Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[C:15]2[N:21]([CH3:33])[C:22](=[O:32])[C:23]([C:25]4[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][CH:26]=4)=[CH:24][C:14]3=2)[NH:8][N:7]=1)=[O:5])[CH3:2].I[CH3:35]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:35])[N:8]=[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[C:15]2[N:21]([CH3:33])[C:22](=[O:32])[C:23]([C:25]4[CH:26]=[CH:27][C:28]([Br:31])=[CH:29][CH:30]=4)=[CH:24][C:14]3=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CI
Reactant: CCOC(=O)c1cc(-c2ccc3c(c2)c2cc(-c4ccc(Br)cc4)c(=O)n(C)c2n3C)[nH]n1
Product: CCOC(=O)c1cc(-c2ccc3c(c2)c2cc(-c4ccc(Br)cc4)c(=O)n(C)c2n3C)nn1C

Procedure:
The process is carried out as in Example 36 above, with compound B 5-[3-(4-bromophenyl)-1,9-dimethyl-2-oxo-2,9-dihydro-1H-pyrido[2,3-b]indol-6-yl]-1H-pyrazole-3-carboxylic acid ethyl ester and iodomethane
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=O)[C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][N:11]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:22]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]([Cl:22])[C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][N:11]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CS(=O)(=O)c1ccc(C(=O)Nc2ccccc2Cl)nc1
Solvent: c1ccccc1
Product: CS(=O)(=O)c1ccc(C(Cl)=Nc2ccccc2Cl)nc1

Procedure:
N-(2-chlorophenyl)-5-(methylsulfonyl)picolinamide 5 (1.26 g, 0.0040 mol) in anhydrous benzene (20 mL) was added to PCl5 (1.26 g, 0.0060 mol) and the mixture was heated to reflux overnight. The solvent was removed and the residue was further dried under high vacuum. Crude N-(2-chlorophenyl)-5-(methylsulfonyl)picolinimidoyl chloride 6 was obtained as a yellow solid (1.60 g). The compound 6 was dissolved into anhydrous THF (30 mL) and the reaction was cooled down to 0° C. and hydrazine hydrate (9.0 mL) was added. The reaction was kept at 0° C. for 10 min and warmed to ambient temperature in 0.5 h. The solvent was removed and the residue was purified by column chromatography (eluting with hexane and ethyl acetate 1:1) to give N′-(2-chlorophenyl)-5-(methylsulfonyl) picolinimidohydrazide 7 as a yellow solid. Yield: 1.22 g, 92.0%.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:20][C:21](O)=[O:22].[F:24][C:25]1[CH:26]=[C:27]([CH:35]=[CH:36][C:37]=1[F:38])[O:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(N=C=NCCCN(C)C)C.CCOCC>CN(C)C1C=CN=CC=1.C(Cl)Cl>[F:24][C:25]1[CH:26]=[C:27]([CH:35]=[CH:36][C:37]=1[F:38])[O:28][CH:29]1[CH2:34][CH2:33][N:32]([C:21](=[O:22])[CH2:20][N:3]2[CH2:4][CH2:5][CH2:6][C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:2]2=[O:1])[CH2:31][CH2:30]1
Reactant: Fc1ccc(OC2CCNCC2)cc1F
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(CN1CCCC(c2ccccc2)(c2ccccc2)C1=O)N1CCC(Oc2ccc(F)c(F)c2)CC1
Reaction time: 18 h

Procedure:
To a mixture of the product of Example 68E (225 mg, 0.73 mmol), 4-(3,4-difluorophenoxy)piperidine (155 mg, 0.73 mmol), and 4-(dimethylamino)pyridine (8.9 mg, 0.07 mmol) in CH2Cl2 (3 mL) at ambient temperature was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (0.129 mL, 0.727 mmol) via syringe. The reaction was stirred for 18 hours, then diluted with 50 mL CH2Cl2 and washed with 1 N aqueous HCl, saturated aqueous NaHCO3 solution and brine, dried with Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (Analogix® Intelliflash™ 280; SF15-24 g column; 50% ethyl acetate/hexanes). Hexanes (20 mL) were added and the flask was placed in an ultrasonic bath for 10 minutes resulting in a milky mixture. Ether (6 mL) was added to help precipitate the solid, which was collected by vacuum filtration and air-dried to give the titled compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.39-7.15 (m, 10H), 7.06 (dd, J=19.1, 9.1, 1H), 6.72 (ddd, J=11.9, 6.6, 3.0, 1H), 6.64-6.55 (m, 1H), 4.49-4.32 (m, 2H), 4.11 (d, J=15.6, 1H), 3.80-3.33 (m, 6H), 2.73-2.56 (m, 2H), 2.01-1.72 (m, 6H); MS (ESI+) m/z 505 (M+H)+.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19]#[C:20][CH2:21][O:22][CH3:23])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:24](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:42][S:43]([C:46]1[CH:51]=[CH:50][C:49](B(O)O)=[CH:48][CH:47]=1)(=[O:45])=[O:44].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19]#[C:20][CH2:21][O:22][CH3:23])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:24]([C:49]2[CH:50]=[CH:51][C:46]([S:43]([CH3:42])(=[O:45])=[O:44])=[CH:47][CH:48]=2)=[CH:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COCC#Cc1cnc2c(c1)cc(C(=CC1CCCC1)OS(=O)(=O)c1ccc(C)cc1)n2S(=O)(=O)c1ccccc1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COCC#Cc1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(S(C)(=O)=O)cc1)n2S(=O)(=O)c1ccccc1
Yield: 45.5 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-[1-benzenesulfonyl-5-(3-methoxy-prop-1-ynyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2-cyclopentyl-vinyl ester (900 mg, 1.53 mmol), 4-(methanesulfonyl)phenylboronic acid (763 mg, 3.81 mmol) and dichlorobis(triphenylphosphine)palladium (II) (107 mg, 0.15 mmol) in dioxane (5 mL) was added an aqueous sodium carbonate solution (2 M, 1.9 mL). The mixture was subjected to microwave irradiation for 1 h at 100° C. The resulting mixture was diluted with ethyl acetate (150 mL), washed with a saturated aqueous sodium bicarbonate solution (2×50 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 33% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-(3-methoxy-prop-1-ynyl)-1H-pyrrolo[2,3-b]pyridine (400 mg, 45.6%) as an orange oil: LC/MS m/e calcd for C31H30N2O5S2 [M+H]+ 575.72, observed 575.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[H-].[Na+].[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1/[CH:24]=[CH:25]/[CH2:26]Br.Cl>CN(C)C=O.C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:26]/[CH:25]=[CH:24]/[C:15]2[CH:16]=[CH:17][C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:14]=2)[C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=1
Reactant: BrC/C=C/c1ccc2ccccc2c1
Reactant: CC(=O)Cc1ccc(Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)C(C/C=C/c1ccc2ccccc2c1)c1ccc(Cl)cc1
Yield: 78 %

Procedure:
2.56 g of p-chlorophenylacetone was dissolved in a mixed solution of 5 ml of dimethylformamide and 5 ml of benzene, and a dimethylformamide 8 ml/benzene 8 ml solution containing 0.62 g of 60% oily sodium hydride and 3.50 g of (E)-3-(2-naphthyl)-2-propenyl bromide, was added under cooling with ice with stirring, followed by stirring at room temperature for 2 hours. The reaction solution was acidified by an addition of 1N hydrochloric acid and extracted by an addition of water and ethyl ether. Then, the organic layer was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The drying agent was filtered off, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1) to obtain 3.70 g of the above-identified compound.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[N:11]=[C:10]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[OH:25])[N:9]=2)[CH2:4]1.C(N(CC)CC)C.Cl[C:34]([O:36][CH2:37][CH2:38][CH3:39])=[O:35]>C(Cl)Cl>[CH2:37]([O:36][C:34](=[O:35])[NH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[N:11]=[C:10]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[OH:25])[N:9]=2)[CH2:4]1)[CH2:38][CH3:39]
Reactant: Cc1ccc2c(N3CC[C@@H](CN)C3)nc(-c3ccccc3O)nc2c1
Reactant: CCCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCOC(=O)NC[C@@H]1CCN(c2nc(-c3ccccc3O)nc3cc(C)ccc23)C1
Temperature: -30 °C
Yield: 62.4 %

Procedure:
A solution of 2-(4-((S)-3-(aminomethyl)pyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol (301 mg, 0.9 mmol) in CH2Cl2 (10 ml) was stirred under an N2 atmosphere. Triethylamine (0.25 mL, 1.8 mmol) was added, and the solution was cooled to −30° C. A 1 M propyl chloroformate solution (0.1 mL in 0.9 mL CH2Cl2, 0.9 mmol) was added, and the reaction mixture was allowed to warm to room temperature over a period of 30 minutes. After adding CH2Cl2 to the reaction mixture, it was washed 2 times with water, before it was dried over Na2SO4, filtered, and concentrated. Purification via silica gel chromatography using 0-20% EtOAc in CH2Cl2 gave propyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate (236 mg, 62%). LC/MS: m/z 421 (M+H)+ at 2.54 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) δ 8.43 (dd, J=8.2, 1.8 Hz, 1H), 8.21 (d, J=8.7 Hz, 1H), 7.58 (s, 1H), 7.39-7.31 (m, 3H), 6.93-6.89 (m, 2H), 4.09-3.86 (m, 6H), 3.78-3.73 (m, 1H), 3.21-3.09 (m, 2H), 2.49 (s, 3H), 2.15-2.09 (m, 1H), 1.83-1.74 (m, 1H), 1.62-1.48 (m, 2H), 0.89-0.86 (m, 3H).
Reaction SMILES: [CH2:1]([C@@:4]1([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:12])[CH2:6][CH2:5]1)[CH:2]=C.[O:24]=[O+][O-].[BH4-].[Na+]>C(Cl)Cl>[CH3:14][C:13]([CH3:15])([CH3:16])[C@@H:11]([N:7]1[CH2:6][CH2:5][C@@:4]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)([CH2:1][CH2:2][OH:24])[O:9][C:8]1=[O:10])[CH3:12]
Reactant: O=[O+][O-]
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)C(C)(C)C)C(=O)O1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H](N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
A solution of (R)-6-allyl-3-((2S)-3,3-dimethylbutan-2-yl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one [Isomer 1] (450 mg, 1.41 mmol) in dry CH2Cl2 (10 mL) was treated with O3 at −78° C. till the mixture turned blue. NaBH4 (157 mg, 4.23 mmol) was added, and the mixture was stirred at rt overnight. The solution was concentrated, and the residue was purified by preparative TLC followed by preparative HPLC to give (S)-3-((S)-3,3-dimethylbutan-2-yl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one [Isomer 1] (265 mg, 58%). LC-MS Method 2 tR=3.83, min, m/z=669.03; 1H NMR (CDCl3): 0.71 (s, 9H), 1.06-1.11 (d, 3H), 2.07-2.19 (m, 2H), 2.31-2.28 (m, 1H), 2.67-2.76 (m, 1H), 3.12-3.18 (m, 1H), 3.47-3.58 (m, 1H), 3.69-3.78 (m, 1H), 4.38-4.47 (m, 1H), 7.03-7.09 (m, 2H), 7.26-7.33 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:20])[C:5]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[C:13]([Cl:19])[CH:12]=2)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH2:21]([SH:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CCOC(C)=O.O.C(=O)([O-])O.[Na+]>[CH2:21]([S:28][C:2]1[CH:3]=[C:4]([F:20])[C:5]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[C:13]([Cl:19])[CH:12]=2)=[C:6]([CH:9]=1)[C:7]#[N:8])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: N#Cc1ccc(Oc2c(F)cc(Br)cc2C#N)cc1Cl
Reactant: SCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Oc2c(F)cc(SCc3ccccc3)cc2C#N)cc1Cl
Temperature: 25 °C
Yield: 28 %

Procedure:
The title compound was prepared according to the method described for Preparation at reflux using 5-bromo-2-(4-cyano-3-chlorophenoxy)-3-fluorobenzonitrile (Preparation 41) and benzyl mercaptan. The reaction was allowed to cool to room temperature and diluted with EtOAc (100 mL), water (50 mL) and saturated aqueous sodium hydrogen carbonate solution (100 mL). The organic was separated and the aqueous was re-extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was absorbed onto silica and purified by silica gel column chromatography eluting with 10% EtOAc in heptanes to afford the title compound as a yellow solid (115 mg, 28%).
Reaction SMILES: [K].[OH:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]([N+:13]([O-:15])=[O:14])[C:4]=1[CH:5]=[O:6].[C:16](=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O.[K]>CC(C)=O>[CH3:16][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]([N+:13]([O-:15])=[O:14])[C:4]=1[CH:5]=[O:6]
Reactant: COc1ccc([N+](=O)[O-])c(C=O)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Agent: [K]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COc1ccc([N+](=O)[O-])c(C=O)c1OC
Yield: 80 %

Procedure:
2-Hydroxy-3-methoxy-6-nitrobenzaldehyde potassium salt was slurried in acetone (500 mL) containing potassium carbonate (50 g) and the suspension was treated with dimethylsulfate (18.5 mL) and heated to reflux for one hour. An additional aliquot (18.5 mL) of dimethylsulfate was then added and the mixture was heated overnight. After 24 hours the red color of the potassium salt was virtually absent. The salts were removed by filtration, the filtrate was concentrated and the residue was recrystallized from isopropanol to give the title compound 40.0 g (80% from 3) mp 109°-110° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[S:11](=[O:20])(=[O:19])[NH:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.S(Cl)([Cl:23])=O.Cl.C(OC(C)C)(C)C>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:23])=[O:7])=[CH:4][C:3]=1[S:11](=[O:20])(=[O:19])[NH:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(Cl)c(S(=O)(=O)NC2CCCCC2)c1
Agent: Cl
Solvent: CC(C)OC(C)C
Product: O=C(Cl)c1ccc(Cl)c(S(=O)(=O)NC2CCCCC2)c1

Procedure:
30 g of 4-chloro-3-cyclohexylsulfamoylbenzoic acid were reacted as prescribed in Example 74a) with thionyl chloride and worked up analogously after HCl had finished to develop. Colorless crystals, melting point 119° C (from diisopropyl ether).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[O:7]([C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl>CCO>[O:7]([C:14]1[CH:15]=[C:16]([NH:17][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)[CH:18]=[CH:19][CH:20]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Brc1nccs1
Reactant: Nc1cccc(Oc2ccccc2)c1
Agent: Cl
Solvent: CCO
Product: c1ccc(Oc2cccc(Nc3nccs3)c2)cc1
Temperature: 90 °C
Reaction time: 24 h
Yield: 75 %

Procedure:
Following the general procedure for the synthesis of 2-R-5-(thiazol-2-ylamino)phenol, 2-bromothiazole (0.09 mL, 1.02 mmol), 3-phenoxyaniline (94 mg, 0.51 mmol) and 37% HCl solution (0.09 mL, 1.02 mmol) in 10% aqueous EtOH solution (1 mL) was stirred at 90° C. for 24 h. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 9/1) in 75% yield (102 mg).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[CH:15](O)[CH3:16])(C)(C)C.O.Cl.[S-:21][C:22]#[N:23].[K+]>C(O)C>[Cl:14][C:11]1[CH:10]=[C:9]2[C:8](=[CH:13][CH:12]=1)[NH:7][C:22](=[S:21])[NH:23][CH:15]2[CH3:16]
Reactant: CC(O)c1cc(Cl)ccc1NC(=O)OC(C)(C)C
Reactant: N#C[S-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC1NC(=S)Nc2ccc(Cl)cc21
Yield: 84.5 %

Procedure:
[4-Chloro-2-(1-hydroxy-ethyl)-phenyl]-carbamic acid tert-butyl ester (525 mg, 1.93 mmol) was suspended in a mixture of ethanol (1.5 ml), water (2.3 ml) and aqueous concentrated hydrogen chloride solution (0.6 ml). Potassium thiocyanate (206 mg, 2.1 mmol) was added and the reaction was heated to reflux for 3 hours. The product precipitated from the reaction and was filtered off after cooling, washed with water and ethanol and dried in vacuo to give the title compound (347 mg, 84%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([F:10])[CH:3]=1.[C:11](=O)([O-])[O-].[K+].[K+].IC.Cl>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([F:10])[C:5]([O:9][CH3:11])=[CH:6][C:7]=1[CH3:8]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(O)c(F)cc1Br
Agent: Cl
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cc(C)c(Br)cc1F
Temperature: 25 °C
Yield: 93.4 %

Procedure:
To a mixture of 4-bromo-2-fluoro-5-methylphenol (29.6 g, 144.2 mmol) and potassium carbonate (30.0 g, 218 mmol) in acetone (500 mL) was added iodomethane (69.0 g, 486 mmol). The resulting suspension was stirred at reflux for 4 hours. The reaction mixture was cooled to RT, poured into HCl (250 mL of 1 N solution) and extracted with ethyl acetate (3×250 mL). The combined organic layers were washed with sodium bicarbonate solution, dried over sodium sulfate and filtered. Evaporation of the solvent and purification on a silica column (5% ethyl acetate—hexanes) yielded 29.50 g (93%) of the title compound as a clear, colorless oil: 1H NMR (CDCl3): δ 2.33 (3H, s), 3.85 (3H, s), 6.82 (1H, d, J=8.79 Hz), 7.23 (1H, d, J=10.25 Hz); MS m/z,
Reaction SMILES: Br[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=2[Cl:17])[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[K].[CH3:21][SH:22].O>O1CCCC1>[Cl:17][C:8]1[CH:9]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:11]=[CH:12][C:7]=1[N:6]1[C:2]([S:22][CH3:21])=[C:3]([C:18]#[N:19])[CH:4]=[N:5]1
Reactant: N#Cc1cnn(-c2ccc(C(F)(F)F)cc2Cl)c1Br
Reactant: CS
Agent: [K]
Solvent: O
Solvent: C1CCOC1
Product: CSc1c(C#N)cnn1-c1ccc(C(F)(F)F)cc1Cl
Reaction time: 8 h
Yield: 97.6 %

Procedure:
A solution of 3.5 g (0.01 mol) of 5-bromo-1-(2-chloro-4-trifluoromethyl-phenyl)-4-cyano-pyrazole is added dropwise at 20°-25° C. to a suspension of 0.011 mol of potassium methylmercaptide, prepared by passing 0.6 g (0.011 mol) of methyl mercaptan into a solution of 1.4 g (0.012 mol) of potassium t-butylate in 50 ml of tetrahydrofuran. The mixture is stirred overnight, poured into water, and extracted by shaking three times with 100 ml of methylene chloride in each case. After drying the combined phases over sodium sulphate, the solution is concentrated in vacuo. An oily residue remains which crystallizes after standing overnight. 3.1 g (98% of theory) of 1-(2-chloro-4-trifluoromethyl-phenyl)-4-cyano-5-methylthio-pyrazole of melting point 59°-62° C. are obtained.
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[Br:14][CH2:15][CH:16]([OH:19])[CH:17]=[CH2:18].O>CN(C=O)C>[Br:14][CH2:15][CH:16]([O:19][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7])[CH:17]=[CH2:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=CC(O)CBr
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: C=CC(CBr)O[Si](C)(C)C(C)(C)C
Reaction time: 16 h

Procedure:
Imidazole (2.25 g) and tert-butyldimethylsilylchloride (4.75 g) were added to a solution of 1-bromo-3-buten-2-ol (4.5 g) in DMF (30 ml) at room temperature. The mixture was stirred at the same temperature for 16 hours, and water was added thereto, followed by extraction with hexane. The organic layer was washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound as a light-yellow, oily substance (7.0 g).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[N:10]=2)[C:5](O)=[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:3]1=[O:19].S(Cl)([Cl:22])=O>>[Cl:22][C:5]1[C:6]2[C:11](=[N:10][C:9]([CH3:12])=[CH:8][CH:7]=2)[N:2]([CH3:1])[C:3](=[O:19])[C:4]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)c1c(O)c2ccc(C)nc2n(C)c1=O
Reactant: O=S(Cl)Cl
Product: CCOC(=O)c1c(Cl)c2ccc(C)nc2n(C)c1=O

Procedure:
A stirred mixture of 1 g. of 1,2-dihydro-1,7-dimethyl-4-hydroxy-2-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester in 25 ml. of thionyl chloride was heated under reflux for 5 hours. The thionyl chloride was removed in a rotary evaporator and the residue was triturated with 10 ml. of ethyl acetate. The insoluble material was collected to give 0.8 g. of material. A small amount of this solid was recrystallized from ethyl acetate to give the analytical sample, m.p. 180°-184° C. of 4-chloro-1,2-dihydro-1,7-dimethyl-2-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester.
Reaction SMILES: [Na].CO.[CH:4]1[C:9]([CH:10]=[O:11])=[CH:8][C:7]2[O:12][CH2:13][O:14][C:6]=2[CH:5]=1.[N+:15]([CH:18]([CH3:20])[CH3:19])([O-:17])=[O:16]>C(O)(=O)C>[CH2:13]1[O:14][C:6]2[CH:5]=[CH:4][C:9]([CH:10]([OH:11])[C:18]([CH3:20])([N+:15]([O-:17])=[O:16])[CH3:19])=[CH:8][C:7]=2[O:12]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: CC(C)[N+](=O)[O-]
Agent: [Na]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C(O)c1ccc2c(c1)OCO2)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.8 %

Procedure:
7.7 g of sodium are added to 220 ml of anhydrous methanol, and 50 g of piperonal and 90 g of 2-nitropropane are added thereto. The mixture is stirred at room temperature for one hour, and then refluxed for 4 hours. After cooling, the reaction mixture is poured into ice-water containing 21 g of acetic acid, and then extracted with ether. The extract is washed with a saturated sodium chloride solution, a saturated sodium bisulfite solution and a saturated sodium chloride solution, successively. The washed extract is dried and then evaporated to remove solvent. 15 g of 1-(3,4-methylenedioxyphenyl)-2-methyl-2-nitropropanol are thereby obtained as a crude oil.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[C:12]([O:14][CH2:15][CH:16]=[CH2:17])[C:11]([CH2:18][C:19]#[C:20][CH3:21])=[CH:10][C:6]=1[C:7]([OH:9])=O)[CH:2]=[CH2:3].[N:22]1([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[CH2:1]([O:4][C:5]1[CH:13]=[C:12]([O:14][CH2:15][CH:16]=[CH2:17])[C:11]([CH2:18][C:19]#[C:20][CH3:21])=[CH:10][C:6]=1[C:7]([NH:35][C:32]1[CH:31]=[CH:30][C:29]([CH2:28][N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)=[CH:34][CH:33]=1)=[O:9])[CH:2]=[CH2:3]
Reactant: Nc1ccc(CN2CCOCC2)cc1
Reactant: C=CCOc1cc(OCC=C)c(C(=O)O)cc1CC#CC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1cc(OCC=C)c(C(=O)Nc2ccc(CN3CCOCC3)cc2)cc1CC#CC
Reaction time: 4 h
Yield: 86.8 %

Procedure:
2,4-bis-allyloxy-5 (but-2-ynyl)-benzoic acid (Example 1-4, IM07-c: 287 mg, 1 mmol) and 4-(morpholin-4-ylmethyl)-phenylamine (IM08-02: 193 mg, 1 mmol) were dissolved in dimethylformamide (4 mL) and mixed with 1-hydroxybenzotriazole monohydrate (176 mg, 1.3 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (249 mg, 1.3 mmol) at 0° C., and the resulting mixture was stirred for 4 hours under ice cold conditions. The reaction mixture was mixed with water (40 mL) and extracted twice with ethyl acetate (50 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and then were concentrated. The residue was purified by silica gel column chromatography (hexane-ethylacetate=1:2-1:5) to obtain the title compound (F470-IM09: 0.40 g, yield 82%).
Reaction SMILES: [N:1]([C:4]1[S:8][C:7]2[CH2:9][CH2:10][CH2:11][CH2:12][C:6]=2[C:5]=1[C:13]([O:15]CC)=O)=[C:2]=[S:3].[N:18]1([CH2:23][CH2:24][CH2:25][NH2:26])[CH:22]=[CH:21][N:20]=[CH:19]1>>[N:18]1([CH2:23][CH2:24][CH2:25][N:26]2[C:13](=[O:15])[C:5]3[C:6]4[CH2:12][CH2:11][CH2:10][CH2:9][C:7]=4[S:8][C:4]=3[NH:1][C:2]2=[S:3])[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: CCOC(=O)c1c(N=C=S)sc2c1CCCC2
Reactant: NCCCn1ccnc1
Product: O=c1c2c3c(sc2[nH]c(=S)n1CCCn1ccnc1)CCCC3

Procedure:
The compound was synthesized starting from ethyl 4,5,6,7-tetrahydro-2-isothiocyanatobenzo[b]thiophene-3-carboxylate (1.09 g, 4.0 mmol) and 3-(1H-imidazol-1-yl)propan-1-amine (0.5 g, 4.0 mmol) as described above.