Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([CH3:27])([CH3:26])[CH2:11][NH:12][S:13]([C:16]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:17]=1[CH:18]=[CH:19][N:20]=[CH:21]2)(=[O:15])=[O:14])=O)(C)(C)C.Cl>CO>[CH:21]1[C:22]2[C:17](=[C:16]([S:13]([NH:12][CH2:11][C:10]([CH3:27])([CH3:26])[CH2:9][NH2:8])(=[O:14])=[O:15])[CH:25]=[CH:24][CH:23]=2)[CH:18]=[CH:19][N:20]=1
Reactant: CC(C)(CNC(=O)OC(C)(C)C)CNS(=O)(=O)c1cccc2cnccc12
Agent: Cl
Solvent: CO
Product: CC(C)(CN)CNS(=O)(=O)c1cccc2cnccc12
Yield: 92.4 %

Procedure:
According to Reference Example 5, Step C, a reaction was performed by using Intermediate 57 (11 g) and 10% hydrogen chloride in methanol (80 ml) to obtain the title compound (7.58 g).
Reaction SMILES: [C:1]([NH:6][C@H:7]([C:29]([OH:31])=O)[CH2:8][S:9][C:10]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].Cl.[C:33]([S:39][CH2:40][CH2:41][NH2:42])(=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>>[C:1]([NH:6][C@H:7]([C:29]([NH:42][CH2:41][CH2:40][S:39][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[O:31])[CH2:8][S:9][C:10]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)SCCN
Reactant: CC(C)C(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Agent: Cl
Product: CC(C)C(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)NCCSC(=O)C(C)(C)C

Procedure:
The coupling reaction of 13 (3.93 mmol) of S-pivaloylcysteamine hydrochloride is carried out according to method B described in the first synthetic route (example 1). After the various treatments, the expected compound is isolated by flash chromatography on a silica gel column (eluent: AcOEt/petroleum ether 70%). 16 is collected in the form of a foam which, after trituration in hexane, provides a colorless powder (Yd=88%). Rf (CH2Cl2/ether, 6/4): 0.82. M.p.=85-88° C. [α]D20=+5.9° (c 1.02, CHCl3).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[C:7]#[N:8].C(N(CC)CC)C.[CH2:24]([O:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>CCOCC>[C:7]([C:6]1[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=1[O:4][C:3]1[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=1[NH:1][C:35](=[O:36])[C:34]1[CH:33]=[CH:32][C:31]([O:30][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:39][CH:38]=1)#[N:8]
Reactant: N#Cc1ccccc1Oc1ccccc1N
Reactant: CCCCCCOc1ccc(C(=O)Cl)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCCCCCOc1ccc(C(=O)Nc2ccccc2Oc2ccccc2C#N)cc1
Yield: 77.3 %

Procedure:
In 20 ml of ether was dissolved 2.0 g of 2-(2-aminophenoxy)benzonitrile followed by addition of 2.04 g of triethylamine. Then, with ice-cooling and stirring, a solution of 2.67 g of 4-hexyloxybenzoyl chloride in 5 ml of ether was added dropwise. The mixture was further stirred at the same temperature for 1 hour. The reaction mixture was then washed with diluted hydrochloric acid and aqueous sodium hydrogen carbonate solution in that order, dried and concentrated. The residue was purified by silica gel column chromatography using ethyl acetate-n-hexane as the eluent and the relevant fraction was crystallized from diisopropyl ether to give 3.05 g of the title compound as white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[CH:4][CH:3]=1.[NH2:12][C:13]1[C:14]([CH2:22][CH2:23][CH3:24])=[N:15][N:16]([CH3:21])[C:17]=1[C:18]([NH2:20])=[O:19].C(N(CC)CC)C>ClCCl>[C:18]([C:17]1[N:16]([CH3:21])[N:15]=[C:14]([CH2:22][CH2:23][CH3:24])[C:13]=1[NH:12][C:9](=[O:10])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:19])[NH2:20]
Reactant: O=C(Cl)Cc1ccc(Br)cc1
Reactant: CCCc1nn(C)c(C(N)=O)c1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1nn(C)c(C(N)=O)c1NC(=O)Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of this 4-bromophenylacetyl chloride in dry dichloromethane (5 ml) was then added dropwise to a solution of 4-amino-1-methyl-3-propyl-1H-5-pyrazolecarboxamide (6 g, 0.033 mol) and triethylamine (7 ml, 0.050 mol) in dichloromethane (250 ml), and the reaction stirred at room temperature for 18 hours.
Reaction SMILES: [CH3:1][N:2]([CH2:14][CH2:15][CH2:16][CH3:17])[C:3](=[O:13])[CH2:4][C:5]([N:7]([CH3:12])[CH2:8][CH2:9][CH2:10][CH3:11])=[O:6].C(=O)=O.C([Li])CCC.[CH2:26](I)[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>O1CCCC1.C(Cl)Cl.O.C(O)C>[CH2:26]([CH:4]([C:3]([N:2]([CH3:1])[CH2:14][CH2:15][CH2:16][CH3:17])=[O:13])[C:5]([N:7]([CH3:12])[CH2:8][CH2:9][CH2:10][CH3:11])=[O:6])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCI
Reactant: CCCCN(C)C(=O)CC(=O)N(C)CCCC
Agent: O=C=O
Agent: [Li]CCCC
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: CCCCCCC(C(=O)N(C)CCCC)C(=O)N(C)CCCC

Procedure:
Preparation of 2-hexyl-N-N'-dimethyl-N,N'-dibutyl-propane diamide of formula: ##STR27## 0.1 mol of N,N'-dimethyl-N,N'-dibutyl-propane diamide dissolved in 400 ml of tetrahydrofuran are introduced into a one liter reactor, scavenged by a nitrogen stream. Cooling takes place to -50° C. using an acetone bath and solid carbon dioxide and pouring takes place of a solution of n-butyl lithium prepared from 0.1 mol of n-butyl lithium in 100 ml of anhydrous tetrahydrofuran. Under the same conditions is poured a solution of hexyl iodide prepared from 0.1 mol of hexyl iodide and 100 ml of anhydrous tetrahydrofuran. When pouring is at an end, the temperature is allowed to rise to ambient temperature again, followed by refluxing the tetrahydrofuran for three hours. Cooling is allowed to take place, followed by hydrolysis with a water-ethanol mixture. The tetrahydrofuran is expelled and in this way a precipitate is formed. This is taken up with methylene chloride, followed by washing with water, drying the organic layer, expelling the solvent and then distillation. The boiling point is 145° to 148° C. under 0.4 mm of mercury and the product is a yellow liquid. Its characterization by nuclear magnetic resonance of the proton and by potentiometric dosage confirms that it corresponds to the above formula.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:25])[C:13](=[O:24])[N:14]([C:15]4[C:16]([CH3:23])=[N:17][N:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.C([N:29](C(=O)C)[C:30]1[C:35]([CH2:36][O:37]C(=O)C)=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][N:31]=1)(=O)C.[Li+].[OH-]>CN(C=O)C.C([O-])([O-])=O.[K+].[K+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:29][C:30]1[N:31]=[CH:32][C:33]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:25])[C:13](=[O:24])[N:14]([C:15]5[C:16]([CH3:23])=[N:17][N:18]([CH:20]([CH3:21])[CH3:22])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)=[CH:34][C:35]=1[CH2:36][OH:37]
Reactant: CC(=O)OCc1cc(B2OC(C)(C)C(C)(C)O2)cnc1N(C(C)=O)C(C)=O
Reactant: Cc1nn(C(C)C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nn(C(C)C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cnc(N)c(CO)c4)cc3c21
Temperature: 105 °C
Reaction time: 1 h

Procedure:
A mixture of 8-bromo-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate G, 0.098 mmol), crude acetic acid 2-diacetylamino-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-ylmethyl ester (stage 169.1.1, 0.92 mg) and PdCl2(PPh3)2 (0.0057 mmol) in DMF (1.2 ml) and 1 M aqueous K2CO3 (0.245 ml) was stirred under argon at 105° C. for 1 h. Then the RM was cooled to it and 2 M aqueous LiOH (0.245 ml) was added. The RM was stirred for 1 h 15 min at rt then quenched with 2 M aqueous HCl (0.245 ml), diluted with MeOH and purified directly by Prep.HPLC. The fractions containing product were collected together, basified with NaHCO3, concentrated and extracted with dichloromethane (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered, evaporated and dried under vacuum to give the title compound as a white solid. (HPLC: tR 2.04 min (Method A); M+H=444 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.91 (s, 1H), 8.20 (s, 1H), 8.06-8.02 (m, 1H), 7.97-7.94 (m, 1H), 7.83-7.78 (m, 1H), 7.57-7.54 (m, 1H), 7.45-7.42 (m, 1H), 5.95 (s, br, 2H), 5.20 (t, 1H), 4.55 (hp, 1H), 4.37 (d, 2H), 3.57 (s, 3H), 1.95 (s, 3H), 1.47 (d, 6H))
Reaction SMILES: C([O-])(O)=O.[Na+].C([O-])([O-])=O.[K+].[K+].[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[C:22](=O)[C:21](=[CH:24]N(C)C)[CH2:20][C:19](=[O:28])[NH:18][C:17]=2[CH:29]=1.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([NH:40][C:41]([NH2:43])=[NH:42])[CH:35]=[CH:36][C:37]=1[O:38][CH3:39]>CCO.CN(C=O)C>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[C:22]3[N:42]=[C:41]([NH:40][C:34]4[CH:35]=[CH:36][C:37]([O:38][CH3:39])=[C:32]([O:31][CH3:30])[CH:33]=4)[N:43]=[CH:24][C:21]=3[CH2:20][C:19](=[O:28])[NH:18][C:17]=2[CH:29]=1
Reactant: COc1ccc(NC(=N)N)cc1OC
Reactant: CN(C)C=C1CC(=O)Nc2cc(Cl)ccc2C1=O
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCO
Product: COc1ccc(Nc2ncc3c(n2)-c2ccc(Cl)cc2NC(=O)C3)cc1OC

Procedure:
In a manner similar to method I (DMF and NaHCO3 were used in place of EtOH and K2CO3), 8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]-azepine-2,5-dione (v-j) and 1-(3,4-dimethoxyphenyl)guanidine were converted to I-2 (87%): HRMS Calcd. for C20H17ClN4O3: 397.1067, Found 397.109.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:8])[NH:4][CH:5]=[CH:6][CH:7]=1.C(O[CH:12]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])C.CCOCC>C(O)(C)C>[O:8]=[C:3]1[C:2]([NH:1][CH:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:7][CH:6]=[CH:5][NH:4]1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccc[nH]c1=O
Solvent: CCOCC
Solvent: CC(C)O
Product: CCOC(=O)C(=CNc1ccc[nH]c1=O)C(=O)OCC
Temperature: 100 °C
Reaction time: 3 h
Yield: 63.3 %

Procedure:
3-Aminopyridin-2(1H)-one (9.00 g, 81.7 mmol) was treated with diethyl ethoxymethylenemalonate (24.6 ml, 123 mmol) and heated to 100° C. After 3 hours, the reaction was cooled down and diluted with isopropyl alcohol. The solid that crashed out was collected by suction filtration and washed well with IPA and then ether to give diethyl 2-((2-oxo-1,2-dihydropyridin-3-ylamino)methylene)malonate (14.5 g, 63.3% yield) as a greenish solid. MS(M+H)+ 281.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:26])[C:9]([C:15]2[CH:16]=[CH:17][C:18]3[O:22][C:21](=[O:23])[N:20]([CH3:24])[C:19]=3[CH:25]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:27])[CH:3]=1.[CH3:28][O:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[C:36]([O:38][CH3:39])=[O:37]>>[CH3:39][O:38][C:36]([C:35]1[CH:34]=[CH:33][C:32]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:26])[C:9]([OH:14])([C:15]3[CH:16]=[CH:17][C:18]4[O:22][C:21](=[O:23])[N:20]([CH3:24])[C:19]=4[CH:25]=3)[C:10]([F:11])([F:13])[F:12])=[C:4]([Cl:27])[CH:3]=2)=[CH:31][C:30]=1[O:29][CH3:28])=[O:37]
Reactant: COC(=O)c1ccc(B(O)O)cc1OC
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc2oc(=O)n(C)c2c1)C(F)(F)F
Product: COC(=O)c1ccc(-c2ccc(C(C)C(O)(c3ccc4oc(=O)n(C)c4c3)C(F)(F)F)c(Cl)c2)cc1OC

Procedure:
The title compound was prepared in analogy to Example 117 from 5-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-3-methyl-3H-benzooxazol-2-one (obtained in Example 116, step 8) by Suzuki coupling with 3-methoxy-4-methoxycarbonylphenylboronic acid [CAS Reg. No. 603122-41-4]. MS (m/e)=550.3 [M+H+].
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>N1C=CC=CC=1>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Reactant: C1CCNC1
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCCC3)c(F)c21
Yield: 66.5 %

Procedure:
A mixture of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (0.43 g), pyrrolidine (1.2 g), and pyridine (3 ml) was refluxed for 6 hours. The solvent was evaporated off. The residue was treated with water, acidified with acetic acid, and extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous sodium sulfate, and evaporated. The solid was recrystallized from a mixture of DMF and ethanol and gave 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-pyrrolidinyl)quinoline-3-carboxylic acid (0.34 g), mp 284°-286° C. (decomp.).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH3:17])=[C:11]([CH2:18][NH:19][CH:20]3[CH2:25][CH2:24][CH:23]([N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH2:21]3)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[Cl:35][C:36]1[C:37]2[CH:47]=[CH:46][CH:45]=[CH:44][C:38]=2[S:39][C:40]=1[C:41](Cl)=[O:42]>>[Cl:35][C:36]1[C:37]2[CH:47]=[CH:46][CH:45]=[CH:44][C:38]=2[S:39][C:40]=1[C:41]([N:19]([CH2:18][C:11]1[CH:10]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH2:16][CH3:17])[CH:20]1[CH2:25][CH2:24][CH:23]([N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:32])[CH3:31])[CH2:22][CH2:21]1)=[O:42]
Reactant: CCOc1ccc(-c2cccc(C#N)c2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Product: CCOc1ccc(-c2cccc(C#N)c2)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 81 (390 mg, 0.84 mmol) is treated with 3-chlorobenzo-[b]thiophene-2-carbonyl chloride (233 mg, 1.01 mmol) using Method D to give the title compound.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]([CH3:15])[CH:7]=1)[CH2:2][CH2:3][CH3:4].CC1C=C(OCCC)C=CC=1N>>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]([CH3:15])[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc([N+](=O)[O-])c(C)c1
Agent: CCCOc1ccc(N)c(C)c1
Product: CCCCOc1ccc(N)c(C)c1
Yield: 89.7 %

Procedure:
This compound was prepared from 404d (1.92 g, 9.2 mmol) in a manner similar to that for 405b yielding an amber oil (1.48 g, 90%): TLC Rf 0.28 (20% EtOAc/hexanes). 1NMR (600 MHz, CDCl3) δ 6.67 (s, 1H), 6.62 (m, 2H), 3.89-3.87 (t, 2H, J=6.54 Hz), 2.16 (s, 3H), 1.73-1.70 (quin, 2H, J=6.6 Hz), 1.49-1.45 (sex, 2H, J=7.5 Hz), 0.97-0.95 (t, 3H, J=7.38 Hz). 13C NMR (150 MHz, CDCl3) δ 152.4, 137.8, 124.2, 117.24, 116.13, 112.9, 68.3, 31.5, 19.3, 17.7, 13.9. Elemental analysis calculated for C11H17NO: C, 73.70; H, 9.56; N, 7.81. Found: C, 73.55; H, 9.51; N, 7.96.
Reaction SMILES: [Cl:1][C:2]([Cl:6])([Cl:5])[C:3]#[N:4].C1CCN2C(=NCCC2)CC1.[CH2:18]([O:25][C@@H:26]1[C@@H:32]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@H:31]([CH3:41])[O:30][C@@H:28]([OH:29])[C@@H:27]1[O:42][C:43](=[O:49])[CH2:44][CH2:45][C:46]([CH3:48])=[O:47])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[Cl:1][C:2]([Cl:6])([Cl:5])[C:3](=[NH:4])[O:29][C@@H:28]1[O:30][C@@H:31]([CH3:41])[C@H:32]([O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C@@H:26]([O:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:27]1[O:42][C:43](=[O:49])[CH2:44][CH2:45][C:46]([CH3:48])=[O:47]
Reactant: CC(=O)CCC(=O)O[C@@H]1[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](C)O[C@H]1O
Reactant: N#CC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)CCC(=O)O[C@H]1[C@H](OC(=N)C(Cl)(Cl)Cl)O[C@@H](C)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reaction time: 2 h
Yield: 74.1 %

Procedure:
Trichloroacetonitrile (1.3 mL, 13 mmol) and DBU (51 μL, 0.3 mmol) were added to a solution of the residue 211 (1.0 g, 2.3 mmol) in anhydrous DCM (6 mL) at 0° C. After 2 h, the mixture was concentrated. The residue was eluted from a column of silica gel with 3:1 cyclohexane-EtOAc and 0.2% Et3N to give 212 as a white foam (1.0 g, 95%); 1H NMR: δ 8.67 (s, 1H, NH), 7.40-7.30 (m, 10H, Ph), 6.19 (d, 1H, J1,2=1.9 Hz, H-1), 5.48 (dd, 1H, J1,2=2.0, J2,3=3.3 Hz, H-2), 4.95 (d, 1H, CH2Ph), 4.73 (d, 1H, CH2Ph), 4.66 (d, 1H, CH2Ph), 4.58 (d, 1H, CH2Ph), 4.51 (d, 1H, CH2Ph), 4.00 (dd, 1H, J3,4=9.5 Hz, H-3), 3.95 (dq, 1H, J4,5=9.6, J5,6=6.3 Hz, H-5), 3.52 (pt, 1H, H-4), 2.80 (m, 4H, Lev), 2.20 (s, 3H, Ac), 1.36 (d, 3H, H-6). Anal. Calcd for C27H30Cl3NO7.0.5H2O: C, 54.42; H, 5.24; N, 2.35. Found: C, 54.06; H, 5.06; 2.05.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[C:4](Cl)[N:3]=1.[NH3:13].C(=O)([O-])[O-].[K+].[K+]>C(O)(C)(C)C>[Cl:1][C:2]1[N:3]=[C:4]([NH2:13])[C:5]([N+:9]([O-:11])=[O:10])=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc([N+](=O)[O-])c(Cl)nc1Cl
Reactant: N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: Cc1cc([N+](=O)[O-])c(N)nc1Cl
Temperature: 60 °C
Reaction time: 8 h
Yield: 45.1 %

Procedure:
A mixture of 2,6-dichloro-3-methyl-5-nitropyridine (10.41 g, 50.3 mmol), 28% aqueous ammonia solution (17 ml, 0.25 mol), potassium carbonate (10.4 g, 75.5 mmol) and t-butanol (167 ml) was stirred overnight at 60° C. under nitrogen atmosphere. After stirring at room temperature for 3 hours, a precipitate was filtered and then washed three times with water, thereby yielding the title compound (4.25 g, 22.7 mmol, 45%) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])[N:6]=[CH:5]2.[CH3:17][O:18][C:19](=[O:25])[CH2:20][CH2:21][S:22]([O-:24])=[O:23].[Na+]>[Cu]I>[CH3:15][CH:14]([S:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([S:22]([CH2:21][CH2:20][C:19]([O:18][CH3:17])=[O:25])(=[O:24])=[O:23])=[CH:10][CH:9]=2)[CH:5]=[N:6]1)(=[O:13])=[O:12])[CH3:16]
Reactant: COC(=O)CCS(=O)[O-]
Reactant: CC(C)S(=O)(=O)n1ncc2cc(Br)ccc21
Agent: [Cu]I
Agent: [Na+]
Product: COC(=O)CCS(=O)(=O)c1ccc2c(cnn2S(=O)(=O)C(C)C)c1
Temperature: 110 °C

Procedure:
5-bromo-1-(propan-2-ylsulfonyl)-1H-indazole (0.85 g, 2.79 mmol), sodium 3-methoxy-3-oxopropane-1-sulfinate (2.42 g, 13.9 mmol) and CuI (2.66 g, 13.9 mmol) were charged in a sealable microwave flask. The flask was closed and degassed twice, after which dry DMSO (3.0 mL) was added and the reaction mixture degassed before being heated at 110° C. in an oil bath overnight. The reaction mixture was cooled and diluted with ethyl acetate (40 mL), and then filtered on a silica gel pad and eluted with ethyl acetate. The organic phases were concentrated under reduced pressure. The crude was purified on silica gel eluting with hexanes and ethyl acetate, then with DCM and methanol to afford the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[O:13])[N:11]([CH:14]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)[CH:20]=3)[CH2:15][C:16]([OH:18])=O)[C:9](=[O:10])[C:8]2=[CH:33][CH:34]=1)(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:48][OH:49]>O1CCCC1>[C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[O:13])[N:11]([CH:14]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH:28]4[CH2:29][CH2:30][CH2:31][CH2:32]4)[CH:20]=3)[CH2:15][C:16]([NH:48][OH:49])=[O:18])[C:9](=[O:10])[C:8]2=[CH:33][CH:34]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(C(CC(=O)O)N2C(=O)c3ccc(NC(C)=O)cc3C2=O)cc1OC1CCCC1
Reactant: NO
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1ccc(C(CC(=O)NO)N2C(=O)c3ccc(NC(C)=O)cc3C2=O)cc1OC1CCCC1
Yield: 59.8 %

Procedure:
3-(4-Acetoamidophthalimido)-3-(3-cyclopentyloxy-4-methoxyphenyl)-N-hydroxypropionamide was prepared by the procedure of Example 1 from 3-(4-acetoamidophthalimido)-3-(3-cyclopentyloxy-4-methoxyphenyl)propanoic acid (1.78 g, 3.82 mmol), carbonyldiimidazole (0.74 g, 4.6 mmol) and hydroxylamine hydrochloride (0.38 g, 5.3 mmol) in tetrahydrofuran (12 mL) to afford 3-(4-acetoamidophthalimido)-3-(3-cyclopentyloxy-4-methoxyphenyl)-N-hydroxypropionamide as a white solid (1.1 g, 60% yield): mp, 177–180° C.; 1H NMR (DMSO-d6) δ 1.87–1.56 (m, 8H, C5H8), 2.12 (s, 3H, CH3), 3.11 (d, J=7.5 Hz, 2H, CH2), 3.70 (s, 3H, CH3), 4.72 (m, 1H, OCH), 5.64 (t, J=7.5 Hz, 1H, NCH), 6.88 (br s, 2H, Ar), 7.01 (br s, 1H, Ar), 7.81 (m, 2H, Ar), 8.17 (br s, 1H, OH), 8.78 (s, 1H, Ar), 10.56 (br s, 1H, NH); 13C NMR (DMSO-d6) δ 21.13, 21.81, 29.79, 31.89, 47.78, 53.15, 77.18, 109.68, 110.16, 111.75, 117.29, 120.85, 121.95, 122.40, 128.89, 131.50, 142.48, 144.33, 163.63, 165.20, 165.50, 166.92; Anal Calcd for C25H27N3O7+1.2 H2O: C, 59.68; H, 5.89; N, 8.35. Found: C, 59.69; H, 8.19; H2O, 6.91.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[CH:7][S:6][C:5]=1[C:9]([OH:11])=[O:10])(=[O:3])[CH3:2].IC.[C:14](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:14][O:10][C:9]([C:5]1[S:6][CH:7]=[CH:8][C:4]=1[C:1](=[O:3])[CH3:2])=[O:11]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1ccsc1C(=O)O
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1sccc1C(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.5 %

Procedure:
3-Acetyl-2-thiophenecarboxylic acid (3.0 g) was dissolved in N,N-dimethylformamide (50 ml), and iodomethane (4.0 ml) and potassium carbonate (6.0 g) were added. The mixture was stirred at room temperature for 3 hours, poured into water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 3-acetyl-2-thiophenecarboxylic acid methyl ester (3.07 g) as crystals.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[CH:5][C:4]([CH3:8])=[N:3]1.C([N:17]=[C:18]=[S:19])(=O)C1C=CC=CC=1>>[CH3:1][N:2]1[C:6]([NH:7][C:18]([NH2:17])=[S:19])=[CH:5][C:4]([CH3:8])=[N:3]1
Reactant: Cc1cc(N)n(C)n1
Reactant: O=C(N=C=S)c1ccccc1
Product: Cc1cc(NC(N)=S)n(C)n1

Procedure:
1,3-Dimethyl-5-amino pyrazole (111.0 g.) and benzoyl iso thiocyanate (180.0 g.) were reacted as described in Example IV to give 110.3 g. of the product, mp 221°-224° C.
Reaction SMILES: Cl[C:2]([O:4][CH:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:3].[NH2:10][C:11]1[CH:12]=[CH:13][C:14]2[O:19][CH2:18][CH2:17][N:16]([CH2:20][C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=3[O:31][CH3:32])[C:15]=2[CH:33]=1.CN1CCOCC1>ClCCl>[CH:5]1([O:4][C:2]([NH:10][C:11]2[CH:12]=[CH:13][C:14]3[O:19][CH2:18][CH2:17][N:16]([CH2:20][C:21]4[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=4[O:31][CH3:32])[C:15]=3[CH:33]=2)=[O:3])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: O=C(Cl)OC1CCCC1
Reactant: COC(=O)c1ccc(CN2CCOc3ccc(N)cc32)c(OC)c1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)c1ccc(CN2CCOc3ccc(NC(=O)OC4CCCC4)cc32)c(OC)c1
Reaction time: 1 h
Yield: 52.2 %

Procedure:
Cyclopentyl chloroformate (0.5 g.) was added in a single portion to a stirred solution of methyl 4-(6-amino-2,3-dihydrobenz-1,4-oxazin-4-ylmethyl)-3-methoxybenzoate (L) (1.0 g.) and N-methylmorpholine (0.314 g.) in dichloromethane (30 ml.), under an atmosphere of nitrogen. After one hour, the mixture was diluted with dichloromethane and washed successively with 1M hydrochloric acid, 5% w/v sodium bicarbonate solution, and saturated brine, then dried (MgSO4) and evaporated. The residue was purified by flash chromatography on silica gel (4 cm. diameter column), eluting with dichloromethane to give the title compound (0.7 g, 52%) as an oil; NMR (80 MHz, CDCl3): 1.69[m,8H, (CH2)4 ], 3.39(t,2H, OCH2CH2N), 3.90(s,3H, OCH3), 3.91 (s,3H, OCH3), 4.23(t,2H, OCH2CH2N), 4.45(s,2H, CH2.Ar), 5.10(m,1H, --CHO--), 6.2(br s,1H, NHCO), 6.59-7.62(m,6H).