Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=3)[N:12]=[C:11]([C:20]3[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=3[OH:27])[N:10]=2)[CH2:4]1.C(N(C(C)C)CC)(C)C.Cl[C:38]([O:40][CH2:41][CH3:42])=[O:39]>C1COCC1>[F:26][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]([OH:27])[C:20]=1[C:11]1[N:10]=[C:9]([N:5]2[CH2:6][CH2:7][CH2:8][C@@H:3]([CH2:2][NH:1][C:38](=[O:39])[O:40][CH2:41][CH3:42])[CH2:4]2)[C:18]2[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=2)[N:12]=1
Reactant: Cc1ccc2c(N3CCC[C@@H](CN)C3)nc(-c3c(O)cccc3F)nc2c1
Reactant: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)NC[C@@H]1CCCN(c2nc(-c3c(O)cccc3F)nc3cc(C)ccc23)C1
Temperature: -60 °C
Yield: 38.9 %

Procedure:
To a stirred solution of 2-(4-((S)-3-(aminomethyl)piperidin-1-yl)-7-methylquinazolin-2-yl)-3-fluorophenol (200 mg, 0.54 mmol) in 12 mL THF was added diisopropyl ethylamine (188 μL, 1.08 mmol) at room temperature. The mixture was cooled to −60° C., and a solution of ethyl chloroformate (52 μL, 0.54 mmol) in 0.6 mL THF was added dropwise. After allowing the reaction to warm to room temperature, the mixture was partitioned between H2O and CH2Cl2. The layers were separated, and the aqueous layer was extracted twice more with CH2Cl2. The organic layers were combined, dried over Na2SO4, filtered, and concentrated. Purification via silica gel chromatography using 0-10% EtOAc in 50:50 hexanes:CH2Cl2 gave ethyl ((S)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate (92 mg, 38%). LC/MS: m/z 439.5 (M+H)+ at 2.40 min (10% -99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:11]([O:13][CH3:14])=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[N:15]1([C:41]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:42])[CH2:40][CH2:39][CH2:38][C@H:16]1[C:17]([NH:19][C@H:20]([C:24]([NH:26][C@H:27]([C:35](O)=[O:36])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:25])[CH:21]([CH3:23])[CH3:22])=[O:18].[OH-].[Na+]>C(O)(=O)CC(CC(O)=O)(C(O)=O)O.O>[N:15]1([C:41]([O:43][CH2:44][C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)=[O:42])[CH2:40][CH2:39][CH2:38][C@H:16]1[C:17]([NH:19][C@H:20]([C:24]([NH:26][C@H:27]([C:35]([NH:2][C@H:3]([C:11]([O:13][CH3:14])=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:36])[CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:25])[CH:21]([CH3:23])[CH3:22])=[O:18]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: CC(C)[C@H](NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)C(C)C
Yield: 37.2 %

Procedure:
A solution of 0.216 g (10 mmol) of HCl.H-Phe-OCH3 (MW 215.5) in 40 ml of citric acid buffer solution (pH = 4.0) was added to a solution of 0.495 g (10 mmol) of Z-Pro-Val-Phe-OH (MW 495) in 10 ml of 1N-NaOH, and 30 ml of water was further added with stirring. A 0.1 g sample of pepsin (1:10000) was added to the mixture with stirring at 40°C for 24 hours to react them. The resulting white precipitate was filtered by a glass filter (G-3) and was sequentially washed with 5% ammonia water, 5% citric acid aqueous solution and water. The product was dried above P2O5 under reduced pressure at 50°C to obtain 0.244 g of Z-Pro-Val-Phe-Phe-OCH3 having a melting point of 199°-201°C and [α]D30 = -33.2 (c = 1, DMF). The yield was 37.2%.
Reaction SMILES: C(N=C=NC(C)C)(C)C.[C:10]([OH:14])([CH3:13])([CH3:12])[CH3:11].ClCCl.C([O:20][C:21]([C:23]1([C:26](O)=[O:27])[CH2:25][CH2:24]1)=[O:22])C>[Cu]Cl.CCCCCC>[C:10]([O:14][C:26]([C:23]1([C:21]([OH:22])=[O:20])[CH2:25][CH2:24]1)=[O:27])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)O
Reactant: CCOC(=O)C1(C(=O)O)CC1
Agent: Cl[Cu]
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)C1(C(=O)O)CC1
Reaction time: 96 h

Procedure:
At room temperature under shielded light, to N,N′-diisopropylcarbodiimide (99.75 g) was added copper(I) chloride (1.57 g), and then tert-butanol (83 ml) was added dropwise over 20 minutes, followed by stirring for 4 days. The supernatant (12.7 ml) was added to a dichloromethane solution (40 ml) of 1-(ethoxycarbonyl)cyclopropanecarboxylic acid (6.37 g), and heated at reflux for 3 hours. Hexane (50 ml) was added to the reaction solution, and the precipitate was filtered off. After the filtrate was concentrated under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the residue, and extracted with dichloromethane. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After hexane was added to the resulting residue, the precipitate was filtered off, and the filtrate was concentrated. The resulting residue was dissolved in tetrahydrofuran (25 ml), and 1 N aqueous sodium hydroxide solution (25 ml) was added, and stirred at room temperature overnight. After the reaction solution was concentrated under reduced pressure, 1 N aqueous sodium hydroxide solution (15 ml) was added to the residue, and washed with dichloromethane. A 10% aqueous citric acid solution was added to the aqueous layer to render it acidic, and extracted with dichloromethane. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford 1-(tert-butoxycarbonyl)cyclopropanecarboxylic acid (1.80 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C@H:15]2[CH2:20][CH2:19][C@@H:18]([OH:21])[CH2:17][CH2:16]2)[C:10]=1[C:11]([F:14])([F:13])[F:12])=[O:5])C.[OH-].[Li+].O>CO>[OH:21][C@@H:18]1[CH2:19][CH2:20][C@H:15]([N:9]2[C:10]([C:11]([F:12])([F:13])[F:14])=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]2)[CH2:16][CH2:17]1
Reactant: CCOC(=O)c1cnn([C@H]2CC[C@@H](O)CC2)c1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cnn([C@H]2CC[C@@H](O)CC2)c1C(F)(F)F
Temperature: 80 °C

Procedure:
cis-1-(4-Hydroxy-cyclohexyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (94.7 mg, 0.309 mmol) was dissolved in methanol (0.5 mL). Lithium hydroxide (10.3 mg, 0.430 mmol) and water (0.5 mL) were added and the mixture was heated at 80° C. for 1 hour. After cooling to room temperature, the methanol was removed in vacuo. Tetrahydrofuran was added and removed in vacuo to insure complete removal of methanol. The residue was diluted with water and acidified with 6N HCl (75 μL; pH 1.5-2). The solid which precipitated out of solution was collected by filtration, washed with water and dried under high vacuum at 50° C. to give cis-1-(4-hydroxy-cyclohexyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (70 mg; 81%). Mass spectrum: m/z: 279.1 (M+H).
Reaction SMILES: S(=O)(=O)(O)O.[NH:6]1[CH2:14][CH2:13][CH2:12][CH:8]([C:9]([NH2:11])=[O:10])[CH2:7]1.[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[Na+]>>[C:15]([N:6]1[CH2:14][CH2:13][CH2:12][C@@H:8]([C:9]([NH2:11])=[O:10])[CH2:7]1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NC(=O)C1CCCNC1
Reactant: O=C(Cl)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: NC(=O)[C@@H]1CCCN(C(=O)c2ccccc2)C1
Temperature: 15 °C
Reaction time: 3 h
Yield: 27.7 %

Procedure:
Concentrated sulfuric acid is added to the reaction mixture obtained in Example 4 (amount: 10 g, net weight of (R)-nipecotamide: 1 g) to adjust the pH to 9. Benzoyl chloride (3.5 g, 2.5 equivalents) was slowly added dropwise, and the pH of the reaction mixture was kept from 7 to 9 by a 30% aqueous sodium hydroxide solution. After completion of the dropwise addition, the solution was stirred at 15° C. for 3 hours to obtain a solution containing the title compound (1.6 g, yield: 88%).
Reaction SMILES: O[C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=1)([CH3:6])[C:3]([OH:5])=[O:4].O>O1CCOCC1.S(=O)(=O)(O)O>[CH2:13]([C:9]1[CH:8]=[C:7]([C:2](=[CH2:6])[C:3]([OH:5])=[O:4])[CH:12]=[CH:11][CH:10]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(O)(C(=O)O)c1cccc(Cc2ccccc2)c1
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: O
Product: C=C(C(=O)O)c1cccc(Cc2ccccc2)c1

Procedure:
136 g (0.531 mol) of 2-hydroxy-2-(3-benzyl-phenyl)-propanoic acid (product from Example 11) are refluxed in a mixture of 3 l of dioxane and 180 ml of concentrated sulphuric acid. Water is added to the mixture which has been concentrated to approximately 500 ml and the mixture is extracted three times with ether. After drying the organic phases using saturated NaCl and magnesium sulphate, a brown oil remains, which is purified by filtration on 1 kg of silica gel (ethyl acetate/cyclohexane 5:1). Yield: 83 g (66%).
Reaction SMILES: [I-].C[S+](C)C.[CH2:6]([Li])CCC.[Cl:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[CH:17][C:18]([CH:22]=[CH:23][C:24]3[CH:25]=[C:26]([CH:30]4[O:34][CH2:33][CH2:32][O:31]4)[CH:27]=[CH:28][CH:29]=3)=[N:19]2)=[CH:14][CH:13]=1>C1COCC1>[Cl:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[CH:17][C:18]([CH:22]3[CH2:6][CH:23]3[C:24]3[CH:25]=[C:26]([CH:30]4[O:34][CH2:33][CH2:32][O:31]4)[CH:27]=[CH:28][CH:29]=3)=[N:19]2)=[CH:14][CH:13]=1
Reactant: [Li]CCCC
Reactant: Clc1ccc2ccc(C=Cc3cccc(C4OCCO4)c3)nc2c1
Agent: C[S+](C)C
Agent: [I-]
Solvent: C1CCOC1
Product: Clc1ccc2ccc(C3CC3c3cccc(C4OCCO4)c3)nc2c1
Temperature: 21 °C
Reaction time: 8 h

Procedure:
To a solution of trimethylsulfonium iodide (2.128 g, 10.4 mmoles) in 20 mL of anhydrous THF at -10° C. was added dropwise a solution of n-butyllithium 1.6M in hexanes (4.9 mL, 0.75 equiv.). Then the temperature was raised to 21° C. for 2 hours. To this mixture cooled to 0° C., the alkene (step 2) (967 mg, 2.86 mmoles) in 5 mL THF was added and the solution stirred overnight. Hydrolysis with 25% aqueous NH4OAc, extraction with EtOAc and flash chromatography on silica using EtOAc:toluene 2.5:97.5 afforded the title compound.
Reaction SMILES: [CH3:1]/[C:2](/[CH2:10]O)=[CH:3]\[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:24]=[N+:25]=[N-:26].[Na+]>C(Cl)Cl>[N:24]([CH2:10][C:2]([CH3:1])=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[N+:25]=[N-:26]
Reactant: C/C(=C\c1ccccc1)CO
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=Cc1ccccc1)CN=[N+]=[N-]
Temperature: 0 °C
Yield: 88.9 %

Procedure:
To a 100 mL round-bottomed flask equipped with a magnetic stir was added trans-2-methyl-3-phenyl-2-propen-1-ol (2.00 g, 13.5 mmol) and 75 mL of methylene chloride. The solution was then cooled to 0° C. while stirring. Then, triethylamine (2.75 g, 27.0 mmol) is added followed by a dropwise addition of methanesulfonyl chloride (2.34 g, 20.4 mmol) and a two hour stir period. The reaction mixture is washed with water (2×75 mL), dried with sodium sulfate and then concentrated de vacuo. The crude mixture is then dissolved in 75 mL of DMF and then stirred via magnetic stir bar. To this mixture, sodium azide (1.76 g, 27.0 mmol) is added. The reaction mixture is then heated to 80° C. and allowed to stir for two hours. At this time, volatiles are concentrated de vacuo and the resulting residue is purified via column chromatography (1:9 ethyl acetate/hexane) providing (3-Azido-2-methyl propenyl)-benzene (2.08 g, 89%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.36-7.25 (m, 5H), δ 6.53 (s, 1H), δ 3.87 (s, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 129.4, 129.2, 128.9, 128.6, 128.4, 127.1, 59.9, 52.0, 22.3, 16.5 ppm; LRMS (EI) calcd for C10H11N3 (M+) 173. Found 173.
Reaction SMILES: [C:1]([C:4]1[O:9][Si:8]([CH3:11])([CH3:10])[CH:7]([CH3:12])[CH2:6][N:5]=1)([CH3:3])=[CH2:2].[CH3:13][OH:14]>>[CH3:10][Si:8]([CH3:11])([O:14][CH3:13])[CH:7]([CH3:12])[CH2:6][NH:5][C:4](=[O:9])[C:1]([CH3:3])=[CH2:2]
Reactant: C=C(C)C1=NCC(C)[Si](C)(C)O1
Reactant: CO
Product: C=C(C)C(=O)NCC(C)[Si](C)(C)OC

Procedure:
The addition of 2 parts methanol to 1 part 2-isopropenyl-4,4,5-trimethyl-1-aza-3-oxa-4-silacyclohex-1-ene resulted inthe instantaneous evolution of heat and completion of the reaction. Removalof methanol by stirring the reaction mixture in a vacuum for 1 hour at roomtemperature yielded the essentially pure methanol adduct, N-[2-(dimethylmethoxysilyl)propyl]methacrylamide.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]#[CH:5].C(N(CC)CC)C.Cl[C:14]([O:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)=[O:15]>ClCCl>[CH3:1][N:2]([CH2:3][C:4]#[CH:5])[C:14](=[O:15])[O:16][C:17]1[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=1
Reactant: C#CCNC
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCN(C)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 3 h
Yield: 88.5 %

Procedure:
N-Methylpropargylamine (600 mg, 8.70 mmol) and triethylamine (878 mg, 8.68 mmol) in dichloromethane (10 ml) were added dropwise, with ice cooling, to a stirred solution of 4-nitrophenyl chloroformate (1.75 g, 8.68 mmol) in dichloromethane (10 ml). The reaction was stirred at ice temperature for 3 hr. then the resulting solution purified by column chromatography on silica using 25% ethyl acetate in iso-hexane as eluent. Thus was obtained 4-nitrophenyl methyl(prop-2-yn-1-yl)carbamate (1.80 g, 89%) as a colourless oil. Dimethylamine (3.0 ml of a 2.0M solution in THF, 6.0 mmol) and 4-nitrophenyl methyl(prop-2-yn-1-yl)carbamate (600 mg, 2.56 mmol), in dichloromethane (7 ml) were stirred at room temperature for 6 days then the reaction solution purified by chromatography on silica using ethyl acetate as eluent to give N,N,N′-trimethyl-N′-prop-2-yn-1-ylurea (164 mg, 46%) as a colourless oil.
Reaction SMILES: [CH:1]1([O:7][CH2:8][CH2:9]O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Br)(Br)(Br)[Br:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:12][CH2:9][CH2:8][O:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCCOC1CCCCC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCOC1CCCCC1
Temperature: 25 °C

Procedure:
A mixture of 2-(cyclohexyloxy)ethanol (0.5 g, 3.47 mmol), carbon tetrabromide (1.49 g, 4.51 mmol), and dichloromethane (6 mL) was placed in a 20 mL scintillation vial with a magnetic stirring bar and cooled on an ice-water bath. Triphenylphosphine (1.18 g, 4.51 mmol) was added in three portions over 5 min with stirring. The mixture was allowed to warm to ambient temperature and progress was monitored with TLC using ethyl acetate:hexanes (1:1) (Rf starting material=0.6, Rf product=0.9). The mixture was concentrated under reduced pressure. Hexanes (5 mL) and ethyl ether (10 mL) were added twice and removed by decanting, leaving an oily residue that was purified by silical gel chromatography using hexanes as eluant. The title compound was obtained as a yellow oil (0.189 g, 26% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:10]([CH2:20][C:21]([OH:23])=O)[N:9]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:26])=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:10]([CH2:20][C:21]([Cl:26])=[O:23])[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1
Product: O=C(Cl)Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1

Procedure:
1.2 g of ((3,5-bis-(4-fluoro-phenyl)-(1,2,4)triazol-1-yl)-acetic acid in 15 mL thionylchloride was stirred 30 min at 60° C. The solvent was removed to give 1.3 g of the desired product.
Reaction SMILES: Cl[CH2:2][N:3]1[C:7](=[O:8])[CH:6]([CH:9]([CH3:11])[CH3:10])[N:5]([CH3:12])[S:4]1(=[O:14])=[O:13].[P:15]([O-:23])([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])=[O:16].C(N(CC)CC)C>C(Cl)Cl>[CH2:18]([O:17][P:15]([O:20][CH2:21][CH3:22])([O:23][CH2:2][N:3]1[C:7](=[O:8])[CH:6]([CH:9]([CH3:11])[CH3:10])[N:5]([CH3:12])[S:4]1(=[O:14])=[O:13])=[O:16])[CH3:19]
Reactant: CCOP(=O)([O-])OCC
Reactant: CC(C)C1C(=O)N(CCl)S(=O)(=O)N1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOP(=O)(OCC)OCN1C(=O)C(C(C)C)N(C)S1(=O)=O
Yield: 48 %

Procedure:
2-Chloromethyl-4-isopropyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (0.5 g) was added to a solution of diethyl phosphate (Formula III: A=B=Et) (0.48 g) in methylene chloride containing triethylamine (0.31 g), and the mixture was allowed to reflux for 48 hours and then cooled. The mixture was concentrated in vacuo and the residue purified by silica gel flash chromatography (ethyl acetate/hexane) to afford 0.36 g (48%) of 2-(diethoxyphosphinyloxymethyl)-4-isopropyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula I: R1 =H; R2 =isopropyl; R3 =CH3 ; A=B=Et) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[N:16]=[C:15]([CH2:17][C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[F:25])[C:14]([CH2:26][NH:27][S:28]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]#[N:38])[CH:32]=3)(=[O:30])=[O:29])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CO.[C:41]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>CCCCCC.O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[N:16]=[C:15]([CH2:17][C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[F:25])[C:14]([CH2:26][N:27]([CH3:41])[S:28]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]#[N:38])[CH:32]=3)(=[O:30])=[O:29])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: N#Cc1cccc(S(=O)(=O)NCc2ccc(S(=O)(=O)c3ccc(Cl)cc3)nc2Cc2cc(F)ccc2F)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: C1CCOC1
Solvent: CO
Solvent: CCCCCC
Product: CN(Cc1ccc(S(=O)(=O)c2ccc(Cl)cc2)nc1Cc1cc(F)ccc1F)S(=O)(=O)c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.8 %

Procedure:
To a tetrahydrofuran (0.5 ml) solution of N-[[6-(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methylpyridin-3-yl]methyl]-3-cyanobenzenesulfonamide (21 mg, 0.037 mmol) were added methanol (0.003 ml, 0.073 mmol), triphenylphosphine (19 mg, 0.073 mmol) and diisopropyl azodicarboxylate (0.014 ml, 0.073 mmol) sequentially at 0° C. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel chromatography. The fraction obtained from the hexane:ethyl acetate=2:1 eluate was concentrated under reduced pressure to give the title compound (13 mg, 0.021 mmol, 58%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=3)=[CH:7][C:6]=2[CH:18]=1.[CH2:19]([N:21]([CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)[CH2:22][CH3:23])[CH3:20].[Cl-]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=3)=[C:7]([C:32](=[O:33])[C:31]3[CH:30]=[CH:29][C:28]([O:27][CH2:26][CH2:25][CH2:24][N:21]([CH2:22][CH3:23])[CH2:19][CH3:20])=[CH:36][CH:35]=3)[C:6]=2[CH:18]=1
Reactant: COc1ccc(-c2cc3cc(Cl)ccc3o2)cc1
Reactant: CCN(CC)CCCOc1ccc(C(=O)Cl)cc1
Agent: [Cl-]
Solvent: ClCCl
Product: CCN(CC)CCCOc1ccc(C(=O)c2c(-c3ccc(OC)cc3)oc3ccc(Cl)cc23)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 5-chloro-2-(4-methoxyphenyl)benzofuran (1 g, 3.9 mmol) in DCM (100 mL) was stirred at 0° C. under nitrogen. The compound of Example 2(iii) (1.68 g, 6.9 mmol) was added followed by the drop-wise addition of tinIV chloride solution (1M DCM, 11.6 mmol). The colour became a deep red and the reaction was stirred at RT. for 3 hrs. The resulting suspension was poured onto ice-water (250 mL) and the organic portion separated. The aqueous layer was extracted with DCM and the organic portions were combined, dried (Na2SO4) and evaporated. The residue was purified by flash chromatography to give the title compound as a yellow tar (1.34 g, 72%).
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13](=O)[CH3:14])=[CH:8][CH:7]=1)(=[O:5])=[O:4].[CH3:16][O:17][C:18]1[N:23]=[C:22]([NH:24][C:25]([NH2:27])=[S:26])[CH:21]=[N:20][CH:19]=1.CC1N=C(NC2C=NC=CN=2)SC=1C1C=CC(S(N)(=O)=O)=CC=1>>[CH3:16][O:17][C:18]1[N:23]=[C:22]([NH:24][C:25]2[S:26][C:12]([C:9]3[CH:10]=[CH:11][C:6]([S:3]([NH:2][CH3:1])(=[O:5])=[O:4])=[CH:7][CH:8]=3)=[C:13]([CH3:14])[N:27]=2)[CH:21]=[N:20][CH:19]=1
Reactant: COc1cncc(NC(N)=S)n1
Reactant: CNS(=O)(=O)c1ccc(CC(C)=O)cc1
Agent: Cc1nc(Nc2cnccn2)sc1-c1ccc(S(N)(=O)=O)cc1
Product: CNS(=O)(=O)c1ccc(-c2sc(Nc3cncc(OC)n3)nc2C)cc1

Procedure:
Using N-methyl-4-(2-oxo-propyl)-benzenesulfonamide (18a) and (6-methoxy-pyrazin-2-yl)-thiourea in an identical process to that described for the preparation of 4-[4-methyl-2-(pyrazin-2-ylamino)-thiazol-5-yl]-benzenesulfonamide (Example 1) afforded the title compound.
Reaction SMILES: N[C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].[BrH:10].N([O-])=O.[Na+].BrBr>O>[Br:10][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccnc(Cl)c1N
Reactant: Br
Agent: BrBr
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccnc(Cl)c1Br
Temperature: 25 °C
Reaction time: 12 h

Procedure:
3-amino-2-chloro-4-methylpyridine (2 g) was added to a mixed solvent of a 48% aqueous hydrogen bromide solution (17 mL) and water (12 mL). Sodium nitrite (2.5 g) was added to the solution at 0° C. Further, bromine (22 mL) was added. The reaction mixture was warmed to room temperature and stirred for 12 hours. The reaction mixture was partitioned by adding a 5 N aqueous sodium hydroxide solution and ethyl acetate. The organic layer was washed with brine and then dried over anhydrous magnesium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure to give the title compound (1.7 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][N:13]=[C:12](OS(C(F)(F)F)(=O)=O)[C:11]=1[N+:24]([O-:26])=[O:25].Cl.[CH3:28][O:29][CH2:30][CH:31]([NH2:34])[CH2:32][CH3:33]>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:34][CH:31]([CH2:30][O:29][CH3:28])[CH2:32][CH3:33])[C:11]=1[N+:24]([O-:26])=[O:25]
Reactant: CCC(N)COC
Reactant: COc1ccc(-c2ccnc(OS(=O)(=O)C(F)(F)F)c2[N+](=O)[O-])c(Cl)c1
Agent: Cl
Product: CCC(COC)Nc1nccc(-c2ccc(OC)cc2Cl)c1[N+](=O)[O-]
Yield: 28.2 %

Procedure:
Trifluoro-methanesulfonic acid 4-(2-chloro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl ester (0.40 g, 0.97 mmol), prepared substantially as described in Part C of Example 19a, and 1-methoxymethyl-propylamine HCl (0.27 g, 1.94 mmol) were treated substantially as described in Part C of Example 19a to produce 0.10 g (28%) of [4-(2-chloro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl]-(1-methoxymethyl-propyl)-amine: MS (AP) m/z 365.8 [(M+H)+, 100].
Reaction SMILES: [Cl:1][C:2]1[CH:40]=[CH:39][CH:38]=[CH:37][C:3]=1[C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH3:12])[S:8][C:7]=1[N:13]1[C:17]([CH2:18][NH:19][C:20]([C:22]2[N:23]([CH2:31][C:32]([O:34]CC)=[O:33])[C:24]3[C:29]([CH:30]=2)=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])=[N:16][N:15]=[N:14]1)=[O:5].[OH-].[Na+]>>[Cl:1][C:2]1[CH:40]=[CH:39][CH:38]=[CH:37][C:3]=1[C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH3:12])[S:8][C:7]=1[N:13]1[C:17]([CH2:18][NH:19][C:20]([C:22]2[N:23]([CH2:31][C:32]([OH:34])=[O:33])[C:24]3[C:29]([CH:30]=2)=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])=[N:16][N:15]=[N:14]1)=[O:5]
Reactant: CCOC(=O)Cn1c(C(=O)NCc2nnnn2-c2sc(CC)cc2C(=O)c2ccccc2Cl)cc2ccccc21
Agent: [Na+]
Agent: [OH-]
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2nnnc2CNC(=O)c2cc3ccccc3n2CC(=O)O)s1

Procedure:
Ethyl 2-(1-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-1,2,3,4-tetrazol-5-ylmethylcarbamoyl)indole-1-acetate is hydrolyzed using a 2M aqueous sodium hydroxide solution to give 2-(1-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-1,2,3,4-tetrazol-5-ylmethylcarbamoyl)indole-1-acetic acid.