Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]1(=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=[O:19].Br[CH2:22][C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>CN1C2C(N=C(N)NC=2NCC1CNC1C=CC(C(NC(C(O)=O)CCC(O)=O)=O)=CC=1)=O>[C:27]1([CH2:26][O:25][C:23](=[O:24])[CH2:22][C:18]2[CH2:17][CH2:16][CH2:15][C:14](=[O:19])[C:13]=2[OH:20])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C1CCCCC1=O
Reactant: O=C(CBr)OCc1ccccc1
Agent: CN1c2c([nH]c(N)nc2=O)NCC1CNc1ccc(C(=O)NC(CCC(=O)O)C(=O)O)cc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Product: O=C(CC1=C(O)C(=O)CCC1)OCc1ccccc1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
A 1.6M solution of n-butyl lithium (81 mL, 130 mmol) was added to a stirred solution of diisopropylamine (18.26 mL) in methyl-THF (150 mL) at −10° C. The resulting solution was stirred at −10° C. for 15 mins. 1,2-cyclohexanedione (6.84 g) was added to the reaction mixture as a solution in methyl-THF (30 mL). During the addition the internal temperature of the reaction was maintained between −15° C. and −5° C. by modulation of delivery rate. The resulting dark orange/brown solution was stirred at −10 to −20° C. for a further 15 mins. The reaction mixture was then cooled to −50° C. and benzyl bromoacetate (12.62 mL, 79 mmol) was added dropwise via syringe. The mixture was stirred at this temperature for 10 minutes then aged at −78° C. for 1½ hours. The reaction mixture was quenched at −78° C. by dropwise addition of 1M HCl (300 ml). Ethyl acetate (200 mL) was added and the mixture allowed to warm to room temperature. The layers were separated and the organic phase washed with saturated brine (150 mL) and dried over sodium sulfate then reduced in vacuo. The resulting solid was purified by column chromatography, eluting with 0-25% ethyl acetate in cyclohexane. The appropriate fractions were reduced in vacuo to provide the product as a 1:1 mixture of thermodynamic enol:kinetic enol (registered as thermodynamic enol)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(NC(NC2C=CC=CC=2)=O)C=CC=CC=1.NC(N)=O.[C:28](=[O:33])([O:30][CH2:31][CH3:32])N>C(O)C>[CH2:31]([O:30][C:28](=[O:33])[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:32]
Reactant: Nc1ccccc1
Reactant: CCOC(N)=O
Agent: NC(N)=O
Agent: O=C(Nc1ccccc1)Nc1ccccc1
Solvent: CCO
Product: CCOC(=O)Nc1ccccc1

Procedure:
Following the procedure of Example 1, 745 g of aniline, 849 g of N,N'-diphenyl urea, 480 g of urea, 356 g of ethyl carbamate and 1350 g of ethanol (approximately 96%) were reacted for 5.5 hours at 200° C. in the pressure apparatus described in Example 1. After cooling and venting of the apparatus, the reaction mixture was removed, filtered and subjected to fractional distillation. After the excess alcohol had been separated (at normal pressure), the remaining fraction was subjected to distillation at 0.2 mbar. 1934 g (73.2% of the theoretical yield) of N-phenyl carbamic acid ethyl ester melting at from 49° to 51° C. were produced.
Reaction SMILES: [CH3:1][C:2]([CH2:4][C:5]([OH:7])=[O:6])=[O:3].[CH2:8]([OH:13])[CH:9]([OH:12])[CH2:10]O>C(OCC)(=O)C>[C:5]([O:7][CH2:10][CH:9]([CH2:8][OH:13])[O:12][C:5](=[O:6])[CH2:4][C:2]([CH3:1])=[O:3])(=[O:6])[CH2:4][C:2]([CH3:1])=[O:3]
Reactant: CC(=O)CC(=O)O
Reactant: OCC(O)CO
Solvent: CCOC(C)=O
Product: CC(=O)CC(=O)OCC(CO)OC(=O)CC(C)=O

Procedure:
A portion of the crude reaction product (3600 g) was dissolved in approximately 6 liters of ethyl acetate and extracted with distilled water (3×3 L) to provide a first aqueous fraction and again extracted with water (6× 3 L) to provide a second aqueous fraction. Analysis of the aqueous extracts by HPLC indicated that essentially all of the monoacetoacetin contained in the crude reaction product was removed in the first aqueous fraction. Using a freeze-dryer, water was removed from the second aqueous fraction until constant weight was achieved (1029.5 g, ca. 30%). This material was tested without further purification for efficacy as a parenteral nutrient.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH2:13]([C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=1[S:25](=[O:39])(=[O:38])[NH:26][CH2:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[N:33]([CH3:37])[N:32]=[CH:31]2)[C:18]([O:20][CH3:21])=[O:19])[CH3:14]>>[Cl:8][C:7]1[C:2]([N:26]([CH2:27][C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[N:33]([CH3:37])[N:32]=[CH:31]3)[S:25]([C:24]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=2[CH2:13][CH3:14])(=[O:39])=[O:38])=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: CCc1cc(C(=O)OC)ccc1S(=O)(=O)NCc1ccc2c(cnn2C)c1
Product: CCc1cc(C(=O)OC)ccc1S(=O)(=O)N(Cc1ccc2c(cnn2C)c1)c1ncc(C(F)(F)F)cc1Cl

Procedure:
The titled compound was prepared according to the procedure described in step-2 of Example 1 from 2,3-dichloro-5-(trifluoromethyl)pyridine and methyl 3-ethyl-4-(N-((1-methyl-1H-indazol-5-yl)methyl)sulfamoyl)benzoate (step-2 of Example 4).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[N:43]1([CH:48]2[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]2)[CH2:47][CH2:46][CH2:45][CH2:44]1>CN(C=O)C>[Br:1][C:2]1[C:3]([CH3:11])=[C:4]([C:5]([N:51]2[CH2:52][CH2:53][CH:48]([N:43]3[CH2:47][CH2:46][CH2:45][CH2:44]3)[CH2:49][CH2:50]2)=[O:7])[CH:8]=[CH:9][CH:10]=1
Reactant: Cc1c(Br)cccc1C(=O)O
Reactant: C1CCN(C2CCNCC2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1c(Br)cccc1C(=O)N1CCC(N2CCCC2)CC1
Reaction time: 3 h
Yield: 93.9 %

Procedure:
0.22 g (1.0 mmol) of 3-bromo-2-methyl-benzoic acid was dissolved in 10 ml of DMF and the solution was treated with 0.38 g (1.0 mmol) of HATU. Then, 0.42 ml=0.30 g (3.0 mmol) of Et3N was added and after 30 min, a solution of 0.16 g (1.0 mmol) of 4-pyrrolidin-1-yl-piperidine in 5 ml of DMF. After 3 hours, the reaction mixture was poured into crashed ice and extracted three times with CH2Cl2; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 9:1) to give 0.33 g (95%) of the title compound as light red solid. MS: 351.2 (MH+, 1 Br).
Reaction SMILES: [CH2:1]([OH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[CH:9](Br)([CH3:11])[CH3:10]>>[CH:9]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:8])([CH3:11])[CH3:10]
Reactant: CC(C)Br
Reactant: OCCCCCCO
Product: CC(C)OCCCCCCO

Procedure:
The above compound is produced in analogous manner to that described in Example 32, but using 1,6-hexandiol in the place of 1,4-butanol and isopropylbromide in the place of isopentylbromide. B.P.: 73°-75° /0.22 mm Hg.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([NH2:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[O:21])=[CH:15][CH:14]=1.Cl.NC(N)=O>C(OCCCC)(=O)C.O>[Br:1][C:2]1[CH:10]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:11][C:20](=[O:21])[N:19]([C:16]1[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=1)[C:7]2=[O:9]
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: Nc1ccc(Br)cc1C(=O)O
Agent: Cl
Agent: NC(N)=O
Solvent: O
Solvent: CCCCOC(C)=O
Product: O=c1[nH]c2ccc(Br)cc2c(=O)n1-c1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 89.6 %

Procedure:
21.6 g of 5-bromoanthranilic acid and 15.4 g of 4-chlorophenyl isocyanate were reacted in a similar procedure as described in Example 1 in 200 ml of butyl acetate at 100° C. and with a further stirring time of 4 hours. 18 g of hydrogen chloride gas were then introduced into the suspension of the urea formed in the course of 30 minutes and the mixture was then further stirred at 100° C. for 3 hours. For the work-up of the reaction mixture, sufficient butyl acetate was first distilled off at atmospheric pressure until a thick suspension had resulted, then 200 ml of water were added and the product precipitated out was filtered off. After drying, 31.5 g (90% of theory) of 6-bromo-3-(4-chlorophenyl)-quinazoline-2,4-dione were obtained having a melting point of 212-214° C. (decomposition).
Reaction SMILES: [C:1]([CH2:3][C:4]1[N:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH2:11]2)=[CH:6][C:5]=1[C:13]([O:15][CH3:16])=[O:14])#[N:2].[H][H].[ClH:19]>[Pt]=O.C(O)C.C(OCC)(=O)C>[ClH:19].[NH2:2][CH2:1][CH2:3][C:4]1[N:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH2:11]2)=[CH:6][C:5]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1cc2n(c1CC#N)CCCC2
Reactant: [H][H]
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2n(c1CCN)CCCC2

Procedure:
Methyl 3-(Cyanomethyl)-5,6,7,8-tetrahydroindolizine-2-carboxylate 120b was hydrogenated with platinum oxide catalyst under 50 psi of hydrogen in ethanol and ethyl acetate in the presence of hydrogen chloride overnight at room temperature to give 120c (380 mg, 1.74 mmol) which was used in the next step.
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH:5]1[CH2:18][C:8]2=[CH:9][C:10]3[C:11](=[O:17])[NH:12][C:13](=O)[C:14]=3[CH:15]=[C:7]2[CH2:6]1)[CH2:2][CH3:3]>CC(O)=O.CO.[Zn]>[CH2:19]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:18][C:8]2=[CH:9][C:10]3[C:11](=[O:17])[NH:12][CH2:13][C:14]=3[CH:15]=[C:7]2[CH2:6]1)[CH2:20][CH3:21]
Reactant: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)NC3=O
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)NC3
Temperature: 113 °C

Procedure:
(Ref. Brewster, J. H.; Fusco A. M. J.Org. Chem., 28, 501-503 (1963)) A solution of 6-(dipropylamino)-6,7-dihydrocyclopent[f]isoindole-1,3(2H,5H)-dione 93 (0.45 g, 1.6 mmol) in glacial HOAc (50 mL) was treated with Zinc dust (1.05 g, 16.0 mmol) then refluxed at 113° C. for 24 h. The reaction was cooled to r.t., diluted with MeOH and filtered through a pad of celite. The filtrate was concentrated and the residue was diluted with H2O, basified with sat'd Na2CO3, and extracted with CH2Cl2. The organic layers were washed with brine, dried (MgSO4), and concentrated. The resulting solid was purified using silica gel, eluting with 2:1 heptane/acetone to give 94 as a white solid (m.p. 206-208° C.).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:15]([C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])=[CH:16][CH:17]=1)[O:7][CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)([O-:3])=[O:2].C=O.O.[BH3-][C:29]#N.[Na+].CC(O)=O>CC#N>[CH3:29][N:12]1[CH2:11][CH2:10][CH:9]([CH2:8][O:7][C:6]2[C:15]([C:18]([F:24])([F:23])[C:19]([F:20])([F:21])[F:22])=[CH:16][CH:17]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccc(C(F)(F)C(F)(F)F)c(OCC2CCNCC2)c1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CC(=O)O
Product: CN1CCC(COc2cc([N+](=O)[O-])ccc2C(F)(F)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(3-Nitro-6-pentafluoroethyl-phenoxymethyl)-piperidine (316.5 mg) was dissolved in 2.7 mL CH3CN, then added 37% formaldehyde/H2O (360 ul) and then NaBH3CN (90 mg). Upon addition of NaCNBH3 the reaction was found to be slightly exothermic. The reaction was stirred at RT and pH was maintained at ˜7 by addition of drops of glacial AcOH. After about 1 h, the mixture was concentrated in vacuo, treated with 8 mL 2N KOH and extracted two times with 10 mL Et2O. The organic layers were washed with 0.5N KOH and then the combined organic layers were extracted two times with 1N HCl. The aqueous layer was basified with solid KOH and extracted two times with Et2O. This organic layer was then washed with brine/1N NaOH, dried over Na2SO4, filtered, concentrated in vacuo and dried under high vacuum to give pure compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH2:10][CH:11]([O:14][CH3:15])[O:12][CH3:13])[CH:5]=[CH:4][C:3]=1[C:16](=[O:18])[CH3:17].[CH:19]([C:22]1[S:23][CH:24]=[C:25]([C:27](O)=[O:28])[N:26]=1)([CH3:21])[CH3:20].O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[C:16]([C:3]1[C:2]([NH:1][C:27]([C:25]2[N:26]=[C:22]([CH:19]([CH3:21])[CH3:20])[S:23][CH:24]=2)=[O:28])=[C:7]([Cl:8])[C:6]([O:9][CH2:10][CH:11]([O:12][CH3:13])[O:14][CH3:15])=[CH:5][CH:4]=1)(=[O:18])[CH3:17]
Reactant: COC(COc1ccc(C(C)=O)c(N)c1Cl)OC
Reactant: CC(C)c1nc(C(=O)O)cs1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: COC(COc1ccc(C(C)=O)c(NC(=O)c2csc(C(C)C)n2)c1Cl)OC
Temperature: -10 °C
Reaction time: 2 h
Yield: 89.5 %

Procedure:
1-[2-amino-3-chloro-4-(2,2-dimethoxy-ethoxy)phenyl]-ethanone (3.98 g, 14.6 mmol) and 2-isopropyl-thiazole-4-carboxylic acid (2.5 g, 14.6 mmol) was dissolved in pyridine (40 mL) and was cooled to −10° C. POCl3 (1.74 mL, 19.0 mmol) was added dropwise. The reaction was stirred at −10° C. for 2 hours. The reaction was quenched with CH3OH (5 mL). After 15 minutes, the reaction was taken up in EtOAc and extracted with 2N HCl(aq). The organic layer was dried with Na2SO4, filtered and was concentrated. 2-Isopropyl-thiazole-4-carboxylic acid [6-acetyl-2-chloro-3-(2,2-dimethoxy-ethoxy)-phenyl]-amide (5.58 g, 89%) was isolated by silica gel chromatography as a white solid.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)=[O:2].[CH3:12][CH2:13]O.CCOCC>ClCCCl>[CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH2:12][CH3:13])=[O:8])=[CH:5][CH:4]=1)=[O:2]
Reactant: CCO
Reactant: O=Cc1ccc(C(=O)O)cc1
Solvent: ClCCCl
Solvent: CCOCC
Product: CCOC(=O)c1ccc(C=O)cc1
Yield: 68 %

Procedure:
A mixture of 4-formylbenzoic acid (25 g) conc sulfuric acid (2 ml) and EtOH (19.5 ml) was refluxed gently for 5 days in 100 ml of 1,2-dichloroethane. The solvent was then stripped, and Et2O was added to the residue. The Et2O solution was washed (satd aq NaHCO3) dried (Na2SO4), filtered, and evaporated. Bulb to bulb distillation afforded 20.1 g (68%) of the title ester as a clear liquid, bp 145°-150° (2,900 Pascals, 22 torr).
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([N+:26]([O-])=O)[CH:23]=[CH:22][C:21]=3[C:29]3[CH:34]=[C:33]([CH:35]([CH3:37])[CH3:36])[CH:32]=[CH:31][C:30]=3[Cl:38])[C@H:14]2[CH3:39])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1>CO>[NH2:26][C:24]1[CH:23]=[CH:22][C:21]([C:29]2[CH:34]=[C:33]([CH:35]([CH3:37])[CH3:36])[CH:32]=[CH:31][C:30]=2[Cl:38])=[C:20]([CH2:19][N:15]2[C@@H:14]([CH3:39])[C@@H:13]([C:5]3[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([C:2]([F:41])([F:40])[F:1])[CH:4]=3)[O:17][C:16]2=[O:18])[CH:25]=1
Reactant: CC(C)c1ccc(Cl)c(-c2ccc([N+](=O)[O-])cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1
Solvent: CO
Product: CC(C)c1ccc(Cl)c(-c2ccc(N)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1

Procedure:
A solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(2′-chloro-5′-isopropyl-4-nitrobiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one (425 mg, 0.71 mmol) in methanol (10 mL) was subject to H2 (40 psi., Parr shaker) at 20° C. for 6 h. The crude mixture was filtered through a bed of Celite (521). The filtrate was evaporated in vacuo to afford a glass. The titled compound was obtained after a preparative TLC plate developed by 20% EtOAc in hexanes. LC-MS: 571.22 (M+1)+. 1H NMR (CDCl3, 500 MHz) a 6:4 mixture of rotamers δ 7.82-7.86 (m, 1 H), 7.65-7.71 (m, 2 H), 7.34-7.38 (m, 1 H), 7.11-7.17 (m, 2 H), 7.02-7.06 (m, 1 H), 6.76-6.82 (m, 1 H), 6.68-6.74 (m, 1 H), 5.58 (d, J=8.0 Hz, 0.4 H), 5.51 (d, J=8.2 Hz, 0.6H), 4.82 (d, J=15.3 Hz, 0.6H), 4.70 (d, J=15.6 Hz, 0.4H), 3.69-4.00 (m, 4 H), 2.84-2.94 (m, 1 H), 1.19-1.28 (m, 6 H), 0.45 (d, J=6.6 Hz, 1.2 H), 0.40 (d, J=6.6 Hz, 1.8 H).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][OH:12])=[C:6]([CH3:13])[CH:5]=1.[C:14]([C:16]1[CH:17]=[C:18]([NH:27][C:28](=O)[O:29]C2C=CC=CC=2)[CH:19]=[CH:20][C:21]=1[S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])#[N:15]>C1COCC1>[C:14]([C:16]1[CH:17]=[C:18]([NH:27][C:28](=[O:29])[O:12][CH2:11][CH2:10][C:7]2[CH:8]=[CH:9][C:4]([Br:3])=[CH:5][C:6]=2[CH3:13])[CH:19]=[CH:20][C:21]=1[S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])#[N:15]
Reactant: CCS(=O)(=O)c1ccc(NC(=O)Oc2ccccc2)cc1C#N
Reactant: Cc1cc(Br)ccc1CCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1ccc(NC(=O)OCCc2ccc(Br)cc2C)cc1C#N
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
NaH (230 mg, 4.4 mmol, 60% disperson in oil) was added portionwise to a solution of 30B (490 mg, 2.3 mmol) in THF (12 mL) and the mixture was stirred for 30 min. The solution was cooled to −40° C. and 25A (760 mg, 2.3 mmol) was added in one portion. The cooling bath was removed and the reaction was stirred for 2 h. The reaction mixture was cooled to −40° C. and quenched by the addition of NH4Cl (5 mL, sat. aq.). The resulting mixture was partitioned between water (50 mL) and EtOAc (100 mL). The organic phase washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromoatography (0 to 100% EtOAc in hexanes) to yield 31A (745 mg, 72%) as a white solid. 1H NMR (400 MHz, MeOD) δ ppm 1.94 (t, J=7.42 Hz, 3 H) 3.11 (s, 3 H) 4.19 (q, J=7.15 Hz, 2 H) 5.14 (t, J=6.87 Hz, 2 H) 7.99 (d, J=8.24 Hz, 1 H) 8.14 (dd, J=7.70, 2.20 Hz, 1 H) 8.21 (d, J=1.65 Hz, 1 H) 8.72-8.77 (m, 1 H) 8.79-8.84 (m, 1 H) 8.90 (d, J=2.20 Hz, 1 H).
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[CH:8]=[C:7]([NH2:9])[N:6]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:5]=1.Cl[C:17]1[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:18]=1[C:19]([OH:21])=[O:20].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.O>[F:26][C:24]1[C:23]([F:27])=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[C:17]([NH:9][C:7]2[N:6]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)[N:5]=[C:4]([CH3:3])[CH:8]=2)[CH:25]=1
Reactant: O=C(O)c1cc(F)c(F)cc1Cl
Reactant: Cc1cc(N)n(-c2cccnc2)n1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Nc2cc(F)c(F)cc2C(=O)O)n(-c2cccnc2)n1
Temperature: 25 °C
Yield: 62.9 %

Procedure:
A solution of 3-methyl-1-(3-pyridinyl)-1H-pyrazol-5-ylamine dihydrochloride (11.0 g, 44.5 mmol), 2-chloro-4,5-difluorobenzoic acid (8.57 g, 44.5 mmol), copper acetate (II) (0.808 g, 4.45 mmol) and potassium carbonate (12.3 g, 89.0 mmol) in N,N-dimethylformamide (50 mL) was heated under reflux under an argon atmosphere for 3 hours. The solution was allowed to cool to room temperature, and poured into water. The solution was made weakly acidic by the addition of 1N hydrochloric acid, and the resulting crude crystals were collected by filtration. The crystals were washed with water and air dried to give crude 4,5-difluoro-2-[[3-methyl-1-(3-pyridinyl)-1H-pyrazol-5-yl]amino]benzoic acid (9.24 g, 63% yield). A solution of the compound (9.24 g, 28.0 mmol) in phosphorous oxychloride (13 mL, 139 mmol) was heated under reflux for 3 hours. The solution was allowed to cool to room temperature, and the reaction solvent was concentrated and evaporated under reduced pressure. The residue was poured into iced water. The solution was neutralized by the addition of a sodium hydroxide solution, and the organic matter was extracted with chloroform. The extract was washed with saturated brine and water, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (chloroform) to give the title compound (0.77 g, 8% yield).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])([OH:3])=O.C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1.[CH2:44]([S:49]([NH2:52])(=[O:51])=[O:50])[CH2:45][CH2:46][CH2:47][CH3:48]>O>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[CH2:13][C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([C:1](=[O:3])[NH:52][S:49]([CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])(=[O:51])=[O:50])[CH:5]=2)[NH:9][CH:8]=1
Reactant: O=C(O)c1ccc2[nH]cc(Cc3ccc(Cl)cc3Cl)c2c1
Reactant: CCCCCS(N)(=O)=O
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: O
Product: CCCCCS(=O)(=O)NC(=O)c1ccc2[nH]cc(Cc3ccc(Cl)cc3Cl)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.5 %

Procedure:
N,N′-Carbonyldiimidazole (0.282 g) is added to an N,N-dimethylfornamide (4.3 ml) solution of 5-carboxy-3-(2,4-dichlorobenzyl)indole (0.429 g), and stirred at room temperature for 1 hour. Diazabicycloundecene (0.306 g) and 1-pentanesulfonamide (0.304 g) are added thereto, and stirred at 100° C. for 40 hours. The reaction mixture is cooled, and then made acidic with water and 1M HCI added thereto. Then, the gummy residue formed is collected. This is dissolved in ethyl acetate, washed with water, and dried. The solvent is evaporated away, and the resulting residue is crystallized from ether. The crystal formed is collected and dried to obtain 3-(2,4-dichlorobenzyl)-5-(1-pentanesulfonylcarbamoyl)indole (88) (0.258 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[H][H]>CO.[Pd]>[CH2:1]([O:3][C:4]([CH:6]1[CH2:7][CH2:8][N:9]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)C1CCN(c2ccc(N)cc2)CC1

Procedure:
A solution of 1-fluoro-4-nitrobenzene (2.0 g, 1.50 mL, 14 mmol), piperidine-4-carboxylic acid ethyl ester (2.2 g, 2.15 mL, 14 mmol), and potassium carbonate (9.7 g, 70 mmol) in CH3CN (20 mL) was stirred at room temperature overnight. The resulting mixture was filtered and concentrated. The residue was purified by chromatography on silica gel (gradient elution with 5-50% ethyl acetate in hexanes) to produce 2.0 g of 1-(4-nitro-phenyl)-piperidine-4-carboxylic acid ethyl ester as a yellow solid. 1.0 g of the above 1-(4-nitro-phenyl)-piperidine-4-carboxylic acid ethyl ester was hydrogenated using 10% Pd/C (200 mg) in MeOH, under 50 psi pressure of hydrogen for 2 hours. The catalyst was filtered, and the residue was concentrated to produce 1-(4-amino-phenyl)-piperidine-4-carboxylic acid ethyl ester. This material was directly used in the next step without further purification.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C@@H:9]([N:16](CS)[C:17]2[CH:22]=[CH:21][C:20]([S:23]([NH:26][C:27]3[N:31]4[CH2:32][CH2:33][NH:34][CH2:35][C:30]4=[N:29][N:28]=3)(=[O:25])=[O:24])=[CH:19][C:18]=2[S:36]([C:39]([F:42])([F:41])[F:40])(=[O:38])=[O:37])C2C=CC=CC=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:45]([O:49][C:50]([N:52]1[CH2:57][CH2:56][C:55](=O)[CH2:54][CH2:53]1)=[O:51])([CH3:48])([CH3:47])[CH3:46].C([BH3-])#N.[Na+]>C(O)(=O)C.CO>[C:45]([O:49][C:50]([N:52]1[CH2:57][CH2:56][CH:55]([N:34]2[CH2:33][CH2:32][N:31]3[C:27]([NH:26][S:23]([C:20]4[CH:21]=[CH:22][C:17]([NH:16][C@@H:9]([CH2:39][S:36][C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][CH:17]=5)[CH2:8][CH2:7][N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)=[C:18]([S:36]([C:39]([F:40])([F:41])[F:42])(=[O:38])=[O:37])[CH:19]=4)(=[O:25])=[O:24])=[N:28][N:29]=[C:30]3[CH2:35]2)[CH2:54][CH2:53]1)=[O:51])([CH3:48])([CH3:47])[CH3:46]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O=S(=O)(Nc1nnc2n1CCNC2)c1ccc(N(CS)[C@H](CCN2CCOCC2)c2ccccc2)c(S(=O)(=O)C(F)(F)F)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(N2CCn3c(nnc3NS(=O)(=O)c3ccc(N[C@H](CCN4CCOCC4)CSc4ccccc4)c(S(=O)(=O)C(F)(F)F)c3)C2)CC1
Reaction time: 0.17 h
Yield: 204.5 %

Procedure:
To a vial containing 4-((R)-3-morpholin-4-yl-1-phenyl-sulfanylmethyl-propylamino)-N-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-3-trifluoromethanesulfonyl-benzenesulfonamide (50 mg, 0.074 mmol) and 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (14.74 mg, 0.074 mmol) was added methanol (2 mL) under nitrogen. The reaction mixture was stirred in an ice bath for 10 minutes, and then acetic acid (0.424 μL, 7.40 μmol) was added. The reaction mixture was stirred for another 30 minutes. Sodium cyanoborohydride (41.85 mg, 0.666 mmol) was then added, and the reaction was stirred at ambient temperature for 72 hours. The reaction mixture was concentrated, filtered and purified via flash chromatography on silica gel (10-50% 7N NH3 in methanol in CH2Cl2) to afford 4-{3-[4-((R)-3-Morpholin-4-yl-1-phenylsulfanylmethyl-propylamino)-3-trifluoromethanesulfonyl-benzenesulfonylamino]-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl}-piperidine-1-carboxylic acid tert-butyl ester (65 mg, 100% yield). MS [m/z; (M+1)+]: 859.7