Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH3:10])=[CH:5][CH:4]=1.[NH2:12][C:13]([NH2:15])=[S:14]>>[NH2:15][C:13]1[S:14][CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:12]=1
Reactant: NC(N)=S
Reactant: COc1ccc(C(C)=O)cc1
Product: COc1ccc(-c2csc(N)n2)cc1
Yield: 85.2 %

Procedure:
Using 4′-methoxyacetophenone and thiourea as the raw materials, the same operation as the Example 395(1) gave the title compound.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16](Cl)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:27].[N:37]1([CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH2:41][CH2:40][CH2:39][CH2:38]1>>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16]([N:45]3[CH2:46][CH2:47][CH:42]([N:37]4[CH2:41][CH2:40][CH2:39][CH2:38]4)[CH2:43][CH2:44]3)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:27]
Reactant: Cc1ccccc1-c1cc(Cl)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCO2
Reactant: C1CCN(C2CCNCC2)C1
Product: Cc1ccccc1-c1cc(N2CCC(N3CCCC3)CC2)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCO2
Yield: 47.6 %

Procedure:
In a similar manner to Example 1, 5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (100 mg) was reacted with 4-(pyrrolidine-1-yl)piperidine (70.2 mg) to obtain 5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-6-oxo-9-[4-(pyrrolidine-1-yl)piperidine-1-yl]-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (58.2 mg, 48%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=3)=[CH:12][C:11]([C:22]([O:24]CC)=[O:23])=[N:10]2)=[CH:5][CH:4]=1)#[N:2].[OH-].[Na+]>C(O)C.O1CCCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=3)=[CH:12][C:11]([C:22]([OH:24])=[O:23])=[N:10]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)c1cc(-c2ccc(SC)cc2)n(-c2ccc(C#N)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CSc1ccc(-c2cc(C(=O)O)nn2-c2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.8 %

Procedure:
A mixture of ethyl 1-(4-cyanophenyl)-5-[4-(methylthio)phenyl]pyrazole-3-carboxylate (2.8 g) and 1N sodium hydroxide (10 ml) in ethanol (50 ml) and tetrahydrofuran (20 ml) was stirred at ambient temperature for 3 hours. The solvent was evaporated, and the residue was dissolved in water, acidified with hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, dried, and evaporated to give 1-(4-cyanophenyl)-5-[4-(methylthio)phenyl]pyrazole-3-carboxylic acid (2.5 g).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]([OH:19])=O)[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1.[NH2:20][C@@H:21]([CH2:39][O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:22]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)=[CH:27][CH:26]=1)=[O:23]>>[CH2:41]([O:40][CH2:39][C@H:21]([NH:20][C:17](=[O:19])[CH2:16][N:13]1[CH2:12][CH2:11][N:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH3:2])[CH:5]=2)[CH2:15][CH2:14]1)[C:22]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)=[CH:27][CH:26]=1)=[O:23])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: COc1cccc(N2CCN(CC(=O)O)CC2)c1
Agent: Cl
Product: COc1cccc(N2CCN(CC(=O)N[C@@H](COCc3ccccc3)C(=O)Nc3ccc(Oc4ccc(F)cc4)cc3)CC2)c1
Yield: 32 %

Procedure:
Proceeding as in Example 1, but substituting 2-(4-(3-methoxyphenyl)piperazin-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 42, (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(4-(3-methoxyphenyl)piperazin-1-yl)acetamido)propanamide (15.7 mg, 32%). 1H-NMR (400 MHz, DMSO-D6): σ 10.22 (s, 1H), 8.01 (d, 1H), 7.60 (d, 2H), 7.26 (m, 7H), 7.11 (t, 1H), 7.01 (m, 4H), 6.50 (d, 1H), 6.43 (s, 1H), 6.37 (d, 1H), 4.70 (m, 1H), 4.52 (s, 2H), 3.77 (m, 1H), 3.73 (m, 4H), 3.13 (m, 4H), 3.06 (s, 2H), 2.61 (m, 4H). MS (EI) for C35H37FN4O5: 613.7 (MH+).
Reaction SMILES: C(=O)(O)[O-:2].[Na+].Cl.NO.[C:9]([C:11]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][N:12]=1)#[N:10]>C(O)C>[F:19][C:17]([F:20])([F:18])[C:15]1[CH:14]=[CH:13][N:12]=[C:11]([C:9]([NH2:10])=[O:2])[CH:16]=1
Reactant: N#Cc1cc(C(F)(F)F)ccn1
Reactant: O=C([O-])O
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1cc(C(F)(F)F)ccn1
Yield: 75.4 %

Procedure:
To 72 ml of ethanol were added 6.18 g of sodium bicarbonate and 5.11 g of hydroxylamine hydrochloride, and the mixture was heated to reflux for 45 minutes. After allowing to cool, 6 g of 2-cyano-4-trifluoromethylpyridine was added at 0° C., and the mixture was stirred, and concentrated. To the residue was added water, the resultant solution was extracted with ethyl acetate three times, and the organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 5 g of 4-trifluoromethylpyridine-2-carboxamide=oxime.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.Cl.Cl[CH2:16][CH2:17][N:18]([CH2:26][CH2:27]Cl)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([N:18]1[CH2:26][CH2:27][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:12])([F:13])[F:1])=[CH:8][CH:7]=2)([C:10]#[N:11])[CH2:16][CH2:17]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: N#CCc1ccc(C(F)(F)F)cc1
Reactant: ClCCN(CCCl)Cc1ccccc1
Agent: Cl
Product: N#CC1(c2ccc(C(F)(F)F)cc2)CCN(Cc2ccccc2)CC1

Procedure:
Prepare by the method of example 76.1 using 4-trifluoromethylphenyl-acetonitrile (1.5 g, 8.1 mmol) and N,N-bis(2-chloroethyl)-N-benzylamine hydrochloride (1.9 g, 8.1 mmol) to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([NH2:8])=[CH:6][CH:7]=1.[CH2:16]([O:23][C@H:24]([CH3:37])[C@H:25]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:26](O)=[O:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:33]([O:32][C:30](=[O:31])[NH:29][C@H:25]([C:26](=[O:27])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@H:24]([O:23][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH3:37])([CH3:35])([CH3:34])[CH3:36]
Reactant: Nc1ccc(F)cc1Nc1ccccc1
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)cc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 102.9 %

Procedure:
A mixture of 4-fluoro-N2-phenylbenzene-1,2-diamine (525 mg, 2.6 mmol), (2S,3R)-3-benzyloxy-2-tertbutoxycarbonylaminobutyric acid (880 mg, 2.9 mmol), HOAt (390 mg, 2.9 mmol), 4-methylmorpholine (0.60 mL, 5.7 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (560 mg, 2.9 mmol) in DCM (13 mL) was stirred at RT for 18 h. The reaction mixture was partitioned between DCM and a saturated aqueous solution of NaHCO3. The organic phase was washed with brine, dried (MgSO4), concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-30% EtOAc in cyclohexane) to afford [(1S,2R)-2-benzyloxy-1-(4-fluoro-2-phenylaminophenylcarbamoyl)propyl]carbamic acid tert-butyl ester (1.32 g). LCMS (Method B): RT 4.32 min [M+H]+ 494.3.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([S:7](O)(=[O:9])=[O:8])=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:18]>O>[C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([S:7]([Cl:18])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: O=S(=O)(O)c1ccc(-c2ccccc2)cc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O
Product: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C

Procedure:
4-Biphenyl sulfonic acid (2.4 g, 10 mmol) was heated to 100 C. with phosphorus pentachloride (2.1 g, 10 mmol) overnight. The reaction was cooled to RT, diluted with water, filtered and washed with water. The solid was then triturated with EtOAc-ether and the beige solid was used in the next reaction without further purification.
Reaction SMILES: [OH:1][CH:2]([CH2:14][CH2:15][CH3:16])[C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([F:12])[C:6]=1[F:13].[H][H]>C(O)C.[C].[Pd]>[OH:1][CH:2]([CH2:14][CH2:15][CH3:16])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([F:12])[C:6]=1[F:13]
Reactant: [H][H]
Reactant: CCCC(O)C#Cc1ccc(F)c(F)c1F
Agent: [Pd]
Solvent: CCO
Product: CCCC(O)CCc1ccc(F)c(F)c1F
Reaction time: 8 h

Procedure:
After 1-(3-hydroxy-1-hexynyl)-2,3,4-trifluorobenzene was dissolved in ethanol, 5% palladium carbon (50% in water) was added thereto, and stirred for 6 hours at a hydrogen pressure of 0.5 MPa, and the mixture was left to stand overnight. After palladium carbon was removed by filtration, the solvent was evaporated under a reduced pressure to obtain 1-(3-hydroxy-1-hexyl)-2,3,4-trifluorobenzene.
Reaction SMILES: [C:1]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>O1CCCC1.CO>[C:1]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1ccc(C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCC(=O)c1ccc(C(=O)O)cc1
Temperature: 50 °C
Yield: 65.1 %

Procedure:
Methyl 4-butyrylbenzoate (256.1 mg, 1.242 mmol) was dissolved in tetrahydrofuran (3 mL) and methanol (3.0 mL). 1N aqueous sodium hydroxide (3.73 mL) was added and the reaction mixture was heated to 50° C. for 3 h. The reaction mixture was then cooled to room temperature and concentrated. The crude residue was taken up in water and acidified to pH 5 by addition of 1N aqueous HCl. A colorless precipitate formed. The solids were filtered off and dried under vacuum to give 4-butyrylbenzoic acid (155.4 mg, 65%) as a colorless solid. 1H NMR (400 MHz, CDCl3, δ) 8.16-8.21 (m, 2H), 8.01-8.05 (m, 2H), 2.98 (t, J=7.2 Hz, 2H), 1.78 (m, 2H), 1.01 (t, J=7.41 Hz, 3H).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[Br:39][C:40]1[CH:41]=[CH:42][C:43]([C:46]([OH:48])=O)=[N:44][CH:45]=1>CN(C)C=O>[Br:39][C:40]1[CH:41]=[CH:42][C:43]([C:46]([N:3]([O:4][CH3:5])[CH3:2])=[O:48])=[N:44][CH:45]=1
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: CNOC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102 %

Procedure:
N,O-dimethylhydroxylamine hydrochloride (500 mg, 5 mmol) was added to a mixture of N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (1400 mg, 3.7 mmol), N,N-diisopropylethylamine (1000 μL, 7 mmol) and 5-bromopyridine-2-carboxylic acid (500 mg, 2 mmol, Frontier Scientific catalog# B1704) in N,N-dimethylformamide (10 mL). The reaction mixture was stirred overnight at room temperature and was complete by LC/MS. The reaction was partitioned between water and EtOAc. The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated to give the crude product. The product was purified on by FCC on silica gel eluting a hexane: EtOAc (0-30%) gradient to give 5-bromo-N-methoxy-N-methylpyridine-2-carboxamide clear oil (0.50 g, 60%). LCMS calculated for C8H10BrN2O2(M+H)+: m/z=244.9, 246.9; found: 244.9, 246.9.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:13]([OH:15])=[O:14])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[CH2:16](N(CC)CC)C.IC>CC(C)=O>[CH3:4][C:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:6]=1)([CH3:1])[CH3:3]
Reactant: COc1ccc(C(C)(C)C)cc1S(=O)O
Reactant: CCN(CC)CC
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc(C(C)(C)C)cc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
17.4 g (0.076 mol) of 3-(1,1-dimethylethyl)-6-methoxybenzenesulfinic acid are suspended in 120 ml of acetone, and 13.3 ml (0.095 mol) of triethylamine and 8.5 ml (0.12 mol) of iodomethane are added. The mixture is stirred at room temperature for 2 hours and then poured onto ice-water. The precipitate which separates out is filtered off with suction and recrystallized from N-butanol.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[C:10]1(=[O:16])[O:15][C:13](=[O:14])[CH2:12][CH2:11]1>O1CCCC1>[C:8]([C:5]1[N:6]=[CH:7][C:2]([NH:1][C:10](=[O:16])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[N:3][CH:4]=1)#[N:9]
Reactant: N#Cc1cnc(N)cn1
Reactant: O=C1CCC(=O)O1
Solvent: C1CCOC1
Product: N#Cc1cnc(NC(=O)CCC(=O)O)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
The 5-aminopyrazine-2-carbonitrile (commercially available, 1.0 g, 8.32 mmol) was dissolved in tetrahydrofuran then succinic anhydride (1.04 g, 10.4 mmol) was added, the mixture was stirred at room temperature for 2 h and at reflux overnight. Then 1.0 equivalent of succinic anhydride was added and the solution was refluxed for 4 days. The reaction was stopped and the solution was partitioned between ethyl acetate and water. The aqueous layer was separated, acidified and extracted with ethyl acetate (3×). The combined organic layer was dried on magnesium sulfate and concentrated under vacuum. The residue was purified by flash chromatography eluting with cyclohexane-ethyl acetate (1/3) with acid acetic (1%) to give 4-[(5-cyanopyrazin-2-yl)amino]-4-oxo-butanoic acid A1 (1.30 g, 71%). M.p.=201-202° C., 1H NMR (400 MHz, DMSO-d6) δ 12.09 (bs, 1H), 11.40 (s, 1H), 9.41 (s, 1H), 8.96 (s, 1H), 2.73 (t, 2H), 2.55 (t, 2H) ppm. LC-MS (Method B): RT 0.96, 219 (M−H+)
Reaction SMILES: [CH3:1][S@:2]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1)=[O:3].O1CCCC1.C([N-]C(C)C)(C)C.[Li+].[F:24][C:25]([F:41])([F:40])[C:26](=[O:39])[CH2:27][C:28]([C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[CH3:38])([CH3:30])[CH3:29]>C1COCC1.C1CCCCC1>[F:41][C:25]([F:24])([F:40])[C@@:26]([CH2:1][S@:2]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1)=[O:3])([OH:39])[CH2:27][C:28]([C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[CH3:38])([CH3:30])[CH3:29]
Reactant: Cc1ccc(F)cc1C(C)(C)CC(=O)C(F)(F)F
Reactant: Cc1ccc([S@@](C)=O)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: Cc1ccc([S@](=O)C[C@](O)(CC(C)(C)c2cc(F)ccc2C)C(F)(F)F)cc1
Reaction time: 0.25 h
Yield: 55.1 %

Procedure:
To a suspension of (R)-(+)-methyl p-tolylsulfoxide (23.6 g, 153 mmol) in 200 mL of anhydrous THF at −78° C. was added lithium diisopropylamide mono(tetrahydrofuran) (LDA), 1.5 M solution in cyclohexane, 102 mL, 153 mmol) over 20 minutes. The resulting clear yellow solution was stirred for an additional 15 minutes. 1,1,1-Trifluoro-4-(5-fluoro-2-methylphenyl)-4-methylpentan-2-one (36.4 g, 139 mmol) was then added via cannula with the aid of 125 mL of THF over 30 minutes. After 1.5 hours at −78° C., the reaction mixture was quenched with 600 mL of water and extracted with two 500 mL portions of ethyl acetate. The combined organic phases were washed with saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification by column chromatography with silica gel (eluted with 10%-30% EtOAc/hexanes) afforded sequentially (S)-1,1,1-trifluoro-4-(5-fluoro-2-methylphenyl)-4-methyl-2-((R)-toluene-4-sulfinylmethyl)pentan-2-ol (31.9 g, 55%, 99% de) and (R)-1,1,1-trifluoro-4-(5-fluoro-2-methylphenyl)-4-methyl-2-((R)-toluene-4-sulfinylmethyl)pentan-2-ol.
Reaction SMILES: [C:1]1([C:11]([O:13]C)=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.O.[NH2:16][NH2:17]>CO>[C:1]1([C:11]([NH:16][NH2:17])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: NN
Reactant: COC(=O)c1cccc2ccccc12
Solvent: O
Solvent: CO
Product: NNC(=O)c1cccc2ccccc12
Yield: 86 %

Procedure:
A mixture of 21.5 g (0.116 mol) of methyl α-naphthoate, 50 ml of 80% water containing hydrazine, and 30 ml of methanol was refluxed for 3 hours and then the reaction mixture obtained was cooled to form crystals, which were recovered and washed with water to provide 19.0 g (yield 86%) of α-naphthoic acid hydrazide.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][C:27]=1[O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:11]([N+:22]([O-])=O)[CH:10]=1)=[O:8])([O-])=O.[H][H]>[Pd].COCCO>[NH2:22][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[O:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:7]([C:6]1[CH:25]=[CH:26][C:27]([O:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[C:4]([NH2:1])[CH:5]=1)=[O:8]
Reactant: O=C(c1ccc(Oc2ccccc2)c([N+](=O)[O-])c1)c1ccc(Oc2ccccc2)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: COCCO
Product: Nc1cc(C(=O)c2ccc(Oc3ccccc3)c(N)c2)ccc1Oc1ccccc1
Yield: 86.6 %

Procedure:
To a reaction apparatus equipped with a thermometer, reflux condenser and stirrer, 60 g (0.131 mol) of 3,3'-dinitro-4,4'-diphenoxybenzophenone, 150 g of methyl cellosolve and 3.0 g of 5%-Pd/C (50% moisture content) were charged and reacted in a hydrogen atmosphere at 70°~80° C. for 4 hours. After finishing the reaction, the catalyst was filtered and the filtrate was concentrated under reduced pressure to obtain 45 g (86% yield) of 3,3'-diamino-4,4'-diphenoxybenzophenone as light yellow crystals.
Reaction SMILES: [CH2:1]([C@H:8]([NH:40]C(=O)OC(C)(C)C)[C@@H:9]([OH:39])[CH2:10][C@@H:11]([NH:26][C:27](=[O:38])[C@@H:28]([NH:33][C:34]([O:36][CH3:37])=[O:35])[C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:40][C@@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@@H:9]([OH:39])[CH2:10][C@@H:11]([NH:26][C:27]([C@@H:28]([NH:33][C:34](=[O:35])[O:36][CH3:37])[C:29]([CH3:32])([CH3:31])[CH3:30])=[O:38])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=2)=[CH:15][CH:14]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccc(C)cn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccc(C)cn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution containing the product from Example 92I (0.120 g, 0.183 mmol) in dichloromethane (1 mL) was treated with trifluoroacetic acid (1 mL), stirred at 25° C. for 1 hour. The solvent was concentrated and the mixture was partitioned between chloroform and saturated NaHCO3 solution. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated, and the crude product (0.098 g) was used without further purification.
Reaction SMILES: [CH2:1]([N:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[CH:5]=1)[CH3:2].O.O.[Sn](Cl)Cl>C(O)(=O)C>[CH2:1]([N:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[CH:5]=1)[CH3:2]
Reactant: CCN(c1ccccc1)c1cccc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: CC(=O)O
Solvent: O
Product: CCN(c1ccccc1)c1cccc(N)c1
Temperature: 40 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
N-Ethyl-3-nitro-N-phenylaniline (400 mg, 1.65 mmol) was dissolved in acetic acid (5 ml) at 40° C. followed by slow addition of tin (II) chloride dihydrate (1.50 g, 6.60 mmol). The reaction mixture was stirred at 40° C. for 2 hours and then for a further 2 hours at 75° C. The mixture was concentrated in vacuo and the obtained residue was diluted with ether (10 ml). Aqueous sodium hydroxide solution (2 ml) was added dropwise to the cooled (0° C.) solution. A solid formed was separated by filtration and was rinsed twice with hot ethyl acetate (25 ml). The filtrate was concentrated to approximately 30 ml and washed with 1 N sodium hydroxide, brine, dried over sodium sulfate and concentrated in vacuo to give N-ethyl-N-phenylbenzene-1,3-diamine as a yellow oil (117 mg, 1.04 mmol, 63% yield). 1H NMR (400 MHz, CDCl3): 6.87-7.28 (m, 7H), 6.28-6.83 (m, 2H), 3.74 (q, 2H), 3.59 (s, 2H), 1.20 (t, 3H); MS (EI) for C14H16N2: 212 (MH+).
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([C:8]([O-:10])=[O:9])[C:5]([N+:11]([O-:13])=[O:12])=[C:4]([OH:14])[N:3]=1.[K+].S(=O)(=O)(O)O.[CH3:21]O>>[OH:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:21])=[O:9])[C:5]([N+:11]([O-:13])=[O:12])=[C:4]([OH:14])[N:3]=1
Reactant: CO
Reactant: O=C([O-])c1nc(O)nc(O)c1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COC(=O)c1nc(O)nc(O)c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Potassium 2,6-dihydroxy-5-nitropyrimidine-4-carboxylate (25 gm, 105 mmol) was dissolved in MeOH (75 mL) and sulphuric acid (21 mL) was added dropwise. The reaction was heated at reflux overnight. After cooling to room temperature, the precipitate was collected by filtration, washed with water, and dried to give methyl 2,6-dihydroxy-5-nitropyrimidine-4-carboxylate (17.1 g) as a white solid. 1H NMR (DMSO-d6) δ ppm 12.04 (2H, br. s.), 3.90 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH2:7][N:6]1[C:14](=S)[CH2:15][C:16](=O)[CH3:17])=[O:4].[F:20][C:21]([F:31])([F:30])[C:22]1[CH:27]=[CH:26][C:25]([NH:28][NH2:29])=[CH:24][CH:23]=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH2:7][N:6]1[C:14]1[N:28]([C:25]2[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:30])[F:31])=[CH:27][CH:26]=2)[N:29]=[C:16]([CH3:17])[CH:15]=1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](S(C)(=O)=O)CN1C(=S)CC(C)=O
Reactant: NNc1ccc(C(F)(F)F)cc1
Product: COC(=O)[C@@H]1C[C@@H](S(C)(=O)=O)CN1c1cc(C)nn1-c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-4-methanesulfonyl-1-(3-oxo-thiobutyryl)-pyrrolidine-2-carboxylic acid methyl ester (example 448c) was reacted with 4-(trifluoromethyl)phenylhydrazine (CAS Reg. No. 368-90-1) to give the title compound. MS (ESI): m/z=432.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])=[CH:12][CH:11]=2)[S:7][C:6]=1[C:22]([NH2:24])=[O:23])=[O:3].Cl[CH2:26][CH2:27]N1CCCC1>>[NH2:1][C:2]([NH:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][N:19]3[CH2:21][CH2:27][CH2:26][CH2:20]3)=[CH:14][CH:15]=2)[S:7][C:6]=1[C:22]([NH2:24])=[O:23])=[O:3]
Reactant: CN(C)CCOc1ccc(-c2cc(NC(N)=O)c(C(N)=O)s2)cc1
Reactant: ClCCN1CCCC1
Product: NC(=O)Nc1cc(-c2ccc(OCCN3CCCC3)cc2)sc1C(N)=O

Procedure:
Prepared by the method of Example 9(b) using the product of Example 10 (a) and N-(2-chloroethyl)pyrrolidine.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[N:5]([CH2:8][CH2:9][CH2:10][NH:11][C:12]1[N:17]=[C:16](Cl)[N:15]=[C:14]([Cl:19])[N:13]=1)=[N+:6]=[N-:7]>CC(C)=O>[N:5]([CH2:8][CH2:9][CH2:10][NH:11][C:12]1[N:13]=[C:14]([Cl:19])[N:15]=[C:16]([NH:4][CH2:3][CH2:1][OH:2])[N:17]=1)=[N+:6]=[N-:7]
Reactant: [N-]=[N+]=NCCCNc1nc(Cl)nc(Cl)n1
Reactant: NCCO
Solvent: CC(C)=O
Product: [N-]=[N+]=NCCCNc1nc(Cl)nc(NCCO)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 84.2 %

Procedure:
Ethanolamine (2.47 g, 40.4 mmol) in acetone (20 mL) was added to a solution of 1 (2.0 g, 8.1 mmol) in acetone (30 mL). The reaction was stirred at room temperature for 24 hours. The acetone was removed by rotary evaporation and the residue was suspended in CH2Cl2. The mixture was filtered off. The solid collected was washed with CH2Cl2 with H2O and dried under reduced pressure to afford 2 as a white solid (1.86 g, 85%). The product is sufficiently pure for further reactions. ESI-MS m/z 273.1 (M+H+) calculated for C8H14ClN8O 273.1.