Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[S:18]1[CH2:24][C:22](=[O:23])[NH:21][C:19]1=[S:20].C(O)C.O>C(O)(=O)C>[CH3:4][C:1]([C:5]1[CH:6]=[C:7]([CH:8]=[C:24]2[S:18][C:19](=[S:20])[NH:21][C:22]2=[O:23])[CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: O=C1CSC(=S)N1
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(C=C2SC(=S)NC2=O)cc(C(C)(C)C)c1O
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, 117.2 g of 3,5-di-tert-butyl-4-hydroxybenzaldehyde, 66.6 g of rhodanine, and 143.5 g of fused sodium acetate were heated at reflux in 2500 ml of glacial acetic acid. After heating for 23 hours, the reaction mixture was cooled and poured into a mixture of 1 liter of ethanol and 1 liter of ice with stirring. 500 ml of water were added and, after stirring for 30 minutes, the resulting precipitate was recovered by filtration. The solid was slurried with 500 ml of ethyl acetate and filtered. The precipitate was then dissolved in 3 liters of ethanol, heated to boiling, and water was added until the solution remained cloudy, approximately 450 ml. Upon cooling to room temperature, 99.6 g of the desired title product were recovered by filtration, m.p. approximately 260° C.
Reaction SMILES: [C:1](=[O:16])([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)OC1C=CC=CC=1.[NH2:17][C@H:18]([C:26]([O-:28])=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([N+]1C=CN(C)C=1)C.Cl>CC(=O)CC>[O:9]([C:1]([NH:17][C@H:18]([C:26]([OH:28])=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)[O-]
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Agent: CC[n+]1ccn(C)c1
Agent: Cl
Solvent: CCC(C)=O
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)O)Oc1ccccc1
Temperature: -20 °C

Procedure:
Under a nitrogen atmosphere, 430 mg (2 mmol) of diphenyl carbonate and 5 mL of 2-butanone were loaded into a round bottom flask having a volume of 100 mL, and then the mixture was stirred at −20° C. A solution prepared by dissolving 550 mg (2 mmol) of 1-ethyl-3-methylimidazolium phenylalanine salt in 15 mL of 2-butanone was slowly dropped to the solution, and then the mixture was stirred at −20° C. for 8 hours. After that, a 1M aqueous HCl solution was added to the mixture to terminate the reaction. The resultant was concentrated with an evaporator. Next, water was added to the concentrated product, and then the resultant was extracted with ethyl acetate. After that, the resultant was concentrated with an evaporator. Thus, a crude product was obtained. Next, the crude product was purified by column chromatography. Thus, N-phenoxycarbonyl-L-phenylalanine was obtained. An isolation amount and an isolation yield were 528.9 mg and 93%, respectively.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:11]2[CH:15]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:13]=[N:12]2)[CH:6]=[CH:7][C:8]=1[O:9]C)#[N:2].[Cl-].[Al+3].[Cl-].[Cl-].O>ClC(Cl)C>[C:1]([C:3]1[CH:4]=[C:5]([N:11]2[CH:15]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:13]=[N:12]2)[CH:6]=[CH:7][C:8]=1[OH:9])#[N:2]
Reactant: CCOC(=O)c1cnn(-c2ccc(OC)c(C#N)c2)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: O
Product: CCOC(=O)c1cnn(-c2ccc(O)c(C#N)c2)c1
Temperature: 70 °C
Yield: 84.7 %

Procedure:
To a solution (280 ml) of ethyl 1-(3-cyano-4-methoxyphenyl)pyrazole-4-carboxylate (28 g) in dichloroethane was added aluminum chloride (47.6 g with stirring, and the mixture was heated at 70° C. for 4 hours. After the completion of the reaction, the reaction mixture was poured into water, extracted with ethyl acetate, washed with water and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was recrystallized from ethyl acetate to give 22.5 g of ethyl 1-(3-cyano-4-hydroxyphenyl)pyrazole-4-carboxylate, melting point 233-234° C. ##STR19##
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])=[CH:4][C:3]=1[CH3:14].B([C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O>[CH3:14][C:3]1[CH:4]=[C:5]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH:6]=[CH:7][C:2]=1[C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Cc1cc(N2CCCC2=O)ccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1cc(N2CCCC2=O)ccc1-c1ccc(C(=O)O)cc1
Yield: 51.3 %

Procedure:
A stirred mixture of 1-(4-bromo-3-methylphenyl)pyrrolidin-2-one (D46, 50 g, 0.20 mole) and 4-boronobenzoic acid (32 g, 0.20 mole) in 1,2-dimethoxyethane (500 ml) was treated with a solution of Na2CO3 (94 g, 0.88 mole) in water (500 ml), then de-gassed by bubbling argon through for 0.25 hrs. Tetrakis (triphenylphosphine)palladium (O) (5 g) was added and the mixture heated under reflux for 22 hours, then allowed to cool and concentrated in vacuo to approx. 50% volume. The aqueous residue was diluted with water to approx. 1000 ml, washed with ethyl acetate, then acidified with conc. HCl acid. The precipitate was filtered off, washed with water, dried and recrystallised from ethanol to afford the title compound as a cream solid (30.3 g, 52%).
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][C@@H:4]([CH2:9]C(=O)N[C@H](C1C=CC=CC=1)C)[CH2:5][C:6]([OH:8])=[O:7].C([N:24](CC)CC)C.ClC(OC)=O.[N-]=[N+]=[N-].[Na+].Cl.C1(O)C=CC=CC=1.[Cl-].[Na+].[OH-].[Na+]>CC(C)=O>[CH3:1][CH:2]([CH2:3][C@H:4]([CH2:9][NH2:24])[CH2:5][C:6]([OH:8])=[O:7])[CH3:21]
Reactant: CCN(CC)CC
Reactant: CC(C)C[C@H](CC(=O)O)CC(=O)N[C@@H](C)c1ccccc1
Agent: COC(=O)Cl
Agent: Cl
Agent: [Cl-]
Solvent: Oc1ccccc1
Solvent: CC(C)=O
Product: CC(C)C[C@H](CN)CC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
A three-necked flask equipped with an addition funnel, thermometer pocket, drying tube and a mechanical stirrer, was charged with acetone (200 ml), (3S)-5-methyl-3-(2-oxo-2{[(1S)-1-phenylethyl]amino}ethyl) hexanoic acid compound (50 g, 0.172 mole), and with triethylamine (21.7 g, 0.215 mole), and cooled to −10° to −20° C. followed by addition of solution of methyl chloroformate (18.67 g, 0.196 mole in 50 ml acetone). The mixture was stirred for 1 hour at a temperature of −10° to −20° C., followed by addition of solution of sodium azide (27.92 g, 0.429 mole in water). The resulted slurry was maintained for 1 hour at −10° to −20° C., quenched over ice water followed by extracting the mass with sufficient amount of toluene. The toluene layer was slowly added over a refluxing mixture of toluene and methyl alcohol, followed by stirring for 2 to 4 hours followed by stripping of solvents results into an oily mass. 4N hydrochloric acid (600 ml), phenol (2.42 g, 0.0257 mole), sodium chloride (40.2 g, 0.687 mole) was added to the oily mass and was heated to 105°-110° C. for 15-24 hours, and then cooled to room temperature, i.e., about 20° to about 25° C. An aqueous 40% sodium hydroxide solution was added in an amount sufficient to provide a pH of 1. The solution was then extracted with 150 ml of iso-butanol, the organic layer was separated, and Bu3N was added in an amount sufficient to provide a pH of 4-4.5. The (S)-Pregabalin was precipitated, filtered, and washed with 25 ml of iso-butanol which on crystallization from isobutanol water mixture resulted in (S)-Pregabalin as white crystals in a 67% yield. Purity: 99.9% area by HPLC.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](O)=[O:6].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.Cl.[CH3:32][NH:33][O:34][CH3:35]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([N:33]([O:34][CH3:35])[CH3:32])=[O:6]
Reactant: O=C(O)c1ccc(Cl)c(Br)c1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(Cl)c(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.1 %

Procedure:
To a stirred solution of 10.0 g of 3-bromo-4-chlorobenzoic acid in 275 ml of anhydrous dichloromethane at OOC were added 7.6 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 5.5 ml of triethylamine followed by 3.9 g of N,O-dimethylhydroxylamine hydrochloride. After stirring overnight at room temperature the mixture was washed with 200 ml of water and then with 200 ml of a 1M solution of hydrochloric acid. The organic solution was dried over anhydrous sodium sulphate and concentrated under reduced pressure to give 10.7 g of 3-bromo-4-chloro-N-methoxy-N-methylbenzamide as a cream solid.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1B(O)O>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([C:14]3[CH:15]=[C:16]([C:19]([F:21])([F:22])[F:20])[CH:17]=[CH:18][C:13]=3[F:12])=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: OB(O)c1cc(C(F)(F)F)ccc1F
Reactant: Clc1nc2c(Br)cccn2n1
Product: Fc1ccc(C(F)(F)F)cc1-c1cccn2nc(Cl)nc12

Procedure:
2-Chloro-8-(2-fluoro-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine and 2-fluoro-5-trifluoromethylphenylboronic acid in a manner analogous to Example 2c (0.150 g, 22%). MP=88-89° C. MS=317 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([OH:16])[N:6]=[C:7]3[C:12]=2[CH:11]=[CH:10][CH:9]=[CH:8]3)[CH:3]=1.BrC1C=CC(S(O[C@@H:28]2[CH2:32][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C@H:30]([C:40]([O:42][CH3:43])=[O:41])[CH2:29]2)(=O)=O)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN1C(=O)CCC1.CCOC(C)=O>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([O:16][C@H:28]3[CH2:32][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C@H:30]([C:40]([O:42][CH3:43])=[O:41])[CH2:29]3)[N:6]=[C:7]3[C:12]=2[CH:11]=[CH:10][CH:9]=[CH:8]3)[CH:3]=1
Reactant: COC(=O)[C@@H]1C[C@H](OS(=O)(=O)c2ccc(Br)cc2)CN1C(=O)OC(C)(C)C
Reactant: Oc1nc2ccccc2c2ccc(Br)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)[C@@H]1C[C@@H](Oc2nc3ccccc3c3ccc(Br)cc23)CN1C(=O)OC(C)(C)C
Temperature: 60 °C

Procedure:
To a solution of the product mixture from Step 2 (176 mg, 0.642 mmol) in NMP (1.5 mL) was added 1-tert-butyl 2-methyl (2S,4S)-4-{[(4-bromophenyl)sulfonyl]oxy}pyrrolidine-1,2-dicarboxylate (373 mg, 0.803 mmol) and Cs2CO3 (418 mg, 1.29 mmol). The mixture was then heated to 60° C. for 18 h, and worked up with water and EtOAc. The organic layer was washed with brine, dried over MgSO4, and the solvent was removed in vacuo. The crude material was purified on silica (gradient elution, 10-50% EtOAc/hex) to yield the title compound as a 1:1 mixture with the expected regioisomer. LRMS ((M-Boc)+H)+=401.2.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH:20]3[CH2:22][CH2:21]3)=[CH:18][C:17]([CH:23]3[CH2:25][CH2:24]3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH:20]1([C:19]2[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[N:15][CH:16]=[C:17]([CH:23]3[CH2:25][CH2:24]3)[CH:18]=2)[CH2:21][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: c1nc(N2CCNCC2)c(C2CC2)cc1C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.7 %

Procedure:
4-(3,5-Dicyclopropylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (7.4 g), which is the intermediate described in Preparation Example 50, was dissolved in chloroform (54 mL), 4N hydrogen chloride/ethyl acetate (21.5 mL) was added, and the mixture was stirred at room temperature overnight. To the reaction mixture was added chloroform and saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with chloroform. The solvent was evaporated to give the title compound (4.6 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=1.[C:11](Cl)(=O)C(Cl)=O.CN(C=O)C.CO>C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cnccc1Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cnccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 123 %

Procedure:
To a solution of 4-chloronicotinic acid (0.5 g, 3.17 mmol) in CH2Cl2 (60 mL) was added oxalyl chloride (1.007 g, 7.93 mmol) dropwise at room temperature followed by the addition of DMF (0.4 mL). The solution was stirred at room temperature for 3 h. Methanol (1.9 mL, 46.8 mmol) was added dropwise and the clear solution was further stirred for 30 min. The solvent was evaporated under reduced pressure to yield methyl 4-chloronicotinate (0.67 g, 3.90 mmol, 50% yield). LCMS (ESI) m/e 172.5 [(M+H)+, calcd for C7H7ClNO2 172.0]; LCMS retention time (Method D): tR=1.15 min.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.[CH3:14][S-:15].[Na+].C(#N)C>O>[CH3:13][C:4]1[CH:3]=[C:2]([S:15][CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=1
Reactant: Cc1ccc2nc(C)cc(Cl)c2c1
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CSc1cc(C)nc2ccc(C)cc12
Yield: 98 %

Procedure:
A mixture of 4-chloro-2,6-dimethylquinoline (0.5 g, prepared as described in Example 1), sodium thiomethoxide (0.55 g) and dry acetonitrile (20 ml) was heated to reflux under an atmosphere of argon for 15 hours. After cooling to laboratory temperature the mixture was poured into water (50 ml) and extracted with ethyl acetate (2×50 ml). The combined organic layers were dried over magnesium sulphate and evaporated to leave 2,6-dimethyl-4methylthioquinoline as a white solid (0.52 g) which was used without further purification.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][CH:20]([OH:24])[CH2:21][CH2:22][OH:23])[CH:13]=1.C(N(CC)CC)C.CO>ClCCl>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:23][CH2:22][CH2:21][CH:20]([OH:24])[CH2:19][CH2:18][C:14]2[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: OCCC(O)CCc1cccnc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(S(=O)(=O)OCCC(O)CCc2cccnc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 47.4 %

Procedure:
Solid para-toluenesulfonyl chloride (1.26 g) was added to a solution of (±)-5-(3-pyridyl)-1,3-pentanediol (1.20 g) and triethylamine (1.11 ml) in anhydrous dichloromethane (20 ml) at -30° C. under nitrogen. The solution was allowed to warm to room temperature over 1 hour and stirring was continued for 24 hours. Methanol (1 ml) was added and the solution concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with hexane:acetone (3:2) to give the sub-title compound as an oil (1.05 g).
Reaction SMILES: [C:1]1([C:7]2[CH2:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][C:10]=3Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]1([Mg]Br)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1>>[C:1]1([C:7]2[CH2:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][C:10]=3[C:25]2[C:26]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:22]=[CH:23][CH:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Clc1cccc2c1CC(c1ccccc1)=C2
Reactant: Br[Mg]c1cccc2ccccc12
Product: C1=C(c2ccccc2)Cc2c1cccc2-c1cccc2ccccc12

Procedure:
2-phenyl-7-napthylindene is prepared in like manner from 2-phenyl-7-chloroindene (see Example I(a)) and naphthyl magnesium bromide.
Reaction SMILES: [CH3:1][C:2]1([CH2:9][CH3:10])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[CH:11]([O:13][CH2:14][CH2:15]Cl)=[CH2:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:11]([O:13][CH2:14][CH2:15][N:4]1[C:3](=[O:8])[C:2]([CH3:1])([CH2:9][CH3:10])[NH:6][C:5]1=[O:7])=[CH2:12]
Reactant: CCC1(C)NC(=O)NC1=O
Reactant: C=COCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=COCCN1C(=O)NC(C)(CC)C1=O
Reaction time: 0.58 h

Procedure:
A mixture of 71.04 g (0.5 mol) of 5-methyl-5-ethylhydantoin, 55.94 g (0.5 mol+5% excess) of 2-chloroethyl vinyl ether, 36.28 g (0.25 mol+5% excess) of anhydrous potassium carbonate and 150 ml of dimethylformamide is stirred, analogously to Example 1, for 4 hours and 35 minutes at 122°-129° C. After completion of the reaction, the reaction mixture is filtered and the clear filtrate is concentrated on a rotary evaporator at 80° C. under vacuum from a waterpump. The residue is taken up in 200 ml of acetone, 2 g of active charcoal are added and the mixture is kept at the boil for 15 minutes. It is then filtered and the filtrate is concentrated on a rotary evaporator at 60° C. under vacuum from a waterpump. The residue is freed from non-volatile constituents at 60° C. and 0.5 mm Hg and 86.9 g (81.9% of theory) of a yellowish, viscous crude product are obtained. This is purified by distillation in a high vacuum and 80.34 g (75.7% of theory) of the desired product, of boiling point 132° C./0.2 mm Hg, are obtained.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.[CH3:48][C:49]1[O:50][CH:51]=[CH:52][C:53]=1[C:54](O)=[O:55]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][N:43]([C:54]([C:53]2[CH:52]=[CH:51][O:50][C:49]=2[CH3:48])=[O:55])[CH2:42][CH2:41]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: Cc1occc1C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: Cc1occc1C(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 60 %

Procedure:
The desired compound was prepared according to the procedure of Example A27, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and 2-methyl-3-furoic acid as starting materials in 60% yield. LCMS for C30H31ClN7O3 (M+H)+: m/z=572.2.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]([CH2:8][C:9]#[N:10])[CH3:7]>[Ni].CCO>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]([CH3:7])[CH2:8][CH2:9][NH2:10]
Reactant: COCCCN(C)CC#N
Agent: [Ni]
Solvent: CCO
Product: COCCCN(C)CCN
Reaction time: 4 h
Yield: 80.6 %

Procedure:
A mixture of nitrile 273 (1.94 g, 14.0 mmol), cNH3 (8 mL) and Raney Nickel (50% slurry in water, 5.3 g) in EtOH (100 mL) was stirred under H2 (60 psi) for 4 h. The mixture was filtered through Celite, washed with EtOH (50 mL) and the solvent was evaporated to give crude diamine 274 (1.65 g, 83%) as a yellow oil, which was used without further purification: 1H NMR δ 3.42 (t, J=6.4 Hz, 2H, CH2N), 3.33 (s, 3H, OCH3), 2.76 (t, J=6.1 Hz, 2H, CH2), 2.43 (t, J=7.2 Hz, 2H, CH2), 2.40 (t, J=6.2 Hz, 2H, CH2), 2.21 (s, 3H, NCH3), 1.74 (tt, J=7.2, 6.2 Hz, 2H, CH2), NH2 not observed; MS (APCI) m/z 147 (MH+, 100%); HRMS calcd for C7H18N2O (M+) m/z 146.1419, found 146.1424.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH:3]=[N:4][S:5]([C:8]1[O:16][C:15]2[CH:14]=[C:13]([CH3:17])[N:12]=[CH:11][C:10]=2[CH:9]=1)(=[O:7])=[O:6].ClC1C=CC=C(C(OO)=[O:27])C=1>C(Cl)(Cl)Cl>[CH3:1][N:2]([CH3:18])[CH:3]=[N:4][S:5]([C:8]1[O:16][C:15]2[CH:14]=[C:13]([CH3:17])[N+:12]([O-:27])=[CH:11][C:10]=2[CH:9]=1)(=[O:6])=[O:7]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc2oc(S(=O)(=O)N=CN(C)C)cc2cn1
Solvent: ClC(Cl)Cl
Product: Cc1cc2oc(S(=O)(=O)N=CN(C)C)cc2c[n+]1[O-]
Reaction time: 20 h
Yield: 97 %

Procedure:
To a solution of N,N-dimethyl-N'-(6-methylfuro[3.2-c]pyridine-2-sulfonyl)formamidine (5.61 g, 21 mmol) in chloroform (65 ml) was added dropwise a solution of commercial 80% pure m-chloroperbenzoic acid (5.0 g, 23 mmol) in chloroform (45 ml). The reaction was stirred for 20 hours and then concentrated on a rotary evaporator to near dryness. The residue was digested in diethyl ether and the precipitated product filtered. This solid (6.06 g) was digested in ethyl acetate/chloroform/methanol and then cooled and pure product collected by filtration (5.76 g, 97% yield), m.p. 248°-249° C.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([O:9][C:10](=[O:29])[C:11]([C:17](=[O:28])[C:18]1[C:23](F)=[C:22]([F:25])[CH:21]=[C:20]([F:26])[C:19]=1[F:27])=[CH:12][NH:13][CH:14]1[CH2:16][CH2:15]1)[CH3:8]>C1COCC1.O1CCOCC1>[CH2:7]([O:9][C:10]([C:11]1[C:17](=[O:28])[C:18]2[C:23](=[C:22]([F:25])[CH:21]=[C:20]([F:26])[C:19]=2[F:27])[N:13]([CH:14]2[CH2:16][CH2:15]2)[CH:12]=1)=[O:29])[CH3:8]
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1c(F)c(F)cc(F)c1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CCOC(=O)c1cn(C2CC2)c2c(F)cc(F)c(F)c2c1=O
Temperature: 0 °C
Reaction time: 5 h
Yield: 83.9 %

Procedure:
Potassium tert-butoxide (2.36 g, 21 mmol) was slowly added to a stirred solution of example 1b (6.62 g, 20 mmol) in 1:1 THF/dioxane (60 mL) at 0° C. The reaction mixture was stirred at 0° C. for 5 h. The precipitate was collected by filtration to give 5.22 g (79%) of clean desired product as a beige solid. The filtrate contained product contaminated with some starting material and was concentrated in vacuo. The residue (1.3 g) was treated by potassium tert-butoxide (350 mg, 3.12 mmol) in 1:1 THF/dioxane (60 mL) for 18 h. Purification by silica gel chromatography gave an additional 1.1 g (18%) of the title compound as a beige solid. 1H NMR (400 MHz, DMSO-d6): δ 8.41 (s, 1H), 8.09-8.19 (m, 1H), 4.21 (q, 211, J=7.2 Hz), 3.88-3.97 (m, 1H), 1.27 (t, 3H, J=7.2 Hz), 1.08-1.14 (m, 4H). MS (ES) [m+H] calc'd for C15H12F3NO3, 312; found 312.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[CH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=1[O:24][CH3:25])=[O:2].[CH3:26][N:27]1[CH2:31][CH2:30][CH2:29][C:28]1=[O:32]>>[OH:2][CH:1]([CH:29]1[CH2:30][CH2:31][N:27]([CH3:26])[C:28]1=[O:32])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[CH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=1[O:24][CH3:25]
Reactant: CN1CCCC1=O
Reactant: COC(=O)c1ccc(Cc2cn(C)c3ccc(C=O)cc23)c(OC)c1
Product: COC(=O)c1ccc(Cc2cn(C)c3ccc(C(O)C4CCN(C)C4=O)cc23)c(OC)c1

Procedure:
Using a similar procedure to that described in Example 1, part d, except starting from methyl 4-(5-formyl-1-methylindol-3-ylmethyl)-3-methoxybenzoate and N-methylpyrrolidone, methyl 4-[5-[(hydroxy)-(1-methyl -2-oxopyrrolidin-3-yl)methyl]-1-methylindol-3-ylmethyl]-3-methoxybenzoate was obtained (40%) as a foam; NMR (300 MHz, DMSO-d6): 1.43-1.65 (m, 1.5H), 1.95 (m, 0.5H), 2.40-2.60 (m, 2.5H), 2.65-2.80 (m, 2H), 2.90-3.25 (m, 1.5H), 3.70 (s, 3H), 3.83 (s, 3H), 3.85-4.08 (m, 5H), 4.92 (d, 0.5H), 5.17 (s, 0.5H), 7.0-7.55 (m, 7H).