Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[Cl:8][CH2:9][C:10](Cl)=[O:11].[NH2:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[CH:19][C:18]([C:24]#[N:25])=[C:17]2[NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Br:33])[CH:28]=1>O1CCCC1>[Br:33][C:29]1[CH:28]=[C:27]([NH:26][C:17]2[C:16]3[C:21](=[CH:22][CH:23]=[C:14]([NH:13][C:10](=[O:11])[CH2:9][Cl:8])[CH:15]=3)[N:20]=[CH:19][C:18]=2[C:24]#[N:25])[CH:32]=[CH:31][CH:30]=1
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#Cc1cnc2ccc(NC(=O)CCl)cc2c1Nc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.9 %

Procedure:
Triethylamine(0.359 g, 3.55 mmol) and chloroacetyl chloride (0.402 g, 3.55 mmol) were added to an ice cold solution of 1.00 g (2.96 mmol) of 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile in 12 mL of tetrahydrofuran under N2. After stirring overnight at 25° C., volatile material was removed and the residue was slurried in water and collected. Recrystallization from methanol gave 0.540 g of tan solid: mass spectrum (electrospray, m/e): M+H 415, 417.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-])=O.C(Cl)Cl.CO>[Pd].CO>[NH2:1][C:4]1[CH:12]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: Nc1cc(C(F)(F)F)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.2 %

Procedure:
A mixture of 2-nitro-4-(trifluoromethyl)benzoic acid (646 g, 2.75 mol) and 10% palladium on carbon (50% in water, 71 g) in MeOH (3.6 L) was allowed to stir at rt under an atmosphere of H2 (15 psi). After 3 h, TLC (DCM:MeOH 10:1) showed no remaining starting material. The mixture was filtered and the filtrate was concentrated to give 2-amino-4-(trifluoromethyl)benzoic acid (520 g, 92%) as a white solid.
Reaction SMILES: [Li]CCCC.[C:6]1([C:12]2[CH:16]=[CH:15][O:14][CH:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:17][C:18]1([CH3:29])[C:22]([CH3:24])([CH3:23])[O:21][B:20](OC(C)C)[O:19]1>O1CCCC1>[CH3:17][C:18]1([CH3:29])[C:22]([CH3:24])([CH3:23])[O:21][B:20]([C:15]2[O:14][CH:13]=[C:12]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:16]=2)[O:19]1
Reactant: c1ccc(-c2ccoc2)cc1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)OB(c2cc(-c3ccccc3)co2)OC1(C)C
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 7.1 %

Procedure:
A solution of n-BuLi (6.2 mL, 2.5 M solution in hexane) was added drop-wise to a solution of 3-phenylfuran (1.5 g, 10.40 mmol) in dry tetrahydrofuran (100 mL) at −78° C. under nitrogen. It was warmed slowly to −40° C. over 45 min and stirred at this temperature for another 30 min. The mixture was cooled again to −78° C. followed by the dropwise addition of 4,4,5,5-tetramethyl-2-(propan-2-yloxy)-1,3,2-dioxaborolane (3.72 g, 19.99 mmol). After warming to room temperature, the mixture was quenched with NH4Cl (aq) and extracted with ethyl acetate (3×80 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the residue, which was precipitated by cooling to afford 4,4,5,5-tetramethyl-2-(3-phenylfuran-2-yl)-1,3,2-dioxaborone as a white solid (400 mg, 14.0%). The mother liquid was purified by silica gel column chromatography eluting with 2% ethyl acetate in petroleum ether to afford 4,4,5,5-tetramethyl-2-(4-phenylfuran-2-yl)-1,3,2-dioxaborolane (200 mg, crude), which was used to the next step without further purification.
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[NH2:16][CH2:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[S:25]([N:28]([CH3:30])[CH3:29])(=[O:27])=[O:26].C(N(CC)CC)C>CO>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:16]([CH2:17][C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[S:25](=[O:27])(=[O:26])[N:28]([CH3:29])[CH3:30])[CH:10]=1
Reactant: CN(C)S(=O)(=O)c1ccc(F)cc1CN
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)c1ccc(F)cc1Cn1cc(Cl)cc(C(N)=O)c1=N
Temperature: 50 °C
Reaction time: 8 h
Yield: 12.2 %

Procedure:
(Step 2) To a suspension of 2-cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (1.0 g) in methanol (10 ml) was added a solution of 2-(aminomethyl)-4-fluoro-N,N-dimethylbenzenesulfonamide hydrochloride obtained in Step 1 (1.37 g) and triethylamine (1.6 ml) in methanol (5 ml) at room temperature, and the mixture was stirred overnight at 50° C. The reaction solvent was evaporated under reduced pressure, acetic acid (5 ml) was added, and the mixture was stirred at 50° C. for 2 hr. The solvent was evaporated under reduced pressure, the residue was extracted with 1N hydrochloric acid, and the extract was washed with ethyl acetate. The aqueous layer was basified with 1N aqueous sodium hydroxide solution, the mixture was partitioned with ethyl acetate, and the organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=7:3→1:0). The obtained residue was dissolved in methanol, and 4N hydrogen chloride-ethyl acetate solution (1 ml) was added. The mixture was crystallized from methanol-ethyl acetate. The precipitated crystals were collected by filtration, and recrystallized from methanol-ethyl acetate to give the title compound (0.11 g).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[C@@H:10]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11][CH2:12][C:13]([OH:15])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:58]([NH2:65])[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:24])[C@@H:10]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11][CH2:12][C:13](=[O:15])[NH:65][CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)O)C(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CCC(=O)NCc1ccccc1)C(=O)OCc1ccccc1

Procedure:
To a solution of 1.00 g (S)-2-tert-butoxycarbonylamino-pentanedioic acid 1-benzyl ester in 15 ml DMF were added 1.24 g HATU, 1.1 ml DIPEA and 0.32 ml benzylamine at 0° C.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[C:16]2[C:7](=[CH:8][C:9]3[CH2:10][CH2:11][CH:12]([CH3:19])[N:13](CC)[C:14]=3[CH:15]=2)[NH:6][C:5](=[O:20])[CH:4]=1.C(O[CH:26](O)[C:27]([F:30])([F:29])[F:28])C>>[F:22][C:2]([F:1])([F:21])[C:3]1[C:16]2[C:7](=[CH:8][C:9]3[CH2:10][CH2:11][CH:12]([CH3:19])[N:13]([CH2:26][C:27]([F:28])([F:29])[F:30])[C:14]=3[CH:15]=2)[NH:6][C:5](=[O:20])[CH:4]=1
Reactant: CCN1c2cc3c(C(F)(F)F)cc(=O)[nH]c3cc2CCC1C
Reactant: CCOC(O)C(F)(F)F
Product: CC1CCc2cc3[nH]c(=O)cc(C(F)(F)F)c3cc2N1CC(F)(F)F

Procedure:
This compound was prepared in a similar fashion as that described in Example 84 from Compound 187 (Structure 33 of Scheme VI, where R1=methyl, n=1) and trifluoroacetaldehyde ethyl hemiacetal. 1H NMR (400 MHz, CDCl3) 11.08 (br. s, 1H), 7.06 (s, 1H), 7.00 (s, 1H), 6.99 (s, 1H), 3.99 (m, 1H), 3.81 (m, 1H), 3.67 (m, 1H), 3.10–2.95 (m, 1H), 2.92–2.82 (m, 1H), 2.07–1.97 (m, 1H), 1.93–1.80 (m, 1H), 1.19 (d, 3H, J=6.5).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[N:19]([O-])=O.[Na+].Cl[Sn]Cl>Cl.O>[C:13]1([S:10]([C:7]2[CH:6]=[C:3]3[C:2](=[CH:9][CH:8]=2)[NH:1][N:5]=[C:4]3[NH2:19])(=[O:12])=[O:11])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: N#Cc1cc(S(=O)(=O)c2ccccc2)ccc1N
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: Nc1n[nH]c2ccc(S(=O)(=O)c3ccccc3)cc12
Temperature: 4 °C
Reaction time: 3 h
Yield: 40.4 %

Procedure:
2-Amino-5-benzenesulfonyl-benzonitrile (0.81 g, 3.15 mmol) in 37% HCl (5 mL) was treated dropwise at 4° C. with NaNO2 (261 mg, 3.78 mmol) in 5 mL of water. After 1.75 hours the suspension was added dropwise to a solution of SnCl2 (4.88 g, 25.21 mmol) in 5 mL of 37% HCl. After stirring at 4° C. for 3 hours the solid was filtered, taken up with water (30 mL) and boiled for 1.5 hours. The hot mixture was filtered and washed thoroughly with boiling water. The filtrate was cooled to 4° C. and treated under stirring with 17% NaOH (approximately 5 mL) dropwise. After overnight cooling in a fridge the solid was filtered and washed with water to neutral pH affording 0.348 g of title compound (40% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:22]([N:25]2[CH:29]=[N:28][N:27]=[N:26]2)=[CH:21][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([CH2:12][CH2:13][OH:14])[CH2:8]1)=[O:6].[CH3:30][S:31](Cl)(=[O:33])=[O:32]>>[CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:22]([N:25]2[CH:29]=[N:28][N:27]=[N:26]2)=[CH:21][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([CH2:12][CH2:13][O:14][S:31]([CH3:30])(=[O:33])=[O:32])[CH2:8]1)=[O:6]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCO)(c2ccccc2)C1
Product: COc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCOS(C)(=O)=O)(c2ccccc2)C1

Procedure:
Prepare by the method of Example 2.5.2 using 1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (2.6 g, 6.50 mmol) and methanesulfonyl chloride (0.8 mL, 10.4 mmol) to give the title compound: Rf=0.20 (silica gel, ethyl acetate).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[N:8][CH:7]=1)=[O:5])C.[OH-].[K+]>C1COCC1.CO>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([NH:11][C:9]2[S:10][C:6]([C:4]([OH:5])=[O:3])=[CH:7][N:8]=2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1cnc(Nc2ccc(Cl)cc2)s1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cnc(Nc2ccc(Cl)cc2)s1
Temperature: 50 °C

Procedure:
A mixture of 3.0 g (11.1 mmol) 2-(4-Chloro-phenylamino)-thiazole-5-carboxylic acid ethyl ester and 6.7 ml 5M KOH in 50 ml THF and 10 ml MeOH was heated to 50° C. for 4 h and subsequently concentrated. The residue was taken up in water, acidified with acetic acid and extracted with ethyl acetat. The combined organic layers were washed with water, dried with MgSO4 and evaporated. The residue was recrystallised from ethyl acetate to obrain 2.0 g (70%) of the title compound as white crystals. (m/e): 254.9 (M+H+, 100%)
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][C:5]([NH:7][C:8]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:9]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11])=[O:6].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[ClH:22].[C:25]([CH2:24][N:3]([CH3:2])[CH2:4][C:5]([NH:7][C:8]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:9]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11])=[O:6])([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CNCC(=O)Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CN(C)CC(=O)Nc1ccc(Cl)cc1C(=O)c1ccccc1
Yield: 122 %

Procedure:
1.7 g of 2-(methylamino-acetamido)-5-chlorobenzophenone hydrochloride, 0.85 g of ethyl bromacetate and 0.7 g of anhydrous potassium carbonate were heated for 20 hours under a reflux in 100 mls. of anhydrous acetone whilst stirring. After cooling, the inorganic salt was filtered off under suction concentrated in vacuo, and the oily residue was dried in vacuo. The yield of oily crude base was 1.4 g. It was dissolved in 30 mls. of absolute dioxane, the solution was filtered and diluted with 30 mls. absolute ether, 1.3 g of 2-(4-carbethoxy-3-methyl-3-aza-butyramido)-5-chlorobenzophenone hydrochloride with a melting point of 178°-180° being obtained by passing in dry hydrogen chloride. The product was identical with that obtained in Example 5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([N:10]1[CH2:15][CH2:14][NH:13][C:12](=O)[CH2:11]1)=[O:9].F[B-](F)(F)F.C([O+](CC)CC)C.[F:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]([NH:38][NH2:39])=O)=[N:34][CH:35]=1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([N:10]1[CH2:15][CH2:14][N:13]2[C:36]([C:33]3[CH:32]=[CH:31][C:30]([F:29])=[CH:35][N:34]=3)=[N:38][N:39]=[C:12]2[CH2:11]1)=[O:9]
Reactant: O=C1CN(C(=O)c2ccccc2Cl)CCN1
Reactant: NNC(=O)c1ccc(F)cn1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: O=C(c1ccccc1Cl)N1CCn2c(nnc2-c2ccc(F)cn2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The title compound was prepared in an analogous method to that described in E111. To a solution of 4-[(2-chlorophenyl)carbonyl]-2-piperazinone (I4) (225 mg, 0.943 mmol) in Dichloromethane (5 ml) stirred under argon at room temp was added solid triethyloxonium tetrafluoroborate (179 mg, 0.943 mmol). The reaction mixture was stirred at RT for 2 hr. Solid 5-fluoro-2-pyridinecarbohydrazide (I24) (161 mg, 1.037 mmol) was added and the reaction mixture stirred at RT for 18 hr. The solvent was evaporated in vacuo, and the residue dissolved in n-butanol (5 ml) and stirred at 120° C. for 4 hr. The reaction mixture was cooled to room temperature and partitioned between Dichloromethane (˜25 ml) and saturated brine (˜25 ml). The aqueous phase was extracted with Dichloromethane (2×25 ml) and the combined organic extracts washed with saturated brine (˜25 ml), dried over sodium sulphate, and evaporated in vacuo to afford the crude product as a yellow oil. This was dissolved in 1:1 MeOH:DMSO and purified by Open Access Mass Directed AutoPrep on Sunfire C18 column using Acetonitrile Water with a Formic acid modifier. The solvent was evaporated in vacuo and the residue dried overnight in a vacuum oven at 40° C. to give the required product as a white powder in 126.4 mg.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl.CN(C=O)C>[Br:17][C:18]1[CH:19]=[CH:20][C:21]([OH:24])=[C:22]([C:8](=[O:10])[CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:23]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: COc1ccc(Br)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cc1ccccc1)c1cc(Br)ccc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.3 %

Procedure:
Phenylacetic acid (1.09 g, 80 mmoles) was dissolved in 5 ml dichloromethane. To this mixture, oxalylchloride (1.01 g, 80 mmoles) and DMF (3 drops) were added at 0° C. and stirred for 30 min. The solvent was evaporated and dissolved in 5 ml dichloromethane. To this mixture, 4-bromoanisole (1 g, 5.34 mmoles) was added and cooled to 0° C. At 0° C. AlCl3 (1.06 g, 80 mmoles) was added and the reaction mixture was warmed to RT and stirred overnight. The reaction mixture was quenched by the addition of 2N HCl and extracted with ethyl acetate, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography to afford the title compound as white solid (1 g, 66% yield). MP: 83-86° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): δ 11.56(s,1H), 8.01(d, J=2.2 Hz, 1H), 7.64(dd, J=8.8, 2.5 Hz, 1H), 7.32(t, 2H), 7.29(m,3H), 6.96(d, J=8.8 Hz,1H), 4.43(s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]4[CH2:19][O:20][C:21](=[O:22])[C:14]=34)=[CH:11][N:10]([CH3:23])[N:9]=2)=[CH:4][CH:3]=1.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)(=O)C>[CH2:24]([N:31]1[C:21](=[O:22])[C:14]2[C:15](=[N:16][CH:17]=[CH:18][C:13]=2[C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9][N:10]([CH3:23])[CH:11]=2)[C:19]1=[O:20])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NCc1ccccc1
Reactant: Cn1cc(-c2ccnc3c2C(=O)OC3)c(-c2ccc(F)cc2)n1
Solvent: CC(=O)O
Product: Cn1cc(-c2ccnc3c2C(=O)N(Cc2ccccc2)C3=O)c(-c2ccc(F)cc2)n1
Reaction time: 0.17 h

Procedure:
4-[3-(4-Fluorophenyl)-1-methyl-1H-pyrazol-4-yl]furo[3,4-b]pyridin-5(7H)-one (Example 1, step 5, 472 mg, 1.46 mmol) and benzyl amine (0.167 mL, 1.53 mmol) in acetic acid (4.7 mL) were heated at reflux for 18 hr, cooled and then concentrated to a brown solid. This material was stirred with diethyl ether (20 mL) for 10 min and then filtered to yield 450 mg (75%) of Ex 5-Step 1 product as a tan colored solid: LCMS m/z 413.5 (M+1); 1H NMR (400 MHz, CDCl3) δ 8.57 (d, J=5.2, 1H), 8.15 (s, 1H), 7.26-7.42 (m, 7H), 7.13 (d, J=5.3, 1H), 7.01 (dd, J=8.6, 8.6, 2H), 4.87 (s, 2H), 4.00 (s, 3H).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[S:5](Cl)([C:8]1[CH:14]=[CH:13][C:11]([CH3:12])=[CH:10][CH:9]=1)(=[O:7])=[O:6]>N1C=CC=CC=1>[C:11]1([CH3:12])[CH:13]=[CH:14][C:8]([S:5]([CH:1]([OH:4])[CH:2]([OH:3])[S:5]([C:8]2[CH:14]=[CH:13][C:11]([CH3:12])=[CH:10][CH:9]=2)(=[O:7])=[O:6])(=[O:7])=[O:6])=[CH:9][CH:10]=1
Reactant: OCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)C(O)C(O)S(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 0 °C
Yield: 75 %

Procedure:
Twenty-eight ml of ethylene glycol and 100 ml of pyridine were added over a 2.5 hour period to a stirred mixture of tosyl chloride (210 g) in pyridine (225 ml), with the mixture being cooled by a water bath. After stirring for several hours, the mixture was shaken with one liter of ice water for about ten minutes and then filtered. The residue was washed with ether, dilute sulfuric acid, water, and finally ether. (Each of the washed liquids was ice cold.) The residue was then dried by vacuum pumping and recrystallized from boiling acetonitrile. The recrystallized residue, yield 75%, had a melting point of 123° to 125° C.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[C:7]1([CH3:17])[CH:12]=CC(S(O)(=O)=O)=C[CH:8]=1>CCCCC>[CH3:4][CH:2]1[O:3][CH:8]([CH:7]([CH3:17])[CH3:12])[O:5][C:1]1=[O:6]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(O)C(=O)O
Solvent: CCCCC
Product: CC1OC(C(C)C)OC1=O
Yield: 82.5 %

Procedure:
43.6 g (0.60 mol) of isobutyl aldehyde, 62.5 g (0.55 mol) of ferment lactic acid, and 1.06 g (0.05 mmol) of p-toluene sulfonic acid were dissolved in 50 ml of n-pentane, and the mixture was refluxed for 8 hours in a 500-ml flask attached to a reflux condenser comprising a Dean-Stark fractionator. After the reaction, the reaction mixture was neutralized and washed with a sodium bicarbonate aqueous solution, followed by extraction with ether. Thereafter, the ether solution was dried with anhydrous magnesium sulfate. Thereafter, ether was distilled off, and 65.3 g (yield=82.5%) of the target 5-methyl-2-isopropyl-1,3-dioxolan-4-one was obtained from the reaction mixture through distillation under reduced pressure. The target product was a diastereomer mixture wherein the ratio of cis-isomer/trans-isomer (see Production Example 1) was 80/20. The product was subjected to the next reaction without optical resolution. The following step was performed according to the monomer synthesis of Production Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7]([O-:9])=O.[Li+].Cl.[NH2:29][C@H:30]([C:32]1[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=1)[CH3:31]>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:24])[F:26])=[CH:19][CH:18]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7]([NH:29][C@H:30]([C:32]1[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=1)[CH3:31])=[O:9]
Reactant: O=C([O-])c1cc(Cl)cnc1N1CCC(Oc2ccc(C(F)(F)F)cc2)C1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: Cl
Agent: [Li+]
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2N2CCC(Oc3ccc(C(F)(F)F)cc3)C2)cc1
Yield: 27.6 %

Procedure:
The title compound (D191) (50 mg) was prepared according to the experimental procedure described in Description 148 starting from lithium 5-chloro-2-(3-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)nicotinate (D136) (130 mg, 0.331 mmol) and (S)-methyl 4-(1-aminoethyl)benzoate (D3) (71.19 mg, 0.331 mmol)
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([N+:9]([O-:11])=[O:10])[C:2]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[F:12]
Reactant: O=[N+]([O-])c1cccc(F)c1Br
Reactant: OB(O)c1ccccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cccc(F)c1-c1ccccc1F
Temperature: 110 °C
Reaction time: 16 h
Yield: 48.8 %

Procedure:
To a solution of 2-bromo-3-fluoronitrobenzene (1.500 g, 6.8 mmol), 2-fluorophenylboronic acid (1.145 g, 8.2 mmol), N,N-dimethylformamide (50 mL), and 2.0 M aqueous potassium carbonate (10 mL) under argon was added tetrakis(triphenylphosphine)palladium (0) (0.394 g, 0.3 mmol). The mixture was stirred at 110° C. for 16 hrs. After cooling to room temperature, the mixture was diluted with ethyl acetate (100 mL) and washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0-30% methylene chloride/hexanes) to afford a pale yellow solid (0.780 g, 49%). 1H NMR (300 MHz, CDCl3) δ 7.86 (dt, 1H, J=7.8, 1.2 Hz), 7.56 (td, 1H, J=8.1, 5.7 Hz), 7.52-7.40 (m, 2H), 7.35-7.15 (m, 3H).
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19]([O:21][C:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23])[CH3:20]>CS(C)=O>[CH2:19]([O:21][C:22]([N:24]1[CH2:25][CH2:26][N:27]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)[CH2:28][CH2:29]1)=[O:23])[CH3:20]
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: CCOC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(N2CCN(C(=O)OCC)CC2)cc1
Yield: 69.9 %

Procedure:
Ethyl 4-fluorobenzoate (0.93 ml, 6.3 mmol), anhydrous potassium carbonate (0.96 g, 7.0 mmol), ethoxycarbonyl piperazine (0.92 ml, 6.3 mmol)and dry DMSO (30 ml) were heated under dry conditions at 90° C. for 72h. The mixture was partitioned between ethyl acetate and water, dried (sodium sulphate) and evaporated to dryness under reduced pressure. The product was purified by flash column chromatography on silica eluting with 10%MeOH/chloroform to afford the title compound as an oil (1.35 g, 70%).