Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1]O.O.[CH2:4]([O:11][C:12]1[CH:13]=[CH:14][C:15]2[C:19]([S:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:18]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[S:17][C:16]=2[CH:32]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(O)(=O)C.O1CCCC1>[CH2:4]([O:11][C:12]1[CH:13]=[CH:14][C:15]2[C:19]([S:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:1])=[C:18]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[S:17][C:16]=2[CH:32]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)c1sc2cc(OCc3ccccc3)ccc2c1Sc1ccccc1
Reactant: OO
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1sc2cc(OCc3ccccc3)ccc2c1S(=O)c1ccccc1
Temperature: 100 °C

Procedure:
Hydrogen peroxide in water (0.15 ml of 30% w/v, 1.3 mmol) was added to a solution of ethyl 6-(benzyloxy)-3-(phenylsulfanyl)benzo[b]thiophene-2-carboxylate (Example 17--500 mg, 1.2 mmol) in acetic acid (5 ml) and tetrahydrofuran (5 ml). The mixture was heated to 100° C. for 3 hours. The solvents were removed by evaporation under reduced pressure, and the residue was partitioned between diethyl ether and aqueous sodium bicarbonate solution. The organic layer was separated, dried (magnesium sulfate) and concentrated under vacuo, and the residue was crystallised from dichloromethane and diisopropyl ether to give the title compound as a colourless solid (455 mg).
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:16]#[N:17].[Na+].C([O-])(O)=O.[Na+]>CCOCC.O>[CH2:1]([NH:8][CH:9]1[CH2:14][CH2:13][C:12]([OH:15])([C:16]#[N:17])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(NCc2ccccc2)CC1
Reactant: [C-]#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: N#CC1(O)CCC(NCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 85.3 %

Procedure:
A suspension of 4-(benzylamino)cyclohexanone (5.8 g, 28.5 mmol) in ether (112 mL) was cooled to 0° C. To this mixture was added NaCN (1.538 g, 31.4 mmol) as a solution in NaHCO3 (4.79 g, 57.1 mmol) and water (71.4 mL, 3966 mmol). The reaction mixture was stirred at RT for 16 hours. The resulting mixture was diluted with ether (110 mL) and water (50 mL). The layers were separated, and the organic portion was dried over sodium sulfate and concentrated under reduced pressure to afford 4-(benzylamino)-1-hydroxycyclohexanecarbonitrile as a light yellow solid (5.6 g, 85% yield). MS m/z=231.2 [M+H]. Calc'd for C14H18N2O: 230.1.
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C@H:23]([NH2:30])[CH2:24][N:25]2[CH2:28][CH:27]([OH:29])[CH2:26]2)=[CH:19][C:18]=1[C:31]([F:34])([F:33])[F:32]>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C@H:23]([NH:30][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:24][N:25]2[CH2:26][CH:27]([OH:29])[CH2:28]2)=[CH:19][C:18]=1[C:31]([F:34])([F:32])[F:33]
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Reactant: N[C@H](CN1CC(O)C1)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Product: NC(=O)c1ccnc2c(N[C@H](CN3CC(O)C3)c3ccc(Cl)c(C(F)(F)F)c3)ncnc12

Procedure:
Compound 70 was prepared following general synthesis scheme 7 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with (S)-1-(4-chloro-3-trifluoromethyl-phenyl)-2-(3-hydroxy-azetidin-1-yl)-ethylamine hydrochloride to give the title compound. LC/MS [467 (M+H)].
Reaction SMILES: CN(C)S(C1C=C(C=C(C(F)(F)F)C=1)C([N:11]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:17]=1[C:18]1[C:19]([O:24][CH3:25])=[N:20][CH:21]=[CH:22][CH:23]=1)=O)(=O)=O.[F:39][C:40]([F:55])([F:54])[C:41]1[CH:42]=[C:43]([CH:47]=[C:48]([C:50]([F:53])([F:52])[F:51])[N:49]=1)[C:44]([OH:46])=O>>[CH3:25][O:24][C:19]1[C:18]([C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[N:11]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[C:44](=[O:46])[C:43]2[CH:47]=[C:48]([C:50]([F:53])([F:52])[F:51])[N:49]=[C:41]([C:40]([F:39])([F:55])[F:54])[CH:42]=2)=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: COC(=O)CN(C(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)N(C)C)c1)c1cnccc1-c1cccnc1OC
Reactant: O=C(O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Product: COC(=O)CN(C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1)c1cnccc1-c1cccnc1OC

Procedure:
The title compound was prepared in analogy to example 90, from (2-methoxy-[3,4′]bipyridinyl-3′-ylamino)-acetic acid methyl ester (example 178, intermediate) and 2,6-bis(trifluoromethyl)isonicotinic acid (Key Organics Ltd.) after a reaction time of 48 hours. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 20:80). Light yellow solid (55%). MS (ESI): m/z=515.114 [M+H]+.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH2:9])[CH:5]=[CH:4][CH:3]=[N:2]1.[N:10]1[C:18]2[C:13]3[C:14](=[CH:19][CH:20]=[CH:21][C:12]=3[C:11]=1S)[CH:15]=[CH:16][CH:17]=2.C(O)C.[C:26]([OH:33])(=[O:32])/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30]>CC(C)=O>[C:26]([OH:33])(=[O:32])/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30].[N:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:11]2[C:12]3[CH:21]=[CH:20][CH:19]=[C:14]4[C:13]=3[C:18](=[CH:17][CH:16]=[CH:15]4)[N:10]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: SC1=Nc2cccc3cccc1c23
Reactant: NCCCn1cccn1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: CC(C)=O
Product: c1cc2c3c(cccc3c1)C(NCCCn1cccn1)=N2

Procedure:
A mixture consisting of 2.8 grams of 3-(1H-pyrazol-1-yl)propanamine, 3.7 grams of benz(cd)indol-2-thiol, 7.0 grams of mercuric acetate, and 400 ml of ethanol was stirred and heated under reflux, by the conditions of Example 55. The isolated crude free base, weight 4.0 grams, was dissolved in 150 ml of acetone and added to stirred boiling solution of 3.5 grams of fumaric acid in 800 ml of acetone. After cooling, the precipitate of the title compound was collected, washed with acetone, and dried. The yield was 4.1 grams; mp 178° C.-180° C. was decomposition.
Reaction SMILES: Cl[C:2](=[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=2)[NH:12][C:11]1=[O:22])[C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][CH:4]=1.[N:23]1([CH2:28][C:29]2[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1.CCN(C(C)C)C(C)C.O>CN(C=O)C.C(Cl)Cl.CO>[N:23]1([CH2:28][C:29]2[CH:35]=[CH:34][C:32]([NH:33]/[C:2](=[C:10]3\[C:11](=[O:22])[NH:12][C:13]4[C:18]\3=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=4)/[C:3]3[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][CH:4]=3)=[CH:31][CH:30]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C1Nc2ccc([N+](=O)[O-])cc2C1=C(Cl)c1ccc(Br)cc1
Reactant: Nc1ccc(CN2CCCC2)cc1
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1Nc2ccc([N+](=O)[O-])cc2/C1=C(/Nc1ccc(CN2CCCC2)cc1)c1ccc(Br)cc1

Procedure:
Prepared by reacting 3-[1-chloro-1-(4-bromo-phenyl)methylidene]-5-nitro-2-indolinone with 1 equivalent of 4-(pyrrolidin-1-yl-methyl)aniline and 2 equivalents of Hunig's base in DMF (1 hours, 120° C.), pouring into water, extraction with EtOac, separation of the organic phase and purification thereof by column chromatography on SiO2 with CH2Cl2 /MeOH (15:1) as eluant.
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[CH:3]([C:20]1[CH:29]=[CH:28][C:23]([C:24]([NH:26][NH2:27])=[O:25])=[CH:22][CH:21]=1)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:12][CH3:13])=[CH:6][CH:5]=1.C(=O)(O)[O-].[Na+].[N:37]#[C:38]Br.C(=O)(O)[O-].[Na+].[Cl-].[Na+].O>O1CCOCC1.O.O.O1CCOCC1>[CH3:31][C:2]([CH3:30])([CH3:1])[CH:3]([C:20]1[CH:21]=[CH:22][C:23]([C:24]2[O:25][C:38]([NH2:37])=[N:27][N:26]=2)=[CH:28][CH:29]=1)[C:4]1[CH:5]=[CH:6][C:7]([O:10][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:12][CH3:13])=[CH:8][CH:9]=1
Reactant: N#CBr
Reactant: CCC(Oc1ccc(C(c2ccc(C(=O)NN)cc2)C(C)(C)C)cc1)c1ccccn1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCC(Oc1ccc(C(c2ccc(-c3nnc(N)o3)cc2)C(C)(C)C)cc1)c1ccccn1
Temperature: 5 °C
Reaction time: 0.08 h

Procedure:
Crude 3d (40.0 mg, 0.0967 mmol) was suspended in dioxane/water (1.3 mL of a 3:1 mixture) and cooled to approximately 5° C. A solution of aqueous sodium bicarbonate (22.0 mg, 0.237 mmol) in water (150 μL) was added followed by a solution of cyanogen bromide (15.0 mg, 0.142 mmol) in dioxane (100 μL). After 5 min, the reaction mixture was warmed to ambient temperature and aged for approximately 1 h. The reaction mixture was poured into saturated aqueous sodium bicarbonate/brine (1:1) and extracted twice with DCM. The combined organic extracts were dried (MgSO4) and concentrated in vacuo. Purification of the crude residue by flash chromatography on silica gel (isocratic elution; 80% EtOAc/hexanes as eluent) afforded the title compound 3e. m/z (ES) 443 (M)+. 1HNMR (500 MHz, CDCl3): δ 1H NMR (500 MHz, CDCl3) δ 8.61 (t, 1H, J==2.6 Hz), 7.79 (d, 2H, J=8.8 Hz), 7.66 (m, 1H), 7.48 (d, 2H, J=8.7 Hz), 7.40 (d, 1H, J=7.7 Hz), 7.25 (d, 2H, J=8.7 Hz), 7.20 (m, 1H), 6.81 (d, 2H, J=8.7 Hz), 5.5-5.8 (bs, 2H), 5.18 (t, 1H, J=6.9 Hz), 3.67 (s, 1H), 2.0 (m, 2H), 1.05 (t, 3H, J=7.3 Hz), 1.0 (s, 9H).
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([F:21])[C:7]([NH2:20])=[C:8]2[C:13]=1[O:12][CH2:11][C:10]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)=[N:9]2>C(O)C.O>[Br:3][C:4]1[CH:5]=[C:6]([F:21])[C:7]([NH2:20])=[C:8]2[C:13]=1[O:12][CH2:11][CH:10]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[NH:9]2
Reactant: Nc1c(F)cc(Br)c2c1N=C(c1cccnc1)CO2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1c(F)cc(Br)c2c1NC(c1cccnc1)CO2
Temperature: 90 °C

Procedure:
Sodium tetrahydroborate (44 mg, 1.2 mmol) was added to a solution of 8-bromo-6-fluoro-3-pyridin-3-yl-2H-1,4-benzoxazin-5-amine (190 mg, 0.58 mmol) in ethanol (4 mL) and water (1 mL), and heated at 90° C. for 15 minutes. The mixture was concentrated, diluted with water, and extracted with ethyl acetate. The organic solvents were evaporated to afford the product. LCMS calc. for C13H12BrFN3O (M+H)+: m/z=324.0. found: 324.0.
Reaction SMILES: BrC1C=CC(C2C(N)=CC(OC)=CC=2)=CC=1OC.[Br:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](/[N:30]=[C:31](/[O:38][CH2:39][CH3:40])\[CH2:32][C:33]([O:35]CC)=O)=[CH:22][CH:21]=1>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[Br:19][C:20]1[CH:21]=[C:22]2[C:23](=[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=13)[N:30]=[C:31]([O:38][CH2:39][CH3:40])[CH:32]=[C:33]2[OH:35]
Reactant: CCOC(=O)C/C(=N\c1ccc(Br)c2ccccc12)OCC
Agent: COc1ccc(-c2ccc(Br)c(OC)c2)c(N)c1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOc1cc(O)c2cc(Br)c3ccccc3c2n1
Temperature: 25 °C

Procedure:
To refluxing DOWTHERM A (50 mL) was added the product from Step 2, ethyl (3E)-3-[(4-bromo-1-naphthyl)imino]-3-ethoxypropanoate (5.61 g, 15.4 mmol) in DOWTHERM A (5 mL). The mixture was then heated at this temperature for 5 min, and then cooled to r.t. The mixture was then diluted with hexanes and the resulting solid was removed by filtration. The solid was washed with additional hexanes to yield the title compound as a brown solid. LRMS (M+H)+=318.1.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1.N1C=CC=CC=1.[C:23](OC(=O)C)(=[O:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+]>ClCCl.O>[C:23]([O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1ccc(O)c(-n2cccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(OC(C)=O)c(-n2cccc2)c1

Procedure:
A solution of methyl 4-hydroxy-3-(pyrrol-1-yl)benzoate (15.0 g), pyridine (8.4 ml) and acetic anhydride (9.8 ml) in dichloromethane (75 ml) was stirred for 15 hours at ambient temperature. To the reaction mixture was added the mixture of dichloromethane and water and the mixture was adjusted to pH 8 with 20% aqueous potassium carbonate solution. The separated organic layer was washed with 1N-hydrochloric acid and water respectively. The organic layer was dried over magnesium sulfate and evaporated in vacuo to give methyl 4-acetoxy-3-(pyrrol-1-yl)benzoate (15.9 g).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][N:4]=1.S(Cl)([Cl:12])=O>C1C=CC=CC=1>[Cl:12][CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][N:4]=1
Reactant: Cc1ccnc(CO)c1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: Cc1ccnc(CCl)c1
Reaction time: 8 h

Procedure:
A mixture of 2-hydroxymethyl-4-methylpyridine (5.48 g, 44.5 mmol) and thionyl chloride (60 mL, 822 mmol) in benzene (150 mL) was stirred at room temp. overnight. The product mixture was concentrated under vacuum. The residue was partitioned between dichloromethane and aqueous sodium bicarbonate. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to provide the title compound as oil. This alkylating reagent was passed through a small plug of activated basic alumina immediately before use.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:12]1[C:20]2[C:15](=[CH:16][C:17]([NH:21]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:18][CH:19]=2)[CH2:14][O:13]1.Cl.CO.CO>C1COCC1>[NH2:21][C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][CH:18]=1)[C:12](=[C:5]1[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=3)[NH:7][C:6]1=[O:11])[O:13][CH2:14]2
Reactant: O=C1Nc2ccc(Cl)cc2C1=C1OCc2cc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)ccc21
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc2c(c1)COC2=C1C(=O)Nc2ccc(Cl)cc21
Reaction time: 0.17 h
Yield: 71.5 %

Procedure:
To a solution of 5-chloro-3-[5-(trityl-amino)-3H-isobenzofuran-1-ylidene]-1,3-dihydro-indol-2-one (200 mg, 0.37 mmol) in THF (4.0 ml) at room temperature was added 1.55M HCl/MeOH (0.5 ml). After stirring for 10 minutes, MeOH (3 ml) was added to the thick mixture, and then the resulting mixture was stirred for another 30 minutes. The precipitant was filtered, and rinsed with MEOH, CHCl3, MeOH and then 30% EtOAc in hexane to give 3-(5-amino-3H-isobenzofuran-1-ylidene)-5-chloro-1,3-dihydro-indol-2-one as a bright yellow solid (79 mg, 72%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[NH:7][C:8]([CH3:28])=[C:9]([C:24]([O:26][CH3:27])=[O:25])[CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([S:36](Cl)(=[O:38])=[O:37])[CH2:32][CH2:31]1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH:10]1[C:9]([C:24]([O:26][CH3:27])=[O:25])=[C:8]([CH3:28])[NH:7][C:6]([CH2:5][O:4][CH2:3][CH2:2][NH:1][S:36]([N:33]2[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]2)(=[O:38])=[O:37])=[C:11]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CN1CCN(S(=O)(=O)Cl)CC1
Reactant: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1=C(COCCNS(=O)(=O)N2CCN(C)CC2)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Temperature: 25 °C
Yield: 43 %

Procedure:
2-(2-Aminoethoxymethyl)-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (0.5 g) was dissolved in a mixture of chloroform (dried over alumina) (20 ml) and triethylamine (2 ml) and the mixture stirred at room temperature. 4-Methyl-1-piperazinylsulphonyl chloride (0.25 g) was added in one portion and the mixture stirred at room temperature for 17 hours. After evaporation to dryness, the resultant oil was partitioned between 5% aqueous sodium carbonate and methylene chloride. The organic layer was dried (MgSO4), filtered and evaporated to give 0.3 g of a colourless oil, which was dissolved in diisopropyl ether (15 ml) and kept in a refrigerator for 14 days. The resultant crystals were collected by filtration to afford the title compound (0.1 g), m.p. 137°-139° C. Found: C, 52.58; H, 6.18; N, 9.81%. C25H35ClN4O7S requires C, 53.03; H, 6.14; N, 9.20%.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[C:15]([CH:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)O)=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[N:11]2>C(Cl)Cl>[Cl:5][C:6]1[C:15]([CH:16]([Cl:3])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[N:11]2
Reactant: OC(c1cccc(C(F)(F)F)c1)c1ccc2ncccc2c1Cl
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: FC(F)(F)c1cccc(C(Cl)c2ccc3ncccc3c2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Thionyl chloride (8 ml) was added dropwise to a solution of intermediate 5 (8 g) in CH2Cl2 (400 ml) at 0° C. and the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was partitioned between CH2Cl2 and water which was alkalized with a saturated K2CO3 solution. The separated organic layer was dried over MgSO4, filtered and the filtrate evaporated, yielding 8.4 g (100%) (±)-5-chloro-6-[chloro[3-(trifluoromethyl) phenyl]methyl]quinoline (intermediate 6).
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].[OH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1.OS(O)(=O)=O.C([O-])(O)=O.[Na+]>O1CCOCC1>[OH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:12][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:11])=[CH:8][CH:7]=1
Reactant: C=C(C)C
Reactant: O=C(O)c1ccc(O)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Excess isobutylene gas was condensed at -78° C. in a high-pressure tube containing 13.8 g (0.1 mol) of 4-hydroxybenzoic acid dissolved in 50 ml of dioxane and 1 ml of conc. H2SO4 was then added to the mixture. The tube was then sealed and the reaction mixture warmed to room temperature and stirred for 2 h. The mixture was then cooled to -78° C. and the tube was opened and its contents poured slowly into an excess of saturated NaHCO3 solution. Any excess isobutylene was removed by means of a nitrogen stream and the mixture was extracted with ether. The ether solution was extracted with 1N NaOH solution and the ether layer was discarded. The aqueous extract was acidified with dilute H2SO4 and then extracted with ether. The ether extract was washed with NaHCO3 solution and then dried (Na2SO4). The solution was filtered and the solvent removed in-vacuo. The residue was purified by flash chromatography (silica; 40% ethyl acetate in hexanes) to give the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[C:11]([C:15]([CH3:18])([CH3:17])[CH3:16])[NH:12]2)=[CH:8][C:7]=1[N+:19]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>CO.[Ni]>[C:1]([O:5][C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[C:11]([C:15]([CH3:18])([CH3:17])[CH3:16])[NH:12]2)=[CH:8][C:7]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)Oc1cc2[nH]c(C(C)(C)C)cc2cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)Oc1cc2[nH]c(C(C)(C)C)cc2cc1N
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 32 %

Procedure:
A suspension of 6-tert-butoxy-2-tert-butyl-5-nitro-1H-indole (100 mg, 0.36 mmol) and Raney Ni (0.5 g) in MeOH (15 mL) was stirred under H2 atmosphere (1 atm) at the room temperature for 2.5 h. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to dryness. The residue was recrystallized in ether to give 6-tert-butoxy-2-tert-butyl-1H-indol-5-amine (30 mg, 32%). 1H-NMR (300 MHz, MeOD) 6.98 (s, 1H), 6.90 (s, 1H), 5.94 (d, J=0.6 Hz, 1H), 1.42 (s, 9H), 1.36 (s, 9H); MS (ESI) m/e 205.0.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8]([CH2:9]Cl)=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[N:5]1.[CH3:14][O:15][CH2:16][CH2:17][CH2:18][NH2:19].CS(C)=O>C(OCC)(=O)C>[CH3:14][O:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:2][CH2:3][N:4]2[N:5]=[C:6]([N+:11]([O-:13])=[O:12])[CH:7]=[C:8]2[CH2:9]1
Reactant: COCCCN
Reactant: O=[N+]([O-])c1cc(CCl)n(CCBr)n1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COCCCN1CCn2nc([N+](=O)[O-])cc2C1
Temperature: 120 °C
Yield: 66.2 %

Procedure:
A microwave vial equipped with a magnetic stirrer was charged with 1-(2-bromoethyl)-5-(chloromethyl)-3-nitro-1H-pyrazole 296c (600 mg, 2.2 mmol), 3-methoxypropan-1-amine (595 mg, 6.6 mmol), and DMSO (6 mL). It was heated at 120° C. under microwave irradiation for 0.5 h. The mixture was then cooled to room temperature and diluted with ethyl acetate (30 mL). The resulting mixture was washed with water (3×10 ml). The organic layer was dried and filtered. The filtrate was concentrated under pressure and the residue was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 309a (350 mg, 66%) as a yellow solid. MS-ESI: [M+H]+ 241.1
Reaction SMILES: C([C@H]([C@@H](C(OC(C)C)=O)O)O)(OC(C)C)=[O:2].C(OO)(C)(C)C.[Cl:23][C:24]1[CH:29]=[CH:28][C:27](/[CH:30]=[CH:31]/[CH2:32][OH:33])=[CH:26][C:25]=1[F:34]>ClCCl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C@H:30]2[O:2][C@@H:31]2[CH2:32][OH:33])=[CH:26][C:25]=1[F:34]
Reactant: OC/C=C/c1ccc(Cl)c(F)c1
Reactant: CC(C)OC(=O)[C@@H](O)[C@H](O)C(=O)OC(C)C
Agent: [Ti+4]
Agent: CC(C)(C)OO
Agent: CC(C)[O-]
Solvent: ClCCl
Product: OC[C@H]1O[C@@H]1c1ccc(Cl)c(F)c1
Temperature: -20 °C
Reaction time: 3 h
Yield: 647.8 %

Procedure:
Diisopropyl D-tartrate (1.690 mL, 8.038 mmol) was dissolved in dichloromethane (500 mL) and cooled to −20° C. Activated powdered 4 Å molecular sieves (3 g), titanium(IV) isopropoxide (1.570 mL, 5.359 mmol) and tert-butyl hydroperoxide (19.49 mL, 107.2 mmol; in decane) were added sequentially, and the mixture was agitated for 1 hour at −20° C. (E)-3-(4-Chloro-3-fluorophenyl)prop-2-en-1-ol (10.0 g, 53.59 mmol) was dissolved in dichloromethane (25 mL) and treated with 4 Å molecular sieves (1.0 g) for 1 hour. This mixture was added to the initial mixture over 20 minutes and agitation was continued for another 3 hours at −20° C. The reaction was then quenched by addition of a mixture of a saturated NaCl solution (3 mL) and 50% w/v NaOH (3 mL). Ether was added (100 mL), and the mixture was allowed to warm up to 10° C. After agitating for 10 minutes at this temperature, MsSO4 (5 g) and Celite® (2 g) were added, and the mixture was agitated for an additional 15 minutes. The mixture was then allowed to settle and filtered through a pad of Celite®, washing with ether. Solvents were then evaporated, and resulting solid was triturated with hexane to give ((2R,3R)-3-(4-chloro-3-fluorophenyl)oxiran-2-yl)methanol (10.55 g, 52.07 mmol, 97.17% yield) as a solid.
Reaction SMILES: [K].[C:2]1(=[O:19])[N:6]([CH2:7][CH2:8][CH2:9][S:10]([O-])(=[O:12])=[O:11])[C:5](=[O:14])[C:4]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:3]12.P(Cl)(Cl)(Cl)(Cl)[Cl:21]>C1(C)C=CC=CC=1>[C:2]1(=[O:19])[N:6]([CH2:7][CH2:8][CH2:9][S:10]([Cl:21])(=[O:12])=[O:11])[C:5](=[O:14])[C:4]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:3]12
Reactant: O=C1c2ccccc2C(=O)N1CCCS(=O)(=O)[O-]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: [K]
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1CCCS(=O)(=O)Cl
Reaction time: 1.5 h
Yield: 100.4 %

Procedure:
Potassium-3-phthalimidopropane-1-sulfonate (6.0 g) was suspended in dry toluene (25 ml) under a nitrogen atmosphere and heated to reflux. Then 4.11 g of PCl5 was added in portions and the mixture was heated at reflux for 60 minutes. A second portion of 4.11 g of PCl5 was added and heating was continued for 90 minutes. The reaction mixture was evaporated to dryness and crushed ice was added to the residual solid. When the ice had just molten, the solid was filtered off and dried in vacuo to yield 5.64 g (87%) of a solid. 1H-NMR (CDCl3) δ (ppm) 7.88-7.81 (m, 2H), 7.78-7.71 (m, 2H), 3.87 (t, J=6.5 Hz, 2H), 3.77-3.69 (m, 2H), 2.48-2.34 (m, 2H).