Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:18][CH:17]4[NH:19][CH2:20][CH:12]3[CH2:13][CH:14]=[CH:15][CH2:16]4)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[O:21]1[CH2:23][CH:22]1[CH2:24][O:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:27]=1[CH:28]=[CH:29][NH:30]2.CCN(C(C)C)C(C)C>C(O)C>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:18][CH:17]4[N:19]([CH2:23][CH:22]([OH:21])[CH2:24][O:25][C:26]5[CH:34]=[CH:33][CH:32]=[C:31]6[C:27]=5[CH:28]=[CH:29][NH:30]6)[CH2:20][CH:12]3[CH2:13][CH:14]=[CH:15][CH2:16]4)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: c1cc(OCC2CO2)c2cc[nH]c2c1
Reactant: C1=CCC2CNC(C1)CN2c1ccc2c(c1)OCCO2
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: OC(COc1cccc2[nH]ccc12)CN1CC2CC=CCC1CN2c1ccc2c(c1)OCCO2
Temperature: 120 °C

Procedure:
7-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-7,9-diaza-bicyclo[4.2.2]dec-3-ene (15 mg, 0.055 mmol) and 4-oxiranylmethoxy-1H-indole (20 mg, 0.106 mmol) were placed in a μW tube with ethanol (2 ml), DiPEA (0.2 mL) and heated to 120° C. for 900 sec. The solvent was evaporated to yield a crude oil, which was purified via reverse phase chromatography (20% CH3CN to 90% CH3CN in water) to yield the title compound as a residue.
Reaction SMILES: [BH4-].[Li+].[C:3]1([S:9][C:10]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:11]=2[C:12](OC)=[O:13])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.O>O1CCCC1>[C:3]1([S:9][C:10]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][C:11]=2[CH2:12][OH:13])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1cc(C(F)(F)F)ccc1Sc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cc(C(F)(F)F)ccc1Sc1ccccc1
Temperature: 2 °C

Procedure:
21.5 g of lithium borohydride are suspended in 375 ml of tetrahydrofuran under a nitrogen atmosphere and heated to reflux. This suspension is treated dropwise under reflux over a period of 20 minutes with a solution of 130 g of methyl 2-(phenylthio)-5-trifluoromethyl-benzoate in 600 ml of tetrahydrofuran. The mixture is stirred under reflux for 2 hours and subsequently cooled to 2° C. The mixture is treated over a period of 10 minutes with 450 ml of 2-N aqueous hydrochloric acid in such a manner that the temperature does not exceed 10° C. After the addition of 750 ml of water, the mixture is extracted with 1000 ml of ether. The organic phase is washed twice with 300 ml of water each time, dried over sodium sulphate, filtered and evaporated. There is obtained 2-(phenylthio)-5-trifluoromethyl-benzyl alcohol as a light-yellow oil which crystallises spontaneously; melting point 84° C.
Reaction SMILES: [C:1]([C:3]1[C:8](=[NH:9])[N:7]2[CH:10]=[CH:11][CH:12]=[C:13]([CH3:14])[C:6]2=[N:5][CH:4]=1)#[N:2].[N-:15]=[N+:16]=[N-:17].[Na+].Cl>CN(P(N(C)C)(N(C)C)=O)C>[CH3:14][C:13]1[C:6]([NH:5][CH:4]=[C:3]([C:8]2[NH:9][N:17]=[N:16][N:15]=2)[C:1]#[N:2])=[N:7][CH:10]=[CH:11][CH:12]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cccn2c(=N)c(C#N)cnc12
Agent: Cl
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Cc1cccnc1NC=C(C#N)c1nnn[nH]1
Temperature: 70 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
To 100 ml of HMPA were added 10.0 g (54.3 mmoles) of 3-cyano-4-imino-9-methyl-4H-pyrido[1,2-a]-pyrimidine and 3.53 g (54.3 mmoles) of sodium azide, and the reaction was carried out with stirring at 70° C. for 3 hours. After cooling, the reaction mixture was neutralized with diluted hydrochloric acid, and the crystals precipitated were collected by filtration to obtain 9.8 9 of light-brown power of 3-(3-methyl-2-pyridyl)amino-2-(1H-tetrazol-5-yl)-2-propenonitrile. Yield: 79%.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>[OH-].[K+]>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([O:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Reactant: Oc1ccccc1
Agent: [K+]
Agent: [OH-]
Product: O=[N+]([O-])c1ccc(Cl)cc1Oc1ccccc1

Procedure:
Aryl ethers have been formed by reacting aryl halides with phenols under various conditions. Roberts and Turner disclose (J. Chem. Soc., 1925, Vol. 127, p. 2004) that 2, 4-dichloronitrobenzene reacts with phenol in aqueous KOH, at 100° C., to give a quantitative yield of 4-chloro-2-phenoxynitrobenzene.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:20])[N:9]([CH3:19])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](=[S:18])[NH2:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:21][CH2:22][C:23](=O)[CH2:24]Cl>O1CCOCC1>[Cl:1][C:2]1[C:7]2[C:8](=[O:20])[N:9]([CH3:19])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[S:18][CH:24]=[C:23]([CH2:22][Cl:21])[N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1Cc2c(C(N)=S)ncn2-c2cccc(Cl)c2C1=O
Reactant: O=C(CCl)CCl
Solvent: C1COCCO1
Product: CN1Cc2c(-c3nc(CCl)cs3)ncn2-c2cccc(Cl)c2C1=O
Yield: 87.1 %

Procedure:
A yellow suspension of 10.3 g (0.0336 mol) of 7-chloro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-thiocarboxamide in 220 ml of dioxan was treated with 4.69 g (0.0370 mol) of 1,3-dichloro-2-propanone. The solution was boiled at reflux for 16 hrs., cooled and suction filtered. There were obtained 11.1 g (87%) of 7-chloro-3-(4-chloromethyl-thiazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as brown crystals. An analytical sample was recrystallized from hot acetonitrile. White crystals; m.p. 277°-279°.
Reaction SMILES: Cl[CH2:2][C:3]1([CH3:9])[CH2:7][O:6][C:5](=[O:8])[NH:4]1.[Br-:10].[Na+]>CN(C=O)C>[Br:10][CH2:2][C:3]1([CH3:9])[CH2:7][O:6][C:5](=[O:8])[NH:4]1
Reactant: [Br-]
Reactant: CC1(CCl)COC(=O)N1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(CBr)COC(=O)N1
Temperature: 80 °C
Yield: 68.9 %

Procedure:
To a solution of 4-(chloromethyl)-4-methyloxazolidin-2-one (1.49 g, 9.96 mmol) in DMF (100 ml) was added sodium bromide (11.02 g, 107 mmol), and the suspension heated to 80° C. for 6 h. The suspension was concentrated in vacuo and the residue purified by flash chromatography (30% to 60% ethyl acetate in hexanes) to give the title compound as a white solid (1.33 g, 6.86 mmol, 66%). 1H NMR (CDCl3, 400 MHz) δ 1.54 (s, 3H), 3.47 (s, 2H), 4.14 (d, J=9.2 Hz, 1H), 4.35 (d, J=8.8 Hz, 1H), 6.24 (br s, 1H). LRMS (ESI/APCI): 194 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[O-2].[Ca+2:7].[Ca]>O>[NH2:1][CH2:2][C:3]([O-:5])=[O:4].[NH2:1][CH2:2][C:3]([O-:5])=[O:4].[Ca+2:7]
Reactant: NCC(=O)O
Agent: [Ca+2]
Agent: [Ca]
Agent: [O-2]
Solvent: O
Product: NCC(=O)[O-]

Procedure:
About 2400 grams of water was used to dissolve 475 grams of glycine. Next, 175 grams of calcium oxide, which was 70% calcium by weight, was stirred into the aqueous solution. The solution was continually stirred for about 15 minutes until all of the calcium oxide was dissolved and a calcium bisglycinate chelate or complex solution was formed.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:4]=2[N:3]=1.[CH3:27][NH2:28].C(O)(C(F)(F)F)=O>>[CH3:26][C:24]1[CH:23]=[CH:22][C:5]2=[C:6]3[C:11](=[C:2]([NH2:1])[N:3]=[C:4]2[CH:25]=1)[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH:28][CH3:27])=[CH:16][CH:15]=1)=[CH:7]3
Reactant: CN
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C=O)cc3)cc12
Solvent: O=C(O)C(F)(F)F
Product: CNCc1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)cc1

Procedure:
8-Methyl-2-(4-((methylamino)methyl)phenethyl)benzo[f][1,7]naphthyridin-5-amine was prepared from 4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)benzaldehyde (from Example 172/Step 1) and methylamine following the procedures described for Example 172, step 2. 1H NMR (Acetone-d6) TFA Salt: δ 8.95 (s, 1H), 8.88 (s, 1H), 8.43 (d, 1H), 7.58 (s, 1H), 7.54 (d, 2H), 7.42 (d, 1H), 7.37 (d, 2H), 4.30 (s, 2H), 3.32-3.37 (m, 4H), 2.75 (s, 3H), 2.55 (s, 3H). LRMS [M+H]=357.2
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH2:7]([S:9][CH2:10][C:11]1[N:12]([CH2:38][CH2:39][CH3:40])[C:13]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:37])(=[O:36])[NH:30][CH2:31][CH2:32][O:33][CH2:34][CH3:35])=[CH:25][CH:24]=3)[N:17]=2)=[CH:14][N:15]=1)[CH3:8]>O.CO>[CH2:7]([S:9]([CH2:10][C:11]1[N:12]([CH2:38][CH2:39][CH3:40])[C:13]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([S:29](=[O:37])(=[O:36])[NH:30][CH2:31][CH2:32][O:33][CH2:34][CH3:35])=[CH:27][CH:28]=3)[N:17]=2)=[CH:14][N:15]=1)=[O:2])[CH3:8]
Reactant: CCCn1c(-c2ccnc(Nc3ccc(S(=O)(=O)NCCOCC)cc3)n2)cnc1CSCC
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCn1c(-c2ccnc(Nc3ccc(S(=O)(=O)NCCOCC)cc3)n2)cnc1CS(=O)CC
Reaction time: 18 h
Yield: 50.8 %

Procedure:
A solution of sodium periodate (43 mg, 0.2 mmol) in water (0.5 ml) was added to a stirred solution of 4-[2-(ethylthiomethyl)-1-(propyl)imidazol-5-yl]-2-{4-[N-(2-ethoxyethyl)sulphamoyl]anilino}pyrimidine (Example 82; 70 mg, 0.14 mmol) in MeOH (2 ml) and the solution was stirred for 18 hours. The MeOH was removed by evaporation and the aqueous residue was extracted with EtOAc. The extracts were combined, washed with brine, dried and the volatiles removed by evaporation. The residue was purified by chromatography on silica gel eluting with DCM/MeOH (95:5 increasing in polarity to 90:10) and the purified product triturated with ether to give the title compound (37 mg, 51%). NMR: 0.68 (t, 3H), 1.05 (t, 3H), 1.22 (t, 3H), 1.52 (m, 2H), 2.85 (m, 4H), 3.33 (m, 4H), 4.31 (d of d, 2H), 4.63 (m, 2H), 7.23 (d, 1H), 7.46 (t, 1H), 7.70 (d, 2H), 7.78 (s, 1H), 7.86 (d, 2H), 8.48 (d, 1H), 9.90 (s, 1H); m/z 521.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].C(O)(=O)C.[H][H]>[Pd].C(O)C>[NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: [H][H]
Reactant: CCOC(=O)Cc1ccccn1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)CC1CCCCN1

Procedure:
50 ml of ethyl 2-(2-pyridyl)acetate, 18.7 ml of acetic acid, 5 g of Pd—C (water-containing product) and 200 ml of ethanol were charged in an auto clave, and the mixture was stirred at 70° C. for 9 hours at a hydrogen pressure of 56 kg/cm2. The Pd—C was filtered off and ethanol was evaporated, to give 72.3 g of white crystals.
Reaction SMILES: C([N:4]1[C:9](=[O:10])[NH:8][C:7](=[O:11])[C:6]([CH3:12])=[N:5]1)(=O)C.N1C=CC=CC=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCOCC1>[CH3:12][C:6]1[C:7](=[O:11])[N:8]([C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:26])[C:9](=[O:10])[NH:4][N:5]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(=O)n1nc(C)c(=O)[nH]c1=O
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: Cc1n[nH]c(=O)n(C(=O)c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.2 %

Procedure:
To a solution of 2-acetyl-6-methyl-1,2,4-triazine-3,5(2H,4H)-dione (P1, 196 mg, 1.159 mmol) in 1,4-Dioxane (2 mL) and dry pyridine (0.281 mL, 3.48 mmol) at 5° C. was treated benzoyl chloride (0.155 mL, 1.333 mmol) was added dropwise, then the mixture was stirred at room temperature overnight. The day after 0.1 eq of Benzoyl chloride were added and the mixture stirred at rt for further 4 hours. The reaction mixture was then filtered to remove the piridinium salt and the solvents evaporated under vacuum. The residue was dissolved in EtOH (5 mL), then HCl 37% (126 μL) was added and the reaction was refluxed for 15 minutes. Solvent was evaporated under reduced pressure and the residue was purified by flash chromatography (eluent: DCM to DCM/MeOH 6:4) providing the title compound 6-methyl-4-(phenylcarbonyl)-1,2,4-triazine-3,5(2H,4H)-dione (180 mg, 0.779 mmol, 67% yield).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:18]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[N:19][C:20]4[C:25]([N:26]=3)=[CH:24][C:23]([C:27]([O:29]C)=[O:28])=[CH:22][CH:21]=4)[CH2:13][CH2:12]2)[N:2]=1.[OH-].[Na+].Cl>CO.O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:18]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)=[N:19][C:20]4[C:25]([N:26]=3)=[CH:24][C:23]([C:27]([OH:29])=[O:28])=[CH:22][CH:21]=4)[CH2:13][CH2:12]2)[N:2]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCN(c4cc5ccccc5cn4)CC3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(N3CCN(c4cc5ccccc5cn4)CC3)nc2c1

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-(4-(isoquinolin-3-yl)piperazin-1-yl)-2-phenylquinoxaline-6-carboxylate (216.6 mg, 0.46 mmol, 1.00 equiv) in methanol (15 mL). This was followed by the addition of a solution of sodium hydroxide (91.2 mg, 2.28 mmol, 5.00 equiv) in water (2 mL), which was added dropwise with stirring. The resulting solution was stirred overnight at 50° C. in an oil bath. The pH value of the solution was adjusted to 3-4 with 1N hydrochloric acid. The resulting mixture was concentrated under vacuum. The resulting mixture was washed with methanol. This resulted in 56 mg (26%) of 3-(4-(isoquinolin-3-yl)piperazin-1-yl)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:17][C:18]1[CH:23]=[C:22]([OH:24])[CH:21]=[CH:20][N:19]=1>CN(C=O)C.C(OCC)(=O)C>[Cl:17][C:18]1[CH:23]=[C:22]([O:24][C:2]2[CH:7]=[N:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH:21]=[CH:20][N:19]=1
Reactant: Oc1ccnc(Cl)c1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccnc(Cl)c2)cn1
Temperature: 0 °C
Reaction time: 24 h
Yield: 43.5 %

Procedure:
5-Bromo-2-nitropyridine (1 g, 4.93 mmol) was dissolved in DMF (32 ml) and cooled to 0° C. Cesium carbonate (2.408 g, 7.39 mmol) was added, followed by 2-chloro-4-hydroxypyridine (0.702 g, 5.42 mmol). The mixture was stirred in an 80° C. oil bath for 24 hours. The reaction mixture was then cooled to RT, diluted with ethyl acetate (150 mL), washed with water (2×100 mL) and brine (50 mL), dried (MgSO4), evaporated under reduced pressure and purified via silica gel chromatography (ethyl acetate-hexanes) to yield 2-chloro-4-(6-nitropyridin-3-yloxy)pyridine as a clear oil (0.540 g, 44% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.62 (d, 1H), 8.41 (m, 2H), 8.06 (d, 1H), 7.37 (d, 1H), 7.23 (dd, 1H); MS (ESI) m/z: 252.0 (M+H+).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[C:6]([C:8]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9]N(C)C)=O.Cl.[F:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH2:30])=[NH:29])=[CH:26][CH:25]=1.C[O-].[Na+]>CO>[F:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]2[N:30]=[C:6]([C:5]3[CH:17]=[CH:18][CH:19]=[C:3]([C:2]([F:1])([F:20])[F:21])[CH:4]=3)[C:8]([S:13]([CH3:16])(=[O:14])=[O:15])=[CH:9][N:29]=2)=[CH:26][CH:25]=1
Reactant: N=C(N)c1ccc(F)cc1
Reactant: CN(C)C=C(C(=O)c1cccc(C(F)(F)F)c1)S(C)(=O)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CS(=O)(=O)c1cnc(-c2ccc(F)cc2)nc1-c1cccc(C(F)(F)F)c1
Yield: 81.1 %

Procedure:
6 g of 1-(3-trifluoromethylbenzoyl)-1-methane-sulfonyl-2-(N,N-dimethylamino)ethene and 4 g of 4-fluorobenzamidine hydrochloride were dissolved in 30 ml of methanol at room temperature. After adding 1.2 g of sodium methoxide thereto, the mixture was heated under reflux for 1 hour. The solvent was distilled away under reduced pressure. The residue was washed with water, and then dried to obtain 6 g of 2-(4-fluorophenyl)-4-(3-trifluoromethylphenyl)-5-methanesulfonylpyrimidine (Compound 112).
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH3:24])[CH2:20][C:21](O)=[O:22])=[CH:15][CH:14]=1>C1C=CC=CC=1>[F:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH3:24])[CH2:20][C:21]([Cl:3])=[O:22])=[CH:15][CH:14]=1
Reactant: O=S(Cl)Cl
Reactant: CC(CC(=O)O)c1ccc(-c2ccc(F)cc2F)cc1
Solvent: c1ccccc1
Product: CC(CC(=O)Cl)c1ccc(-c2ccc(F)cc2F)cc1
Reaction time: 24 h

Procedure:
6 g. of thionyl chloride and 10 g. of 3-(2',4'-difluoro-4-biphenylyl)butyric acid in 80 ml. of benzene are allowed to stand at 25° for 24 hours and the mixture is evaporated under reduced pressure to give 3-(2',4'-difluoro-4-biphenylyl)butyryl chloride.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][C:5]1[N:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1>C1COCC1.CCOC(C)=O>[Cl:4][C:5]1[N:10]=[CH:9][C:8]([S:11]([N:2]([CH3:3])[CH3:1])(=[O:13])=[O:12])=[CH:7][CH:6]=1
Reactant: CNC
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)c1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 92.7 %

Procedure:
To a mixture of 4.7 mL (9.43 mmol) of dimethylamine (2N in THF) and 2.6 mL (18.86 mmol) of TEA in 20 mL of THF is added dropwise, at 0° C., a solution of 2 g (9.43 mmol) of 6-chloropyridine-3-sulfonyl chloride (prepared according to patent WO 9840332) in 5 mL of THF. After stirring for 40 minutes at 0° C., the reaction medium is taken up in 40 mL of EtOAc, washed with water (2×40 mL) and brine (40 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. 1.93 g of 6-chloro-N,N-dimethylpyridine-3-sulfonamide are obtained in the form of a brown solid, which is used without further purification in the following step.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:13][CH2:14][CH3:15])[NH:6]2.Br[CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1>>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:13][CH2:14][CH3:15])[N:6]2[CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1
Reactant: CCCc1cc2c(Cl)c(C#N)ccc2[nH]1
Reactant: Fc1ccc(OCCBr)cc1
Product: CCCc1cc2c(Cl)c(C#N)ccc2n1CCOc1ccc(F)cc1

Procedure:
Synthesized as described in Example 4 from 4-chloro-2-propyl-1H-indole-5-carbonitrile and 1-[(2-bromoethyl)oxy]-4-fluorobenzene: 1H NMR (400 MHz, DMSO-d6) δ 7.89 (s, 1 H), 7.80 (d, J=8.7 Hz, 1 H), 7.54 (d, J=8.5 Hz, 1 H), −7.11-6.97 (m, 2 H), 6.83-6.71 (m, 2 H), 4.64 (t, 2 H), 4.20 (t, 2 H), 2.88 (t, 2 H), 1.70-1.58 (m, 2 H), 0.94 (t, J=7.3 Hz, 3 H); MS (ES) m/z 357 (M+1).
Reaction SMILES: [H-].[Na+].O1CCCC1.[C:8]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]=[CH2:27]>O>[CH2:27]([CH:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:8]([O:16][CH2:17][CH3:18])=[O:15])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH:21]=[CH2:20]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: C=CCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCCCCCCC(C(=O)OCC)C(=O)OCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 56.6 %

Procedure:
Sodium hydride (60%, 6.3 g, 156.96 mmol) was added to anhydrous tetrahydrofuran (200 ml) under argon atmosphere and cooled to 0° C. To this mixture, diethyl malonate (23.8 ml, 156.95 mmol) was slowly added dropwise, followed by stirring for 1 hour at room temperature. After cooling to 0° C., 8-bromo-1-octene (20 g, 104.64 mmol) was slowly added to the reaction mixture, followed by stirring for 12 hours at room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/30) to give diethyl 2-(7-octenyl)malonate (16 g, Yield 56.56%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:10][CH:9]=1)=O.CC(C)([O-])C.[K+].[C:29]([O:37]C)(=[O:36])[CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33].Cl>O.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:10][CH:9]=2)=[C:31]([C:32]([O:34][CH3:35])=[O:33])[CH2:30][C:29]([OH:37])=[O:36])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: COC(=O)CCC(=O)OC
Reactant: COc1ccc(C(=O)c2ccc(C(C)(C)C)cc2)cc1OC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)C(CC(=O)O)=C(c1ccc(C(C)(C)C)cc1)c1ccc(OC)c(OC)c1
Temperature: 90 °C

Procedure:
To a 2 L four-neck flask with overhead stirring was added the product from Step 1 (101 g), toluene (1.5 L) and potassium t-butoxide (50 g). Dimethyl succinate (60 mL) was added to the flask through addition funnel over 30 minutes. The reaction mixture was heated to 90° C. for 3 hours. The slurry was cooled and poured into ice water (1 L). The bottom water layer was acidified by hydrochloric acid (12N, 100 mL). The resulting slurry was extracted with ethyl acetate (1 L) and the top layer was washed with water and dried over sodium sulfate. The final solution was condensed to oily residue and the residue was dried in vacuum oven at 60° C. for 8 hours to afford 147 g of waxy solid, 4-(3,4-dimethoxyphenyl)-4-(4-t-butylphenyl)-3-methoxycarbonyl-3-butenoic acid. The product was used as is in next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][NH:9][CH2:8][CH2:7][N:6]1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26]/[CH:27]=[C:28]1/[C:29]2[CH:42]=[C:41]([C:43]([OH:46])([CH3:45])[CH3:44])[CH:40]=[CH:39][C:30]=2[O:31][CH2:32][C:33]2[N:38]=[CH:37][CH:36]=[CH:35][C:34]/1=2>C(#N)C.O>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][N:9]([CH2:25][CH2:26][CH:27]=[C:28]2[C:34]3[CH:35]=[CH:36][CH:37]=[N:38][C:33]=3[CH2:32][O:31][C:30]3[CH:39]=[CH:40][C:41]([C:43]([OH:46])([CH3:45])[CH3:44])=[CH:42][C:29]2=3)[CH2:8][CH2:7][N:6]1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=[O:4]
Reactant: CC(C)(O)c1ccc2c(c1)/C(=C/CCBr)c1cccnc1CO2
Reactant: COC(=O)C1CNCCN1c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)C1CN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)CCN1c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
To a solution of 1-(4-chloro-phenyl)-piperazine-2-carboxylic acid methyl ester (0.14 g, 0.53 mmol) in acetonitrile:water (4:1) was added potassium carbonate (0.083 g, 0.6 mmol) and (E)-2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (150 mg, 0.4 mmol) and the resulting mixture was stirred at 50° C. for 5 hours. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate, and dried over sodium sulfate. The crude product was purified by flash chromatography on silica using gradient elution from ethyl acetate (100%) to ethyl acetate/methanol (5%). 1H-NMR (CDCl3) δ: 1.05 (6H, s), 2.20-2.70 (8H, 2×m), 3.00 (1H, m), 3.10-3.40 (3H, 2×m), 3.55 (3H, s), 4.50 (1H, br, s), 5.30 (2H, br, s), 6.20 (1H, t), 6.70-6.90 (3H, 2×d), 7.10-7.35 (4H, m), 7.50 (2H, d), 8.50 (1H, dd). ESI-MS m/z: 548 (M+1), UV retention time: 1.62 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]([C:13]2[N:14]=[N:15][S:16][C:17]=2[CH2:18][O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])SC)[CH:5]=[CH:6][C:7]=1[F:8].[NH2:30][OH:31]>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:13]2[N:14]=[N:15][S:16][C:17]=2[CH2:18][O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])=[N:30][OH:31])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CSC(=Nc1ccc(F)c(Cl)c1)c1nnsc1CO[Si](C(C)C)(C(C)C)C(C)C
Reactant: NO
Solvent: CCO
Product: CC(C)[Si](OCc1snnc1C(=NO)Nc1ccc(F)c(Cl)c1)(C(C)C)C(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
Methyl N-(3-chloro-4-fluorophenyl)-5-[(triisopropylsilyl)oxy]methyl-1,2,3-thiadiazole-4-carbimidothioate (90 mg, 0.0002 mol) was dissolved in EtOH (2 mL) followed by addition of hydroxylamine (116 μL, 0.00190 mol) (50% by wt, 99.9% in water solution). The reaction was stirred at 60° C. for 4 h and overnight at room temperature. The reaction was evaporated and purified by flash chromatography to give the desired product (85 mg, 98%). 1H NMR (400 MHz, CDCl3): δ 7.32 (s, 1H), 7.25 (s, 1H), 6.90 (m, 2H), 6.62 (m, 2H), 5.17 (s, 2H), 1.05 (m, 21H). MF=C19H28ClFN4O2SSi; LCMS calculated for C19H29ClFN4O2SSi (M+H)+: m/z=459.2.