Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH3:12][C:13]([S:16]([NH2:18])=[O:17])([CH3:15])[CH3:14].C([O-])(O)=O.[Na+]>[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[O:1]1[C:5]2([CH2:10][CH2:9][C:8](=[N:18][S:16]([C:13]([CH3:15])([CH3:14])[CH3:12])=[O:17])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: CC(C)(C)S(N)=O
Agent: [Ti+4]
Agent: CC[O-]
Agent: O=C([O-])O
Product: CC(C)(C)S(=O)N=C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 4 h
Yield: 45.8 %

Procedure:
An oven dried round-bottom flask was cooled to room temperature by flushing with N2(g) for 30 min. 1,4-Dioxa-spiro[4.5]decan-8-one (1.35 g, 8.66 mmol) (dissolved in 12 mL THF), 2-Methyl-propane-2-sulfinic acid amide (1.0 g, 8.25 mmol) (dissolved in THF), and titanium(IV) ethoxide (3.77 g, 16.50 mmol) were added. The reaction was stirred for 4 h at room temperature. To the mixture was added 15 mL saturated NaHCO3 followed by filtration and an EtOAc rinse. The organic layer was dried with MgSO4, filtered and concentrated under reduced pressure yielding 0.98 g of Compound 15.
Reaction SMILES: C([O:3][C:4](=[O:26])[C@@:5]([CH3:25])([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH3:27][C:28]1[O:32][C:31]([C:33]2[S:34][CH:35]=[CH:36][CH:37]=2)=[N:30][C:29]=1[CH2:38][CH2:39]OS(C1C=CC(C)=CC=1)(=O)=O>>[CH3:25][C@:5]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][CH:16]=1)([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:39][CH2:38][C:29]2[N:30]=[C:31]([C:33]3[S:34][CH:35]=[CH:36][CH:37]=3)[O:32][C:28]=2[CH3:27])=[CH:9][CH:8]=1)[C:4]([OH:3])=[O:26]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccs3)oc2C)cc1
Reactant: CCOC(=O)[C@](C)(Cc1ccc(O)cc1)Oc1ccc(C(F)(F)F)cc1
Product: Cc1oc(-c2cccs2)nc1CCOc1ccc(C[C@](C)(Oc2ccc(C(F)(F)F)cc2)C(=O)O)cc1

Procedure:
The title compound was prepared from (S)-3-(4-hydroxyphenyl)-2-methyl-2-(4-trifluoromethyl-phenoxy)-propionic acid ethyl ester (95% ee; Chiralpak AD separation, 8×27 cm, 10% IPA/heptane, 275 nm) and toluene-4-sulfonic acid 2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethyl ester by the procedure described in Example 1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=3)[NH:9]2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:33](Cl)(=[O:37])[CH:34]([CH3:36])[CH3:35]>ClCCl>[C:33]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:17]([CH3:18])([CH3:19])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=3)[NH:9]2)=[CH:6][CH:7]=1)(=[O:37])[CH:34]([CH3:36])[CH3:35]
Reactant: CC(C)C(=O)Cl
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(N)cc1)N2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(NC(=O)C(C)C)cc1)N2
Yield: 68 %

Procedure:
To a solution of methyl 2-(4-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (70 mg, 0.23 mmol) and N,N-diisopropylethylamine (0.09 mL, 0.52 mmol,) in dichloromethane (5 mL) was added isobutyryl chloride (0.04 mL, 0.34 mmol). The resultant mixture was stirred at room temperature for 16 hrs under nitrogen. The solvent was removed and the residue was washed with dichloromethane/petroleum ether, the precipitate was collected to afford methyl 2-(4-isobutyramidophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a yellow solid, 61 mg, yield: 68%.
Reaction SMILES: CN(C)[N:3]=[CH:4][C:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]=1.Cl[C:13](=[CH2:16])[C:14]#[N:15].C(N(CC)CC)C>O1CCOCC1>[C:14]([C:13]1[N:3]=[CH:4][C:5]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:16]=1)#[N:15]
Reactant: CN(C)N=CC1=CCCCC1
Reactant: C=C(Cl)C#N
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: N#Cc1cc2c(cn1)CCCC2

Procedure:
7.6 g cyclohex-1-ene-carboxaldehyde-N,N-dimethylhydrazone, 4.4 g of 2-chloroacrylonitrile and 10.1 g of triethylamine are heated in 75 ml of dioxane for 18 hours to 90° C. The reaction mixture is concentrated by evaporation and the residue is acidified with 1N HCl and extracted three times with chloroform. The combined extracts are dried and concentrated by evaporation and the residue is chromatographed over silica gel. Pale yellow crystals of the title compound are isolated. Melting point: 56°-59° C.
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13]CC)=O)=[CH:9][N:8]=1.[CH:19]1([C:22]2[CH:23]=[C:24]([CH3:34])[C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:26][CH:27]=2)[CH2:21][CH2:20]1>>[CH:19]1([C:22]2[CH:23]=[C:24]([CH3:34])[C:25]([N:28]3[CH2:29][CH2:30][N:31]([C:11]([C:10]4[CH:9]=[N:8][C:7]([N:3]5[CH2:4][CH2:5][CH2:6][S:2]5(=[O:1])=[O:18])=[CH:17][CH:16]=4)=[O:13])[CH2:32][CH2:33]3)=[N:26][CH:27]=2)[CH2:21][CH2:20]1
Reactant: CCOC(=O)c1ccc(N2CCCS2(=O)=O)nc1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCS3(=O)=O)nc2)CC1
Yield: 30 %

Procedure:
Using ethyl 6-(1,1-dioxo-1λ6-isothiazolidin-2-yl)nicotinate (194 mg) described in Preparation Example 25 and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (170 mg) described in Preparation Example 83 and by the reaction and treatment in the same manner as in Example 109, the title compound (95 mg) was obtained.
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2.NC(N)=[S:19].[OH-].[Na+].S(=O)(=O)(O)O>C(O)C>[CH:13]1[C:4]2[CH2:5][CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[CH:2]([SH:19])[C:3]=2[CH:16]=[CH:15][CH:14]=1
Reactant: ClC1c2ccccc2CCc2ccccc21
Reactant: NC(N)=S
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: SC1c2ccccc2CCc2ccccc21
Temperature: 25 °C
Yield: 99.9 %

Procedure:
5-Chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (6.86 g, 0.030 mol) and thiourea (2.28 g, 0.030 mol) were dissolved in ethanol (50 ml) and heated at reflux temperature for 2.5 h. After cooling to room temperature, 2 N sodium hydroxide (20 ml) was added and the mixture was subsequently heated to reflux temperature under a nitrogen atmosphere for 2 h. The reaction mixture was cooled to room temperature, made acidic by addition of a slight excess of sulfuric acid and extracted with diethyl ether (50 ml). The organic phase was washed with water (50 ml) and brine (30 ml). Evaporation in vacuo afforded 6.78 g (100%) of 10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-thiol as an oil . The crude product was directly used in the next step without further purification.
Reaction SMILES: [S:1]=[C:2]=[N:3][CH2:4][C:5]([O:7]C)=[O:6].[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]([NH:16][NH2:17])=O>C(O)(C)C>[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]1[N:3]([CH2:4][C:5]([OH:7])=[O:6])[C:2](=[S:1])[NH:17][N:16]=1
Reactant: NNC(=O)c1cccs1
Reactant: COC(=O)CN=C=S
Solvent: CC(C)O
Product: O=C(O)Cn1c(-c2cccs2)n[nH]c1=S
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl N-(thioxomethylene)glycinate (2.06 g) and thiophene-2-carbohydrazide (2.57 g) in isopropanol (50 ml) was heated at 70° C. while stirring for 16 h. The mixture was allowed to come to r.t. and the formed precipitate collected and heated at reflux in 1.0 M aqueous NaHCO3 solution for 2 h. After cooling to r.t. and acidification with conc. HCl (aq.) the product was extracted into EA, which was washed with brine and then dried over MgSO4 before concentration to dryness to yield crude title compound which was used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[N:13]=[CH:12][C:11]3[C:6](=[N:7][C:8](O)=[C:9]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:10]=3)[N:5]2[N:21]=1.CN(C=O)C.C(Cl)(Cl)[Cl:28]>>[Cl:28][C:8]1[N:7]=[C:6]2[C:11]([CH:12]=[N:13][C:4]3[N:5]2[N:21]=[C:2]([CH3:1])[CH:3]=3)=[N:10][C:9]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClC(Cl)Cl
Reactant: Cc1cc2ncc3nc(-c4ccccc4)c(O)nc3n2n1
Solvent: CN(C)C=O
Product: Cc1cc2ncc3nc(-c4ccccc4)c(Cl)nc3n2n1
Temperature: 70 °C

Procedure:
A 40 mL scintillation vial containing Compound [CCXXX] (220 mg, 0.8 mmol, 1 eq.), CHCl3 (12 mL), DMF (12 mg, 0.16 mmol, 2 eq.), and SOCK (0.56 g, 3.2 mmol, 4 eq.) was heated at 70° C. under nitrogen for 1.5 hours. Then the mixture was allowed to cool and the solvent was removed in vacuo. The residue was dissolved in CHCl3 (20 mL) and washed with saturated NaHCO3 (5 mL). The water solution was extracted with CHCl3 (2×5 mL). The combined organic phases were dried over MgSO4. After filtration and concentration, the residue was purified by silica gel chromatography using EtOAc and heptanes as the mobile phases to furnish Compound [CCXXXI] as a yellowish solid: LCMS (m/e) 296 (M+H); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.57 (s, 3H) 6.71 (s, 1H) 7.46-7.52 (m, 3H) 7.79 (dd, J=6.61, 3.00 Hz, 2H) 9.02 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([C:12]([OH:14])=O)=[C:5]2[OH:15].[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([C:12]([NH:22][CH2:21][C:20]1[CH:23]=[CH:24][C:17]([Cl:16])=[CH:18][CH:19]=1)=[O:14])=[C:5]2[OH:15]
Reactant: NCc1ccc(Cl)cc1
Reactant: O=C(O)c1ncc2ccc(Br)cc2c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCc1ccc(Cl)cc1)c1ncc2ccc(Br)cc2c1O
Temperature: 25 °C

Procedure:
A mixture of 6-bromo-4-hydroxyisoquinoline-3-carboxylic acid (Preparation 8, 0.4 g), 4-chlorobenzylamine (0.219 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.305 g) and 1-hydroxybenzotriazole monohydrate (0.217 g) in DMF (20 mL) is stirred at room temperature until judged complete. The solution is then poured into ice water and the resulting solid collected and dried.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:16]=[C:15]2[C:25]([F:28])([F:27])[F:26])=[CH:10][CH:9]=1)(=O)=O.[N-:29]=[N+:30]=[N-:31].[Na+].[I-].[K+]>CN(C=O)C>[N:29]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:16]=[C:15]2[C:25]([F:28])([F:27])[F:26])=[CH:10][CH:9]=1)=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCCc1ccc(-n2cc(-c3ccccc3)nc2C(F)(F)F)cc1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCc1ccc(-n2cc(-c3ccccc3)nc2C(F)(F)F)cc1
Temperature: 100 °C
Yield: 93 %

Procedure:
A mixture of 2-{4-[4-phenyl-2-(trifluoromethyl)-1H-imidazol-1-yl]phenyl}ethyl methanesulfonate and sodium azide (175 mg, 2.70 mmol) and potassium iodide (224 mg, 1.35 mmol) in DMF (7 mL) was heated at 100° C. for overnight. After cooling, the reaction mixture was partitioned between ethyl acetate (20 mL) and water (10 mL). The aqueous phase was extracted with ethyl acetate (3×10 mL) and the combined organic phase was dried (MgSO4) and concentrated under reduced pressure. Purification by flash column chromatography on silica gel eluting with hexane/ethyl acetate (gradient elution from 10:1 to 4:1) to afford 450 mg (93%) of the title compound as colorless amorphous: MS (EI) m/z 357 [M]+.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:10]1(=[O:15])[O:14][CH2:13][CH2:12][CH2:11]1>>[CH2:1]([NH:9][C:13](=[O:14])[CH2:12][CH2:11][CH2:10][OH:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C1CCCO1
Reactant: CCCCCCCCN
Product: CCCCCCCCNC(=O)CCCO

Procedure:
1 mol of octylamine was heated to 100° C. with stirring. 1 mol of gamma-butyrolactone was added dropwise over a period of 30 minutes. The mixture was heated for three hours to 120° C. At the end of the reaction, a vacuum of 50 mbar was applied. The product was obtained after cooling in the form of a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@H:4]([OH:12])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl.C(OCC)C>[CH3:1][O:2][C:3](=[O:13])[C@H:4]([O:12][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@H](O)Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COC(=O)[C@@H](Cc1ccccc1)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
To a solution of (R)-2-hydroxy-3-phenylpropionic acid methyl ester from Step A (1.62 g, 10.9 mol) and triethylamine (3.0 mL, 21.8 mol) in dichloromethane (21.8 mL) at 0° C. was added dropwise methanesulfonyl chloride (1.28 mL, 16.4 mol). The reaction mixture was stirred at 0° C. for 1 h and was diluted with diethyl ether (200 mL) and washed with saturated ammonium chloride solution and brine. The organic layer was separated, dried with magnesium sulfate, filtered and concentrated in vacuo to give a light yellow solid 2.43 g (73%), which was used without further purification.
Reaction SMILES: [CH:1]([NH:5][C:6]1[C:11]([CH:12]=[O:13])=[C:10](Cl)[N:9]=[C:8]([S:15][CH3:16])[N:7]=1)([CH2:3][CH3:4])[CH3:2].[F:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[C:20]([CH3:27])[CH:19]=1>>[CH:1]([NH:5][C:6]1[C:11]([CH:12]=[O:13])=[C:10]([C:21]2[CH:22]=[CH:23][C:18]([F:17])=[CH:19][C:20]=2[CH3:27])[N:9]=[C:8]([S:15][CH3:16])[N:7]=1)([CH2:3][CH3:4])[CH3:2]
Reactant: Cc1cc(F)ccc1B(O)O
Reactant: CCC(C)Nc1nc(SC)nc(Cl)c1C=O
Product: CCC(C)Nc1nc(SC)nc(-c2ccc(F)cc2C)c1C=O

Procedure:
Prepared as described above in Example 11 starting from 4-sec-butylamino-6-chloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde and 4-fluoro-2-methylphenylboronic acid to give the title compound 4-sec-butylamino-6-(4-fluoro-2-methyl-phenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde. 1H-NMR: δ 1.02 (m, 3H), 1.30 (m, 3H), 1.70 (m, 2H), 2.28 (m, 3H), 2.59 (s, 3H), 4.37 (m, 1H), 6.98 (m, 2H), 7.20 (m, 1H), 9.04 (br s, 1H), 9.50 (s, 1H). LC MS (m/e)=334 (MH+).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][C@H:12]3[CH2:14][C@H:9]2[N:10]([CH3:15])[CH2:11]3)=[N:6][CH:7]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[CH:25][C:26]([C:29]#[CH:30])=[N:27][CH:28]=2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:24]=[CH:25][C:26]([C:29]#[C:30][C:2]3[CH:3]=[CH:4][C:5]([N:8]4[CH2:13][C@H:12]5[CH2:14][C@H:9]4[N:10]([CH3:15])[CH2:11]5)=[N:6][CH:7]=3)=[N:27][CH:28]=2)=[CH:21][CH:22]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: CN1C[C@@H]2C[C@@H]1N(c1ccc(I)cn1)C2
Product: CN1C[C@@H]2C[C@@H]1N(c1ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cn1)C2

Procedure:
Prepared according to general working method I from (1S,4S)-2-(5-iodo-pyridin-2-yl)-6-methyl-2,6-diaza-bicyclo[2.2.1]heptane (45 mg, 0.14 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (51 mg, 0.24 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]([CH2:20]COC1CCCCO1)[C:7]1([C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=2)[CH2:9][CH2:8]1)=[O:5])C.Cl.CO>CO>[O:5]=[C:4]1[N:6]([C:7]2([C:10]3[CH:11]=[CH:12][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:18][CH:19]=3)[CH2:9][CH2:8]2)[CH2:20][CH2:1][O:3]1
Reactant: CCOC(=O)N(CCOC1CCCCO1)C1(c2ccc(C(=O)OC)cc2)CC1
Agent: Cl
Solvent: CO
Product: COC(=O)c1ccc(C2(N3CCOC3=O)CC2)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 62 %

Procedure:
Methyl 4-(1-{ethoxycarbonyl-[2-(tetrahydropyran-2-yloxy)ethyl]amino}cyclopropyl)benzoate (128 mg) described in Preparation Example 68 was dissolved in methanol (4 mL), 5% hydrogen chloride/methanol was added under ice-cooling, and the mixture was stirred at room temperature for 3.5 hr. The solvent was evaporated from the reaction mixture, N,N-dimethylformamide (4 mL) and potassium carbonate (9 mg) were added, and the mixture was stirred at 140° C. for 6 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (53 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:17]1[CH:18]=[CH:19][C:20]([N+:25]([O-:27])=[O:26])=[C:21]([CH:24]=1)[NH:22][CH3:23].CNCCNC.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu](I)I>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:17]2[CH:18]=[CH:19][C:20]([N+:25]([O-:27])=[O:26])=[C:21]([NH:22][CH3:23])[CH:24]=2)[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNc1cc(Br)ccc1[N+](=O)[O-]
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Agent: I[Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: CNc1cc(-n2ccc(OCc3ccccc3)cc2=O)ccc1[N+](=O)[O-]
Temperature: 150 °C
Reaction time: 1 h
Yield: 58.4 %

Procedure:
The mixture of 4-(benzyloxy)pyridin-2(1H)-one (5.0 g), 5-bromo-N-methyl-2-nitroaniline (5.74 g), copper iodide (4.73 g), N,N′-dimethylethylenediamine (2.8 ml) and potassium carbonate (10.30 g) in DMSO (250 ml) was stirred at 150° C. under N2 for 1 h. After cooling to room temperature, 28% NH3solution was added to the resulting mixture. The resulting suspension was filtered. The precipitate was washed with water and IPA and dried to give the title compound (5.1 g) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([CH3:10])=[N:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=[O:4].C1C(=O)N([Br:26])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([CH2:10][Br:26])=[N:7][C:6]=1[C:11]1[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=1)=[O:4]
Reactant: COC(=O)c1sc(C)nc1-c1ccc(OC)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1sc(CBr)nc1-c1ccc(OC)cc1
Temperature: 100 °C
Yield: 24.2 %

Procedure:
To the solution of 4-(4-Methoxy-phenyl)-2-methyl-thiazole-5-carboxylic acid methyl ester (0.25 g, 0.94 mmol) in the 20 ml of CCl4 was added NBS (0.16 g, 0.94 mmol) and AIBN (0.015 g, 0.094 mmol). The reaction mixture was heated at 100° C. for 2 h under nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (230-400 M) using 10% ethyl acetate/hexane as a eluent to give the desired product (0.078 g, 24%).
Reaction SMILES: O.[N:2]1([C:7]2[CH:16]=[C:15]([N:17]3[CH:21]=[CH:20][N:19]=[CH:18]3)[CH:14]=[C:13]3[C:8]=2[NH:9][C:10](=[O:23])[C:11](=[O:22])[NH:12]3)[CH:6]=[CH:5][N:4]=[CH:3]1.[N+:24]([O-])([O-:26])=[O:25].[K+].[OH-].[Na+]>S(=O)(=O)(O)O>[N:2]1([C:7]2[C:16]([N+:24]([O-:26])=[O:25])=[C:15]([N:17]3[CH:21]=[CH:20][N:19]=[CH:18]3)[CH:14]=[C:13]3[C:8]=2[NH:9][C:10](=[O:23])[C:11](=[O:22])[NH:12]3)[CH:6]=[CH:5][N:4]=[CH:3]1
Reactant: O=[N+]([O-])[O-]
Reactant: O=c1[nH]c2cc(-n3ccnc3)cc(-n3ccnc3)c2[nH]c1=O
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: O=c1[nH]c2cc(-n3ccnc3)c([N+](=O)[O-])c(-n3ccnc3)c2[nH]c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.4 %

Procedure:
In 3 ml of concentrated sulfuric acid was dissolved 290 mg of 5,7-di-(1-imidazolyl)quinoxaline-2,3-(1H,4H)-dione hydrate followed by addition of 220 mg of potassium nitrate with ice-cooling. After cooling to room temperature, the reaction mixture was further stirred at 80° C. for 30 minutes. After cooling to room temperature, the reaction mixture was poured in ice-water and adjusted to pH 7 with sodium hydroxide. The resulting crystals were recovered by filtration and washed with water to provide 124 mg of 5,7-di(1-imidazolyl)-6-nitroquinoxaline-2,3-(1H,4H)-dione.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:10])[C:5](=[CH:7][C:8]=1[CH3:9])[OH:6].C(=O)([O-])[O-].[K+].[K+].Br[C:18](Br)([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>CC(C)=O>[CH3:1][C:2]1[C:8]([CH3:9])=[CH:7][C:5]2[O:6][CH:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:24][O:10][C:4]=2[CH:3]=1
Reactant: Cc1cc(O)c(O)cc1C
Reactant: CCOC(=O)C(C)(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1COc2cc(C)c(C)cc2O1
Yield: 319.7 %

Procedure:
A stirred solution of 4,5-dimethylcatechol (7.0 g.) in dry acetone (45 ml.) was heated under reflux, then potassium carbonate (5 g.) was added followed by the dropwise addition of ethyl dibromopropionate (3.5 g.). The addition procedure was repeated a further three times over 11/4 hours then the reaction was stirred under reflux for a further 33/4 hours. After cooling, the mixture was filtered, the solids washed well with acetone then the combined filtrate concentrated in vacuo. Water (35 ml.) was added, the resulting solid collected, washed with petrol then taken up in ether. The ethereal solution was washed with water, dried (Na2SO4) and evaporated in vacuo to give ethyl 6,7-dimethyl-1,4-benzodioxan-2-carboxylate (10.17 g.), m.p. 70°-71° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([CH2:14][S:15]([NH:18][C:19](=[O:23])[C:20]([O-])=[O:21])(=[O:17])=[O:16])[N:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].CC(C)([O-])C.[K+].O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:14]3[S:15](=[O:17])(=[O:16])[NH:18][C:19](=[O:23])[C:20]=3[OH:21])[N:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C([O-])C(=O)NS(=O)(=O)Cc1csc(-c2ccc(Cl)c(Cl)c2)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1NS(=O)(=O)C(c2csc(-c3ccc(Cl)c(Cl)c3)n2)=C1O
Reaction time: 8 h

Procedure:
To a solution of the ethyl oxamate intermediate prepared in Step E above (4.4 g., 0.010 mol) in dimethylformamide (26 ml) was added potassium tert-butoxide (3.5 g., 0.032 mol) in portions over 15 minutes. After stirring overnight, the reaction mixture was poured into water (250 ml). Acidification with 6 N hydrochloric acid, followed by filtration, yielded 3.5 g. of crude product. Recrystallization from tetrahydrofuran-ether-petroleum ether gave 1.74 g. of the title compound, m.p. 301° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=2)[C:7]([CH:18]=[O:19])=[C:6]1[CH2:20][CH2:21][CH3:22].CC(=CC)C.P([O-])(O)(O)=[O:33].[Na+].Cl([O-])=O.[Na+].Cl>C(O)(C)(C)C.O>[Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=2)[C:7]([C:18]([OH:33])=[O:19])=[C:6]1[CH2:20][CH2:21][CH3:22]
Reactant: CCCc1c(C=O)c2ccc(C(=O)OC)cc2n1Cc1ccccc1Cl
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CCCc1c(C(=O)O)c2ccc(C(=O)OC)cc2n1Cc1ccccc1Cl
Temperature: 40 °C
Reaction time: 2 h
Yield: 34.3 %

Procedure:
To a mixture of methyl 1-(2-chlorobenzyl)-3-formyl-2-propylindole-6-carboxylate (263 mg), 2-methyl-2-butene (220 mg) and sodium dihydrogenphoshate (128 mg) in a mixture of tert-butanol (7 ml) and water (1.3 ml) was added sodium chlorite (219 mg) at 20° C. The reaction mixture was stirred at 40° C. for 2 hours. The reaction mixture was acidified with 1N hydrochloric acid at 0° C. and extracted with chloroform three times. The organic phase was dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:2) to give 1-(2-chlorobenzyl)-6-methoxycarbonyl-2-propylindole-3-carboxylic acid (94 mg) as pale yellow crystals.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[F:7][C:8]([F:29])([F:28])[C:9]1[CH:27]=[CH:26][C:12]([O:13][C:14]2[CH:25]=[CH:24][C:17]([O:18][CH:19]([CH3:23])[C:20](O)=[O:21])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1>CN(C)C=O.CCOCC>[F:7][C:8]([F:29])([F:28])[C:9]1[CH:27]=[CH:26][C:12]([O:13][C:14]2[CH:25]=[CH:24][C:17]([O:18][CH:19]([CH3:23])[C:20]([Cl:4])=[O:21])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Oxalyl chloride (1.56 g, 1.1 ml, 12.32 mmol) is added to a stirring solution of 2-[4-(4-trifluoromethylphenoxy)phenoxy]propionic acid (2.00 g, 6.16 mmol), dimethylformamide (DMF; 4 drops) and ether (50 ml). The mixture is stirred at RT for 3 hours. Insoluble material is filtered off and solvent is removed in vacuo to give 2-[4-(4-trifluoromethylphenoxy)phenoxy]propionic acid chloride.