Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[Cl:15].C(=O)(O)[O-].[Na+].Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24]>ClCCl>[Cl:15][C:9]1[CH:10]=[C:11]([Cl:14])[CH:12]=[CH:13][C:8]=1[C:7]([C:3]1[N:2]([NH:1][C:23](=[O:24])[O:25][CH2:26][CH3:27])[CH:6]=[CH:5][CH:4]=1)=[O:16]
Reactant: CCOC(=O)Cl
Reactant: Nn1cccc1C(=O)c1ccc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)Nn1cccc1C(=O)c1ccc(Cl)cc1Cl
Yield: 35.5 %

Procedure:
To a stirred slurry of 1-amino-2-(2,4-dichlorobenzoyl)pyrrole (377.6 g) and sodium bicarbonate (286.0 g) in 2.0 L of dichloromethane was added ethyl chloroformate (176.90 g) over 10 min. The reaction mixture was heated at reflux for 4 hrs and then quenched with H2O. The organic layer was washed with brine, dried (MgSO4), charcoaled, filtered and concentrated to a maroon oil. This oil was purified by flash chromatography (silica, dichloromethane) and concentrated to a green powder which was recrystallized from ether to give 171.8 g of white crystals, mp 114°-116°.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]1[C:15]2([CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)[S:14][CH:13]([CH:27]([N:35]2C(=O)C3=CC=CC=C3C2=O)[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[NH:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN.Cl.O>CN(C=O)C>[NH2:35][CH:27]([CH:13]1[NH:12][CH:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[C:15]2([CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)[S:14]1)[C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29]
Reactant: CC(C)(C)OC(=O)C(C1NC(C(=O)OCc2ccccc2)C2(CCN(c3ccccc3)CC2)S1)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: NN
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(N)C1NC(C(=O)OCc2ccccc2)C2(CCN(c3ccccc3)CC2)S1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.7 %

Procedure:
18.6 g (0.03 mole) of tert-butyl 4-benzyloxycarbonyl-8-phenyl-alpha-phthalimido-1-thia-3,8-diazaspiro[4.5]decane-2-acetate (obtained in 3.3) are suspended in 50 ml of N,N'-dimethylformamide. A solution containing 2 g (0.04 mole) of hydrazine hydrate in 20 ml of N,N-dimethylformamide is added dropwise at 0° C. under an atmosphere of nitrogen. The reaction mixture is allowed to warm up to ambient temperature and stirred for 1 hour. The reaction mixture is then again cooled to 0° C. and slowly neutralized by the addition of 33.75 ml of 1N hydrochloric acid, whereafter it is stirred at ambient temperature for 2 hours after which time it solidifies. 300 ml of water are added, followed by extraction with chloroform. The organic phase is washed with water, dried with anhydrous sodium sulfate and evaporated to dryness. The residue is triturated with diethyl ether, filtered and the precipitate washed with diethyl ether. There are obtained 12.8 g of tert-butyl alpha-amino-4-benzyloxycarbonyl-8-phenyl-1 -thia-3,8-diazaspiro[4.5]decane-2-acetate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:14][CH:15](Cl)[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CC#N>[Cl:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]2)=[CH:18][CH:17]=1
Reactant: Cc1ccc(C(Cl)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(CCl)cc2)CC1
Yield: 47.2 %

Procedure:
To a CH3CN (250 mL) solution of piperazine-1-carboxylic acid tert-butyl ester (19.8 g) and alpha,alpha-dichloro-p-xylene (18.6 g) was added DIPEA (18.5 mL) under a N2 atmosphere, then the resultant mixture was stirred at room temperature for 3 days. The reaction mixture was poured into saturated aqueous NaHCO3 (600 mL) and extracted with AcOEt (900 mL). The organic layer was washed with saturated aqueous NaCl (300 mL), dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=3/1) to afford tert-butyl 4-[4-(chloromethyl)benzyl]piperazine-1-carboxylate (16.3 g) as a white powder.
Reaction SMILES: [Cl:1][C:2]([F:9])([C:5]([F:8])([F:7])[F:6])[CH2:3][OH:4].[C:10](OC(=O)C)(=[O:12])[CH3:11]>>[C:5]([C:2]([CH2:3][O:4][C:10]([CH3:11])=[O:12])([F:9])[Cl:1])([F:8])([F:7])[F:6]
Reactant: OCC(F)(Cl)C(F)(F)F
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OCC(F)(Cl)C(F)(F)F

Procedure:
Example 6 illustrates the esterification of 2-chloro-2,3,3,3-tetrafluoropropanol (CF3CClFCH2OH) with acetic anhydride to produce CF3CClFCH2OC(═O)CH3 and the reaction products obtained from this esterification.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH2:12][C@@H:11]([NH:14][C:15](=[O:17])[CH3:16])[CH2:10]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.N1(/[C:32](/[NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[N:33]\[C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])C=CC=N1>C1COCC1>[C:44]([O:43][C:42](=[O:48])[NH:41]/[C:32](/[NH:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:13][CH2:12][C@@H:11]([NH:14][C:15](=[O:17])[CH3:16])[CH2:10]2)=[CH:7][CH:8]=1)=[N:33]/[C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(C)(C)OC(=O)/N=C(/NC(=O)OC(C)(C)C)n1cccn1
Reactant: CC(=O)N[C@@H]1CCN(c2ccc(N)cc2)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)N[C@@H]1CCN(c2ccc(N/C(=N\C(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc2)C1
Yield: 69.8 %

Procedure:
N-[(3R)-1-(4-aminophenyl)pyrrolidin-3-yl]acetamide mono hydrochloride (Method 43; 2.47 g, 9.67 mmol) and Hunigs base (2.02 ml, 1.16 mmol) were reacted with di-tert-butyl [(Z)-1H-pyrazol-1-ylmethylylidene]biscarbamate (2.95 g, 9.5 mmol) in THF (50 ml) at room temperature for 72 hours. After evaporation under reduced pressure, chromatography on silica gel with EtOAc/isohexane (50:50 to 100) gave the title compound as a yellow oil (3.06 g, 69%). NMR: 1.39 (s, 9H), 1.52 (s, 9H), 1.81 (s, 3H), 1.82-1.93 (m, 1H), 2.11-2.24 (m, 1H), 3.00-3.08 (m, 1H), 3.21-3.51 (m, 3H), 4.29-4.40 (m, 1H), 6.50 (d, 2H), 7.29 (d, 2H), 8.12 (d, 1H), 9.74 (s, 1H), 11.49 (s, 1H); m/z 462.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:9]#[CH:10])[CH:5]=[CH:6][C:7]=1[OH:8].[CH3:11][O:12][C:13]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[C:14]=1[CH2:15][SH:16].[Na]>>[OH:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[OH:8])/[CH:9]=[CH:10]\[CH:15]([S:16][CH:15](/[CH:10]=[CH:9]\[C:4]1[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([OH:1])[CH:3]=1)[C:14]1[C:17]([O:23][CH3:24])=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:13]=1[O:12][CH3:11])[C:14]1[C:17]([O:23][CH3:24])=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:13]=1[O:12][CH3:11]
Reactant: C#Cc1ccc(O)c(O)c1
Reactant: COc1cc(OC)c(CS)c(OC)c1
Agent: [Na]
Product: COc1cc(OC)c(C(/C=C\c2ccc(O)c(O)c2)SC(/C=C\c2ccc(O)c(O)c2)c2c(OC)cc(OC)cc2OC)c(OC)c1

Procedure:
A solution of 3,4-dihydroxyphenylacetylene (0.02 mol), 2,4,6-trimethoxybenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) is subjected to General Procedure 2 to form (Z)-3,4-dihydroxystyryl-2,4,6-trimethoxybenzylsulfide. The title compound is obtained following oxidation of the sulfide, according to General Procedure 2.
Reaction SMILES: C(O[C:4](=[O:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6])C.[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1>C(O)C>[CH3:9][CH2:8][O:7][C:5]([C:4]([NH:16][C:15]1[CH:17]=[CH:18][C:12]([F:11])=[CH:13][CH:14]=1)=[O:10])=[O:6]
Reactant: Nc1ccc(F)cc1
Reactant: CCOC(=O)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)C(=O)Nc1ccc(F)cc1
Yield: 60 %

Procedure:
Diethyloxalate (133 g) and p-fluoroaniline (100 g) were refluxed together for 2 hours, during which time the temperature dropped from 160° to 100°. The dark coloured mixture (with suspended crystalline solid) so produced was allowed to cool to 90°, and then diluted with ethanol (100 ml). After cooling overnight, the crystalline product was filtered off and washed thoroughly with cyclohexane. The white solid so obtained, was thoroughly dried to give ethyl 4'-fluorooxanilate (114 g; 60% yield), m.p. 117°-119° (with softening at 116°).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[C:12]3[N:13]([CH2:29][CH2:30][N:31]=3)[C:14]([NH:20][C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=3)=[N:15][C:16]=2[C:17]=1[O:18][CH3:19].[C:32]1([S:38](Cl)(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH3:19][O:18][C:17]1[C:16]2[N:15]=[C:14]([NH:20][C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=3)[N:13]3[CH2:29][CH2:30][N:31]=[C:12]3[C:11]=2[CH:10]=[CH:9][C:8]=1[O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][S:38]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:40])=[O:39]
Reactant: COc1c(OCCOCCN)ccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21
Reactant: O=S(=O)(Cl)c1ccccc1
Product: COc1c(OCCOCCNS(=O)(=O)c2ccccc2)ccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21

Procedure:
The procedure used for the preparation of Example 31, Step 5 was used to prepare the title compound from N-{8-[2-(2-aminoethoxy)-ethoxy]-7-methoxy-2,3-dihydro-imidazo[1,2-c]quinazolin-5-yl}-nicotinamide (Example 31, Step 4) and phenylsulfonyl chloride. HPLC MS RT=2.25 min, MH+=565.3.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[C:10]=2[CH3:18])=[N:5]1.[CH3:20][N:21]1[CH:25]=[C:24]([C:26](O)=[O:27])[N:23]=[CH:22]1>>[Cl:17][C:11]1[C:10]([CH3:18])=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:26]([C:24]3[N:23]=[CH:22][N:21]([CH3:20])[CH:25]=3)=[O:27])[CH3:19])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: Cc1c(-c2ccn(C[C@H](C)N)n2)ccc(C#N)c1Cl
Reactant: Cn1cnc(C(=O)O)c1
Product: Cc1c(-c2ccn(C[C@H](C)NC(=O)c3cn(C)cn3)n2)ccc(C#N)c1Cl
Yield: 38.7 %

Procedure:
(S)—N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)-1-methyl-1H-imidazole-4-carboxamide was prepared using the method of Example 34(d) starting from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile (300 mg, 1.092 mmol) and 1-methyl-1H-imidazole-4-carboxylic acid (207 mg, 1.638 mmol). The product was purified twice by Flash-chromatography (normal phase and reverse phase). Yield 38.7%. 1H-NMR (400 MHz; CDCl3): δ 1.26 (d, 3H), 2.56 (s, 3H), 3.74 (s, 3H), 4.30-4.43 (m, 2H), 4.49-4.61 (m, 1H), 6.41 (d, 1H), 7.35 (d, 1H), 7.39 (d, 1H), 7.49-7.56 (m, 3H), 7.60 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[N:8][NH:9][C:10]2=O)=[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:4]=1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:10]1[C:11]2[C:6](=[C:5]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[CH:7]=[N:8][N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc(-c2ccccc2)c2cn[nH]c(=O)c2c1
Product: COc1cc(-c2ccccc2)c2cnnc(Cl)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.3. by reacting 7-methoxy-5-phenyl-2H-phthalazin-1-one with phosphoryl chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:44])=[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[S:27](=[O:39])(=[O:38])[NH:28][C:29](=[O:37])[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[Cl:36])=[CH:17][CH:16]=3)[C:10]([CH2:40][CH2:41][CH2:42][CH3:43])=[N:9]2)[CH:7]=1.[CH2:45]([N:48]=[C:49]=[O:50])[CH2:46][CH3:47]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[CH2:40]([C:10]1[N:11]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[S:27](=[O:38])(=[O:39])[NH:28][C:29](=[O:37])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])=[CH:19][CH:20]=2)[C:12](=[O:13])[N:8]([C:6]2[CH:7]=[C:2]([NH:1][C:49]([NH:48][CH2:45][CH2:46][CH3:47])=[O:50])[CH:3]=[CH:4][C:5]=2[Cl:44])[N:9]=1)[CH2:41][CH2:42][CH3:43]
Reactant: CCCN=C=O
Reactant: CCCCc1nn(-c2cc(N)ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCCCc1nn(-c2cc(NC(=O)NCCC)ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1
Yield: 60.1 %

Procedure:
At room temperature, under N2, a solution of 34 mg (0.052 mmole) of 2-(5-amino-2-chlorophenyl)-5-n-butyl-4-[[2'-[N-(2-chlorobenzoyl)sulfamoyl]biphenyl-4-yl]methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (from Example 60), 6.4 mg (0.052 mmole) of DMAP, 23 mg (0.26 mmole) of propyl isocyanate, and 1 mL of pyridine was stirred overnight. After quenching with water, the organic material was extracted with EtOAc, washed with water and brine, and dried over sodium sulfate. The crude product obtained after filtration and removal of volatiles was flash chromatographed over silica gel (gradient elution with 0.5-5% MeOH/CH2Cl2) to give 23 mg (61%) of the desired compound as a white solid, mp >208° C. (gradual), homogeneous by TLC (9:1 MeOH/CH2Cl2), mass spectrum (FAB) m/e 773 (M+K)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([C:8]2([F:22])[C:16]3[C:11](=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:21])[CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl[CH2:36][S:37][CH3:38]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([C:8]2([F:22])[C:16]3[C:11](=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=3)[N:10]([CH2:36][S:37][CH3:38])[C:9]2=[O:21])[CH:7]=1
Reactant: CSCCl
Reactant: COc1ccc(Cl)cc1C1(F)C(=O)Nc2cc(C(F)(F)F)ccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1C1(F)C(=O)N(CSC)c2cc(C(F)(F)F)ccc21
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a 1 L, 3-necked round bottom flask equipped with an addition funnel was added 3-(5-chloro-2-methoxy-phenyl)-3-fluoro-6-trifluoromethyl-1,3-dihydro-indol-2-one (25 g, 69.8 mmol) and anhydrous THF (150 mL). The solution was cooled to 0° C. and potassium bis(trimethylsilyl)amide (0.5M in toluene, 153.6 mL, 76.8 mmol) was added over 25 minutes in order to keep the reaction temperature between 0° C. and 5° C. The reaction mixture immediately turned dark orange. The solution was allowed to warm to room temperature after which chloromethyl methylsulfide (6.39 mL, 76.8 mmol) was added. The dark brown reaction was then allowed to stir at reflux. After 3 hours, the reaction mixture contained 84% (AP) of the desired product. The reaction was allowed to reflux overnight. No further reaction took place during this period (82% AP of product after overnight stirring). The reaction mixture was then allowed to cool, and 1 N HCl (100 mL) was added slowly in order to keep the reaction temperature under 30° C. After stirring for 5 minutes, heptane (200 mL) was added and the layers were separated. The organic layer was then washed with saturated NaCl (200 mL), dried over anhydrous sodium sulfate and concentrated to yield crude product (29.3 g). The crude material was then recrystallized from heptane: THF (15:1) to provide 3-(5-chloro-2-methoxy-phenyl)-3-fluoro-1-methylsulfanylmethyl-6-trifluoromethyl-1,3-dihydro-indol-2-one as a light yellow powder (19.5 g, 67%). 1H NMR (CDCl3, 400 MHz): δ=7.78 (dd, 1H, J=2.7, 0.9 Hz), 7.32 (m, 2H), 7.21 (m, 2H), 6.73 (dd, 1H, J=8.9, 1.2 Hz), 4.95 (d, 1H, J=14.6 Hz), 4.79 (d, 1H, J=14.6 Hz), 3.48 (s, 3H), 2.23 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[CH:18]=[C:12]2[CH:13]=[N:14][CH:15]=[C:16]([F:17])[C:11]2=[N:10]1.ClC1C=CC=C(C(OO)=[O:27])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[CH:18]=[C:12]2[CH:13]=[N+:14]([O-:27])[CH:15]=[C:16]([F:17])[C:11]2=[N:10]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Fc1cccc(Cl)c1-n1cc2cncc(F)c2n1
Solvent: ClCCl
Product: [O-][n+]1cc(F)c2nn(-c3c(F)cccc3Cl)cc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 68.4 %

Procedure:
2-(2-Chloro-6-fluorophenyl)-7-fluoro-2H-pyrazolo[4,3-c]pyridine (9.95 g, 37.5 mmol) was suspended in DCM (150 mL) at 0° C. and meta-chloroperbenzoic acid (12.9 g, 75 mmol) was added. The reaction mixture was stirred at 0° C. for 2 hours then allowed to reach room temperature and stirred for another 3 hours. The resultant mixture was quenched with saturated aqueous sodium thiosulfate solution and the layers were separated. The organic layer was washed with saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with diethyl ether and the solid obtained was filtered off and dried to afford the title compound as a white solid (7.22 g, 68% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.04 (d, J=2.6 Hz, 1H), 8.88 (d, J=1.4 Hz, 1H), 8.35 (dd, J=6.4, 1.5 Hz, 1H), 7.82-7.73 (m, 1H), 7.72-7.62 (m, 2H).
Reaction SMILES: [CH3:1][CH:2]([NH:4][C:5]([CH:7]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:8]1)=[O:6])[CH3:3].[Cl:16][C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1.[H-].[Na+].C1OCCOCCOCCOCCOCCOC1>C(#N)C>[OH:8][CH:7]([CH:9]([O:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([Cl:16])[CH:18]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:5]([NH:4][CH:2]([CH3:1])[CH3:3])=[O:6]
Reactant: CC(C)NC(=O)C1OC1c1ccccc1
Reactant: Oc1cccc(Cl)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)NC(=O)C(O)C(Oc1cccc(Cl)c1)c1ccccc1

Procedure:
This compound was prepared from N-(1-methylethyl)-3-phenyl-2-oxiranecarboxamide (6.16 g.) m-chlorophenol (3.9 g.), sodium hydride (50% oil dispersion, 1.5 g.), 18-crown-6 (0.9 g.), and acetonitrile (250 ml.) as described in Example 12. The product which was purified by recrystallization from ether melted at 151°-153°, and weighed 1.4 g.
Reaction SMILES: [NH2:1][C:2]1[S:10][C:5]2[CH2:6][O:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:11]#[N:12].C(N(CC)CC)C.[C:20]1([CH:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:27](Cl)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[C:11]([C:3]1[C:4]2[CH2:9][CH2:8][O:7][CH2:6][C:5]=2[S:10][C:2]=1[NH:1][C:27](=[O:28])[CH:26]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)#[N:12]
Reactant: N#Cc1c(N)sc2c1CCOC2
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1c(NC(=O)C(c2ccccc2)c2ccccc2)sc2c1CCOC2
Reaction time: 72 h
Yield: 37.3 %

Procedure:
To a stirred solution of 2-Amino-3-cyano-4,7-dihydro-5H-thieno[2,3-c]pyran (400 mg; 2.22 mmol) and triethylamine (0.93 mL; 6.66 mmol) in dry methylene chloride (10 mL) under nitrogen at room temperature was added diphenylacetyl chloride (768 mg; 3.33 mmol). After 72 h, the mixture was diluted with methylene chloride and washed with 1N HCl. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was triturated with cold diethyl ether and filtered to give 310 mg (37%) of N-(3-Cyano-4,7-dihydro-5H-thieno[2,3-c]pyran-2-yl)-2,2-diphenyl-acetamide as a white solid. ES-HRMS m/e calcd for C22H18N2O2S (M+H+) 375.1162, found 375.1165.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[CH:17][C:18]=2[O:20][CH3:21])[C:13]([C:24](O)=[O:25])=[CH:12][N:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][NH:28][CH2:29][C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[CH:17][C:18]=2[O:20][CH3:21])[C:13]([C:24](=[O:25])[N:28]([CH3:27])[CH2:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)=[CH:12][N:11]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1cc(OC)c2c(CNC(=O)OC(C)(C)C)ncc(C(=O)O)c2c1
Reactant: CNCc1cccnc1
Product: COc1cc(OC)c2c(CNC(=O)OC(C)(C)C)ncc(C(=O)N(C)Cc3cccnc3)c2c1

Procedure:
As described in example 1E, 100 mg of 1-(tert-butoxycarbonylamino-methyl)-6,8-dimethoxy-isoquinoline-4-carboxylic acid was coupled with methyl-pyridin-3-ylmethyl-amine to give 98 mg of [6,8-dimethoxy-4-(methyl-pyridin-3-ylmethyl-carbamoyl)-isoquinolin-1-ylmethyl]-carbamic acid tert-butyl ester. MS: APCI (M+H) calc'd for C20H22N4O3+H 367.2; found 367.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[CH:18]=[CH:19]/[C:20]2[CH:25]=[CH:24][C:23]([O:26]C(=O)C)=[CH:22][CH:21]=2)[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][F:17].C([O-])([O-])=O.[K+].[K+]>CCO.C1COCC1>[Br:1][C:2]1[CH:3]=[C:4](/[CH:18]=[CH:19]/[C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][F:17]
Reactant: CC(=O)Oc1ccc(/C=C/c2cnc(OCCOCCOCCF)c(Br)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: C1CCOC1
Product: Oc1ccc(/C=C/c2cnc(OCCOCCOCCF)c(Br)c2)cc1
Temperature: 25 °C
Yield: 96.9 %

Procedure:
Acetate 11d (0.145 g, 0.31 mmol) and K2CO3 (0.064 g, 0.465 mmol) were placed in EtOH/THF (5 mL/5 mL) and the reaction mixture was stirred at r.t. 2 h. After standard workup with EtOAc, the crude product was purified by PTLC to give 11e as a white solid (0.128 g, 97%). 1H NMR δ8.07 (d, 1H, J=2.1 Hz), 7.99 (d, 1H, J=2.1 Hz), 7.35 (d, 2H, J=8.6 Hz), 6.96-6.74 (m, 4H), 5.22 (br s, 1H), 4.69 (t, 1H, J=4.2 Hz), 4.54 (t, 2H, J=4.8 Hz), 4.45 (t, 1H, J=4.2 Hz), 3.94-3.68 (m, 8H). 13C NMR δ 158.5, 156.4, 143.6, 138.2, 129.2, 129.0, 127.9, 120.7, 116.0, 107.6, 84.9, 81.6, 71.1, 71.0, 70.8, 70.4, 69.6, 66.8. HRMS calcd for C19H21BrFNO4 (M+), 425.0638; found, 425.0651.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][N:19]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: N#Cc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C#N)cn2)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 94.9 %

Procedure:
Add dropwise a solution of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (1210 mg, 6.01 mmol) in DMF (1.8 mL) to a suspension of NaH (360 mg, 9.02 mmol) in DMF (7.2 mL). Stir at room temperature for 45 min then at 50° C. for additional 40 min. Add a solution of 6-chloro-nicotinonitrile (1000 mg, 7.22 mmol) in DMF (3.6 mL) dropwise and stir overnight at 60° C. Cool down the reaction mixture and evaporate the solvent. Wash the residue with water (10) and extract with EtOAc/hex (2/1, 15 mL). Combine the organic layers and dry over sodium sulfate. Filter and concentrate. Purify the resulting residue through an SCX column. Further purified by chromatography [CH2Cl2/NH3 (2.0M in methanol) 20/1] to provide the title compound (1.73 g, 94%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.N1C=CN=C1.[CH3:13][Si:14](Cl)([CH3:16])[CH3:15]>C(Cl)Cl>[CH3:13][Si:14]([CH3:16])([CH3:15])[O:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: C[Si](C)(C)Cl
Reactant: OC1CCOCC1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C[Si](C)(C)OC1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
Tetrahydro-4-pyranol (1 g, 9.8 mmol) was dissolved in 30 mL of methylene chloride. To it was added imidazole (1.7 g, 24.5 mmol) followed by TMSCl (1.5 mL, 11.76 mmol). The reaction was allowed to stir at room temperature overnight. Insoluble material was removed by filtration, and the filtrate was washed with half saturated aqueous sodium bicarbonate and brine, and dried over MgSO4. The solids were filtered and solvent removed under reduced pressure to afford 1.6 g of trimethyl(tetrahydro-2H-pyran-4-yloxy)silane as a clear liquid.