Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]([OH:28])([CH2:16][N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20](=[O:27])[CH:19]=[CH:18]1)[CH2:4][C:5]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=O)([CH3:7])[CH3:6].ClC(Cl)C.C(O)(=O)C.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>>[OH:28][C:3]([C:2]([F:30])([F:1])[F:29])([CH2:4][C:5]([CH3:6])([C:8]1[CH:15]=[CH:14][CH:13]=[C:10]([CH2:11][N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)[CH:9]=1)[CH3:7])[CH2:16][N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20](=[O:27])[CH:19]=[CH:18]1
Reactant: CC(C)(CC(O)(Cn1ccc(=O)c2ccccc21)C(F)(F)F)c1cccc(C=O)c1
Reactant: C1COCCN1
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)(CC(O)(Cn1ccc(=O)c2ccccc21)C(F)(F)F)c1cccc(CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.2 %

Procedure:
To a solution of 3-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(4-oxo-4H-quinolin-1-ylmethyl)butyl]benzaldehyde (0.05 g, 0.12 mmol), dichloroethane (3.0 mL), and acetic acid (0.09 mL, 1.46 mmol) in an ice bath was added morpholine (0.26 μL, 3.00 mmol). The solution was warmed to room temperature and stirred for 0.5 hours. Triacetoxy sodium borohyride (0.06 g. 0.30 mmol) was added and the reaction stirred at room temperature. After 3.0 hours, the solution was partitioned between EtOAc and 3% NH4OH (3 mL). The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and the solvent was evaporated in vacuo. The product was eluted from a flash chromatography column with EtOAc/hexanes, and concentrated in vacuo to afford 1-[2-hydroxy-4-methyl-4-(3-morpholin-4-ylmethylphenyl)-2-trifluoromethylpentyl]-1H-quinolin-4-one as a colorless solid (0.03 g, 45%).
Reaction SMILES: [CH3:1][N:2]1[CH2:29][CH2:28][CH2:27][C@:3]1([CH3:30])[C:4]([NH:6][C@H:7]([C:11]([N:13]([C@@H:15]([C@@H:23]([CH3:26])[CH2:24][CH3:25])[C@H:16]([O:21][CH3:22])[CH2:17][C:18]([OH:20])=[O:19])[CH3:14])=[O:12])[CH:8]([CH3:10])[CH3:9])=[O:5].N1C=CC=CC=1.FC(F)(F)C(O[C:42]1[C:47]([F:48])=[C:46]([F:49])[C:45]([F:50])=[C:44]([F:51])[C:43]=1[F:52])=O>ClCCl>[CH3:1][N:2]1[CH2:29][CH2:28][CH2:27][C@:3]1([CH3:30])[C:4]([NH:6][C@H:7]([C:11]([N:13]([C@@H:15]([C@@H:23]([CH3:26])[CH2:24][CH3:25])[C@H:16]([O:21][CH3:22])[CH2:17][C:18](=[O:20])[O:19][C:42]1[C:43]([F:52])=[C:44]([F:51])[C:45]([F:50])=[C:46]([F:49])[C:47]=1[F:48])[CH3:14])=[O:12])[CH:8]([CH3:10])[CH3:9])=[O:5]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)[C@@]1(C)CCCN1C)C(C)C
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)Oc1c(F)c(F)c(F)c(F)c1F)OC)N(C)C(=O)[C@@H](NC(=O)[C@@]1(C)CCCN1C)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cooled solution (0° C.) of #196 (4.0 g, 9.4 mmol, 1 eq.) in dichloromethane (40 mL) was added dropwise pyridine (2.95 g, 37.6 mmol, 4 eq.) followed by a solution of pentafluorophenyl trifluoroacetate (3.9 g, 13.6 mmol, 1.4 eq.) in dichloromethane (5 mL). The mixture was stirred at room temperature for one hour, and the solvent was concentrated in vacuo. The residue was purified by silica gel chromatography (Gradient: 1 to 10% methanol in dichloromethane) to afford compound #197 (4.5 g, 81.2% (over three steps) as white solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[N:11]2[CH2:14][CH:13]([NH:15][CH2:16][C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=3)[CH2:12]2)=[CH:6][CH:5]=1.Cl[C:33]([O:35][CH3:36])=[O:34].O>O1CCCC1>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH:10]([C:7]2[CH:8]=[CH:9][C:4]([Cl:3])=[CH:5][CH:6]=2)[N:11]2[CH2:12][CH:13]([N:15]([CH2:16][C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=3)[C:33](=[O:34])[O:35][CH3:36])[CH2:14]2)=[CH:26][CH:27]=1
Reactant: Fc1cc(F)cc(CNC2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1
Reactant: COC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)N(Cc1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
24.4 mg of a 75% dispersion of sodium hydride in mineral oil are added, at room temperature under an argon atmosphere, to a solution of 330 mg of {1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}(3,5-difluorobenzyl)amine in 25 cm3 of tetrahydrofuran. The mixture is stirred at room temperature for 1 hour before adding thereto 59 mm3 of methyl chloroformate, and then the stirring is maintained for 18 hours under the same conditions. The reaction mixture is supplemented with 0.3 cm3 of distilled water and the tetrahydrofuran is expelled in a rotary evaporator. The residue obtained is extracted with dichloromethane, the organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is purified by flash chromatography on silica gel [eluent: dichloromethane/methanol (97.5/2.5 by volume)]. 328 mg of methyl {1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-(3,5-difluorobenzyl)carbamate are obtained in the form of a colorless oil [1H NMR spectrum (300 MHz, CDCl3, δ in ppm): 2.97 (mt: 2H); 3.39 (mt: 2H); 3.71 (s: 3H); 4.24 (broad s: 1H); 4.45 (unresolved complex: 1H); 4.57 (s: 2H); from 6.65 to 6.80 (mt: 3H); from 7.15 to 7.30 (mt: 8H)].
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([Br:9])=[CH:4][C:3]=1[F:10].[Cl:11][C:12]1[N:17]=[CH:16][C:15]([C:18](N(C)OC)=[O:19])=[CH:14][CH:13]=1.[Cl-].[NH4+]>C1COCC1.[Li]CCCC.CCCCCC>[Br:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([C:18]([C:15]2[CH:16]=[N:17][C:12]([Cl:11])=[CH:13][CH:14]=2)=[O:19])=[C:3]([F:10])[CH:4]=1
Reactant: Fc1cc(Br)c(F)cc1Br
Reactant: CON(C)C(=O)c1ccc(Cl)nc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(c1ccc(Cl)nc1)c1cc(F)c(Br)cc1F
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 35.9 %

Procedure:
A mixture of 1,4-dibromo-2,5-difluorobenzene (1.36 g) in anhydrous THF (20 ml) and 1.6M n-BuLi in hexane (3.43 ml) was stirred at −78° C. under nitrogen for 20 min. The reaction mixture was added to 6-chloro-N-methyl-N-(methyloxy)-3-pyridinecarboxamide (0.921 g) in THF (20 ml) and stirred at −78° C. The mixture was then stirred at −70° C. for 30 min allowed to warm to room temperature then cooled again to −70° C. and treated with 10% aqueous ammonium chloride. The reaction mixture was warmed to room temperature and partitioned between ethyl acetate and 10% aqueous ammonium chloride. The organic layer was separated using a hydrophobic filter tube and the solvent was removed under vacuum. The residue was purified using a silica SPE cartridge eluting with petroleum ether/ethyl acetate (9:1 to 1:3) to give impure title compound (0.548 g).
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[O:11][CH2:12][CH2:13][OH:14]>C(OCC)C>[S:1]([O:14][CH2:13][CH2:12][O:11][C:10]1[CH:15]=[CH:16][CH:17]=[C:8]([O:7][CH3:6])[CH:9]=1)(=[O:4])(=[O:3])[NH2:2]
Reactant: NS(=O)(=O)Cl
Reactant: COc1cccc(OCCO)c1
Solvent: CCOCC
Product: COc1cccc(OCCOS(N)(=O)=O)c1

Procedure:
The title compound was prepared by procedures of Example 12 from sulfamoyl chloride and 2-(3-methoxyphenoxy)ethanol through the first evaporation step to give a brown, viscous, oily residue. The oil was dissolved in 300 ml of ethyl ether. The organic solution was washed with two 300 ml portions of water, dried over magnesium sulfate and the solvent evaporated under reduced pressure to give a viscous, oily residue for the second time. The oil was purified by chromatography using silica gel and methylene chloride-acetone in 90:1 ratio as eluting agent. Fractions containing the title compound were combined and solvents evaporated under reduced pressure to give a viscous oil which solidified on standing. The solid was recrystallized from ethyl-petroleum ether (bp range 30°-60° C.) to give the title compound as white solid, mp 78°-82° C., in 46% yield.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[O:16])=[CH:10][CH:9]=2)[CH2:4]1.C(=O)([O-])[O-].[K+].[K+].[F:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>CN1CCCC1=O>[CH3:1][N:2]([CH3:23])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]([CH:17]3[CH2:22][CH2:21][N:20]([S:37]([C:34]4[CH:35]=[CH:36][C:31]([F:30])=[CH:32][CH:33]=4)(=[O:39])=[O:38])[CH2:19][CH2:18]3)=[O:16])=[CH:12][CH:13]=2)[CH2:4]1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CN(C)C1CCN(c2ccc(NC(=O)C3CCNCC3)cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CN(C)C1CCN(c2ccc(NC(=O)C3CCN(S(=O)(=O)c4ccc(F)cc4)CC3)cc2)C1
Reaction time: 12 h

Procedure:
Piperidine-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide (70 mg) dissolved in N-methylpyrrolidone (2 ml) was mixed with potassium carbonate (45 mg) and 4-fluorobenzenesulfonyl chloride (40 mg). After 12 hours, the mixture was filtered and the filtrate was purified by preparative HPLC. This resulted in the product with the molecular weight of 474.60 (C24H31FN4O3S); MS (ESI): 475 (M+H+).
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[CH2:8]Cl>C(O)C>[CH3:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[CH2:8][NH:2][NH2:3]
Reactant: Cc1cc(CCl)ccc1[N+](=O)[O-]
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1cc(CNN)ccc1[N+](=O)[O-]
Yield: 96.6 %

Procedure:
To an ethanol solution (60 ml) of hydrazine monohydrate (5.00 g), an ethanol solution (20 ml) of 3-methyl-4-nitrobenzyl chloride (3.71 g) was added dropwise while refluxing it, and the mixture was continuously refluxed for 6 hours. After finishing the reaction, the solvent was distilled off and (3-methyl-4-nitrobenzyl)-hydrazine (3.50 g) was obtained.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([C:16]2[N:20]=[N:19][C:18](=[S:21])[N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].I[CH3:23].[OH-].[Na+]>C(O)C>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([C:16]2[NH:20][N:19]=[C:18]([S:21][CH3:23])[N:17]=2)[CH:8]=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:10]=1[OH:11])([CH3:1])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)c1cc(C2=NC(=S)N=N2)cc(C(C)(C)C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CSc1n[nH]c(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 6.00 g (19.64 mmol) of triazolethione (Example 19) and 9.1 g (60.0 mmol) of iodomethane in 50 ml of absolute ethanol is stirred at 50° to 60° C. for 0.5 hour, then cooled to room temperature. The reaction is treated with 300 ml aqueous 0.7N NaOH, stirred for 30 minutes, and filtered. Recrystallization of the resulting solid from ethanol-water gives 5.26 g (6.27 g theor., 84%) of the S-methylated product as a fluffy, white solid, mp 271°-272° C.
Reaction SMILES: [OH-].[K+].[CH3:3][C@@H:4]1[CH2:8][CH2:7][C:6](=O)[CH:5]1[C:10]([O:12]CC)=O.[NH2:15][C:16]([NH2:18])=[S:17]>O.C(O)C>[SH:17][C:16]1[N:15]=[C:10]([OH:12])[C:5]2[C@H:4]([CH3:3])[CH2:8][CH2:7][C:6]=2[N:18]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)C1C(=O)CC[C@H]1C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C[C@@H]1CCc2nc(S)nc(O)c21
Yield: 56 %

Procedure:
KOH (8.3 g, 147.9 mmol) in water (60 mL) was added to a solution of a mixture of (2R)-ethyl 2-methyl-5-oxocyclopentanecarboxylate (20 g, 117.5 mmol) and thiourea (9.2 g, 120.9 mmol) in ethanol (100 mL). The mixture was refluxed for 10 hours. After cooling, the solvent was removed, and the residue was neutralized with concentrated HCl (12 mL) at 0° C. The mixture was then extracted with DCM (3×150 mL). The solvent was removed, and the residue was purified by silica gel chromatography, eluting with hexane/ethyl acetate (2:1) to give (R)-2-mercapto-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (12 g, 56%). MS (APCI+) [M+H]+183.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13](OC(C)(C)C)=[O:14])[CH2:9][C:8]1=[O:20])#[N:2].[C:24](O)(C(F)(F)F)=O.C(OC(=O)C)(=O)C>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13](=[O:14])[CH3:24])[CH2:9][C:8]1=[O:20])#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(C#N)c2)C(=O)C1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1CCN(Cc2cccc(C#N)c2)C(=O)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 1-(3-cyanobenzyl)-4-Boc-2-piperazinone (2.5 g, 7.9 mmol) in CH2Cl2 (20 mL) at 0° C. was added TFA (10 mL). The mixture was stirred at 0° C. for 2 h, then the solvents were removed in vacuo. The crude 1-(3-cyanobenzyl)-2-piperazinone TFA salt was partitioned between EtOAc (30 mL) and saturated aqueous sodium bicarbonate solution (30 mL). To the stirred two-phase mixture was added acetic anhydride (1.5 mL, 15 mmol) dropwise over a period of 5 min. The mixture was stirred at ambient temperature for 16 h. The EtOAc layer was separated, dried (MgSO4), filtered, and the solvent was removed in vacuo. The residue was purified on a silica gel column using a gradient mobile phase of 2%, 3%, 4% MeOH in CH2Cl2. 1-(3-cyanobenzyl)-4-acetyl-2-piperazinone was obtained as a solid.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:43])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([C:28]3[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=3)(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:42])[CH:14]=2)[CH:9]=1>C1COCC1.O>[F:37][C:34]([F:35])([F:36])[C:32]1[CH:33]=[C:28]([S:25]([C:22]2[CH:21]=[CH:20][C:19]([C:16]3[C:15]4[C:10](=[CH:11][CH:12]=[C:13]([Cl:42])[CH:14]=4)[CH:9]=[C:8]([CH2:7][C:6]([OH:43])=[O:5])[C:17]=3[CH3:18])=[CH:24][CH:23]=2)(=[O:26])=[O:27])[CH:29]=[C:30]([C:38]([F:39])([F:40])[F:41])[CH:31]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(S(=O)(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)cc2ccc(Cl)cc2c1-c1ccc(S(=O)(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.8 %

Procedure:
Lithium hydroxide monohydrate (0.011 g, 0.26 mmol) was added to a stirred solution of {4-[4-(3,5-bis-trifluoromethyl-benzenesulfonyl)-phenyl]-6-chloro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.038 g, 0.063 mmol) in a 3:1 THF—H2O mixture (4 mL). The reaction mixture was stirred for 16 hours at room temperature. The THF was distilled off under reduced pressure, and the crude residue was diluted with water, acidified [pH˜2] via the drop-wise addition of an aqueous solution of hydrochloric acid (6.0 N). The mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Trituration with hexanes afforded {4-[4-(3,5-bis-trifluoromethyl-benzenesulfonyl)-phenyl]-6-chloro-3-methyl-naphthalen-2-yl}-acetic acid (0.031 g, 84%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.49 (br. s, 1 H) 8.71 (s, 2 H) 8.59 (s, 1 H) 8.35 (d, J=7.82 Hz, 2 H) 7.97 (d, J=8.40 Hz, 1 H) 7.91 (s, 1 H) 7.58 (d, J=7.82 Hz, 2 H) 7.48 (d, J=8.60 Hz, 1 H) 6.95 (s, 1 H) 3.84 (s, 2 H) 2.03 (s, 3 H). MS calcd. for C27H16ClF6O4S [(M−H)−] 585, obsd. 585.3.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[S:17][C:16]=2[C:24]([O:26]C)=[O:25])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O>O1CCCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[S:17][C:16]=2[C:24]([OH:26])=[O:25])(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1sc2ncccc2c1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2c(C(=O)O)sc3ncccc23)cc1
Temperature: 50 °C
Yield: 100.9 %

Procedure:
To a solution of 94 (0.070 g; 0.17 mmol) in tetrahydrofuran (2 mL), aqueous sodium hydroxide (2 mL; 4 mmol; 2N) and water (4 mL) were added. The reaction mixture was heated at 50° C. for 5 hours, cooled to room temperature, and then extracted with diethyl ether (2×). The ether solution was discarded. The aqueous layer was acidified with aqueous hydrochloric acid (2N) and extracted with ethyl acetate. The organic layer was separated and washed with aqueous saturated sodium chloride, dried over magnesium sulfate filtered, and evaporated under reduced pressure to yield the title compound as an off-white solid (0.067 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([F:12])[F:11])=[CH:6][C:5]=1[NH2:13].[I:15]I>CCO.[O-]S([O-])(=O)=O.[Ag+].[Ag+]>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([I:15])[C:7]([CH:10]([F:12])[F:11])=[CH:6][C:5]=1[NH2:13]
Reactant: II
Reactant: COC(=O)c1ccc(C(F)F)cc1N
Agent: [Ag+]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: COC(=O)c1cc(I)c(C(F)F)cc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.1 %

Procedure:
To a solution of 2-amino-4-difluoromethyl-benzoic acid methyl ester (1.98 g, 9.84 mmol) in EtOH (75 mL) were added Ag2SO4 (3.08 g, 1 equiv) and I2 (2.50 g, 1 equiv) and the resulting mixture was stirred at r.t. for 1 hour. The mixture was filtered through a pad of celite and washed with EtOH. The solution was concentrated in vacuo and then diluted with AcOEt. The organic phase was washed with sat. aq NaHCO3, 1M aq Na2S2O3 and brine and dried (Na2SO4). The solution was concentrated in vacuo to afford the title compound as an off-white solid (2.9 g, 90% yield). ES-MS: m/z 369.2 [M+CH3CN+H]+, rt 5.87 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[C:22]2[C:17](=[CH:18][C:19]([S:23]([O:26]C3C(F)=C(F)C(F)=C(F)C=3F)(=O)=[O:24])=[CH:20][CH:21]=2)[C:16](=[O:38])[NH:15][N:14]=1.[N:39]1[CH:44]=[CH:43][C:42]([NH2:45])=[N:41][CH:40]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:6]=[CH:5][C:4]=1[C:13]1[C:22]2[C:17](=[CH:18][C:19]([S:23]([NH:45][C:42]3[CH:43]=[CH:44][N:39]=[CH:40][N:41]=3)(=[O:26])=[O:24])=[CH:20][CH:21]=2)[C:16](=[O:38])[NH:15][N:14]=1
Reactant: COc1cc(C(F)(F)F)ccc1-c1n[nH]c(=O)c2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Reactant: Nc1ccncn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(C(F)(F)F)ccc1-c1n[nH]c(=O)c2cc(S(=O)(=O)Nc3ccncn3)ccc12
Reaction time: 0.25 h
Yield: 21.7 %

Procedure:
A vial was charged with perfluorophenyl 1-(2-methoxy-4-(trifluoromethyl)phenyl)-4-oxo-3,4-dihydrophthalazine-6-sulfonate (From Step 5, Example 293; 126 mg, 0.222 mmol), pyrimidin-4-amine (31.7 mg, 0.334 mmol), and THF (1.11 mL). The resulting solution was cooled in an ice-water bath for 10 min, then lithium bis(trimethylsilyl)amide (1M in THF) (489 μl, 0.489 mmol) was added drop wise. LCMS after 15 min showed complete conversion of SM to product. The reaction was quenched with 1 mL of MeOH and concentrated. Purification was done on OJ-H column, with 20% methanol and 0.2% diethylamine. Since the product contained some DEA, it was purified further by mass directed LC purification with TFA to afford 1-(2-methoxy-4-(trifluoromethyl)phenyl)-4-oxo-N-(pyrimidin-4-yl)-3,4-dihydrophthalazine-6-sulfonamide (23 mg, 21.7% yield). m/z (ESI) 478.0 (M+H)+.
Reaction SMILES: [NH:1]([C:8]1[CH2:17][C:16]([C:18]([O:20]C)=O)=[C:15]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:14][C:9]=1[C:10]([O:12]C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>>[CH:26]1[CH:27]=[C:28]2[C:18]([C:16]3[C:15]([NH:22][C:23]2=[CH:24][CH:25]=1)=[CH:14][C:9]1[C:10]([C:7]2[C:2]([NH:1][C:8]=1[CH:17]=3)=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:12])=[O:20]
Reactant: COC(=O)C1=C(Nc2ccccc2)CC(C(=O)OC)=C(Nc2ccccc2)C1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12
Temperature: 140 °C
Reaction time: 1.5 h
Yield: 89 %

Procedure:
(b.1) A suspension of 37.8 parts of dimethyl 3,6-dihydro-2,5-dianilinoterephthalate in 200 parts of ®Dowtherm A is added dropwise to 150 parts of boiling ®Dowtherm A. The mixture is then kept at the boil for a further 90 minutes. After approx. 100 parts of the solvent have been distilled off, the mixture is cooled to approx. 140° C., after which 25.4 parts of iodine are added and the mixture is kept at the boil for a further 4 hours. Working up is effected as described earlier in the text under "Method A". 27.8 parts of quinacridone in the β-crystal phase are obtained, which corresponds to a yield of 89% of theory (relative to dimethyl 3,6-dihydro-2,5-dianilinoterephthalate.
Reaction SMILES: [S:1]1[C:5]2[CH2:6][CH:7]3[CH:12]([C:4]=2[CH:3]=[CH:2]1)[CH2:11][NH:10][CH2:9][CH2:8]3.C(N(CC)CC)C.Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(Cl)Cl>[CH2:24]([O:23][C:21]([N:10]1[CH2:11][CH:12]2[CH:7]([CH2:6][C:5]3[S:1][CH:2]=[CH:3][C:4]=32)[CH2:8][CH2:9]1)=[O:22])[CH3:25]
Reactant: c1cc2c(s1)CC1CCNCC21
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCC2Cc3sccc3C2C1
Temperature: 22 °C
Yield: 73 %

Procedure:
A 0° C. solution of product from Example 29, step h) (885 mg, 4.1 mmol) in CH2Cl2 (20 ml) was treated with triethylamine (1.71 ml, 12.3 mmol) and ethyl chloroformate (472 μl, 4.92 mmol) and the reaction was warmed to 22° C. Next, the reaction mixture was diluted with CH2Cl2 (20 ml) and washed with brine (25 ml). The organic layer was dried (MgSO4) and the solvent evaporated in vacuo to give the crude product that was purified by silica-gel chromatography (hexanes:EtOAc-50:50) to give 748 mg (73%) of the subtitle compound. MS calculated for C13H17NO2S+H 252, observed 252.
Reaction SMILES: [ClH:1].[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][Cl:9])[CH:3]=1.Cl.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:21]2[C@@H:30]3[C@@H:25]([CH2:26][CH:27]=[CH:28][CH2:29]3)[C:24](=[O:31])[N:23]([CH:32]3[CH2:37][CH2:36][N:35](CC4C=C5C(C=CC(=O)O5)=CC=4)[CH2:34][CH2:33]3)[N:22]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]>>[ClH:9].[ClH:1].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:21]2[C@@H:30]3[C@@H:25]([CH2:26][CH:27]=[CH:28][CH2:29]3)[C:24](=[O:31])[N:23]([CH:32]3[CH2:37][CH2:36][N:35]([CH2:8][C:4]4[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=4)[CH2:34][CH2:33]3)[N:22]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]
Reactant: COc1ccc(C2=NN(C3CCN(Cc4ccc5ccc(=O)oc5c4)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC
Reactant: ClCc1cccnc1
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(Cc4cccnc4)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC

Procedure:
Prepared from starting compound A1 and 3-picolylchloride hydrochloride as described for compound 18. M. p. 252-254° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:9]=[N:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=1.[Br:18]N1C(=O)CCC1=O>CO>[Br:18][C:5]1[N:4]=[CH:3][C:2]([NH:7][C:8]2[CH:9]=[N:10][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:12][CH:13]=2)=[N:1][CH:6]=1
Reactant: FC(F)(F)c1ccc(Nc2cnccn2)cn1
Reactant: O=C1CCC(=O)N1Br
Solvent: CO
Product: FC(F)(F)c1ccc(Nc2cnc(Br)cn2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of pyrazin-2-yl-(6-trifluoromethyl-pyridin-3-yl)-amine (0.47 g) was dissolved in 50 Ml MeOH and then charged with N-bromosuccinimide (0.35 g) in a single portion as a solid. The reaction was stirred overnight at room temperature, then concentrated in vacuo. Purification by silica gel chromatography (25% EtOAc in hexanes) afforded the title compound: 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 6.7 (s, 1H) 7.5 (s, 1H) 7.9 (s, 1H) 8.2 (s, 2H) 8.6 (s, 1H); (M+H)+320.9.