Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.C([SiH2][O:8][C:9](C)(C)[C:10]1[O:11][CH:12]=[C:13]([C:15](=[O:17])[CH3:16])[N:14]=1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CC(=O)OCC>[OH:8][CH2:9][C:10]1[O:11][CH:12]=[C:13]([C:15](=[O:17])[CH3:16])[N:14]=1
Reactant: CC(=O)c1coc(C(C)(C)O[SiH2]C(C)(C)C)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N#N
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)c1coc(CO)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-[2-(tert-butyl-dimethyl-silanyloxymethyl)-oxazol-4-yl]-ethanone (192 mg, 0.75 mmol) in dry THF (5.0 mL) was treated at rt with TBAF (1.1 mL of a 1M solution in THF, 1.10 mmol). The reaction mixture was stirred at rt for 1.5 h. The mixture was then diluted with EA (10 mL), washed with brine (3×10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. Purification of the residue by FC (1:1 to 2:1 EA-Hept) gave the title compound as a pale yellow solid. TLC: rf (EA)=0.37. LC-MS-conditions 02: tR=0.34 min, [M+H]+=142.46.
Reaction SMILES: [ClH:1].CO[C:4](=O)[CH:5]([NH2:9])[CH2:6][C:7]#[CH:8].[N:11]#[C:12][NH2:13]>>[ClH:1].[CH2:6]([C:5]1[N:9]=[C:12]([NH2:13])[NH:11][CH:4]=1)[C:7]#[CH:8]
Reactant: C#CCC(N)C(=O)OC
Reactant: N#CN
Agent: Cl
Product: C#CCc1c[nH]c(N)n1
Yield: 59 %

Procedure:
2-Amino-pent-4-ynoic acid methyl ester hydrochloride (2.91 g, 17.8 mmol) was treated to an Akabori reduction followed by a cyanamide condensation employing conditions previously reported to produce 4-Prop-2-ynyl-1H-imidazol-2-ylamine hydrochloride (1.65 g, 59%) as a yellow oil (Olofson et al., Journal of Organic Chemistry 1997, 62, (23), 7918-7919). 1H NMR (300 MHz, CD3OD) δ 6.30 (s, 1H), δ 5.02 (d, 2H), δ 2.26 (t, 1H) ppm; 13C NMR (75 MHz, CD3OD) δ 150.1, 127.2, 109.6, 83.6, 69.8, 15.9 ppm; HRMS (ESI) calcd for C6H7N3 (M+) 122.0712. found 122.0713.
Reaction SMILES: [C:1]([NH2:11])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:12][CH2:13][C:14]([CH2:16]Cl)=O.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:12][CH2:13][C:14]1[N:11]=[C:1](/[CH:2]=[CH:3]/[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:10][CH:16]=1
Reactant: NC(=O)C=Cc1ccccc1
Reactant: O=C(CCl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: ClCc1coc(/C=C/c2ccccc2)n1
Temperature: 130 °C
Reaction time: 1 h
Yield: 46.7 %

Procedure:
A mixture of cinnamamide (25.3 g) and 1,3-dichloroacetone (20.9 g) was stirred for one hour at 130° C. The reaction mixture was diluted with water, neutralized with potassium carbonate, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography. From the fraction eluted with diethyl ether-hexane, 4-chloromethyl-2-[(E)-2-phenylethenyl]oxazole (16.9 g, 47%) was obtained. Recrystallization from diethyl ether-hexane gave colorless needles, mp 72-73° C.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CC(C)=O>[CH2:18]([O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=[N+]([O-])c1cc(O)ccc1I
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1I
Temperature: 50 °C
Reaction time: 6 h

Procedure:
To a solution of 4-iodo-3-nitrophenol (5.00 g, 18.9 mmol) in acetone (50 ml) were added potassium carbonate (3.39 g, 24.6 mmol) and benzyl bromide (2.92 ml, 24.6 mmol), and the mixture was stirred at 50° C. for 6 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to give 4-benzyloxy-1-iodo-2-nitrobenzene. The obtained crude product (6.20 g) was used for Step 2 without further purification.
Reaction SMILES: O1[CH:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8].CC(C)CCCCC=C.C=CCCCCCCCCCC>>[CH3:9][CH:7]([CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH3:8]
Reactant: CCCCCCCCCCC1OC1CCCCC(C)C
Agent: C=CCCCCC(C)C
Agent: C=CCCCCCCCCCC
Product: CCCCCCCCCCC=CCCCCC(C)C

Procedure:
7,8-Epoxy-2-methyloctadecane is economically prepared by a metathesis reaction of 7-methyl-1-octene and 1-dodecene to form 2-methyl-7-octadecene which is then epoxidized to give the desired product.
Reaction SMILES: Br[CH2:2][C:3]1[C:7]2[CH:8]=[C:9]([Cl:12])[CH:10]=[CH:11][C:6]=2[S:5][CH:4]=1.[N:13]1([C:19]2[N:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]2[S:5][CH:4]=[C:3]([CH2:2][N:16]3[CH2:17][CH2:18][N:13]([C:19]4[N:20]=[CH:21][CH:22]=[CH:23][N:24]=4)[CH2:14][CH2:15]3)[C:7]=2[CH:8]=1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: Clc1ccc2scc(CBr)c2c1
Product: Clc1ccc2scc(CN3CCN(c4ncccn4)CC3)c2c1

Procedure:
3-(Bromomethyl)-5-chloro-1-benzothiophene and 2-(1-piperazinyl)pyrimidine were processed as described in Example 2 to provide the title compound. 1H NMR (CDCl3, 300 MHz) δ (2.62-2.9 (m, 4H), 3.75 (m, 6H), 6.6 (m, 1H), 7.38 (m, 2H), 7.85 (m, 2H), 8.31 (M, 2H). MS (DCI/NH3) m/z 345.0 (M+H)+; Anal. Calcd for C17H17ClN4S: C, 53.04;H, 4.74; N, 14.55. Found: C, 52.79;H, 4.41; N, 14.55.
Reaction SMILES: [ClH:1].[CH2:2]([C:4]1[S:5][CH:6]=[C:7]2[CH2:11][NH:10][CH2:9][C:8]=12)[CH3:3].[CH:12]([N:15](CC)[CH:16]([CH3:18])C)([CH3:14])C.C[N:22](C)C=O>>[ClH:1].[ClH:1].[CH2:2]([C:4]1[S:5][CH:6]=[C:7]2[CH2:11][N:10]([CH2:14][C:12]3[NH:15][CH2:16][CH2:18][N:22]=3)[CH2:9][C:8]=12)[CH3:3]
Reactant: CCc1scc2c1CNC2
Reactant: CN(C)C=O
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Product: CCc1scc2c1CN(CC1=NCCN1)C2

Procedure:
0.53 g of 1-ethyl-5,6-dihydro-4H-thieno-[3,4-c]pyrrole hydrochloride, 1.47 ml of N,N-diisopropylethylamine and 15 ml of dimethylformamide are introduced into a 25 ml round-bottomed flask and then a solution of 0.75 g of 2-chloromethyl-1H-4,5-dihydroimidazole hydrochloride and 0.5 ml of N,N-diisopropylethyl-amine in 15 ml of dimethylformamide is added. The reaction mixture is subjected to ultrasound for 8 h, the solvent is then evaporated and the residue is purified by chromatography on silica gel with ethanol as eluent. The product is recrystallized from 5 ml of isopropanol saturated with hydrochloric acid. 0.233 g of product is obtained. Melting point: 207°-208° C. (with decomposition).
Reaction SMILES: C1C(=O)N([Cl:8])C(=O)C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:28][C:29]1[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=1[C@@H:36]1[CH2:46][CH2:45][C@@H:44]([O:47][Si:48]([CH:55]([CH3:57])[CH3:56])([CH:52]([CH3:54])[CH3:53])[CH:49]([CH3:51])[CH3:50])[C:39]2=[N:40][CH:41]=[CH:42][CH:43]=[C:38]2[C@H:37]1O>O1CCCC1>[Cl:8][C@H:37]1[C:38]2[C:39](=[N:40][CH:41]=[CH:42][CH:43]=2)[C@H:44]([O:47][Si:48]([CH:55]([CH3:57])[CH3:56])([CH:52]([CH3:54])[CH3:53])[CH:49]([CH3:51])[CH3:50])[CH2:45][CH2:46][C@H:36]1[C:30]1[CH:31]=[CH:32][CH:33]=[C:34]([F:35])[C:29]=1[F:28]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)[Si](O[C@@H]1CC[C@@H](c2cccc(F)c2F)[C@H](O)c2cccnc21)(C(C)C)C(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)[Si](O[C@@H]1CC[C@@H](c2cccc(F)c2F)[C@@H](Cl)c2cccnc21)(C(C)C)C(C)C
Reaction time: 0.08 h
Yield: 82.9 %

Procedure:
In an oven-dried 250 mL round-bottom flask was suspended NCS (0.751 g, 5.62 mmol) in tetrahydrofuran (15 mL). Triphenylphosphine (1.475 g, 5.62 mmol) was added. After stirring under nitrogen for 5 min, (5S,6S,9R)-6-(2,3-difluorophenyl)-9-(triisopropylsilyloxy)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-ol (1.007 g, 2.250 mmol) was added in one portion to the gray suspension. The resulting reddish suspension was stirred at room temperature. The solids gradually dissolved to give a tan solution. After 5 h, LCMS indicated complete conversion. Tetrahydrofuran was removed in vacuo and the remaining red oil was directly purified by ISCO (240 g silica column) up to 60% ethyl acetate/hexane. Pure ethyl acetate eluted the non polar component and the product was eluted by 10% methanol (with 2.0M NH4OH) in methylene chloride. The product fractions were combined and re-purified by FCC up to 50% ethyl acetate/hexane to afford the desired product as a colorless oil (869 mg, 83%). MS (ESI) [M+H+]=466.22; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.55 (d, J=3.53 Hz, 1H) 7.63 (br. s., 1H) 7.20 (dd, J=7.68, 4.91 Hz, 1H) 7.01-7.15 (m, 1H) 6.90-7.01 (m, 1H) 6.66-6.90 (m, 1H) 5.55-5.85 (m, 1H) 5.40-5.56 (m, 1H) 3.96-4.33 (m, 1H) 2.33 (br. s., 3H) 2.09-2.20 (m, 1H) 1.14-1.23 (m, 3H) 1.04-1.14 (m, 9H) 1.01 (d, J=7.30 Hz, 9H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]1[C:8](=[O:15])[NH:9][C:10](SC)=[N:11][CH:12]=1.[CH3:16][C:17]1[NH:21][CH:20]=[N:19][C:18]=1[CH2:22][S:23][CH2:24][CH2:25][NH2:26]>>[CH3:16][C:17]1[NH:21][CH:20]=[N:19][C:18]=1[CH2:22][S:23][CH2:24][CH2:25][NH:26][C:10]1[NH:9][C:8](=[O:15])[C:7]([CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[CH:12][N:11]=1
Reactant: Cc1[nH]cnc1CSCCN
Reactant: CSc1ncc(Cc2cccs2)c(=O)[nH]1
Product: Cc1[nH]cnc1CSCCNc1ncc(Cc2cccs2)c(=O)[nH]1

Procedure:
An intimate mixture of 5-(2-thienylmethyl)-2-methylthio-4-pyrimidone (1.43 g) and 2-(5-methyl- 4-imidazolylmethylthio)ethylamine (1.03 g) was heated at 140° for 6 hours. The cooled residue was washed with water to give 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(2-thienylmethyl)-4-pyrimidone, and this product was treated with dilute ethanolic HCl to give the title compound in 40% yield, m.p. 172°-176° (ethanol-acetonitrile). The dihydrochloride was passed down an ion-exchange column of IRA 400 eluting with 1 N hydrobromic acid, and the eluate was evaporated to dryness and recrystallised from ethanol acetonitrile to give the corresponding dihydrobromide m.p. 199°-203°.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[N:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=3)[C:6]=2[N:5]=[C:4]([C:25]([OH:27])=[O:26])[CH:3]=1.[CH3:28][S:29]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)(=[O:31])=[O:30].C(N(CC)CC)C>C1COCC1.O>[OH:18][C:14]1[CH:13]=[C:12]([C:11]2[C:6]3[N:5]=[C:4]([C:25]([OH:27])=[O:26])[CH:3]=[C:2]([N:35]4[CH2:36][CH2:37][N:32]([S:29]([CH3:28])(=[O:31])=[O:30])[CH2:33][CH2:34]4)[C:7]=3[N:8]=[C:9]([N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[N:10]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)c1cc(Cl)c2nc(N3CCOCC3)nc(-c3cccc(O)c3)c2n1
Reactant: CS(=O)(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)N1CCN(c2cc(C(=O)O)nc3c(-c4cccc(O)c4)nc(N4CCOCC4)nc23)CC1

Procedure:
A mixture of Example 9 (130 mg; 0.34 mmol), 1-(methylsulfonyl)piperazine (276 mg; 1.68 mmol) and N,N-diethylethanamine (170 mg; 1.68 mmol) in THF (3 mL) and water (3 mL) was stirred at 115° C. for 48 hours then concentrated in vacuo. The residue was taken up in EA, washed with aq. citric acid, dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (EA/EtOH/AcOH, 90/10/1) afforded the title compound as an orange solid.
Reaction SMILES: Cl[CH2:2][CH2:3][S:4](Cl)(=[O:6])=[O:5].[CH3:8][O:9][C:10]1[CH:11]=[C:12]([C:18]2[C@@H:27]3[C@@H:22]([CH2:23][CH:24]=[CH:25][CH2:26]3)[C:21](=[O:28])[N:20]([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[N:19]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17].C(N(C(C)C)CC)(C)C>ClCCl>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([C:18]2[C@@H:27]3[C@@H:22]([CH2:23][CH:24]=[CH:25][CH2:26]3)[C:21](=[O:28])[N:20]([CH:29]3[CH2:34][CH2:33][N:32]([S:4]([CH:3]=[CH2:2])(=[O:6])=[O:5])[CH2:31][CH2:30]3)[N:19]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: O=S(=O)(Cl)CCCl
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CS(=O)(=O)N1CCC(N2N=C(c3ccc(OC)c(OC)c3)[C@H]3CC=CC[C@H]3C2=O)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 20 mmol of 2-chloroethylsulfonylchloride in 20 ml of dichloromethane is added to a solution of 15 mmol of compound 5c and 25 ml of diisopropylethylamine in 50 ml of dichloromethane. The resulting mixture is stirred at RT for 18 h, after which it is washed first with diluted hydrochloric acid and then with a saturated solution of sodium bicarbonate. After drying over magnesium sulfate and evaporating the solvent, the compound is crystallised from diethyl ether. M. p. 89-90° C.
Reaction SMILES: [CH2:1]([O:19][C:20](=[O:66])[CH2:21][CH2:22][N:23](C(OC(C)(C)C)=O)[CH2:24][CH2:25][CH2:26][CH2:27][N:28](C(OC(C)(C)C)=O)[CH2:29][CH2:30][C:31]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH:41]=[CH:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[O:32])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[ClH:67]>C(Cl)Cl.CCOC(C)=O>[ClH:67].[ClH:67].[CH2:1]([O:19][C:20](=[O:66])[CH2:21][CH2:22][NH:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH:42]=[CH:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[O:32])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCC=CCCCCCCCOC(=O)CCN(CCCCN(CCC(=O)OCCCCCCCC=CCCCCCCCCC)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCCCCCC=CCCCCCCCCOC(=O)CCNCCCCNCCC(=O)OCCCCCCCCC=CCCCCCCCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
The ester 5 (n=4, R=oleyl; 13.0 g, 13.9 mmol) was dissolved in CH2Cl2 (70 mL) and treated with 4M HCl in EtOAc (140 mL). The resulting mixture was stirred at rt. for 2 h, then the solvent was removed in vacuo and the residue was triturated with anhydrous diethyl ether (150 mL) to afford a solid which was dried in vacuo to afford bis hydrochloride 6 as a white powder (10.23 g, 91%).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[CH:6]1[CH2:10][CH:9]=[CH:8]C=1.[CH:11]1C=CC=CC=1>>[CH:3]12[CH2:11][CH:10]([CH:9]=[CH:8]1)[CH2:6][CH:2]2[C:1]([OH:5])=[O:4]
Reactant: c1ccccc1
Reactant: C1=CCC=C1
Reactant: C=CC(=O)O
Product: O=C(O)C1CC2C=CC1C2
Reaction time: 12 h
Yield: 97.9 %

Procedure:
In 300 ml of benzene was dissolved 324.3 g of acrylic acid. Below 40° C., 327.2 g of cyclopentadiene was added dropwise to the solution over 2 hours. After agitation was continued for 12 hours at room temperature, the reaction mixture was concentrated in vacuum, yielding 608.5 g of 5-norbornene-2-carboxylic acid. The yield was 97.9%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: C1COCCN1
Reactant: Cc1cc(Cl)nc(Cl)n1
Solvent: C1CCOC1
Product: Cc1cc(N2CCOCC2)nc(Cl)n1
Yield: 69.7 %

Procedure:
To a solution of 2,4-dichloro-6-methylpyrimidine (998 mg, 6.0 mmol) in tetrahydrofurane (30 mL) was added at 0° C. under stirring N,N-diisopropyl ethyl amine (853 mg, 6.6 mmol) and morpholine (627 mg, 6.6 mmol) and the reaction was stirred over night at 20° C. The solvent was evaporated under reduced pressure and the residue was taken up in water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated under reduced pressure to dryness. The residue was purified by column chromatography on silica gel using heptane/ethyl acetate (7:3 v/v) as eluent to yield the title compound (893 mg, 70%) as white crystals. MS ISP (m/e): 214.1/216.2 (100/34) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=6.73 (s, 1H), 3.65 (m, 4H), 3.58 (m, 2H), 2.25 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][C:10]2[C:5]3=[C:6]([N:12]([CH2:14][C:15]([O:17]CC)=[O:16])[CH:13]=[C:4]3[NH:3]1)[CH:7]=[CH:8][CH:9]=2.[OH-].[Li+:21].Cl>C1COCC1.CCO.O>[O:1]=[C:2]1[CH2:11][C:10]2[C:5]3=[C:6]([N:12]([CH2:14][C:15]([O-:17])=[O:16])[CH:13]=[C:4]3[NH:3]1)[CH:7]=[CH:8][CH:9]=2.[Li+:21]
Reactant: CCOC(=O)Cn1cc2c3c(cccc31)CC(=O)N2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: O=C([O-])Cn1cc2c3c(cccc31)CC(=O)N2
Reaction time: 0.25 h

Procedure:
To a solution of ethyl (4-oxo-4,5-dihydropyrrolo[2,3,4-#]isoquinolin-1(3H)-yl)acetate from Step G (200 mg, 0.77 mmol) in THF (1 mL), EtOH (1 mL) and H2O (1 mL) was added 1.0 N lithium hydroxide (0.85 mL, 0.85 mmol). After 15 min, 1 N aqueous HCl was added to adjust the solution to pH 7 and the mixture was concentrated in vacuo to give the title compound. MS: m/z=231 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1C=CC=CC=1.C(O)(=O)C>O>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=Cc1ccc(F)cc1
Solvent: CC(=O)O
Solvent: c1ccccc1
Solvent: O
Product: Fc1ccc(C=Nc2ccccc2)cc1

Procedure:
To 4-fluorobenzaldehyde (24.8 g, 0.200 mol) and aniline (18.6 g, 0.200 mol) was added benzene (200 mL) and acetic acid (0.7 mL) and the mixture is heated under reflux until all the water (3.6 mL) was azeotropically removed. The solvent is evaporated and the residual oil upon cooling and stirring crystallized. The white mass was then recrystallize as needles (28 g, 70%): mp 39°-40° C. (PE) (lit.1 mp 40° C.).
Reaction SMILES: [CH2:1]([CH:3]1[C:8](=[O:9])[CH2:7][CH2:6][CH2:5][C:4]1=[O:10])[CH3:2].N1C=CC=CC=1.C(N(CC)[CH2:20][CH2:21][C:22](=[O:34])[CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=1)C.COC1C=C(CCCC(=O)C=C)C=CC=1>C1C=CC=CC=1>[CH3:33][O:32][C:28]1[CH:27]=[C:26]([CH2:25][CH2:24][CH2:23][C:22](=[O:34])[CH2:21][CH2:20][C:3]2([CH2:1][CH3:2])[C:8](=[O:9])[CH2:7][CH2:6][CH2:5][C:4]2=[O:10])[CH:31]=[CH:30][CH:29]=1
Reactant: CCC1C(=O)CCCC1=O
Reactant: CCN(CC)CCC(=O)CCCc1cccc(OC)c1
Agent: C=CC(=O)CCCc1cccc(OC)c1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCC1(CCC(=O)CCCc2cccc(OC)c2)C(=O)CCCC1=O

Procedure:
Reflux 2-ethylcyclohexane-1,3-dione (30.6 g), pyridine (20 cc), benzene (372 cc) and a mixture of 1-diethylamino-6-m-methoxyphenylhexan-3-one and 6-m-methoxyphenylhex-1-en-3-one (40.3 g, produced by the distillation of the former substance) for 15 hours. Wash the cooled reaction mixture with water, 10% aqueous sulfuric acid, water, 10% aqueous sodium carbonate, water and brine, and filter. Evaporate the solvent to leave as residue 2-(6-m-methoxyphenyl-3-oxohexyl)-2-ethylcyclohexane-1,3-dione, 38.1 g, 56.2%.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:26]=[CH:27][CH:28]=1)[CH2:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH2:21][CH2:22][Br:23])=[C:15]([O:18][CH3:19])[CH:16]=2)[C:11]([CH:24]=[O:25])=[CH:10][N:9]=1)[CH3:2].[Se](=O)=[O:30].C(OCC)(=O)C.CCCCCC>C(O)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:26]=[CH:27][CH:28]=1)[C:7]([C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH2:21][CH2:22][Br:23])=[C:15]([O:18][CH3:19])[CH:16]=2)[C:11]([CH:24]=[O:25])=[CH:10][N:9]=1)=[O:30])[CH3:2]
Reactant: O=[Se]=O
Reactant: CCOc1cccc(Cc2ncc(C=O)c3cc(OCCBr)c(OC)cc23)c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC(=O)O
Product: CCOc1cccc(C(=O)c2ncc(C=O)c3cc(OCCBr)c(OC)cc23)c1
Temperature: 120 °C

Procedure:
To a stirred solution of 6-hydroxy-7-methoxy-1-(3-ethoxy-benzyl)-isoquinoline-4-carbaldehyde (90 mg, 0.25 mmol) in N,N-dimethylformamide (2 mL) was added potassium carbonate (352 mg, 2.50 mmol) and 1,2-dibromoethane (0.129 μL, 1.25 mmol) at room temperature. The reaction mixture was heated 85° C. for 2 hrs. The solvent was evaporated and the residue was purified on a flash chromatography (Merck Silica gel 60, 70–230 mesh, 50% ethyl acetate/hexane) to afford product 1-(3-ethoxy-benzyl)-6-(2-bromo-ethoxy)-7-methoxy-isoquinoline-4-carbaldehyde as a colorless oil. The crude product was used without further purification. To a stirred solution of 1-(3-ethoxy-benzyl)-6-(2-bromo-ethoxy)-7-methoxy-isoquinoline-4-carbaldehyde in acetic acid (2 mL) was added selenium dioxide (278 mg, 2.50 mmol). The reaction mixture was heated at 120° C. for 1 hr. The solvent was evaporated and the residue was diluted with dichloromethane (30 mL). The organic layer was washed with saturated aqueous sodium bicarbonate solution (20 mL), saturated aqueous sodium chloride solution (20 μL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a crude oil. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 40% ethyl acetate/hexane) afforded 1-(3-ethoxy-benzoyl)-6-(2-bromo-ethoxy)-7-methoxy-isoquinoline-4-carbaldehyde as a major product (80 mg, 100% yield).
Reaction SMILES: [O-:1][CH2:2]C.[Na+].C(O)C.[Cl:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].C(OCC)=O>C(OCC)C>[Cl:8][CH:9]([CH:2]=[O:1])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)CCl
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCOC=O
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)C(Cl)C=O
Reaction time: 8 h

Procedure:
139 ml of a 21% strength solution of sodium ethoxide in ethanol (371 mmol, 0.91 equivalent) were initially charged in 200 ml of diethyl ether, and a solution of 43.7 ml of ethyl chloroacetate (408 mmol, 1 equivalent) and 32.9 ml of ethyl formate (408 mmol, 1 equivalent) in 150 ml of diethyl ether was added dropwise at RT. The reaction mixture was stirred overnight and the solid was filtered off and washed with diethyl ether. The solid was dissolved in water and the aqueous phase was, with ice bath cooling, adjusted to pH4 using concentrated hydrochloric acid. The mixture was extracted repeatedly with diethyl ether and the combined organic phases were washed with saturated aqueous sodium chloride solution, dried with magnesium sulphate, filtered and concentrated. The crude product obtained (8.2 g) was freed from residual solvent under high vacuum and used without further purification for the next reaction.
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[CH:12]=[CH:11][CH:10]=[CH:9]1.[CH3:20][CH:21]1[CH2:26][C:25](=O)[CH2:24][CH2:23][N:22]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>ClCCl>[CH3:20][CH:21]1[CH2:26][C:25]2([O:19][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:8]3[CH:9]=[CH:10][CH:11]=[C:12]23)[CH2:24][CH2:23][N:22]1[C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29]
Reactant: Oc1ccccc1-n1cccc1
Reactant: CC1CC(=O)CCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1CC2(CCN1C(=O)OC(C)(C)C)Oc1ccccc1-n1cccc12
Reaction time: 16 h

Procedure:
Trifluoroacetic acid (443 μL, 5.75 mmol) was added to a solution of 2-pyrrol-1-ylphenol (457 mg, 2.87 mmol) and tert-butyl 2-methyl-4-oxo-piperidine-1-carboxylate (613 mg, 2.87 mmol) in dichloromethane (19 mL) and the solution was vigorously stirred for 16 h. The reaction mixture was quenched with saturated aqueous NaHCO3, and the organics were extracted with EtOAc (3×200 mL). The combined organics were washed with water, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel: 0-10% EtOAc in dichloromethane) to give tert-butyl 2′-methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-carboxylate as a brown oil. The crude residue was dissolved in a solution of HCl in dioxane (1.4 mL of 4.0 M, 5.6 mmol) and stirred for 30 min at room temperature. The volatiles were removed in vacuo and the residue was dissolved in diethylether. The solids were collected by filtration to provide 2′-methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]hydrochloride (386 mg, 46%) as a reddish brown solid. ESI-MS m/z calc. 254.1. found 255.5 (M+1)+; Retention time: 1.12 minutes (3 min run).