Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]([CH3:14])[C:11]([CH3:15])=[N+:10]1[O-].FC(F)(F)C(OC(=O)C(F)(F)F)=[O:20]>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]([CH2:14][OH:20])[C:11]([CH3:15])=[N:10]1
Reactant: Cc1nn(-c2ccc(F)cc2F)[n+]([O-])c1C
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nn(-c2ccc(F)cc2F)nc1CO
Temperature: 110 °C
Reaction time: 1.25 h

Procedure:
To a solution of 2-(2,4-difluorophenyl)-4,5-dimethyl-2H-1,2,3-triazole 1-oxide (i.e. the product of Step A, 1.78 g, 7.0 mmol) in tetrahydrofuran (14 mL) was added trifluoroacetic anhydride (2.5 mL, 17.5 mmol). The reaction mixture was stirred at 110° C. in the microwave for 75 min. The mixture was diluted with ethyl acetate, washed successively with 1.0 M aqueous sodium hydroxide and 50% aqueous sodium hydroxide, dried (MgSO4) and concentrated under reduced pressure to afford the crude product. The crude material was purified by chromatography on silica gel eluting with 0 to 100% ethyl acetate in hexanes to obtain the title compound (0.59 g) as a colorless solid.
Reaction SMILES: [OH-].[Na+].C1COCC1.[Cl:8][C:9]1[CH:14]=[C:13]([NH:15][CH2:16][C:17]2[C:22]([CH:23]([CH3:25])[CH3:24])=[CH:21][C:20]([C:26]([F:29])([F:28])[F:27])=[CH:19][C:18]=2[C:30]2[CH:31]=[CH:32][C:33]([C:36]([NH:38][CH2:39][CH2:40][C:41]([O:43]CC)=[O:42])=[O:37])=[N:34][CH:35]=2)[CH:12]=[CH:11][C:10]=1[C:46]1[CH:51]=[CH:50][C:49]([C:52]([F:55])([F:54])[F:53])=[CH:48][C:47]=1[CH3:56].Cl>CO>[Cl:8][C:9]1[CH:14]=[C:13]([NH:15][CH2:16][C:17]2[C:22]([CH:23]([CH3:24])[CH3:25])=[CH:21][C:20]([C:26]([F:28])([F:29])[F:27])=[CH:19][C:18]=2[C:30]2[CH:31]=[CH:32][C:33]([C:36]([NH:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42])=[O:37])=[N:34][CH:35]=2)[CH:12]=[CH:11][C:10]=1[C:46]1[CH:51]=[CH:50][C:49]([C:52]([F:55])([F:53])[F:54])=[CH:48][C:47]=1[CH3:56]
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)cc(C(C)C)c2CNc2ccc(-c3ccc(C(F)(F)F)cc3C)c(Cl)c2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(C(F)(F)F)ccc1-c1ccc(NCc2c(-c3ccc(C(=O)NCCC(=O)O)nc3)cc(C(F)(F)F)cc2C(C)C)cc1Cl
Temperature: 25 °C

Procedure:
A 3M aqueous NaOH solution (0.04 mL, 0.11 mmol) was added to a THF (2.0 mL) and MeOH (1.0 mL) solution of ethyl 3-(5-(2-(((2-chloro-2′-methyl-4′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)amino)methyl)-3-isopropyl-5-(trifluoromethyl)phenyl)picolinamido)propanoate (13 mg, 0.02 mmol) and the resulting mixture was stirred at room temperature. After 2 h the resulting mixture was acidified with 1N aqueous HCl and extracted with EtOAc. The combined organics were dried (Na2SO4), concentrated and purified via column chromatography to yield the title compound.
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[CH:10]=[N:9][CH:8]=[C:7]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)[C:6]=2[CH2:5][CH2:4][CH2:3]1.[CH2:20]([S:22](Cl)(=[O:24])=[O:23])[CH3:21].CCN(CC)CC>C(Cl)Cl>[C:16]([C:15]1[CH:14]=[CH:13][C:12]([C:7]2[C:6]3[CH2:5][CH2:4][CH2:3][CH:2]([NH:1][S:22]([CH2:20][CH3:21])(=[O:24])=[O:23])[C:11]=3[CH:10]=[N:9][CH:8]=2)=[CH:19][CH:18]=1)#[N:17]
Reactant: CCS(=O)(=O)Cl
Reactant: N#Cc1ccc(-c2cncc3c2CCCC3N)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)NC1CCCc2c(-c3ccc(C#N)cc3)cncc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A cooled (0° C.) solution of (rac)-4-(8-amino-5,6,7,8-tetrahydroisoquinolin-4-yl)benzonitrile (example 1) (62.3 mg, 250 μmol) in CH2Cl2 (3.6 ml) was treated with ethanesulfonyl chloride (26.6 μL, 275 μmol) and Et3N (41.8 μL, 300 μmol). After ½ h the mixture was stirred at room temperature for 3 h, cooled down (0° C.) and treated again with ethanesulfonyl chloride (7.3 μL, 75 μmol) and Et3N (11.5 μL, 82.5 μmol). After 2 h at room temperature, the mixture was concentrated in vacuo and purified by flash chromatography (20 g SiO2, Telos-cartridge, CH2Cl2/MeOH (0.5 to 1.5%)) to give after precipitation from CH2Cl2 with n-pentane the pure title compound (43 mg, 50%) as a off-white powder. MS: 342.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:24]2[CH:38]=[CH:37][C:27]([O:28][CH2:29][C:30]([NH:32][CH2:33][C:34](O)=[O:35])=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:68]([O:75][CH2:76][C@@H:77]([C:79]([OH:81])=[O:80])[NH2:78])[C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][CH:15]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[OH:16])[C@H:9]2[C:24]2[CH:25]=[CH:26][C:27]([O:28][CH2:29][C:30]([NH:32][CH2:33][C:34]([NH:78][C@H:77]([C:79]([OH:81])=[O:80])[CH2:76][O:75][CH2:68][C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=3)=[O:35])=[O:31])=[CH:37][CH:38]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Reactant: N[C@@H](COCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)NCC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Temperature: 30 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycine, (20.3 mg, 0.038 mmol) in DMF (2 ml) was added N-methylmorpholine (15 μl, 0.14 mmol). TBTU (14.8 mg, 0.046 mmol) was added the mixture was stirred at 30° C. for 1.5 hours. O-benzyl-L-serine (8.8 mg, 0.045 mmol) was added and the mixture was stirred overnight. The formation of the ketone of the title compound was confirmed. M/z: 718.04 (M+1) and 716.02 (M−1). Methanol (3 ml) and sodium borohydride (10.3 mg, 0.27 mmol) were added and the mixture was stirred for 1.5 hours. Ammonium acetate (20 mg) was added and the methanol was removed under reduced pressure. The remaining DMF-solution was purified by preparative HPLC on a C8 column, UV 240/260 nm. A gradient from 20 to 45% MeCN in 0.1M NH4OAc buffer was used as eluent. The pure fractions were collected and the MeCN was removed under reduced pressure. The remaining water solution was acidified to pH 1 with HCl (1M) and extracted with DCM. The combined organic phases were concentrated and the residue was dissolved in MeCN and water. After lyophilisation, the title compound was obtained as a white solid (2.3 mg, 8.5%).
Reaction SMILES: [CH3:1]O.[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[S:12][CH:13]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=1)[C:14]#[N:15].C[O-].[Na+].CI>O>[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[S:12][C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=1)([CH3:1])[C:14]#[N:15]
Reactant: N#CC(Sc1nc2ccccc2s1)c1cccc(Oc2ccccc2)c1
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CC(C#N)(Sc1nc2ccccc2s1)c1cccc(Oc2ccccc2)c1
Reaction time: 2.5 h
Yield: 77 %

Procedure:
Methanol (5 ml) was added to 945 mg of alpha-(2-benzothiazolylthio)(m-phenoxyphenyl)acetonitrile, and the mixture was stirred under ice cooling in an argon atmosphere. Then, 1.0 ml of a 2.7 M methanol solution of sodium methoxide was added, and the mixture was stirred under ice cooling for 10 minutes. Methyl iodide (0.25 ml) was then added. The mixture was stirred under ice cooling for 30 minutes, and then at room temperature for 2.5 hours. Then, 30 ml of water was added, and the reaction mixture was extracted with 20 ml of methylene chloride three times. The extract was washed with 10 ml of water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel; benzene and methylene chloride) to afford 752 mg (yield 77%) of alpha-(2-benzothiazolylthio)-alpha-(m-phenoxyphenyl)propionitrile as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=[C:4]([CH:16]=O)[CH:3]=1.Cl.[F:19][C:20]([F:35])([F:34])[C:21]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:22]=1[CH2:23][O:24][NH2:25].CC([O-])=O.[Na+]>CCO>[F:19][C:20]([F:34])([F:35])[C:21]1[CH:29]=[C:28]([C:30]([F:33])([F:31])[F:32])[CH:27]=[CH:26][C:22]=1[CH2:23][O:24][N:25]=[CH:16][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[NH:8][S:9]([C:12]([F:13])([F:14])[F:15])(=[O:10])=[O:11]
Reactant: O=Cc1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Reactant: NOCc1ccc(C(F)(F)F)cc1C(F)(F)F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=S(=O)(Nc1ccc(Cl)cc1C=NOCc1ccc(C(F)(F)F)cc1C(F)(F)F)C(F)(F)F
Yield: 57.6 %

Procedure:
A solution of N-(4-chloro-2-formylphenyl)trifluoromethanesulfonamide 24 (180 mg, 0.63 mmol), O-(2,4-bistrifluoromethylbenzyl)hydroxylamine hydrochloride (342 mg, 1.16 mmol) and anhydrous NaOAc (141 mg, 1.72 mmol) in EtOH (10 mL) was stirred for 15 hours at RT. The reaction mixture was concentrated under vacuum and the residue filtered through a pad of silica (eluting with CHCl3). Purification by radial thin layer chromatography (eluting with CH2Cl2/PE, 1:9 to 3:7) afforded N-{2-[(2,4-bistrifluoromethylbenzyloxyimino)methyl]-4-chlorophenyl}-trifluoromethanesulfonamide 65 (192 mg, 58%), as a yellow solid. M.p. 65-67° C. 1H n.m.r. (200 MHz, CDCl3) δ 10.38, br s, 1H; 8.20, s, 1H; 7.97, s, 1H; 7.86, d, J=8.0 Hz, 1H; 7.75, d, J=8.0 Hz, 1H; 7.65, d, J=8.8 Hz, 1H; 7.35, dd, J=2.4 and 8.8 Hz, 1H; 7.28, d, J=2.4 Hz, 1H; 5.44, s, 2H.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:15][CH2:14][C:9]2([O:13][CH2:12][CH2:11][O:10]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:26][C:27]1[CH:28]=[CH:29][C:30](F)=[N:31][CH:32]=1.O>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1([C:30]2[CH:29]=[CH:28][C:27]([Br:26])=[CH:32][N:31]=2)[CH2:15][CH2:14][C:9]2([O:10][CH2:11][CH2:12][O:13]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCC2(CC1)OCCO2
Reactant: Fc1ccc(Br)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C1(c2ccc(Br)cn2)CCC2(CC1)OCCO2
Reaction time: 1.5 h
Yield: 65.6 %

Procedure:
A solution of 1,4-dioxaspiro[4,5]decane-8-carboxylic acid ethyl ester (6.09 g) in tetrahydrofuran (14 ml) was added dropwise to a tetrahydrofuran solution (32 ml) of 1.0M tetrahydrofuran solution of lithium bis(trimethylsilyl)amide (39.8 ml) at −78° C., and stirred at the same temperature for 1.5 hours. Next, a solution of 5-bromo-2-fluoropyridine (5.0 g) in tetrahydrofuran (14 ml) was added dropwise and stirred at the same temperature for 0.5 hour and at room temperature for an hour. After completion of the reaction, water was added to the reaction solution and extracted with ethyl acetate twice. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give 8-(5-bromopyridin-2-yl)-1,4-dioxaspiro[4,5]decane-8-carboxylic acid ethyl ester (6.9 g) as a colorless oil.
Reaction SMILES: [C:1]([Cl:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([NH:21][NH2:22])=[N:13][N:12]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C1(C)C(C)=CC=CC=1>[Cl:9][C:1]1[C:2]2[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:14]2=[N:13][N:12]=[C:11]([C:20]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:21]2[N:22]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NNc1nnc(Cl)c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: Clc1nn2c(-c3ccccc3)nnc2c2ccccc12
Reaction time: 8 h
Yield: 74.1 %

Procedure:
128 μl (1.1 mmol) of benzoyl chloride was added to a xylene solution (10 ml) of 194 mg (1.0 mmol) of (4-chloro-phthalazin-1-yl)-hydrazine and 182 μl (1.3 mmol) of triethylamine, and stirred overnight under reflux. Aqueous saturated sodium hydrogencarbonate solution was added to the reaction liquid, and extracted with chloroform. The organic layer was washed with saturated saline solution, dried and concentrated under reduced pressure to obtain 208 mg (yield: 74%) of 6-chloro-3-phenyl-[1,2,4]triazolo[3,4-a]phthalazine as a yellow solid.
Reaction SMILES: Cl.[F:2][C:3]([F:34])([F:33])[C:4]1[CH:5]=[C:6]([CH2:14][O:15][C@@H:16]2[CH2:22][CH2:21][C@@H:20]3[N:23]([CH2:24][CH2:25][OH:26])[C@@:17]2([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:18][CH2:19]3)[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1.C(N(CC)CC)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>ClCCl>[F:13][C:10]([F:11])([F:12])[C:8]1[CH:7]=[C:6]([CH2:14][O:15][C@@H:16]2[CH2:22][CH2:21][C@@H:20]3[N:23]([CH2:24][CH2:25][O:26][S:43]([CH3:42])(=[O:45])=[O:44])[C@@:17]2([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:18][CH2:19]3)[CH:5]=[C:4]([C:3]([F:33])([F:2])[F:34])[CH:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCCN1[C@H]2CC[C@@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@]1(c1ccccc1)CC2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCN1[C@H]2CC[C@@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@]1(c1ccccc1)CC2
Temperature: 0 °C
Yield: 98.5 %

Procedure:
(1R*,2R*,5R*)-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-8-(2-hydroxyethyl)-1-phenyl-8-azabicyclo[3.2.1]octane (Example 67; 173 mg, 0.37 mmol) was dissolved in dichloromethane (2 ml) and cooled to 0° C. Triethylamine (0.062 ml, 0.44 mmol) was added followed by methanesulphonyl chloride (0.029 ml, 0.37 mmol). The mixture was extracted between water and dichloromethane (×3) and the organics dried (MgSO4) and concentrated in vacuo to give the title compound as a clear oil (201 mg, 100%).
Reaction SMILES: [F:1][C:2]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])=[CH:7][C:6]=1[C:17]1[C:18]2[CH:27]=[CH:26][NH:25][C:19]=2[C:20](=[O:24])[N:21]([CH3:23])[CH:22]=1.[CH3:33][N:34]([CH3:38])[CH2:35][CH2:36]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)(C)C)=O)=N\C(OC(C)(C)C)=O>O1CCCC1>[F:1][C:2]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:36][CH2:35][N:34]([CH3:38])[CH3:33])[S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])=[CH:7][C:6]=1[C:17]1[C:18]2[CH:27]=[CH:26][NH:25][C:19]=2[C:20](=[O:24])[N:21]([CH3:23])[CH:22]=1
Reactant: CN(C)CCO
Reactant: CCS(=O)(=O)Nc1ccc(Oc2ccc(F)cc2F)c(-c2cn(C)c(=O)c3[nH]ccc23)c1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCS(=O)(=O)N(CCN(C)C)c1ccc(Oc2ccc(F)cc2F)c(-c2cn(C)c(=O)c3[nH]ccc23)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.9 %

Procedure:
A mixture of Example 36e (0.15 g, 0.326 mmol), 2-(dimethylamino)ethanol (0.029 g, 0.326 mmol), and triphenylphosphine (0.128 g, 0.490 mmol) in tetrahydrofuran (3 mL) was stirred at ambient temperature for 10 minutes. To this solution was added (E)-di-tert-butyl diazene-1,2-dicarboxylate (0.113 g, 0.490 mmol). The solution was stirred for three hours at ambient temperature. The solvent was removed, and the residue was purified by preparative HPLC (10-80% acetonitrile in 0.1% TFA water) to give the title compound (0.055 g, 0.104 mmol, 31.8% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 12.06 (s, 1H), 7.51 (d, J=2.44 Hz, 1H), 7.41-7.47 (m, 1H), 7.35-7.37 (m, 2H), 7.23-7.31 (m, 2H), 7.06-7.11 (m, 1H), 6.85 (d, J=8.85 Hz, 1H), 3.57 (t, J=6.71 Hz, 2H), 3.56 (s, 3H), 3.17 (q, J=7.32 Hz, 1H), 2.25 (m, 2H), 2.13 (s, 6H), 1.25 (q, J=7.48 Hz, 3H). MS (ESI+) m/z 531.2 (M+H)+.
Reaction SMILES: [CH2:1]([NH:6][C:7]1[N:8]=[CH:9][NH:10][C:11]=1[C:12]#[N:13])[CH2:2][CH2:3][CH2:4][CH3:5].[C:14]([NH:17][NH2:18])(=O)[CH3:15].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:15][C:14]1[N:13]=[C:12]([C:11]2[NH:10][CH:9]=[N:8][C:7]=2[NH:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[NH:18][N:17]=1
Reactant: CCCCCNc1nc[nH]c1C#N
Reactant: CC(=O)NN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCCCCNc1nc[nH]c1-c1nc(C)n[nH]1
Temperature: 165 °C
Reaction time: 14 h
Yield: 9.6 %

Procedure:
To the mixture of 4-(pentylamino)-1H-imidazole-5-carbonitrile (0.40 g, 2 mmol), acetic acid, hydrazide (0.33 g, 4.5 mmol) in1-butanol (10 mL) was added potassium carbonate (0.10 g, 0.72 mmol). The mixture was sealed and stirred at 165° C. for 14 hours. The reaction mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative LCMS (method A) to yield the desired product (45 mg, 10% yield). LCMS calculated for C11H19N6(M+H): 235.2. found: 235.1.
Reaction SMILES: [BH4-].[Li+].C[Si](C)(C)Cl.[CH:8]1[CH:9]=[CH:10][C:11]([C@@H:14]([NH2:18])[C:15](O)=[O:16])=[CH:12][CH:13]=1.CO>O1CCCC1>[NH2:18][C@H:14]([C:11]1[CH:12]=[CH:13][CH:8]=[CH:9][CH:10]=1)[CH2:15][OH:16]
Reactant: N[C@@H](C(=O)O)c1ccccc1
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: N[C@@H](CO)c1ccccc1

Procedure:
20 g (920 mmol) of lithium borohydride are dissolved in 420 ml of absolute tetrahydrofuran. 233.5 ml (1.84 mol) of trimethylchlorosilane are added dropwise, while stirring, and 69.5 g (0.46 mol) of (R)-phenylglycine are then added in portions within the space of 4 hours. The reaction mixture is stirred at room temperature overnight. 690 ml of methanol are then added and the mixture is stirred at room temperature for 2 hours and concentrated in vacuo. The residue is dissolved, while stirring, in 690 ml of a 20% aqueous solution of potassium hydroxide. The aqueous phase is extracted three times with ethyl acetate. The combined organic phases are washed with water, dried over magnesium sulphate and concentrated in vacuo.
Reaction SMILES: [CH:1]1([C:7]2[S:11][C:10]([NH2:12])=[N:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:13](OCC)(=[O:15])C>>[CH:1]1([C:7]2[S:11][C:10]([N:12]=[C:13]=[O:15])=[N:9][N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(C)=O
Reactant: Nc1nnc(C2CCCCC2)s1
Product: O=C=Nc1nnc(C2CCCCC2)s1
Reaction time: 16 h

Procedure:
A saturated solution of phsogene in ethyl acetate (100 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer. A slurry of 5-cyclohexyl-2-amino-1,3,4-thiadiazole (50 grams) in ethyl acetate (300 ml) is added to the reaction vessel and the resulting mixture is stirred for a period of about 16 hours, resulting in the formation of a precipitate. The reaction mixture is then purged with nitrogen gas to remove unreacted phosgene. The purged mixture is then filtered to recover the precipitate. The precipitate is then recrystallized to yield the desired product 5-cyclohexyl-1,3,4-thiadiazol-2-yl isocyanate dimer.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[NH2:19][C:20]1[S:21][C:22]2[C:23](=[C:25]([S:30](Cl)(=[O:32])=[O:31])[CH:26]=[C:27]([F:29])[CH:28]=2)[N:24]=1>C(Cl)Cl>[NH2:19][C:20]1[S:21][C:22]2[C:23](=[C:25]([S:30]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=3)(=[O:32])=[O:31])[CH:26]=[C:27]([F:29])[CH:28]=2)[N:24]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: Nc1nc2c(S(=O)(=O)Cl)cc(F)cc2s1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(NS(=O)(=O)c2cc(F)cc3sc(N)nc23)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of the ethyl 4-aminobenzoate (413 mg, 2.5 mmol) in 20 mL of DCM was added pyridine (600 mg, 7.5 mmol) and 2-amino-6-fluorobenzo[d]thiazole-4-sulfonyl chloride (668 mg, 2.5 mmol). The resulting mixture was stirred at 50° C. overnight. After removal of DCM, the residue was partitioned between water and EtOAc. The organic layer was washed with 2 N HCl, water and brine, dried over Na2SO4 and concentrated to give crude product, which was purified by chromatography to give pure compound 26C. 1H NMR (CHLOROFORM-d) δ: 8.10 (s, 1H), 7.93-7.82 (m, 2H), 7.59 (dd, J=8.2, 2.6 Hz, 1H), 7.47 (dd, J=7.5, 2.6 Hz, 1H), 7.20-7.09 (m, 2H), 5.73 (s, 2H), 4.32 (q, J=7.1 Hz, 2H), 1.35 (t, J=7.1 Hz, 3H). LC-MS: m/z 396.5 (M+H)+
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[CH:11][CH:10]=1)([O-:8])=[O:7].CCN(CC)CC.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[CH3:1][S:2]([O:17][CH2:16][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([N+:6]([O-:8])=[O:7])=[CH:14][CH:13]=1)(=[O:4])=[O:3]
Reactant: O=[N+]([O-])c1ccc(CCO)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under a nitrogen atmosphere, MsCl (13.9 mL) was dropwise added to a suspension of 2-(4-nitrophenyl)ethanol (25.0 g) and Et3N (31.3 mL) in CHCl3 (including amylene, 625 mL) over 10 minutes under ice cooling, followed by stirring at room temperature for 2 hours. A saturated aqueous NaHCO3 solution was added to the reaction solution, and the aqueous layer was extracted with CHCl3. The combined organic layer was dried over MgSO4, and then the desiccant was removed by filtration. The filtrate was concentrated under reduced pressure to yield the title compound (41.8 g, light yellow solid).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:22][OH:23])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[C:30](OC(=O)C)(=[O:32])[CH3:31]>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:24][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:22][O:23][C:30](=[O:32])[CH3:31])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CC(=O)OC(C)=O
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCO)n2)cc1Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)OCCn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.9 %

Procedure:
2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(2-hydroxy-ethyl)-1H-pyrazol-3-yl]-propionamide (prepared in Example 67, 102 mg, 0.27 mmol) was dissolved in pyridine (2 mL) and acetic anhydride (27 umL, 0.29 mmol) was added. The reaction stirred at 25° C. for 16 h. The solution was diluted with ethyl acetate (40 mL), washed with aqueous 1.0 M hydrochloric acid solution (3×15 mL), saturated aqueous brine solution (1×10 mL), dried over magnesium sulfate and concentrated in vacuo. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 50% ethyl acetate/hexanes to 75% ethyl acetate/hexanes) afforded acetic acid 2-{3-[2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-ethyl ester (78 mg, 60%) as a white foam: ESI-LRMS m/e calcd for C22H28ClN3O5S [M+] 481.1, found 482.3 [M+H+]; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.02-1.20 (m, 2 H, CH2), 1.39-1.79 (m, 8H, 4×CH2), 1.95 (s, 3H, COCH3), 2.01-2.19 (m, 1H, CH), 3.33 (s, 3H, SO2CH3), 3.86-3.95 (m, 1H, CH), 4.18-4.24 (m, 2H, OCH2), 4.29 (t, J=5.0 Hz, Hz, 2H, NCH2), 6.43 (d, Jo=2.3 Hz, 1H, Ar), 7.55-7.61 (m, 2H, Ar), 7.68 (d, Jm=1.7 Hz, 1H, Ar), 7.99 (d, Jo=8.2 Hz, 1H, Ar), 10.77 (s, 1H, NH).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6]3=[C:7]([S:22][CH2:23][CH2:24][N:5]3[C:4](=[O:25])[CH:3]=1)[CH:8]=[C:9]([C:12]([OH:21])([C:17]([F:20])([F:19])[F:18])[C:13]([F:16])([F:15])[F:14])[CH:10]=2.[H-].[Na+].S(OC)(O[CH3:32])(=O)=O.C(O)C>CN(C)C=O>[CH3:1][C:2]1[C:11]2[C:6]3=[C:7]([S:22][CH2:23][CH2:24][N:5]3[C:4](=[O:25])[CH:3]=1)[CH:8]=[C:9]([C:12]([O:21][CH3:32])([C:13]([F:14])([F:15])[F:16])[C:17]([F:20])([F:18])[F:19])[CH:10]=2
Reactant: Cc1cc(=O)n2c3c(cc(C(O)(C(F)(F)F)C(F)(F)F)cc13)SCC2
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: COC(c1cc2c3c(c1)c(C)cc(=O)n3CCS2)(C(F)(F)F)C(F)(F)F

Procedure:
To a solution of 2,3-dihydro-7-methyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-5H-1,4-thiazino-[2,3,4-ij]-quinolin-5-one in dimethyl formamide can be added sodium hydride and dimethyl sulfate. The mixture can be stirred and heated in a nitrogen atmosphere until the reaction is complete, treated with ethanol and purified to give 2,3-dihydro-7-methyl-9-[2,2,2-trifluoro-1-methoxy-1-(trifluoromethyl)ethyl]-5H-1,4-thiazino-[2,3,4-ij]-quinolin-5-one.