Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C@H:4]1[C:17]2[CH:16]=[CH:15][C:14]3[CH2:13][N:12](C(=O)C(F)(F)F)[CH2:11][CH2:10][C:9]=3[C:8]=2[CH2:7][CH2:6][CH2:5]1)=[N+:2]=[N-:3].[OH-].[Na+]>C1COCC1.CO.O>[N:1]([C@H:4]1[C:17]2[CH:16]=[CH:15][C:14]3[CH2:13][NH:12][CH2:11][CH2:10][C:9]=3[C:8]=2[CH2:7][CH2:6][CH2:5]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=N[C@@H]1CCCc2c1ccc1c2CCN(C(=O)C(F)(F)F)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: [N-]=[N+]=N[C@@H]1CCCc2c1ccc1c2CCNC1

Procedure:
A solution of (R)-1-(7-azido-1,2,7,8,9,10-hexahydrobenzo[f]isoquinolin-3(4H)-yl)-2,2,2-trifluoroethanone(972 mg, 3.0 mmol) and NaOH (240 mg, 6 mmol) in 21 mL of THF/MeOH/H2O (10/10/1) was stirred at RT for 4 h. The solvent was evaporated and the residue was submitted to flash chomatograph (SiO2, EtOAc/MeOH=100:10 to 100:20 to 100:30) to give (R)-7-azido-1,2,3,4,7,8,9,10-octahydrobenzo[f]isoquinoline as a colorless oil.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].C[O-].[Na+].[CH3:9][C:10]1[O:11][C:12]([CH2:15]Cl)=[N:13][N:14]=1>CO>[CH3:9][C:10]1[O:11][C:12]([CH2:15][S:5][CH2:4][CH2:3][NH2:2])=[N:13][N:14]=1
Reactant: NCCS
Reactant: Cc1nnc(CCl)o1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1nnc(CSCCN)o1
Reaction time: 1 h
Yield: 110.8 %

Procedure:
Cysteamine hydrochloride (1.13 g; 0.01 mole) was added to a stirred solution of sodium methylate (1.08 g; 0.02 mole) in 20 ml of methanol at 0° under an argon atmosphere. The mixture was stirred for 1 hour at 0° and the resultant suspension was added dropwise over a period of 25 minutes to a stirred solution of 2-methyl-5-chloromethyl-1,3,4-oxadiazole (1.32 g; 0.01 mole) [prepared by the procedure described in Hel. Chim. Acta, 55, 1979 (1972)] in 15 ml of methanol at 0°. The reaction mixture was stirred at ambient temperature for 45 minutes, concentrated to near dryness, and then diluted with methylene chloride, filtered and evaporated under reduced pressure to give the title compound (1.92 g) as a yellow oil. The NMR spectrum (60 MHz) in CDCl3 gave the following resonances δ: 3.87 (s, 2H); 2.8 (m, 4H); 2.53 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]([CH2:18][CH2:19][CH3:20])[N:6]=[C:7]2[C:16]=1[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:9]=[C:8]2[NH2:17].C(N(CC)CC)C.[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[NH2:17][C:8]1[C:7]2=[N:6][N:5]([CH2:18][CH2:19][CH3:20])[C:4]([CH2:3][CH2:2][NH:1][C:33](=[O:34])[C:32]3[CH:36]=[CH:37][C:29]([F:28])=[CH:30][CH:31]=3)=[C:16]2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: CCCn1nc2c(N)nc3ccccc3c2c1CCN
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCn1nc2c(N)nc3ccccc3c2c1CCNC(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Under a nitrogen atmosphere, a solution of 1-(2-aminoethyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine (0.250 g, 0.928 mmol), triethylamine (0.30 g, 3.0 mmol), and 4-fluorobenzoyl chloride (0.18 g, 1.1 mmol) in dichloromethane (7 mL) was stirred for two hours and then concentrated under reduced pressure. The residue was dissolved in methanol, and 1 N hydrochloric acid was added. The reaction was stirred for three days at room temperature and then heated at reflux overnight. A precipitate was present and was isolated by filtration and stirred with 2 M aqueous sodium carbonate. The resulting mixture was extracted with dichloromethane. The combined extracts were then concentrated under reduced pressure. The residue was purified by chromatography using an INTELLIFLASH system (eluting with 0% to 30% CMA in chloroform). The pure product was dried in a vacuum oven overnight at 90° C. to provide N-[2-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)ethyl]-4-fluorobenzamide as a white powder, mp 198-199° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][C@@H:11]([CH2:13][O:14][CH3:15])[O:10][C:9]2=[O:16])=[CH:4][CH:3]=1>CO>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][C@H:11]([CH2:13][O:14][CH3:15])[O:10][C:9]2=[O:16])=[CH:6][CH:7]=1
Reactant: COC[C@@H]1CN(c2ccc(O)cc2)C(=O)O1
Solvent: CO
Product: COC[C@H]1CN(c2ccc(O)cc2)C(=O)O1

Procedure:
the 3-(4-hydroxyphenyl)-5(S)-methoxymethyl-2-oxazolidinone derivative (code number MD 200717): m.p.: 114° C.; [α]D20 =+66° (c=1, CH3OH),
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:39]1([CH2:45][C:46](Cl)=[O:47])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:18])([F:19])[F:17])[CH2:11][CH2:10][N:9]1[C:46](=[O:47])[CH2:45][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Reactant: O=C(Cl)Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Yield: 81.5 %

Procedure:
200 mg (0.468 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted in analogy to Example 35a with 72 μl (0.5 15 mmol) of triethylamine and 62 μl (0.468 mmol) of phenylacetyl chloride to give the title compound (208 mg, 81%). TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.54, FD-MS: M+ =545.
Reaction SMILES: [CH3:1][C:2]1([CH3:41])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][Si](CC(CC)CC)(C)C)[CH:13]=2)[C:8]2[CH:7]=[C:6]([C:28]#[C:29][C:30]3[CH:40]=[CH:39][C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:32][CH:31]=3)[CH:5]=[CH:4][C:3]1=2.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOC(C)=O>[CH3:41][C:2]1([CH3:1])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)[C:8]2[CH:7]=[C:6]([C:28]#[C:29][C:30]3[CH:31]=[CH:32][C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:39][CH:40]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2cccc(O[Si](C)(C)CC(CC)CC)c2)=CCC3(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2cccc(O)c2)=CCC3(C)C)cc1
Reaction time: 8 h

Procedure:
To a solution of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(3-((2,2 diethylethyl)-dimethylsiloxy)-phenyl)-2-naphthalenyl)ethynyl]benzoate (Compound H) 60.0 mg (0.114 mmol) in 1.0 ml of THF at room temperature was added 91.5 mg (0.35 ml, 0.35 mmol) of tetrabutylamonium flouride (1 M solution in THF). After stirring overnight, the solution was diluted with EtOAc and washed with H2O and saturated aqueous NaCl, before being dried over MgSO4. Removal of the solvents under reduced pressure, followed by column chromatography (4:1, Hexanes:EtOAc) afforded the title compound as a colorless solid. 1H NMR (CDCl3): δ 7.98 (2H, d, J=7.8 Hz), 7.52 (2H, d, J=8.3 Hz), 7.39-7.21 (4H, m), 6.93 (1H, d, J=7.5 Hz), 6.84 (1H, d, 7.1 Hz), 6.83 (1H, s), 6.01 1H, t, J=4.7 Hz), 4.91 (1H, s), 4.39 (2H, q, J=7.1 Hz), 2.35 (2H, d, J=4.7 Hz), 1.39 (3H, t, J=7.1 Hz), 1.34 (6H, s).
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:17]([CH:18]([OH:23])[C:19]([F:22])([F:21])[F:20])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([NH:24]C(=O)OC(C)(C)C)[S:14]2)[C@H:10]1[O:32]CC1C=CC=CC=1)C1C=CC=CC=1.B(Cl)(Cl)Cl.CO.[NH4+].[OH-]>ClCCl>[NH2:24][C:13]1[S:14][C@H:15]2[O:16][C@H:17]([C@H:18]([OH:23])[C:19]([F:22])([F:21])[F:20])[C@@H:9]([OH:8])[C@H:10]([OH:32])[C@H:11]2[N:12]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](C(O)C(F)(F)F)O[C@@H]2S1
Agent: ClB(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: NC1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H]([C@H](O)C(F)(F)F)O[C@@H]2S1

Procedure:
A solution of 142 (1 g, 1.7 mmol) in dichloromethane (30 mL) was treated with BCl3 (17 mL, 17 mmol, 1M dichloromethane) at −78° C. for 4 hours. The reaction was quenched by addition of methanol (10 mL). Removal of volatiles gave a residue, which was dissolved into methanol (5 mL) and neutralized with concentrated NH4OH (2 mL). After concentrated under reduced pressure, the crude product was purified by a silica gel column, eluted with 5%-20% methanol in dichloromethane to give a mixture of the above two compounds. Separation by Prep-HPLC with the following conditions (Column, Sun fire prep. C18; mobile phase, water with 0.03% NH4OH and CH3CN (10% up to 45% in 10 min); Detector, UV 220 nm) gave (3aR,5S,6S,7R,7aR)-2-amino-5-[(1S)-2,2,2-trifluoro-1-hydroxyethyl]-3aH,5H,6H,7H,7aH-pyrano[3,2-d][1,3]thiazole-6,7-diol Example 164 as a light yellow solid (49 mg, 20%, faster eluting isomer); (ES, m/z): [M+H]+ 289.0; 1H NMR (400 MHz, D2O) δ 6.25 (d, J=6.8 Hz, 1H), 4.29-4.26 (m, 2H), 4.07 (t, J=4.0 Hz, 1H), 3.93 (dd, J=8.4, 3.2 Hz, 1H), 3.73 (dd, J=8.4, 4.8 Hz, 1H); and (3aR,5S,6S,7R,7aR)-2-amino-5-[(1R)-2,2,2-trifluoro-1-hydroxyethyl]-3aH,5H,6H,7H,7aH-pyrano[3,2-d][1,3]thiazole-6,7-diol as a light yellow solid (74 mg, 30%, slower eluting isomer); (ES, m/z): [M+H]+ 289.0; 1HNMR (400 MHz, D2O) δ 6.32 (d, J=6.4 Hz, 1H), 4.31 (q, J=7.6 Hz, 1H), 4.15 (t, J=6.0 Hz, 1H), 4.00 (t, J=5.0 Hz, 1H), 3.83-3.76 (m, 2H).
Reaction SMILES: [N:1]#[C:2][NH2:3].[Na].[C:5]1([N:11]=[C:12]=[S:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(O)C>[C:2]([NH:3][C:12]([NH:11][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[S:13])#[N:1]
Reactant: N#CN
Reactant: S=C=Nc1ccccc1
Agent: [Na]
Solvent: CCO
Product: N#CNC(=S)Nc1ccccc1
Temperature: 25 °C
Yield: 76.7 %

Procedure:
To a suspension of monosodium cyanamide (6.4 g, 100 mmol) in absolute ethanol (170 mL), phenylisothiocyanate (12.5 mL, 104.5 mmol) was added slowly with stirring at room temperature. The reaction was allowed to stir at room temperature for 1 hour and then heated at 75° C. for 4 hours. The reaction was cooled to room temperature and the colorless solid was filtered and washed with ethanol to give the title A compound (13.6 g), m.p. >250° C.
Reaction SMILES: Br[CH:2]([CH3:13])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])=O.[CH3:14][O:15][C:16](=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][C:21](=[O:23])[NH2:22]>CO>[CH3:14][O:15][C:16](=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][C:21]1[O:23][C:2]([CH3:13])=[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:11][CH3:12])[N:22]=1
Reactant: COc1ccccc1C(=O)C(C)Br
Reactant: COC(=O)CCCCC(N)=O
Solvent: CO
Product: COC(=O)CCCCc1nc(-c2ccccc2OC)c(C)o1

Procedure:
Combine 2-Bromo-1-(2-methoxy-phenyl)-propan-1-one (7.25 g, 29.8 mmol) with 5-carbamoyl-pentanoic acid methyl ester (9.5 g, 60.5 mmol) and heat the neat mixture in a sealed vessel at 140-150° C. for about 4 h. Cool the mixture, transfer to a flask using methanol and concentrate. Partition the residue between water and EtOAc. Dry the combined extracts over Na2SO4 and concentrate. Chromatography over silica gel (MeOH/CH2Cl2) allows for recovery of 5-[4-(2-methoxy-phenyl)-5-methyl-oxazol-2-yl]-pentanoic acid methyl ester (3.63 g, 40%). MS (ES): (M+1)+ 304.2 m/z.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([OH:9])=[O:8].[CH3:10][Si](C=[N+]=[N-])(C)C>CO.O1CCOCC1>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([O:9][CH3:10])=[O:8]
Reactant: Cn1cccc1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)c1cccn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a solution of 1-methyl-2-pyrrolecarboxylic acid (1.03 g, 8.22 mmol) in MeOH (5 mL) and dioxane (5 mL) at room temperature, trimethylsilyldiazomethane (2M in ether, 5.0 mL, 10.0 mmol) was added. After being stirred at room temperature for 1 h, the mixture was concentrated in vacuo to give methyl 1-methyl-2-pyrrolecarboxylate as a volatile oil (1.14 g).
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].[NH2:5][C@@H:6]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)[C:7]([OH:9])=[O:8].S(=O)(=O)(O)O>O1CCOCC1>[NH2:5][C@@H:6]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)[C:7]([O:9][C:2]([CH3:3])([CH3:1])[CH3:4])=[O:8]
Reactant: C=C(C)C
Reactant: N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Liquid isobutylene (45 ml) was slowly added to a mixture of (2S)-2-amino-3-(4-nitrophenyl)propionic acid (7.2 g), 1,4-dioxane (45 ml) and concentrated sulphuric acid (4.5 ml) in a pressure bottle. The vessel was sealed and the reaction mixture was agitated at ambient temperature for 24 hours and then carefully opened. The excess of isobutylene was allowed to evaporate. The reaction mixture was poured into an ice-cold mixture of ethyl acetate (250 ml) and 0.25M NaOH(aq) (300-400 ml). The pH of the two-phase system was adjusted to between 9 and 10, and the ethyl acetate layer was separated. The aqueous layer was re-extracted with ethyl acetate (200 ml) and the combined organic extracts were washed with water, dried (MgSO4) and evaporated to give t-butyl (2S)-2-amino-3-(4-nitrophenyl)propionate (6.9 g) as a brown oil which was used without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:19]=[CH:18][C:11]([O:12][CH2:13][CH:14]([OH:17])[CH2:15][NH2:16])=[CH:10][CH:9]=1.[CH3:20][C:21]1[CH:32]=[CH:31][C:24]([C:25]([CH2:27][C:28](=O)[CH3:29])=[O:26])=[CH:23][N:22]=1.C(O)C>C(O)=O>[CH3:20][C:21]1[CH:32]=[CH:31][C:24]([C:25]([CH:27]=[C:28]([NH:16][CH2:15][CH:14]([OH:17])[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:8]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:19][CH:18]=2)[CH3:29])=[O:26])=[CH:23][N:22]=1
Reactant: CC(=O)CC(=O)c1ccc(C)nc1
Reactant: COCCCCOc1ccc(OCC(O)CN)cc1
Solvent: CCO
Solvent: O=CO
Product: COCCCCOc1ccc(OCC(O)CNC(C)=CC(=O)c2ccc(C)nc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 89 %

Procedure:
54.0 g of 1-(p-[4-methoxybutoxy]-phenoxy)-3-aminopropan-2-ol ##STR76## 37.3 g of 6-methylnicotinoyl-acetone ##STR77## 400 ml of ethanol and 0.1 ml of formic acid are heated to 50° for 1 hour and stirred at room temperature for a further 20 hours. Filtration gives 61.3 g of 1-(2-[6-methylnicotinoyl]-1-methylvinylamino)-3-(p-[4-methoxybutoxy]-phenoxy)-propan-2-ol ##STR78## Melting point: 143°-145°. A further 15.0 g of the same substance can be obtained from the filtrate. Yield: 89% of theory.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[CH3:4].[Cl:6][C:7]1[C:16]2[N:17]=[C:18]([CH2:23][O:24][CH2:25][CH3:26])[N:19]([CH2:20][C:21]#[CH:22])[C:15]=2[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:8]=1.C(N(CC)CC)C>ClCCl>[Cl:6][C:7]1[C:16]2[N:17]=[C:18]([CH2:23][O:24][CH2:25][CH3:26])[N:19]([CH2:20][C:21]3[O:1][N:2]=[C:3]([CH3:4])[CH:22]=3)[C:15]=2[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:8]=1
Reactant: C#CCn1c(COCC)nc2c(Cl)nc3ccccc3c21
Reactant: CC(Cl)=NO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCc1nc2c(Cl)nc3ccccc3c2n1Cc1cc(C)no1

Procedure:
N-Hydroxyethanimidoyl chloride (prepared as described in Part D of Example 1, 2.10 g, 22.5 mmol) was added to a solution of 4-chloro-2-(ethoxymethyl)-1-prop-2-ynyl-1H-imidazo[4,5-c]quinoline prepared as described in Part D of Example 3, 5.39 g, 18.0 mmol) and triethylamine (3.70 mL, 27.0 mmol) in dichloromethane (60 mL). The solution was heated at reflux for 16 hours and then was concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, gradient elution from 7:3 to 2:3 hexanes/ethyl acetate) to provide 4-chloro-2-(ethoxymethyl)-1-[(3-methylisoxazol-5-yl)methyl]-1H-imidazo[4,5-c]quinoline (4.21 g) as a white solid.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[NH:7][C:6](=[O:8])[C@H:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4]1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:23][S:24]([O:1][CH2:2][C@H:3]1[NH:7][C:6](=[O:8])[C@H:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4]1)(=[O:26])=[O:25]
Reactant: O=C1N[C@H](CO)C[C@H]1Cc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@@H]1C[C@@H](Cc2ccccc2)C(=O)N1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of the crude product from Step 2, in 5 ml of methylene chloride cooled to 0° C. was added triethylamine (42 mg, 0.41 mmol) and methanesulfonyl chloride (47 mg, 0.41 mmol). The reaction was slowly allowed to warm to room temperature and was stirred for 18 hr after which time it was diluted with 30 ml of methylene chloride, washed with 30 ml of 10% citric acid solution, dried filtered and concentrated to afford the product as an oil.
Reaction SMILES: [OH:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[N:3]1.[CH3:13][N:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:15](Cl)=[O:16]>>[N:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:4]1[CH:5]=[CH:6][N:2]([O:1][C:15](=[O:16])[N:14]([CH3:13])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:3]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: On1ccc(-c2ccccn2)n1
Product: CN(C(=O)On1ccc(-c2ccccn2)n1)c1ccccc1

Procedure:
The title compound was prepared from 1-hydroxy-3-(2-pyridyl)pyrazole and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (90%, oil).
Reaction SMILES: C([C:3]1([CH2:17][CH3:18])[S:7][CH:6]([C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])[CH:5]=[C:4]1[C:14]([NH2:16])=[S:15])C.Br[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=O>>[CH2:17]([C:3]1[S:7][C:6]([C:8]([O:10][CH:11]([CH3:12])[CH3:13])=[O:9])=[CH:5][C:4]=1[C:14]1[S:15][CH:20]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:16]=1)[CH3:18]
Reactant: O=C(CBr)c1ccccc1
Reactant: CCC1(CC)SC(C(=O)OC(C)C)C=C1C(N)=S
Product: CCc1sc(C(=O)OC(C)C)cc1-c1nc(-c2ccccc2)cs1
Yield: 48.4 %

Procedure:
A solution of 450 mg (1.75 mmol) of isopropyl 5-ethyl-4-(aminothioxomethyl)-5-ethylthiophene-2-carboxylate was reacted with 348 mg (1.75 mmol) of 2-bromoacetophenone (Aldrich, Milaukee, Wis., USA) in a manner similar to Example 8, step (a) to give isopropyl 5-ethyl-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxylate (303 mg, 49%) as an off-white solid. 1H-NMR (DMSO-d6; 300 MHz) δ8.22 (s, 1H), 8.07 (s, 1H), 8.03 (m, 2H), 7.49 (m, 2H), 7.38 (m, 1H), 5.13 (septet, 1H, J=6.2 Hz), 3.34 (q, 2H, J=7.4 Hz), 1.39 (t, 3H, J=7.4 Hz), 1.33 (d, 6H, J=6.2 Hz). Mass spectrum (ESI, m/z): Calcd. for C19H19NO2S2 358.1 (M+H), found 358.1.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]1[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=1)=[O:36]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]3[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=3)=[O:36])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: Cc1ccc(C(=O)CCCCCBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2ccc(C)cc2)CC1
Yield: 44.2 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.5 g) as starting compound, potassium carbonate (2.5 g) and 6-bromo-1-(4-methylphenyl)-1-hexanone (1.3 g) were reacted and treated in the same manner as in Example 172 to give 0.87 g of 4-amino-5-chloro-2-methoxy-N-((1-(6-(4-methylphenyl)-6-oxohexyl)piperidin-4-yl)-methyl)benzamide.
Reaction SMILES: O[CH2:2][CH2:3][O:4]/[N:5]=[C:6](/[C:8]1[CH:9]=[CH:10][C:11]2[N:12]([C:14]([CH2:17][C:18]3[C:19]([F:29])=[C:20]4[C:25](=[CH:26][C:27]=3[F:28])[N:24]=[CH:23][CH:22]=[CH:21]4)=[N:15][N:16]=2)[N:13]=1)\[CH3:7].COCCN(S(F)(F)[F:40])CCOC.C([O-])(O)=O.[Na+]>C(Cl)Cl.C1(C)C=CC=CC=1>[F:40][CH2:2][CH2:3][O:4]/[N:5]=[C:6](/[C:8]1[CH:9]=[CH:10][C:11]2[N:12]([C:14]([CH2:17][C:18]3[C:19]([F:29])=[C:20]4[C:25](=[CH:26][C:27]=3[F:28])[N:24]=[CH:23][CH:22]=[CH:21]4)=[N:15][N:16]=2)[N:13]=1)\[CH3:7]
Reactant: C/C(=N\OCCO)c1ccc2nnc(Cc3c(F)cc4ncccc4c3F)n2n1
Reactant: COCCN(CCOC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C/C(=N\OCCF)c1ccc2nnc(Cc3c(F)cc4ncccc4c3F)n2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
To a solution of (E)-1-(3-((5,7-difluoroquinolin-6-yl)methyl)-[1,2,4]-triazolo[4,3-b]pyridazin-6-yl)ethanone O-2-hydroxyethyl oxime (example 54) (20 mg, 0.05 mmol) in dry DCM (4 mL) was added bis-(2-methoxyethyl)aminosulfur trifluoride (a 3.2 M solution in toluene, 0.13 mL, 0.4 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h, and then at 35° C. overnight. LC-MS showed the reaction was complete, and 5 mL of saturated NaHCO3 solution was added. The mixture was extracted with DCM; the organic phase was dried over Na2SO4, filtered, concentrated, and purified by column chromatography to afford 6.8 mg (34%) of the title compound as a white solid. 1H-NMR (400 MHz, CDCl3) δ ppm 8.95 (dd, 1H), 8.41 (dd, 1H), 8.00 (d, 1H), 7.81 (d, 1H), 7.66 (d, 1H), 7.46 (dd, 1H), 4.83 (s, 2H), 4.78 (dd, 1H), 4.67 (dd, 1H), 4.56 (dd, 1H), 4.49 (dd, 1H), 2.33 (s, 3H). LCMS (method A): [MH]+=401, tR=5.44 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][NH:6][CH:7]1[C:15]2[C:10](=[C:11]([O:16][CH3:17])[CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8]1)[CH3:2].[C:19]([S:22][CH2:23][CH:24]([CH3:28])[C:25](Cl)=[O:26])(=[O:21])[CH3:20].O>CC(N(C)C)=O>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][N:6]([C:25](=[O:26])[CH:24]([CH3:28])[CH2:23][S:22][C:19](=[O:21])[CH3:20])[CH:7]1[C:15]2[C:10](=[C:11]([O:16][CH3:17])[CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8]1)[CH3:2]
Reactant: CC(=O)SCC(C)C(=O)Cl
Reactant: CCOC(=O)CNC1CCc2c(OC)cccc21
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)CN(C(=O)C(C)CSC(C)=O)C1CCc2c(OC)cccc21
Temperature: 25 °C
Yield: 67.6 %

Procedure:
N-(4-Methoxy-1-indanyl)glycine ethyl ester (3.0 g) is dissolved in 30 ml of dimethylacetamide, then 3.3 g of 3-acetylthio-2-methylpropionyl chloride is added dropwise with stirring at room temperature, and the mixture is stirred at room temperature for 2 hours. The reaction mixture is poured into 200 ml of water, and extracted with ethyl acetate. The extract is washed with 10 ml of 10% hydrochloric acid and with water and dried, and ethyl acetate is distilled off under reduced pressure. The residue is purified by subjecting to silica gel column chromatography eluted with acetone-benzene (1:20), to give 3.2 g of N-(3-acetylthio-2-methylpropionyl)-N-(4-methoxy-1-indanyl)glycine ethyl ester as a colorless oil.
Reaction SMILES: [CH:1]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[C:19]1[CH:33]=[CH:32][C:22]([CH2:23]P(=O)(OCC)OCC)=[CH:21][CH:20]=1.[CH2:34]([N:36]1[C:48]2[CH:47]=[CH:46][C:45]([CH:49]=O)=[CH:44][C:43]=2[C:42]2[C:37]1=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH3:35].CC(C)([O-])C.[K+]>C1COCC1>[CH2:34]([N:36]1[C:48]2[CH:47]=[CH:46][C:45](/[CH:49]=[CH:23]/[C:22]3[CH:32]=[CH:33][C:19]([C:2]4[CH:3]=[CH:4][C:5]5[C:6]6[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=6)[C:12]6[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=6)[C:18]=5[CH:1]=4)=[CH:20][CH:21]=3)=[CH:44][C:43]=2[C:42]2[C:37]1=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH3:35]
Reactant: CCn1c2ccccc2c2cc(C=O)ccc21
Reactant: CCOP(=O)(Cc1ccc(-c2ccc3c4ccccc4c4ccccc4c3c2)cc1)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCn1c2ccccc2c2cc(/C=C/c3ccc(-c4ccc5c6ccccc6c6ccccc6c5c4)cc3)ccc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 78 %

Procedure:
Compound E (100 mg, 0.22 mmol) or E1 and N-ethylcarbazole-3-carboxaldehyde) (59 mg, 0.26 mmol) and dry THF (10 ml) were charged in two-necked bottle in an ice bath, potassium-tert-butoxide (49 mg, 0.44 mmol) in dry THF (10 ml) was added under nitrogen. The reaction mixture was stirred for 15 min at 0° C., followed by 1 h at room temperature. The solution mixture was extracted with ethyl acetate and washed with water. The combined organic layers were dried over MgSO4 and the solvent removed under reduced pressure to afford a crude product that was purified by sublimating at a temperature of 260° C. to obtain TSCz (90 mg, yield=78%) as yellow solid.