Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH2:14]O)=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[OH-:16].[Na+].Br[CH2:19][CH2:20][CH2:21][Cl:22]>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.CC1C=CC=CC=1>[Cl:22][CH2:21][CH2:20][CH2:19][O:16][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[C:13]1[CH:14]=[N:9][CH:10]=[CH:11][CH:12]=1.[ClH:22].[Cl:22][CH2:21][CH2:20][CH2:19][O:16][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[C:13]1[CH:14]=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: OCc1cccnc1-c1ccc(F)cc1
Reactant: ClCCCBr
Reactant: [OH-]
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cl
Product: Fc1ccc(C(OCCCCl)c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 55 %

Procedure:
To a stirred and heated (50° C.) mixture of 15 parts of ° -(4-fluorophenyl)-3-pyridinemethanol, 3.4 parts of N,N,N-triethylbenzenemethanaminium chloride, 50 parts of a sodium hydroxide solution 50% and 135 parts of methylbenzene were added dropwise 10 parts of 1-bromo-3-chloropropane. Upon complete addition, stirring was continued for 4 hours. Another portion of 5 parts of 1-bromo-3-chloropropane were added and the whole was stirred for 4 hours at 50° C. After cooling to room temperature, the reaction mixture was poured into ice water and the product was extracted twice with methylbenzene. The combined extracts were washed with a sodium carbonate solution, dried, filtered and evaporated. The excess of 1-bromo-3-chloropropane was distilled off at on oil pump. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (97:3 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 6 parts (34.3%) of a mixture of 55% of 3-[(3-chloropropoxy)(4-fluorophenyl)methyl]pyridine and 45% of 3-[(3-chloropropoxy)(4-fluorophenyl)methyl]pyridine monohydrochloride as a residue (int. 64).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([CH2:14][C:15]2[N:20]=[C:19]3[S:21][C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[N:23][C:18]3=[CH:17][CH:16]=2)SCCCS1.CC(C)=[O:30].CC1C=CC(S(O)(=O)=O)=CC=1.O>CO.O.Cl[Hg]Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:30])[CH2:14][C:15]1[N:20]=[C:19]2[S:21][C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[N:23][C:18]2=[CH:17][CH:16]=1
Reactant: CC(C)=O
Reactant: CC(C)Nc1nc2ccc(CC3(c4ccccc4F)SCCCS3)nc2s1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl[Hg]Cl
Solvent: CO
Solvent: O
Product: CC(C)Nc1nc2ccc(CC(=O)c3ccccc3F)nc2s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 42 %

Procedure:
To a solution of 5-((2-(2-fluorophenyl)-1,3-dithian-2-yl)methyl)-N-isopropylthiazolo[5,4-b]pyridin-2-amine (0.61 g, 1.45 mmol, 1.0 eq.) in MeOH (73 mL) and water (6 mL) were added HgO (0.83 g, 3.83 mmol, 2.6 eq.) and HgCl2 (1.83 g, 6.74 mmol, 4.6 eq.). After stirring for 15 min., the solution was refluxed for another 15 min. and cooled to room temperature. The precipitate was removed, and the filtrate was concentrated in vacuo. The residue was diluted with EtOAc and water, and the layers were separated. The organic layer was washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered and concentrated in vacuo. Acetone (7 mL), water (0.1 mL, 5.56 mmol, 3.8 eq.), and TsOH.H2O (0.0342 g, 0.180 mmol, 0.1 eq.) were added, and the reaction was stirred overnight and concentrated in vacuo. The residue was diluted with CH2Cl2 and water, and the layers were separated. The organic layer was washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered and concentrated in vacuo. Silica gel chromatography using CH2Cl2:MeOH (15:0.1) as eluent afforded 1-(2-fluorophenyl)-2-(2-(isopropylamino)thiazolo[5,4-b]pyridin-5-yl)ethanone as a yellow solid (0.1994 g, 42% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1.S(=O)(=O)(O)O.[I:21]N1C(=O)CCC1=O.O>ClCCl.C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([I:21])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Oc1ccc(-c2cccc(F)c2)c(Cl)c1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: Oc1cc(Cl)c(-c2cccc(F)c2)cc1I
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.8 %

Procedure:
2-Chloro-3′-fluorobiphenyl-4-ol (Preparation 69, 500 mg, 2.25 mmol) was dissolved in dichloromethane (5 mL) and acetic acid (5 mL). Concentrated sulfuric acid (0.05 mL) was added followed by N-iodosuccinimide (480 mg, 2.13 mmol) and the reaction stirred at room temperature for 18 hours. A further portion of N-iodosuccinimide (50 mg, 0.22 mmol) was added and stirring continued at room temperature for 3 hours. Water and dichloromethane were added and the two layers separated. The organic layer was washed twice with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (20% ethyl acetate in heptane) to afford the title compound (496 mg, 63%) as a yellow oil that solidified on standing.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[CH3:15][CH:16]1[N:21](C(OCC2C=CC=CC=2)=O)[CH:20]([CH:32]2[CH2:34][O:33]2)[CH2:19][CH2:18][CH2:17]1>C(O)(C)(C)C.O>[CH3:15][CH:16]1[CH2:17][CH2:18][CH2:19][CH:20]([CH:32]([OH:33])[CH2:34][O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[NH:21]1
Reactant: CC1CCCC(C2CO2)N1C(=O)OCc1ccccc1
Reactant: Oc1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: CC1CCCC(C(O)COc2ccc(F)cc2)N1

Procedure:
A solution of a p-fluorophenol in t-butanol is treated with one equivalent of potassium t-butoxide, followed by the compound of example 35A. The reaction mixture is then refluxed until all epoxide has reacted. The reaction is cooled, diluted with water, and extracted with ethyl acetate. The organic extracts are dried and concentrated. The carbobenzyloxy protecting group is removed by standard hydrogenolysis and the final product purified by chromatography.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=[C:17]4[CH:29]=O)[CH:7]=2)[CH2:3][CH2:2]1.[OH:32][CH2:33][C@@H:34]1[CH2:39][NH:38][CH2:37][CH2:36][N:35]1C(OC(C)(C)C)=O>>[CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:27][CH2:28]3)[CH:18]=[C:17]4[CH2:29][N:38]3[CH2:37][CH2:36][NH:35][C@H:34]([CH2:33][OH:32])[CH2:39]3)[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Reactant: CC(C)(C)OC(=O)N1CCNC[C@H]1CO
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CN3CCN[C@H](CO)C3)c2c1

Procedure:
The title compound was prepared as a solid according to the method of Example 81 using the product of Example 75 step i) and (S)-2-(hydroxymethyl)-piperazine-1-carboxylic acid, tert-butyl ester.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:16][NH:17][C:18]([C:20]2[CH:34]=[CH:33][C:23]([O:24][CH2:25][C:26]([O:28]C(C)(C)C)=[O:27])=[C:22]([O:35][CH2:36][C:37]([O:39]C(C)(C)C)=[O:38])[CH:21]=2)=[O:19])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[C:44]([OH:50])([C:46]([F:49])([F:48])[F:47])=[O:45]>ClCCl>[F:47][C:46]([F:49])([F:48])[C:44]([OH:50])=[O:45].[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:16][NH:17][C:18]([C:20]2[CH:34]=[CH:33][C:23]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:22]([O:35][CH2:36][C:37]([OH:39])=[O:38])[CH:21]=2)=[O:19])=[O:15])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)COc1ccc(C(=O)NNC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)cc1OCC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)COc1ccc(C(=O)NNC(=O)C2CCNCC2)cc1OCC(=O)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of t-butyl 4-[3-(1-t-butoxycarbonylpiperidin-4-ylcarbonyl)carbazoyl]-2-(t-butoxycarbonylmethoxy)phenoxyacetate (360 mg) and TFA (4 ml) in dichloromethane (8 ml) was stirred at ambient temperature for 5 hours. The solvent was removed by evaporation and the residue was triturated with ether to give the title compound as a solid; NMR Spectrum (d6 -DMSO) 1.68-2.02 (m, 4H), 2.55-2.68 (m, 1H), 2.85-3.05 (dt, 2H), 3.2-3.4 (br d, 2H), 4.74 (s, 2H), 4.78 (s, 2H), 6.97 (d, 1H), 7.4 (s, 1H), 7.47 (dd, 1H), 8.5 (br s, 2H), 9.9 (s, 1H), 10.2 (s, 1H); Mass Spectrum (+ve FAB, MeOH/NBA): 396 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[C:5]([CH:11]([F:13])[F:12])=[N:4]1)C.ClC1[N:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=1.C([O-])([O-])=O.[K+].[K+].O.CN1C(=O)C[CH2:32][CH2:31]1>>[F:12][CH:11]([F:13])[C:5]1[C:6]([C:8]([O:10][CH2:31][CH3:32])=[O:9])=[CH:7][N:3]([C:1]2[N:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=2)[N:4]=1
Reactant: Fc1cnc(Cl)nc1
Reactant: CCn1cc(C(=O)O)c(C(F)F)n1
Reactant: CN1CCCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1cn(-c2ncc(F)cn2)nc1C(F)F

Procedure:
A solution of ethyl 3-(difluoromethyl)-1H-pyrazole-4-carboxylic acid (190 mg, 1.0 mmol), 2-chloro-5-fluoro-pyrimidine (132 mg, 1.0 mmol) and K2CO3 (276 mg, 2.0 mmol) in NMP (2.0 mL) is heated in a microwave reactor at 150° C. for 1 h. The mixture is poured into H2O, extracted with EtOAc (3×25 mL) and dried over anhydrous MgSO4. The crude product is purified by silica gel column chromatography using 15-25% EtOAc/hexane to afford the title compound as a white solid.
Reaction SMILES: [C:1]([NH:4][C@H:5]1[CH2:8][C@H:7]([O:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[NH:17][C:18]2[C:19]3[C:26]([CH3:27])=[C:25]([C:28](O)=[O:29])[S:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH2:6]1)(=[O:3])[CH3:2].Cl.[NH2:32][C@@H:33]1[CH2:35][C@H:34]1[NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40]>>[C:39]([O:38][C:37](=[O:43])[NH:36][CH:34]1[CH2:35][CH:33]1[NH:32][C:28]([C:25]1[S:24][C:20]2[N:21]=[CH:22][N:23]=[C:18]([NH:17][C:11]3[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:10]=3[O:9][C@H:7]3[CH2:6][C@H:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:8]3)[C:19]=2[C:26]=1[CH3:27])=[O:29])([CH3:40])([CH3:42])[CH3:41]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1N
Reactant: CC(=O)N[C@H]1C[C@H](Oc2cc(F)ccc2Nc2ncnc3sc(C(=O)O)c(C)c23)C1
Agent: Cl
Product: CC(=O)N[C@H]1C[C@H](Oc2cc(F)ccc2Nc2ncnc3sc(C(=O)NC4CC4NC(=O)OC(C)(C)C)c(C)c23)C1

Procedure:
Prepared analogously to 35.3 from 0.080 g 4-[2-(trans-3-acetylamino-cyclobutoxy)-4-fluoro-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid (cpd. 35.2) and 0.050 g tert-butyl (1R,2R)-2-aminocyclopropylcarbamate hydrochloride.
Reaction SMILES: [CH:1]12[O:10][CH:7]([CH:8]=[CH:9]1)[CH:6]1[CH:2]2[C:3](=[O:12])[CH2:4][C:5]1=[O:11].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Cl:39][C:40]1[CH:53]=[CH:52][C:43]([C:44]2[CH:45]=[CH:46][C:47]([CH3:51])=[C:48]([Pb+3])[CH:49]=2)=[CH:42][CH:41]=1.Cl>C(OCC)(=O)C.C1(C)C=CC=CC=1>[Cl:39][C:40]1[CH:41]=[CH:42][C:43]([C:44]2[CH:45]=[CH:46][C:47]([CH3:51])=[C:48]([CH:4]3[C:3](=[O:12])[CH:2]4[CH:6]([CH:7]5[O:10][CH:1]4[CH:9]=[CH:8]5)[C:5]3=[O:11])[CH:49]=2)=[CH:52][CH:53]=1
Reactant: Cc1ccc(-c2ccc(Cl)cc2)cc1[Pb+3]
Reactant: O=C1CC(=O)C2C3C=CC(O3)C12
Agent: CC(=O)[O-]
Agent: Cl
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2ccc(Cl)cc2)cc1C1C(=O)C2C3C=CC(O3)C2C1=O
Temperature: 25 °C

Procedure:
To a mixture of (1RS,2SR,6RS,7SR)-10-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (374 mg, 2.3 mmol) and phenanthroline (610 mg, 5 mmol) under an atmosphere of nitrogen is added dry toluene (20 ml) and 4′-chloro-4-methylbiphen-3-yllead triacetate (2.0 g, 3.4 mmol). The reaction mixture is heated at reflux for 3.5 hours, then cooled to room temperature, acidified to pH1 with 2N aqueous hydrochloric acid (20 ml), ethyl acetate (20 ml) added and the mixture is filtered to remove solids. The filtrate is poured into a separating funnel and extracted with ethyl acetate. The organic extracts are combined, dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated under reduced pressure. The crude product is purified by column chromatography on silica gel to give (1RS,2SR,6RS,7SR)-4-(4′-chloro-4-methylbiphenyl-3-yl)-10-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione.
Reaction SMILES: OO.S(=O)(=O)(O)O.[NH2:8][C:9]1[C:13]([NH2:14])=[N:12][O:11][N:10]=1.[N:15]([C:17]1[C:18]([NH2:22])=[N:19][O:20][N:21]=1)=[O:16]>>[NH2:22][C:18]1[C:17]([N+:15](=[N:14][C:13]2[C:9]([NH2:8])=[N:10][O:11][N:12]=2)[O-:16])=[N:21][O:20][N:19]=1
Reactant: Nc1nonc1N=O
Reactant: Nc1nonc1N
Agent: O=S(=O)(O)O
Agent: OO
Product: Nc1nonc1N=[N+]([O-])c1nonc1N
Temperature: 18 °C
Yield: 88 %

Procedure:
This procedure was modeled from the original Russian preparation. To 30% hydrogen peroxide (100.0 g, 0.88 mol) in a 500 ml jacketed flask maintained at 18° C. was added 98% sulfuric acid (55.0 g, 0.56 mol) over 10 minutes with stirring. Then, 3,4-diaminofurazan (10.0 g, 0.10 mole) was added. The suspension was stirred for 24 hours in which time the soluble green nitroso-amino-furazan was converted to the insoluble orange DAAF. The product was filtered on a glass frit, washed with water and air dried to yield 9.29 g (88%) of crude material. For recrystallization the crude compound was dissolved in the minimum amount of room temperature DMSO (approximately 22 ml) and then water (45 ml) was added over 5 minutes with stirring. The pure DAAF was filtered, washed with water and air-dried. This material had the same properties as previously reported by the Russians. 1H NMR (deuteriomethylsulfoxide)δ 6.65 (s, 2H), 6.93 (s, 2H); 13C NMR (deuteriomethylsulfoxide) δ 148.3, 151.2, 152.6, 153.9.
Reaction SMILES: ClC1C=CC=CC=1C(N[C@H]1CCC[C@@H]1N[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=1)=O.Cl.[NH2:28][C@H:29]1[CH2:33][CH2:32][CH2:31][C@@H:30]1[NH:34][C:35](=[O:44])[C:36]1[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=1[F:43].ClC1C=CC(C(F)(F)F)=CN=1>>[F:42][C:41]1[CH:40]=[CH:39][CH:38]=[C:37]([F:43])[C:36]=1[C:35]([NH:34][C@H:30]1[CH2:31][CH2:32][CH2:33][C@@H:29]1[NH:28][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=1)=[O:44]
Reactant: O=C(N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1)c1ccccc1Cl
Reactant: N[C@H]1CCC[C@@H]1NC(=O)c1c(F)cccc1F
Agent: Cl
Agent: FC(F)(F)c1ccc(Cl)nc1
Product: O=C(N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1)c1c(F)cccc1F

Procedure:
Prepared according to the procedure for 2-chloro-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]benzamide (Example 69) from N-[(1S,2S)-2-amino cyclopentyl]-2,6-difluorobenzamide hydrochloride (Intermediate 21; 100 mg, 0.36 mmol) and 2-chloro-5-(trifluoromethyl)pyridine (CAS number 52334-81-3; 79 mg, 0.43 mmol) to afford the title compound.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]([CH2:11]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:2]1.[C-:23]#[N:24].[Na+]>CN(C=O)C>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]([CH2:11][C:23]#[N:24])[CH2:2]1
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3ccccc3C2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCC1COc2ccccc2C1
Yield: 126.4 %

Procedure:
Compound 18B (1.25 g), NaCN (0.15 g) in 25 mL of DMF, were heated to 60° C. for 12 h. The solvent was removed, the reaction mixture was mixed with water (125 mL) and ether (125 mL). The ether layer was separated, washed with water, brine, dried (MgSO4), concentrated to afford compound 18C (0.67 g). mp 54-55.5° C.; MS: 174 (M+1)+. Preparation of 3-Cyanomethyl-chroman-6-sulfonyl chloride (Compound 18D)
Reaction SMILES: [ClH:1].[NH:2]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]3[N:21]=[CH:20][NH:19][C:17]3=2)[N:12]=[C:11]([CH3:22])[CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:23]([C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1)([CH3:25])[CH3:24].C([OH:35])C.C>C(O)(C)C>[OH2:35].[ClH:1].[CH:23]([C:6]1[CH:7]=[CH:8][C:3]([NH:2][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]4[N:21]=[CH:20][NH:19][C:17]4=3)[N:12]=[C:11]([CH3:22])[CH:10]=2)=[CH:4][CH:5]=1)([CH3:25])[CH3:24].[CH:23]([C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]4[N:21]=[CH:20][NH:19][C:17]4=3)[N:12]=[C:11]([CH3:22])[CH:10]=2)=[CH:28][CH:27]=1)([CH3:25])[CH3:24].[ClH:1]
Reactant: Cc1cc(Nc2ccccc2)c2c(ccc3nc[nH]c32)n1
Reactant: CCO
Reactant: CC(C)c1ccc(N)cc1
Agent: Cl
Solvent: CC(C)O
Product: Cc1cc(Nc2ccc(C(C)C)cc2)c2c(ccc3nc[nH]c32)n1
Product: O

Procedure:
A mixture of the compound of Example I, C. (32.1 g., 0.148 mole), p-isopropylaniline (20 g., 0.148 mole) and ethanol (300 ml.) was stirred while heating at reflux for 4 hours. The mixture was chilled and the crystals were collected by filtration and dried at 60°C to yield 3.6 g. off-white crystals, m.p. 215°-230°C. The filtrate was concentrated to 150 ml. by rotary evaporator and chilled. The solid was collected and dried to yield 29.7 g. off white crystals, m.p. 249°-256°C. A third crop was collected and dried to yield 7.1 g. off white crystals, m.p. 249°-256°C. Crop I was dissolved in isopropanol (900 ml.), treated with charcoal and filtered while hot. The filtrate was concentrated to 50 ml. The grayish mixture was chilled for several hours and the crystals were collected and dried to yield 0.1 g. gray crystals, m.p. 224°-232°C - discarded. A second crop was collected and dried to yield 0.3 g. yellow crystals, m.p. 248°-254°C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[NH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[C:12]#N.CC[O:20]CC>>[NH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[C:12]([C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1)=[O:20]
Reactant: N#Cc1ccccc1N
Reactant: CCOCC
Reactant: Fc1ccc(Br)cc1
Product: Nc1ccccc1C(=O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A dry 500 ml 3-neck flask fitted with a reflux condenser and an addition funnel was charged with Mg turnings (2.80 gm, 0.115 mol) and dry Et2 O (35 ml). A solution of 1-bromo-4-fluorobenzene (18.5 gm, 0.106 mol) in Et2O (20 ml) was added to the addition funnel and approximately 15% of this solution was added to the Mg/Et2O mixture. Once the exothermic reaction had begun (ultrasound was required), the aryl bromide solution was added at such a rate as to maintain a gentle reflux. After the addition was complete, the mixture was refluxed for an additional 30 minutes, then cooled to 0° C. Dropwise addition of a solution of 2-aminobenzonitrile (5.00 gm, 0.042 mol) in dry Et2O (20 ml) over a 10 minute period resulted in the formation of a thick yellow slurry. The resulting mixture was warmed to room temperature and stirred overnight. The solution was then cooled to 0° C. and cautiously quenched with 10% HCl (50 ml). After stirring for 5 minutes, the solution was made basic with 10% NaOH (70 ml) and the aqueous layer was extracted three times with Et2O. The combined Et2O layers were pooled, washed with brine, dried (Na2SO4), filtered and stripped to yield an orange oil. The oil was chromatographed (Flash, Merck SiO2, 25% EtOAc in hexane) to give impure 2-aminophenyl 4-fluorophenyl methanone (~1 gm) and the corresponding impure imine (~5.8 gm, Rf 0.28 in 30% EtOAc in hexane). The imine was stirred with 10% HCl (100 ml) and silica gel (750 mg) for 45 minutes. The mixture was then basicified with NaOH pellets (14 gm) and the aqueous layer was extracted twice with Et2O. The combined Et2O layers were washed with brine, dried (Na2 SO4), filtered and stripped to yield a solid. This solid was pooled with impure 2-amino-phenyl 4-fluorophenyl methanone from above and recrystallized in hot EtOH/H2O to give analytically pure 2-aminophenyl 4-fluorophenyl methanone as yellow crystals (3.28 gm, 36%).
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH:5]=1.[B-](F)(F)(F)[F:20].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C.C(OCC)(=O)C>[F:20][CH:9]1[C:4](=[O:3])[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8]1
Reactant: F[B-](F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC=C(O[Si](C)(C)C)CC1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(=O)C(F)C1
Reaction time: 1.25 h
Yield: 88 %

Procedure:
A solution of compound 129 (4.5 g, 16.578 mmol) in dry acetonitrile (175 mL) was treated with Selectfluor™ (6.46 g, 18.236 mmol) at room temperature and resulting solution was stirred for 75 min. at same temperature. The reaction was diluted with ethyl acetate (500 mL), washed with unsaturated brine (300 mL, water: saturated brine 1:1), saturated brine (100 mL) and dried (Na2SO4). The solvent was evaporated and crude was purified by column chromatography (ethyl acetate to 5% methanol in ethyl acetate) to obtain compound 130 (3.18 g, 88%) as a syrup. 1H NMR (CDCl3) δ: 1.50 (s, 9H), 2.46-2.64 (m, 2H), 3.20-3.37 (m, 2H), 4.13-4.20 (m, 1H), 4.44-4.48 (m, 1H), 4.72-4.77, 4.88-4.93 (2m, 1H). 1H NMR comparable with literature (J. Med. Chem. 1999, 42, 2087-2104).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][CH:17]([CH:21]([C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=1)[C:22]([OH:24])=[O:23])[C:18]([OH:20])=[O:19]>CS(C)=O>[C:12]([C:11]1[C:2]([NH:16][CH:17]([CH:21]([C:25]2[CH:26]=[C:27]([F:32])[CH:28]=[C:29]([F:31])[CH:30]=2)[C:22]([OH:24])=[O:23])[C:18]([OH:20])=[O:19])=[N:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([Cl:15])=[CH:6][CH:5]=2)([OH:14])=[O:13]
Reactant: NC(C(=O)O)C(C(=O)O)c1cc(F)cc(F)c1
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Solvent: CS(C)=O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1NC(C(=O)O)C(C(=O)O)c1cc(F)cc(F)c1

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 2-amino-3-(3,5-difluoro-phenyl)-succinic acid [prepared by analogy to J. Med. Chem. 1973, 16, 1277-1280.; using alkylation of diethyl acetamidomalonate by methyl bromo-(3,5-difluoro-phenyl)-acetate] in DMSO to provide the title compound in good yield.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](SC)[N:5]=[C:4]([NH:10][C:11]2[NH:15][N:14]=[C:13]([CH3:16])[CH:12]=2)[CH:3]=1.O[O:18][S:19]([O-:21])=O.[K+].[C:23](=O)(O)[O-]>CO.O>[Cl:1][C:2]1[N:7]=[C:6]([S:19]([CH3:23])(=[O:21])=[O:18])[N:5]=[C:4]([NH:10][C:11]2[NH:15][N:14]=[C:13]([CH3:16])[CH:12]=2)[CH:3]=1
Reactant: O=S([O-])OO
Reactant: O=C([O-])O
Reactant: CSc1nc(Cl)cc(Nc2cc(C)n[nH]2)n1
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1cc(Nc2cc(Cl)nc(S(C)(=O)=O)n2)[nH]n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a stirred solution of 6-chloro-N-(3-methyl-1H-pyrazol-5-yl)-2-(methylthio)pyrimidin-4-amine (8 g, 31.19 mmol) in MeOH (200 ml) cooled in an ice bath was added portionwise a slurry of oxone (44 g, 71.73 mmol) in water (100 ml) over 10 minutes. The reaction mixture was stirred at this temperature for a further 30 minutes before being allowed to warm up to room temperature for 2 hours. The solid, isolated by filtration, was stirred vigorously in a 1:1 mixture of water and saturated bicarbonate solution. The solid was then filtered and dried in a pistol under vacuo to afford the title compound as a yellow solid (7.17 g, 80% yield). 1H NMR (DMSO D6, 400 MHz) δ2.23 (3H, s), 3.32 (3H, s), 5.80-8.10 (2H, br m), 10.92 (1H, br s), 12.26 (1H, br s); MS (ES+) 288, (ES−) 286.