Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH:7]([NH:14][S:15]([C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([OH:23])=[O:22])(=[O:17])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:28][C:29]1[CH:30]=[N+:31]([O-:49])[CH:32]=[C:33]([Cl:48])[C:34]=1[CH2:35][C@@H:36]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[C:40]([O:46][CH3:47])[CH:39]=1)O.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[C:1]([O:5][C:6](=[O:27])[CH:7]([NH:14][S:15]([C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([O:23][C@H:36]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[C:40]([O:46][CH3:47])[CH:39]=1)[CH2:35][C:34]1[C:33]([Cl:48])=[CH:32][N+:31]([O-:49])=[CH:30][C:29]=1[Cl:28])=[O:22])(=[O:17])=[O:16])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C(NS(=O)(=O)c1cccc(C(=O)O)c1)c1ccccc1
Reactant: COc1ccc([C@@H](O)Cc2c(Cl)c[n+]([O-])cc2Cl)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2cccc(S(=O)(=O)NC(C(=O)OC(C)(C)C)c3ccccc3)c2)cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 60 %

Procedure:
3-[(2-tert-Butoxy-2-oxo-1-phenyl-ethyl)sulfamoyl]benzoic acid (1.216 g, 3.11 mmol) was added to a stirred suspension of (S)-3,5-dichloro-4-(2-(3,4-dimethoxyphenyl)-2-hydroxyethyl)pyridine 1-oxide (1.07 g, 3.11 mmol) in N,N-dimethylformamide (12 mL). To the resultant solution was added N,N-4-(dimethylamino)pyridine (0.189 g, 1.55 mmol) followed by N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.192 g, 6.22 mmol) and the reaction was stirred at room temperature for 18 hours. After this time, the reaction mixture was concentrated under reduced pressure and water (30 mL) was added; the resulting off-white precipitate was filtered and dried in air. The crude material was purified over a 50 g silica cartridge on an ISOLERA system; eluting initially with iso-hexane with an increasing solvent gradient to 100% ethyl acetate over four column volumes, after which 100% ethyl acetate was maintained for six column volumes. The desired fractions were combined and concentrated under reduced pressure to yield the title product as a white solid (1.340 g, 60%).
Reaction SMILES: [ClH:1].[C:2]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][C@@H:14]3[CH2:16][C@H:11]2[C@@H:12]([NH:17][C@@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]2[NH:24]C(=O)OC(C)(C)C)[CH2:13]3)=[CH:6][CH:5]=1)#[N:3].CO>O1CCOCC1>[ClH:1].[ClH:1].[NH2:24][C@@H:19]1[CH2:20][CH2:21][CH2:22][CH2:23][C@H:18]1[NH:17][C@@H:12]1[C@H:11]2[CH2:16][C@H:14]([CH2:15][N:10]2[C:7]2[CH:8]=[CH:9][C:4]([C:2]#[N:3])=[CH:5][CH:6]=2)[CH2:13]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1N[C@H]1C[C@H]2C[C@@H]1N(c1ccc(C#N)cc1)C2
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: N#Cc1ccc(N2C[C@@H]3C[C@H](N[C@@H]4CCCC[C@H]4N)[C@H]2C3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A solution of HCl (4.0 N in 1,4-dioxane, 2 ml)) was added to a mixture of tert-butyl (1R,2R)-2-((1S,4S,6S)-2-(4-cyanophenyl)-2-azabicyclo[2.2.1]heptan-6-ylamino)cyclohexylcarbamate (445 mg, 1.084 mmol) in 1,4-dioxane (2 ml). The starting material formed a gum. MeOH (1 mL) was then added. Eventually all solids went into solution. The reaction was stirred at rt for 2 hrs. The reaction mixture was concentrated to give 4-((1R,4R,6S)-6-((1R,2R)-2-aminocyclohexylamino)-2-azabicyclo[2.2.1]heptan-2-yl)benzonitrile bishydrochloride (440 mg, 1.084 mmol, 100% yield) of an off white solid. Calcd. for C19H26N4 m/z 310.4, found: 311.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH3:17][O:18][C:19]1[CH:40]=[CH:39][C:22]([CH2:23][N:24]2[C:32]3[C:27](=[CH:28][C:29](/[C:33](/[CH3:38])=[CH:34]/[C:35](O)=[O:36])=[CH:30][CH:31]=3)[CH:26]=[CH:25]2)=[CH:21][CH:20]=1>>[CH3:17][O:18][C:19]1[CH:40]=[CH:39][C:22]([CH2:23][N:24]2[C:32]3[C:27](=[CH:28][C:29](/[C:33](/[CH3:38])=[CH:34]/[C:35]([NH:1][C:2]4[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=4[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:36])=[CH:30][CH:31]=3)[CH:26]=[CH:25]2)=[CH:21][CH:20]=1
Reactant: CCOC(=O)CCCOc1ccccc1N
Reactant: COc1ccc(Cn2ccc3cc(/C(C)=C/C(=O)O)ccc32)cc1
Product: COc1ccc(Cn2ccc3cc(/C(C)=C/C(=O)Nc4ccccc4OCCCC(=O)O)ccc32)cc1

Procedure:
270 mg of compound 35 was obtained in a similar manner to those described in the Examples 1 and 2 using 615 mg of ethyl 4-(2-aminophenoxy)butyrate and 443 mg of 3-[1-(4-methoxybenzyl)indol-5-yl]isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([CH:12](O)[CH2:13][C:14](=[O:16])[CH3:15])[CH:9]=[CH:10][CH:11]=2)=[CH:2]1.CS(Cl)(=O)=O.C(N(CC)CC)C>C(OCC)(=O)C>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8](/[CH:12]=[CH:13]/[C:14](=[O:16])[CH3:15])[CH:9]=[CH:10][CH:11]=2)=[CH:2]1
Reactant: CC(=O)CC(O)c1cccc(-c2ccsc2)c1
Agent: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)/C=C/c1cccc(-c2ccsc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The resulting alcohol compound was dissolved in 2 ml of ethyl acetate, and 207 mg of methanesulfonyl chloride and 366 mg of triethylamine were added. The mixture was stirred overnight at room temperature, and then the precipitate was removed by filtration. The filtrate was worked up in a customary manner, and the product was purified by silica gel column chromatography [hexane/ethyl acetate=5/1] to give 327 mg of the captioned compound as a pale yellow powder.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[C:24](Cl)(=[O:29])[CH2:25][CH:26]([CH3:28])[CH3:27].C(N(CC)C(C)C)(C)C>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:24](=[O:29])[CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: CC(C)CC(=O)Cl
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)N1c2ccc(NC(=O)CC(C)C)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Acylation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with isovaleryl chloride (7.8 mg) and N,N-diisopropylethylamine (22 l) in tetrahydrofuran (1 ml) was performed according to the method described in example 6.
Reaction SMILES: [C:1]([C:4]1[C:9]([CH3:10])=[CH:8][C:7]([NH:11]C(=O)C)=[CH:6][C:5]=1[Cl:15])(=[O:3])[CH3:2].Cl.[OH-].[Na+]>C(O)C>[NH2:11][C:7]1[CH:8]=[C:9]([CH3:10])[C:4]([C:1](=[O:3])[CH3:2])=[C:5]([Cl:15])[CH:6]=1
Reactant: CC(=O)Nc1cc(C)c(C(C)=O)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)c1c(C)cc(N)cc1Cl
Yield: 87.6 %

Procedure:
An ethanol solution (4.0 mL) containing N-(4-acetyl-3-chloro-5-methylphenyl)acetamide (0.53 g, 2.3 mmol) and concentrated hydrochloric acid (1.6 mL) was heated at reflux for 15 h. The solution was added with 10% aqueous NaOH and the resultant solids were collected to give 1-(4-amino-2-chloro-6-methylphenyl)ethanone (0.37 g) as light yellow solids in 88% yield: 1H NMR (500 MHz, CDCl3) δ 6.46 (d, J=1.77 Hz, 1H), 6.34 (s, 1H), 3.85 (bs, 2H), 2.49 (s, 3H), 2.14 (s, 3H): ESI-MS: m/z 183.4 (M+H)+.
Reaction SMILES: CC1(C)[O:7][CH2:6][CH:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][C:16]3[N:17]=[C:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:19][C:20]=3[CH3:21])[CH:10]=2)[CH2:4][O:3]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)C>[OH:7][CH2:6][CH:5]([CH2:4][OH:3])[CH2:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[CH2:15][C:16]1[N:17]=[C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:19][C:20]=1[CH3:21]
Reactant: Cc1oc(-c2ccccc2)nc1Cc1cccc(CC2COC(C)(C)OC2)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1Cc1cccc(CC(CO)CO)c1
Yield: 106.6 %

Procedure:
A mixture solution of 320 mg of 2,2-dimethyl-5-{3-[(5-methyl-2-phenyloxazol-4-yl)methyl]benzyl}-1,3-dioxane, 21 ml of ethanol and 21 mg of pyridinium p-toluenesulfonate (PPTS) was stirred for 2 hours at 55–60° C. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (Wakogel® C-200, chloroform) to provide 305 mg of the objective compound as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:9]2[C:17]3[C:12](=[C:13]([CH2:18][S:19][CH3:20])[CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[C:4]([CH3:28])[CH:3]=1.ClCCl.ClC1C=CC=C(C(OO)=[O:40])C=1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)[C:9]2[C:17]3[C:12](=[C:13]([CH2:18][S:19]([CH3:20])=[O:40])[CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[C:4]([CH3:28])[CH:3]=1
Reactant: CSCc1cccc2c(C(c3ccc(F)cc3)c3ccc(Cl)cc3C)c[nH]c12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(Cl)ccc1C(c1ccc(F)cc1)c1c[nH]c2c(CS(C)=O)cccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
130 mg (0.32 mmol) of the compound from Example 102 were introduced into 15 ml of dichloromethane at 0° C., 78 mg (0.32 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT for 2 h. 2 ml of methanol were added, and the solution was concentrated. The residue was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 129 mg (96% of theory) of the title compound were obtained as mixture of diastereomers.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([CH:11]=[O:12])[O:10][C:6]=2[C:5]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]2=[O:25])=[C:4]([F:26])[CH:3]=1.CC(C)=[O:29].OS(O)(=O)=O.O=[Cr](=O)=O.O>CC(C)=O>[C:11]([C:9]1[O:10][C:6]2[C:5]([N:13]3[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]3=[O:25])=[C:4]([F:26])[CH:3]=[C:2]([Cl:1])[C:7]=2[CH:8]=1)([OH:29])=[O:12]
Reactant: CC(C)=O
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3cc(C=O)oc23)c1=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3cc(C(=O)O)oc23)c1=O
Yield: 76.9 %

Procedure:
1.5 g (3.84 mmol) of 3-(4-chloro-6-fluoro-2-formylbenzofuran-7-yl)-1-methyl-6-trifluoromethyluracil was dissolved in 20 ml of acetone, and a Jones' reagent was dropwise added thereto at 5° C. until the orange color no longer disappeared. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed sequentially with water and a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 1.2 g (yield: 76.9%) of the desired product as white crystals. Melting point: 267-268° C. (decomposed).
Reaction SMILES: [CH:1]([C:3]1[N:7]([CH3:8])[CH:6]=[C:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:4]=1)=O.[CH3:16][C:17]([S@@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18].O>C(Cl)Cl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[C:17]([S@@:20](/[N:22]=[CH:1]/[C:3]1[N:7]([CH3:8])[CH:6]=[C:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:4]=1)=[O:21])([CH3:19])([CH3:18])[CH3:16]
Reactant: Cn1cc(C(=O)OC(C)(C)C)cc1C=O
Reactant: CC(C)(C)[S@@](N)=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: O
Solvent: ClCCl
Product: Cn1cc(C(=O)OC(C)(C)C)cc1/C=N/[S@@](=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 64 %

Procedure:
To a solution of tert-butyl 5-formyl-1-methyl-1H-pyrrole-3-carboxylate (3.0 g, 14.5 mmol), (S)-2-methylpropane-2-sulfinamide (2.6 g, 21.8 mmol) in DCM (200 mL) was added titanium isopropoxide (24.8 g, 87 mmol). The mixture was stirred at rt for 20 h then water (30 mL) was added to quench the reaction. The solid precipitate was filtered and the filtrate was concentrated and purified by flash column chromatography (petroleum ether:EtOAc, 5:1) to give (S,E)-tert-butyl 5-((tert-butylsulfinylimino)methyl)-1-methyl-1H-pyrrole-3-carboxylate (2.9 g, 63%). 1H NMR (CDCl3, 400 MHz) δ 8.30 (s, 1H), 7.29 (s, 1H), 7.02 (s, 1H), 3.89 (s, 3H), 1.48 (s, 9H), 1.16 (s, 9H).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:24]=[CH:23][C:22]2[C:13](=[CH:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[C:1]1([C:18]2[CH:17]=[CH:16][C:15]3[C:20](=[CH:21][C:22]4[C:13]([CH:14]=3)=[CH:12][CH:11]=[CH:24][CH:23]=4)[CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Brc1ccc2cc3ccccc3cc2c1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: c1ccc(-c2ccc3cc4ccccc4cc3c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.1 %

Procedure:
Under an argon atmosphere, 14.5 g of phenylboronic acid, 25.7 g of 2-bromoanthracene, 4.62 g of tetraxis(triphenylphosphine)palladium(0), 400 mL of toluene and 200 mL of a 2M aqueous solution of sodium carbonate were mixed. The resultant was refluxed with stirring for 8 hours. After cooling to room temperature, deposited crystals were separated by filtration. By repetition of recrystallization and washing of the obtained solids using toluene-hexane, 19.1 g (yield: 75%) of 2-phenylanthracene was obtained.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([CH3:10])=[O:9].O=S(Cl)Cl.[CH3:25][CH2:26]O>>[C:8]([NH:7][CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]([NH2:1])[C:11]([O:13][CH2:25][CH3:26])=[O:12])(=[O:9])[CH3:10]
Reactant: CC(=O)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)[C@H](N)CCCCNC(C)=O
Temperature: -10 °C
Yield: 80 %

Procedure:
Boc-Lys(Ac)-OH (1 equivalent, 0.2 g, 0.69 mmol) was dissolved in EtOH (2 mL). The reaction mixture was cooled at −10° C., and SOCl2 (1.5 equivalent, 76 μl, 1.035 mmol) was added dropwise. The mixture was allowed to warm to room temperature, then heated at 40° C. for 20 h (TLC control). The reaction mixture was concentrated and the crude was purified by flash chromatography (CH2Cl2/MeOH) to afford the compound (120 mg, 80%) as a white solid Rf=0.62 (CH2Cl2/MeOH 70/30).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]([CH2:28][CH2:29][OH:30])[C:12]([C:14]1[S:27][C:17]2[C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1)=[O:13])[C:5](O)=[O:6].[CH3:31][N:32]([CH3:37])[CH2:33][CH2:34][NH:35][CH3:36]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[N:35]([CH2:34][CH2:33][N:32]([CH3:37])[CH3:31])[CH3:36])[CH:8]=[CH:9][C:10]=1[N:11]([CH2:28][CH2:29][OH:30])[C:12]([C:14]1[S:27][C:17]2[C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1)=[O:13]
Reactant: CNCCN(C)C
Reactant: O=C(O)c1ccc(N(CCO)C(=O)c2cc3c(s2)-c2ccccc2OCC3)c(Cl)c1
Product: CN(C)CCN(C)C(=O)c1ccc(N(CCO)C(=O)c2cc3c(s2)-c2ccccc2OCC3)c(Cl)c1
Yield: 35 %

Procedure:
Following Example 91, 3-chloro-4-(N-(2-hydroxyethyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)benzoic acid and N1,N1,N2-trimethylethane-1,2-diamine were reacted to give 118 (yield 35% of theoretical). MS: (ESI+) 528.2
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].[H-].[Na+].[CH:30]1([OH:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>O1CCOCC1.CN(C=O)C>[CH:30]1([O:36][C:2]2[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=2)[C:5]([NH:7][C:8]2[S:9][C:10]3[C:16]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=3[N:12]=2)=[O:6])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: OC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(OC4CCCCC4)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with sodium hydride and cyclohexanol in dioxane and DMF. ES-MS m/e (%): 469 (M+H+, 100).
Reaction SMILES: Cl([O-])(=O)(=O)=O.[CH:6]1([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][N+:17]([CH2:20][CH2:21][CH2:22][C:23](=[O:31])[C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[CH:16][CH:15]=3)[N:10]=2)[CH2:8][CH2:7]1.CO.[BH4-].[Na+]>O>[CH:6]1([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][CH:23]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[OH:31])[CH2:16][CH:15]=3)[N:10]=2)[CH2:7][CH2:8]1
Reactant: O=C(CCC[n+]1ccc(-c2noc(C3CC3)n2)cc1)c1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CO
Solvent: O
Product: OC(CCCN1CC=C(c2noc(C3CC3)n2)CC1)c1ccc(F)cc1

Procedure:
To a 1.8 g. portion of 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-1-[3-(p-fluorobenzoyl)-propyl]pyridinium perchlorate, prepared as described in Example 3, in 80 ml. of methanol is added, portionwise with stirring, 1.8 g. of sodium borohydride. The mixture is stirred for 2 hours and then poured into 300 ml. of cold water, causing a white solid to separate. This solid is collected and recrystallized from acetonitrile, m.p. 89°-92°C.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].[F:7][CH:8]([C:12](=O)[CH3:13])[C:9](=O)[CH3:10].N1CCCCC1>CCO>[F:7][C:8]1[C:12]([CH3:13])=[C:3]([C:1]#[N:2])[C:4](=[O:5])[NH:6][C:9]=1[CH3:10]
Reactant: N#CCC(N)=O
Reactant: CC(=O)C(F)C(C)=O
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(=O)c(C#N)c(C)c1F
Reaction time: 3 h
Yield: 58.8 %

Procedure:
To a stirred solution of 2-cyanoacetamide (689 mg, 8.2 mmol) in anhydrous EtOH (7.0 ml) at 75° C., was added 3-fluoropentane-2,4-dione (880 mg, 7.5 mmol), followed by piperidine (96 μl, 0.97 mmol). The reaction mixture was stirred at this temperature for 3 hours and the reaction mixture left to reach room temperature before being stored in the refrigerator for 4 days. The beige solid was collected by filtration and rinsed with cold EtOH (4×0.4 ml) until the filtrate ran clear. The resulting beige solid was dried in-vacuo at 40° C. for 5 hours to give the title compound (733 mg, 58%) as a beige solid. LC-MS 97%, 1.18 min (3.5 minute LC-MS method); m/z=166.9, 1H NMR (500 MHz, Chloroform-d) δ ppm 13.67 (br. s., 1H) 2.46 (d, J=2.05 Hz, 3H) 2.45 (d, J=2.84 Hz, 3H).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:16])[O:4][C:5]1[C:13]2[O:12][C:11]([CH3:15])([CH3:14])[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[C:17]([CH2:19][CH2:20][N:21]([CH2:24][CH2:25][C:26]#[N:27])[S:22]Cl)#[N:18].N1C=CC=CC=1>C(Cl)Cl>[C:17]([CH2:19][CH2:20][N:21]([CH2:24][CH2:25][C:26]#[N:27])[S:22][N:2]([CH3:1])[C:3](=[O:16])[O:4][C:5]1[C:13]2[O:12][C:11]([CH3:14])([CH3:15])[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)#[N:18]
Reactant: N#CCCN(CCC#N)SCl
Reactant: CNC(=O)Oc1cccc2c1OC(C)(C)C2
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(SN(CCC#N)CCC#N)C(=O)Oc1cccc2c1OC(C)(C)C2
Reaction time: 20 h

Procedure:
4.4 g (0.02 mole) of 2,3-dihydro-2,2-dimethylbenzofuran-7-yl N-methyl-carbamate, 3.8 g (0.02 mole) of bis(cyanoethyl)aminosulfenyl chloride obtained in Example 31, and 4.7 g (0.06 mole) of pyridine were dissolved in 35 ml of methylene chloride, and the resulting solution was stirred for 20 hours at 25° to 30° C. After completion of the reaction, the reaction solution was washed successively with water, diluted hydrochloric acid and water. The methylene chloride layer was dried over sodium sulfate and concentrated under reduced pressure to obtain an oily product which was almost entirely composed of the desired product although containing small amounts of the starting materials and impurities. Yield: 6.2 g (82.7%).
Reaction SMILES: [C:1]1([C@H:7]2[CH2:11][C@@H:10]([N:12]3[C:20](=[O:21])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:22])[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.[F-].[Na+].[F:32][C:33]([F:45])(S(F)(=O)=O)C(O[Si](C)(C)C)=O>CCOC(C)=O>[F:32][C:33]1([F:45])[C@@H:9]2[C@H:8]1[C@@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:11][C@H:10]2[N:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22]
Reactant: C[Si](C)(C)OC(=O)C(F)(F)S(=O)(=O)F
Reactant: O=C1c2ccccc2C(=O)N1[C@H]1C=C[C@@H](c2ccccc2)C1
Agent: [F-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1[C@@H]1C[C@H](c2ccccc2)[C@@H]2[C@H]1C2(F)F
Reaction time: 2 h
Yield: 29.4 %

Procedure:
A mixture of Example 54A (419 mg, 1.45 mmol), toluene (0.2 mL), and sodium fluoride (21.3 mg, 0.507 mmol) was heated in a 120° C. oil bath and trimethylsilyl 2,2-difluoro-2-(fluorosulfonyl)acetate (1.43 mL, 7.24 mmol) was added via syringe pump over 2 hours. After 2 hours, the mixture was diluted with EtOAc (50 mL) and washed with saturated aqueous NaHCO3 (25 mL) and brine (10 mL), dried (Na2SO4), and concentrated. The residue was purified by flash column chromatography (0-25% EtOAc/hexanes, gradient elution) to provide the title compound (145 mg, 0.427 mmol, 30% yield). MS (DCI) M/Z 357 [M+NH4]+.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:21][CH:22]([SH:24])[CH3:23].Cl>CN(C)C(=O)C>[CH:22]([S:24][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])([CH3:23])[CH3:21]
Reactant: CS(=O)(=O)c1ccc(F)c(C(=O)O)c1
Reactant: CC(C)S
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CC(C)Sc1ccc(S(C)(=O)=O)cc1C(=O)O
Temperature: 90 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
To a solution of 4.58 mmol 2-fluoro-5-methanesulfonyl-benzoic acid in 6 ml N,N-dimethylacetamide were added 15.2 mol cesium carbonate and 10.1 mmol 2-propanethiol, and the mixture was stirred at 90° C. for 3 h. The reaction mixture was then cooled to room temperature and acidified to pH 1 by addition of hydrochloric acid before being extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo to afford the title compound as a light yellow liquid which was used in the next step without further purification (yield 99%). EI-MS (m/e): 274.1 (M+, 35%), 232.1 ([M-C3H6]+, 30%, 214.1 (M-C3H6—H2O)+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH:16]=[CH:17][N:18]4[CH2:23][C:24]([NH2:26])=[O:25])[N:10]=2)[CH:5]=[N:6][C:7]=1Cl.[CH:27]([NH2:30])([CH3:29])[CH3:28]>O1CCOCC1.CN1C(=O)CCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH:16]=[CH:17][N:18]4[CH2:23][C:24]([NH2:26])=[O:25])[N:10]=2)[CH:5]=[N:6][C:7]=1[NH:30][CH:27]([CH3:29])[CH3:28]
Reactant: CC(C)N
Reactant: NC(=O)Cn1ccc2c(-c3noc(-c4cnc(Cl)c(Cl)c4)n3)cccc21
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: CC(C)Nc1ncc(-c2nc(-c3cccc4c3ccn4CC(N)=O)no2)cc1Cl
Temperature: 150 °C
Reaction time: 1 h

Procedure:
To a mixed solution of 2-{4-[5-(5,6-dichloropyridin-3-yl)-1,2,4-oxadiazol-3-yl]-1H-indol-1-yl}acetamide (100 mg) in dioxane (2 ml) and NMP (2 ml) was added isopropylamine (2200, followed by stirring at 150° C. for 1 hour in a microwave reaction vessel. The reaction mixture was concentrated under reduced pressure, and then the residue was purified by silica gel chromatography (n-hexane:EtOAc=40:60 to 0:100), and the obtained residue was suspended in diisopropyl ether under heating, and collected by filtration to obtain 2-(4-{5-[5-chloro-6-(isopropylamino)pyridin-3-yl]-1,2,4-oxadiazol-3-yl}-1H-indol-1-yl)acetamide (62 mg) as white powders.