Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)=[O:3].CN1CCOCC1.ClC(OCC(C)C)=O.N[CH2:33][C:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:35]>CN(C=O)C.CCOCC>[C:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(=[O:35])[CH3:33].[OH:3][C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)=[O:1]
Reactant: NCC(=O)c1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The D-biotin (1 g, 4.1 mmol) is solubilized in 45 ml of anhydrous DMF in the hot state. The mixture is cooled to 0° C. under argon, and then N-methylmorpholine (590 μl, 5.33 mmol) and isobutyl chloroformate (840 μl, 6.60 mmol) are successively added. The mixture is kept stirred for 30 min, and then 2-aminoacetophenone (824 mg, 6.10 mmol) is added. The solution is maintained stirred at room temperature for 3 h 30 min, and then evaporated to dryness. The residue is taken up in 50 ml of water. The precipitate obtained is filtered, washed with water and then with 50 ml of MeOH in the hot state. The precipitate obtained is filtered and washed with water. Recrystallization is carried out by dissolving the product in MeOH in the hot state and reprecipitating by addition of water. The precipitate is filtered, washed with water, and then with ether to give 1.1 g (2.95 mmol, 72%) of crude product 1c.
Reaction SMILES: [Br:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][N:7]1[C:16]2[CH:11]([CH2:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][C:8]1=[O:17].[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[Br:1][CH2:2][C:3]([C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:7]([CH3:6])[C:8](=[O:17])[CH2:9][CH2:10]2)=[O:4]
Reactant: O=C(Cl)CBr
Reactant: CN1C(=O)CCC2CC=CC=C21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CN1C(=O)CCc2cc(C(=O)CBr)ccc21
Temperature: 25 °C

Procedure:
Bromoacetyl chloride (28.3 g) is added dropwise to a suspension of N-methyl-tetrahydroquinolin-2-one (14.7 g) and AlCl3 (26.7 g) in methylene chloride (400 ml), and the reaction mixture is refluxed for 5 hours. The reaction mixture is cooled to RT, stirred with an ice/water mixture for 30 minutes, diluted with methylene chloride (200 ml) and separated. The aqueous layer is extracted with methylene chloride, and the combined organic extracts are washed with H2O, dried, filtered and concentrated in vacuo, yielding a crude solid which is recrystallized from isopropanol affording the desired product as a solid.
Reaction SMILES: [Cl:1][C:2]1[S:28][C:5]2[NH:6][C:7]([C:9]([NH:11][CH:12]3[CH2:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]([CH2:22][CH:23]([OH:26])CO)[C:13]3=[O:27])=[O:10])=[CH:8][C:4]=2[CH:3]=1.[NH2:29][CH2:30][CH:31]([OH:34])[CH2:32][OH:33]>>[Cl:1][C:2]1[S:28][C:5]2[NH:6][C:7]([C:9]([NH:11][CH:12]3[CH2:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]([CH2:22][C:23]([NH:29][CH2:30][CH:31]([OH:34])[CH2:32][OH:33])=[O:26])[C:13]3=[O:27])=[O:10])=[CH:8][C:4]=2[CH:3]=1
Reactant: NCC(O)CO
Reactant: O=C(NC1Cc2ccccc2N(CC(O)CO)C1=O)c1cc2cc(Cl)sc2[nH]1
Product: O=C(CN1C(=O)C(NC(=O)c2cc3cc(Cl)sc3[nH]2)Cc2ccccc21)NCC(O)CO
Yield: 47 %

Procedure:
In an similar manner to Example 3, using 2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxylic acid (Method 9) as the carboxylic acid and 3-aminopropane-1,2-diol as the amine the title compound (47%) was prepared as a solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[O:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:17][O:18][C:19]1[CH:24]=[C:23]([CH2:25]O)[CH:22]=[CH:21][N:20]=1>>[Cl:3][CH2:25][C:23]1[CH:22]=[CH:21][N:20]=[C:19]([O:18][CH2:17][C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:10][C:6]=2[CH3:5])[CH:24]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1oc(-c2ccccc2)nc1COc1cc(CO)ccn1
Product: Cc1oc(-c2ccccc2)nc1COc1cc(CCl)ccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To thionyl chloride (4 mL) was added [2-(5-methyl-2-phenyl-4-oxazolylmethoxy)-4-pyridyl]methanol (1.19 g) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated, and saturated aqueous sodium hydrogencarbonate was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals of 4-chloromethyl-2-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine from a fraction eluted with ethyl acetate-hexane (1:3, v/v). Recrystallization from ethyl acetate-hexane gave colorless needle crystals (0.68 g, 54%). melting point: 104-105° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:23])([CH2:17][N:18]1[CH:22]=[N:21][CH:20]=[N:19]1)[C:10]([F:16])([F:15])SCCO.ClC1C=CC=[C:27]([C:31](OO)=[O:32])C=1.[S:35]([O-:39])([O-])(=[O:37])=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>ClCCl.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:23])([CH2:17][N:18]1[CH:22]=[N:21][CH:20]=[N:19]1)[C:10]([F:16])([F:15])[S:35]([CH2:27][CH2:31][OH:32])(=[O:39])=[O:37]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: OCCSC(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: O=S([O-])([O-])=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=S(=O)(CCO)C(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.6 %

Procedure:
To a solution of 2-(2,4-difluorophenyl)-1,1-difluoro-1-(2-hydroxyethyl)thio-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (9.10 g, 0.026 mol) in dichloromethane (250 ml), 85% m-chloroperbenzoic acid (14.8 g, 0.073 mol) was added at room temperature, followed by stirring at room temperature for one hour. After the completion of the reaction, a saturated aqueous solution of sodium thiosulfate and a saturated solution of sodium bicarbonate were added to the reaction mixture and they were stirred. The dichloromethane solution was separated, washed with water, dried over anhydrous magnesium sulfate and then distilled off under reduced pressure. The residue so obtained was recrystallized from isopropyl ether--ethyl acetate, whereby 2-(2,4-difluorophenyl)-1,1-difluoro-1-(2-hydroxyethyl)sulfonyl-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (4.43 g, yield: 44.6%) was obtained as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:15]1([CH2:18]Br)[CH2:17][CH2:16]1>CN(C)C=O.C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:18][CH:15]2[CH2:17][CH2:16]2)=[CH:4][CH:3]=1
Reactant: BrCC1CC1
Reactant: Sc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Brc1ccc(SCC2CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.4 %

Procedure:
4-Bromothiophenol (37.8 g) in N,N-dimethylformamide (200 mL) was treated with potassium carbonate (30.4 g) and cyclopropylmethyl bromide (29.7 g). The suspension was stirred at ambient temperature for 16 hrs then diluted with diethyl ether (500 mL). The organic phase was washed with water (2×500 mL), dried (MgSO4) and concentrated to give the title compound as an oil (46.4 g). 1H NMR (360 MHz, CDCl3): δ 7.38 (2H, d, J=8.0 Hz), 7.21 (2H, d, J=8.0 Hz), 2.83 (2H, d, J=7.0 Hz), 1.08-0.98 (1H, m), 0.58 (2H, q, J=5.1 Hz), 0.24 (2H, q, J=5.1 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=O)[C:6]([C:13]#[N:14])=[C:5]2[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:23])[CH3:22])[CH:16]=1.P(Cl)(Cl)([Cl:26])=O>O>[Cl:26][C:7]1[C:6]([C:13]#[N:14])=[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:23])[CH3:22])[CH:16]=2)[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)c1cccc(-c2c(C#N)c(=O)[nH]c3ccc(Cl)cc23)c1
Solvent: O
Product: CC(C)c1cccc(-c2c(C#N)c(Cl)nc3ccc(Cl)cc23)c1
Yield: 83.9 %

Procedure:
A mixture of 6-chloro-4-(3-isopropyl-phenyl)-2-oxo-1,2-dihydro-quinoline-3-carbonitrile (142 mg, 440 μmol, Eq: 1.00) and phosphorus oxychloride (2.02 g, 1.23 ml, 13.2 mmol, Eq: 30) was heated to reflux for 3 h. The reaction mixture was then poured into water and extracted with DCM (3×). The combined organic layers were washed with water and brine, dried with Na2SO4 and evaporated to afford the title compound (126 mg, light yellow solid). MS (ESI): 343.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C@@H:21]1[CH2:25][CH2:24][CH2:23][N:22]1[C:26](=[O:45])[CH2:27][C@@H:28]([O:43][CH3:44])[C@@H:29]([N:34]([CH3:42])[C:35](=[O:41])[C@H:36]([CH:38]([CH3:40])[CH3:39])[NH2:37])[C@@H:30]([CH3:33])[CH2:31][CH3:32])[C@@H:4]([CH3:20])[C:5]([NH:7][C@H:8]([C:16]([O:18][CH3:19])=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6].C1C2C(COC([NH:63][C@@:64]([C:68](O)=[O:69])([CH3:67])[CH2:65][CH3:66])=O)C3C(=CC=CC=3)C=2C=CC=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(NCC)C>ClCCl>[NH2:63][C@@:64]([C:68]([NH:37][C@H:36]([C:35]([N:34]([C@@H:29]([C@@H:30]([CH3:33])[CH2:31][CH3:32])[C@H:28]([O:43][CH3:44])[CH2:27][C:26]([N:22]1[CH2:23][CH2:24][CH2:25][C@H:21]1[C@H:3]([O:2][CH3:1])[C@@H:4]([CH3:20])[C:5]([NH:7][C@@H:8]([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:16]([O:18][CH3:19])=[O:17])=[O:6])=[O:45])[CH3:42])=[O:41])[CH:38]([CH3:39])[CH3:40])=[O:69])([CH3:67])[CH2:65][CH3:66]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC)OC)N(C)C(=O)[C@@H](N)C(C)C
Reactant: CC[C@](C)(NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCNCC
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC)OC)N(C)C(=O)[C@@H](NC(=O)[C@@](C)(N)CC)C(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 29.8 %

Procedure:
A solution of #114 (447 mg, 0.707 mmol, 1.0 eq.) in 2 mL of dichloromethane was added to a solution of N-[(9H-fluoren-9-ylmethoxy)carbonyl]-D-isovaline (240 mg, 0.707 mmol, 1.0 eq.) in 4 mL of dichloromethane. Hunig's base (0.373 mL, 2.12 mmol, 3 eq.) was added followed by HATU (332 mg, 0.425 mmol, 1.2 eq.). The reaction was allowed to stir at room temperature for 12 hours. The reaction was concentrated in vacuo and then taken up in ethyl acetate before being washed two times with 1M HCl and once with brine. The organic layer was dried over sodium sulfate and decanted. The organic solvent was removed in a genevac. THF (4 mL) was added followed by diethylamine (2 mL, 19 mmol, 26.9 eq.). The reaction was allowed to stir for ˜12 hours. Reaction was concentrated using a genevac followed by silica chromatography (Gradient: 0%-30% methanol in ethyl acetate) producing #149 (154 mg, 30%) as a solid. LC-MS (Protocol Q): m/z 732.0 [M+H+] retention time=1.24 minutes. 1H NMR (400 MHz, DMSO-d6), δ 8.55 (d), 8.38-8.46 (m), 8.29 (d), 8.03-8.14 (m), 7.97 (d), 7.81 (d), 7.40-7.53 (m), 7.14-7.28 (m), 7.02 (s), 4.71-4.79 (m), 4.43-4.69 (m), 3.96-4.05 (m), 3.71-3.80 (m), 3.62-3.70 (m), 3.49-3.60 (m), 3.40-3.48 (m), 3.15-3.34 (m), 3.10-3.14 (m), 3.01-3.09 (m), 2.94-3.00 (m), 2.83-2.93 (m), 2.65-2.71 (m), 2.55-2.59 (m), 2.32-2.48 (m), 2.04-2.31 (m), 1.61-1.89 (m), 1.37-1.52 (m), 1.21-1.35 (m), 1.15-1.20 (m), 1.02-1.10 (m), 0.75-1.01 (m).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:9][C:10]([I:13])=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=1.[NH2:14][CH2:15][CH2:16][N:17]1[C:21]([CH3:23])([CH3:22])[C:20](=[O:24])[NH:19][C:18]1=[O:25].C(N(CC)CC)C>CC(O)C>[I:13][C:10]1[S:9][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:14][CH2:15][CH2:16][N:17]3[C:21]([CH3:22])([CH3:23])[C:20](=[O:24])[NH:19][C:18]3=[O:25])[N:7]=2)=[CH:12][CH:11]=1
Reactant: Clc1nccc(-c2ccc(I)s2)n1
Reactant: CC1(C)C(=O)NC(=O)N1CCN
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC1(C)C(=O)NC(=O)N1CCNc1nccc(-c2ccc(I)s2)n1

Procedure:
A solution of 205 mg (0.64 mmol) of 2-chloro-4-(5-iodothiophen-2-yl)pyrimidine, 186 mg (1.1 mmol) of 1-(2-aminoethyl)-5,5-dimethylimidazolidine-2,4-dione and 0.15 mL (1.1 mmol) of triethylamine in 5 mL of iPrOH was heated in a microwave to 180° C. for 10 min then concentrated in vacuo. The crude solid product was purified by flash chromatography eluting with a linear gradient of 40% EtOAc in hexane to 100% EtOAc to deliver the title compound. MS (M+H)+ 458.
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH:4]([OH:9])[CH2:5][CH2:6][CH2:7][CH3:8])[CH3:3].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH3:1][C:2]([CH3:10])([C:4](=[O:9])[CH2:5][CH2:6][CH2:7][CH3:8])[CH3:3]
Reactant: CCCCC(O)C(C)(C)C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCCCC(=O)C(C)(C)C
Temperature: 0 °C
Yield: 89.2 %

Procedure:
2,2-Dimethyl-heptan-3-ol (0.23 mol) was dissolved in 350 mL of CH2Cl2 in a 500 mL round bottom flask with a magnetic stirbar. The flask was partially cooled with ice 76.6 g (0.355 mol) of pyridinium chlorochromate was added, while vigorously stirring. The reaction turned black and warmed up slightly. The reaction mixture was stirred at room temperature for 24 hours. The solution was decanted away from the black sludge, which was rinsed with hexane. The organic extracts were combined and chromatographed directly on silica gel. (Note: only silica has been found to trap and remove the reduced non-reacted chromium compounds). The product, 2,2-dimethyl-heptan-3-one, eluted with CH2Cl2/hexane and in a subsequent 10% ethyl acetate/hexane fraction to yield 29.19 g of product at 83% yield. 1H NMR (CDCl3, 500 MHz) δ (ppm): 2.48 (t, 2H), 1.54 (m, 2H), 1.28 (m, 2H), 1.13 (s, 9H), 0.90 (m, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]([CH3:21])([O:10][C:11]1[CH:12]=[C:13]([CH2:17][C:18]([OH:20])=O)[CH:14]=[CH:15][CH:16]=1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[CH:28]1([NH2:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C(Cl)(Cl)Cl>ClCCl>[CH:28]1([NH:34][C:18]([CH2:17][C:13]2[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=2)[O:10][C:8]([CH3:9])([CH3:21])[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:20])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: NC1CCCCC1
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1cccc(CC(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)C(C)(C)Oc1cccc(CC(=O)NC2CCCCC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-(1-tert-Butoxycarbonyl-1-methylethoxy)phenylacetic acid (250 mg, 0.849 mmol) was dissolved in solvent mixture of dimethylformamide (10 μL)-dichloromethane (6 mL). Subsequently, oxalyl chloride [(COCl)2 (148 μL, 1.70 mmol)] was added at 0° C., the mixture was stirred for one hour at room temperature. The reaction mixture was added to a solution obtained by dissolving cyclohexylamine (0.97 mL, 8.49 mmol) in dichloromethane (1 mL) at 0° C., the mixture was stirred for one hour at room temperature. Chloroform was added to the reaction mixture. Washing was performed sequentially with 1M hydrochloric acid, water, and saturated brine, followed by drying over sodium sulfate. The mixture was subjected to concentration under reduced pressure and purification by silica gel column chromatography (chloroform/methanol=50/1), whereby the target compound was obtained (280 mg, 0.746 mmol, 87.8%).
Reaction SMILES: C1([NH:4][S:5]([NH2:8])(=[O:7])=[O:6])CC1.[CH:9]1[N:13]=[C:12]([NH2:14])[S:11][CH:10]=1>>[S:11]1[CH:10]=[CH:9][N:13]=[C:12]1[NH:14][NH:4][S:5]([NH2:8])(=[O:6])=[O:7]
Reactant: Nc1nccs1
Reactant: NS(=O)(=O)NC1CC1
Product: NS(=O)(=O)NNc1nccs1

Procedure:
The titled compound was prepared according to the same procedures described for the synthesis of N-cyclopropylsulfamide above, substituting cyclopropyl amine with 2-amino thiozol. However, the Boc-protected intermediate was never isolated due to loss of the protection group during reaction work-up and the following recrystallization steps. The titled product was isolated after silica gel column chromatography (Biotage 40 M, eluent=5-10% MeOH in DCM). 1H NMR (d6-DMSO, 400 MHz) 6.52 (br s, 2H), 6.75 (d, 1H), 7.19 (d, 1H), 12.1 (br s, 1H). MS m/z 180 (ESI+, MH+).
Reaction SMILES: [CH3:1][C:2]1[CH2:6][C:5](=[O:7])[N:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[N:3]=1.C1(C)C=CC(S([N:26]=[N+:27]=[N-])(=O)=O)=CC=1.C(N(CC)CC)C>CO>[N+:26](=[C:6]1[C:5](=[O:7])[N:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[N:3]=[C:2]1[CH3:1])=[N-:27]
Reactant: CC1=NN(c2ccc(C(=O)O)cc2)C(=O)C1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: CCN(CC)CC
Solvent: CO
Product: CC1=NN(c2ccc(C(=O)O)cc2)C(=O)C1=[N+]=[N-]
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 4-(3-methyl-5-oxo-2-pyrazolin-1-yl)benzoic acid (5.0 g, 0.023 mol) and p-toluenesulfonylazide (5.03 g, 0.026 mol) in methanol (30.0 mL) was treated with triethylamine (5.2 g; 0.051 mol.) and the reaction was stirred at room temperature for 5 hours.
Reaction SMILES: [ClH:1].[C:2]([NH:9][CH2:10][CH2:11]CCCCN)(OC(C)(C)C)=O.O.O[N:19]1[C:23]2C=CC=CC=2N=N1.[CH2:28]([N:30]([CH2:33][CH3:34])[CH2:31]C)C>CN(C)C=O>[ClH:1].[CH2:10]([N:9]=[C:2]=[N:19][CH2:23][CH2:34][CH2:33][N:30]([CH3:28])[CH3:31])[CH3:11]
Reactant: On1nnc2ccccc21
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)NCCCCCCN
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCN=C=NCCCN(C)C

Procedure:
Prepared according to the method described in Example 10, from N-boc-1,6-diamino-hexane hydrochloride (0.202 g), 1-hydroxybenzotriazole hydrate (0.065 g), triethylamine (0.11 ml), (2R)-1-[2-(6-(3-propanoic acid)naphthyloxy]-4-(3-pyridyl)-2-butanol (0.147 g, Example 9), dry N,N-dimethylformamide (20 ml) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (0.092 g) to give the title compound as a pale yellow solid (0.116 g).
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[CH:14][N:15]([CH2:17]O)[CH:16]=2)=[CH:8][CH:7]=1.C1(C)C=CC=CC=1>C(Cl)Cl>[ClH:3].[Cl:3][CH2:17][N:15]1[CH:16]=[C:12]([C:9]2[CH:10]=[CH:11][C:6]([F:5])=[CH:7][CH:8]=2)[N:13]=[CH:14]1
Reactant: O=S(Cl)Cl
Reactant: OCn1cnc(-c2ccc(F)cc2)c1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cl
Product: Fc1ccc(-c2cn(CCl)cn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a stirred solution of thionyl chloride (18 mL) in anhydrous methylene chloride (180 mL) was added (4-(4-fluorophenyl)-1H-imidazol-1-yl)methanol (11.4 g, 59 mmol) portionwise at RT under nitrogen. The reaction mixture was stirred at RT for 3.5 hr before anhydrous toluene (90 mL) was added. The mixture was stirred at RT for 30 min. Concentration under reduced pressure gave 1-(chloromethyl)-4-(4-fluorophenyl)-1H-imidazole hydrochloride (14.5 g, 59 mmol, 100% yield) as a solid. MS found: (M+H)+=211.3.
Reaction SMILES: [C:1]([O:4][C:5]([CH3:19])([CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[C:11]=1[C:17]#[N:18])[CH3:6])(=[O:3])[CH3:2].[S:20](Cl)(=[O:23])(=[O:22])[NH2:21]>>[C:1]([O:4][C:5]([CH3:19])([CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][S:20](=[O:23])(=[O:22])[NH2:21])[C:11]=1[C:17]#[N:18])[CH3:6])(=[O:3])[CH3:2]
Reactant: NS(=O)(=O)Cl
Reactant: CC(=O)OC(C)(C)CCOc1cccc(N)c1C#N
Product: CC(=O)OC(C)(C)CCOc1cccc(NS(N)(=O)=O)c1C#N
Yield: 100 %

Procedure:
Prepared as in Example 215a from 4-(3-amino-2-cyanophenoxy)-2-methylbutan-2-yl acetate (Example 231b) and sulfamoyl chloride in 100% yield. MS 342 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:12]=[CH:13][N:14](COCC[Si](C)(C)C)[C:10]=2[C:9]2[O:8][C:7]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:6]([I:29])[C:5](=[O:30])[C:4]=2[CH:3]=1.ClC1C2N(COCC[Si](C)(C)C)C=NC=2C2OC(C3C=CC=CC=3)=C(I)C(=O)C=2C=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[C:11]2[N:12]=[CH:13][NH:14][C:10]=2[C:9]2[O:8][C:7]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:6]([I:29])[C:5](=[O:30])[C:4]=2[CH:3]=1
Reactant: C[Si](C)(C)CCOCn1cnc2c(Cl)cc3c(=O)c(I)c(-c4ccccc4)oc3c21
Agent: C[Si](C)(C)CCOCn1cnc2c3oc(-c4ccccc4)c(I)c(=O)c3cc(Cl)c21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1c(I)c(-c2ccccc2)oc2c1cc(Cl)c1nc[nH]c12
Reaction time: 18 h
Yield: 100 %

Procedure:
To a solution of 4-chloro-7-iodo-8-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-chromeno[7,8-d]imidazol-6-one and 4-chloro-7-iodo-8-phenyl-3-(2-trimethylsilanyl-ethoxymethyl)-3H-chromeno[7,8-d]imidazol-6-one (80 mg, 0.14 mmol) in DCM (4 mL) was added TFA (1.0 mL) at RT. After 18 h, the reaction mixture was evaporated to dryness. The crude residue was triturated with DCM and concentrated in vacuo to afford the title compound as a white solid (59 mg, 100%). LCMS (Method A): RT=4.38 min, [M+H]+=423/425.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[N:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[N:16]=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].Br[CH2:30][C:31]([N:33]([CH3:35])[CH3:34])=[O:32]>O1CCCC1.CCCCCCC.O1CCCC1.C(C1C=CC=CC=1)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[N:14]=[C:15]([C:17]([F:18])([F:19])[F:20])[N:16]=[C:10]2[CH:9]1[CH2:30][C:31]([N:33]([CH3:35])[CH3:34])=[O:32])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCn2nc(C(F)(F)F)nc2C1
Reactant: CN(C)C(=O)CBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCc1ccccc1
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: CN(C)C(=O)CC1c2nc(C(F)(F)F)nn2CCN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2.13 g (7.30 mmol) of 7-N-(tert-butoxycarbonyl)-2-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-α]pyrazine (Example 2, Step A) in 10 mL of tetrahydrofuran at −78° C. was added lithium diisopropylamide (4.02 mL of a 2.0M solution in heptane/tetrahydrofuran/ethylbenzene, 8.03 mmol). The mixture was allowed to stir at −78° C. for 15 min, and then 2-bromo-N,N-dimethylacetamide from Step A in 5 mL of tetrahydrofuran was added, and the mixture slowly warmed to ambient temperature over 18 h. The reaction was quenched with aqueous ammonium chloride and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated. Purification by flash chromatography (silica gel, gradient of 50% to 75% ethyl acetate/hexane) yielded the title compound. LC/MS 322 ((M+1)-t-butyl).
Reaction SMILES: CS(NC1C(NC(=O)C2C=CC(F)=CC=2)=CC(C(F)(F)F)=CN=1)(=O)=O.[CH3:26][S:27]([NH2:30])(=[O:29])=[O:28].[H-].[Na+].Cl[C:34]1[C:39]([N+:40]([O-:42])=[O:41])=[CH:38][C:37]([C:43]([F:46])([F:45])[F:44])=[CH:36][N:35]=1>O1CCCC1.O>[N+:40]([C:39]1[C:34]([NH:30][S:27]([CH3:26])(=[O:29])=[O:28])=[N:35][CH:36]=[C:37]([C:43]([F:46])([F:44])[F:45])[CH:38]=1)([O-:42])=[O:41]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1Cl
Reactant: CS(N)(=O)=O
Agent: CS(=O)(=O)Nc1ncc(C(F)(F)F)cc1NC(=O)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)Nc1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Yield: 65.8 %

Procedure:
Preparation of N-(2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl)-4-fluorobenzamide (Compound No. 10) (1) 4.4 g of methanesulfonamide was dissolved in 70 ml of dry tetrahydrofuran, and 1.9 g of 60% sodium hydride was added thereto under cooling with ice. After completion of the addition, the mixture was reacted for one hour under reflux. After cooling, 7.0 g of 2-chloro-3-nitro-5-trifluoromethylpyridine was added thereto, and the mixture was reacted for 6 hours under reflux. After completion of the reaction, the reaction product was poured into 300 ml of water and washed with ethyl ether. Then, the aqueous layer was weakly acidified with dilute hydrochloric acid. Precipitated crystals were collected by filtration and dried to obtain 5.8 g of N-(3-nitro-5-trifluoromethyl-2-pyridyl)methanesulfonamide having a melting point of from 138° to 139° C.