Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[N:8][O:9][C:5]=2[CH:4]=1.[C:18]([O-:21])([O-])=O.[K+].[K+].Br[CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36](=[O:38])[CH3:37])=[CH:32][C:31]=1OC.CN(C)C=O>O>[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:11][CH2:12][N:13]([CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]4[CH:31]=[CH:32][C:33]([C:36](=[O:38])[CH3:37])=[C:34]([O:21][CH3:18])[CH:35]=4)[CH2:14][CH2:15]3)=[N:8][O:9][C:5]=2[CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cc(C(C)=O)ccc1OCCCCBr
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OCCCCN2CCC(c3noc4cc(F)ccc34)CC2)ccc1C(C)=O
Temperature: 75 °C
Yield: 87.4 %

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (5.1 g, 0.02 mol), K2CO3 (5.2 g, 0.04 mol), 1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone(6.6 g, 22 mmol), and dimethylformamide (60 ml) was heated at 75° C. for 5 hours. The reaction was poured into water, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate was washed (water), dried (MgSO4), and the solvent was concentrated to yield initially an oil, which solidified upon standing. The solid was triturated with hexane and collected to afford 7.7 g of the product as a waxy solid. The compound was chromatographed on a Waters Prep 500 utilizing silica gel columns and eluting with dichloromethane/methanol (5%). Concentration of the appropriate fractions yielded 5.1 g of off-white solid 1-[4-[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-butoxy]-3-methoxyphenyl]ethanone, which when recrystallized from ethyl alcohol yielded 3.2 g (36%) of feathery-white needles, m.p.=88°-90° C.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[S:20]1[CH:24]=[CH:23][N:22]=[C:21]1[C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=O>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[C:25]([C:21]3[S:20][CH:24]=[CH:23][N:22]=3)[CH:26]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cccc(-c2nccs2)c1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cccc(-c2nccs2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with commercially available 3-(thiazol-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.82 min.; [M+H]+: 409.14 g/mol.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:4][N:3]=1.[CH3:16][O-:17].[Na+]>CO>[CH3:16][O:17][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:4][N:3]=1
Reactant: O=S(c1ccccc1)c1ccc(Br)nc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(S(=O)c2ccccc2)cn1

Procedure:
A solution of 2-bromo-5-phenylsulfinylpyridine (2.82 g., 0.01 mole) and 0.50 g. of sodium methoxide is heated in 50 ml. of refluxing methanol for 5 hours. The reaction mixture is evaporated in vacuo, and the residue is diluted with water. The solids are collected by filtration, washed with water and dried to yield 2-methoxy-5-phenylsulfinylpyridine.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][O:21][CH3:22])[CH2:15][CH2:14]1>CCOC(C)=O.CO>[CH3:1][C:2]1[C:3]([N:13]2[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][O:21][CH3:22])[CH2:17][CH2:18]2)=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:7]=1)[NH2:8]
Reactant: COCCN1CCN(c2cc(OC)c([N+](=O)[O-])cc2C)CC1
Solvent: CO
Solvent: CCOC(C)=O
Product: COCCN1CCN(c2cc(OC)c(N)cc2C)CC1
Reaction time: 8 h
Yield: 366.3 %

Procedure:
1-[2-methyl-5-(methyloxy)-4-nitrophenyl]-4-[2-(methyloxy)ethyl]piperazine (1.44 g, 4.66 mmol) was placed in a 100 mL high pressure vessel and dissolved in 60 mL of 1 to 1 EtOAc/MeOH. 5 wt % Platinum(sulfided)/C (1.09 g, 0.28 mmol) was added followed quickly by a rubber septum. The vial was evacuated and filled with N2 six times to remove any oxygen. The vial was then pressurized with H2 (60 psi). The solution stirred overnight. The next morning the vessel was evacuated and filled with N2 six times to remove any H2. The solution was filtered through celite and evaporated to afford the title compound of step B (1.15 g, 17.07 mmol, 88%). 1H NMR (400 MHz, DMSO-d6) δ ppm 6.56 (s, 1H), 6.42 (s, 1H), 4.30 (s, 2H), 3.70 (s, 3H), 3.43 (t, J=5.87 Hz, 2H), 3.23 (s, 3H), 2.71 (t, J=4.58 Hz, 4H), 2.45-2.56 (m, 6H), 2.04 (s, 3H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Cl[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(O)C>[CH:12]1[C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=[C:10]([S:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:11]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1ccc(Sc2ccc(Cl)cc2)cc1
Temperature: 100 °C
Yield: 100.7 %

Procedure:
A mixture of 43.5 g of p-chlorothiophenol, 47.1 g of p-chloronitrobenzene, 39.0 g of sodium carbonate, 120 ml of water and 150 ml of ethanol was heated at 100° C. for 19 hours, giving 80.0 g of 4-chloro4'-nitrodiphenylsulfide, which was then dissolved in a mixture of 400 ml of acetic acid and 100 ml of 30% hydrogen peroxide and stirred at 100° C. for one hour, giving 80.2 g of the corresponding sulfonyl derivative.
Reaction SMILES: [CH2:1]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[Br:11]N1C(=O)CCC1=O.C(O)(=O)C.C(Cl)(Cl)Cl>O>[Br:11][C:8]1[S:7][C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:10][CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCc1cccs1
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: CCCCCc1ccc(Br)s1
Yield: 97.6 %

Procedure:
A solution of 2-pentylthiophene, (25.2 g) N-bromosuccinimide (25.5 g) and a 1:1 chloroform acetic acid mixture (100 cm3) was heated under reflux for 1 h. Water (10 cm3) was added and the resultant solution stirred for 10 min under an atmosphere of nitrogen. The organic layer was separated off and the aqueous layer extracted with diethyl ether (2×50 cm3). The combined organic layers were washed with brine (2×100 cm3), dried (MgSO4), filtered and then evaporated down. The residue was purified by distillation (Bp 132-134° C. at 15-20 mm Hg.) to yield 32.6 g of 2-bromo-5-pentylthiophene.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][N:11]1[CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:10][N:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:13][CH2:12]1
Reactant: N#Cc1ccc(F)cc1
Reactant: CN1CCCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CN1CCCN(c2ccc(C#N)cc2)CC1

Procedure:
4-Fluorobenzonitrile (25.5 g), 4-methylhomopiperazine (26.2 ml) and potassium carbonate (28 g) were heated in DMSO for 15 hr. After heating, the reaction mixture was poured into water (1 L). The precipitated crystals were collected by filtration to give the objective 4-(4-methylhomopiperazin-1-yl)benzonitrile (34.6 g), melting point 82-84° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([CH2:12][NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+]>C1COCC1.CO.O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([CH2:12][NH:13][C:14](=[O:19])[C:15]([CH3:17])([CH3:16])[CH3:18])=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cc(CNC(=O)C(C)(C)C)ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1
Yield: 94.7 %

Procedure:
The title compound was prepared following the procedure described in step-3 of Intermediate-2 using methyl 2-chloro-5-(pivalamidomethyl)benzoate (2.00 g, 7.05 mmol) in THF:MeOH:H2O (3:2:1; 6 mL) and NaOH (564 mg, 14.1 mmol) to afford 1.8 g of the title product. 1H NMR (300 MHz, DMSO d6): 12.3 (br s, 1H), 8.14 (br t, 1H), 7.61 (s, 1H), 7.47-7.44 (d, J=8.1 Hz, 1H), 7.34-7.32 (d, J=7.8 Hz, 1H), 4.22 (d, J=6.0 Hz, 2H), 1.18 (s, 9H).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=1)[OH:3].[CH3:17][CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[N:21]=1)[OH:19].[F:34][C:35]1[CH:40]=[CH:39][C:38]([CH:41]=[CH:42][CH:43]([CH:47]([CH3:49])[CH3:48])[C:44](O)=[O:45])=[CH:37][CH:36]=1>>[F:34][C:35]1[CH:36]=[CH:37][C:38]([CH:41]=[CH:42][CH:43]([CH:47]([CH3:49])[CH3:48])[C:44]([O:3][CH:2]([CH3:1])[C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:5]=2)=[O:45])=[CH:39][CH:40]=1.[F:34][C:35]1[CH:36]=[CH:37][C:38]([CH:41]=[CH:42][CH:43]([CH:47]([CH3:49])[CH3:48])[C:44]([O:19][CH:18]([CH3:17])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[N:21]=2)=[O:45])=[CH:39][CH:40]=1
Reactant: CC(O)c1cccc(Oc2ccccc2)n1
Reactant: CC(O)c1cccc(Oc2ccc(F)cc2)n1
Reactant: CC(C)C(C=Cc1ccc(F)cc1)C(=O)O
Product: CC(OC(=O)C(C=Cc1ccc(F)cc1)C(C)C)c1cccc(Oc2ccc(F)cc2)n1
Product: CC(OC(=O)C(C=Cc1ccc(F)cc1)C(C)C)c1cccc(Oc2ccccc2)n1

Procedure:
Following the procedure of Example 3, each of methyl(6-phenoxy-2-pyridyl)methanol and methyl[6-(4-fluorophenoxy)-2-pyridyl]methanol is reacted with 4-(4-fluorophenyl)-2-isopropyl-3-butenoic acid to yield methyl(6-phenoxy-2-pyridyl)methyl 4-(4-fluorophenyl)-2-isopropyl-3-butenoate and methyl[6-(4-fluorophenoxy)-2-pyridyl]methyl 4-(4-fluorophenyl)-2-isopropyl-3-butenoate, respectively.
Reaction SMILES: O([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1)C1C=CC=CC=1.[NH2:17][CH2:18][C:19]1[CH:20]=[C:21]([CH2:27][CH:28]([O:34][CH:35]([CH3:37])[CH3:36])[C:29]([O:31]CC)=[O:30])[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]>>[CH:35]([O:34][CH:28]([CH2:27][C:21]1[CH:22]=[CH:23][C:24]([O:25][CH3:26])=[C:19]([CH2:18][NH:17][C:12](=[O:14])[C:11]2[CH:10]=[CH:9][C:8]([C:8]3[CH:16]=[CH:15][CH:11]=[CH:10][CH:9]=3)=[CH:16][CH:15]=2)[CH:20]=1)[C:29]([OH:31])=[O:30])([CH3:36])[CH3:37]
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CN)c1)OC(C)C
Reactant: O=C(O)c1ccc(Oc2ccccc2)cc1
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1CNC(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Using 4-phenoxybenzoic acid and ethyl 3-[3-(aminomethyl)-4-methoxyphenyl]-2-isopropoxypropanoate, 2-isopropoxy-3-(4-methoxy-3-[(4-phenylbenzoyl)amino]methylphenyl)propanoic acid was obtained in the same method as in Example 19d) and then in Example 19e)
Reaction SMILES: C([O:5][C@@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH:21]([C:23]2[O:27][N:26]=[C:25]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[CH:24]=2)[CH3:22])[N:15]=1)[CH3:7])(C)(C)C.C(O)(C(F)(F)F)=O.O>>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([C:25]2[CH:24]=[C:23]([C@@H:21]([NH:20][C:16]3[N:15]=[C:14]([N:9]4[C@@H:8]([C@H:6]([OH:5])[CH3:7])[CH2:12][O:11][C:10]4=[O:13])[CH:19]=[CH:18][N:17]=3)[CH3:22])[O:27][N:26]=2)=[CH:29][CH:30]=1.[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([C:25]2[CH:24]=[C:23]([C@H:21]([NH:20][C:16]3[N:15]=[C:14]([N:9]4[C@@H:8]([C@H:6]([OH:5])[CH3:7])[CH2:12][O:11][C:10]4=[O:13])[CH:19]=[CH:18][N:17]=3)[CH3:22])[O:27][N:26]=2)=[CH:29][CH:30]=1
Reactant: CC(Nc1nccc(N2C(=O)OC[C@@H]2[C@@H](C)OC(C)(C)C)n1)c1cc(-c2ccc(Cl)cc2)no1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: C[C@@H](Nc1nccc(N2C(=O)OC[C@@H]2[C@@H](C)O)n1)c1cc(-c2ccc(Cl)cc2)no1
Product: C[C@H](Nc1nccc(N2C(=O)OC[C@@H]2[C@@H](C)O)n1)c1cc(-c2ccc(Cl)cc2)no1

Procedure:
(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-chlorophenyl)isoxazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one (3.50 g, 2.88 mmol) was treated with 90% TFA/water for 2 hours. Concentrated in vacuo and neutralized by passing through a column of MP-carbonate resin (6.0 g, 0.55 mmol/g eluting with MeOH/DCM/MeOH afforded the diastereomeric mixture. Chiral SFC chromatography on an OJ-H column (75 g/min, 120 bar, 21×250 mm) eluting 30% IPA+10 mM NH4OH/CO2 (v/v) to give (R)-3-(2-(((S)-1-(3-(4-chlorophenyl)isoxazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((R)-1-(3-(4-chlorophenyl)isoxazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[C:11]([O:15][C:16]([NH:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](O)=O)=[O:17])([CH3:14])([CH3:13])[CH3:12].N>>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:3]2[N:10]=[C:22]([C:21]3[CH:20]=[C:19]([NH:18][C:16](=[O:17])[O:15][C:11]([CH3:13])([CH3:12])[CH3:14])[CH:27]=[CH:26][CH:25]=3)[O:1][N:2]=2)[CH:5]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(C(=O)O)c1
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: CC(C)(C)OC(=O)Nc1cccc(-c2nc(-c3cccnc3)no2)c1

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 3-(tert-butoxycarbonylamino)benzoic acid (Aldrich). 1H NMR (300 MHz, CDCl3) δ 1.56 (s, 9H), 6.71 (s, 1H), 7.39-7.58 (m, 2H), 7.68 (d, J=7.9 Hz, 1H), 7.89 (d, J=9.1 Hz, 1H), 8.24 (s, 1H), 8.45 (d, J=7.9 Hz, 1H), 8.77 (d, J=4.8 Hz, 1H), 9.40 (s, 1H) ppm; MS (DCI/NH3) m/z 339 (M+H)+, 356 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[CH2:7][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>CN(C=O)C>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([C:6]2[C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CCOC(=O)C1=Nc2cc(Cl)ccc2C(=O)C1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(N2CCN(C(=O)OC(C)(C)C)CC2)c2ccc(Cl)cc2n1
Temperature: 50 °C
Reaction time: 15 h

Procedure:
Ethyl 7-chloro-4-quinolone-2-carboxylate (1.0 g, 4 mmol) is stirred with sodium hydride (0.144 g, 6 mmol) in DMF (50 mL) for 1 h at 40° C. N-Phenyl (trifluoromethylsulfon)imide (2.0 g, 5.6 mmol) is added and, after an hour, 1-tert-butoxycarbonylpiperazine (3.0 g, 6 mmol). The reaction mixture is stirred at 50° C. for 15 h, concentrated, diluted with EtOAc, washed with water and brine, dried (Na2SO4), and concentrated. The residue is purified by column chromatography with CH2Cl2-MeOH yielding the title product as a colorless solid.
Reaction SMILES: [O:1]=[C:2]1[CH:17]2[CH:5]([CH:6]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:7][C:8]3[NH:9][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[C:16]=32)[C:4](=[O:24])[NH:3]1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.CC(C)=O.C(OC(C)C)(C)C>C1(C)C=CC=CC=1>[O:1]=[C:2]1[C:17]2[C:16]3[C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[NH:9][C:8]=3[CH:7]=[C:6]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:5]=2[C:4](=[O:24])[NH:3]1
Reactant: O=C1NC(=O)C2C(c3ccccc3)Cc3[nH]c4ccccc4c3C12
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CC(C)OC(C)C
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: O=C1NC(=O)c2c1c(-c1ccccc1)cc1[nH]c3ccccc3c21

Procedure:
1.2 g (3.8 mmole) 1,2,3,3a,4,5,6,10c-octahydro-1,3-dioxo-4-phenylpyrrolo[3,4-c]carbazole and 2.2 g (9.7 mmole) DDQ are heated under reflux for 20 hours in 30 ml toluene. The solvent is distilled off in a vacuum and the residue chromatographed on silica gel with toluene/ethyl acetate 3:1. The fraction with the Rf of 0.3 is isolated, stirred up with acetone/diisopropyl ether, and the crystals formed are filtered off. One obtains 1,2,3,6-tetrahydro-1,3-dioxo-4-phenyl-pyrrolo[3,4-c]carbazole in the form of yellow crystals of the mp 262°-263° C.
Reaction SMILES: [OH-].[Na+].CO.[CH:5]1([C:8]2[CH:13]=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([N:21]4[CH2:30][CH2:29][C:28]5[N:27]=[C:26]([CH2:31][CH2:32][CH3:33])[C:25]([C:34]([O:36]C)=[O:35])=[CH:24][C:23]=5[C:22]4=[O:38])[CH2:17][CH2:16]3)[CH:11]=[C:10]([O:39][CH2:40][CH3:41])[C:9]=2[C:42]2[CH:47]=[CH:46][C:45]([F:48])=[C:44]([F:49])[CH:43]=2)[CH2:7][CH2:6]1.Cl>C(OCC)(=O)C.C1COCC1>[CH:5]1([C:8]2[CH:13]=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([N:21]4[CH2:30][CH2:29][C:28]5[N:27]=[C:26]([CH2:31][CH2:32][CH3:33])[C:25]([C:34]([OH:36])=[O:35])=[CH:24][C:23]=5[C:22]4=[O:38])[CH2:17][CH2:16]3)[CH:11]=[C:10]([O:39][CH2:40][CH3:41])[C:9]=2[C:42]2[CH:47]=[CH:46][C:45]([F:48])=[C:44]([F:49])[CH:43]=2)[CH2:6][CH2:7]1
Reactant: CCCc1nc2c(cc1C(=O)OC)C(=O)N(C1CCN(Cc3cc(OCC)c(-c4ccc(F)c(F)c4)c(C4CC4)c3)CC1)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1nc2c(cc1C(=O)O)C(=O)N(C1CCN(Cc3cc(OCC)c(-c4ccc(F)c(F)c4)c(C4CC4)c3)CC1)CC2
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
A 2 M aqueous sodium hydroxide solution (1.50 mL) was added at room temperature to methanol (5 mL)-THF (5 mL) solution of methyl 6-(1-((2-cyclopropyl-6-ethoxy-3′,4′-difluorobiphenyl-4-yl)methyl)piperidin-4-yl)-5-oxo-2-propyl-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate (580 mg), and the mixture was stirred at 60° C. for 30 minutes. The reaction mixture was neutralized with hydrochloric acid at room temperature. Then, ethyl acetate was added thereto, and the solvent was distilled off under reduced pressure. The deposited solid was collected by filtration and washed with diethyl ether. The obtained solid was recrystallized (DMSO/ethanol/hexane) to obtain the title compound (487 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.F[C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([NH:19][C:20]2[N:25]=[C:24]([C:26]3[CH:27]=[N:28][N:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=34)[CH:23]=[CH:22][N:21]=2)=[C:12]([O:35][CH3:36])[CH:11]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH3:1][N:2]([CH3:8])[C@@H:3]1[CH2:7][CH2:6][N:5]([C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([NH:19][C:20]3[N:25]=[C:24]([C:26]4[CH:27]=[N:28][N:29]5[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=45)[CH:23]=[CH:22][N:21]=3)=[C:12]([O:35][CH3:36])[CH:11]=2)[CH2:4]1
Reactant: CN(C)[C@@H]1CCNC1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3ccccc23)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COc1cc(N2CC[C@@H](N(C)C)C2)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3ccccc23)n1
Temperature: 85 °C
Yield: 85.6 %

Procedure:
(3R)—N,N-Dimethylpyrrolidin-3-amine (0.166 mL, 1.31 mmol) was added to a suspension of N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine (Intermediate 155, 415 mg, 1.09 mmol) and DIPEA (0.227 mL, 1.31 mmol) in DMA (3.2 mL) and the mixture was heated at 85° C. for 1 h. Part purification was achieved by ion exchange chromatography, using an SCX column, eluting with 7M methanolic ammonia. Clean fractions were combined and concentrated. Further purification by FCC, eluting with 0-7% CH3OH in CH2Cl2 gave the title compound (443 mg, 86%) as an orange solid; 1H NMR: 1.77-1.88 (1H, m), 2.13-2.20 (1H, m), 2.23 (6H, s), 2.75-2.84 (1H, m), 3.14-3.26 (3H, m), 3.43-3.51 (1H, m), 3.96 (3H, s), 6.58 (1H, s), 7.08 (1H, td), 7.27 (1H, d), 7.34-7.39 (1H, m), 8.24 (1H, s), 8.35 (1H, d), 8.40 (1H, s), 8.49 (1H, d), 8.78 (1H, s), 8.80 (1H, d); m/z: ES+ MH+ 475.31.
Reaction SMILES: [CH2:1]([NH:8][OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:17][C:18]1([CH:22]=[CH:23][C:24](OC)=[O:25])[CH2:21][CH2:20][CH2:19]1>ClCCl.O>[CH2:1]([N:8]1[CH:22]([C:18]2([CH3:17])[CH2:21][CH2:20][CH2:19]2)[CH2:23][C:24](=[O:25])[O:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ONCc1ccccc1
Reactant: COC(=O)C=CC1(C)CCC1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC1(C2CC(=O)ON2Cc2ccccc2)CCC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
N-benzylhydroxylamine (hydrochloric acid) (0.28 g, 1.80 mmol) and triethylamine (0.28 mL, 2.00 mmol) were added to a solution of methyl 3-(1-methylcyclobutyl)acrylate, 114a, (0.26 g, 1.50 mmol) in dichloromethane (9.5 mL). The reaction mixture was stirred at 50° C. overnight. The reaction mixture was cooled to room temperature and the mixture was diluted with dichloromethane and water. The layers were separated with a phase separator and the aqueous layer was washed with dichloromethane. The organic layers were combined and the volatiles removed under reduced pressure. The residue was purified on silica gel (EtOAc/Hexanes) to afford the desired product as a racemic mixture: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=1.47 minutes (M+H) 246.10.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([CH2:10]Br)[CH:7]=[CH:6][C:5]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([CH2:10][N:27]2[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]2)[CH:7]=[CH:6][C:5]=1[N+:12]([O-:14])=[O:13]
Reactant: CN1CCNCC1
Reactant: COC(=O)c1cc(CBr)ccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(CN2CCN(C)CC2)ccc1[N+](=O)[O-]
Temperature: 50 °C

Procedure:
To a solution of 5-bromomethyl-2-nitrobenzoic acid methyl ester (3.00 g, 10.9 mmol) in CH2Cl2 (100 mL) was added triethylamine (3.30 g, 33.0 mmol) and 1-methylpiperazine (3.30 g, 33.0 mmol). The mixture was heated at 50° C. under nitrogen for 16 hours, then concentrated to give crude 5-(4-methylpiperazin-1-ylmethyl)-2-nitrobenzoic acid methyl ester, which was purified by column chromatography (silica gel 230-400 mesh; 1-5% methanol in dichloromethane as eluent). Yield: 3.0 g (93%). It was further converted to its hydrochloride salt (3.7 g) by stirring in 1 M HCl in ether and was isolated by filtration.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]#[N:14])=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[O:22])[CH2:17][CH2:16]1.[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([F:1])=[CH:11][N:10]=2)[C:5]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[O:22])[CH2:17][CH2:16]2)=[C:6]([C:13]#[N:14])[C:7]1=[O:12])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2cc(F)cnc2[nH]c1=O
Reactant: BrCc1ccccc1
Product: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2cc(F)cnc2n(Cc2ccccc2)c1=O

Procedure:
This compound was prepared from 6-fluoro-2-oxo-4-[4-(thiophene-2-carbonyl)-piperazine-1-yl]-1,2-dihydro-[1,8]-naphthyridine-3-carbonitrile (98) and benzyl bromide according to General Procedure B. Yield 317 mg (43%), MP 173° C.; 1H-NMR (DMSO-d6): δ 3.73 (m, 4H), 3.92 (m, 4H), 5.53 (s, 2H), 7.22-7.30 (m, 6H), 7.49 (d, J=3.6 Hz, 1H), 7.80 (dd, J=1.2, 5.2 Hz, 1H), 8.16 (dd, J=2.8, 9.2 Hz, 1H), 8.77 (d, J=2.8 Hz, 1H); EIMS: 474 (M+1). Anal. (C25H20FN5O2S) C, H, N.