Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:25]=3)=[CH:8][N:9]2[S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:5][CH:4]=1.[CH3:32][O:33][C:34](=[O:40])[CH2:35][CH2:36][C:37](O)=[O:38]>CN(C=O)C>[F:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:31][CH2:30][N:29]([C:37](=[O:38])[CH2:36][CH2:35][C:34]([O:33][CH3:32])=[O:40])[CH2:28][CH2:27]4)[CH:25]=3)=[CH:8][N:9]2[S:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)(=[O:13])=[O:14])=[CH:5][CH:4]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cnn(C3CCNCC3)c2)c2ccc(F)cc21
Reactant: COC(=O)CCC(=O)O
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)CCC(=O)N1CCC(n2cc(-c3cn(S(=O)(=O)c4ccccc4)c4cc(F)ccc34)cn2)CC1
Yield: 109.2 %

Procedure:
Following the general method as outlined in Example 83, starting from 6-fluoro-1-(phenylsulfonyl)-3-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1H-indole hydrochloride (Intermediate 17; 400 mg; 0.86 mmol) and succinic acid monomethyl ester (249 mg; 1.88 mmol) in DMF (10 mL), 506 mg of the title compound was obtained as a yellow oil after purification by a silica gel chromatography (EA).
Reaction SMILES: CC([O:5][C:6](=[O:36])[CH2:7][N:8]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15][N:14]([CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])[CH2:13][CH2:12][N:11]([CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])[CH2:10][CH2:9]1)(C)C.Br[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]>CC#N>[CH2:55]([N:17]1[CH2:16][CH2:15][N:14]([CH2:20][C:21]([OH:23])=[O:22])[CH2:13][CH2:12][N:11]([CH2:28][C:29]([OH:31])=[O:30])[CH2:10][CH2:9][N:8]([CH2:7][C:6]([OH:5])=[O:36])[CH2:19][CH2:18]1)[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH3:38]
Reactant: CC(C)(C)OC(=O)CN1CCNCCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1
Reactant: CCCCCCCCCCCCCCCCCCBr
Solvent: CC#N
Product: CCCCCCCCCCCCCCCCCCN1CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC1
Reaction time: 72 h

Procedure:
A mixture of 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid tris(1,1-dimethylethyl)ester (37.5 g; 72.8 mmol) and 1-bromooctadecane (24.5 g; 73.5 mmol) in CH3CN (500 mL) was heated to reflux. After 2 h the reaction mixture was evaporated and the residue was dissolved in CHCl3 and a portion of CF3COOH was added. After 16 h at room temperature the reaction mixture was evaporated and the oily residue dissolved in CF3COOH. After 3 days at room temperature, the solution was evaporated, the residue taken up in CHCl3 and the solution evaporated. This operation was repeated three times. The oily residue was purified by flash chromatography as follows:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([C:12]2[CH:21]=[C:20]([CH3:22])[C:15]3[NH:16][C:17](=[O:19])[O:18][C:14]=3[CH:13]=2)=[O:11])[CH:7]=[C:6]([O:23][CH3:24])[N:5]=1.I[CH3:26]>CN(C=O)C>[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([C:12]2[CH:21]=[C:20]([CH3:22])[C:15]3[N:16]([CH3:26])[C:17](=[O:19])[O:18][C:14]=3[CH:13]=2)=[O:11])[CH:7]=[C:6]([O:23][CH3:24])[N:5]=1
Reactant: COc1cc(C(=O)c2cc(C)c3[nH]c(=O)oc3c2)cc(Cl)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C(=O)c2cc(C)c3c(c2)oc(=O)n3C)cc(Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere 0.13 g (2.9 mmol) sodium hydride (55%, suspension in mineral oil) were added 0.90 g (2.8 mmol) 6-(2-chloro-6-methoxy-pyridine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one in 10 mL DMF at RT. The reaction mixture was stirred for 30 min at RT. Then 0.18 mL (5.0 mmol) iodomethane in 1 mL DMF were added dropwise and the mixture was stirred overnight at RT. The reaction mixture was poured onto water and the precipitate formed was suction filtered and washed with water. The residue was extracted with diethyl ether, suction filtered and dried.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19](O)=O)=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH3:18])(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:6][N:7]=1.[CH3:22][NH:23][C:24]1[C:25]([NH2:30])=[CH:26][CH:27]=[CH:28][CH:29]=1.C(OP(C#N)(OCC)=O)C.C(N(CC)CC)C>COCCOC>[CH2:17]([S:14]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[N:4]=[C:3]([C:19]3[N:23]([CH3:22])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[N:30]=3)[C:2]([NH2:1])=[N:7][CH:6]=2)[CH2:9][CH2:10]1)(=[O:16])=[O:15])[CH3:18]
Reactant: CCS(=O)(=O)N1CCN(c2cnc(N)c(C(=O)O)n2)CC1
Reactant: CNc1ccccc1N
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: CCS(=O)(=O)N1CCN(c2cnc(N)c(-c3nc4ccccc4n3C)n2)CC1
Temperature: 150 °C
Yield: 62.1 %

Procedure:
A mixture of 3-amino-6-(4-ethylsulfonylpiperazin-1-yl)pyrazine-2-carboxylic acid (100 mg, 0.3171 mmol), N-methylbenzene-1,2-diamine (42.61 mg, 39.64 μL, 0.3488 mmol), diethoxyphosphorylformonitrile (56.89 mg, 51.72 μL, 0.3488 mmol) and triethylamine (64.17 mg, 88.39 μL, 0.6342 mmol) in DME (3.000 mL) was heated in the microwave at 150° C. for 20 mins. The reaction mixture was allowed to cool and concentrated in vacuo. The resultant residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, passed through a sodium bicarbonate cartridge and freeze-dried to give the title compound as a yellow solid (79 mg, 60% Yield).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([N:22]1[CH2:21][CH2:20][N:16]2[C:17]3[CH:18]=[CH:19][C:11]([O:10][CH:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)=[CH:12][C:13]=3[CH:14]=[C:15]2[C:23]1=[O:24])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCNC2=O)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCN(Cc3ccccc3)C2=O)CC1
Yield: 66 %

Procedure:
The title compound was synthesized in analogy to example 17, from 8-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 1), sodium hydride and benzyl bromide, to give the desired product as a white solid (66%).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:12]([CH2:15][CH3:16])=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:17][O:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[NH2:26].C1(N)CCCC1>>[Cl:25][C:23]1[CH:22]=[CH:21][C:20]([NH:26][C:2]2[C:3]3[N:4]([C:12]([CH2:15][CH3:16])=[N:13][N:14]=3)[C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)=[C:19]([O:18][CH3:17])[CH:24]=1
Reactant: CCc1nnc2c(Cl)nc3ccccc3n12
Reactant: COc1cc(Cl)ccc1N
Agent: NC1CCCC1
Product: CCc1nnc2c(Nc3ccc(Cl)cc3OC)nc3ccccc3n12

Procedure:
The title compound was prepared essentially as described in Example 2 substituting 4-chloro-1-ethyl [1,2,4]triazolo[4,3-a]quinoxaline and 2-methoxy-4-chlorobenzenamine for 4-chloro-1-methyl1,2,4]triazolo[4,3-a]quinoxaline and cyclopentanamine respectively; mp 245°-248° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[C:12]3[C:29](=[CH:30][CH:31]=2)[O:28][C:15]2([CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)[CH2:14][C:13]3=[O:32])=[N:8][CH:9]=1)(=[O:3])[NH2:2].[ClH:33].CCOCC>O1CCOCC1>[ClH:33].[ClH:33].[O:32]=[C:13]1[C:12]2[C:29](=[CH:30][CH:31]=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([C:1]([NH2:2])=[O:3])=[CH:9][N:8]=3)[CH:11]=2)[O:28][C:15]2([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(-c3ccc(C(N)=O)cn3)ccc1O2
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: NC(=O)c1ccc(-c2ccc3c(c2)C(=O)CC2(CCNCC2)O3)nc1
Reaction time: 18 h

Procedure:
To a suspension of tert-butyl 6-(5-carbamoylpyridin-2-yl)-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate in dioxane (125 ml) was added 4N HCl in dioxane (125 ml) and the mixture was stirred for 18 h. After Et2O was added to the mixture, the resulted precipitate was collected by aeration, washed with Et2O to give intended compound as a colorless solid.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][CH:19]=1)[CH2:16][C@:6]1([C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]1=[O:15])[CH2:5]2.N([O-])=O.[Na+].[BrH:24]>O>[Br:24][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][CH:19]=1)[CH2:16][C@:6]1([C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]1=[O:15])[CH2:5]2
Reactant: Br
Reactant: Nc1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C1Nc2ncccc2[C@]12Cc1ccc(Br)cc1C2
Temperature: 100 °C

Procedure:
To a cooled 0° C. solution of (R)-5-Amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (0.5 g, 2 mmol, Intermediate 1), in 48% HBr (4 mL) was added slowly over 10 minutes a solution of sodium nitrite (137 mg, 2 mmol) in water (0.6 mL with a 0.2 mL wash). After 5 minutes CuBr (285 mg, 2 mmole) was added and a condenser with nitrogen flow was attached. The reaction mixture was placed into a 100° C. bath and heated to 100° C. for 20 minutes. The reaction was diluted with water to obtain a large amount of precipitate. The reaction was quenched with concentrated aqueous NH4OH (about 2.5 mL) and the subsequently formed solid was collected by filtration and washed with water. The solid was air dried to obtain 740 mg of a free flowing solid, to which was added about 2 g of silica gel. The mixture was dry-loaded onto a silica gel column and the product was eluted using a tertiary solvent mixture/gradient (10-70%/80%-20%/10% EtOAc/Hex/DCM). The product containing fractions were combined and concentrated at reduced pressure to give the title compound. MS: m/z=315 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][C:4]=1[C:11]1[C:20]([CH3:21])=[CH:19][C:18]2[C:17]([CH3:23])([CH3:22])[CH2:16][CH:15]([CH3:24])[CH:14]([CH3:25])[C:13]=2[CH:12]=1.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][C:4]=1[C:11]1[C:20]([CH3:21])=[CH:19][C:18]2[C:17]([CH3:23])([CH3:22])[CH2:16][CH:15]([CH3:24])[CH:14]([CH3:25])[C:13]=2[CH:12]=1
Reactant: COc1ccc(C=O)cc1-c1cc2c(cc1C)C(C)(C)CC(C)C2C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CO)cc1-c1cc2c(cc1C)C(C)(C)CC(C)C2C
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
To a solution of 4-methoxy-3-(3,5,5,8,7-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl) benzaldehyde (200 mg, 0.59 mmol) in methanol (5 mL) was added at 0° C. in small portions sodium borohydride (70 mg, 1.77 mmol). The solution was stirred 1 hour at 0° C. then quenched with 2N HCl. The reaction mixture was diluted with ethyl acetate and washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated to afford 195 mg (98%) of 4-methoxy-3-(3,5,5,8,7-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl) benzyl alcohol. 1H NMR (500 MHz; CDCl3): δ 1.27 (s, 6 H); 1.31 (s, 6 H); 1.69 (s, 4 H); 2.10 (s, 3 H); 3.78 (s, 3 H); 4.65 (s, 2 H); 6.94 (d, J=8.5 Hz, 1 H); 7.10 (s, 1 H); 7.14 (s, 1 H); 7.17 (d, J=2.0 Hz, 1 H); 7.33 (dd, J1=8.5 Hz, J2=2.0 Hz, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.C[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][C:22]([C:25]5[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=5)=[CH:21][CH:20]=4)[CH2:15]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2ccc(-c3ccncc3)cc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: O=C(c1cc2ncc(Br)cn2n1)N1CCc2ccc(-c3ccncc3)cc2C1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-7-pyridin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:30]2[C:13](=[CH:14][C:15]3[C:28]4[N:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[C:19]=4[CH:18]=[CH:17][C:16]=3[CH:29]=2)[CH:12]=[CH:11][C:10]=1[O:31][CH3:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.Br[CH2:41][CH2:42][CH2:43][OH:44].C[Si]([SiH]([Si](C)(C)C)[Si](C)(C)C)(C)C.N(C(C)(C)C#N)=NC(C)(C)C#N.C(=O)([O-])O.[Na+]>C(#N)C>[OH:44][CH2:43][CH2:42][CH2:41][C:29]1[C:16]2[CH:17]=[CH:18][C:19]3[C:20]4[C:25]([CH:26]=[N:27][C:28]=3[C:15]=2[CH:14]=[C:13]2[C:30]=1[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[C:10]([O:31][CH3:32])[CH:11]=[CH:12]2)=[CH:24][CH:23]=[CH:22][CH:21]=4
Reactant: COc1ccc2cc3c(ccc4c5ccccc5cnc34)cc2c1OCc1ccccc1
Reactant: OCCCBr
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: C[Si](C)(C)[SiH]([Si](C)(C)C)[Si](C)(C)C
Agent: O=C([O-])O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2cc3c(ccc4c5ccccc5cnc34)c(CCCO)c2c1OCc1ccccc1
Temperature: 80 °C
Yield: 31.3 %

Procedure:
8-Benzyloxy-9-methoxy-naphtho[2,3-c]phenanthridine (231 mg, 0.56 mmol) was suspended in acetonitrile (80 mL), and trifluoroacetic acid (43 μL, 0.56 mmol), 3-bromo-1-propanol (51 μL, 0.56 mmol) and tris(trimethylsilyl)silane (346 μL, 1.12 mmol) were added to the suspension. The mixture was stirred at 80° C. on an oil bath. After the suspended matter was dissolved, azobis(isobutyronitrile) (184 mg, 1.12 mmol) was added to the solution followed by heating under reflux. An hour later, the reaction mixture was cooled to room temperature. Saturated sodium hydrogencarbonate aqueous solution (50 mL) was added to the residue followed by extraction with methylene chloride. After the organic layer was washed with water and dried over anhydrous sodium sulfate, the solvent was distilled off in vacuo. The residue was passed through a silica gel column (eluted with 1% methanol-methylene chloride). The main fractions were collected and the solvent was distilled off in vacuo. The residue was dissolved in toluene (3 mL) and activated manganese dioxide (100 mg) was added to the solution. The mixture was stirred at room temperature for 90 minutes. Manganese dioxide was filtered off and the filtrate was concentrated in vacuo to provide crude 7-(3-hydroxypropyl)-8-benzyloxy-9-methoxy-naphtho[2,3-c]phenanthridine (83 mg) as brown dry mass.
Reaction SMILES: N[C:2]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:5]2[O:6][C:7]([CH3:11])([CH3:10])[CH:8]=[CH:9][C:4]=2[CH:3]=1.N(OS(=O)(=O)O)=O.N([O-])=O.[Na+].[I-:28].[K+]>C(O)(=O)C.S(=O)(=O)(O)O.O.C1(C)C=CC=CC=1>[CH3:10][C:7]1([CH3:11])[O:6][C:5]2[CH:12]=[C:13]([N+:14]([O-:16])=[O:15])[C:2]([I:28])=[CH:3][C:4]=2[CH:9]=[CH:8]1
Reactant: [I-]
Reactant: CC1(C)C=Cc2cc(N)c([N+](=O)[O-])cc2O1
Agent: O=NOS(=O)(=O)O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)C=Cc2cc(I)c([N+](=O)[O-])cc2O1
Temperature: 8 °C
Reaction time: 18 h
Yield: 39.4 %

Procedure:
To a cooled solution of 6-amino-2,2-dimethyl-7-nitro-2H-benzo[b]pyran (20.0 g)* in glacial acetic acid (800 ml) was added concentrated sulphuric acid (400 ml) and the solution stirred at 8° C. Nitrosyl sulphuric acid (prepared by dissolving sodium nitrite (6.62 g) in cold concentrated sulphuric acid (200 ml) the mixture being warmed to dissolved the solid then re-cooled to approximately 4° C.) was added keeping the temperature of the reaction mixture below 12° C. The dark, viscous mixture was stirred at approximately 7° C. for a further hour then poured into a cold (approximately 5° C.) solution of potassium iodide (15.27 g) in water (200 ml). Toluene (800 ml) was added to dissolve the resulting precipitate and the mixture stirred in an ice bath for 20 minutes, then at room temperature for 18 hours. The reaction mixture was diluted with water (500 ml), the organic phase was separated, washed with water, dried and evaporated in vacuo to afford the required 2,2-dimethyl-6-iodo-7-nitro-2H-benzo[b]pyran (11.84 g, 39%) as a red gum.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH:5]([C:11]#[N:12])[CH2:6][C:7](=[O:10])[CH2:8][CH3:9])[CH3:2].[CH2:14](O)[CH2:15][OH:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O>[CH2:1]([O:3][C:4](=[O:13])[CH:5]([C:11]#[N:12])[CH2:6][C:7]1([CH2:8][CH3:9])[O:16][CH2:15][CH2:14][O:10]1)[CH3:2]
Reactant: OCCO
Reactant: CCOC(=O)C(C#N)CC(=O)CC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)C(C#N)CC1(CC)OCCO1
Temperature: 25 °C

Procedure:
In a 500 mL flask equipped with a reflux condenser and Dean-Stark trap were combined 40.0 g (218 mmol) of 2-cyano-4-oxohexanoic acid ethyl ester, 20.3 g (327 mmol) of ethylene glycol, 0.83 g (4.3 mmol) of p-toluenesulfonic acid monohydrate, and 100 mL of benzene. The reaction was heated to reflux until approximately 4.5 mL of water had been collected in the trap. The reaction was cooled to ambient temperature, washed with 50 mL of water, 50 mL of saturated δsodium bicarbonate solution and dried over sodium sulfate. The mixture was then concentrated to 46.0 g (93%) of α-cyano-2-ethyl-1,3-dioxolane-2-propanoic acid ethyl ester as a light tan oil. An NMR of the crude product showed less than 10% residual ketone remained and the crude product was used without further purification. nmr (500 MHz, CDCl3) δ0.92 (t, J=7.5 Hz, 3H), 1.31 (t, J=7.2 Hz, 3H), 1.64 (q, J=7.5 Hz, 2H), 2.29 (dd, J=6.8, 14.6 Hz, 1H), 2.41 (dd, J=6.3, 14.6 Hz, 1H), 3.59 (dd, J=6.3, 6.8 Hz, 1H), 3.59 (m, 4H), 4.24 (q, J=7.2 Hz, 2H).
Reaction SMILES: [CH:1]([S:4]([C:7]1[C:8]([C@H:13]2[C@@H:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][CH2:15][N:14]2C(OC(C)(C)C)=O)=[N:9][CH:10]=[CH:11][CH:12]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2].[ClH:30].O1CCOCC1>CCOC(C)=O>[ClH:30].[CH:1]([S:4]([C:7]1[C:8]([C@H:13]2[C@@H:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][CH2:15][NH:14]2)=[N:9][CH:10]=[CH:11][CH:12]=1)(=[O:5])=[O:6])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@H]1CCN(C(=O)OC(C)(C)C)[C@H]1c1ncccc1S(=O)(=O)C(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)[C@H]1CCN[C@H]1c1ncccc1S(=O)(=O)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To 65J (0.38 g, 0.89 mmol) in EtOAc (5 mL) at rt was added 4.0 N HCl in dioxane (5 mL, 20 mmol). The mixture was stirred at rt for 8.0 h. After removal of the solvent, the crude was diluted in methylene chloride and washed with sat. NaHCO3. The aqueous was extracted with methylene chloride (3×80 mL). The combined organic layer was dried over Na2SO4. After removal of solvent 65K (0.28 g, 95% yield) was obtained as viscous oil. 1H NMR (400 MHz, Methanol-d4) δ ppm 1.15 (t, J=7.03 Hz, 3H) 1.23-1.27 (d, J=7.03 Hz, 3H) 1.30 (d, J=7.03 Hz, 3H) 2.21-2.27 (m, 2H) 3.07 (ddd, J=11.10, 7.47, 7.36 Hz, 1H) 3.41 (ddd, J=9.34, 7.25, 7.14 Hz, 1H) 3.54-3.63 (m, 1H) 4.03-4.12 (m, 2H) 5.14 (d, J=7.03 Hz, 1H) 7.58 (dd, J=7.91, 4.83 Hz, 1H) 8.32 (dd, J=8.35, 1.76 Hz, 1H) 8.86-8.91 (m, 1H), LC-MS 327 (M+H).
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([O:26][CH:27]([F:29])[F:28])=[C:9]([S:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[C:10]([CH3:17])=[N:11]2.[OH-].[Na+].Cl>O1CCCC1>[Cl:16][C:13]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:30])=[O:2])=[C:7]2[C:12]=1[N:11]=[C:10]([CH3:17])[C:9]([S:18][C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1)=[C:8]2[O:26][CH:27]([F:28])[F:29]
Reactant: COC(=O)COc1ccc(Cl)c2nc(C)c(Sc3ccc(Cl)cc3)c(OC(F)F)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1nc2c(Cl)ccc(OCC(=O)O)c2c(OC(F)F)c1Sc1ccc(Cl)cc1

Procedure:
A solution of [8-chloro-3-(4-chlorophenylsulfanyl)-4-difluoromethoxy-2-methylquinolin-5-yloxy]acetic acid methyl ester (0.044 g), tetrahydrofuran (3.0 mL) and 1.0 M aqueous sodium hydroxide solution (0.15 mL) was stirred at room temperature for 1 hour. The solution was acidified by the addition of 1.0 M aqueous hydrochloric acid and the solvent removed under reduced pressured. The residue was diluted with ethyl acetate and this mixture washed with water and then dried over magnesium sulfate. The solvent was removed under reduced pressure and the resulting solid washed with dichloromethane and dried to afford title compound, 0.024 g.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[NH:4][C:5]([C:21](F)([F:23])[F:22])=[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:7]([CH2:14][CH3:15])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].N12CCCNC1C=CCCC2.Cl>O1CCCC1>[F:23][CH:21]([F:22])[C:5]1[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:7]([CH2:14][CH3:15])[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:3]([C:2]([F:26])([F:1])[F:25])[N:4]=1
Reactant: CCOC(=O)C1=C(C(F)(F)F)NC(C(F)(F)F)=C(C(=O)OCC)C1CC
Agent: C1=CC2NCCCN2CCC1
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)OCC)c1CC
Temperature: 0 °C
Yield: 78.4 %

Procedure:
A mixture of 1558 g (4.00 moles) of diethyl 2,6-bis(trifluoromethyl)-l,4-dihydro-4-ethyl-3,5-pyridinedicarboxylate, 628 g (4.0 moles) of 1,8-diazabicyclo-[5.4.0]-undec-5-ene (DBU), and 500 ml of tetrahydrofuran is held at reflux for 19 hours, cooled and poured into a mixture of 2 kg of ice and 250 ml of concentrated hydrochloric acid. The organic layer is separated and the aqueous layer extracted with 500 ml of CH2Cl2 twice. The combined organic materials are dried (MgSO4) and concentrated. The residue is kugelrohr distilled at 1 torr (pot temperature of 150°-160 ° C.) to give 1158 g (78.5%) of desired product, nD25 1.4458.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C([O-])([O-])=O.[K+].[K+].I[CH:20]([CH3:22])[CH3:21]>CC(C)=O>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:3]=[C:2]([O:1][CH:20]([CH3:22])[CH3:21])[CH:11]=[C:10]([OH:12])[CH:9]=1
Reactant: CC(C)I
Reactant: COC(=O)c1cc(O)cc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(O)cc(OC(C)C)c1
Yield: 44.4 %

Procedure:
To a stirred solution of methyl 3,5-dihydroxybenzoate (20.0 g, 119 mmol) in acetone (500 mL) was added K2CO3 (19.7 g, 143 mmol) and 2-iodopropane (13.1 mL, 131 mmol) at rt. The resulting mixture was refluxed for 12 hr. Then the mixture was filtered through a pad of Celite to remove insoluble salts and the cake was rinsed with acetone. Combined filtrates were concentrated under vacuum to afford a residue which was purified by silica gel flash chromatography (7.5×30 cm, hexane/EtOAc, v/v 10:1, 5:1). Fractions containing the mono-alkylation product were pooled and concentrated to give 3-hydroxy-5-isopropoxy-benzoic acid methyl ester (11.1 g, 44%) as a white solid. 1H NMR (300 MHz, CDCl3): δ 7.11-7.14 (m, 2H), 6.60 (m, 1H), 4.56 (m, 1H), 3.89 (s, 3H), 1.32 (d, J=6 Hz, 6H).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[C:6]1(=[O:12])[CH2:11][CH2:10][CH2:9][CH:8]=[CH:7]1>CSC.CCCCCC.[Cu](I)I>[CH2:1]([CH:8]1[CH2:9][CH2:10][CH2:11][C:6](=[O:12])[CH2:7]1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C1C=CCCC1
Reactant: [Li]CCCC
Agent: I[Cu]I
Solvent: CCCCCC
Solvent: CSC
Product: CCCCC1CCCC(=O)C1
Temperature: -78 °C

Procedure:
A solution of copper iodide (6.3 mmol) in dimethyl sulphide (12 ml) is cooled to 50° C. A solution of butyl lithium (6.2 mmol) is added dropwise accompanied by stirring and stirred for a further 5 to 15 mins. The reaction mixture is cooled to −78° C. and then a solution precooled to −78° C. of cyclohex-2-enone (6 mmol), dissolved in dimethyl sulphide (1 ml), is slowly added dropwise. After stirring for one hour at −78° C. the mixture is quenched with saturated aqueous ammonium chloride solution. The reaction mixture which has been heated to room temperature is extracted with diethyl ether. The combined ether phases are washed with saturated aqueous ammonium chloride solution and dried over sodium sulphate. After evaporating-off of the solvent the residue obtained is taken up in hexane, the solution is filtered and concentrated by evaporation. After chromatography of the residue on silica gel with ethyl acetate/hexane 1:4 pure 3-butylcyclohexanone is obtained (Tetrahedron 1989, 45 (2), 425-434).