Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)C)(=[O:3])C.[C:8]([C:10]1[C:14]([CH3:15])=[C:13]([CH3:16])[O:12][C:11]=1[NH:17][C:18](=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20])#[N:9]>C(O)=O>[CH3:15][C:14]1[C:10]2[C:8](=[O:3])[NH:9][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:17][C:11]=2[O:12][C:13]=1[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C(=O)Nc1oc(C)c(C)c1C#N
Solvent: O=CO
Product: CCOC(=O)c1nc2oc(C)c(C)c2c(=O)[nH]1
Temperature: 60 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
To a solution of the compound obtained in the above step (1) (13.6 g) in methylene chloride (200 mL) is added piperidine (18.9 g) and thereto is added dropwise a solution of ethyl chlorooxoacetate (16.3 g) in methylene chlorode (200 mL) under ice-cooling. The mixture is stirred at 0° C. for 1.5 hours. The reaction mixture is diluted with chloroform (100 mL) and thereto is added water (300 mL). After stirring, the organic layer is separated and the aqueous layer is extracted with chloroform. The organic layers are combined and washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated and the residue is purified by column chromatography on silica gel (Solvent; chloroform:ethyl acetate=9:1) to give ethyl [(3-cyano-4,5-dimethylfuran-2-yl)amino](oxo)acetate (17 g, yield; 72%) as a colorless powder. A mixture of formic acid (30 mL) and acetic anhydride (30 mL) is stirred at 60° C. under argon gas atmosphere for 2 hours and thereto is added ethyl [(3-cyano-4,5-dimethylfuran-2-yl)amino](oxo)acetate (7.07 g). The mixture is refluxed for 14 hours. The reaction mixture is concentrated and the residue is purified by column chromatography on silica gel (Solvent; chloroform:ethyl acetate=9:1→chloroform:methanol=19:1) to give ethyl 5,6-dimethyl-4-oxo-3,4-dihydrofuro[2,3-d]pyrimidine-2-carboxylate (4.30 g, yield; 61%) as a colorless powder. M.p. 180-182° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][N:6]=1)=[O:4].Cl[C:13]([F:18])([F:17])C([O-])=O.[Na+].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[F:17][CH:13]([F:18])[O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc(O)cn1
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OC(F)F)cn1
Temperature: 100 °C
Yield: 74.1 %

Procedure:
To a RBF were added 5-hydroxy-2-pyridinecarboxylic acid methyl ester (1.2 ml, 9.94 mmol), sodium chlorodifluoroacetate (3.3 g, 21.54 mmol), and cesium carbonate (9.7 g, 29.8 mmol) in DMF (20 ml). The reaction mixture was heated to 100° C. for 3 h. Then it was cooled to RT. The reaction mixture was diluted with water and extracted with EtOAc. The organic extract was washed with water, brine and dried over MgSO4. It was filtered and concentrated. The crude product was purified by flash chromatography eluting with a gradient of 5% to 50% EtOAc in hexane, to provide methyl 5-(difluoromethoxy)picolinate (1.4962 g, 7.37 mmol, 74.1% yield). MS m/z: 204.3 [M+H].
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45](F)[CH:44]=2)[CH:11]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:22]=2[CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O:54][C:55](=[O:72])C1C=C(O)C=C(C2C=CC3OCOC=3C=2)C=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:7])[C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:22]=2[CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH:11]=[C:10]([C:43]2[CH:48]=[CH:47][C:46]3[O:54][CH2:55][O:72][C:45]=3[CH:44]=2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1cc(O)cc(-c2ccc3c(c2)OCO3)c1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)OC(C)(C)C)cc(-c3cccc(F)c3)c2)c1CCC(=O)OCC
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)OC(C)(C)C)cc(-c3ccc4c(c3)OCO4)c2)c1CCC(=O)OCC

Procedure:
The title compound was prepared in the same way as 5-{6-[2-(2-ethoxycarbonyl-ethyl)-3-(3-ethoxycarbonyl-propoxy)-phenyl]-hexyloxy}-3′-fluoro-biphenyl-3-carboxylic acid tert-butyl ester starting from 3-benzo[1,3]dioxol-5-yl-5-hydroxy-benzoic acid tert-butyl ester.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[S:11][C:10]=1[CH2:18]O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.S(Cl)([Cl:29])=O>ClCCl>[C:4]([Si:1]([O:8][C:9]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[S:11][C:10]=1[CH2:18][Cl:29])([CH3:3])[CH3:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(C(F)(F)F)sc1CO
Reactant: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cc(C(F)(F)F)sc1CCl
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a solution of [3-(tert-butyldimethylsilanyloxy)-5-trifluoromethylthiophen-2-yl]methanol in anhydrous dichloromethane (100 mL) was added triethylamine (4.05 g, 40.0 mmol) followed by thionyl chloride (2.38 g, 20.0 mmol) at 0° C. The reaction mixture was stirred for 30 min and quenched with water (50.0 mL). After separation, the organic layer was washed with water (3×50.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography eluting with hexane to afford the title compound (2.31 g, 70%) as a yellow oil, which was directly used.
Reaction SMILES: [CH:1]1[CH2:5][CH2:4][CH2:3][CH:2]=1.[CH:6]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13]>>[CH3:13][C:7]1[CH:6]=[C:11]([OH:12])[C:10]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:9][CH:8]=1
Reactant: C1=CCCC1
Reactant: Cc1cccc(O)c1
Product: Cc1ccc(C2CCCC2)c(O)c1
Reaction time: 1 h
Yield: 19.9 %

Procedure:
130 g of cyclopentene are added dropwise to 108 g of m-cresol and 10 g of an acid-activated fuller's earth at 140° C. The mixture is stirred at this temperature for 1 h. After removal of the catalyst by filtration the mixture is fractionated. 35 g of 3-methyl-6-cyclopentylphenol boiling at 113° C (1.4 mm Hg) are obtained. A further fraction (112 g) boiling at 154° C (0.9 mm Hg) consists of 3-methyl-4,6-dicyclopentylphenol (melting point: 45° C).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:11]2[C:6](=[CH:7][CH:8]=[C:9](/[C:12](/[CH3:23])=[CH:13]/[C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=3)[CH:10]=2)[O:5][CH2:4][CH2:3]1.[CH2:25]([NH2:28])[CH2:26][CH3:27]>C(Cl)(Cl)Cl.C(OCC)C.[OH-].[Na+]>[CH2:25]([NH:28][C:18](=[O:19])[C:17]1[CH:21]=[CH:22][C:14](/[CH:13]=[C:12](/[C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[O:5][CH2:4][CH2:3][C:2]3([CH3:24])[CH3:1])\[CH3:23])=[CH:15][CH:16]=1)[CH2:26][CH3:27]
Reactant: CCCN
Reactant: C/C(=C\c1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCO2
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CCCNC(=O)c1ccc(/C=C(\C)c2ccc3c(c2)C(C)(C)CCO3)cc1

Procedure:
A 15 ml aliquot of the chloroform solution of the mixed anhydride of 4-[(E)-2-(4,4-dimethyl-6-chromanyl)-2-methylvinyl]benzoic acid from Preparation 13 was added to a solution of 0.1 g (1.71 mmole) of n-propylamine in ca. 25 ml of chloroform at 0° C. The reaction mixture was filtered and then it was extracted twice with 1N hydrochloric acid. The resulting chloroform solution was dried (MgSO4) and evaporated in vacuo to give an oily solid. This solid was dissolved in diethyl ether and 2N sodium hydroxide. The layers were separated and the ether layer was filtered, dried (MgSO4) and evaporated in vacuo. The residue was recrystallized from diethyl ether-hexane, to give 0.127 g of the title compound, mp 138°-139° C.
Reaction SMILES: BrN1C(=O)CCC1=O.[CH3:9][C:10]1[CH:11]=[C:12]([CH:38]=[CH:39][C:40]=1[S:41][CH3:42])[CH2:13][NH:14][C:15]([C:17]1[C:22](=[O:23])[C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)=[C:20]([CH3:34])[N:19]([CH:35]([CH3:37])[CH3:36])[CH:18]=1)=[O:16].[N:43]#[C:44][NH2:45].CC(C)([O-])C.[K+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CO>[CH3:9][C:10]1[CH:11]=[C:12]([CH:38]=[CH:39][C:40]=1[S:41]([CH3:42])=[N:45][C:44]#[N:43])[CH2:13][NH:14][C:15]([C:17]1[C:22](=[O:23])[C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)=[C:20]([CH3:34])[N:19]([CH:35]([CH3:37])[CH3:36])[CH:18]=1)=[O:16]
Reactant: N#CN
Reactant: CSc1ccc(CNC(=O)c2cn(C(C)C)c(C)c(-c3cccc(C(F)(F)F)c3)c2=O)cc1C
Agent: CC(C)(C)[O-]
Agent: O=C1CCC(=O)N1Br
Agent: O=S([O-])([O-])=S
Solvent: CO
Product: Cc1cc(CNC(=O)c2cn(C(C)C)c(C)c(-c3cccc(C(F)(F)F)c3)c2=O)ccc1S(C)=NC#N

Procedure:
N-Bromosuccinimide (63 mg, 0.35 mmol) is added to a mixture of 1-isopropyl-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyridine-3-carboxylic acid 3-methyl-4-methylsulfanyl-benzylamide (preparation 66c, 115 mg, 0.24 mmol), cyanamide (14 mg, 0.33 mmol) and potassium tert-butoxide (32 mg, 0.29 mmol) in methanol (1.1 mL). After 20 min saturated aqueous sodium thiosulfate solution is added, and the mixture is extracted twice with dichloromethane. The combined organic layers is dried over Na2SO4 and concentrated under reduced pressure. The residue is directly used in the next step without further purification. Yield: 99 mg (80% of theory); ESI mass spectrum: [M+H]+=529; r.t. HPLC: 0.58 min (X012_S01).
Reaction SMILES: [O:1]1[C:5]2[C:6]([CH:10]3[C:16]4[CH:17]=[C:18]([OH:24])[C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:15]=4[CH2:14][CH2:13][N:12]([CH3:25])[CH2:11]3)=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[CH3:26][O:27][CH2:28]Cl>O1CCCC1>[O:1]1[C:5]2[C:6]([CH:10]3[C:16]4[CH:17]=[C:18]([O:24][CH2:26][O:27][CH3:28])[C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:15]=4[CH2:14][CH2:13][N:12]([CH3:25])[CH2:11]3)=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: CN1CCc2cc([N+](=O)[O-])c(O)cc2C(c2cccc3c2OCC3)C1
Reactant: COCCl
Solvent: C1CCOC1
Product: COCOc1cc2c(cc1[N+](=O)[O-])CCN(C)CC2c1cccc2c1OCC2
Reaction time: 22 h

Procedure:
(+)-5-(2,3-dihydrobenzofuran-7-yl)-3-methyl-8-nitro-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ol (68.0 mg, 2.0 mmol) and potassium-tert-butylate (24.0 mg, 2.2 mmol) are dissolved in dry tetrahydrofuran (10 ml) at 23° C. Chloromethyl methyl ether (20.0 mg, 2.5 mmol) is added. The reaction mixture is stirred for 22 hours, filtered and the filtrate evaporated to dryness under reduced pressure. The resulting light yellow oil is purified using reverse phase HPLC (column 16 mm×250 mm, C18 7μ; eluent aceticnitril/0.1M ammoniumsulphate pH 3.3 (30:70), isocratic). The fractions containing the product are pooled. The pH is adjusted to 9.0, and the product extracted into dichloromethane. The organic phase is evaporated to dryness under reduced pressure.
Reaction SMILES: [Na].Cl[C:3]1[N:8]=[N:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][OH:17])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH3:18][OH:19]>>[CH3:18][O:19][C:3]1[N:8]=[N:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][OH:17])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: CO
Reactant: OCCC1CCN(c2ccc(Cl)nn2)CC1
Agent: [Na]
Product: COc1ccc(N2CCC(CCO)CC2)nn1
Temperature: 0 °C
Reaction time: 8 h
Yield: 61.5 %

Procedure:
5.7 Parts of sodium (in pieces) were added to 86 parts of methanol. After the dropwise addition of 12.1 parts of 1-(6-chloro-3-pyridazinyl)-4-piperidineethanol, the reaction mixture was stirred overnight at reflux temperature. After cooling, the whole was poured into ice water and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of methylbenzene and methanol (90:10 by volume) as eluent. The desired fraction was collected and the eluent was evaporated, yielding 7.3 parts (61.5%) of 1-(6-methoxy-3-pyridazinyl)-4-piperidineethanol as a residue (int. 95).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12].[NH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18]>>[OH:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:13][S:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([F:12])[CH:4]=1)(=[O:10])=[O:9]
Reactant: NCCCCO
Reactant: O=S(=O)(Cl)c1ccc(Br)c(F)c1
Product: O=S(=O)(NCCCCO)c1ccc(Br)c(F)c1

Procedure:
Using a method analogous to that described in Example 1, 4-bromo-3-fluorophenyl sulphonyl chloride was reacted with 4-aminobutanol, and the title compound obtained as a white solid after recrystallisation from ether/petrol. δC (CDCl3, 62.9 MHz): 26.5, 29.4, 43.2, 62.2, 114.5 (d, J 20.5), 115.3 (d, J 25.4), 123.7 (d, 3.9), 134.5, 141.2 (d, 5.9) and 158.9 (d, J 252).
Reaction SMILES: C1(S([C:10]2[CH:11]3[CH2:21][CH2:20][CH:18]([CH:19]=2)[C:17]2[C:12]3=[CH:13][CH:14]=[CH:15][CH:16]=2)(=O)=O)C=CC=CC=1.[N+:22]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])#[C-:23].C(O[K])(C)(C)C.Cl>C1COCC1>[CH2:28]([O:27][C:25]([C:24]1[NH:22][CH:23]=[C:19]2[C:10]=1[CH:11]1[CH2:21][CH2:20][CH:18]2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=21)=[O:26])[CH3:29]
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: O=S(=O)(C1=CC2CCC1c1ccccc12)c1ccccc1
Agent: CC(C)(C)O[K]
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]cc2c1C1CCC2c2ccccc21
Temperature: 0 °C
Yield: 90.9 %

Procedure:
Under an argon atmosphere, 0.296 g (1.0 mmol) of the obtained 1,4-dihydro-2-phenylsulfonyl-1,4-ethanonaphthalene, 0.13 ml (1.15 mmol) of ethyl isocyano-acetate and 30 ml of anhydrous THF were charged and cooled to 0° C. Into the mixture, 1.7 ml of tert-BuOK (1 M THF solution) was dropped over two hours and the resultant mixture was stirred for three hours at room temperature. After the completion of reaction, the reaction mixture was added with dilute hydrochloric acid, washed in turn with an aqueous saturated sodium bicarbonate solution, distilled water and saturated saline and dried with anhydrous sodium sulfate. The product was purified with silica gel column chromatography (chloroform) to obtain ethyl-4,9-dihydro-4,9-ethano-2H-benz[f]isoindole-1-carboxylate (0.243 g, yield: 91%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:13].[C:17]([NH2:20])(=[S:19])[CH3:18]>>[CH3:1][O:2][C:3]([C:4]1[N:20]=[C:17]([CH3:18])[S:19][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:13])=[O:16]
Reactant: COC(=O)C(=O)C(Cl)c1ccccc1OC
Reactant: CC(N)=S
Product: COC(=O)c1nc(C)sc1-c1ccccc1OC

Procedure:
prepared by reaction of 3-chloro-3-(2-methoxy-phenyl)-2-oxo-propionic acid methyl ester with thioacetamide. LC-MS: tR=0.88 min; [M+H]+=264.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[F:13][C:14]([F:26])([F:25])[C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[S:21]([C:18]2[CH:17]=[CH:16][C:15]([C:14]([F:13])([F:25])[F:26])=[CH:20][CH:19]=2)(=[O:23])=[O:22])=[CH:6][CH:7]=1
Reactant: Fc1ccc(C2CCCN2)cc1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Product: O=S(=O)(c1ccc(C(F)(F)F)cc1)N1CCCC1c1ccc(F)cc1

Procedure:
The title compound, white solid, m.p. 85° C. and MS: m/e=373 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-(4-fluoro-phenyl)-pyrrolidine and 4-trifluoromethyl-benzenesulfonyl chloride.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21]([CH3:23])=[O:22].[H-].[K+].[CH2:26]([S:28]([CH:31]=[CH2:32])(=[O:30])=[O:29])[CH3:27].[Cl-].[NH4+]>CN(C=O)C>[Cl:18][C:8]1[CH:9]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:11]=[C:12]([Cl:13])[C:7]=1[N:6]1[C:2]([NH:1][CH2:27][CH2:26][S:28]([CH2:31][CH3:32])(=[O:30])=[O:29])=[C:3]([S:21]([CH3:23])=[O:22])[C:4]([C:19]#[N:20])=[N:5]1
Reactant: CS(=O)c1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Reactant: C=CS(=O)(=O)CC
Agent: [Cl-]
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCS(=O)(=O)CCNc1c(S(C)=O)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 20 °C
Reaction time: 0.33 h
Yield: 31.1 %

Procedure:
A solution of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-methylsulfinylpyrazole (10 g) in dry DMF was added during 10 minutes to potassium hydride (0.7 g of a 35% suspension in oil) in dry DMF at 4° C. and stirred for 20 min. Vinyl ethyl sulfone (3.13 g) in dry DMF was added over 5hr at 4° C. and the mixture stirred overnight whilst warming to 20° C. under a nitrogen atmosphere. The mixture was recooled, ammonium chloride solution added and the organic layer washed (water), dried (sodium sulfate) and evaporated. The residue was crystallized (ethyl acetate/hexane) to give 1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-5-(2-ethylsulfonylethylamino)-4-methylsulfinylpyrazole (4.08 g), m.p. 131-132° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]([CH3:16])[CH3:15])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:17]([O-])([O-])=O.[Cs+].[Cs+].CI>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH:14]([CH3:16])[CH3:15])[CH3:17])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Br)cc(NC(C)C)c1C
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CI
Product: COC(=O)c1cc(Br)cc(N(C)C(C)C)c1C
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a stirred solution of methyl 5-bromo-3-(isopropylamino)-2-methylbenzoate (0.5 g, 1.75 mmol) in acetonitrile (10 mL), Cs2CO3 (1.02 g, 2.63 mmol) and methyl iodide (1.45 g, 3.5 mmol) were added to it. The resulting reaction mixture was stirred at 80° C. for 4 h. Upon completion, the solvent was removed under reduced pressure and residue dissolved in water and extracted with ethyl acetate. Crude material obtained was purified by column chromatography over silica gel affording the desired compound product without further purification (0.39 g)
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[C:16]([O:18]COC)=[CH:15][CH:14]=[CH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22]N(C)CCN(C)C.C([Li])CCC.CI.[Cl-].[NH4+]>CCOCC.CCCCCC>[CH2:1]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[C:16]([OH:18])=[C:15]([CH3:22])[CH:14]=[CH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)CCN(C)C
Reactant: COCOc1cccc2cccc(Cc3ccccc3)c12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CI
Solvent: CCOCC
Solvent: CCCCCC
Product: Cc1ccc2cccc(Cc3ccccc3)c2c1O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
10 g of 8-benzyl-1-methoxymethoxynaphthalene was dissolved in 100 ml of anhydrous ether, followed by the addition of 6.5 ml of tetramethylethylenediamine. 27 ml of a 1.6M solution of n-butyllithium in hexane was dropped into the obtained mixture under cooling with ice. The obtained mixture was stirred at 0° C. for one hour, followed by the dropwise addition of 2.7 ml of methyl iodide. The obtained mixture was stirred at room temperature for one hour and poured into a saturated aqueous solution of ammonium chloride. The obtained mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and distilled in a vacuum to remove the solvent. The residue was dissolved in 150 ml of acetone, followed by the addition of 60 ml of 6N hydrochloric acid. The obtained mixture was stirred at room temperature for one hour, followed by the addition of water. The obtained mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and distilled in a vacuum to remove the solvent. The residue was purified by silica gel column chromatography (developer: 3% ethyl acetate/hexane) to give 6 g of the title compound as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH2:24]([NH:26][C:27](=[O:45])[C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30][C:29]=1[NH:43][CH3:44])[CH3:25]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:32]5[CH:31]=[N:30][C:29]([NH:43][CH3:44])=[C:28]([CH:33]=5)[C:27]([NH:26][CH2:24][CH3:25])=[O:45])[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CCNC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cnc1NC
Product: CCNC(=O)c1cc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cnc1NC

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and N-ethyl-2-methylamino-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-nicotinamide (Stage 242.1.1) to give the title compound as a yellowish foam. (HPLC: tR 2.17 min (Method A); M+H=471 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.92 (s, 1H), 8.58 (t, 1H), 8.25-8.20 (m, 2H), 8.11-8.06 (m, 2H), 8.05-8.02 (m, 1H), 7.96-7.92 (m, 1H), 7.47-7.44 (m, 1H), 3.89 (s, 3H), 3.57 (s, 3H), 3.40-3.19 (m, 2H), 2.93 (d, 3H), 1.97 (s, 3H), 1.15 (t, 3H))
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][C:7](=[O:13])[CH2:6][CH2:5]2.N(C(OCC)=O)=N[C:16](OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO>C1COCC1.ClCCl.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:16])[O:8][C:7](=[O:13])[CH2:6][CH2:5]2
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: O=C1CCc2cc(Br)c(O)cc2O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1cc2c(cc1Br)CCC(=O)O2
Reaction time: 4 h
Yield: 56.7 %

Procedure:
A solution of Intermediate 2 (5.0 g) in THF (20 ml) was added with diethyl azodicarboxylate (4.1 g, Ald), triphenylphosphine (8.0 g, WAKO), and methanol (990 μl, KANTO), and stirred for 4 hours. The reaction mixture was added with water (100 ml) and dichloromethane (20 ml×2) and extracted, the organic layer was successively washed with saturated aqueous sodium hydrogencarbonate, saturated aqueous ammonium chloride, and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (Yamazen, n-hexane:ethyl acetate=3:1) to obtain the title compound (3.0 g).
Reaction SMILES: ClCCCl.[N:5]([C:8]1[C:9]([C:30]([O:32][CH3:33])=[O:31])=[N:10][C:11]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[N:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)=[N+]=[N-]>ClCCl.CCOC(C)=O.CCCCCCCC(O)=O.CCCCCCCC(O)=O.CCCCCCCC(O)=O.CCCCCCCC(O)=O.[Rh].[Rh]>[CH3:21][O:20][C:17]1[CH:16]=[CH:15][C:14]2[C:13]3[N:12]=[C:11]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)[N:10]=[C:9]([C:30]([O:32][CH3:33])=[O:31])[C:8]=3[NH:5][C:19]=2[CH:18]=1
Reactant: COC(=O)c1nc(-c2ccc(OC)cc2)nc(-c2ccc(OC)cc2)c1N=[N+]=[N-]
Agent: [Rh]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: ClCCCl
Product: COC(=O)c1nc(-c2ccc(OC)cc2)nc2c1[nH]c1cc(OC)ccc12
Temperature: 60 °C
Yield: 70 %

Procedure:
1,2-Dichloroethane (0.25 mL) was added to a mixture of methyl 5-azido-2,6-bis(4-methoxyphenyl)pyrimidine-4-carboxylate (154 mg, 0.393 mmol), rhodium octanoate dimer (31 mg, 0.039 mmol) and crushed 4 A° molecular sieves (154 mg) in a microwave vial. The vial was sealed and heated at 60° C. overnight. This was diluted with mixture of dichloromethane and EtOAc (9:1), filtered, and the solvent removed from the filtrate. Radial silica chromatography (step gradient elution with methylene chloride containing 0 to 5% EtOAc) afforded methyl 7-methoxy-2-(4-methoxyphenyl)-5H-pyrimido[5,4-b]indole-4-carboxylate (100 mg) as a yellow solid. MS (ESI) m/z 364.0 (M+H). 1H NMR (DMSO-d6) δ ppm 11.68 (1H, s), 8.48 (2H, d, J=8.85 Hz), 8.23 (1H, d, J=8.85 Hz), 7.24 (1H, d, J=2.14 Hz), 7.11 (2H, d, J=8.85 Hz), 6.99 (1H, dd, J=8.85, 2.14 Hz), 4.09 (3H, s), 3.93 (3H, s), 3.86 (3H, s).