Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:6]([S:16]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17])[C@H:5]2[CH3:26].[S:27](Cl)(=[O:30])(=[O:29])[NH2:28].O>CC(N(C)C)=O>[S:27](=[O:30])(=[O:29])([O:25][C:22]1[CH:21]=[CH:20][C:19]([S:16]([N:6]2[C@@H:5]([CH3:26])[C:4]3[C:13](=[CH:14][CH:15]=[C:2]([F:1])[CH:3]=3)[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]2=3)(=[O:18])=[O:17])=[CH:24][CH:23]=1)[NH2:28]
Reactant: NS(=O)(=O)Cl
Reactant: C[C@H]1c2cc(F)ccc2-c2ccccc2N1S(=O)(=O)c1ccc(O)cc1
Solvent: O
Solvent: CC(=O)N(C)C
Product: C[C@H]1c2cc(F)ccc2-c2ccccc2N1S(=O)(=O)c1ccc(OS(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.2 %

Procedure:
To a stirred solution of 4-{[(6S)-8-fluoro-6-methylphenanthridin-5(6H)-yl]sulfonyl}phenol (1.11 g, 3.0 mmol) in dimethyacetamide (10 mL), cooled to 0° C., was added sulfamoyl chloride (1.39 g, 12.0 mmol). The mixture was allowed to warm to room temperature and stirring continued for 16 hours. Water (100 mL) was added and a white precipitate deposited on the inside of the reaction vessel. The water was removed and the flask was washed with additional water. The white solid was dissolved in dichloromethane and purified by preparative liquid chromatography on a Biotage® 40 Mi column of prepacked silica gel (90 g), eluting with a gradient of 30% -50% methyl tert-butyl ether in hexane, to afford the title compound (1.16 g, 87% ) as a white solid, m.p.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]2[C:9]([O:31][CH2:32][CH2:33][OH:34])=[N:10][N:11]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]=2[CH:3]=1.[F:35][C:36]([F:44])(S(F)(=O)=O)C(O)=O>>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]2[C:9]([O:31][CH2:32][CH2:33][O:34][CH:36]([F:44])[F:35])=[N:10][N:11]([C:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:4]=2[CH:3]=1
Reactant: Cc1nc(Cl)cc2c1c(OCCO)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Product: Cc1nc(Cl)cc2c1c(OCCOC(F)F)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 59 %

Procedure:
In a manner similar to that previously described (e.g. synthesis of Intermediate 59B/Step 2), 2-((6-chloro-4-methyl-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)oxy)ethanol was reacted with 2,2-difluoro-2-(fluorosulfonyl)acetic acid (copper(I) iodide, acetonitrile, 80° C. 30 min) to provide 6-chloro-3-(2-(difluoromethoxy)ethoxy)-4-methyl-1-trityl-1H-pyrazolo[4,3-c]pyridine 59% yield) as a white crystalline solid. MS: [M+H]+ m/z 520.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[OH:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([O:11][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH:13]=1
Reactant: Oc1cccnc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2cccnc2)cc1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
1-Chloro-4-nitrobenzene (40 g, 0.25 mol) and 3-hydroxypyridine (36 g, 0.38 mol) were dissolved in N,N-dimethylformamide (100 mL). Potassium carbonate (52.6 g, 0.38 mol) was added thereto, and the mixture was stirred for 20 h at 100° C. After completion of the reaction, water was added. The reaction mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, and dried over anhydrous magnesium sulfate to give the title compound.
Reaction SMILES: [O:1]1[CH2:17][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])=[CH:7][CH:6]=1.[C:18]([CH2:21][N:22]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29][N:28]([CH2:34][C:35]([OH:37])=[O:36])[CH2:27][CH2:26][N:25]([CH2:38][C:39]([OH:41])=[O:40])[CH2:24][CH2:23]1)([OH:20])=[O:19].[OH-].[K+]>O1CCOCC1.O>[OH:1][CH:2]([CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])=[CH:7][CH:6]=1)[CH2:17][N:31]1[CH2:32][CH2:33][N:22]([CH2:21][C:18]([OH:20])=[O:19])[CH2:23][CH2:24][N:25]([CH2:38][C:39]([OH:41])=[O:40])[CH2:26][CH2:27][N:28]([CH2:34][C:35]([OH:37])=[O:36])[CH2:29][CH2:30]1
Reactant: OCCCCCc1ccc(OCC2CO2)cc1
Reactant: O=C(O)CN1CCNCCN(CC(=O)O)CCN(CC(=O)O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CN1CCN(CC(=O)O)CCN(CC(O)COc2ccc(CCCCCO)cc2)CCN(CC(=O)O)CC1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
12.3 g (51.97 mmol) of 2,3-epoxy-1-[4-(5-hydroxypentyl)-phenoxy]-propane and 10 g (28.87 mmol) of 1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane (=DO3A) are dissolved in a mixture of 50 ml of dioxane and 80 ml of water, and the pH is brought to pH 10 with 6N potassium hydroxide solution. It is stirred for 24 hours at 40° C. It is evaporated to dryness, the residue is taken up with 200 ml of water/50 ml of methanol and extracted twice with 100 ml of tert-butyl methyl ether. The aqueous solution is adjusted to pH 3 with 5N hydrochloric acid and evaporated to dryness. The residue is concentrated by evaporation in a vacuum and boiled out (extracted) with 200 ml of methanol/50 ml of methylene chloride. It is cooled in an ice bath and filtered off from precipitated potassium chloride. The filtrate is concentrated by evaporation in a vacuum, the residue is dissolved in 50 ml of water/20 ml of ethanol and then added to a column of poly-(4-vinylpyridine). The product is eluted with a solution of ethanol/water. After concentration by evaporation in a vacuum, 8.92 g (53% of theory) of the title compound is obtained as strongly hygroscopic, vitreous solid.
Reaction SMILES: [N+](C1C=CC(C[O:9][C:10](=[O:24])[C@H:11]([CH3:23])[N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:13]2[CH2:15][CH2:14]2)=CC=1)([O-])=O.[OH-].[Na+].O>CO>[C:16]([N:12]([CH:13]1[CH2:15][CH2:14]1)[C@H:11]([C:10]([OH:24])=[O:9])[CH3:23])([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17]
Reactant: C[C@@H](C(=O)OCc1ccc([N+](=O)[O-])cc1)N(C(=O)OC(C)(C)C)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1CC1
Reaction time: 3 h
Yield: 84.6 %

Procedure:
To a solution of Boc-cyclopropylalanine p-nitrobenzyl Ester (4) (450 mg, 1.34 mmol) in MeOH (20 ml) was added 1N NaOH (2.6 ml, 2.6 mmol) at room temperature. After the mixture was stirred for 3 hr, water (10 ml) was added and the MeOH was removed in vacuo. The aqueous residue was washed with Et2O to remove p-nitrobenzyl alcohol and the aqueous layer was separated, cooled in an ice bath and 10% citric acid solution was added to pH 3. The mixture was saturated with NaCl and extracted with AcOEt and the extracts were washed with sat. NaCl solution, dried over Na2SO4 and evaporated in vacuo to give a white solid which was recrystallized from AcOEt-n-hexane to afford 260 mg of Boc-cyclopropyl Alanine (5) (96.3%) as colorless needles, mp 176°-177° C. (dec.); IR (KBr): 3230(NH), 1630-1680 (C=0). NMR (CDCl3 +DMSO)δ: 9.45 (br, s, IH, COOH), 5.88 (br, s, 1H, NH) 1.3-1.7 (m, 2H, CH2), 1.0-1.2 (m, 2H, CH2), 1.50 (s, 9H, Boc).
Reaction SMILES: [C:1]1(=[O:12])[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][C:3](=[O:11])[CH2:2]1.C(N(CC)CC)C.C1(C)C=CC(S([N:29]=[N+:30]=[N-])(=O)=O)=CC=1>C(O)C>[N+:29](=[C:2]1[C:3](=[O:11])[CH2:4][CH:5]2[CH:10]([CH2:9][CH2:8][CH2:7][CH2:6]2)[C:1]1=[O:12])=[N-:30]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: O=C1CC(=O)C2CCCCC2C1
Solvent: CCN(CC)CC
Solvent: CCO
Product: [N-]=[N+]=C1C(=O)CC2CCCCC2C1=O
Temperature: -10 °C
Reaction time: 1 h
Yield: 35.4 %

Procedure:
A solution of 10.0 g (0.0768 mol) of decalin-1,3-dione in 50 ml of ethanol was magnetically stirred under nitrogen and cooled to -10° C. To the solution was added 7.77 g (0.0768 mol) of triethylamine followed by 15.14 g (0.0768 mol) of p-toluenesulfonylazide added all at once. The mixture was stirred for one hour at 0° C., and the solvent removed at reduced pressure at a temperature of less than 40° C. To the residue was added 200 ml of ether, and the ether removed to yield a yellow solid. This was recrystallized from ethanol to give 5.23 g of yellow crystals, mp 81°-83° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([OH:13])=O)[CH2:8][CH2:7][C:6]=2[CH:14]=1.[CH2:15]([NH2:18])[CH:16]=[CH2:17]>S(Cl)(Cl)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([NH:18][CH2:15][CH:16]=[CH2:17])=[O:13])[CH2:8][CH2:7][C:6]=2[CH:14]=1
Reactant: C=CCN
Reactant: O=C(O)C1CCc2cc(Cl)ccc2O1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: C=CCNC(=O)C1CCc2cc(Cl)ccc2O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3.1 g of 6-chloro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (1A) (Witiak et al. (1971), supra) in 15 ml of thionyl chloride was refluxed for 45 minutes. The excess thionyl chloride then was stripped off and the residual liquid taken up in 50 ml of methylene chloride. To this stirred solution was added dropwise a solution of 2.5 g of 2-propenamine in 10 ml of methylene chloride. The resulting mixture was stirred at room temperature overnight, then was washed with water, dried (MgSO4) and stripped of solvent. Dry column chromatography of the solid product through silica gel, using Solvent No. 3 (a 4:30:66 by volume mixture of tetrahydrofuran, ethyl acetate and hexane) as eluent, followed by recrystallization of the product from ethylene chloride and hexane gave 1, as a pale yellow solid, mp: 112.5°-114° C. Example 2
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[CH:20][CH:19]=2)[C:8]2[C:13]([C:14]=1[CH:15]=[O:16])=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:5])[CH3:2].[C:28]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)([CH3:31])([CH3:30])[CH3:29]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[CH:20][CH:19]=2)[C:8]2[C:13]([C:14]=1[CH:15]=[O:16])=[CH:12][C:11]([C:35]1[CH:36]=[CH:37][C:32]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:33][CH:34]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C=O)c2cc(Br)ccc2n1-c1ccc(OC(C)C)cc1
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Product: CCOC(=O)c1c(C=O)c2cc(-c3ccc(C(C)(C)C)cc3)ccc2n1-c1ccc(OC(C)C)cc1

Procedure:
The sub-title compound was prepared in accordance with step (a) Example 67 from 5-bromo-3-formyl-1-(4-isopropoxyphenyl)indole-2-carboxylic acid ethyl ester (4.07 g, 9.46 mmol; see step (b) above) and 4-tert-butylphenylboronic acid (2.53 g, 14.19 mmol). Yield 4.16 g (91%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:20]3[CH2:21][CH2:22][CH2:23][C:19]=3[N:18]=[C:17]([Cl:24])[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>CO.Cl.O1CCOCC1>[ClH:24].[ClH:24].[Cl:24][C:17]1[N:16]=[C:15]([NH:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[C:20]2[CH2:21][CH2:22][CH2:23][C:19]=2[N:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc(Cl)nc3c2CCC3)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Clc1nc2c(c(NC3CCNCC3)n1)CCC2

Procedure:
A solution of 4-(2-chloro-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (2.34 g, 6.63 mmol) in MeOH (10 mL) and 4 M HCl in dioxane (20 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 253.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([S:9]([N:12]([CH2:14][C:15]2[O:19][CH:18]=[C:17]([C:20]([OH:22])=O)[CH:16]=2)[CH3:13])(=[O:11])=[O:10])=[C:4]([CH3:23])[CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH:36]1[CH2:40][CH2:39][N:38]=[C:37]1[C:41]1[CH:46]=[CH:45][C:44]([CH2:47][CH2:48][NH:49][CH3:50])=[CH:43][CH:42]=1.Cl.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([S:9]([N:12]([CH2:14][C:15]2[O:19][CH:18]=[C:17]([C:20]([N:49]([CH2:48][CH2:47][C:44]3[CH:43]=[CH:42][C:41]([C:37]4[NH:38][CH2:39][CH2:40][N:36]=4)=[CH:46][CH:45]=3)[CH3:50])=[O:22])[CH:16]=2)[CH3:13])(=[O:11])=[O:10])=[C:4]([CH3:23])[CH:3]=1
Reactant: Cc1cc(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)cc1Cl
Reactant: CNCCc1ccc(C2=NCCN2)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(S(=O)(=O)N(C)Cc2cc(C(=O)N(C)CCc3ccc(C4=NCCN4)cc3)co2)c(C)cc1Cl

Procedure:
5-({[(4-chloro-2,5-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (30 mg, 0.08 mmol) was dissolved in DMF (1 mL) and CDI (20 mg, 0.12 mmol) was added. The mixture was stirred until acid activation was complete. 2-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]-N-methylethanamine.HCl (19 mg, 0.08 mmol) and DIPEA (0.042 mL, 0.24 mmol) were sonicated in DMF (1 mL) for 15 min, 0.5 mL of activated acid solution was added to 0.25 mL of amine solution and the reaction was microwaved (120° C., 200 W) for 20 min, then 2×60 min. A portion of the reaction was concentrated and purified using prep method A.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([S:15]([CH3:18])(=O)=O)[N:3]=1.C(S)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([S:15][CH2:18][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: SCc1ccccc1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(SCc2ccccc2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile, benzyl mercaptan and DBU in DME. EI-MS m/e (%): 308 (M+, 68), 307 ([M—H]+, 48), 275 (24), 91 (100).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:14][C@@H:15]([CH3:19])[C:16](O)=[O:17])(=[O:13])=[O:12].C1C=CC=CC=1.S(Cl)([Cl:28])=O>CCCCCC>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:14][C@@H:15]([CH3:19])[C:16]([Cl:28])=[O:17])(=[O:13])=[O:12]
Reactant: O=S(Cl)Cl
Reactant: C[C@H](NS(=O)(=O)c1ccc2ccccc2c1)C(=O)O
Solvent: CCCCCC
Solvent: c1ccccc1
Product: C[C@H](NS(=O)(=O)c1ccc2ccccc2c1)C(=O)Cl
Reaction time: 18 h

Procedure:
2 g of (S)-2-(2-naphthylsulfonylamino)propionic acid are added to 50 ml of anhydrous benzene, and 2.04 ml of thionyl chloride are added thereto. The mixture is stirred at 40° to 50° C for 18 hours. The reaction mixture is condensed to dryness under reduced pressure, and the residue is recystallized from a mixture of benzene and n-hexane. 1.6 g of (S)-2-(2-naphthylsulfonylamino)propionyl chloride are obtained.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[CH2:11]O)=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:35].O>CC(N(C)C)=O>[Br:35][CH2:11]/[CH:10]=[CH:9]/[C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:14])([F:13])[F:1])=[CH:4][CH:5]=1
Reactant: OC/C=C/c1ccc(C(F)(F)F)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Solvent: O
Product: FC(F)(F)c1ccc(/C=C/CBr)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
To a solution of the alcohol obtained in step 2 (10 g) in dimethylacetamide (100 ml) at room temperature were added triphenylphosphine (23 g) and carbon tetrabromide (29 g). The resulting solution was stirred at room temperature for 1 h, poured into water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulfate and filtered over silica gel to give 13 g of the desired product as a white solid (95%) which was characterized by its mass and NMR spectra.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][CH2:7][C@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]([O:11]C(C)C)=[O:10])[CH:2]=[CH2:3].O.[OH-].[Li+]>C1COCC1.O.O>[CH2:1]([O:4][CH2:5][CH2:6][CH2:7][C@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]([OH:11])=[O:10])[CH:2]=[CH2:3]
Reactant: C=CCOCCC[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C=CCOCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of isopropyl 5-allyloxy-2(S)-(tert-butoxycarbonylamino)pentanoate (product of step 26D, 16.1 g, 51.1 mmol) and lithium hydroxide hydrate (4.19 g, 102 mmol) in THF/water (100 mL/20 mL) was stirred at room temperature under nitrogen for 16 hours. The reaction was diluted with water, washed with ether, pH of aqueous fraction adjusted to ˜4, extracted with ether, combined organic fractions washed with saturated NaCl, dried (MgSO4) and evaporated giving 5-allyloxy-2(S)-(tert-butoxycarbonylamino)pentanoic acid as a light yellow syrup: 1H NMR (300 MHz, Chloroform-D) δ 5.89 (ddt, 1H, J=17.4, 10.4, 5.5), 5.25 (dd, 1H, J=17.4, 1.6 Hz), 5.17 (dd, 1H, J=10.4, 1.6 Hz), 4.30 (br d, 1H, J=6.2), 3.96 (dt, 2H, J=5.9, 1.5 Hz), 3.46 (t, 2H, J=5.9 Hz), 1.96-1.86 (m, 1H), 1.85-1.77 (m, 1H), 1.75-1.64 (m, 2H), 1.43 (s, 9H). LCMS m/z 274 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=O.O.[NH2:21][NH2:22]>C(O)COCCO>[NH2:1][C:2]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:3]=1[C:4](=[N:21][NH2:22])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12]
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1Cl
Reactant: NN
Solvent: OCCOCCO
Solvent: O
Product: NN=C(c1cc([N+](=O)[O-])ccc1N)c1ccccc1Cl

Procedure:
In the manner given in Preparation 1, 2-amino-2'-chloro-5-nitrobenzophenone is refluxed with hydrazine hydrate in diethylene glycol to give 2-amino-2'-chloro-5-nitrobenzophenone hydrazone.
Reaction SMILES: C([O:8][C:9]([C@@H:11]1[CH2:16][C@@H:15]2[C@@H:13]([CH2:14]2)[N:12]1[C:17](=[O:31])[CH2:18][N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([C:28](=[O:30])[NH2:29])=[N:20]1)=[O:10])C1C=CC=CC=1>C1COCC1.CCOC(C)=O>[C:28]([C:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:19]([CH2:18][C:17]([N:12]2[C@H:11]([C:9]([OH:10])=[O:8])[CH2:16][C@@H:15]3[C@H:13]2[CH2:14]3)=[O:31])[N:20]=1)(=[O:30])[NH2:29]
Reactant: NC(=O)c1nn(CC(=O)N2[C@@H]3C[C@@H]3C[C@H]2C(=O)OCc2ccccc2)c2ccccc12
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NC(=O)c1nn(CC(=O)N2[C@@H]3C[C@@H]3C[C@H]2C(=O)O)c2ccccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(1R,3S,5R)-2-[2-(3-carbamoyl-indazol-1-yl)-acetyl]-2-aza-bicyclo[3.1.0]hexane-3-carboxylic acid benzyl ester (3.9 g, 8.85 mmol) was dissolved in THF (120 mL) and EtOAc (120 mL). Air was removed from the flask and replaced with nitrogen three times. Pd/C 10% (390 mg) was added to the solution which was again degassed, placed under a hydrogen atmosphere, and stirred at RT for 4 h. The catalyst was removed through a pad of Celite and washed with EtOAc. Solvents were removed under reduced pressure and the foam thus obtained was used without further purification in the next step. MS (LCMS): 346.2 [M+NH4]+, 327.1 [M−H]−; tR (HPLC conditions b): 1.12 min.
Reaction SMILES: COC1C=CC(NC2N=NC(C(NC(C3CCOCC3)=O)C)=CN=2)=CC=1.[NH2:27][CH:28]([C:30]1[N:35]=[N:34][C:33]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)=[N:32][CH:31]=1)[CH3:29].[Cl:45][C:46]1[CH:54]=[CH:53][CH:52]=[CH:51][C:47]=1[C:48](O)=[O:49]>>[Cl:45][C:46]1[CH:54]=[CH:53][CH:52]=[CH:51][C:47]=1[C:48]([NH:27][CH:28]([C:30]1[N:35]=[N:34][C:33]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)=[N:32][CH:31]=1)[CH3:29])=[O:49]
Reactant: O=C(O)c1ccccc1Cl
Reactant: COc1ccc(Nc2ncc(C(C)N)nn2)cc1
Agent: COc1ccc(Nc2ncc(C(C)NC(=O)C3CCOCC3)nn2)cc1
Product: COc1ccc(Nc2ncc(C(C)NC(=O)c3ccccc3Cl)nn2)cc1
Yield: 80.7 %

Procedure:
In a similar manner as described for Intermediate 50, using 6-(1-aminoethyl)-N-[4-(methyloxy)phenyl]-1,2,4-triazin-3-amine (Intermediate 47) (100 mg, 0.41 mmol), and 2-chlorobenzoic acid (70 mg, 0.45 mmol) to give 2-chloro-N-[1-(3-{[4-(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]benzamide (127 mg) as a yellow solid. MS m/z 384 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][CH:8]([NH2:11])[CH2:9][CH3:10].C(N(CC)CC)C.[N+:19]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([O-:21])=[O:20]>C(Cl)Cl>[Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][C@H:8]([NH:11][S:28]([C:25]1[CH:24]=[CH:23][C:22]([N+:19]([O-:21])=[O:20])=[CH:27][CH:26]=1)(=[O:29])=[O:30])[CH2:9][CH3:10]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CCC(N)Cc1sccc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H](Cc1sccc1Cl)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
Six grams of 3-chloro-2-(2-aminobutyl)thiophene is dissolved in 10 ml of methylene chloride in a 3-neck round bottomed flask blanketed with an inert atmosphere at 0° C. Triethylamine (6.6 ml) is added in one portion followed by 7.8 g of 4-nitrobenzenesulfonyl chloride which had been previously dissolved in 10 ml of methylene chloride. After stirring for 1 hour at ambient temperature, the methylene chloride is removed under vacuum and 40 ml of methanol is added with warming to dissolve all solids. The resulting solution is poured into cold water, agitated for 30 minutes, filtered and washed with cold water, and the isolated material is dried in a vacuum oven to provide (R)-N-[1-[(3-chlorothien-2-yl)methyl]propyl]-4-nitrobenzenesulfonamide (11.3 g) as a tan solid. MS: m/z (E1, 70EV) 375(10%). 1H NMR (200 MHz; CDCl3): δ 0.95 (3H, t, CH3), 1.7 (2H, m, CH2), 2.85 (2H, m, CH2), 3.5 (1H, m, CH), 6.65 (1H, d, CH), 7.0 (1H, d, CH), 7.9 (2H, d, Ph), 8.2 (2H, d, Ph).
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](Cl)=[S:4].[CH3:12][NH:13][NH2:14]>CCOCC>[CH3:12][N:13]([C:3]([N:2]([CH3:1])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[S:4])[NH2:14]
Reactant: CNN
Reactant: CN(C(=S)Cl)c1ccccc1
Solvent: CCOCC
Product: CN(N)C(=S)N(C)c1ccccc1
Temperature: 25 °C
Yield: 83.4 %

Procedure:
To a solution of N-methyl-N-phenylthiocarbamyl chloride (79.6 g, 0.43 mole) in 250 ml dry ether, a solution of 39.5 g (0.86 mole) methylhydrazine in 100 ml of dry ether was added dropwise with stirring below 10° C. The reaction temperature was allowed to increase to room temperature and the mixture was filtered. The filtrate was evaporated to low volume and diluted with about 300 ml hexane. After stirring for a few hours the hexane layer was decanted. The hexane immiscible layer was reevaporated to remove organic solvents, giving the desired product, (70.0 g) as a thick orange liquid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:10](#[N:13])[CH:11]=[CH2:12].N12CCN(CC1)CC2>[OH-].[Na+]>[O:1]1[C:2]2[C:3](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:11]([C:10]#[N:13])[CH2:12]1
Reactant: C=CC#N
Reactant: O=Cc1ccccc1O
Agent: C1CN2CCN1CC2
Agent: [Na+]
Agent: [OH-]
Product: N#CC1=Cc2ccccc2OC1
Temperature: 90 °C

Procedure:
A microwave vessel was charged with 2-hydroxybenzaldehyde (Aldrich, 3.0 mL, 28.6 mmol), acrylonitrile (9.4 mL, 143 mmol) and 1,4-diazabicyclo[2.2.2]octane (0.80 g, 7.2 mmol), and heated in a microwave Personal Chemistry at 90° C. for 13 hours. Sodium hydroxide (1N, 200 mL) was added and the mixture was extracted twice with ethyl acetate (200 mL), and the combined organic layer washed with brine, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with O-to-20% ethyl acetate in hexane providing the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 4.88 (d, J=1.36 Hz, 2H), 6.90 (d, J=8.14 Hz, 1H), 7.01 (td, J=7.46, 1.01 Hz, 1H), 7.30 (m, 2H), 7.58 (s, 1H). MS (DCI) m/z 175.05 (M+NH4)+.