Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([O:20][CH3:21])=[C:14]([S:16](Cl)(=[O:18])=[O:17])[CH:15]=1>>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([O:20][CH3:21])=[C:14]([S:16]([NH:1][C:2]2[O:6][N:5]=[C:4]([CH3:7])[C:3]=2[Br:8])(=[O:17])=[O:18])[CH:15]=1
Reactant: Cc1noc(N)c1Br
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Product: COc1ccc(Cl)cc1S(=O)(=O)Nc1onc(C)c1Br
Yield: 61 %

Procedure:
5-Chloro-2-methoxy-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 5-chloro-2-methoxybenzenesulfonyl chloride according to the procedures described in Example 5. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 180°-184° C., yield 61%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[CH:4][C:3]=1[NH:21][C:22]([C:24]1[C:28]2[N:29]=[CH:30][N:31]=[C:32](S(C)=O)[C:27]=2[S:26][CH:25]=1)=[O:23].[CH3:36][O:37][C:38]1[CH:39]=[C:40]([CH:42]=[C:43]([O:47][CH3:48])[C:44]=1[O:45][CH3:46])[NH2:41]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:17])[F:18])[CH:11]=2)=[CH:4][C:3]=1[NH:21][C:22]([C:24]1[C:28]2[N:29]=[CH:30][N:31]=[C:32]([NH:41][C:40]3[CH:42]=[C:43]([O:47][CH3:48])[C:44]([O:45][CH3:46])=[C:38]([O:37][CH3:36])[CH:39]=3)[C:27]=2[S:26][CH:25]=1)=[O:23]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1NC(=O)c1csc2c(S(C)=O)ncnc12
Product: COc1cc(Nc2ncnc3c(C(=O)Nc4cc(C(=O)Nc5cccc(C(F)(F)F)c5)ccc4C)csc23)cc(OC)c1OC

Procedure:
The procedure of Step 3 of Example 13 was repeated except for using the compound obtained in Step 2 of Example 13 and 3,4,5-trimethoxyaniline to obtain the title compound (see Table 1).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[N-:18]=[N+:19]=[N-:20].[F:21][C:22]1[N:27]=[CH:26][C:25]([CH:28](O)[CH3:29])=[C:24]([I:31])[CH:23]=1>ClCCl>[N:18]([CH:28]([C:25]1[C:24]([I:31])=[CH:23][C:22]([F:21])=[N:27][CH:26]=1)[CH3:29])=[N+:19]=[N-:20]
Reactant: CC(O)c1cnc(F)cc1I
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Product: CC(N=[N+]=[N-])c1cnc(F)cc1I
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
Add tetra-N-butylammonium azide to a solution of triphenylphine (11 g, 42 mmol) and 1,4-cyclohexadiene-2,2-dicarbonitrile,4,5-dichloro-3,6-dioxo-(9 g, 40 mmol) in dichloromethane (150 mL) under ice-bath cooling. Then add 1-(6-fluoro-4-iodo-pyridin-3-yl)-ethanol (6.7 g, 25.1 mmol) to the above solution. Stir the mixture at room temperature for 1 hour. Concentrate the mixture in vacuo to about 50 mL. Purify the residue by flash column chromatography (hexane to 20% ethyl acetate in hexane as gradient) to give target product as colorless oil (5.7 g, 78%). MS (ES) m/z 293 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:34])[CH:5]=[C:6]([Cl:33])[C:7]=1[CH2:8][C@@H:9]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH:25]([F:27])[F:26])=[C:20]([O:28][CH2:29][CH:30]2[CH2:32][CH2:31]2)[CH:19]=1)[O:10][C:11]([C@H:13]1[NH:17][CH2:16][CH2:15][S:14]1)=[O:12].[CH:35]([C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][CH:45]=1)[C:40](O)=[O:41])=[O:36].C(Cl)CCl>CN(C1C=CN=CC=1)C.CN(C=O)C.Cl>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:34])[CH:5]=[C:6]([Cl:33])[C:7]=1[CH2:8][C@@H:9]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH:25]([F:27])[F:26])=[C:20]([O:28][CH2:29][CH:30]2[CH2:32][CH2:31]2)[CH:19]=1)[O:10][C:11]([C@H:13]1[N:17]([C:40](=[O:41])[C:39]2[CH:43]=[CH:44][CH:45]=[C:37]([CH:35]=[O:36])[CH:38]=2)[CH2:16][CH2:15][S:14]1)=[O:12]
Reactant: O=Cc1cccc(C(=O)O)c1
Reactant: O=C(O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1)[C@H]1NCCS1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=Cc1cccc(C(=O)N2CCS[C@H]2C(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.6 %

Procedure:
3,5-dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((S)-thiazolidine-2-carbonyloxy)ethyl)pyridine 1-oxide (Int 4, 208 mg, 0.389 mmol), 3-formylbenzoic acid (87 mg, 0.583 mmol), EDC (149 mg, 0.777 mmol), and DMAP (57.0 mg, 0.466 mmol) were dissolved in DMF (2 ml). The reaction was stirred at RT for 8 hours to achieve completion. The reaction mixture was diluted with HCl 1N, and the precipitate was filtered, washed with HCl 1N, dissolved in DCM and extracted with HCl 1N, Na2CO3 sat and brine. The organic phase was dried over Na2SO4 and concentrated under vacuum to give 3,5-dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((S)-3-(3-formylbenzoyl)thiazolidine-2-carbonyloxy)ethyl)pyridine 1-oxide (108 mg, 0.162 mmol, 41.6% yield). The compound was used in the next step without any further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:11](C(OCC2C=CC=CC=2)=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.C([O-])=O.[NH4+]>[Pd].C(O)C>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:3][C:2]=1[F:1]
Reactant: CCOC(=O)C(C(=O)OCc1ccccc1)c1ccc([N+](=O)[O-])c(F)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)Cc1ccc(N)c(F)c1
Temperature: 60 °C
Yield: 82 %

Procedure:
Ethyl phenylmethyl (3-fluoro-4-nitrophenyl)propanedioate (11.66 g, 32.3 mmol), ammonium formate (10.2 g, 161.5 mmol) and 10% palladium on carbon (wet paste) (1.7 g, 0.8 mmol) was placed under argon and ethanol (300 ml) introduced. The reaction mixture was heated to 60° C. for 3 hours, cooled and filtered through celite under an argon atmosphere. Evaporated and purified by chromatography on silica gel eluting with 2-30% ethyl acetate in hexane to give the title compound as a yellow oil (5.22 g, 26.5 mmol). LC/MS: Rt=2.14, [MH]+ 198.
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)[C:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)=[O:6].Cl.NO>C(O)C>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[O:6][N:2]=[CH:3][C:4]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:8][CH:9]=1
Reactant: CN(C)C=C(C(=O)c1ccc(Cl)cc1)c1ccncc1
Agent: Cl
Agent: NO
Solvent: CCO
Product: Clc1ccc(-c2oncc2-c2ccncc2)cc1
Temperature: 25 °C
Yield: 100.2 %

Procedure:
A solution of 3-dimethylamino-1-(4-chlorophenyl)-2-(pyridin-4-yl)-2-propen-1-one (22.80 g, 79.7 mmol), hydroxylamine hydrochloride (18.01 g, 0.26 mole), and 150 mL ethanol was heated to reflux for 30 minutes. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was dissolved in 1N hydrochloric acid and then treated with an aqueous saturated solution of sodium bicarbonate. The precipitates were collected by filtration, washed with water and ethanol, and dried to yield 5-(4-chlorophenyl)-4-(pyridin-4-yl)isoxazole (20.50 g, 93%). m.p. 120.8-120.9° C. 1H NMR (CDCl3/CD3OD/300 MHz) δ 8.53 (d, 2H), 8.46 (s, 1H), 7.51 (d, 2H), 7.41-7.34 (m, 4H). ESLRMS m/z 257 (M+H). ESHRMS m/z 257.0457 (M+H, C14H9N2OCl requires 257.0482).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([S:10](=[O:13])(=[O:12])[NH2:11])=[CH:4][N:3]=1.O.[NH2:15][NH2:16]>CO>[NH:15]([C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([S:10](=[O:13])(=[O:12])[NH2:11])=[CH:4][N:3]=1)[NH2:16]
Reactant: COc1cc(S(N)(=O)=O)cnc1Cl
Reactant: NN
Solvent: O
Solvent: CO
Product: COc1cc(S(N)(=O)=O)cnc1NN

Procedure:
2-Chloro-3-methoxy-5-sulfamoylpyridine (0.3 g, 1.35×10-3 mole) and hydrazine hydrate (0.53 g, approximately 0.01 mole) were added to methanol (20 ml). After refluxing overnight, the reaction mixture was stripped of methanol in vacuo to yield an oil which was cooled in an ice bath and triturated with water (5 ml). The precipitate was collected by filtration and air dried; yield, 0.22 g (75 percent).
Reaction SMILES: [CH2:1](/[C:3](=[CH:8]\[CH2:9][CH3:10])/[CH:4]=[CH:5]/[CH2:6][OH:7])[CH3:2].[C:11](OC(=O)C)(=[O:13])[CH3:12]>N1C=CC=CC=1>[C:11]([O:7][CH2:6]/[CH:5]=[CH:4]/[C:3](/[CH2:1][CH3:2])=[CH:8]/[CH2:9][CH3:10])(=[O:13])[CH3:12]
Reactant: CC/C=C(/C=C/CO)CC
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC/C=C(/C=C/COC(C)=O)CC
Reaction time: 2 h
Yield: 74.3 %

Procedure:
To a solution of (E,E)-4-ethyl-2,4-heptadien-1-ol (10.1 g) in pyridine (29 g) at 0° C. was added dropwise acetic anhydride (22.2 g). After two hours at room temperature, the reaction mixture was evaporated in vacuo. The residue was diluted with ethyl acetate, washed with 0.5N hydrochloric acid and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel (5% ethyl acetate in hexane) to give (E,E)-1-acetoxy-4-ethyl-2,4-heptadiene (9.75 g) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([CH3:30])[CH3:29])[C:23]=1[N:31]=[C:32]=[O:33])([CH3:21])[CH3:20]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=2)[C:32]([NH:31][C:23]2[C:22]([CH:19]([CH3:20])[CH3:21])=[CH:27][CH:26]=[CH:25][C:24]=2[CH:28]([CH3:30])[CH3:29])=[O:33])=[CH:6][CH:7]=1
Reactant: CN(C)c1ccc(CNc2ccc(Br)cc2)cc1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)N(Cc1ccc(N(C)C)cc1)c1ccc(Br)cc1

Procedure:
By the reaction and treatment in the same manner as in Example 1 using (4-bromophenyl)[(4-dimethylaminophenyl)methyl]amine (0.80 g) and 2,6-diisopropylphenyl isocyanate (0.62 mL) as starting materials, N-(4-bromophenyl)-N′-(2,6-diisopropylphenyl)-N-[(4-dimethylaminophenyl)methyl]urea (0.71 g) was obtained. melting point: 165–166° C.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:19]3[CH:18]=[N:17][C:16]([C:20]([O:22]CC)=O)=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)=[CH:4][CH:3]=1.ClC1C(F)=C(C(F)=CC=1)CN1C2C=NC([C:45]([NH:47][OH:48])=O)=CC=2C2C1=CC=CC=2>>[F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:19]3[CH:18]=[N:17][C:16]([C:20]([N:47]([OH:48])[CH3:45])=[O:22])=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2c3ccccc3n(Cc3ccc(F)cc3)c2cn1
Reactant: O=C(NO)c1cc2c3ccccc3n(Cc3c(F)ccc(Cl)c3F)c2cn1
Product: CN(O)C(=O)c1cc2c3ccccc3n(Cc3ccc(F)cc3)c2cn1

Procedure:
The title compound can be prepared from ethyl 9-(4-fluorobenzyl)-9H-β-carboline-3-carboxylate under the similar conditions as those in steps (a) and (b) of example 7. 1H NMR (400 MHz, CD3OD): δ 8.60–8.95 (2H, m), 8.32 (1H, d, J=8 Hz), 7.60–7.75 (2H, m), 6.95–7.45 (5H, m), 5.76 (2H, s), 3.48 (3H, s). HRMS (M+H)+ found: 350.1297. Calcd for C20H17FN3O2: 350.1305.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[CH2:18]([N:25]=[C:26]=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClCCl>[CH2:18]([NH:25][C:26]([NH:13][CH2:12][CH:8]1[O:9][CH2:10][CH2:11][N:6]([CH2:5][C:4]2[CH:14]=[CH:15][C:16]([Cl:17])=[C:2]([Cl:1])[CH:3]=2)[CH2:7]1)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C=NCc1ccccc1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Solvent: ClCCl
Product: O=C(NCc1ccccc1)NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reaction time: 72 h

Procedure:
To a stirred solution of Intermediate 3 (0.025 g) in dichloromethane (1 ml) was added benzylisocyanate (16.8 pt). The mixture was stirred at 22° C. for 18 h before tris-(2-aminoethyl)amine polystyrene (Argonaut Technologies, 0.04 g @ 3.85 mmol/g) was added. Stirring was continued for a further 72 h before the mixture was poured onto a 1 g solid phase extraction (Isolute SCX sulphonic acid) cartridge. The cartridge was washed with methanol before eluting with 10% 0.880 ammonia solution in methanol. The basic fraction was evaporated in vacuo to give a pale yellow solid. The solid was purified by eluting through a 1 g silica solid phase extraction cartridge (Varian Bondelut) eluting sequentially with dichloromethane, ether, ethyl acetate, acetone, acetonitrile and methanol, to give the title compound as a white solid (0.031 g). LC/MS (System A) Rt 2.22 min, Mass Spectrum m/z 408 [MH+].
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[F:13][CH2:14][CH2:15]Cl.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[F:13][CH2:14][CH2:15][O:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: FCCCl
Reactant: CCOC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cccc(OCCF)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.1 %

Procedure:
Thirty grams of ethyl 3-hydroxybenzoate, 14.9 g of 1-fluoro-2-chloroethane and 37.4 g of anhydrous potassium carbonate were added to 130 ml of dimethylformamide. With stirring, the reaction was carried out at 120° C. for 4 hours. The reaction mixture was cooled to room temperature, poured into water, and extracted with toluene. The toluene layer was washed with water, and dried over anhydrous sodium sulfate. Toluene was evaporated under reduced pressure to give 32.6 g of crude ethyl 3-(2-fluoroethoxy)benzoate. The resulting crude ethyl 3-(2-fluoroethoxy)benzoate (32.6 g) was added at 40° to 45° C. to a solution of 6.0 g of lithium aluminum hydride in 200 ml of dry tetrahydrofuran, and the mixture was heated under reflux for 2 hours. After the reaction, the reaction mixture was cooled to room temperature. Ethanol and water in this order were added to the mixture to decompose the unreacted lithium aluminum hydride. Water was then added, and the mixture was extracted with toluene. The toluene layer was washed with water, and dried over anhydrous sodium sulfate. Toluene was removed to give 26.0 g of crude 3-(2-fluoroethoxy)benzyl alcohol This compound was chlorinated to give 30.0 g of 3-(2-fluoroethoxy)benzyl chloride.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.Cl.[NH2:18][C:19]1[C:24]([NH2:25])=[CH:23][CH:22]=[C:21]([O:26][CH3:27])[N:20]=1.O.N>P(Cl)(Cl)(Cl)=O>[CH3:15][N:2]([CH3:1])[C:3]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:4]=1[C:5]([NH:25][C:24]1[C:19]([NH2:18])=[N:20][C:21]([O:26][CH3:27])=[CH:22][CH:23]=1)=[O:7]
Reactant: COc1ccc(N)c(N)n1
Reactant: CN(C)c1cc([N+](=O)[O-])ccc1C(=O)O
Agent: Cl
Agent: N
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2N(C)C)c(N)n1

Procedure:
An amount of 1.05 gm of 2-dimethylamino-4-nitro-benzoic acid is suspended in 35 ml of phosphorus oxychloride, and 1.05 gm of 2,3-diamino-6-methoxy-pyridine dihydrochloride are added thereto. The mixture is refluxed for 5 minutes, left to cool for 15 minutes with stirring, and finally decomposed with water. The solution obtained is cooled and poured onto a mixture of ice and concentrated ammonia. The product is then precipitated. It is subjected to suction filtration, washed with water, and dried in a circulating air drier at 50° C.
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Br:8])[N:7]=1.[NH2:11][C:12]1[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=1.CN1CCCC1=O.[OH-].[Na+]>ClCCl>[CH2:19]([O:18][C:16](=[O:17])[C:15]1[CH:21]=[CH:22][C:12]([NH:11][C:2]2[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Br:8])[N:7]=2)=[CH:13][CH:14]=1)[CH3:20]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: Cn1cc(Br)nc(Br)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CCOC(=O)c1ccc(Nc2nc(Br)cn(C)c2=O)cc1
Temperature: 25 °C
Yield: 76.1 %

Procedure:
A mixture of 3,5-dibromo-1-methyl-2(1H)pyrazinone (1) (21.3 g; 79.5 mmol), ethyl 4-aminobenzoate (13.1 g; 79.5 mmol), and 1-methyl-2-pyrollidinone (10 mL) was heated at 130 degrees for 1 hr. The mixture was cooled to room temperature, diluted with dichloromethane and filtered to give a dull brown solid. This was slurried with 0.5N NaOH, filtered, washed with water and diethyl ether to give 4-(6-bromo-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino)-benzoic acid ethyl ester (2) as a light brown solid (21.3 g)
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:22])[CH2:13][CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])=[CH:8][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12](=[O:22])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)CCC(=O)c1ccc(OCc2ccccc2F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCC(=O)c1ccc(OCc2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of tert-Butyl 4-(4-(2-fluorobenzyloxy)phenyl)-4-oxobutyrate (Step B, 1.27 g, 4.2 mmol) in dichloromethane (25 ml) was treated with trifluoroacetic acid (5 ml). The reaction mixture was stirred at ambient temperature for 3 hours and concentrated in vacuo. The purification was done by flash chromatography on silica gel column (chloroform:methanol, 95:5 spiked with acetic acid) to afford the title compound as a white powder.
Reaction SMILES: [ClH:1].[OH:2][C@@H:3]([CH2:19][N:20]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]([O:35]CC)=[O:34])=[CH:27][CH:26]=1)[CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[OH-].[Na+].Cl>C(O)C.C1COCC1>[ClH:1].[OH:2][C@@H:3]([CH2:19][N:20]([C:25]1[CH:26]=[CH:27][C:28]([O:31][CH2:32][C:33]([OH:35])=[O:34])=[CH:29][CH:30]=1)[CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: CCOC(=O)COc1ccc(N(CC(C)C)C[C@H](O)COc2cccc3[nH]c4ccccc4c23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)CN(C[C@H](O)COc1cccc2[nH]c3ccccc3c12)c1ccc(OCC(=O)O)cc1
Reaction time: 1 h
Yield: 34.1 %

Procedure:
A solution of the free base (0.25 g, 0.47 mmol) from example 93 in ethanol/THF (50 mL/50 mL) was treated with 1N NaOH (14.1 mL, 14.1 mmol) and refluxed with stirring for 1 h, the reaction was neutralized with 1N HCl (13.6 mL, 13.6 mmol, 29 eq), and concentrated in vacuo. The resulting residue was slurried in ether (30 ml) and anhydrous HCl in ether (30 ml) was added. The resulting slurry was concentrated in vacuo. The residue was dissolved in EtOAc and filtered. The filtrate was concentrated in vacuo to provide 0.08 g (35%) of a tan solid. MS (FD+): m/z 463. Anal Calcd for C27H31N20O5Cl: C, 64.99; H, 6.26; N, 5.61. Found: C, 65.29; H, 6.55; N, 5.35.
Reaction SMILES: [I:1][C:2]1[C:3](C)=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:13]C1C=CC(C(O)=O)=C(C)C=1>>[F:13][C:3]1[C:2]([I:1])=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([CH3:11])[CH:4]=1
Reactant: Cc1cc(C)c(C(=O)O)cc1I
Reactant: Cc1cc(F)ccc1C(=O)O
Product: Cc1cc(F)c(I)cc1C(=O)O

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 1.3, except 4-fluoro-2-methylbenzoic acid was used in place of 2,4-dimethylbenzoic acid.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([C:24]#[C:25][C:26]3[CH:31]=[CH:30][C:29]([CH2:32][C:33]([OH:35])=[O:34])=[CH:28][CH:27]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:36]([F:39])([F:38])[F:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C.C(O)(=O)C.[Pd]>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([CH2:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([CH2:32][C:33]([OH:35])=[O:34])=[CH:30][CH:31]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:36]([F:37])([F:38])[F:39])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccc(C#Cc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(O)Cc1ccc(CCc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
A solution of [4-({3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}ethynyl)-phenyl]acetic acid (50 mg, 0.09 mmol), in ethyl acetate:acetic acid (8:1, 4.0 mL) is treated with Pd/C (10%) (3 mg) and placed on a PARR hydrogenator under 40 psi H2 The reaction filtered through celite and concentrated in vacuo. After chromatography (ethyl acetate:hexane, 33:70) the title saturated compound is obtained, 40 mg (80%). MS (ES) m/z 524.1.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:21]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[C:27]([F:32])[CH:26]=3)=[O:22])=[C:7]([CH:18]([CH3:20])[CH3:19])[N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:4][CH:3]=1.Cl[CH2:34][CH2:35][N:36]=[C:37]=[O:38]>C(Cl)Cl>[F:32][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][C:28]=1[F:31])[CH2:24][NH:23][C:21]([C:6]1[C:5]2[C:9](=[CH:10][C:2]([NH:1][C:37]3[O:38][CH2:34][CH2:35][N:36]=3)=[CH:3][CH:4]=2)[N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[C:7]=1[CH:18]([CH3:20])[CH3:19])=[O:22]
Reactant: O=C=NCCCl
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(N)cc2n1Cc1ccccn1
Solvent: ClCCl
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(NC3=NCCO3)cc2n1Cc1ccccn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 6-amino-N-(3,4-difluorobenzyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 182, 48 mg, 0.11 mmol) in CH2Cl2 (1 ml) was added chloroethyl isocyanate (10 μl, 0.12 mmol). The reaction was stirred at room temperature for 16 h, and the solvent was removed. To the residue was added H2O and the mixture was heated at 80° C. for 3 h, diluted with EtOAc, washed with aqueous K2CO3 and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→100% EtOAc-hexanes) to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH:4]1[CH2:8][CH2:7][CH2:6][NH:5]1.[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>>[CH3:1][O:2][C:3]([CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[S:16]([C:13]1[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=1)(=[O:18])=[O:17])=[O:9]
Reactant: COC(=O)C1CCCN1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: COC(=O)C1CCCN1S(=O)(=O)c1ccc(C)cc1

Procedure:
Reaction of DL-proline methylester with toluene-4-sulfonyl chloride according to the general procedure of example 1d yielded (RS)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid methyl ester as a white solid, m.p.=93° C. and MS: m/e=283 (M+).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[CH3:22])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[S:23]1[CH:27]=[CH:26][N:25]=[CH:24]1.CC([O-])=O.[K+]>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:22][C:21]1[CH:20]=[CH:19][C:4]([C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)=[O:6])=[CH:3][C:2]=1[C:27]1[S:23][CH:24]=[N:25][CH:26]=1
Reactant: c1cscn1
Reactant: Cc1ccc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Product: Cc1ccc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1-c1cncs1
Temperature: 130 °C
Reaction time: 60 h

Procedure:
3-Iodo-4-methyl-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 13.1, 100 mg, 0.237 mmol), thiazole (60 mg, 0.712 mmol), KOAc (69.9 mg, 0.712 mmol) and Pd(OAc)2 (0.267 mg, 1.187 μmol) were added to a vial, which was sealed, evacuated/purged with argon. DMA (720 μL) was added and the RM was stirred at 130° C. for 2.5 days. The RM was diluted with THF (3 mL), stirred overnight with Si-Thiol (1.44 mmol/g, 16.49 mg, 0.024 mmol) and filtered. The filtrate was treated with 2 M HCl (40 mL) and extracted with TBME. The combined extracts were washed with 1 M HCl, sat. NaHCO3, brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a residue which was purified by preparative SFC (Column NH2, from 10% to 15% in 2.4 min) to afford the title compound as a colorless solid. UPLC-MS (Condition 2) tR=1.18 min, m/z=379.2 [M+H]+, m/z=377.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.44 (s, 3H) 7.37 (d, J=8.31 Hz, 2H) 7.54 (d, J=8.07 Hz, 1H) 7.86-7.91 (m, 2H) 7.93 (dd, J=7.82, 1.96 Hz, 1H) 8.02 (d, J=1.96 Hz, 1H) 8.10 (d, J=0.73 Hz, 1H) 9.23 (d, J=0.73 Hz, 1H) 10.43 (s, 1H).