Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][O:18][CH3:19])=[C:10]([C:13]#[N:14])[CH:11]=2)[N:6]=[CH:5][CH:4]=1.[F:20][C:21]1[CH:27]=[C:26]([CH3:28])[C:25]([OH:29])=[CH:24][C:22]=1[NH2:23]>C(O)(C)C>[ClH:2].[C:13]([C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][C:9]=1[O:15][CH2:16][CH2:17][O:18][CH3:19])[N:6]=[CH:5][CH:4]=[C:3]2[NH:23][C:22]1[CH:24]=[C:25]([OH:29])[C:26]([CH3:28])=[CH:27][C:21]=1[F:20])#[N:14]
Reactant: COCCOc1cc2nccc(Cl)c2cc1C#N
Reactant: Cc1cc(F)c(N)cc1O
Agent: Cl
Solvent: CC(C)O
Product: COCCOc1cc2nccc(Nc3cc(O)c(C)cc3F)c2cc1C#N
Yield: 67.6 %

Procedure:
4-Chloro-6-cyano-7-(2-methoxyethoxy)quinoline hydrochloride (300 mg, 1 mmol) and 2-fluoro-5-hydroxy-4-methylaniline (141 mg, 1 mmol) in isopropanol (10 ml) was heated at reflux for 2 hours. The mixture was allowed to cool, the precipitated product collected by filtration, washed with acetone and dried to give 6-cyano-4-(2-fluoro-5-hydroxy-4-methylanilino)-7-(2-methoxyethoxy)quinoline hydrochloride (273 mg, 68%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]#[N:12])[CH:5]=1.CCN(CC)CC.[O:21](S(C(F)(F)F)(=O)=O)[S:22]([C:25]([F:28])([F:27])[F:26])(=O)=[O:23].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][S:22]([C:25]([F:28])([F:27])[F:26])(=[O:23])=[O:21])=[C:6]([C:11]#[N:12])[CH:5]=1
Reactant: COC(=O)c1ccc(O)c(C#N)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C#N)c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
3-cyano-4-hydroxybenzoic acid methyl ester from example 51, step 1 (2 g, 11.3 mmol) was dissolved in CH2Cl2 (57 ml) and cooled to 0° C. in an ice bath. The mixture was treated with Et3N (3 ml, 22.6 mol) followed by the addition of Tf2O (1.9 ml, 11.3 mmol). The reaction mixture was warmed to room temp. and stirred for 4 hours. Saturated NaHCO3 (10 mL) was added and the mixture was extracted with EtOAc (2×10 mL). The organic layers were combined and dried (MgSO4), filtered, and concentrated. The residue was then purified by flash chromatography (15% EtOAc/Hexane) to yield the desired product.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH:14]([CH3:16])[CH3:15])[CH:13]=1)[N:10]=[CH:9][NH:8][C:7]2=[O:17])[CH3:3].[CH3:18][O:19][C:20](=[O:24])/[CH:21]=[CH:22]\Cl.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:18][O:19][C:20](=[O:24])/[CH:21]=[CH:22]/[N:8]1[C:7](=[O:17])[C:6]2[C:11](=[C:12]([CH:14]([CH3:16])[CH3:15])[CH:13]=[C:4]([CH:2]([CH3:1])[CH3:3])[CH:5]=2)[N:10]=[CH:9]1
Reactant: COC(=O)/C=C\Cl
Reactant: CC(C)c1cc(C(C)C)c2nc[nH]c(=O)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)/C=C/n1cnc2c(C(C)C)cc(C(C)C)cc2c1=O
Yield: 74 %

Procedure:
A mixture of 3.10 g (0.013)mol) of 6,8-bis-(1-methylethyl)-quinazolin-4(3H)-one, 1.78 g (0.0148 mol) of (Z)-3-chloro-2-propenoic acid methyl ester and 3.72 g (0.027 mol) of anhydrous potassium carbonate in 100 ml. of anhydrous acetone was stirred at reflux for 17 hr. The reaction mixture was filtered, the solid was washed with acetone and the filtrate was concentrated in vacuo to an oil which soon crystallized. Recrystallization from methanol gave 3.11 g, m.p. 102°-103°, (74% yield) of (E)-3-[6,8-bis-(1-methylethyl)-4-oxo-4H-quinazolin-3-yl]-2-propenoic acid methyl ester.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=2[F:27])=[C:4]([C:9]([N:11]2[CH2:14][C:13]([CH:16]([OH:18])[CH3:17])([OH:15])[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].[CH:28]([C:31]1[CH:36]=[C:35]([CH:37]([CH3:39])[CH3:38])[CH:34]=[C:33]([CH:40]([CH3:42])[CH3:41])[C:32]=1[S:43](Cl)(=[O:45])=[O:44])([CH3:30])[CH3:29].C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[CH3:30][CH:28]([C:31]1[CH:36]=[C:35]([CH:37]([CH3:38])[CH3:39])[CH:34]=[C:33]([CH:40]([CH3:42])[CH3:41])[C:32]=1[S:43]([O:18][CH:16]([C:13]1([OH:15])[CH2:14][N:11]([C:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[C:3]=2[NH:19][C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=2[F:27])=[O:10])[CH2:12]1)[CH3:17])(=[O:44])=[O:45])[CH3:29]
Reactant: CC(O)C1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)Cl)c(C(C)C)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1cc(C(C)C)c(S(=O)(=O)OC(C)C2(O)CN(C(=O)c3ccc(F)c(F)c3Nc3ccc(I)cc3F)C2)c(C(C)C)c1
Reaction time: 3 h
Yield: 48.8 %

Procedure:
1-({3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(1-hydroxyethyl)azetidin-3-ol (267 mg, 0.543 mmol), was dissolved in dichloromethane (10 mL) and treated with 4-(dimethylamino)pyridine (80 mg, 0.661 mmol) and 2,4,6-triisopropylbenzenesulfonyl chloride (183 mg, 0.604 mmol) at ambient for 15 h. Triethylamine (0.076 mL, 0.545 mmol) was added and the mixture was stirred at ambient for 3 h and then at 35° C. for 4 h and then at ambient for a further 15 h. 2,4,6-Triisopropylbenzenesulfonyl chloride (110 mg, 0.363 mmol) was added and the mixture was stirred at 35° C. for 3 h and then 4-(dimethylamino)pyridine (80 mg, 0.661 mmol) was added and the mixture was stirred at 35° C. for 2 h. 2,4,6-Triisopropylbenzenesulfonyl chloride (303 mg, 1.0 mmol) was added and the mixture was stirred at 35° C. for a further 18 h. The mixture was adsorbed on to silica and purified by column chromatography (silica gel, 30-50% ethyl acetate in hexanes) to give 1-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]ethyl 2,4,6-tris(1-methylethyl)benzenesulfonate (201 mg, 0.265 mmol, 49% yield): MS (EI) for C33H38F3IN2O5S: 759 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11]([OH:13])=O)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.Cl>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:8][C:9]3[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:11](=[O:13])[C:6]=2[CH:7]=1
Reactant: O=C(O)c1ccccc1Nc1ccc(F)cc1
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=c1c2ccccc2[nH]c2ccc(F)cc12
Temperature: 115 °C
Reaction time: 2 h
Yield: 59.9 %

Procedure:
N-(4-Fluorophenyl)anthranilic acid (0.70 gm; 3 mmol) and phosphorous oxychloride (3 ml) were stirred together and heated to 115° C. for 3.5 hours, then allowed to cool. The reaction mixture was placed on ice and small pieces of ice added, a vigorous reaction occurred with the evolution of hydrogen chloride. When the reaction had subsided, water (15 ml) was added and the mixture was boiled for 2 hours. On cooling, a solid precipitated out. This was filtered off and washed with water until the filtrate was colourless. The precipitate was further washed with cold methanol then diethyl ether and dried under vacuum to give 383 mg (59%) of 2-fluoroacridone.
Reaction SMILES: O.[OH-].[Li+].[C:4]([O:8][C:9]([N:11]1[C@@H:15]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[C@H:14]([C:23]([O:25]CC)=[O:24])[O:13][C:12]1([CH3:29])[CH3:28])=[O:10])([CH3:7])([CH3:6])[CH3:5]>O.C(O)C>[C:4]([O:8][C:9]([N:11]1[C@@H:15]([C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)[C@H:14]([C:23]([OH:25])=[O:24])[O:13][C:12]1([CH3:29])[CH3:28])=[O:10])([CH3:7])([CH3:5])[CH3:6]
Reactant: CCOC(=O)[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1c1ccc(C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc([C@H]2[C@H](C(=O)O)OC(C)(C)N2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 86.3 %

Procedure:
A solution of 0.19 g of lithium hydroxide hydrate in 3 cm3 of distilled water is added at a temperature in the region of 25° C. to a solution of 0.54 g of ethyl (4S,5R)-3-tert-butoxycarbonyl-2,2-dimethyl-4-(4-methylphenyl)-5-oxazolidinecarboxylate in 10 cm3 of ethanol. The reaction medium is stirred for 20 minutes at a temperature in the region of 25° C. and then concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40° C. The residue obtained is dissolved in 3.5 cm3 of distilled water and then extracted with 2 times 1 cm3 of diisopropyl ether. The aqueous phase is then acidified to a pH in the region of 1 with 5 cm3 of 1N aqueous hydrochloric acid solution and thereafter extracted with 3 times 4 cm3 of dichloromethane. The organic phases are combined, dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40° C. 0.43 g of (4S,5R)-3-tert-butoxycarbonyl-2,2-dimethyl-4-(4-methylphenyl)-5-oxazolidinecarboxylic acid is thereby obtained in the form of an orange-colored oil.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][C@H:21]1[C:26]2[CH:27]=[CH:28][C:29]([CH2:31]O)=[CH:30][C:25]=2[CH2:24][CH2:23][O:22]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[H-].[Na+].[O:47]1[CH2:51][CH2:50][NH:49][C:48]1=[O:52].S([O-])(=O)(=O)C>C(OCC)C.O.C(OCC)(=O)C>[Si:1]([O:18][CH2:19][CH2:20][C@H:21]1[C:26]2[CH:27]=[CH:28][C:29]([CH2:31][N:49]3[CH2:50][CH2:51][O:47][C:48]3=[O:52])=[CH:30][C:25]=2[CH2:24][CH2:23][O:22]1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NCCO1
Reactant: CC(C)(C)[Si](OCC[C@@H]1OCCc2cc(CO)ccc21)(c1ccccc1)c1ccccc1
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)[Si](OCC[C@@H]1OCCc2cc(CN3CCOC3=O)ccc21)(c1ccccc1)c1ccccc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a stirred solution of [(1S)-1-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-3,4-dihydro-1H-2-benzopyran-6-yl]methanol (0.30 g, 0.67 mmol) in dry diethyl ether (5 mL) and triethylamine (0.11 mL, 0.80 mmol) was added methanesulfonyl chloride (0.057 mL, 0.74 mmol), and the mixture stirred for 2 h under nitrogen. In a separate flask, sodium hydride (60% suspension in oil) (0.107 g, 2.68 mmol) was added to a stirred solution of 1,3-oxazolidin-2-one (0.175 g, 2.1 mmol) and the mixture heated at 50° C. for 2 h. To this solution was added the filtered solution of the mesylate and the mixture heated at 50° C. with stirring for a further 1.5 h, then stirred at room temperature overnight. Ethyl acetate and water were added to the reaction, the organic layer washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The crude product was purified by flash chromatography on silica, eluting with ethyl acetate/hexane (1:99 to 60:40), to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[CH:12]1([NH2:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C(#N)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:18][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[N:3]=1
Reactant: NC1CCCCC1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Solvent: CC#N
Product: Clc1nc(NC2CCCCC2)c2nc[nH]c2n1
Temperature: 50 °C

Procedure:
2,6-Dichloropurine (2.5 g, 13.23 mmol) and cyclohexylamine (1.51 mL, 13.2 mmol) were dissolved in acetonitrile (25 mL) and heated to 50° C. for 5 days. The white precipitate was collected by filtration and used without further purification.
Reaction SMILES: I[C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1>[Cl:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([O:19][C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)[CH:10]=1
Reactant: Oc1ccc(F)cc1
Reactant: O=C(O)c1ccc(Cl)cc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: O=C(O)c1ccc(Cl)cc1Oc1ccc(F)cc1

Procedure:
Following the procedures outlined in Example 21, 10.7 g. (0.038 mol) of 2-iodo-4-chlorobenzoic acid, 4.3 g. (0.038 mol) of 4-fluorophenol 5.25 g. (0.038 mol) of potassium carbonate and 1.14 g. of cuprous chloride in 180 ml. of pyridine are heated under reflux overnight to give upon workup 4-chloro-2-(4-fluorophenoxy)-benzoic acid, 154°-173° C. Heating the acid (5.0 g., 0.019 mol) for one hour with 75 g. of sulfuric acid yields the corresponding 2-fluoro-6-chloro-9-xanthone, m.p. 210° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=O)[CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])=[CH:18][C:17]=1[CH3:34].Cl.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])=[CH:18][C:17]=1[CH3:34]
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)COc4ccccc4C)cc3C)c2cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(NCCOc4ccccc4C)cc3C)c2cc1OC
Temperature: 0 °C
Yield: 79.9 %

Procedure:
N1-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-methylphenyl}-2-(2-methylphenoxy)acetamide (200 mg) was dissolved in tetrahydrofuran (10 ml) to prepare a solution. A 1 M solution (1.3 ml) of a borane-tetrahydrofuran complex in tetrahydrofuran was then added to the solution, and the mixture was stirred with heating under reflux for 2 hr. The reaction solution was cooled to 0° C. and was adjusted to pH=1 by the addition of 1 N hydrochloric acid, followed by stirring with heating under reflux for 30 min. The reaction solution was cooled to 0° C., was adjusted to pH=12 by the addition of a 1 N aqueous sodium hydroxide solution, and was extracted with chloroform. After the concentration of the extract, the residue was purified on a column using chloroform/methanol to give the title compound (155 mg, yield 80%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:18][CH3:19])=[C:4]([Cl:17])[C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14]Cl)[C:6]=2[CH:16]=1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-].[CH2:28]([CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[CH2:29][CH2:30][CH3:31]>C(Cl)Cl.CO>[CH2:28]([CH:32]1[CH2:37][CH2:36][N:35]([CH2:14][CH2:13][CH2:12][N:7]2[C:6]3[CH:16]=[C:2]([Cl:1])[C:3]([CH2:18][CH3:19])=[C:4]([Cl:17])[C:5]=3[O:10][CH2:9][C:8]2=[O:11])[CH2:34][CH2:33]1)[CH2:29][CH2:30][CH3:31]
Reactant: CCc1c(Cl)cc2c(c1Cl)OCC(=O)N2CCCCl
Reactant: CCCCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: CCCCC1CCN(CCCN2C(=O)COc3c2cc(Cl)c(CC)c3Cl)CC1
Yield: 59 %

Procedure:
6,8-Dichloro-4-(3-chloro-propyl)-7-ethyl-4H-benzo[1,4]oxazin-3-one ((95MF52(2226)) (0.30 g, 0.93 mmol), K2CO3 (0.26 g, 1.86 mmol), NaI (0.28 g, 1.86 mmol) and 4-butylpiperidine (0.14 g, 0.98 mmol) were mixed according to GP13. CC (SiO2; CH2Cl2/MeOH 10:0.2-4) gave the title compound (95MF60) (0.24 g, 59%). 1H NMR (CDCl3) δ 7.10 (s, 1H), 4.65 (s, 2H), 3.93 (t, J=6.8 Hz, 2H), 2.95-2.81 (m, 4H), 2.33 (t, J=6.8 Hz, 2H), 1.90-1.78 (m, 4H), 1.66 (d, J=10.0 Hz, 2H) 1.30-1.13 (m, 12H), 0.88 (s, 3H); 13C NMR (CDCl3) δ 163.5, 140.6, 135.3, 128.2, 127.7, 123.2, 114.3, 67.9, 55.8, 54.4, 40.1, 36.4, 36.0, 32.7, 29.2, 24.8, 24.6, 23.1, 14.2, 12.7; HPLC-MS (ammonium acetate) [M+H]+=427.2.
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5]CCC1.[Br:7][CH:8]([CH:11]=[O:12])[CH:9]=[O:10].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[Br:7][C:8](=[CH:11][O:12][CH:6]([CH3:5])[CH3:1])[CH:9]=[O:10]
Reactant: O=CC(Br)C=O
Reactant: C1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: CC(C)OC=C(Br)C=O
Temperature: 25 °C
Yield: 103 %

Procedure:
With moderate agitation, a 20 gallon reactor system was charged with cyclohexane (29.12 L), 2-bromo-malonaldehyde (2.33 kg), p-toluenesulfonic acid monohydrate 43.94 g, and 2-propanol (4.65 L). The contents of the reactor were heated to allow for the removal of distillate under atmospheric pressure (jacket temp. 95° C. and process temp. at 66.4° C.). A total of 16 L of distillate was removed from the reaction via the cooling tower. This represents approximately 47% of the total volume of cyclohexane/2-propanol (33.77 L) being removed from the reactor. The reaction solution was cooled to near ambient temperature and transferred to a 10 gallon reactor system at 40° C. An additional 6 L of distillate was removed under vacuum (~64 torr, jacket temp. 62° C., and reaction temp. 25° C.). The mobile dark orange oil was drained from the vessel and transferred to a rotary evaporator receiver flask and further concentrated under house vacuum at ~30° C. using a rotary evaporator. About 0.2 L more of solvent was removed. Total product obtained was 3.072 kg (16 mol, 103% yield). The product was used as obtained in the next step. This material is unstable and must be kept in a freezer (<-5° C., under nitrogen). The shelve-life is about 2 weeks.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1F.C([O-])([O-])=O.[K+].[K+].[CH3:18][C:19]1[N:24]=[C:23]([CH2:25][OH:26])[CH:22]=[CH:21][CH:20]=1>CC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:26][CH2:25][C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:18])[N:24]=1
Reactant: Cc1cccc(CO)n1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cccc(COc2ccc([N+](=O)[O-])cc2Cl)n1
Temperature: 65 °C
Reaction time: 8 h
Yield: 68.2 %

Procedure:
To a solution of 2-chloro-1-fluoro-4-nitro-benzene (8.75 g, 50 mmol) in dry acetone (100 ml) was added 10.0 g of K2CO3 and 6.15 g of 6-methyl-2-pyridylmethanol (50 mmol). The reaction mixture was then stirred at 65° C. overnight. Filtration and concentration gave a solid which was recrystallized to give the desired product as a white solid (9.5 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:16])[C:5](/[CH:8]=[N:9]/[S:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])=[N:6][CH:7]=1.[CH3:17][Mg]Cl.O>C(Cl)Cl.[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[C:4]([F:16])[C:5]([C@H:8]([NH:9][S:10]([C:12]([CH3:13])([CH3:15])[CH3:14])=[O:11])[CH3:17])=[N:6][CH:7]=1
Reactant: C[Mg]Cl
Reactant: CC(C)(C)S(=O)/N=C/c1ncc(Br)cc1F
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C[C@@H](NS(=O)C(C)(C)C)c1ncc(Br)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of N-[(1E)-(5-bromo-3-fluoropyridin-2-yl)methylidene]-2-methyl-propane-2-sulfinamide (18.63 g, 60.65 mmol) in CH2Cl2 (375 mL) was cooled to −50° C. under N2. Methylmagnesium chloride (3M in THF, 30.32 mL, 90.97 mmol) was added dropwise, the reaction was stirred for 1 h. Additional methylmagnesium chloride (5.0 mL, 15.0 mmol) was added after 30 minutes to drive the reaction to completion. Water (200 mL) and brine (200 mL) were added, and the reaction allowed to warm to room temperature. The aqueous layer was extracted 4× with CH2Cl2, and the combined organics were dried over Na2SO4, filtered and concentrated under vacuum. The residue was subjected to silica gel chromatography eluted with 10–40% ethyl acetate in hexanes to provide N-[(1R)-1-(5-bromo-3-fluoropyridin-2-yl)ethyl]-2-methylpropane-2-sulfinamide that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 325.0 for M+H+(81Br).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8]([Br:14])=[CH:9][N:10]=[CH:11]2)=[CH:6][CH:5]=1)([O-])=O.O1CCCC1.[Cl-].[NH4+].[OH-].[Na+]>C(O)C.[Fe].O>[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([Br:14])=[CH:9][N:10]=[CH:11]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc2c(Br)cncc2c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: Nc1ccc2c(Br)cncc2c1
Temperature: 50 °C
Yield: 56.9 %

Procedure:
66 mg (0.26 mmol) of 7-nitro-4-bromoisoquinoline was dissolved in 1 ml of ethanol, 2 ml of tetrahydrofuran and 1 ml of water. To the mixture were added 70 mg of an iron powder and 140 mg of ammonium chloride, followed by heating at 50° C. for 3 hours. A 1N aqueous sodium hydroxide was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated. The resulting residue was crystallized from isopropyl ether, to give 33 mg of the title compound.
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=O)=[O:3].[NH2:10][C:11]1[C:20]([Cl:21])=[C:19]([CH2:22][CH3:23])[CH:18]=[C:17]2[C:12]=1[N:13]=[C:14]([O:26][CH3:27])[C:15]([O:24][CH3:25])=[N:16]2.N1C=CC=CC=1.O>O1CCCC1.C(OCC)(=O)C>[Cl:21][C:20]1[C:11]([NH:10][S:2]([CH3:1])(=[O:5])=[O:3])=[C:12]2[C:17](=[CH:18][C:19]=1[CH2:22][CH3:23])[N:16]=[C:15]([O:24][CH3:25])[C:14]([O:26][CH3:27])=[N:13]2
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: CCc1cc2nc(OC)c(OC)nc2c(N)c1Cl
Solvent: O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCc1cc2nc(OC)c(OC)nc2c(NS(C)(=O)=O)c1Cl
Reaction time: 1 h
Yield: 77.4 %

Procedure:
Methanesulphonic anhydride (671 mg, 3.85 mmol) was added to a stirred solution of 5-amino-6-chloro-7-ethyl-2,3-dimethoxyquinoxaline (207 mg, 0.77 mmol) and anhydrous pyridine (305 mg, 3.85 mmol) in anhydrous tetrahydrofuran (7.7 ml) at room temperature. After 72h, water (3 ml) was added and the mixture was stirred for a further 60 minutes. The mixture was diluted with ethyl acetate and washed with 2M hydrochloric acid (50 ml), water (50 ml), saturated aqueous sodium bicarbonate (50 ml) and saturated aqueous sodium chloride (50 ml). The organic phase was dried (MgSO4) and concentrated under reduced pressure to give N-(6-chloro-7-ethyl-2,3-dimethoxyquinoxalin-5-yl)methanesulphonamide (206 mg, 77%).
Reaction SMILES: [BH4-].[Na+].CO.[Cl:5][C:6]1[CH:29]=[C:28]([F:30])[C:27]([NH:31]C(=O)C(F)(F)F)=[CH:26][C:7]=1[O:8][C:9]1[CH:23]=[CH:22][C:12]2[N:13]=[C:14]([NH:16][C:17]([CH:19]3[CH2:21][CH2:20]3)=[O:18])[S:15][C:11]=2[C:10]=1[C:24]#[N:25]>C(O)C>[NH2:31][C:27]1[C:28]([F:30])=[CH:29][C:6]([Cl:5])=[C:7]([CH:26]=1)[O:8][C:9]1[CH:23]=[CH:22][C:12]2[N:13]=[C:14]([NH:16][C:17]([CH:19]3[CH2:21][CH2:20]3)=[O:18])[S:15][C:11]=2[C:10]=1[C:24]#[N:25]
Reactant: N#Cc1c(Oc2cc(NC(=O)C(F)(F)F)c(F)cc2Cl)ccc2nc(NC(=O)C3CC3)sc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: N#Cc1c(Oc2cc(N)c(F)cc2Cl)ccc2nc(NC(=O)C3CC3)sc12
Temperature: 60 °C
Reaction time: 1 h
Yield: 63.8 %

Procedure:
To a solution of sodium borohydride (266 mg, 7.02 mmol) in ethanol (10 mL) was added dropwise methanol (1 mL), and N-(6-{2-chloro-4-fluoro-5-[(trifluoroacetyl)amino]phenoxy}-7-cyano-1,3-benzothiazol-2-yl)cyclopropanecarboxamide (350 mg, 0.70 mmol) was added to the suspension. The reaction mixture was stirred at 60° C. for 1 hr, and concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (100 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (50 ml) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by preparative thin layer chromatography (ethyl acetate/n-hexane=50/50), and the band containing the object product was scraped off, and eluted with 10% tetrahydrofuran/ethyl acetate. The obtained solution was purified by basic silica gel column chromatography (eluate: ethyl acetate). The obtained solution was concentrated under reduced pressure to give the title compound (180 mg, 64%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:11][S:12][C:13]1[N:18]=[C:17]([OH:19])[CH:16]=[C:15]([CH3:20])[N:14]=1.O.NN>CCO.C(Cl)Cl.O.[Ni]>[NH2:8][C:7]1[C:2]([Cl:1])=[C:3]([CH2:11][S:12][C:13]2[N:18]=[C:17]([OH:19])[CH:16]=[C:15]([CH3:20])[N:14]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cc(O)nc(SCc2cccc([N+](=O)[O-])c2Cl)n1
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: Cc1cc(O)nc(SCc2cccc(N)c2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0 %

Procedure:
2-{[(2-chloro-3-nitrophenyl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (150 mg, 481 mmol) was dissolved in 1:1 EtOH/DCM (6 mL). Hydrazine hydrate (224 mL, 7.2 mmol) and catalytic amount of Ni-Raney solution in water were added. The mixture was stirred overnight at room temperature. The solid material was filtered on Celite and washed with methanol and ethyl acetate. The filtrate was evaporated. The residue was dissolved in DCM and purified on silica gel using 10% DCM/MeOH to afford 2-{[(3-amino-2-chlorophenyl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (10 mg, 7% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.21 (s, 3H), 4.39 (s, 2H), 5.41 (s, 2H), 5.98 (bs, 1H), 6.70-6.75 (m, 2H), 6.95 (t, J=7.7 Hz, 1H); LRMS (ES+) m/z 282 (100%, M+1), 284 (35%, M+3).