Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[F:12][C:13]1[CH:14]=[CH:15][C:16]([O:29][CH3:30])=[C:17]([C:19]([CH3:28])([CH3:27])[CH2:20][C:21]2([CH:24]([F:26])[F:25])[CH2:23][O:22]2)[CH:18]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CS(C)=O.C(OCC)(=O)C>[F:26][CH:24]([F:25])[C:21]([OH:22])([CH2:20][C:19]([C:17]1[CH:18]=[C:13]([F:12])[CH:14]=[CH:15][C:16]=1[O:29][CH3:30])([CH3:28])[CH3:27])[CH2:23][N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2](=[O:1])[CH:3]=[CH:4]1
Reactant: Oc1ccnc2ccccc12
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)F)CO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1ccc(F)cc1C(C)(C)CC(O)(Cn1ccc(=O)c2ccccc21)C(F)F
Temperature: 25 °C
Reaction time: 360 h

Procedure:
To a solution of the 4-hydroxyquinoline and 2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-difluoromethyloxirane in DMSO (1.0 mL) stirred under nitrogen was added NaHMDS (1.2 mL, 1.0M in THF) dropwise. The mixture was stirred at room temperature for 15 days. The mixture was diluted with ethyl acetate, washed with water, dried, filtered, and evaporated in vacuo. Trituration of the residue with diethyl ether gave the product 1-[2-difluoromethyl-4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methylpentyl]-1H-quinolin-4-one as a crystalline solid that was collected by filtration and air dried (77.7 mg, 20%).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=2[N:22]=[C:21]([N:24]2[C:28]4[CH:29]=[CH:30][C:31]([OH:33])=[CH:32][C:27]=4[N:26]=[CH:25]2)[CH:20]=[CH:19]3)[CH2:10][CH2:9]1)(C)(C)C.C([O-])([O-])=O.[Cs+].[Cs+].[Br-].[CH:42]1([CH3:45])[CH2:44][CH2:43]1>CN(C=O)C.C(O)(C(F)(F)F)=O>[CH:42]1([CH2:45][O:33][C:31]2[CH:30]=[CH:29][C:28]3[N:24]([C:21]4[CH:20]=[CH:19][C:18]5[C:23](=[C:14]([N:11]6[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]6)[CH:15]=[CH:16][CH:17]=5)[N:22]=4)[CH:25]=[N:26][C:27]=3[CH:32]=2)[CH2:44][CH2:43]1
Reactant: CC1CC1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cccc3ccc(-n4cnc5cc(O)ccc54)nc23)CC1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Cs+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: NC1CCN(c2cccc3ccc(-n4cnc5cc(OCC6CC6)ccc54)nc23)CC1
Temperature: 65 °C
Reaction time: 4 h
Yield: 65.6 %

Procedure:
{1-[2-(5-Hydroxy-benzoimidazol-1-yl)-quinolin-8-yl]-piperidin-4-yl}-carbamic acid tert-butyl ester 3A (200 mg, 0.435 mMol) was dissolved in 1.5 mL of anhydrous DMF under an atmosphere of dry N2. To this solution was added Cs2CO3 (170 mg, 0.520 mMol) followed by cyclopropyl methane bromide (46 μL, 0.48 mMol). The reaction mixture was subsequently heated to 65° C. and stirred at this temperature for 4 hours. The reaction mixture was then cooled to ambient temperature and partitioned between EtOAc and water. The EtOAc layer was washed 4 more times with water and then with brine. The EtOAc was then dried over Na2SO4, filtered and concentrated under vacuum and the resulting green oil was chromatographed on flash silica gel eluting with MeOH/DCM (2:98) to give the a green oil. The oil was dissolved in 1.5 mL of TFA under an atmosphere of dry N2. The reaction mixture was stirred at ambient temperature for 10 minutes after which time it was concentrated under vacuum and the resulting residue was partitioned between DCM and aqueous 0.1 N NaOH. The DCM layer was then washed with basic brine (pH 10), dried over Na2SO4, filtered and concentrated under vacuum to give 118 mg of the title compound as a yellow solid 32.
Reaction SMILES: C([O:5][C:6](=[O:27])[CH2:7][O:8][CH2:9][C:10]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]2[C:11]=1[N:12]=[C:13]([O:25]C)[C:14]([O:23]C)=[N:15]2)(C)(C)C>Br.C(O)(=O)C.C(OCC)C>[O:23]=[C:14]1[C:13](=[O:25])[NH:12][C:11]2[C:16](=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:10]=2[CH2:9][O:8][CH2:7][C:6]([OH:27])=[O:5])[NH:15]1
Reactant: COc1nc2cc([N+](=O)[O-])cc(COCC(=O)OC(C)(C)C)c2nc1OC
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=C(O)COCc1cc([N+](=O)[O-])cc2[nH]c(=O)c(=O)[nH]c12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
270 mg (0.711 mmol) of 2-(2,3-dimethoxy-7-nitro-quinoxalin-5-ylmethoxy)-acetic acid tert-butyl ester are dissolved in 6 ml of an approximately 16% hydrogen bromide solution in acetic acid and the solution is stirred at room temperature for 20 hours. The reaction mixture is diluted with diethyl ether and the solid is filtered off, washed with diethyl ether and dried. The title compound is obtained in the form of a solid (m.p.>300° C.).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:25])=[C:5]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8](O)=[O:9].[NH:26]1[CH:30]=[CH:29][N:28]=[C:27]1[CH2:31][C:32]1[CH:37]=[CH:36][C:35](/[CH:38]=[CH:39]/[CH2:40][OH:41])=[CH:34][CH:33]=1.C1(N=C=NC2CCCCC2)CCCCC1>C1(C)C=CC=CC=1>[CH3:25][C:4]1[NH:3][C:2]([CH3:1])=[C:7]([C:8]([O:41][CH2:40]/[CH:39]=[CH:38]/[C:35]2[CH:36]=[CH:37][C:32]([CH2:31][C:27]3[NH:26][CH:30]=[CH:29][N:28]=3)=[CH:33][CH:34]=2)=[O:9])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:5]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Reactant: OC/C=C/c1ccc(Cc2ncc[nH]2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC/C=C/c2ccc(Cc3ncc[nH]3)cc2)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
346 mg (1 mM) of 1,4-dihydro-2,6-dimethyl-5-ethoxycarbonyl-4-(3-nitrophenyl)pyridine-3-caboxylic acid together with 215 mg (1 mM) of (E)-3-{4-(1-imidazolylmethyl)phenyl}-2-propen-1-ol, 248 mg (1.2 mM) of dicyclohexylcarbodiimide and 134 mg (1.1 mM) of 4-N,N-dimethylaminopyridine were dissolved in 5 ml of toluene, while heating, and refluxed for six hours. The solution was cooled to room temperature, and the crystals produced were filtered off. The filtrate was washed with water and dried over anhydrous sodium sulfate. After the solvent was distilled away, the residue was purified by chromatography on a silica gel column, whereby the captioned compound was obtained. The yield was 474 mg (87.4%).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC1C=C(C)C=C(C)C=1[O-].[K+].[C:19](=[O:21])=[O:20]>>[OH:7][C:1]1[CH:6]=[CH:5][C:4]([C:19]([OH:21])=[O:20])=[CH:3][CH:2]=1
Reactant: O=C=O
Reactant: Oc1ccccc1
Agent: Cc1cc(C)c([O-])c(C)c1
Agent: [K+]
Product: O=C(O)c1ccc(O)cc1
Yield: 73.1 %

Procedure:
A pressure vessel was charged with 4.70 g of phenol, 17.42 g of potassium 2,4,6-trimethylphenolate being in a dry powder form and 38 ml of NeoSK 1400. With stirring, reaction was carried out at a carbon dioxide pressure of 5 kg/cm2 (G) and at 260° C. for 10 min. An analysis of the reaction mixture after conversion to acid form showed a para-hydroxybenzoic acid yield of 73.1% on the basis of phenol.
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@:11]3([O:25][CH2:26][O:27][CH2:28][CH3:29])[CH:12]=[CH:13][C:14]2=[O:24])[CH2:6]1)(=O)C.[OH-].[Na+]>CO.O>[OH:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@:11]3([O:25][CH2:26][O:27][CH2:28][CH3:29])[CH:12]=[CH:13][C:14]2=[O:24])[CH2:6]1
Reactant: CCOCO[C@]12C=CC(=O)[C@@]1(C)CC[C@H]1[C@H]2CC=C2C[C@@H](OC(C)=O)CC[C@@]21C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCOCO[C@]12C=CC(=O)[C@@]1(C)CC[C@H]1[C@H]2CC=C2C[C@@H](O)CC[C@@]21C
Yield: 91.2 %

Procedure:
A solution of 6.00 g of 3β-acetoxy-14β-ethoxymethoxyandrosta-5.15-dien-17-one and 30 ml of 2N aq. sodium hydroxide in 120 ml of methanol was kept at room temperature for 24 hrs. The mixture was then diluted with water and extracted with dichloromethane. The organic phase was dried over sodium sulfate and evaporated to dryness to give 4.90 g of the title compound (II-a) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:10]3[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12][N:11]3[CH:23]=2)[CH:5]=[CH:6][CH:7]=1.ClS([N:33]=[C:34]=O)(=O)=O.CN(C)C=O.[OH-].[Na+]>ClCCl>[C:34]([C:23]1[N:11]2[CH2:12][CH2:13][N:14]([C:16]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17])[CH2:15][C:10]2=[C:9]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:8]=1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)#[N:33]
Reactant: CCOC(=O)c1c(-c2cccc(F)c2)cn2c1CN(C(=O)OC(C)(C)C)CC2
Reactant: O=C=NS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(-c2cccc(F)c2)c(C#N)n2c1CN(C(=O)OC(C)(C)C)CC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 46.2 %

Procedure:
To a solution, under argon and cooled to 10° C., of 2.52 g (6.49 mmol) of 2-tert-butyl 8-ethyl 7-(3-fluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxylate in 20 ml of dichloromethane is added dropwise 0.62 ml (7.14 mmol) of chlorosulfonyl isocyanate (CAS 1189-71-5) and the mixture is left stirring at 0° C. for 1 hour. 3.3 ml (65 mmol) of dimethylformamide are then added dropwise to the mixture, cooled to −10° C. After stirring for 5 hours at room temperature, the mixture is poured into 60 ml of aqueous 1N sodium hydroxide solution and the product is extracted with dichloromethane. The solution is dried over sodium sulfate and the solvent is evaporated off under reduced pressure, to give a yellow oil, which is chromatographed on a column of g of silica gel, eluting with a mixture of 20% ethyl acetate in cyclohexane, to give 1.24 g of 2-tert-butyl 8-ethyl 6-cyano-7-(3-fluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxylate in the form of a white powder after crystallizing from diisopropyl ether, filtering off and drying.
Reaction SMILES: [N+:1]([CH2:4][C:5]1([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH:10]2[CH:6]1[CH:7]=[CH:8][CH2:9]2)([O-])=O.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:1][CH2:4][C:5]1([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH:10]2[CH:6]1[CH:7]=[CH:8][CH2:9]2
Reactant: CC(C)(C)OC(=O)CC1(C[N+](=O)[O-])CC2CC=CC21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)CC1(CN)CC2CC=CC21
Reaction time: 4.5 h

Procedure:
Tert-butyl [6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-ylacetate] (1.98 g, 7.41 mmol) was dissolved in ethanol (20 mL) and water (10 mL). To the solution, iron powder (2.07 g, 37.0 mmol) and ammonium chloride (392.7 mg, 7.41 mmol) were added, and the mixture was stirred for 4.5 hours under heating to reflux. The mixture was allowed to cool, then diluted with saturated saline, a saturated aqueous solution of sodium bicarbonate, and ethyl acetate, and filtered through Celite to remove insoluble matter. The filtrate was separated into organic and aqueous layers. The organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure to obtain the compound of interest as a pale yellow solid (1.99 g, this compound was used directly in the next reaction without being purified).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH:25]2[CH2:27][CH2:26]2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[C:29](Cl)(=[O:31])[CH3:30]>>[CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][C:14]=2[CH2:23][N:24]([C:29](=[O:31])[CH3:30])[CH:25]2[CH2:26][CH2:27]2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNC2CC2)c1
Reactant: CC(=O)Cl
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(C(C)=O)C2CC2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-cyclopropylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and acetyl chloride.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:8]([O:10][CH3:11])=[O:9])[C:4]([O:6][CH3:7])=[O:5].ClCCl.[Br:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>O>[CH3:7][O:6][C:4](=[O:5])[CH:3]([NH:2][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][C:16]([Br:15])=[CH:17][CH:18]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: COC(=O)C(N)C(=O)OC
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: COC(=O)C(NC(=O)c1ccc(Br)cc1)C(=O)OC
Reaction time: 8 h

Procedure:
To a stirred solution of dimethyl aminomalonate hydrochloride (1.83 g, 10 mmol) in dichloromethane (30 mL) triethylamine (3 mL, 22 mmol) will be added at 0° C. 4-bromobenzoyl chloride (2.19 g, 10 mmol) will be slowly added the resulting solution will be allowed to stand at room temperature overnight. Water will be added and the organic layer will be separated and dried over anhydrous MgSO4. The evaporation of solvent will result in Int P.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[C:5]([S:10][CH3:11])=[N:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CCOC(C)=O>[CH3:15][O:14][C:12]([C:3]1[N:4]=[C:5]([S:10][CH3:11])[N:6]([CH3:9])[C:7](=[O:8])[C:2]=1[O:1][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:13]
Reactant: COC(=O)c1nc(SC)n(C)c(=O)c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(SC)n(C)c(=O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 84 h
Yield: 18.7 %

Procedure:
In a round-bottomed flask, methyl 5-hydroxy-1-methyl-2-(methylthio)-6-oxo-1,6-dihydropyrimidine-4-carboxylate (55.0 g, 239 mmol) and potassium carbonate (33.0 g, 239 mmol) were combined with DMF (200 ml) to give a black suspension. Benzyl bromide (40.9 g, 239 mmol) was added and the resulting mixture was stirred at room temperature for 3.5 days. The reaction was quenched by the addition of cold water. The mixture was filtered to provide a brown solid. Chromatography (SiO2; 10% to 50% EtOAc in hexanes) provided the desired product as an off-white solid (14.3 g; 18%). LCMS: m/z=321 (MH+).
Reaction SMILES: [CH3:1][SH:2].[H-].[Na+].[C:5]([C:7]1([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15](F)[CH:14]=2)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)#[N:6].O>CN(C=O)C>[C:5]([C:7]1([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([S:2][CH3:1])[CH:14]=2)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)#[N:6]
Reactant: CS
Reactant: N#CC1(c2cc(F)cc(F)c2)CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1cc(F)cc(C2(C#N)CCOCC2)c1
Temperature: 100 °C

Procedure:
Methanethiol was bubbled into a stirred suspension of sodium hydride (65% w/w dispersion in mineral oil, 273 mg, 7.4 mmol) in DMF (10 ml) until a clear solution was obtained. 4-Cyano-4-(3,5-difluorophenyl)-3,4,5,6-tetrahydro-2H-pyran (1.65 g, 7.4 mmol) was added and the resulting mixture was heated at 100° C. for 22 h, cooled and poured into water (100 ml). The mixture was extracted with Et2O (100 ml) and extract washed with water (100 ml), brine (100 ml) and dried (MgSO4). Removal of solvent gave 1.87 g (quant.) of the titled compound as a tan oil.
Reaction SMILES: ClCCCS(N[CH2:9][C:10]1([CH2:15][S:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:14][CH2:13][CH2:12][O:11]1)(=O)=O.C(SCC(OC)CN[S:54]([CH2:57][CH2:58][CH2:59][I:60])(=[O:56])=[O:55])CCCCCCCCCCCCCCC>>[CH2:17]([S:16][CH2:15][C:10]1([CH2:9][S:54]([CH2:57][CH2:58][CH2:59][I:60])(=[O:56])=[O:55])[CH2:14][CH2:13][CH2:12][O:11]1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)OC
Reactant: CCCCCCCCCCCCCCCCSCC1(CNS(=O)(=O)CCCCl)CCCO1
Product: CCCCCCCCCCCCCCCCSCC1(CS(=O)(=O)CCCI)CCCO1

Procedure:
2-(3-Chloropropylsulfonylaminomethyl)-2-hexadecylthiomethyltetrahydrofuran IIIb1 is allowed to react and worked by the same procedure as described in (5). m.p. 36° to 37° C. The summary of the experimental condition and the physical data of the prodcut are listed in the Table 8.
Reaction SMILES: [OH-].[Na+].[NH2:3][C@H:4]([C:8]([OH:10])=[O:9])[CH:5]([CH3:7])[CH3:6].C([O-])([O-])=O.[Na+].[Na+].Cl[C:18]([O:20][CH3:21])=[O:19]>O.C(O)C>[CH3:21][O:20][C:18]([NH:3][C@@H:4]([CH:5]([CH3:7])[CH3:6])[C:8]([OH:10])=[O:9])=[O:19]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COC(=O)N[C@H](C(=O)O)C(C)C
Temperature: 0 °C
Reaction time: 15 h
Yield: 65.1 %

Procedure:
1N NaOH in water (1250 mL) was added into to L-Valine (150 g, 1280 mmol) in a 3 L round bottom flask equipped with a magnetic stir bar. To this solution was added Na2CO3 (67.8 g, 640 mmol) and the reaction mixture was cooled to 0° C. in an ice-water bath. Methyl chloroformate (107 mL, 1390 mmol) was added dropwise and the reaction mixture was allowed to warm to room temperature. The reaction mixture was stirred for 15 hours. The reaction mixture was washed with ethyl acetate (3×400 mL). The aqueous layer was cooled over an ice-water bath and acidified by concentrated HCl (aq) to pH=2. The reaction mixture was extracted with CH2Cl2 (3×1000 mL). The combined organic layers were dried over Na2SO4 and the solvent was concentrated to afford the crude product. The crude product was heated at reflux with 150 mL ethanol and 150 mL water for 2 hours. Then the mixture was cooled to room temperature and the crystalline solids were filtered to give (S)-2-(methoxycarbonylamino)-3-methyl-butanoic acid (146 g, 65% yield).
Reaction SMILES: CS([O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[CH:16][C:15]([CH2:18][CH2:19][CH3:20])=[CH:14][N:13]=2)[CH2:8][CH2:7]1)(=O)=O.[Cl:21][C:22]1[C:23](O)=[CH:24][C:25](=[O:28])[NH:26][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[Cl:21][C:22]1[C:23]([O:5][CH:6]2[CH2:11][CH2:10][N:9]([C:12]3[N:17]=[CH:16][C:15]([CH2:18][CH2:19][CH3:20])=[CH:14][N:13]=3)[CH2:8][CH2:7]2)=[CH:24][C:25](=[O:28])[NH:26][CH:27]=1
Reactant: O=c1cc(O)c(Cl)c[nH]1
Reactant: CCCc1cnc(N2CCC(OS(C)(=O)=O)CC2)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1cnc(N2CCC(Oc3cc(=O)[nH]cc3Cl)CC2)nc1
Temperature: 120 °C

Procedure:
A mixture of 1-(5-propylpyrimidin-2-yl)piperidin-4-yl methanesulfonate (800 mg, 2.67 mmol), 5-chloro-4-hydroxypyridin-2(1H)-one (389 mg, 2.67 mmol, AK Scientific) and cesium carbonate (2612 mg, 8.02 mmol) in DMF (20 mL) was heated at 120° C. for 6 h. The reaction was cooled to rt, diluted with EtOAc (30 mL), and washed with H2O (3×). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give a yellow solid. The residue was purified by flash chromatography (SiO2, 0-10% MeOH/CH2Cl2) to give the desired product as a yellow solid. MS (ESI) 379 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([OH:26])=O)[CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([O:31][C:32](=[O:41])[NH:33][C@H:34]([CH2:39][OH:40])[CH2:35][CH2:36][CH2:37][NH2:38])([CH3:30])([CH3:29])[CH3:28].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C@H:12]([C:24]([NH:38][CH2:37][CH2:36][CH2:35][C@H:34]([NH:33][C:32]([O:31][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:41])[CH2:39][OH:40])=[O:26])[CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CCCN
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)NCCC[C@@H](CO)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under argon, 0.155 g (0.42 mmol) of N2-[(benzyloxy)carbonyl]-N5-(tert-butoxycarbonyl)-L-ornithine and 0.12 g (0.55 mmol) of tert-butyl[(1S)-4-amino-1-(hydroxymethyl)butyl]carbamate (Example 247A) are dissolved in 6 ml of dimethylformamide. Then, at 0° C. (ice bath), 0.105 g (0.55 mmol) of EDC and 0.017 g (0.13 mmol) of HOBt are added. The mixture is slowly warmed to RT and stirred at RT for 12 h. The solution is concentrated in vacuo and the residue is taken up with ethyl acetate. The organic phase is washed successively with saturated sodium bicarbonate and sodium chloride solutions, dried over magnesium sulfate and evaporated in vacuo. The remaining solid is purified by preparative HPLC (Kromasil, mobile phase acetonitrile/0.25% aqueous trifluoroacetic acid 5:95→95:5).
Reaction SMILES: [CH:1](=O)[CH2:2][CH:3]([CH3:5])[CH3:4].[NH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.O>C1(C)C=CC=CC=1>[N:7]1([CH:1]=[CH:2][CH:3]([CH3:5])[CH3:4])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: C1CCNC1
Reactant: CC(C)CC=O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)C=CN1CCCC1
Temperature: 0 °C

Procedure:
194 g (2.25 mol) of isovaleraldehyde are diluted in 1115 ml of toluene and cooled to 0° C. with stirring. 190.3 g (2.68 mol) of pyrrolidine, dissolved in 185.8 ml of toluene, were then added dropwise to this solution, such that the reaction temperature did not rise above 5° C. After the addition had ended, the reaction solution was stirred at 5° C. for another 1 hour. Subsequently, the mixture was warmed to room temperature and the water formed was removed completely by extraction with toluene. Thereafter, the solvent was removed by evaporation and the crude product (329.1 g; 95% of theory) was stored at 4° C. in a refrigerator.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:13]=[C:12]([NH:14][C:15](=[O:24])[C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])[C:6]2[O:7][C:8]([CH3:11])=[C:9]([CH3:10])[C:5]=2[CH:4]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].O>C(O)(=O)C>[C:25]([NH:2][C:3]1[CH:13]=[C:12]([NH:14][C:15](=[O:24])[C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])[C:6]2[O:7][C:8]([CH3:11])=[C:9]([CH3:10])[C:5]=2[CH:4]=1)(=[O:27])[CH3:26]
Reactant: Cc1oc2c(NC(=O)c3c(Cl)cccc3Cl)cc(N)cc2c1C
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1cc(NC(=O)c2c(Cl)cccc2Cl)c2oc(C)c(C)c2c1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 82.4 %

Procedure:
A mixture of 5-amino-7-(2,6-dichlorobenzoylamino)-2,3-dimethylbenzo[b]furan hydrochloride (116 mg) and acetic anhydride (74 mg) in acetic acid (1 ml) was stirred at 80° C. for 1.5 hours. The reaction mixture was cooled and to the mixture was added water. The separated solid was collected, washed with water and dried to give 5-acetylamino-7-(2,6-dichlorobenzoylamino)-2,3-dimethylbenzo[b]furan (97 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=[CH2:14])[CH2:9][C:10]([Cl:13])([Cl:12])[Cl:11])[CH:5]=[C:4]([O:15][CH3:16])[N:3]=1.BrC1C=C(C(=C)CC(Cl)(Cl)Cl)C=C([O:31]C)N=1.ClC1C=CC=C(C(OO)=O)C=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2([CH2:9][C:10]([Cl:13])([Cl:12])[Cl:11])[CH2:14][O:31]2)[CH:5]=[C:4]([O:15][CH3:16])[N:3]=1
Reactant: C=C(CC(Cl)(Cl)Cl)c1cc(Br)nc(OC)c1
Reactant: C=C(CC(Cl)(Cl)Cl)c1cc(Cl)nc(OC)c1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: COc1cc(C2(CC(Cl)(Cl)Cl)CO2)cc(Cl)n1

Procedure:
To a solution of 11.8 g of 2-chloro-6-methoxy-4-(3,3,3-trichloro-1-methylenepropyl)pyridine containing the 2-bromo-6-methoxy-4-(3,3,3-trichloro-1-methylenepropyl)pyridine byproduct in 300 ml of chloroform was added 10.3 g of 85% m-chloro-perbenzoic acid. The solution was heated at reflux for 32 hours, cooled, and washed with 2N sodium hydroxide, water, and dried (Na2SO4). The solvent was removed in vacuo, leaving 12.5 g of crude product which was purified by high pressure liquid chromatography using 5% ethyl acetate in hexane as eluent. 5.4 g of pure product containing 16% of the bromo derivative was obtained. Analysis of the mixture was confirmed by gas-liquid chromatography, nuclear magnetic resonance spectroscopy, mass spectroscopy, and elemental analysis. Elemental analysis for the mixture: