Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1)/[CH:3]=[CH:4]/[C:5]1[C:13]2[C:8](=[CH:9][C:10](/[CH:14]=[CH:15]/[C:16]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:17])=[CH:11][CH:12]=2)[N:7]([CH2:23][C:24]2[CH:32]=[CH:31][C:27]([C:28]([OH:30])=O)=[CH:26][C:25]=2[O:33][CH3:34])[CH:6]=1.Cl.CN(C)CCCN=C=NCC.[CH3:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[S:59]([NH2:62])(=[O:61])=[O:60]>CN(C)C1C=CN=CC=1.CN(C)C=O.C(Cl)Cl.CO>[O:1]=[C:2]([N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1)/[CH:3]=[CH:4]/[C:5]1[C:13]2[C:8](=[CH:9][C:10](/[CH:14]=[CH:15]/[C:16]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:17])=[CH:11][CH:12]=2)[N:7]([CH2:23][C:24]2[CH:32]=[CH:31][C:27]([C:28]([NH:62][S:59]([C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=3[CH3:52])(=[O:60])=[O:61])=[O:30])=[CH:26][C:25]=2[O:33][CH3:34])[CH:6]=1
Reactant: COc1cc(C(=O)O)ccc1Cn1cc(/C=C/C(=O)N2CCCC2)c2ccc(/C=C/C(=O)N3CCCC3)cc21
Reactant: Cc1ccccc1S(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NS(=O)(=O)c2ccccc2C)ccc1Cn1cc(/C=C/C(=O)N2CCCC2)c2ccc(/C=C/C(=O)N3CCCC3)cc21
Yield: 84.4 %

Procedure:
A mixture of E,E-4-[3,6-Di(3-oxo-3-pyrrolidino-1-propenyl)indol-1-ylmethyl]-3-methoxybenzoic acid (0.45 g), 4-dimethylaminopyridine (0.13 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.21 g) and 2-methylbenzenesulfonamide (0.19 g), in N,N-dimethylformamide (10 ml) and methylene chloride (25 ml), was stirred for 48 hr. The methylene chloride was evaporated and the remaining solution added slowly to rapidly-stirred 2M hydrochloric acid (100 ml), the precipitate isolated by filtration and washed with water. The solid obtained was heated to reflux in methanol (50 ml), cooled, and the product isolated by filtration to give the title compound (0.49 g, 84%) as a yellow powder, mp 297°-299°.
Reaction SMILES: [NH2:1][C:2]1[CH:42]=[CH:41][C:5]([CH2:6][O:7][CH:8]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[O:32][CH3:33])=[CH:16][CH:15]=3)[CH2:12][CH2:11][N:10]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:9]2)=[CH:4][C:3]=1[O:43][CH2:44][CH2:45][CH2:46][O:47][CH3:48].[C:49](Cl)(=[O:51])[CH3:50]>C(N(CC)CC)C.ClCCl>[C:49]([NH:1][C:2]1[CH:42]=[CH:41][C:5]([CH2:6][O:7][CH:8]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[O:32][CH3:33])=[CH:16][CH:15]=3)[CH2:12][CH2:11][N:10]([C:34]([O:36][C:37]([CH3:39])([CH3:40])[CH3:38])=[O:35])[CH2:9]2)=[CH:4][C:3]=1[O:43][CH2:44][CH2:45][CH2:46][O:47][CH3:48])(=[O:51])[CH3:50]
Reactant: CC(=O)Cl
Reactant: COCCCOc1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCCOc1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1NC(C)=O
Reaction time: 2 h

Procedure:
The solution of 0.380 g of tert-butyl 3-[4-amino-3-(3-methoxypropoxy)benzyloxy]-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 0.168 ml of triethylamine and 10.0 ml of dichloromethane is cooled to 0° C. and admixed slowly with the solution of 0.090 ml of acetyl chloride in 1.0 ml of dichloromethane. The reaction solution is stirred over 2 hours, poured onto ice-water (20 ml) and extracted with tert-butyl methyl ether (2×20 ml). The organic phases are washed with successively with water (20 ml) and brine (20 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.10 (1:1 EtOAc-heptane); Rt=5.73.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:6][CH:5]=[CH:4][N:3]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.C(Cl)Cl.C(Cl)(Cl)Cl>[O:11]([CH2:10][CH2:9][NH:8][C:7]1[C:2]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[N:3][CH:4]=[CH:5][N:6]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Clc1nccnc1NCCOc1ccccc1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: c1ccc(OCCNc2nccnc2N2CCNCC2)cc1
Temperature: 140 °C
Reaction time: 12 h
Yield: 78 %

Procedure:
A mixture of the product from Step 1 above (1.59 g, 6.37 mmol), piperazine (1.56 g, 18.2 mmol), and K2CO3 (0.88 g, 6.4 mmol) in acetonitrile (10 mL) was stirred at 140° C. for 12 h in a sealed tube. After cooling, the reaction mixture was diluted with CH2Cl2, filtered, and concentrated. The semisolid residue was purified by chromatography on silica gel using CHCl3/MeOH (9:1) as eluent to give a beige oil. This oil was redissolved in CHCl3, and filtered through a short (3 cm) plug of alumina covered with K2CO3. The pad was washed with several portions of CHCl3 and the resulting filtrate was concentrated to afford 1.48 g (78%) of the title product as a pale yellow oil. HRMS m/z calcd for C16H21N5O (M)+ 299.1746, found 299.1753. Anal. (C16H21N5O.1/3H2O) C, H, N.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:3]=1[CH:4]([OH:20])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:6]=1.[F:26][C:27]([F:37])([F:36])[C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1.C(O)(=O)C.[BH4-].C([Na])#N>CO>[Cl:25][C:22]1[CH:23]=[CH:24][C:2]([NH:1][CH2:32][C:31]2[CH:30]=[CH:29][C:28]([C:27]([F:26])([F:36])[F:37])=[CH:35][CH:34]=2)=[C:3]([CH:21]=1)[CH:4]([OH:20])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][NH:12][C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[CH:6]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)NCc1cccc(C(O)c2cc(Cl)ccc2N)c1
Agent: N#C[Na]
Agent: [BH4-]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCc1cccc(C(O)c2cc(Cl)ccc2NCc2ccc(C(F)(F)F)cc2)c1
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 83.6 %

Procedure:
In methanol (20 ml) were dissolved 2-amino-5-chloro-α-(3-tert-butoxycarbonylaminomethylphenyl)benzyl alcohol (0.5 g) obtained in Example 1 (2) and 4-trifluoromethylbenzaldehyde (0.28 g). To the solution were added acetic acid (0.1 g) and cyano sodium borohydride (0.17 g). The mixture was stirred for 40 minutes at 60° C. The reaction mixture was concentrated, to which were added ethyl acetate (30 ml) and water (20 ml), followed by extraction. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by means of a silica gel column chromatography to give 5-chloro-2-(4-trifluoromethylbenzylamino)-α-(3-tert-b-utoxycarbonylaminomethylphenyl)benzyl alcohol (0.6 g) as a colorless oily product.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([OH:10])[C:3]=1[OH:11].CC([O-])(C)C.[Na+].Br[CH2:19][CH2:20][CH2:21][O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CS(C)=O>[CH2:23]([O:22][CH2:21][CH2:20][CH2:19][O:11][C:3]1[C:4]([OH:10])=[C:5]([CH:8]=[CH:9][C:2]=1[F:1])[CH:6]=[O:7])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCCCOCc1ccccc1
Reactant: O=Cc1ccc(F)c(O)c1O
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=Cc1ccc(F)c(OCCCOCc2ccccc2)c1O

Procedure:
Synthesized according to the methods of general procedure 4 in U.S. Pat. Pub. No. 20090227541 (U.S. patent application Ser. No. 12/142,692) using the following reactants and amounts: 4-fluoro-2,3-dihydroxy-benzaldehyde (5.15 g, 32.9 mmol), NaOtBu (6.95 g, 72.3 mmol), DMSO (200 mL), (3-bromo-propoxymethyl)-benzene (8.31 g, 36.3 mmol). Purification: Biotage silica gel chromatography (hexanes/ethyl acetate gradient) generated 4.00 g of a mixture of the title compound and the dialkylated product. This material was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.13 (s, 1H), 7.66-7.54 (m, 5H), 7.53-7.33 (m, 1H), 6.92-6.90 (m, 1H), 4.53 (s, 2H), 4.52-4.44 (m, 2H), 3.71-3.62 (m, 2H), 2.18-2.13 (m, 2H). 19F NMR (376 MHz, DMSO-d6 with D2O) δ (ppm): −121.03-−121.08 (m, 1F).
Reaction SMILES: [CH3:1][O:2][C:3]1([O:24][CH3:25])[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20]N)[O:17][C:16]3=[O:22])=[CH:11][CH:10]=2)[CH2:5][CH:4]1[F:23].[N:26]1C=CC=[CH:28][CH:27]=1.C(OC(=O)C)(=[O:34])C>C(OCC)(=O)C>[CH3:1][O:2][C:3]1([O:24][CH3:25])[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[CH:11][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][CH2:28][C:27]([NH2:26])=[O:34])[O:17][C:16]3=[O:22])=[CH:13][CH:14]=2)[CH2:5][CH:4]1[F:23]
Reactant: COC1(OC)CCN(c2ccc(N3C[C@H](CN)OC3=O)cc2)CC1F
Reactant: CC(=O)OC(C)=O
Reactant: c1ccncc1
Solvent: CCOC(C)=O
Product: COC1(OC)CCN(c2ccc(N3C[C@H](CCC(N)=O)OC3=O)cc2)CC1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 49 %

Procedure:
The mixture of (S)-{3-[4-(4,4-dimethoxy-3-fluoropiperidin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-amine (6.73 mmol), pyridine (26.9 mmol), acetic anhydride (9.43 mmol) in ethyl acetate (25 ml) was stirred for 5 hours at room temperature. The reaction mixture was extracted with the ethyl acetate water mixture and combined organic layer was dried over sodium sulfate. The removal of the solvent afforded a residue, which was chromatographed over silica gel to give title compound in 49% yield.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[CH:7][C:8]([CH3:10])=O)[CH2:3][CH2:2]1.O1CCC(CC(C)=O)CC1.[C:21]([O:28][CH2:29][CH3:30])(=[O:27])[C:22](OCC)=O.CC(C)([O-])C.[Na+].[OH:37][CH2:38][CH2:39][NH:40][NH2:41]>C(O)C>[OH:37][CH2:38][CH2:39][N:40]1[C:8]([CH2:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[CH:10][C:22]([C:21]([O:28][CH2:29][CH3:30])=[O:27])=[N:41]1
Reactant: NNCCO
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)C=C1CCOCC1
Agent: CC(=O)CC1CCOCC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc(CC2CCOCC2)n(CCO)n1
Yield: 101.9 %

Procedure:
The method described in Part B of Example 3 was repeated with 1-tetrahydro-4H-pyran-4-ylideneacetone (4.0 g, 28.5 mmol), and the resulting 1-tetrahydro-2H-pyran-4-ylacetone was mixed with diethyl oxalate (4.66 g, 31.9 mmol) and added to a solution of sodium tert-butoxide (3.07 g, 31.9 mmol) in ethanol (22 mL). The reaction was carried out according to the method described in Part C of Example 3 with the following modifications. Hydroxyethylhydrazine (2.43 g, 31.9 mmol) was used instead of ethylhydrazine oxalate. Extractions were carried out seven times with chloroform, and the crude product was not purified. Ethyl 1-(2-hydroxyethyl)-5-(tetrahydro-2H-pyran-4-ylmethyl)-1H-pyrazole-3-carboxylate (8.2 g) was obtained as a viscous yellow oil.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:22]([F:23])=[C:21]([F:24])[C:20](F)=[C:19]([F:26])[C:18]=2[F:27])=[CH:13][CH:12]=1.Cl>CCOCC>[NH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[C:18]([F:27])=[C:19]([F:26])[C:20]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[C:21]([F:24])[C:22]=2[F:23])=[CH:15][CH:16]=1
Reactant: [Li]CCCCCCCC
Reactant: Nc1ccc(-c2c(F)c(F)c(F)c(F)c2F)cc1
Agent: Cl
Solvent: CCOCC
Product: CCCCCCCCc1c(F)c(F)c(-c2ccc(N)cc2)c(F)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
n-Octyllithium in dry ether (9.5 mL) was added slowly to a solution of 4-amino-2′,3′,4′,5′,6′-pentafluorobiphenyl (1.5 g, 5.79 mmol, Example 9) in dry ether (100 mL) at −78° C. The solution was stirred at this temperature for 2 hours and then allowed to warm to room temperature over a period of 5 hours. Hydrochloric acid (3M, 100 mL) was added and a white solid was precipitated from the solution. The solid was filtered and dried. After sublimation, 4-amino-4′-n-octyl-2′,3′,5′,6′-tetrafluorobiphenyl was obtained as a white solid (1.2 g, 63% yield).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:8]([C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])=[CH:9][C:10]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:11]([CH:15]=2)[C:12]([OH:14])=O)[CH:4]=[N:3]1.C(N(C(C)C)CC)(C)C.[NH2:41][C:42]1[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CN(C)C=O>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:8]([C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])=[CH:9][C:10]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[C:11]([CH:15]=2)[C:12]([NH:41][C:42]2[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=2)=[O:14])[CH:4]=[N:3]1
Reactant: Nc1cccnc1
Reactant: Cn1cc(-c2cc(C(=O)O)c(OCc3ccccc3)cc2C(=O)N2CCOCC2)cn1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(-c2cc(C(=O)Nc3cccnc3)c(OCc3ccccc3)cc2C(=O)N2CCOCC2)cn1
Reaction time: 18 h

Procedure:
To a solution of 5-(1-methyl-1H-pyrazol-4-yl)-4-(4-morpholinylcarbonyl)-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 26; 150 mg, 0.36 mmol) in N,N-dimethylformamide (3 ml) was added diisopropylethylamine (0.12 ml, 0.71 mmol), 3-aminopyridine (40.2 mg, 0.43 mmol), 1-hydroxy-7-azabenzotriazole (58.1 mg, 0.43 mmol) and EDC (116 mg, 0.61 mmol). The reaction was stirred for 18 hours and then the solvent was removed in vacuo. The residue was purified by MDAP to yield the title compound as a yellow gum. 111 mg.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5]([Cl:6])=[N:4][C:2]=1Cl.C(N(C(C)C)CC)(C)C.[N:19]([CH2:22][CH2:23][CH2:24][NH2:25])=[N+:20]=[N-:21]>CC(C)=O>[N:19]([CH2:22][CH2:23][CH2:24][NH:25][C:2]1[N:1]=[C:8]([Cl:9])[N:7]=[C:5]([Cl:6])[N:4]=1)=[N+:20]=[N-:21]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: [N-]=[N+]=NCCCN
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)=O
Product: [N-]=[N+]=NCCCNc1nc(Cl)nc(Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.3 %

Procedure:
To a solution of cyanuric chloride (18.42 g, 0.10 mol) in acetone (180 mL) in an ice-water bath was added diisopropylethylamine (DIPEA) (12.92 g, 0.10 mol). 1-azido-3-aminopropane (5.00 g, 0.050 mol) in acetone (50 mL) was added slowly over 2 hours. The reaction was stirred at room temperature overnight. The solvent was removed under reduced pressure. The residue was dissolved in CH2Cl2, washed with water, dried (Na2SO4) and rotary evaporated. The resulting residue was purified by column chromatography on silica gel (eluent CH2Cl2) to give 1 as a white solid (5.62 g, 45%): ESI-MS m/z 248.1 (M+H+) calculated for C6H8Cl2N7 248.0.
Reaction SMILES: C(Cl)(Cl)Cl.[Cl:5][C:6]1[CH:20]=[CH:19][C:9]([CH2:10][CH:11]2[CH2:15][CH2:14][CH:13]([CH2:16][CH3:17])[C:12]2=[CH2:18])=[CH:8][CH:7]=1.ClC1C=CC=C(C(OO)=[O:29])C=1.[OH-].[Ca+2].[OH-]>O>[Cl:5][C:6]1[CH:20]=[CH:19][C:9]([CH2:10][CH:11]2[CH2:15][CH2:14][CH:13]([CH2:16][CH3:17])[C:12]32[O:29][CH2:18]3)=[CH:8][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C1C(CC)CCC1Cc1ccc(Cl)cc1
Agent: [Ca+2]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCC1CCC(Cc2ccc(Cl)cc2)C12CO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into 100 ml of chloroform, 8.0 g of 2-(4-chlorobenzyl)-5-ethyl-1-methylenecyclopentane (the compound No. 129 shown in Table 3) were dissolved, and then 11.6 g of m-chloroperbenzoic acid were added to the thus formed mixture within 5 min, and the whole mixture was stirred for 2 hours at room temperature. In the next place, 11 g of calcium hydroxide were added to the mixture under cooling with iced water, and the whole mixture was stirred for 30 min at room temperature.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH:11][CH2:12][CH2:13][CH2:14][Cl:15])[C:3]=1[N+:16]([O-:18])=[O:17].CI.[C:21](=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:21])=[O:7])=[C:4]([NH:11][CH2:12][CH2:13][CH2:14][Cl:15])[C:3]=1[N+:16]([O-:18])=[O:17]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1NCCCCl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1NCCCCl
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.6 %

Procedure:
A mixture of 4-chloro-2-[(3-chloropropyl)amino]-3-nitrobenzoic acid (150 mg, 0.512 mmol), methyl iodide (0.0319 mL, 0.512 mmol) and potassium carbonate (70.8 mg, 0.512 mmol) in N,N-dimethylformamide (1.5 mL) was stirred at room temperature for 12 h. After addition of ethyl acetate, the resultant mixture was washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on NH silica gel eluting with a 5% ethyl acetate/n-hexane mixture to afford a yellow oil (141 mg, 0.459 mmol, 90%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)([C:14]#[N:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:24].[NH4+]>S(=O)(=O)(O)O>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)([C:14]([NH2:15])=[O:24])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CC1(Nc2ccc(F)cc2)CCN(Cc2ccccc2)CC1
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: NC(=O)C1(Nc2ccc(F)cc2)CCN(Cc2ccccc2)CC1
Reaction time: 24 h

Procedure:
Cautiously combine 1-benzyl-4-(4-fluoro-phenylamino)-piperidine-4-carbonitrile (60 mmol) and concentrated sulfuric acid (270 mL). Let stand for 24 h at ambient temperature. Cautiously pour the reaction mixture into excess dilute ammonium hydroxide solution/ice. Extract with dichloromethane (3×300 mL). Combine the dichloromethane extracts and extract them using saturated NaHCO3 solution (3×300 mL). Dry the dichloromethane solution over magnesium sulfate, filter, and concentrate in vacuo to obtain a residue. Purify to obtain the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[S:15][CH:16]=2)=[CH:8][CH:7]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>C(OCC)(=O)C.CO>[S:15]1[CH:16]=[C:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:7][CH:8]=2)[C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]1=2
Reactant: BrCCCOc1ccc(-c2csc3ccccc23)cc1
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CO
Product: c1ccc2c(-c3ccc(OCCCN4CCCCC4)cc3)csc2c1

Procedure:
The title compound is prepared from 3-[4-(3-bromo-propoxy)-phenyl]-benzo[b]thiophene, piperidine, potassium carbonate and acetonitrile essentially as described above in Example 118 except that the column chromatography is performed with a graded solvent mixture from 100% ethyl acetate to 10% methanol in ethyl acetate. Purity by LC/MS=99%, [M+H]+=352.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])[CH2:7][C:6]2=[O:21])#N.[OH-:22].[K+].Cl.C[OH:26]>>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:8]1[CH2:7][C:6](=[O:21])[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([C:1]([OH:26])=[O:22])[CH:4]=2)[N:9]=1
Reactant: [OH-]
Reactant: CO
Reactant: COc1ccccc1C1=Nc2ccc(C#N)cc2C(=O)C1
Agent: Cl
Agent: [K+]
Product: COc1ccccc1C1=Nc2ccc(C(=O)O)cc2C(=O)C1
Temperature: 0 °C

Procedure:
The compound of example 57 was prepared in the following manner: to 4 grams of 6-cyano-2-(2-methoxyphenyl)-4-quinolone were added 3 grams of potassium hydroxide and 100 ml. of methanol, the mixture was heated to reflux for 4 hours, then poured into ice water. The mixture was adjusted to pH 3 with 10% hydrochloric acid, and crystals which separate out therefrom were collected by filtration and recrystallized from dimethyl formamide to give 2.7 grams of the desired 2-(2-methoxyphenyl)-4-quinolone-6-carboxylic acid, colorless crystals, melting point 290° to 294° C.
Reaction SMILES: CO[C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:6][CH:5]=1.COC(=O)[C:21]1C=[CH:25][C:24]([CH:27]=O)=[N:23][CH:22]=1.[NH:30]1CCC[CH2:32][CH2:31]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.[OH-].[Na+]>[NH3:6].[CH:24]([N:23]1[CH2:22][CH2:21][N:30]([C:3]([C:4]2[CH:5]=[N:6][C:7]([CH2:10][N:11]3[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]3)=[CH:8][CH:9]=2)=[O:17])[CH2:31][CH2:32]1)([CH3:25])[CH3:27]
Reactant: C1CCNCC1
Reactant: COC(=O)c1ccc(CN2CCCCC2)nc1
Reactant: COC(=O)c1ccc(C=O)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)N1CCN(C(=O)c2ccc(CN3CCCCC3)nc2)CC1
Product: N
Reaction time: 18 h
Yield: 74 %
Yield: 1 %

Procedure:
6-Piperidin-1-ylmethyl-nicotinic acid methyl ester. To a solution of 6-formyl-nicotinic acid methyl ester (0.200 g, 1.21 mmol) and piperidine (0.14 mL, 1.33 mmol) in DCM (15 mL) was added NaB(OAc)3H (0.380 g, 1.80 mmol). After 18 h, the reaction was diluted with 1 N NaOH (10 mL) and extracted with DCM (2×50 mL). The organic layers were combined, dried (Na2SO4), and concentrated. Chromatography of the residue (SiO2; 1-3% 2 M NH3 in MeOH/DCM) gave the title compound as an oil (0.210 g, 74%).
Reaction SMILES: CS[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:13]=[C:12]([N:22]3[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]3)[N:11]=2)=[CH:5][CH:4]=1.O[O:30][S:31]([O-:33])=O.[K+].[CH3:35]C(C)=O.O>>[CH3:35][S:31]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:13]=[C:12]([N:22]3[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]3)[N:11]=2)=[CH:7][CH:8]=1)(=[O:33])=[O:30]
Reactant: CSc1ccc(Nc2cc(-c3ccccc3)nc(N3CCC(O)CC3)n2)cc1
Reactant: CC(C)=O
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)c1ccc(Nc2cc(-c3ccccc3)nc(N3CCC(O)CC3)n2)cc1

Procedure:
1-[4-(4-Methylsulfanyl-phenylamino)-6-phenyl-pyrimidin-2-yl]-piperidin-4-ol was oxidized (0.27 g, 0.69 mmol) with oxone (1.6 g, 2.76 mmol) in acetone-water (3:1) at room temperature for 1 hour.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:19]=[C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=1[F:18].C(O)(C)C.[NH4+]=S>O>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:7]2[CH:6]=[CH:5][N:4]=[C:3]([N:19]=[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:2]=2[Cl:1])=[C:10]([F:18])[CH:11]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc(N=C(c3ccccc3)c3ccccc3)c2Cl)c(F)c1
Solvent: CC(C)O
Solvent: O
Product: Nc1ccc(Oc2ccnc(N=C(c3ccccc3)c3ccccc3)c2Cl)c(F)c1
Temperature: 20 °C
Reaction time: 3.5 h
Yield: 103.2 %

Procedure:
The following materials were added to a 2-L CHEMGLASS® reactor: 3-chloro-N-(diphenylmethylene)-4-(2-fluoro-4-nitrophenoxy)pyridin-2-amine (110.00 g, 221 mmol), isopropyl alcohol (990.00 mL), ammonium sulfide (˜40% in water, 297.00 mL, 2324 mmol). The mixture was allowed to stir at 20° C. for 3-4 h. 3-Chloro-N-(diphenylmethylene)-4-(2-fluoro-4-nitrophenoxy)pyridin-2-amine was not detected by HPLC analysis. The reaction mixture was heated to 70° C. and allowed to stir for 3-4 h. Once the reaction was complete, water (14 mL/g·LR) was added. The reaction mixture was cooled to 20° C. (reaction temp) over 1 h. Upon cooling a solid precipitated and was filtered off and washed with water (12.5 mL/g·LR), followed by heptane:MTBE (4:1; 5 mL/g·LR). After LOD (˜25%), 95.3 g of crude 4-(4-amino-2-fluorophenoxy)-3-chloro-N-(diphenylmethylene)pyridin-2-amine (90AP) was obtained. The crude 4-(4-amino-2-fluorophenoxy)-3-chloro-N-(diphenylmethylene)pyridin-2-amine was dissolved into n-BuOAc (7 mL/g·LR) by heating to approximately 85° C. At 85° C., heptane (7 mL/g·LR) was added dropwise until the solution became cloudy. The solution was then allowed to cool to 20° C. with stirring. Once at 20° C., the slurry was aged for 8 h. The solid was filtered, washed with heptane (5 mL/g·LR), and then dried overnight in a vacuum oven at 60° C. to afford 4-(4-amino-2-fluorophenoxy)-3-chloro-N-(diphenylmethylene)pyridin-2-amine (62.53 g; 67.69% yield) as a faint yellow solid. 1H NMR (CDCl3) δ 6.23 (dd, 1H, J=1.0, 5.6 Hz), 6.43 (m, 1H), 6.49 (dd, 1H, J=2.5, 12.1 Hz), 6.92 (t, 1H, J=8.6 Hz), 7.25-7.60 (m, 8H), 7.87 (m, 2H), 7.95 (d, 1H, J=6.1 Hz); MS (ESI+) m/z 418.6 (M+H)+.