Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11]C)[C:6]#[N:7].COC1C=C(C=CC=1O)C#N.[Br-].[Li+]>>[OH:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[OH:11])[C:6]#[N:7]
Reactant: COc1ccc(C#N)cc1OC
Agent: COc1cc(C#N)ccc1O
Agent: [Br-]
Agent: [Li+]
Product: N#Cc1ccc(O)c(O)c1
Yield: 65 %

Procedure:
The preparation was carried out according to the process of Example 2a except that 3,4-Dimethoxybenzonitrile was used as the starting material instead of 3-methoxy-4-hydroxybenzonitrile, and 2-fold of lithium bromide (162.6 g, 1.88 mole) were added to form the reaction mixture. 3,4-Dihydroxybenzonitrile was obtained as a white solid with a yield of 65% and a purity of greater than 98% as indicated by HPLC analysis.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[C:14]([CH:15]=[O:16])=[CH:13][CH:12]=[CH:11][N:10]=1.[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]>ClCCl>[CH:15]([C:14]1[C:9]([NH:8][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[N:10][CH:11]=[CH:12][CH:13]=1)=[O:16]
Reactant: Nc1ncccc1C=O
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1ncccc1C=O
Temperature: 0 °C
Reaction time: 63 h
Yield: 90 %

Procedure:
Triethlyamine (7.6 mL, 54 mmol), was added to a solution of 2-aminopyridine-3-carboxaldehyde (4.45 g, 36 mmol) in dichloromethane (70 mL). Mixture was cooled to 0° C. A solution of pivaloyl chloride (5.3 mL, 43 mmol) in dichloromethane (30 mL) was added to the mixture. Reaction was warmed to room temperature. Mixture stirred at room temperature for 63 hours. Mixture was washed successively with water (2×50 mL) and brine (30 mL). Organic layer was dried (magnesium sulfate), filtered and concentrated in vacuo. Silica gel chromatography afforded the title compound as off-white solid in 90% yield. (M+H)+=207.1.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)C=O.[CH:11]([Cl:14])(Cl)Cl.C[C:16]1[CH:25]=[C:24](C)[CH:23]=[C:22]2[C:17]=1[CH2:18][CH2:19][CH2:20][C:21]2=[O:27]>O>[Cl:14][C:11]1[C:22]2[C:17](=[CH:16][CH:25]=[CH:24][CH:23]=2)[CH2:18][CH2:19][C:20]=1[CH:21]=[O:27]
Reactant: ClC(Cl)Cl
Reactant: Cc1cc(C)c2c(c1)C(=O)CCC2
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=CC1=C(Cl)c2ccccc2CC1
Reaction time: 0.5 h

Procedure:
1.3 mL of phosphorus oxychloride was added dropwise to 1.6 mL of dimethylformamide under ice cooling, after which the system was brought up to room temperature and stirred for 30 minutes. To this was added at room temperature a 50 mL chloroform solution of 1.8 g of 5,7-dimethyltetralone, and the system was refluxed under heating overnight. After the reaction, water was added and the system was stirred for 30 minutes, after which the organic layer was washed first with a saturated sodium hydrogencarbonate aqueous solution and then with saturated brine, dried with magnesium sulfate, and then subjected to reduced-pressure solvent distillation, and the residue was refined by silica gel column chromatography (5% ethyl acetate/hexane) to obtain 2.0 g of 1-chloro-2-formyl-3,4-dihydronaphthalene in the form of a brown solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([CH2:13][C:14]([OH:16])=O)[CH:10]=[CH:11][CH:12]=2)=[CH:5][CH:4]=[N:3]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[NH2:45][CH2:46][CH:47]([OH:59])[CH2:48][N:49]1[CH2:58][CH2:57][C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH2:50]1>C(Cl)Cl.O>[CH2:50]1[C:51]2[C:56](=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH2:57][CH2:58][N:49]1[CH2:48][CH:47]([OH:59])[CH2:46][NH:45][C:14](=[O:16])[CH2:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[CH:8]=1
Reactant: Cn1nccc1-c1cccc(CC(=O)O)c1
Reactant: NCC(O)CN1CCc2ccccc2C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cn1nccc1-c1cccc(CC(=O)NCC(O)CN2CCc3ccccc3C2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 21.5 %

Procedure:
To a solution of 2-(3-(1-methyl-1H-pyrazol-5-yl)phenyl)acetic acid (150 mg, 0.69 mmol) in DCM (6 mL) was added EDCI (265 mg, 1.38 mmol), HOBt (186 mg, 1.38 mmol), Et3N (209 mg, 2.07 mmol) and 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (142 mg, 0.69 mmol). The mixture was stirred at room temperature for 16 h then diluted with water (10 mL) and extracted with DCM (10 mL×3). The combined organic layers were concentrated. The residue was purified by prep-HPLC to give the product as a colorless oil (60 mg, Yield 21%). 1H NMR (400 MHz, MeOD): 7.47 (s, 1H), 7.43-7.33 (m, 4H), 7.08-7.04 (m, 3H), 6.96-6.94 (m, 1H), 6.35 (s, 1H), 3.96-3.91 (m, 1H), 3.83 (s, 3H), 3.60-3.59 (m, 4H), 3.38-3.20 (m, 2H), 2.84 (t, J=6.0 Hz, 2H), 2.72 (t, J=6.0 Hz, 2H), 2.49 (d, J=6.4 Hz, 2H). LCMS (m/z): 405.2 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:13][N:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C.CC(O)=O>[CH3:13][N:14]1[CH2:19][CH2:18][CH:17]([N:10]2[C:11]3[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=3)[CH2:8][CH2:9]2)[CH2:16][CH2:15]1
Reactant: CN1CCC(=O)CC1
Reactant: O=[N+]([O-])c1ccc2c(c1)NCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CN1CCC(N2CCc3ccc([N+](=O)[O-])cc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-Nitroindoline (5 g) was dissolved in 200 mL of dichloroethane, N-methyl-4-piperidone (5 g) was added to the mixture, followed by 12 g NaBH(OAc)3 and 1 mL of glacial AcOH. The mixture was stirred at RT overnight. Saturated NaHCO3 solution (200 mL) was added to the reaction mixture and stirred for 1 h. The resulting mixture was separated by separation funnel, the organic layer was extracted once with saturated NaHCO3 solution and once with brine. The resulting organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel with 2:1 EtOAc:MeOH to afford an orange oil. MS: 262 (M+1). Calc'd. for C14H19N3O2—261.32.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1.N1C=CC=CC=1.O>ClCCl>[F:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:24][CH:25]=1)=[O:5]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1F
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)c1ccc(NC(=O)c2ccc(C(F)(F)F)cc2F)cc1
Temperature: 25 °C
Yield: 84.3 %

Procedure:
A solution of 2-fluoro-4-(trifluoromethyl)benzoyl chloride (3 g, 13.24 mmol) in dichloromethane (27.6 mL) was added dropwise to a mixture of methyl 4-aminobenzoate (2.0 g, 13.24 mmol), pyridine (3.21 mL, 39.72 mmol) and dichloromethane (41.4 mL) at 0° C. The reaction was stirred and allowed to warm up to room temperature over 2 hours. To the reaction, water (30 mL) was added. The solid was isolated by filtration, washed with water (2×30 mL) and hexane (2×30 mL) to yield methyl 4-[[2-fluoro-4-(trifluoromethyl)benzoyl]amino]benzoate (3.811 g, 84%) as a white solid. ESI-MS m/z calc. 341.07, found 342.2 (M+1)+; Retention time: 1.64 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.02-7.96 (m, 2H), 7.96-7.89 (m, 2H), 7.89-7.83 (m, 2H), 7.76 (dd, J=8.0, 1.6 Hz, 1H), 3.85 (s, 3H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][N:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:5]=[CH:6][CH:7]=1.Cl[CH2:27][CH2:28][S:29](Cl)(=[O:31])=[O:30].[CH2:33]([N:35](CC)[CH2:36][CH3:37])[CH3:34].C([O-])([O-])=O.[K+].[K+].C(NCC)C>CN(C=O)C>[CH2:33]([N:35]([CH2:36][CH3:37])[CH2:27][CH2:28][S:29]([N:23]1[CH2:24][CH2:25][CH:20]([C:11]2[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=4)[CH:9]=3)[NH:13][N:12]=2)[CH2:21][CH2:22]1)(=[O:31])=[O:30])[CH3:34]
Reactant: CCN(CC)CC
Reactant: NC(=O)c1cc(-c2cccc(F)c2)cc2c(C3CCNCC3)n[nH]c12
Reactant: O=S(=O)(Cl)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CCN(CC)CCS(=O)(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(-c4cccc(F)c4)cc23)CC1
Reaction time: 0.17 h
Yield: 14.4 %

Procedure:
The title compound was prepared according to the procedure described in Example 33. Thus, 5-(3-fluorophenyl)-3-(4-piperidinyl)-1H-indazole-7-carboxamide (Intermediate 15) (75 mg, 0.167 mmol) was reacted with 2-chloro-1-ethanesulfonyl chloride (17 uL, 0.167 mmol) in the presence of triethyl amine (93 uL, 0.665 mmol) in DMF (2 mL) at 0° C. After 10 mins., K2CO3 (46 mg, 0.334 mmol) and diethyl amine (52 uL, 0.501 mmol) were added to afford the title compound (12.1 mg, 14% for 2 steps).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]([CH2:30][CH:31]([CH3:33])[CH3:32])[C@@H:13]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16][C@H:15]([C:26]([O:28][CH3:29])=[O:27])[CH2:14]1)=[O:11].Br[CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C.O>[CH3:32][CH:31]([CH3:33])[CH2:30][N:12]([C:10]([C:2]1[N:3]([CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=1)=[O:11])[C@@H:13]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:16][C@H:15]([C:26]([O:28][CH3:29])=[O:27])[CH2:14]1
Reactant: COC(=O)[C@@H]1C[C@H](N(CC(C)C)C(=O)c2nc3ccccc3[nH]2)CN(C(=O)OC(C)(C)C)C1
Reactant: BrCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC(=O)[C@@H]1C[C@H](N(CC(C)C)C(=O)c2nc3ccccc3n2CCc2ccccc2)CN(C(=O)OC(C)(C)C)C1
Temperature: 65 °C
Reaction time: 15 h

Procedure:
To a solution of 1-tert-butyl 3-methyl (3R,5S)-5-[(1H-benzimidazol-2-ylcarbonyl)(2-methylpropyl)amino]piperidine-1,3-dicarboxylate (1.38 g) and (2-bromoethyl)benzene (810 μl) in N,N-dimethylacetamide (30 ml) was added cesium carbonate (2.93 g), and the mixture was stirred at 65° C. for 15 hr. (2-Bromoethyl)benzene (810 μl) was added to the reaction mixture, and the mixture was further stirred at 65° C. for 5 hr. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:1) was concentrated under reduced pressure to give the object product (1.40 g).
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][N:8]=[C:9]([C:12]#[N:13])[C:10]#[N:11].NC1C=CC(C)=CC=1.C(#N)CC#N.O.[NH2:29][NH2:30]>>[NH2:11][C:10]1[C:9](=[N:8][NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH3:14])[C:12]([NH2:13])=[N:30][N:29]=1
Reactant: Cc1ccccc1NN=C(C#N)C#N
Reactant: NN
Solvent: N#CCC#N
Solvent: O
Solvent: Cc1ccc(N)cc1
Product: Cc1ccccc1NN=C1C(N)=NN=C1N
Temperature: 25 °C
Yield: 40 %

Procedure:
This compound was prepared using 92 mg (0.5 mmol) of 2-(o-tolylhydrazono)-malononitrile, which was derived from 4-toluidine (107 μL, 1.0 mmol) and malononitrile (1.5 mmol) as described in Example 8, and hydrazine hydrate. Very little solid had formed after heating the reaction at 75° C. for 1 hr, however, analysis of the reaction solution by TLC indicated that no starting material remained. The solution was allowed to cool to room temperature and the solvent was evaporated. The residue was dissolved in ethyl acetate and then precipitated by the addition of hexanes. The resulting solid was isolated by filtration and dried to yield 43 mg (40%) of the title compound as a yellow solid.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=4)[CH:24]=[C:23]([CH3:37])[N:22]=3)[CH:18]=[N:19][CH:20]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:37][C:23]1[N:22]=[C:21]([C:17]2[CH:18]=[N:19][CH:20]=[C:15]([C:11]3[CH:10]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:14]=[CH:13][CH:12]=3)[CH:16]=2)[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:29][CH:28]=2)[CH:24]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cncc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cncc(-c3cccc(S(N)(=O)=O)c3)c2)n1
Yield: 95.5 %

Procedure:
To a stirred and cooled suspension of N-tert-butyl-3-[6-methyl-4-(4-trifluoromethyl-phenyl)-[2,3′]bipyridinyl-5′-yl]-benzenesulfonamide (example 288) (0.150 g, 0.29 mmol) in dichloromethane (0.9 mL) was added TFA (6.3 mL) and the reaction mixture was allowed to stir at room temperature for 16 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (5 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane/diethyl ether and dried to yield the title compound as a white solid (0.130 g, 97%). MS (ISP) 470.3 [(M+H)+]; mp 235° C. (dec.).
Reaction SMILES: [Mg].II.[CH3:4][S:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10]Cl)=[CH:8][CH:7]=1.C(Cl)C1C=CC=CC=1.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[C:28](=O)[CH:27]([CH3:33])[CH2:26]2>CCOCC>[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH:28]([CH2:10][C:9]1[CH:12]=[CH:13][C:6]([S:5][CH3:4])=[CH:7][CH:8]=1)[C:27]([CH3:33])=[CH:26]2
Reactant: CC1Cc2cc(F)ccc2C1=O
Reactant: CSc1ccc(CCl)cc1
Agent: II
Agent: [Mg]
Solvent: CCOCC
Solvent: ClCc1ccccc1
Product: CSc1ccc(CC2C(C)=Cc3cc(F)ccc32)cc1
Reaction time: 0.07 h

Procedure:
13.44 G. (0.56 mole) of magnesium turnings were placed in a dried flask under N2 with 125 ml. of ether and a crystal of iodine. 6 Ml. of 65 ml. solution of 24.2 g. (0.14 mole) of p-methylthiobenzyl chloride in ether was added. After 3 to 5 minutes of stirring, the iodine color disappeared and the reaction began. After aging for 5 minutes, the rest of the benzyl chloride was added dropwise over 45 minutes. It was rinsed in with 10 ml. of ether and the reaction aged for 2 hours with stirring. 21 G. (0.128 mole) of 5-fluoro-2-methyl-1-indanone dissolved in 50 ml. of ether was added dropwise over 30 minutes. After aging for 1 hour, the milky supernatent mixture was decanted from the magnesium into 100 ml. of acetic acid. The flask and residual magnesium were rinsed into the acid solution with 4 × 50 ml. of benzene. 200 Ml. of water were added, the layers were separated and the organic layer was washed with 5 × 200 ml. water. It was stripped to dryness after drying over Na2SO4. The crude reaction product is crystallized from hexane to give pure 5-fluoro-2-methyl-1-(p-methylthiobenzyl)-indene, melting point 58°-59°C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([N:10]([CH2:49][CH3:50])[CH2:11][CH2:12][CH2:13][NH:14][C:15]1[N:16]=[C:17]([C:34]2[CH:35]=[C:36]([CH:44]=[C:45]([F:48])[C:46]=2[CH3:47])[C:37]([O:39]C(C)(C)C)=[O:38])[C:18]2[CH:24]=[CH:23][C:22](=[O:25])[N:21]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])[C:19]=2[N:20]=1)[CH3:9].ClCCl.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:49]([N:10]([CH2:8][CH3:9])[CH2:11][CH2:12][CH2:13][NH:14][C:15]1[N:16]=[C:17]([C:34]2[CH:35]=[C:36]([CH:44]=[C:45]([F:48])[C:46]=2[CH3:47])[C:37]([OH:39])=[O:38])[C:18]2[CH:24]=[CH:23][C:22](=[O:25])[N:21]([C:26]3[C:27]([F:33])=[CH:28][CH:29]=[CH:30][C:31]=3[F:32])[C:19]=2[N:20]=1)[CH3:50]
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)OC(C)(C)C)cc(F)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)cc(F)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
To the crude compound 1,1-dimethylethyl 3-[2-{[3-(diethylamino)-propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-5-fluoro-4-methylbenzoate trifluoroacetate in dichloromethane (1.5 mL, 23.3 mmol) were added TFA (0.703 mL, 9.5 mmol) and triethylsilane (0.281 mL, 1.82 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA afforded the title compound (301 mg, 40%, 2 steps yield). LC-MS m/z 540 (M+H)+.
Reaction SMILES: FC(F)(F)C([NH:5][C@H:6]1[C:15]2[C:10](=[CH:11][C:12]([CH2:19][N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=2)[CH2:9][CH2:8][CH2:7]1)=O.[OH-].[Na+]>C1COCC1.CO.O>[N+:16]([C:13]1[CH:14]=[C:15]2[C:10]([CH2:9][CH2:8][CH2:7][C@H:6]2[NH2:5])=[CH:11][C:12]=1[CH2:19][N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)([O-:18])=[O:17]
Reactant: O=C(N[C@@H]1CCCc2cc(CN3CCCCC3)c([N+](=O)[O-])cc21)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: N[C@@H]1CCCc2cc(CN3CCCCC3)c([N+](=O)[O-])cc21
Temperature: 25 °C
Yield: 115.2 %

Procedure:
A solution of (R)-2,2,2-trifluoro-N-(7-nitro-6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamide (230 mg, 0.6 mmol) and NaOH (108 mg, 2.7 mmol) in a mixed solvent (THF/MeOH/H2O=5 mL/5 mL/1 mL) was heated at 70° C. for 3 h. After cooling to RT, the solvent was evaporated to dryness and the residue was directly loaded on column chomatography (SiO2, EtOAc to EtOAc/2M NH3 in MeOH=100:15 to 100:20) to give (R)-7-nitro-6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-1-amine (200 mg) as a white solid. Similarly (R)-(1-nitro-5-(2,2,2-trifluoroacetamido)-5,6,7,8-tetrahydronaphthalen-2-yl)methyl acetate was converted to (R)-5-nitro-6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-1-amine according to the above sequence of reactions.
Reaction SMILES: [CH:1]1([S:7]Cl)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:9]1([NH:15][S:16]([C:19]2[S:20][C:21]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:22]=3[N:23]=2)(=[O:18])=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C(N(CC)CC)C.C(Cl)(Cl)Cl>CN(C)C=O>[CH:1]1([S:7][N:15]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[S:16]([C:19]2[S:20][C:21]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:22]=3[N:23]=2)(=[O:17])=[O:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: ClSC1CCCCC1
Reactant: O=S(=O)(NC1CCCCC1)c1nc2cc(Cl)ccc2s1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=S(=O)(c1nc2cc(Cl)ccc2s1)N(SC1CCCCC1)C1CCCCC1
Temperature: 0 °C

Procedure:
2.6 grams of cyclohexyl chlorosulfide (0.0172 mole) prepared as in Example 1 is added slowly to a stirred solution containing 5.4 grams (0.0163 mole) of N-cyclohexyl-5-chlorobenzothiazole-2-sulfonamide, and 2 grams of triethylamine (0.0178 mole) in 150 ml anhydrous dimethylformamide. The temperature is maintained between about 15° and 20° C. After stirring, 100 ml of chloroform is added and the reaction mixture is poured into 2 liters of ice water, and treated as in Example 5.
Reaction SMILES: C([C:5]1[S:13][C:8]2=[CH:9][N:10]=[CH:11][CH:12]=[C:7]2[C:6]=1[NH2:14])(OC)=O.[NH:15]1[CH2:20][CH2:19]N[CH2:17][CH2:16]1>CN1CCCC1=O.O>[N:14]1([C:6]2[C:7]3[C:8](=[CH:9][N:10]=[CH:11][CH:12]=3)[S:13][CH:5]=2)[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]1
Reactant: C1CNCCN1
Reactant: COC(=O)c1sc2cnccc2c1N
Solvent: CN1CCCC1=O
Solvent: O
Product: c1cc2c(N3CCNCC3)csc2cn1
Temperature: 25 °C

Procedure:
A mixture of 2-carbomethoxy-3-aminothieno[2,3-c]pyridine (5.0 g), and piperazine (4.13 g) in N-methylpyrrolidinone (30 ml) was heated to 150° until decarboxyalkylation was complete. The mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic extracts were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated in vacuo. The residual 3-aminothieno[2,3-c]pyridine, piperazine (12.5 g), p-toluenesulfonic acid (100 mg), and N-methylpyrrolidinone (50 ml) was heated under reflux (202°) overnight. The mixture was allowed to cool to room temperature, diluted with water, and extracted with dichloromethane. The organic extracts were combined, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated in vacuo, finally at 50° (0.1 mm Hg). The residue was chromatographed on silica, using 1:1 dichloromethane:methanol eluent. The appropriate fractions were combined and concentrated. Crystallization of the residue from ethyl acetate provided 0.66 g (12%) of product, mp 126°-127.5° (dried 80° 0.1 mm Hg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([OH:28])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][CH:17]=2)[C:5]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:6][C:7]=1[CH3:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][CH2:37][CH2:38][CH2:39][OH:40].O>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH2:36][CH2:37][CH2:38][CH2:39][OH:40])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][CH:17]=2)[C:5]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:6][C:7]=1[CH3:8]
Reactant: OCCCCBr
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3cccnc3)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3cccnc3)ccnc2cc1OCCCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.4 %

Procedure:
4-(5,6-Dimethyl-[2,3′]bipyridin-3-yloxy)-6-methoxy-quinolin-7-ol (compound 345) (45 mg) was dissolved in N,N-dimethylformamide (2 ml) to prepare a solution. Potassium carbonate (50 mg) and 4-bromo-1-butanol (55 mg) were added to the solution, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, the mixture was extracted with ethyl acetate, and the ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-acetone to give the title compound (19 mg, yield 35%).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][N:6]([C:8]2[C:21]([CH:22]=O)=[CH:20][C:11]3[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:13][O:14][C:10]=3[C:9]=2[F:24])[CH2:5][C@H:4]([CH3:25])[O:3]1.[NH:26]1[C:33](=[O:34])[CH2:32][C:30](=[O:31])[NH:29][C:27]1=[O:28]>C(O)C>[F:24][C:9]1[C:10]2[O:14][N:13]=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:11]=2[CH:20]=[C:21]2[C:8]=1[N:6]1[CH2:5][C@@H:4]([CH3:25])[O:3][C@@H:2]([CH3:1])[C@@H:7]1[C:32]1([C:30](=[O:31])[NH:29][C:27](=[O:28])[NH:26][C:33]1=[O:34])[CH2:22]2
Reactant: O=C1CC(=O)NC(=O)N1
Reactant: CCOC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(C=O)cc12
Solvent: CCO
Product: CCOC(=O)c1noc2c(F)c3c(cc12)CC1(C(=O)NC(=O)NC1=O)[C@H]1[C@H](C)O[C@H](C)CN31
Yield: 89.5 %

Procedure:
Ethyl 6-((2R,6S)-2,6-dimethylmorpholino)-7-fluoro-5-formylbenzo[d]isoxazole-3-carboxylate (Intermediate 439, 350 mg, 1.00 mmol) and barbituric acid (141 mg, 1.10 mmol) were heated to reflux in ethanol (45 ml) for 64 hours. The reaction was concentrated. The residue was dissolved in DCM, absorbed onto silica and purified by silica gel column chromatography using a gradient of DCM to ethyl acetate, to give the title compound (412 mg, 76%) as a racemic mixture.