in toluene (16 mL) under N2, was cooled to 0° C. DPPA (9.53 g, 34.64 mmol) was added, followed by dropwise addition of DBU (3.16 mL, 20.78 mmol) over 20 min. The mixture was stirred at 0° C. for 4 h then slowly warmed to room temperature over 2 h and then concentrated. The resulting crude mixture was diluted with EA and washed with NaHCO3. The combined organic layers were washed with brine, dried over Na2SO4, and chromatographed (EAI hexane) to provide 2.49 g (72.6%) of (S)-5-azido-5,6,7,8-tetrahydronaphthalene-1-carbonitrile INT-6 as a white solid. LCMS-ESI (m/z) calculated for C11H10N4: 198.2; found 156.1 [M−N3]+, tR=3.65 min. 1H NMR (400 MHz, CDCl3) δ 7.60 (dd, J=7.6, 1.2 Hz, 1H), 7.56 (dd, J=7.8, 0.6 Hz, 1H), 7.33 (t, J=7.7 Hz, 1H), 4.59 (t, J=4.4 Hz, 1H), 3.08 (dt, J=18.0, 5.1 Hz, 1H), 2.99-2.83 (m, 1H), 2.15-1.96 (m, 3H), 2.00-1.81 (m, 1H). 13C NMR (101 MHz, DMSO) δ 141.05, 135.58, 133.47, 132.66, 126.58, 117.43, 113.21, 58.74, 28.28, 27.54, 18.27.
Reaction SMILES: [OH-].[Li+].[CH:3]([N:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]([O:25]C)=[O:24])[CH2:18][CH2:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C1COCC1.O>[CH:3]([N:16]1[CH2:17][CH2:18][N:19]([CH2:22][C:23]([OH:25])=[O:24])[CH2:20][CH2:21]1)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)CN1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An aqueous solution of lithium hydroxide (486 mg, 11.58 mmol, 2 ml water) was added to a solution of (4-benzhydrylpiperazin-1-yl)-acetic acid, methyl ester (2.5 g, 7.72 mmol) in a 5:1 mixture of THF/water (20 ml). The reaction was stirred at room temperature overnight. THF was removed under reduced pressure. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was separated and neutralised to pH7 with 1M HCI. A white gelatinous precipitate of (4-benzhydrylpiperazin-1-yl)-acetic acid was formed which was collected by filtration and dried (1.10 g, 46%).
Reaction SMILES: ClC[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[S].[CH2:19]([NH2:22])[CH2:20][NH2:21].[C:23]1(C)C=CC=CC=1>>[NH:21]1[CH:20]=[CH:19][NH:22][CH:23]1[C:5]1[CH:4]=[CH:3][CH:8]=[CH:7][C:6]=1[C:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[S:11][N:10]=1
Reactant: NCCN
Reactant: Cc1ccccc1
Reactant: ClCc1ccc(-c2nsc3ccccc23)cc1
Agent: [S]
Product: C1=CNC(c2ccccc2-c2nsc3ccccc23)N1
Reaction time: 15 h
Yield: 75 %

Procedure:
26 g of 3-(4-chloromethylphenyl)-1,2-benzisothiazole, 6.4 g of sulfur and 300 ml of toluene are heated to 50° C. and 12 g of ethylenediamine are added slowly at this temperature. The reaction mixture is then stirred for 15 hours under reflux and is filtered hot, and the filtrate is cooled to 10°-15° C. 21 g of 3-(4-imidazolin-2-yl-phenyl)-1,2-benzisothiazole, melting at 177° C., are obtained. This corresponds to a yield of 75% of theory.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[C:19]([F:22])([F:21])[F:20])[CH2:5][CH:6]1[CH2:11][CH:10]([C:12]([O:14][CH3:15])=[O:13])[CH2:9][CH2:8][NH:7]1.CCN(C(C)C)C(C)C.[C:32](Cl)(=[O:35])[O:33][CH3:34]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[C:19]([F:22])([F:20])[F:21])[CH2:5][CH:6]1[CH2:11][CH:10]([C:12]([O:14][CH3:15])=[O:13])[CH2:9][CH2:8][N:7]1[C:32]([O:33][CH3:34])=[O:35]
Reactant: COC(=O)C1CCNC(Cc2ccc(C(F)(F)F)c(F)c2)C1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)OC)C(Cc2ccc(C(F)(F)F)c(F)c2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.8 %

Procedure:
To a solution of methyl 2-(3-fluoro-4-(trifluoromethyl)benzyl)piperidine-4-carboxylate (5.96 g, 18.67 mmol) in DCM (100 mL) cooled in an ice-bath was added DIPEA (4 mL, 22.96 mmol) followed by methyl carbonochloridate (1.617 mL, 20.53 mmol). After completed addition the reaction mixture was stirred at room temperature for 2 h. The solvents were evaporated and the residue partitioned between ethyl acetate and 3.8 M HCl. After phase separation the organic layer was washed with brine, then dried over MgSO4 and evaporated. Dimethyl 2-(3-fluoro-4-(trifluoromethyl)benzyl)piperidine-1,4-dicarboxylate (7.17 g, 102%) was isolated as a pale yellow oil.
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH2:6]([O:13][C:14]1[CH:15]=[C:16]([CH2:20][NH:21][CH2:22][CH2:23][O:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[CH:17]=[CH:18][CH:19]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:31]([O-])(=[O:33])C.[Na+]>CN(C=O)C>[CH2:6]([O:13][C:14]1[CH:15]=[C:16]([CH2:20][NH:21][CH2:22][CH2:23][O:24][C:25](=[O:30])[C:26]([CH3:27])([CH3:29])[CH3:28])[CH:17]=[CH:18][C:19]=1[CH:31]=[O:33])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(=O)[O-]
Reactant: CC(C)(C)C(=O)OCCNCc1cccc(OCc2ccccc2)c1
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCCNCc1ccc(C=O)c(OCc2ccccc2)c1
Reaction time: 0.67 h

Procedure:
POCl3 (3.6 g, 23.4 mmol) was added to 20 ml of DMF in an ice bath. After 40 minutes, 2,2-dimethylpropionic acid 2-[(3-benzyloxyphenyl)methylamino]ethyl ester (8.0 g, 23.4 mmol) dissolved in DMF (10 ml) was added dropwise. The mixture was stirred for 16 hours. After an aqueous sodium acetate solution (20%, 100 ml) was added dropwise, the oily matter was subjected to extraction with ethyl acetate. Washing was performed with a saturated aqueous NaHCO3 solution (100 ml) and then with a saturated saline solution (100 ml). After drying over Na2SO4 and concentration, the residue was purified by silica gel chromatography to give a light yellow crystal (yield: 7.2 g (83.6%)).
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[C:7]1[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](=[O:38])[NH:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH:17]=[C:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[B-](F)(F)(F)F.CN(C(O[N:62]1[C:67](=[O:68])[CH2:66][CH2:65][C:63]1=[O:64])=[N+](C)C)C>C1COCC1>[C:1]([O:5][C:6](=[O:39])[C:7]1[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](=[O:38])[NH:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][N:62]2[C:67](=[O:68])[CH2:66][CH2:65][C:63]2=[O:64])=[O:36])[CH:17]=[C:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:8]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)c1cc(OCCCCCCCCCC(=O)NCCCC(=O)O)cc(C(=O)OC(C)(C)C)c1
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cc(OCCCCCCCCCC(=O)NCCCC(=O)ON2C(=O)CCC2=O)cc(C(=O)OC(C)(C)C)c1
Temperature: 25 °C

Procedure:
To a solution of 5-[9-(3-Carboxy-propylcarbamoyl)-nonyloxy]-isophthalic acid di-tert-butyl ester (62 mg, 0.11 mmol) in dry THF (2 ml) was added DIPEA (0.05 ml) and TSTU (41 mg, 0.14 mmol). The mixture was stirred at room temperature under nitrogen over night. The mixture was concentrated and EtOAc was added to the residue. The precipitate was removed by filtration. The filtrate was washed with 0.1 N HCl (2×) and brine (1×), dried (Na2SO4) and concentrated to give a clear syrup.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][C:5]=2[CH:4]=[CH:3]1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:26]=[CH:27][CH:28]=1)[C:15]([C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=1)=[O:16].C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>ClCCl.O>[Cl:11][C:12]1[CH:13]=[C:14]([CH:26]=[CH:27][CH:28]=1)[C:15]([C:17]1[CH:25]=[CH:24][C:20]([C:21]([N:8]2[CH2:9][CH2:10][C:5]3[CH:4]=[CH:3][O:2][C:6]=3[CH2:7]2)=[O:22])=[CH:19][CH:18]=1)=[O:16]
Reactant: c1cc2c(o1)CNCC2
Reactant: O=C(O)c1ccc(C(=O)c2cccc(Cl)c2)cc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(c1ccc(C(=O)N2CCc3ccoc3C2)cc1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.114 g (0.720 mmol) of 4,5,6,7-tetrahydrofuro[2,3-c]pyridine hydrochloride, 0.188 g (0.7 mmol) of 4-(3-chlorobenzoyl)benzoic acid and 0.40 ml (2.9 mmol) of triethylamine in 30 ml of dichloromethane, 0.18 g (1.1 mmol) of diethyl cyanophosphonate was added dropwise under ice-cooling, followed by overnight stirring at room temperature. This mixture was poured into water and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate/dichloromethane=4/1/1). The resulting purified product was washed with hexane to yield the desired product.
Reaction SMILES: N1C2C(=CC=CC=2)C=C1.C([N:17]1[C:29]2[C:28]([OH:30])=[C:27]3[N:31](C(OC(C)(C)C)=O)[C:32]4[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][C:37]=4[C:26]3=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[C:21]([Cl:46])[CH:22]=2)(OC(C)(C)C)=O.O[CH2:48][CH2:49][CH2:50][N:51]1[CH2:56][CH2:55][CH:54]([NH:57]C(=O)OC(C)(C)C)[CH2:53][CH2:52]1>>[Cl:46][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:29]1[C:28]([O:30][CH2:48][CH2:49][CH2:50][N:51]3[CH2:56][CH2:55][CH:54]([NH2:57])[CH2:53][CH2:52]3)=[C:27]3[NH:31][C:32]4[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][C:37]=4[C:26]3=[CH:25][C:24]2=1
Reactant: CC(C)(C)OC(=O)n1c2ccc(Cl)cc2c2cc3c4cc(Cl)ccc4n(C(=O)OC(C)(C)C)c3c(O)c21
Reactant: CC(C)(C)OC(=O)NC1CCN(CCCO)CC1
Agent: c1ccc2[nH]ccc2c1
Product: NC1CCN(CCCOc2c3[nH]c4ccc(Cl)cc4c3cc3c2[nH]c2ccc(Cl)cc23)CC1

Procedure:
The title compound was prepared in a manner analogous to Example 28 except the starting indole is 5,7-diBOC-2,10-dichloro-6-hydroxyindolo[2,3-b]carbazole and the reagent is tert-butyl 1-(3-hydroxypropyl)piperidin-4-ylcarbamate. 1H-NMR (400 MHz, CDCl3) δ ppm 9.70 (s, 2 H), 8.33 (s, 1 H), 8.07 (d, J=2.0 Hz, 2 H), 7.43 (d, J=8.4 Hz, 2 H), 7.33 (dd, J=8.6, 2.2 Hz, 2 H), 4.33 (t, J=5.4 Hz, 2H), 3.24-3.13 (m, 2 H), 3.03-2.89 (m, 1 H), 2.84 (t, J=6.0 Hz, 2 H), 2.30-2.16 (m, 2 H), 2.15-2.06 (m, 2H), 2.04-1.93 (m, 2 H), 1.78-1.65 (m, 2 H); MS (ESI) m/z 479.1 (M−H)−; MS (ESI) m/z 481.0 (M+H)+
Reaction SMILES: [CH2:1]([C@H:3]1[N:12]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:23])[CH:10]=2)[NH:5][C:4]1=[O:24])[CH3:2].Br[CH2:26][CH2:27][CH2:28][CH3:29].C([C@H]1N(C(=O)C2C=CC=C(OC)C=2)C2C(=CC(F)=CC=2)N(C)C1=O)C>>[CH2:26]([N:5]1[C:6]2[C:11](=[CH:10][C:9]([F:23])=[CH:8][CH:7]=2)[N:12]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C@H:3]([CH2:1][CH3:2])[C:4]1=[O:24])[CH2:27][CH2:28][CH3:29]
Reactant: CC[C@@H]1C(=O)Nc2ccc(F)cc2N1C(=O)c1ccc(OC)cc1
Reactant: CCCCBr
Agent: CC[C@@H]1C(=O)N(C)c2cc(F)ccc2N1C(=O)c1cccc(OC)c1
Product: CCCCN1C(=O)[C@@H](CC)N(C(=O)c2ccc(OC)cc2)c2cc(F)ccc21
Yield: 76 %

Procedure:
(3R)-3-Ethyl-6-fluoro-4-(4-methoxybenzoyl)-3,4-dihydroquinoxalin-2(1H)-one (see Example 8) was treated with 1-bromobutane according to the procedure for the preparation of (3R)-3-ethyl-7-fluoro-4-(3-methoxybenzoyl)-1-methyl-3,4-dihydroquinoxalin-2(1H)-one (see Example 4) to yield (3R)-1-butyl-3-ethyl-6-fluoro-4-(4-methoxybenzoyl)-3,4-dihydroquinoxalin-2(1H)-one (76%). MS (ESI) m/z 385 ([M+H]+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11](N=C=S)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[N+]([O-])(O)=O.C[C:22]1C=C(C)[N:24]([C:28]([NH2:30])=[NH:29])[N:23]=1.CC(C)([O-])C.[K+].[NH2:37]N>CS(C)=O>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=2)[NH:37][C:22]2[N:29]=[C:28]([NH2:30])[NH:24][N:23]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2ccc(N=C=S)cc2)CC1
Reactant: Cc1cc(C)n(C(=N)N)n1
Reactant: NN
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O=[N+]([O-])O
Solvent: CS(C)=O
Product: CN1CCN(c2cccc(Nc3n[nH]c(N)n3)c2)CC1
Temperature: 55 °C
Reaction time: 4 h

Procedure:
4-(4-Methylpiperazino)-phenyl isothiocyanate was reacted with 1 equivalent of 3,5-dimethylpyrazole-1-carboxamidine nitrate and 1.1 equivalents of potassium t-butoxide in DMSO at 55° C. for 4 hours. 10 equivalents of hydrazine were added and stirred at 55° C. for 4 hrs. Subsequent concentration, dissolution in methanol, filtering of impurities and concentration gave 3-(4-methylpiperazino)-anilino-5-amino-1,2,4-triazole Compound 9A (87% yield). 1H NMR (400 MHz, (CD3)2SO) δ 9.05 (s, 1H), 8.60 (s, 1H), 7.35 (d, 2H), 6.77 (d, 2H), 5.70 (s, 2H), 2.97 (m, 4H), 2.48 (m, 4H), 2.23 (s, 3H); MS (ESI) m/z: 274 (M+H+). 3-(4-methylpiperazino)-anilino-5-amino-1,2,4-triazole Compound 9A was acylated with 2,6-difluoro benzoyl chloride Compound 1F in anhydrous pyridine to produce compound 71 (30% yield). 1H NMR (300 MHz, (CD3)2SO) δ 9.07 (s, 1H), 7.88 (s, 1H), 7.72-7.66 (m, 1H), 7.32 (t, 1H), 7.25-7.17 (m, 2H), 6.97-6.92 (m, 1H), 6.71 (d, 1H), 3.39-3.35 (m, 2H), 3.17 (s, 3H), 3.00-2.97 (m, 4H), 2.51-2.46 (m, 4H); MS (ESI) m/z: 414 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:17]=[CH:16][NH:15][N:14]=3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:23]1[N:28]=[CH:27][CH:26]=[CH:25][N:24]=1>C1COCC1>[F:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([C:13]3[CH:17]=[CH:16][N:15]([C:23]4[N:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[N:14]=3)=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: Clc1ncccn1
Reactant: Fc1ccc(Oc2ccc(-c3cc[nH]n3)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1ccc(Oc2ccc(-c3ccn(-c4ncccn4)n3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 81.7 %

Procedure:
To a solution of 3-[4-(4-fluorophenoxy)phenyl]-1H-pyrazole (930 mg, 3.66 mmol) in 15 mL of dry THF was slowly added 240 mg (6.00 mmol) of NaH. After stirring at room temperature for 20 minutes, 500 mg (4.15 mmol) of 2-chloropyrimidine was added in one portion. The reaction was allowed to stir overnight at room temperature and concentrated to dryness. The residue was dissolved in CHCl3 and subjected to flash chromatography. Elution with 3:2 hexane/EtOAc gave 994 mg of the title compound as a solid, mp 123-125° C. 1H NMR (CDCl3): δ 8.77 (d, 2H, J=4.8 Hz), 8.65 (d, 1H, J=3.0 Hz), 7.95 (d, 2H, J=8.7 Hz), 7.20 (t, 1H, J=4.9 Hz), 7.07-6.98 (m, 5H), 6.78 (d, 1H, J=3.0 Hz).
Reaction SMILES: [C:1]([N:8]1[CH2:16][CH2:15][CH:11]([C:12]([OH:14])=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[CH3:18][NH:19][O:20][CH3:21].CN1CCOCC1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][CH:11]([C:12](=[O:14])[N:19]([O:20][CH3:21])[CH3:18])[CH2:15][CH2:16]1)=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.3 %

Procedure:
A solution of 30 g (130.9 mmol) of Boc-isonipecotic acid in 1.5 1 CH2Cl2 was treated with 20.42 g (209.3 mmol) of N,O-dimethylhydroxylamine hydrochloride, 23.1 ml (209.3 mmol) of N-methylmorpholine and at 0° C. with 32.6 g (170.1 mmol) of EDCI and 3.53 g (26.2 mmol) of HOBT. The reaction was stirred overnight at room temperature and partitioned between aqueous 10% KHSO4/Et2O (3×). The organic phases were washed with aqueous saturated NaHCO3, 10% NaCl and dried over Na2SO4 to give 37.54 g (quantitative) of 4-(methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acid tert-butyl ester, MS: 273(MH+).