Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCOCC.Br[CH2:7][C:8]#[C:9][CH2:10][C:11]#[C:12][CH2:13][C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[CH2:24]([NH:26][C:27](=[O:30])[CH2:28][SH:29])[CH3:25]>C(Cl)Cl>[CH2:24]([NH:26][C:27](=[O:30])[CH2:28][S:29][CH2:7][C:8]#[C:9][CH2:10][C:11]#[C:12][CH2:13][C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:25]
Reactant: CCCCCCCCC#CCC#CCC#CCBr
Reactant: CCNC(=O)CS
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCCCCCC#CCC#CCC#CCSCC(=O)NCC
Reaction time: 1 h

Procedure:
The ether solution of 1-bromo-2,5,8-heptadecatriyne, prepared according to the above operating procedure, is added dropwise under an inert atmosphere to a stirred solution, at 0° C., of sodium thiolate of N-ethylthioglycolamide prepared according to operating procedure b) above. The mixture obtained is stirred for 1 hour after the addition is finished. The solvents are then removed by evaporation under vacuum. The product obtained is dissolved in 100 cm3 of methylene chloride. The organic phase is washed with water, dried over magnesium sulphate, concentrated and then deposited onto a silica gel column. The expected amide is eluted with a mixture of methylene chloride and ethyl acetate (97-3). After evaporation of the eluent, 6 g of product are isolated and are recrystallized from isopropyl ether. 4 g of N-ethyl 3-thia-5,8,11-eicosatriynamide are obtained in the form of beige crystals having a melting point of 59° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[C@@H:7]([NH:23][C:24]([O:26][CH2:27][C:28]12[CH2:37][CH:32]3[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]3)[CH2:29]1)[CH2:35]2)=[O:25])[CH2:8][NH:9][C:10]([C:12]1[S:13][C:14]([CH2:17][CH2:18][C:19]([O:21]C)=O)=[CH:15][CH:16]=1)=[O:11])([CH3:4])([CH3:3])[CH3:2].[NH2:39][C:40]1[NH:41][CH2:42][CH2:43][CH2:44][N:45]=1>CN(C)C=O>[C:1]([O:5][C:6](=[O:38])[C@@H:7]([NH:23][C:24]([O:26][CH2:27][C:28]12[CH2:29][CH:30]3[CH2:36][CH:34]([CH2:33][CH:32]([CH2:31]3)[CH2:37]1)[CH2:35]2)=[O:25])[CH2:8][NH:9][C:10]([C:12]1[S:13][C:14]([CH2:17][CH2:18][C:19](=[O:21])[NH:39][C:40]2[NH:45][CH2:44][CH2:43][CH2:42][N:41]=2)=[CH:15][CH:16]=1)=[O:11])([CH3:3])([CH3:4])[CH3:2]
Reactant: NC1=NCCCN1
Reactant: COC(=O)CCc1ccc(C(=O)NC[C@H](NC(=O)OCC23CC4CC(CC(C4)C2)C3)C(=O)OC(C)(C)C)s1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(CCC(=O)NC2=NCCCN2)s1)NC(=O)OCC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 5 h
Yield: 71.5 %

Procedure:
1.37 g (2.5 mmol) of the product obtained in step b) were dissolved in 12 ml of anhydrous dimethylformamide, and after addition of 1.24 g of 2-amino-1,4,5,6-tetrahydropyrimidine the mixture was stirred at room temperature for 5 hours. The solvent was removed in vacuo and the residue was chromatographed (silica gel; ethyl acetate/methanol (1/1; v/v)) to give 1.1 g of the title compound.
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[NH:20][C:19]2[C:21]3[C:26]([CH:27]=[CH:28][C:18]=2[N:17]=1)=[CH:25][C:24]1[C:29]2[C:34]([CH2:35][O:36][C:23]=1[CH:22]=3)=[CH:33][C:32]([C:37]1[NH:41][C:40]([C@@H:42]3[CH2:46][C@H:45]([CH2:47][O:48][CH3:49])[CH2:44][N:43]3[C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])=[N:39][CH:38]=1)=[CH:31][CH:30]=2)=O)C1C=CC=CC=1.C([O-])(O)=O.[Na+]>C(O)C.[Pd]>[CH3:49][O:48][CH2:47][C@@H:45]1[CH2:44][N:43]([C:50]([O:52][C:53]([CH3:56])([CH3:54])[CH3:55])=[O:51])[C@H:42]([C:40]2[NH:41][C:37]([C:32]3[CH:33]=[C:34]4[CH2:35][O:36][C:23]5[CH:22]=[C:21]6[C:26]([CH:27]=[CH:28][C:18]7[N:17]=[C:16]([C@@H:12]8[CH2:13][CH2:14][CH2:15][NH:11]8)[NH:20][C:19]=76)=[CH:25][C:24]=5[C:29]4=[CH:30][CH:31]=3)=[CH:38][N:39]=2)[CH2:46]1
Reactant: COC[C@H]1C[C@@H](c2ncc(-c3ccc4c(c3)COc3cc5c(ccc6nc([C@@H]7CCCN7C(=O)OCc7ccccc7)[nH]c65)cc3-4)[nH]2)N(C(=O)OC(C)(C)C)C1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COC[C@H]1C[C@@H](c2ncc(-c3ccc4c(c3)COc3cc5c(ccc6nc([C@@H]7CCCN7)[nH]c65)cc3-4)[nH]2)N(C(=O)OC(C)(C)C)C1
Reaction time: 8 h

Procedure:
A mixture of tert-butyl (2S,4S)-2-[5-(2-{(2S)-1-[(benzyloxy)carbonyl]pyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate (724 mg, 0.96 mmol) and 70 mg 10% Pd/C in 20 mL ethanol was hydrogenated at latm overnight. Additional 10% Pd/C (300 mg) and a portion of solid NaHCO3 was added and hydrogenation continued for 4 hours. Filtration through celite and concentration of the filtrate under reduced pressure gave the product as a dark brown solid, 454 mg. Purification by reverse phase HPLC gave 65 mg purified product.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:15]([O:17]CC)=[O:16])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]#[N:14])[CH:8]=2)[N:6]=1.[OH-].[K+]>CO.O>[Cl:1][C:2]1[S:3][C:4]([C:15]([OH:17])=[O:16])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]#[N:14])[CH:8]=2)[N:6]=1
Reactant: CCOC(=O)c1sc(Cl)nc1-c1cccc(C#N)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N#Cc1cccc(-c2nc(Cl)sc2C(=O)O)c1
Temperature: 25 °C
Yield: 86 %

Procedure:
To a solution of of 2-chloro-4-(3-cyanophenyl)-5-carboethoxythiazole (0.44 g, 1.45 mmol) in 25 mL of methanol and 25 mL of water was added potassium hydroxide (0.09 g, 1.6 mmol). The resulting solution was stirred at reflux for 2 h and then was cooled to room temperature. The methanol was removed in vacuo and the aqueous layer was diluted with water and washed with hexanes. The hexane layer was discarded. The aqueous layer was acidified and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried (MgSO4) and concentrated to yield 0.33 g (97%) of the title compound which was used without further purification. MS (ESI)−262.9 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH2:16][N:17]3[CH:21]=[C:20]([C:22]([O:24]CC)=[O:23])[CH:19]=[N:18]3)[CH:11]=[N:12][C:13]=2[O:14][CH3:15])[CH:5]=[CH:6][CH:7]=1.[OH-].[Li+]>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH2:16][N:17]3[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[N:18]3)[CH:11]=[N:12][C:13]=2[O:14][CH3:15])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cnn(Cc2cnc(OC)c(-c3cccc(Cl)c3)c2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ncc(Cn2cc(C(=O)O)cn2)cc1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.1 %

Procedure:
To a solution of ethyl 1-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)-1H-pyrazole-4-carboxylate (Example 169, 25.00 mg, 0.07 mmol) in THF (2 mL), methanol (2 mL) was added lithium hydroxide (1.00 mL, 1.00 mol/L, 1.00 mmol). The mixture was stirred at room temperature for 2 h. The solvents were removed under reduced pressure and the crude residue dissolved in water. The aqueous reaction mixture was acidified with 1 N HCl (5 mL), and extracted into ethyl acetate. The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure to afford the title compound (20 mg, 87%). 1H NMR (400 MHz, DMSO-d6) δ 12.30 (br s, 1H), 8.39 (br s, 1H), 8.19 (br s, 1H), 7.80 (br s, 2H), 7.68-7.26 (m, 4H), 5.34 (br s, 2H), 3.87 (br s, 3H). [M+H]=344.31.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH2:4][S:3][CH2:2]1.C([Li])CCC.CCCCCC.[Cl-].Cl[CH2:20]/[CH:21]=[C:22](/[F:31])\[CH2:23][O:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1>O1CCCC1>[S:1]1[CH2:6][CH2:5][CH2:4][S:3][CH:2]1[CH2:20][CH:21]=[C:22]([F:31])[CH2:23][O:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1
Reactant: F/C(=C/CCl)COC1CCCCO1
Reactant: C1CSCSC1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: FC(=CCC1SCCCS1)COC1CCCCO1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
To a solution of 1,3-dithiane (1.55 g, 12.9 mmole) in tetrahydrofuran (60 ml) cooled to -30° C. was added dropwise a 1.32M solution of n-butyllithium in hexane (9.77 ml, 12.9 mmoles), the mixture was stirred at -30° C. for 30 min. Then the mixture was cooled to -40° C. and the chloride prepared in 1C (2.69 g, 12.9 mmoles) in tetrahydrofuran (10 ml) was added dropwise. The reaction was stirred 30 min at -40° C. and 2 hrs at 0° C. The reaction was quenched with saturated aqueous ammonium chloride and the tetrahydrofuran was evaporated under reduced pressure. The residue was diluted with ether and washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. Flash chromatography on silicagel and elution with a 8:2 mixture of hexane and ethyl acetate afforded the title dithialane as an oil (3.34 g, 90%). NMR (H1, CDCl3, 60 MHz) characetristic peaks: 4.00 (t, JHH =7 Hz, 1), 4.21 (d, JHF =20 Hz, 2), 4.7 (broad peak, 1), 5.40 (dt, JHF =20 Hz, JHH =8 Hz, 1).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:19])[N:9]([CH3:18])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]#[N:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.[NH2:21][OH:22].C[O-].[Na+].O>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:19])[N:9]([CH3:18])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](=[N:21][OH:22])[NH2:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: CN1Cc2c(C#N)ncn2-c2cccc(Cl)c2C1=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1Cc2c(C(N)=NO)ncn2-c2cccc(Cl)c2C1=O
Temperature: 1 °C

Procedure:
16.8 g 7-Chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carbonitrile were suspended under stirring and argon atmosphere in 101 ml N,N-dimethylformamide and 13.48 g hydroxylamine hydrochloride were added in one portion. 34.2 ml Sodium methanolate were then added over 60 minutes to the yellow suspension, which turned to a colorless suspension. It was stirred one more hour at r.t., then cooled to 0-2° C. and 202 ml deionized water were added over 30 minutes. After stirring one more hour at 0° C., the precipitate (7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamidoxime (VIII)) was filtered off, washed twice with 40 ml deionized water and dried under vacuum at 70° C. for 18 hours. Crude product: 17.84 g as a white powder. m.p. >250° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]#[CH:14])[C:5](Cl)=[O:6].[CH3:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[NH2:22].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[NH:22][C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([O:11][CH2:12][C:13]#[CH:14])=[C:2]([F:1])[CH:3]=1
Reactant: CC1CCCCC1N
Reactant: C#CCOc1ccc(C(=O)Cl)cc1F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C#CCOc1ccc(C(=O)NC2CCCCC2C)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.1 %

Procedure:
To a mixture of 5 ml of ethyl acetate and 0.30 g of 3-fluoro-4-(2-propynyloxy)benzoyl chloride were added 0.19 g of 2-methylcyclohexylamine and 0.20 g of triethylamine in order at room temperature. The mixture obtained was stirred at room temperature for 1 hour. Then, ethyl acetate was added to the reaction mixture and the mixture was filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was washed in order with methyl tert-butyl ether and hexane to obtain 0.38 g of N-(2-methylcyclohexyl)-3-fluoro-4-(2-propynyloxy)benzamide (hereinafter, described as the compound 34 of the present invention) represented by the formula:
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Cl.[NH2:9][OH:10]>CO.[Pt]>[CH2:1]([N:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[OH:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC=O
Reactant: NO
Agent: [Pt]
Agent: Cl
Solvent: CO
Product: CCCCCCN(O)CCCCCC
Yield: 83.4 %

Procedure:
A solution of hexanal (5.0 g, 50 mmol) and hydroxylamine hydrochloride (3.8 g, 55 mmol) in 60 ml of methanol is shaken under hydrogen at 40-45 psi (2.8-3.15 Kg/cm2) for two hours at room temperature in the presence of a catalytic amount of 5% platinum on carbon (400 mg). The reaction mixture is then treated following the procedure given in Example 1 to give 4.2 g of crude N,N-di-n-hexylhydroxylamine product as a white solid. The product is identified by 90 MHz 1H NMR and is seen to be contaminated with no more than 5% of hexanal oxime.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH:7]1[NH2:19])=[O:5])[CH3:2].Cl.[CH3:21][C:22]1[CH:31]=[C:30]([CH2:32][O:33][C:34]2[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH:7]1[NH:19][S:40]([C:37]1[CH:38]=[CH:39][C:34]([O:33][CH2:32][C:30]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[C:22]([CH3:21])[CH:31]=2)=[CH:35][CH:36]=1)(=[O:41])=[O:42])=[O:5])[CH3:2]
Reactant: Cc1cc(COc2ccc(S(=O)(=O)Cl)cc2)c2ccccc2n1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1NS(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Temperature: 25 °C
Yield: 25.8 %

Procedure:
To a mixture of 2.89 g (10.62 mmol) of 3-amino-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester [WO 01/70673, Example 134] and 4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonyl chloride hydrochloride (4.0 g, 11.8 mmol) in CH2Cl2 (40 mL) at 0° C. was added saturated aqueous NaHCO3 (40 mL). The solution was allowed to warm to 25° C. over 19 h. The reaction was then diluted with CH2Cl2 (100 mL) and water (30 mL), the organic layer was washed with water (2×50 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by Biotage Flash 40M chromatography, eluting with 1:2 ethyl acetate-hexanes, to afford 3-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester as a white solid (1.6 g, 25.8%). MS: 584 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13]Br)=[CH:6][C:5]=1[NH:15][C:16](=[O:31])[C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=1.[C:33]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:38]=[CH:37][C:36]([CH:39]=[N:40][OH:41])=[CH:35][CH:34]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:41]/[N:40]=[CH:39]/[C:36]2[CH:37]=[CH:38][C:33]([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)=[CH:34][CH:35]=2)=[CH:6][C:5]=1[NH:15][C:16](=[O:31])[C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=1
Reactant: ON=Cc1ccc(-c2ccccc2)cc1
Reactant: COC(=O)c1ccc(OCCCBr)cc1NC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCCCO/N=C/c2ccc(-c3ccccc3)cc2)cc1NC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 68.2 %

Procedure:
This compound was produced using similar methods as those used in Step 5, example 27, starting with 2-(3,5-bis-trifluoromethyl-benzoylamino)-4-(3-bromo-propoxy)-benzoic acid methyl ester (0.35 g, 0.66 mmol), biphenyl-4-carbaldehyde oxime (0.14 g, 0.70 mmol) and cesium carbonate (0.86 g, 2.65 mmol) in acetone (25 mL). The crude material was purified by flash chromatography through silica gel using diethyl ether/hexanes (0/100 gradient to 10/90) to give 4-[3-({[(1E)-1,1′-biphenyl-4-ylmethylidene]amino}oxy)propoxy]-2-{[3,5-bis(trifluoromethyl)benzoyl]amino}benzoic acid methyl ester (0.29 g, 68%) as a white solid. 1H NMR (500 MHz, DMSO-d6); δ 11.79 (s, 1H), 8.52 (s, 2H), 8.43 (s, 1H), 8.31 (s, 1H), 8.11 (d, 1H), 7.98 (d, 1H), 7.97-7.64 (AA′BB′, 4H), 7.45 (t, 2H), 7.37 (t, 1H), 6.89 (dd, 1H), 4.31 (t, 2H), 4.23 (t, 2H), 3.84 (s, 3H), 2.18 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:15][NH:16][O:17][CH3:18]>>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH3:10])[C:11]([N:16]([O:17][CH3:18])[CH3:15])=[O:13])([CH3:2])([CH3:3])[CH3:4]
Reactant: CNOC
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Product: CON(C)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Yield: 52.5 %

Procedure:
With 2.00 g of N-(tert-butoxy carbonyl)-L-alanine and 1.55 g of N,O-dimethyl hydroxylamine hydrochloride as starting materials, 1.29 g of the title compound (colorless solid) was obtained by a similar procedure to Step 10-1.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][S:13][C:3]=12.[NH2:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([CH2:21][C:22]#[N:23])[C@H:17]([O:24][CH3:25])[CH2:16]1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[CH3:25][O:24][C@@H:17]1[CH2:16][C@@H:15]([NH:14][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]3[CH:11]=[CH:12][S:13][C:3]=23)[CH2:20][CH2:19][C@@H:18]1[CH2:21][C:22]#[N:23]
Reactant: CO[C@@H]1C[C@@H](N)CC[C@@H]1CC#N
Reactant: O=[N+]([O-])c1cnc2ccsc2c1Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CO[C@@H]1C[C@@H](Nc2c([N+](=O)[O-])cnc3ccsc23)CC[C@@H]1CC#N
Temperature: 90 °C
Yield: 78.7 %

Procedure:
A mixture of 7-chloro-6-nitrothieno[3,2-b]pyridine (381 mg, 1.78 mmol), [(1R,2R,4S)-4-amino-2-methoxycyclohexyl]acetonitrile (racemic) (310 mg, 1.8 mmol) and N,N-diisopropylethylamine (1.2 mL, 7.1 mmol) in isopropyl alcohol (4.2 mL) was heated at 90° C. for 2 h. The crude was concentrated and purified with flash chromatography to give the desired product (485 mg, 78%). LCMS calculated for C15H19N4O3S (M+H)+: m/z=347.1. Found: 347.0.
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]=2)[N:4]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:3]1=[O:25].CCN(C(C)C)C(C)C.[C:35]1([S:41](Cl)(=[O:43])=[O:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CC#N>[CH2:18]([N:4]1[C:5]2[C:10](=[N:9][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:7][CH:6]=2)[CH2:11][CH:2]([NH:1][S:41]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)(=[O:43])=[O:42])[C:3]1=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NC1Cc2nc(-c3ccccc3)ccc2N(Cc2ccccc2)C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C1C(NS(=O)(=O)c2ccccc2)Cc2nc(-c3ccccc3)ccc2N1Cc1ccccc1
Reaction time: 0.08 h
Yield: 69.5 %

Procedure:
To a solution of 2B (63 mg, 0.19 mmol) in CH3CN (2 mL) at RT was added DIPEA (50 μL, 0.285 mmol), followed by benzenesulfonyl chloride (27 μL, 0.21 mmol). After 5 min, white precipitates formed. The reaction was stirred for additional 15 min. The product was collected by filtration and the solid washed with CH3CN (2-3 mL) to give the title compound as a white solid (62 mg, 70%). LC/MS (method A): RT=3.58 min, (M+H)+=470. 1H NMR (CDCl3, 400 MHz): δ 8.41 (d, J=7.4 Hz, 1H), 8.04 (d, J=7.3 Hz, 2H), 7.96 (d, J=7.3 Hz, 2H), 7.82 (d, J=8.6 Hz, 1H), 7.62-7.70 (m, 3H), 7.50 (t, J=7.3 Hz, 2H), 7.44-7.47 (m, 2H), 7.25-7.44 (m, 5H), 5.16 (s, 2H), 4.4-4.55 (m, 1H), 3.25-3.31 (m, 2H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:20]1[CH:24]=[C:23](/[CH:25]=[CH:26]/[C:27]([O:29][CH3:30])=[O:28])[CH:22]=[N:21]1.[CH3:31][N:32]1[CH2:37][CH2:36][CH:35]([CH2:38]O)[CH2:34][CH2:33]1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O1CCCC1>[CH3:31][N:32]1[CH2:37][CH2:36][CH:35]([CH2:38][N:20]2[CH:24]=[C:23](/[CH:25]=[CH:26]/[C:27]([O:29][CH3:30])=[O:28])[CH:22]=[N:21]2)[CH2:34][CH2:33]1
Reactant: COC(=O)/C=C/c1cn[nH]c1
Reactant: CN1CCC(CO)CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1cnn(CC2CCN(C)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
Triphenylphosphine (393 mg, 1.5 mmol) and (E)-methyl 3-(1H-pyrazol-4-yl)acrylate, prepared as described above, (12 mg, 1 mmol) were added to a solution of N-methyl-4-hydroxymethyl-piperidine (165 mg, 1.25 mmol) in tetrahydrofuran (THF, 2 mL). After addition of di-tert-butyl azodicarboxylate (345 mg, 1.5 mmol), the reaction was stirred overnight at room temperature. Solvents were evaporated under reduced pressure and the residue was purified by silica gel chromatography using a gradient of Hexane in EtOAc from 1:1 to 0:100 v/v. Fractions containing product were pooled and evaporated to give 220 mg of pure material (0.84 mmol, 84%).
Reaction SMILES: [CH3:1][S:2][C:3]1[O:7][C:6]2[C:8](=[O:17])[C:9]3[C:14]([C:15](=[O:16])[C:5]=2[CH:4]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3.I(O)(=O)(=O)=[O:19].O>C(#N)C>[CH3:1][S:2]([C:3]1[O:7][C:6]2[C:8](=[O:17])[C:9]3[C:14]([C:15](=[O:16])[C:5]=2[CH:4]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[O:19]
Reactant: CSc1cc2c(o1)C(=O)c1ccccc1C2=O
Reactant: [O-][I+3]([O-])([O-])O
Solvent: O
Solvent: CC#N
Product: CS(=O)c1cc2c(o1)C(=O)c1ccccc1C2=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.6 %

Procedure:
To a solution of 0.5 gram (2.05 mmoles) of 2-methylthio-naphtho[2,3-b]furan-4,9-dione in 20 mL of acetonitrile at room temperature, 0.49 grams (2.15 mmoles) of periodic acid followed by 2 mg of ferric chloride was added. The mixture was stirred for 10 minutes at room temperature, then 50 mL of water was added, and the resulting mixture was evaporated to remove acetonitrile. The remaining aqueous suspension was filtered, and the obtained solid was washed with water and dried under vacuum. The crude solid product was purified with silica gel chromatograph using dichloromethane/ethyl acetate (9:1) as elution solvent. 0.43 grams of product (yield 80%) was obtained and characterized by 1H NMR and mass spectrum. 1H NMR (in DMSO) δ 3.14 (s, 3H), 7.81 (s, 1H), 7.92-7.94 (m, 2H), 8.12-8.17 (m, 2H). Mass (M+H) is 261.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([O:17][CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1.[CH3:19][C:20]1[S:21][C:22]2[CH:28]=[CH:27][C:26](O)=[CH:25][C:23]=2[N:24]=1>>[CH3:18][O:17][C@@H:13]([CH2:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][O:1][C:26]2[CH:27]=[CH:28][C:22]3[S:21][C:20]([CH3:19])=[N:24][C:23]=3[CH:25]=2)=[CH:7][CH:8]=1)[C:14]([OH:16])=[O:15]
Reactant: CO[C@@H](Cc1ccc(OCCCO)cc1)C(=O)O
Reactant: Cc1nc2cc(O)ccc2s1
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc3sc(C)nc3c2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-Hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid linked to Wang's Resin (Example 94, Step D) via Mitsunobu coupling with 2-methyl-5-benzothiazolol and cleavage from the resin (Standard Procedure G) to give an oily solid. 1H-NMR (200.15 MHz, CDCl3): 7.65 (d, 1 H, J=8.9), 7.36–7.35 (m, 1 H), 7.16 (d, 2 H, J=8.9), 7.03 (dd, 1 H, J=8.9, 2.4), 6.86 (dd, 2 H, J=6.5, 1.9), 4.22 (t, 2 H, J=35.9), 4.18 (t, 2 H, J=6.2), 4.01 (dd, 2 H, J=6.4, 5.4), 3.43 (s, 3 H), 3.14–2.94 (m, 2 H), 2.87 (s, 3 H), 2.27 (qn, 2 H, J=6.2) ppm.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9](/[CH:13]=[CH:14]/[CH3:15])=[CH:10][CH:11]=2)[N:6]([CH3:16])[C:5]1=[O:17].[N+](=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N-]>C1(C)C=CC=CC=1>[CH3:18][C:2]([CH3:1])([CH3:19])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([CH:13]3[CH:14]([CH3:15])[CH:22]3[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:10][CH:11]=2)[N:6]([CH3:16])[C:5]1=[O:17]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C/C=C/c1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)C1C(C)C1c1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Temperature: 100 °C

Procedure:
1-(2,2-Dimethylpropyl)-3-methyl-5-[(1E)-prop-1-en-1-yl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (33-1, 600 mg, 2.3 mmol, 1.0 equiv) was added to anhydrous toluene (4.8 mL). Ethyl diazoacetate (720 μL, 6.9 mmol, 3.0 equiv) was added and the resulting solution was heated to 100° C. for 18 h. Following this duration, LCMS showed complete consumption of 33-1. The reaction mixture was diluted with ethyl acetate (50 mL) and saturated NaHCO3 (25 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3×10 mL). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to give an orange oil. Purification by normal-phase HPLC (0-40% EtOAc:hexanes) provided 33-2 as a white solid. MS m/z (M+H): calculated=346.2127; observed=346.2134.