Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([CH2:4][O:5][C:6](=[O:8])[CH3:7])=[O:3].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:11]=1[CH3:17].N1C=CC=CC=1>ClCCl>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:2]([CH2:4][O:5][C:6](=[O:8])[CH3:7])=[O:3])=[CH:12][C:11]=1[CH3:17]
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1cc(N)ccc1Br
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OCC(=O)Nc1ccc(Br)c(C)c1
Temperature: 40 °C
Reaction time: 2.5 h

Procedure:
Acetic acid chlorocarbonylmethyl ester (1.73 ml) was added to a solution of 4-bromo-3-methyl-phenylamine (2.0 g, 10.7 mmol) and pyridine (5.21 ml) in dichloromethane (20 ml), and the mixture was stirred at 40° C. for 2.5 hours. The mixture was cooled, and then quenched with water and extracted with dichloromethane. The organic layer was sequentially washed with water and saturated brine, and then dried over anhydrous sodium sulfate and concentrated under reduced pressure to give acetic acid (4-bromo-3-methyl-phenylcarbamoyl)-methyl ester (3.19 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Br)[N:3]=1.[CH3:9][NH:10][NH2:11]>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:10]([CH3:9])[NH2:11])[N:3]=1
Reactant: CNN
Reactant: Brc1cccc(Br)n1
Product: CN(N)c1cccc(Br)n1
Temperature: 100 °C
Yield: 66 %

Procedure:
A suspension of 2,6-dibromopyridine (10.0 g, 42.0 mmol) in anhydrous methylhydrazine (10 mL) was heated at 100° C. for 2 h. The mixture was cooled to room temperature and washed with water (3×20 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, hexanes/EtOAc, 80:20) gave the title compound (5.70 g, 66%) as white solid: 1H NMR (500 MHz, CDCl3) δ 7.30-7.26 (dd, J=8.5, 7.8 Hz, 1H), 6.83 (d, J=8.0 Hz, 1H), 6.73 (d, J=7.0 Hz, 1H), 4.03 (br s, 2H), 3.36 (s, 3H).
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:34](Cl)(=[O:36])[CH3:35].C(=O)(O)[O-].[Na+]>ClCCl.O>[C:1]1([N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:34](=[O:36])[CH3:35])[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)Cl
Reactant: OCCCCOc1ccc2nc(-c3ccccc3)n(-c3ccccc3)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCCCCOc1ccc2nc(-c3ccccc3)n(-c3ccccc3)c2c1
Reaction time: 15 h

Procedure:
50 mg of 4-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]butan-1-ol was dissolved in 1 ml of dichloromethane, mixed with 0.34 ml of pyridine and 20 μl of acetyl chloride and stirred for 15 hours. It was mixed with saturated sodium bicarbonate solution, diluted with water, extracted twice with dichloromethane, the combined organic phases were washed with saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue was purified using thick-layer chromatography.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([OH:11])[C:8]([OH:12])=[C:7]([CH3:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[C:15](=[O:16])([O:17][CH2:18][CH3:19])[O:11][C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=[C:7]([CH3:13])[C:8]=1[O:12][C:15](=[O:16])[O:17][CH2:18][CH3:19]
Reactant: Cc1cc(C(C)(C)C)cc(O)c1O
Reactant: CCOC(=O)Cl
Product: CCOC(=O)Oc1cc(C(C)(C)C)cc(C)c1OC(=O)OCC
Yield: 81.4 %

Procedure:
Prepared from 5-tert-butyl-3-methylbenzene-1,2-diol and ethyl chloroformate; purified by flash column chromatography on silica gel to yield a sticky colorless oil (81.4%); 1H NMR (500 MHz, CDCl3, ppm) δ 7.09-7.11 (m, 2H), 4.32 (q, 2H, J=9.0 Hz), 4.31 (q, 2H, J=9.0 Hz), 2.25 (s, 3H), 1.38 (t, 3H, J=9.0 Hz), 1.37 (t, 3H, J=9.0 Hz), 1.29 (s, 9H);
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:12]=O.[Br:19][C:20]1[CH:21]=[CH:22][C:23]([NH:29][C:30](=[O:35])[CH2:31]C(O)=O)=[C:24]([CH:28]=1)[C:25]([OH:27])=[O:26].Cl>C1(C)C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:10]=[C:11](/[CH:12]=[CH:31]/[C:30]([NH:29][C:23]2[CH:22]=[CH:21][C:20]([Br:19])=[CH:28][C:24]=2[C:25]([OH:27])=[O:26])=[O:35])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: O=C(O)CC(=O)Nc1ccc(Br)cc1C(=O)O
Reactant: COc1ccc(C=O)cc1OC
Agent: Cl
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: COc1ccc(/C=C/C(=O)Nc2ccc(Br)cc2C(=O)O)cc1OC
Yield: 67.1 %

Procedure:
Piperidine (0.13 mL, 1.4 mmol) was added to a suspension of 3,4-dimethoxybenzaldehyde (0.22 g, 1.4 mmol) and 5-bromo-2-[(carboxyacetyl)amino]benzoic acid (0.34 g, 1.1 mmol) in toluene (4.0 mL) and treated according to Procedure 2, acidifying with 1 M HCl. (E)-2-[[3-(3,4-Dimethoxyphenyl)-1-oxo-2-propenyl]amino]-5-bromobenzoic acid (0.30 g, 66%) was obtained as a yellow crystalline solid; mp 210-213° C.; δH (400 MHz, DMSO-d6) 3.79 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 6.78 (d, J=15.6 Hz, 1H, CH═CHCO), 6.98 (d, J5′,6′=8.4 Hz, 1H, H5′), 7.24 (d, J5′,6′=8.4 Hz, 1H, H6′), 7.36 (s, 1H, H2′), 7.56 (d, J=15.6 Hz, 1H, CH═CHCO), 7.78 (dd, J3,4=8.4, J4,6=2.0 Hz, 1H, H4), 8.06 (d, J4,6=2.0 Hz, 1H, H6), 8.62 (d, J3,4=8.4 Hz, 1H, H3), 11.30 (s, 1H, NH), 13.61 (br s, 1H, CO2H); δC (100 MHz, DMSO-d6) 28.6, 55.5, 55.6, 110.4, 111.6, 114.0, 119.5, 122.5, 122.7, 127.1, 133.1, 136.4, 140.2, 142.0, 149.0, 150.7, 164.2, 168.1; HRMS (ESI) calculated for C13H16BrNO5 [M+Na]+ 428.0104. found 428.0105; vmax 1026, 1247, 1510, 1595, 1698, 2515, 2829, 3226, 3619 cm−1.
Reaction SMILES: [CH3:1][N:2]1[CH:8]2[CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7]2.[NH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[Cl-].[NH4+]>O>[CH3:1][NH:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: C1CCNCC1
Reactant: CN1C2CCCCC21
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: CN[C@@H]1CCCC[C@H]1N1CCCCC1
Yield: 41.8 %

Procedure:
A stirred mixture of 7-methyl-7-azabicyclo[4.1.0]heptane (5.0 ml, 39 mmol), piperidine (3.9 ml, 39 mmol) and 0.2 g of ammonium chloride dissolved in 0.4 ml of water was heated under reflux for 5.5 hours. Normal work-up of the reaction mixture followed by bulb-to-bulb distillation yielded 3.2 g (42%) of trans-N-methyl-2-(1-piperidinyl)cyclohexanamine as a colorless liquid, bp 210° C. (at a pressure of 2666 Pascal).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[NH:12][C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:22]N(C)C=O.[H-].[Na+].S(OC)(OC)=O>O>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[N:12]([CH3:22])[C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=c1[nH]c(=O)n(-c2cccc([N+](=O)[O-])c2)c2ccccc12
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: COS(=O)OC
Solvent: O
Product: Cn1c(=O)c2ccccc2n(-c2cccc([N+](=O)[O-])c2)c1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2.8 g of 1-(m-nitrophenyl)quinazoline-2,4(1H, 3H)-dione and 30 ml of dimethylformamide was added 0.6 g of approximately 55 % sodium hydride, and the solution was stirred for 20 minutes at room temperature. To this was added 2.2 g of dimethyl sulfite and stirring was further continued for 4 hours at room temperature. After the reaction was complete, the solvent was removed from the reaction mixture by distillation under reduced pressure. The residue thus obtained was mixed with water to precipitate a crude product. This product was recrystallized from methanol to afford 2.8 g of 1-(m-nitrophenyl)-3-methylquinazoline-2,4(1H, 3H)-dione as colorless needles, melting at 242°-243° C.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:14][N:15]([CH:17](OC)OC)[CH3:16]>>[CH3:14][N:15]([CH3:17])/[CH:16]=[CH:2]/[C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)=[O:3]
Reactant: COC(=O)c1ccc(C(C)=O)cc1
Reactant: COC(OC)N(C)C
Product: COC(=O)c1ccc(C(=O)/C=C/N(C)C)cc1
Temperature: 105 °C

Procedure:
A mixture of methyl 4-acetylbenzoate (5.00 g, 28.1 mmol) in DMF-DMA (38 mL, 284 mmol) was heated at 105° C. for 20 hours. The reaction was cooled, concentrated, and used crude in the next reaction.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:12](=[O:23])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]1.[Br:24][CH2:25][CH2:26][CH2:27][CH2:28]Br.Cl>CN(C)C=O>[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12](=[O:23])[N:13]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[C:4]1=[O:3]
Reactant: BrCCCCBr
Reactant: COc1ccc(Cn2c(=O)[nH]c3ccccc3c2=O)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)c3ccccc3n(CCCCBr)c2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To a suspension of sodium hydride (60% in oil, 4.34 g) in N,N-dimethylformamide (100 ml), 2,4-dioxo-3-(4-methoxybenzyl)-1,2,3,4-tetrahydroquinazoline (25.5 g) obtained in Reference Example 26 was added, and the mixture was stirred at room temperature for 2 hours. This mixture was treated dropwise with a solution of 1,4-dibromobutane (21.6 ml) in N,N-dimethylformamide (50 ml), and stirred at room temperature for 19 hours. The reaction mixture was admixed with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO4), and the solvent was distilled off under reduced pressure to give the title compound (30.8 g, 82%). Recrystallization from ethyl acetate-ethyl ether yielded a colorless crystal having a melting point of 124 to 125° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][N:3]=1.Cl.[F:13][C:14]([F:19])([F:18])[C@@H:15]([NH2:17])[CH3:16]>N1C=CC=CC=1.C(OCC)(=O)C>[F:13][C:14]([F:19])([F:18])[C@@H:15]([NH:17][S:8]([C:5]1[CH:4]=[N:3][C:2]([Cl:1])=[CH:7][CH:6]=1)(=[O:10])=[O:9])[CH3:16]
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Reactant: C[C@H](N)C(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C[C@H](NS(=O)(=O)c1ccc(Cl)nc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.1 %

Procedure:
2-chloropyridine-5-sulfonyl chloride (12 g, 56.6 mmol) was added to a solution of (S)-1,1,1-trifluoropropan-2-amine hydrochloride (7.8 g, 51.2 mmol) in pyridine (15 mL) at 0° C. The mixture was stirred at room temperature for 10 minutes and diluted with ethyl acetate (200 ml) and washed with 3 N aq. HCl (2×100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The solid was triturated with hexane (2×40 mL) and filtered to provide (S)-6-chloro-pyridine-3-sulfonic acid (2,2,2-trifluoro-1-methyl-ethyl)-amide as an off-white solid (11.84 g, 75%). 1H NMR (500 MHz, CDCl3): δ0.81 (1H, d, J=2.4 Hz), 8.18 (1H, dd, J=2.5 Hz, 2.6 Hz), 7.51 (1H, d, J=8.8 Hz), 4.92 (1H, br s), 4.08 (1H, m), 1.45 (3H, d, J=7.0 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([NH:14][C:15](=O)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].[ClH:26]>CCOCC.CO.O.O1CCCC1>[ClH:26].[ClH:26].[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([NH:14][CH2:15][CH3:16])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CC(=O)N[C@H]1CC[C@H](c2ccc(N)cc2)CC1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CO
Product: CCN[C@H]1CC[C@H](c2ccc(N)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4 g. of trans N-[4-(p-aminophenyl)cyclohexyl]acetamide (prepared as in Example 83) in 150 ml. of tetrahydrofuran is added to 1.4 g. of lithium aluminum hydride in 10 ml. of tetrahydrofuran. The mixture is heated at reflux for about 3 hours and allowed to stand for about 16 hours. The cooled mixture is then heated with 1.4 ml. of water and 1.4 ml. of 15% aqueous sodium hydroxide solution and an additional 1.4 ml. of water. The solid is removed on a filter and the filtrate evaporated to dryness. The residual oily solid is suspended in ether. This mixture is filtered to give 0.63 g. of starting material melting at 190° to 194° C. The filtrate is evaporated to dryness and the residue dissolved in 75 ml. of tetrahydrofuran and added to 2 g. of lithium aluminum hydride in 200 ml. of tetrahydrofuran. After about 17 hours of heating at reflux temperature and about 17 hours at room temperature, the cooled mixture is heated with 2 ml. of water and 2 ml. of 15% aqueous sodium hydroxide solution and an additional 2 ml. of water. The solid is removed on a filter and the filtrate evaporated to dryness to give the crude product, which is dissolved in 50 ml. of methanol and then treated with 6.5 ml. of 4.7N hydrochloric acid in ether. The solution is evaporated to dryness and the residue recrystallized from methanol:ethyl acetate to give 3.55 g. (80% yield) of trans 4-(p-aminophenyl)-N-ethylcyclohexylamine dihydrochloride melting at 291° to 295° C.
Reaction SMILES: C#CCCCCC#C.BrCCCCOC1CCCCO1.[CH2:21]([O:36][CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][O:38]1)[CH2:22][CH2:23][CH2:24][C:25]#[C:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]CC#C>>[CH2:21]([O:36][CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][O:38]1)[CH2:22][CH2:23][CH2:24][C:25]#[C:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]#[CH:32]
Reactant: C#CCCCCCCCC#CCCCCOC1CCCCO1
Agent: BrCCCCOC1CCCCO1
Agent: C#CCCCCC#C
Product: C#CCCCCC#CCCCCOC1CCCCO1
Yield: 65 %

Procedure:
Oct-1,7-diyne (9.0 g, 84.9 mmol; G F Smith) was alkylated with 2-(4-bromobutoxy)-tetrahydropyran (15 g, 63.68 mmol) as described above for the synthesis of 2-(pentadeca-5,14-diynyloxy)tetrahydropyran to give 2-(dodeca-5,11-diynyloxy)tetrahydropyran (10.85 g, 65%) as a colorless oil. TLC: 10% EtOAc/hexanes, Rf≈0.6; 1H NMR (400 MHz, CDCl3) δ 4.57 (t, J=2.5 Hz, 1H), 3.82-3.87 (m, 1H), 3.70-3.77 (m, 1H), 3.46-3.51 (m, 1H), 3.36-3.42 (m, 1H), 2.14-2.20 (m, 6H), 1.93 (t, 1H, J=2.5 Hz), 1.46-1.72 (m, 14 H).
Reaction SMILES: C([O:4][CH:5]([C:33]1[N:37]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:36]=[CH:35][CH:34]=1)[CH:6]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=1)[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][C:12]([NH:21][C:22](=[O:24])[CH3:23])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)(=O)C.C(NC1(C2C=CC=CC=2)CCNCC1)(=O)C.C(OC(C1N(C2C=CC=CC=2)N=CC=1)C(C1C=CC(Cl)=C(Cl)C=1)CC=O)(=O)C>>[Cl:32][C:27]1[CH:26]=[C:25]([CH:6]([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][C:12]([NH:21][C:22](=[O:24])[CH3:23])([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:11][CH2:10]2)[CH:5]([C:33]2[N:37]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:36]=[CH:35][CH:34]=2)[OH:4])[CH:30]=[CH:29][C:28]=1[Cl:31]
Reactant: CC(=O)NC1(c2ccccc2)CCN(CCC(c2ccc(Cl)c(Cl)c2)C(OC(C)=O)c2ccnn2-c2ccccc2)CC1
Agent: CC(=O)NC1(c2ccccc2)CCNCC1
Agent: CC(=O)OC(c1ccnn1-c1ccccc1)C(CC=O)c1ccc(Cl)c(Cl)c1
Product: CC(=O)NC1(c2ccccc2)CCN(CCC(c2ccc(Cl)c(Cl)c2)C(O)c2ccnn2-c2ccccc2)CC1

Procedure:
5-[(1RS,2RS)-1-Acetoxy-2-(3,4-dichlorophenyl)-4-(4-acetamido-4-phenylpiperidino)butyl]-1-phenylpyrazole. Using a procedure similar to that described in Example 7, except using 4-acetamido-4-phenylpiperidine as the amine component and 5-[(1RS,2RS)-1-acetoxy-2-(3,4-dichlorophenyl)-4-oxobutyl]-1-phenylpyrazole as the aldehyde component, the title compound was obtained as a white foam (65%; NMR: 7.58 (d,1), 7.48-7.21 (m,11), 7.09 (d,1), 6.81 (dd,1), 6.22 (d,1), 6.09 (d,1), 5.39 (s,1), 3.06 (m,1), 2.51 (m,2), 2.31 (m,2), 2.15-2.00 (m,7), 1.98 (s,3), 1.96 (s,3), 1.75 (m,1), 1.43 (m,1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[C:14]([N+:19]([O-])=O)[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pt].C1(C)C=CC=CC=1.CC(O)C>[NH2:19][C:14]1[CH:15]=[N:16][C:17]2[C:12]([C:13]=1[NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:11][CH:10]=[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:18]=2
Reactant: CC(C)(C)OC(=O)NCCCCNc1c([N+](=O)[O-])cnc2cc(OCc3ccccc3)ccc12
Agent: [Pt]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)NCCCCNc1c(N)cnc2cc(OCc3ccccc3)ccc12
Reaction time: 12.5 h
Yield: 99.8 %

Procedure:
A mixture of tert-butyl 4-{[7-(benzyloxy)-3-nitroquinolin-4-yl]amino}butylcarbamate (30.0 g, 64.3 mmol) and 5% platinum on carbon (3.0 g) in toluene (675 mL) and 2-propanol (100 mL) was hydrogenated on a Parr apparatus for 12.5 hours at 24 psi (1.7×105 Pa). The mixture was filtered through CELFTE filter agent, which was rinsed afterwards with 1:1 toluene/2-propanol and 2-propanol. The combined filtrates were concentrated under reduced pressure to afford 28 g of tert-butyl 4-{[3-amino-7-(benzyloxy)quinolin-4-yl]amino}butylcarbamate as a viscous black oil that was used in the next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]([CH3:17])[C:15](=[O:18])[N:14]([CH3:19])[C:13](=O)[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]([CH3:17])[C:15](=[O:18])[N:14]([CH3:19])[C:13](=[S:22])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COc1ccc(-c2cc(=O)n(C)c(=O)n2C)cc1OC
Solvent: c1ccncc1
Product: COc1ccc(-c2cc(=S)n(C)c(=O)n2C)cc1OC
Yield: 95.1 %

Procedure:
A mixture of 6-(3,4-dimethoxyphenyl)-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione (1.57 g) and phosphorus pentasulfide (3.3 g) in pyridine was refluxed for 15 hours with stirring. The reaction mixture was evaporated under reduced pressure. The residue was washed with 1N-hydrochloric acid and extracted with dichloromethane. The extract was washed with water, dried over magnesium sulfate and evaporated under reduced pressure. The residue was triturated in diisopropyl ether to give 3,4-dihydro-6-(3,4-dimethoxyphenyl)-1,3-dimethyl-4-thioxo-2(1H)-pyrimidinone (1.58 g).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[CH3:25][N:26]([CH3:36])[S:27]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:29])=[O:28]>CN(C=O)C.CS(C)=O.CO>[CH3:25][N:26]([CH3:36])[S:27]([N:30]1[CH2:35][CH2:34][N:33]([C:2]2[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=3)[CH:3]=2)[CH2:32][CH2:31]1)(=[O:28])=[O:29]
Reactant: CN(C)S(=O)(=O)N1CCNCC1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Solvent: CO
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(N3CCN(S(=O)(=O)N(C)C)CC3)n2n1
Temperature: 25 °C
Yield: 80.8 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 86 mg, 0.25 mmol) and N,N-dimethylpiperazine-1-sulfonamide (145 mg, 0.75 mmol) in DMF (1.0 mL) was stirred at 100° C. for 2 h. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC (35-60% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (101.3 mg, 81%). 1H NMR (DMSO-d6) δ: 10.90 (s, 1H), 8.00 (d, J=8.8 Hz, 2H), 7.60 (d, J=8.6 Hz, 2H), 7.36 (s, 1H), 6.20 (s, 1H), 3.79-3.82 (m, 4H), 3.39-3.48 (m, 4H), 3.07-3.16 (m, 2H), 2.39 (s, 3H), 1.66-1.82 (m, 2H), 1.45 (s, 6H), 1.01 (t, 3H); ESI-MS: m/z 502.3 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N+:14]([O-])=O)[CH2:4][CH2:3]1>CO.[Pd]>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH2:14])[CH2:4][CH2:3]1
Reactant: CN1CC=C(c2ccncc2[N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCC(c2ccncc2N)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-3-nitro-pyridine (300 mg, 1.37 mmol) in Methanol (3.00 mL) was added Pd on C, (10%, wet, Degussa) (29.12 mg, 0.274 mmol) and the mixture was stirred at ambient temperature under an atmosphere of hydrogen, for 18 hours. The catalyst was filtered off and the filtrate was concentrated in vacuo to afford 4-(1-methylpiperidin-4-yl)pyridin-3-amine MS (ES+) 192.1.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:20]=[N:21][C:22](OS(C(F)(F)F)(=O)=O)=[C:23]([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:24]=3)[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.[F:38][C:39]1[CH:44]=[CH:43][C:42]([O:45][CH:46]2[CH2:51][CH2:50][CH2:49][CH2:48][O:47]2)=[CH:41][C:40]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=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>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:20]=[N:21][C:22]([C:40]4[CH:41]=[C:42]([O:45][CH:46]5[CH2:51][CH2:50][CH2:49][CH2:48][O:47]5)[CH:43]=[CH:44][C:39]=4[F:38])=[C:23]([CH2:25][C:26]([CH3:27])([CH3:29])[CH3:28])[CH:24]=3)[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:2][CH2:3]1
Reactant: CC1(C)OB(c2cc(OC3CCCCO3)ccc2F)OC1(C)C
Reactant: CCOC(=O)CC(c1cccc(COc2cnc(OS(=O)(=O)C(F)(F)F)c(CC(C)(C)C)c2)c1)C1CC1
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: O
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(c1cccc(COc2cnc(-c3cc(OC4CCCCO4)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 94.8 %

Procedure:
Under a nitrogen atmosphere, to a solution of ethyl 3-cyclopropyl-3-(3-(((5-neopentyl-6-(((trifluoromethyl)sulfonyl)oxy)pyridin-3-yl)oxy)methyl)phenyl)propanoate (1.04 g) in toluene (19.1 mL) were added 2-(2-fluoro-5-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.84 g), 2.0M aqueous sodium carbonate solution (2.86 mL) and tetrakis(triphenylphosphine)palladium(0) (0.220 g) at room temperature, and the mixture was stirred at 90° C. for 1.5 hr. The reaction mixture was cooled, poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.07 g) as a pale-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][C:10](=[O:20])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])=[C:4]([N+:21]([O-:23])=O)[CH:3]=1.[K+].[Br-]>CCO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[Cl:8])[NH:9][C:10](=[O:20])[C:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])=[N+:21]2[O-:23]
Reactant: COc1ccccc1CC(=O)Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CCO
Product: COc1ccccc1-c1c(=O)[nH]c2cc(Cl)c(Cl)cc2[n+]1[O-]
Yield: 50 %

Procedure:
The title compound was prepared according to the general procedure described in Example 6 by substituting 8 mmol of 131 for 125. Yield: 50%; mp 239°-241° C. (from EtOH); IR (KBr) 3459, 3050, 2958, 2796, 1651, 1618, 1375 and 1257 cm-1 ; 1H NMR (in DMSO-d6) δ3.69 (s, 3H), 7.00 (dd, 1H, JJ=7.4 Hz), 7.10 (d, 1H, J=7.4 Hz), 7.26 (d, 1H, J=7.4 Hz), 7.46 (dd, 1H, JJ=7.4 Hz), 7.54 (s, 1H), 8.26 (s, 1H), 12.58 (br.s, 1H, N--H); HPLC: 98%; HRMS Calcd for C15H10 N2O3Cl2 : 336.0068. Found: 336.0078.