Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3].[CH3:23][O:24][CH2:25][CH2:26][N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1.C([O-])([O-])=O.[K+].[K+].C(=O)=O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1.CCO>[CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:30]3[CH:29]=[N:28][N:27]([CH2:26][CH2:25][O:24][CH3:23])[CH:31]=3)[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3]
Reactant: COCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: O=C=O
Solvent: CCO
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: COCCn1cc(-c2ccc3c(c2)[C@H](NC(=O)OC(C)C)C[C@H](C)N3C(C)=O)cn1
Temperature: 80 °C
Reaction time: 18 h
Yield: 37 %

Procedure:
A flask was charged with 1-methylethyl[(2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Example 4) (0.185 g, 0.500 mmol), 1-[2-(methyloxy)ethyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (for a preparation see Intermediate 117) (151 mg, 0.600 mmol), K2CO3 (90 mg, 0.650 mmol) and tetrakis(triphenylphosphine)palladium(0) (28.9 mg, 0.025 mmol) then filled with EtOH (1 mL) and toluene (1 mL) and the resulting mixture was stirred at 80° C. for 18 h then cooled to room temperature and concentrated in vacuo. The residue was partitioned between AcOEt (10 mL) and water (10 mL) and the layers were separated. The aqueous layer was extracted with AcOEt and the combined organic phases were washed with brine (25 mL), dried over Na2SO4 and concentrated in vacuo. Purification of the residue using MDAP (modifier: formic acid) gave an oil which was dissolved in 1,4-dioxane, freezed using an acetone bath cooled with solid CO2 and left on a freeze drier for 16 h to give 1-methylethyl((2S,4R)-1-acetyl-2-methyl-6-{1-[2-(methyloxy)ethyl]-1H-pyrazol-4-yl}-1,2,3,4-tetrahydro-4-quinolinyl)carbamate (84.7 mg, 0.204 mmol, 37%) as a white solid. LCMS (method A): Retention time 0.84 min, [M+H]+=415.15
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=O)=[C:10]([CH:14]=[S:15](=[O:17])=[O:16])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[N+:18]([CH3:21])([O-:20])=[O:19].C(O)(=O)C.C([O-])(=O)C.[NH4+]>O>[Cl:1][C:2]1[C:11]([CH:12]=[CH:21][N+:18]([O-:20])=[O:19])=[C:10]([CH:14]=[S:15](=[O:17])=[O:16])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(C=S(=O)=O)c(C=O)c1Cl
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1ccc(C=S(=O)=O)c(C=C[N+](=O)[O-])c1Cl

Procedure:
With the exclusion of atmospheric moisture, 50 g (0.18 mol) of methyl 2-chloro-3-formyl-4-sulfonylmethylbenzoate, 220 g (3.6 mol) of nitromethane, 216 g (3.6 mol) acetic acid and 7 g (91 mmol) of ammonium acetate are stirred at 85° C. The reaction mixture is poured into 2 l of distilled water and extracted with diethyl ether. The organic phase is washed with saturated aqueous sodium bicarbonate solution, dried with sodium sulfate, filtered and freed from the solvent under reduced pressure. The crude product is recrystallized from n-hexane/ethyl acetate. Yield: 13.1 g, m.p. 147-150° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.[C:12](OCC)(=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>[O-]CC.[Na+]>[C:10]([CH:9]([C:6]1[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1)[C:12](=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:11]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CSc1ccc(CC#N)cc1
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C(=O)C(C#N)c1ccc(SC)cc1

Procedure:
By following the procedures outlined in Examples 1 and 3, p-methylthiophenylacetonitrile is reacted with diethyl oxalate in alcoholic sodium ethoxide solution to give ethyl 3-cyano-3-(p-methylthiophenyl)-pyruvate. This compound is similarly reacted with p-methylthiophenylacetonitrile which results in the formation of 2,5-di-(p-methylthiophenyl)-3,4-dioxoadiponitrile. The latter is refluxed with water, acetic acid and sulfuric acid to obtain 4,4'-dimethylthiopulvinic acid which is treated with acetic anhydride to give the corresponding acid lactone.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([NH:13][C:14](=[O:23])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[N:10][C:9]=1[C:24]1[CH:29]=[CH:28][C:27]([O:30]C)=[CH:26][CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>>[CH2:1]([C:8]1[S:12][C:11]([NH:13][C:14](=[O:23])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[N:10][C:9]=1[C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)Nc2nc(-c3ccc(OC)cc3)c(Cc3ccccc3)s2)cc1
Agent: BrB(Br)Br
Product: COc1ccc(C(=O)Nc2nc(-c3ccc(O)cc3)c(Cc3ccccc3)s2)cc1
Yield: 41.3 %

Procedure:
A procedure similar to that in Example 7 was used. N-[5-benzyl-4-(4-methoxy-phenyl)-thiazol-2-yl]-4-methyoxy-benzamide prepared in Example 27 and boron tribromide were used as starting materials. The obtained crude product was recrystallized with acetone to give a product as a white solid in a yield of 41.3%, mp: 124-125 └. 1H-NMR (DMSO-d6, 400 MHz) δ: 3.84 (3H, s, CH3O), 4.21 (2H, s, CH2), 6.84 (2H, t, J=8.68 Hz, ArH), 7.06 (2H, t, J=8.68 Hz, ArH), 7.23˜7.26 (3H, m, ArH), 7.32˜7.36 (2H, m, ArH), 7.47 (2H, t, J=8.68 Hz, ArH), 8.08 (2H, t, J=8.96 Hz, ArH), 12.45 (1H, br, CONH); EI-MS m/e (%): 416.2 (M+, 62), 282.1 (4), 135.1 (100); HREI-MS Calcd. for C24H20N2O3S: 416.1195. found: 416.1194.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11](=[O:24])[C:12]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][O:14][CH2:15][F:16].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:9][O:10][C:11](=[O:24])[C:12]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][Br:1])=[CH:13][O:14][CH2:15][F:16]
Reactant: COC(=O)C(=COCF)c1ccccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(=COCF)c1ccccc1CBr
Temperature: 25 °C

Procedure:
Preparation of ##STR7## 11.75 g of N-bromosuccinimide are added in several small portions, under reflux, to a solution of 14.75 g of 3-fluoromethoxy-2-(o-tolyl)-acrylic acid methyl ester and 0.53 g of dibenzoyl peroxide in 90 ml of carbon tetrachloride and then the mixture is refluxed for a further 0.5 hour. The suspension is cooled to room temperature, filtered and concentrated to dryness by evaporation. Chromatography on silica gel with hexane/ethyl acetate (6:1) yields pure 2-(2-bromomethylphenyl)-3-fluoromethoxy-acrylic acid methyl ester; m.p. 73°-76° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22](O)=[O:23])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].[CH3:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([N:29]1[CH2:30][CH2:31][CH:26]([CH3:25])[CH2:27][CH2:28]1)=[O:23])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6]
Reactant: CC1CCNCC1
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC1CCN(C(=O)c2ccc(C(=O)NCc3nc4cc(Cl)ccc4[nH]3)cc2Cl)CC1

Procedure:
Prepared analogously to Example 1d from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide, 4-methylpiperidine, TBTU, and triethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.90 minutes; C22H22Cl2N4O2 (445.35); mass spectrum: (M+H)+=445.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:8][CH2:9][OH:10])=[CH:5][S:6][CH:7]=1.N1C=CC=CC=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([CH2:8][CH2:9][O:10][S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=2)(=[O:25])=[O:24])=[CH:5][S:6][CH:7]=1
Reactant: COc1cscc1CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cscc1CCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 68.9 %

Procedure:
Into a 500 ml three-necked flask (reaction container) with thermometer and dropping funnel, 7.72 g (48.8 mmol) of 2-(4-methoxythiophene-3-yl)ethane-1-ol represented by the formula (VI-A) shown below, 11.58 g (146 mmol) of pyridine, and 135 ml of methylene chloride were transferred. The reaction container (flask) was cooled in an ice bath, then 50 ml of methylene chloride containing 18.6 g (97.6 mmol) of p-toluene sulfonic chloride was added dropwise over a period of 10 minutes, then the ice bath was removed from the flask. The reaction solution was stirred at room temperature for a period of 1.5 hours. After the reaction was completed, 100 ml of water was added to separate the organic layer from the water layer. The organic layer was washed twice each with 100 ml of water, then washed twice with saturated aqueous sodium hydrogen carbonate and then dried over anhydrous sodium sulfate. Then it was condensed under a reduced pressure, thereby obtaining a crude product. This crude product was purified using silica gel column chromatography to obtain p-toluene sulfonic acid-2-(4-methoxythiophene-3-yl)ethyl ester (10.5 g, 33.6 mmol, yield 68.9%), a thiophene derivative represented by the formula (IV-A) having properties described below. The chemical equation (X-A) is shown below.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:12]([C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][CH2:24][NH:25][C:26](=[O:40])[C:27]3[CH:32]=[CH:31][C:30]([C:33]4[CH:38]=[CH:37][N:36]=[C:35](Cl)[N:34]=4)=[CH:29][CH:28]=3)[CH:21]=2)[NH:16][CH:15]=1)#[N:13]>>[C:12]([C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][CH2:24][NH:25][C:26](=[O:40])[C:27]3[CH:32]=[CH:31][C:30]([C:33]4[CH:38]=[CH:37][N:36]=[C:35]([NH:11][CH2:10][CH2:9][CH2:8][CH2:7][N:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)[N:34]=4)=[CH:29][CH:28]=3)[CH:21]=2)[NH:16][CH:15]=1)#[N:13]
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Reactant: NCCCCN1CCCCC1
Product: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(NCCCCN5CCCCC5)n4)cc3)cc12

Procedure:
Using 4-piperidin-1-ylbutylamine (reference example 93 g) and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates. MS (ion spray) m/z 522 (M+H)+.
Reaction SMILES: [CH:1]1([CH:6]=[C:7]([C:18]2[NH:30][C:21]3=[N:22][CH:23]=[C:24]([S:26]([CH2:28][CH3:29])=[O:27])[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd].CO>[CH:1]1([CH2:6][CH:7]([C:18]2[NH:30][C:21]3=[N:22][CH:23]=[C:24]([S:26]([CH2:28][CH3:29])=[O:27])[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCS(=O)c1cnc2[nH]c(C(=CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Agent: [Pd]
Solvent: CO
Product: CCS(=O)c1cnc2[nH]c(C(CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Temperature: 50 °C
Yield: 99.9 %

Procedure:
A mixture of 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-ethanesulfinyl-1H-pyrrolo[2,3-b]pyridine (37 mg, 0.084 mmol) and 10% palladium on activated carbon (40 mg) in methanol (50 mL) was heated at 50° C. under hydrogen (45 psi) for 5 h. After cooling to room temperature, the catalyst was removed by filtration and washed with ethyl acetate. The filtrate was concentrated in vacuo to give 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-5-ethanesulfinyl-1H-pyrrolo[2,3-b]pyridine (37.3 mg, 100%) as a white solid: LC/MS m/e calcd for C23H28N2O3S2 [M+H]+ 445.62, observed 445.1.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[N:26]=[N:27][CH:28]=[CH:29][C:30]=1[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=O)C.C[O-].[Na+]>CO>[CH2:31]([C:30]1[CH:29]=[CH:28][N:27]=[N:26][C:25]=1[O:24][C@@H:6]1[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2nnccc2Cc2ccccc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: OC[C@H]1O[C@@H](Oc2nnccc2Cc2ccccc2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyloxy)-4-benzylpyridazine (0.055 g) in methanol (2 mL) was added sodium methoxide (28% solution in methanol, 0.010 mL), and the mixture was stirred for 30 minutes at room temperature. After the reaction mixture was concentrated under reduced pressure, the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=7/1) to give 4-benzyl-3-(β-D-Glucopyranosyloxy)pyridazine (0.032 g).
Reaction SMILES: [C:1]([N:4]([C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1Br)[CH2:5][CH:6]=[CH:7][CH:8]1[CH:12]([CH3:13])[CH2:11][CH2:10][N:9]1[C:14]([OH:16])=[O:15])(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+]>[N+](CCCC)(CCCC)(CCCC)CCCC.[Cl-].CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:12]([O:16][C:14]([N:9]1[CH2:10][CH2:11][CH:12]([CH3:13])[CH:8]1[CH2:7][C:6]1[C:18]2[C:17](=[CH:22][C:21]([F:23])=[CH:20][CH:19]=2)[N:4]([C:1](=[O:3])[CH3:2])[CH:5]=1)=[O:15])([CH3:13])([CH3:8])[CH3:11]
Reactant: CC(=O)N(CC=CC1C(C)CCN1C(=O)O)c1cc(F)ccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: CC(=O)n1cc(CC2C(C)CCN2C(=O)OC(C)(C)C)c2ccc(F)cc21
Reaction time: 3 h
Yield: 106.8 %

Procedure:
A solution containing 64 (5 g, 0.011 mol), n-Bu4NCl (3.3 g, 0.012 mol), K2CO3 (1.65 g, 0.012 mol), and NaHCO2 (0.81 g, 0.012 mol) in DMF (20 mL) was degassed under high vacuum. Palladium acetate (0.49 g, 0.002 mol) was added and the heterogeneous reaction mixture was immersed in a preheated (80-85° C.) oil bath. After 3 h, TLC analysis revealed complete consumption of 64 [1:1 hexane/EtOAc, Rf(64)=0.4, Rf(65)=0.5]. The reaction mixture was cooled in an ice bath and diethyl ether (100 mL) was added. The mixture was filtered through Celite® and the solids were washed with diethyl ether. The filtrate was washed with water, brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by normal phase HPLC (10-100% EtOAc/hexane over 50 min) to afford 2.2 g (54%) of 65 as brown, viscous oil. 1H NMR (CDCl3, 300 MHz) δ8.22-8.1 (m, 1H), 7.7-7.5 (m, 1H), 7.15-6.97 (m, 2H), 3.8-2.65 (m, 4H), 2.6 (s, 3H), 2.12-1.85 (m, 1H), 1.62 (s, 1H), 1.42 (s, 9H, major rotamer), 1.4 (s, minor rotamer), 0.9 (d, J=6 Hz, 3H) ppm. Mass spectrum, m/z=274.5 (M-BOC)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][N:6]1[C:15]2[C:10](=[C:11]([F:20])[CH:12]=[CH:13][C:14]=2[O:16][CH2:17][CH2:18][CH3:19])[C:9](=[O:21])[C:8]([C:22]2[CH:27]=[CH:26][C:25]([O:28]C)=[CH:24][CH:23]=2)=[CH:7]1)[CH3:2].ClCCl.B(Br)(Br)Br.O>ClCCl>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][N:6]1[C:15]2[C:10](=[C:11]([F:20])[CH:12]=[CH:13][C:14]=2[O:16][CH2:17][CH2:18][CH3:19])[C:9](=[O:21])[C:8]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)=[CH:7]1)[CH3:2]
Reactant: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(CC(=O)OCC)c12
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CCCOc1ccc(F)c2c(=O)c(-c3ccc(O)cc3)cn(CC(=O)OCC)c12
Reaction time: 2 h
Yield: 70.4 %

Procedure:
Ethyl[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]acetate (4.0 g, 9.6 mmol) was dissolved in dichloromethane (20 ml). A 1M-boron tribromide dichloromethane solution (35 ml, 35 mmol) was added dropwise to the dissolution at −10° C. After stirring at the same temperature for 2 hours, water was added to the reaction mixture, followed by extraction with dichloromethane. The thus-obtained organic layer was concentrated under reduced pressure. The residue was purified using silica gel column chromatography (dichloromethane:methanol=50:1→15:1). The purified product was concentrated to dryness under reduced pressure, giving a yellow powder of ethyl[5-fluoro-3-(4-hydroxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]acetate (2.7 g, yield: 57%).
Reaction SMILES: C(N(CC)CC)C.ClS(NC(=O)OC)(=O)=O.[NH2:17][C:18](=O)[C@@H:19]([NH:28][C:29]([C@@H:31]1[CH2:36][CH2:35][CH2:34][CH2:33][N:32]1[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:30])[CH2:20][C:21]1[CH:22]=[N:23][C:24]([Br:27])=[CH:25][CH:26]=1>C(Cl)Cl>[Br:27][C:24]1[N:23]=[CH:22][C:21]([CH2:20][C@H:19]([NH:28][C:29]([C@@H:31]2[CH2:36][CH2:35][CH2:34][CH2:33][N:32]2[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:30])[C:18]#[N:17])=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)N[C@@H](Cc1ccc(Br)nc1)C(N)=O
Agent: COC(=O)NS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)N[C@H](C#N)Cc1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.8 %

Procedure:
Triethylamine (3.46 mL) in DCM (5 mL) was stirred under nitrogen and to the solution was added a solution of methyl chlorosulfonylcarbamate (1.658 g) in DCM (5 mL). The mixture was stirred at room temperature for 15 min then a solution of (S)-tert-butyl 2-((S)-1-amino-3-(6-bromopyridin-3-yl)-1-oxopropan-2-ylcarbamoyl)piperidine-1-carboxylate (1.74 g) in DCM (5 mL) was added. Stirring was continued overnight. The reaction mixture was washed with water then brine, dried over magnesium sulfate, filtered and concentrated in vacuo. Crude product was purified by flash silica chromatography eluting with 40% ethyl acetate in isohexane to give the title compound (1.2 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][C:6](C=O)=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=1.ClC1C=C(C=CC=1)C(OO)=[O:21].FC(F)(F)C(O)=O.[OH-].[Na+].Cl>ClCCl.CO>[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][C:6]([OH:21])=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=1
Reactant: COc1cc(C=O)c([N+](=O)[O-])cc1OC
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COc1cc(O)c([N+](=O)[O-])cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.7 %

Procedure:
To a solution of 4,5-dimethoxy-2-nitro-benzaldehyde (3.75 g, 14.2 mmol) in dichloromethane (75 mL) at 0° C. under a nitrogen atmosphere was added meta-chloroperoxybenzoic acid (75% purity, 4.90 g, 28.4 mmol), then, trifluoroacetic acid (1.05 mL, 14.2 mmol). The reaction was stirred at room temperature for 18 h, then recooled to 0° C. Excess reagent was quenched with 5% sodium bisulfite solution and the precipitate was removed by filtration, washing with dichloromethane. The organic phase of the filtrate was washed with sodium bicarbonate and brine, was dried (sodium sulfate), and was evaporated to provide a yellow solid. This intermediate was suspended in methanol (50 mL), treated with 2N NaOH (16 mL, 32 mmol), and was stirred at room temperature for 1 h. The reaction was acidified with 1N HCl and was filtered, washing with methanol to provide 4,5-dimethoxy-2-nitro-phenol (2.00 g, 71% yield) as a bright yellow solid. 1H-NMR (CDCl3, 500 MHz) 11.0 (s, 1H), 7.39 (s, 1H), 6.48 (s, 1H), 3.90 (s, 3H), 3.83 (s, 3H) ppm; MS (FIA) 197.9 (M−H); HPLC (Method A) 3.357 min.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[N:15]1([C:21]2[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.S([O-])(O)=O.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C.O>[CH3:14][O:13][C:7]1[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:6][C:25]([C:24]1[CH:23]=[CH:22][C:21]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:28][CH:27]=1)=[N:1]2
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: O=Cc1ccc(N2CCOCC2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCOCC4)cc3)nc2c1
Temperature: 155 °C
Reaction time: 14 h
Yield: 38.8 %

Procedure:
A mixture of 2-amino-4,6-dimethoxybenzamide (0.15 g, 0.765 mmol), 4-morpholin-4-yl-benzaldehyde (0.15 g, 0.765 mmol), sodium hydrogensulfite (0.136 g, 0.765 mmol) and p-toluenesulfonic acid (10 mg) in N,N-dimethyl acetamide (10 mL) was stirred at 155° C. for 14 h. The reaction mixture was cooled to room temperature and diluted with water (50 mL). The solid was collected by filtration, washed with water and MeOH to yield 5,7-dimethoxy-2-(4-morpholinophenyl)quinazolin-4(3H)-one (0.109 g, 39%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([NH:12][C:13](=[O:22])[C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[CH3:23].C([OH:26])C>C(O)(=O)C.Cl>[Cl:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[C:13]([NH:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[NH:5][CH:4]=[C:3]([CH3:23])[C:2]2=[O:26])=[O:22]
Reactant: Cc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1Cl
Reactant: CCO
Agent: Cl
Solvent: CC(=O)O
Product: Cc1c[nH]c2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1=O
Temperature: 25 °C

Procedure:
A solution of 4-chloro-8-(2,6-dichlorobenzoylamino)-3-methylquinoline (500 mg) in acetic acid (16 ml) and 6N hydrochloric acid (20 ml) was heated at 130° C. for 5 days. The mixture was concentrated in vacuo and the precipitate was collected and washed with water. The residue was purified by a silica gel column chromatography (methanol:methylene chloride=1:20, V/V) to give a yellow crystal. The solid was treated with hot ethanol (5 ml), allowed to cool to ambient temperature, filtered and washed with water to give 8-(2,6-dichlorobenzoylamino)-1,4-dihydro-3-methyl-4-oxoquinoline (280 mg) as yellow crystal.
Reaction SMILES: [CH2:1]([OH:23])[C@H:2]1[O:7][C@H:6]([O:8][C@H:9]2[C@H:14]([OH:15])[C@@H:13]([OH:16])[C@H:12]([OH:17])[O:11][C@@H:10]2[CH2:18][OH:19])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22].[H][H]>[Ni]>[CH2:1]([OH:23])[C@H:2]1[O:7][C@H:6]([O:8][C@@H:9]([C@H:14]([OH:15])[C@@H:13]([OH:16])[CH2:12][OH:17])[C@H:10]([OH:11])[CH2:18][OH:19])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22]
Reactant: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: [H][H]
Agent: [Ni]
Product: OC[C@@H](O)[C@@H](O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O)[C@H](O)[C@@H](O)CO

Procedure:
A 50% aqueous solution of the highly-purified maltose was placed in an autoclave, and added with Raney nickel catalyst in an amount of 10%. Thereafter, the content was heated to 90°-125° C., and hydrogenation was effected at the temperature and a hydrogen pressure of 20-100 kg/cm2. After completion of the hydrogenation, the Raney nickel catalyst was removed, and the residual aqueous solution was purified by decolorization with activated carbon, and deionization with the ion exchangers according to conventional methods, obtaining a highly-purified maltitol solution with a purity of 98.5%.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].[CH3:11][S:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.[H-].[Na+].C(O)(=O)C>CN(C)C=O>[CH3:11][S:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:2]2[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=2)[C:5]([OH:7])=[O:6])=[CH:15][CH:14]=1
Reactant: CSc1ccc(N)cc1
Reactant: O=C(O)c1ccnc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CSc1ccc(Nc2cc(C(=O)O)ccn2)cc1
Temperature: 85 °C
Reaction time: 5 h

Procedure:
To a solution of 2-fluoroisonicotinic acid (620 mg, 4.95 mmol) and 4-(methylthio)aniline (0.984 mL, 8.42 mmol) in N,N-dimethylformamide (20 mL) was added sodium hydride (792 mg, 19.8 mmol), and the resulting mixture was stirred under an argon atmosphere at 85° C. for 5 hr. After cooling, acetic acid (1.2 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Ethyl acetate and water were added to the residue, the mixture was stirred for 20 min, and the precipitate was collected by filtration to give crude 2-[[4-(methylthio)phenyl]amino]isonicotinic acid.