Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]#[N:13])[CH:7]=[CH:8][CH:9]=1.S([CH2:24][N+:25]#[C-])(C1C=CC(C)=CC=1)(=O)=O.O1CCC[CH2:28]1>C(Cl)(Cl)Cl>[F:3][C:4]1[CH:5]=[C:6]([C:10]2[C:11]([C:24]#[N:25])=[CH:12][NH:13][CH:28]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: N#CC=Cc1cccc(F)c1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: N#Cc1c[nH]cc1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 19.8 g (494 mmol) of sodium hydride at 60% in oil in 350 ml of anhydrous tetrahydrofuran is added dropwise a mixture of 48.5 g (330 mmol) of the mixture of (Z) and (E) 3-(3-fluorophenyl)-2-propenenitrile in a ratio of (7/3) and 64.4 g (330 mmol) of tosylmethyl isocyanide (CAS 36635-61-7) dissolved in 250 ml of tetrahydrofuran, while maintaining the temperature of the reaction medium at about 25° C. The mixture is then stirred for 1 hour at room temperature and is then poured into ice-water. The reaction product is then extracted with ethyl acetate, the organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced pressure to give a brown solid, which is dissolved in 350 ml of hot chloroform and purified by chromatography on a column of 600 g of silica gel, eluting with dichloromethane and then with a mixture of 1% methanol in dichloromethane, to give 41.5 g of 4-(3-fluorophenyl)-1H-pyrrole-3-carbonitrile in the form of a beige-coloured solid after triturating in dichloromethane, filtering off and drying.
Reaction SMILES: O[C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.O.S(Cl)([Cl:30])=O>CN(C)C=O>[Cl:30][C:2]1[CH:7]=[N:6][C:5]([C:8]([N:24]2[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]2)=[O:10])=[CH:4][N:3]=1
Reactant: O=S(Cl)Cl
Reactant: CN1CCNCC1
Reactant: O=C(O)c1cnc(O)cn1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(C(=O)c2cnc(Cl)cn2)CC1
Reaction time: 72 h
Yield: 62 %

Procedure:
Commercially available 5-hydroxypyrazine-2-carboxylic acid (5.00 g, 39.0 mmol) was dissolved in thionyl chloride (64 mL), and a few drops of N,N-dimethylformamide were added, followed by heating to reflux for 5 hours under nitrogen atmosphere. The solvent was distilled off under reduced pressure, and the resulting residue was diluted with methylene chloride (50 mL). While being cooled in an ice bath, diisopropylethylamine (18.7 mL, 107 mmol) and 1-methylpiperazine (4.37 mL, 39.2 mmol) were added, and stirring was carried out at room temperature for 3 days under nitrogen atmosphere. To the reaction solution, water (100 mL) was added, and extraction was carried out with methylene chloride (100 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=3%-5%) to afford the desired compound (5.32 g, yield 62%) as a brown solid.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[C:12]([F:13])[C:6]=2[CH2:5][O:4]1.[NH:18]1[CH2:21][CH2:20][CH2:19]1>CCO>[F:13][C:12]1[C:6]2[CH2:5][O:4][CH:3]([CH2:2][N:18]3[CH2:21][CH2:20][CH2:19]3)[O:8][C:7]=2[CH:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=1
Reactant: C1CNC1
Reactant: CS(=O)(=O)c1cc(F)c2c(c1)OC(CBr)OC2
Solvent: CCO
Product: CS(=O)(=O)c1cc(F)c2c(c1)OC(CN1CCC1)OC2

Procedure:
Preparation according to Example 34 using 2-(bromomethyl)-5-fluoro-7-(methylsulfonyl)-4H-1,3-benzodioxine (8.5 mg, 0.026 mmol), azetidine (0.1 ml) and EtOH (3 ml). MS m/z (rel. intensity, 70 eV) 301 (M+, 2), 141 (7), 95 (7), 75 (7), 71 (6), 70 (bp).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:11][C:12]1[C:13](Cl)=[N:14][C:15]([CH3:19])=[N:16][C:17]=1[Cl:18].C(N(C(C)C)CC)(C)C.[NH2:30][C@H:31]([CH3:34])[CH2:32][OH:33]>O.CN1CCCC1=O>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:11][C:12]1[C:17]([Cl:18])=[N:16][C:15]([CH3:19])=[N:14][C:13]=1[NH:30][C@H:31]([CH3:34])[CH2:32][OH:33])=[O:5]
Reactant: Cc1nc(Cl)c(N)c(Cl)n1
Reactant: C[C@@H](N)CO
Reactant: O=C(Cl)c1ccccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1nc(Cl)c(NC(=O)c2ccccc2Cl)c(N[C@H](C)CO)n1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 75.7 %

Procedure:
Combine 2-chlorobenzoyl chloride (10.44 g, 57.86 mmol), 5-amino-4,6-dichloro-2-methylpyrimidine (10 g, 56.17 mmol) and N-methylpyrrolidone (44 mL) in a 250 mL three-necked round bottom flask equipped with reflux condenser, stirrer bar, and nitrogen inlet/outlet and heat to 80° C. for 5 h. Add water (506 μL) and continue stirring under the heating conditions for 20 min before adding diisopropylethylamine (29.4 mL, 168.52 mmol). Then add (R)-(−)-2-amino-1-propanol (6.23 mL, 79.77 mmol) in one portion followed by a rinse with N-methylpyrrolidone (10 mL). Continue heating at 80° C. for 17 h. Allow the reaction solution to cool to room temperature and then add water (112 mL) dropwise via an addition funnel over 10 min. Continue stirring at room temperature for 35 min and then pour into ethyl acetate (300 mL). Separate the phases and extract the aqueous with ethyl acetate (2×200 mL). Wash the combined organic portions with water (200 mL) and then brine (200 mL), dry over magnesium sulfate, filter, and evaporate to afford an orange oil. Triturate this with tert-butyl methyl ether to afford a white solid, after collection by filtration. Dry the solids on the filter for 0.5 h and then in a vacuum oven at 50° C. to afford the title compound (15.1 g). ES/MS m/z 355.0/357.0 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#N)=[CH:4][CH:3]=1.[CH2:10]([Mg]Cl)[CH:11]([CH3:13])[CH3:12].[OH:16]S(O)(=O)=O>C(OCC)C>[F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[O:16])[CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1
Reactant: CC(C)C[Mg]Cl
Reactant: N#Cc1ccc(F)cc1
Reactant: O=S(=O)(O)O
Solvent: CCOCC
Product: CC(C)CC(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
To a solution of 4-fluoro-benzonitrile (6 g, 49.5 mmol) in diethyl ether (200 mL) was added i-BuMgCl (1 M soln in THF) and the reaction mixture heated to reflux for 16 hours. The reaction mixture was cooled to room temperature and poured into a mixture 6 N H2SO4 (60 mL) and ice (500 mL), then stirred at 0° C. for 30 min. The aqueous layer was extracted with ethyl acetate (200 mL), the combined organic layers were washed with brine (100 mL), dried (MgSO4), and concentrated. The residue was purified by column chromatography (80 g, SiO2, 0 to 40% diethyl ether/dichloromethane 1:1 in hexanes) to provide 1-(4-fluorophenyl)-3-methylbutan-1-one as a colorless oil (3.72 g, 42%): 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.00 (d, J=6.78 Hz, 6H), 2.29 (dt, J=13.47, 6.64 Hz, 1H), 2.81 (d, J=6.78 Hz, 2H), 7.06-7.19 (m, 2H), 7.94-8.02 (m, 2H); MS m/z 172 (Dimer-OH)++.
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][N:3]=1.O.[CH2:12]([NH2:16])[CH2:13][CH2:14][NH2:15]>>[S:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:2]([NH:15][CH2:14][CH2:13][CH2:12][NH2:16])=[N:3]1
Reactant: NCCCN
Reactant: Clc1nsc2ccccc12
Solvent: O
Product: NCCCNc1nsc2ccccc12
Temperature: 80 °C

Procedure:
3-Chlorobenzo[d]isothia-zole (300 mg, 3.0 mmol) was dissolved in propane-1,3-diamine (3 mL) and heated at 80° C. for 3 h. The reaction mixture was cooled to room temperature, poured into water and extracted with ethyl acetate. The organic extract was dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure to yield N1-(benzo[d]isothiazol-3-yl)propane-1,3-diamine as a yellow solid, (530 mg). 1H NMR (300 MHz, CDCl3): 7.8 (m, 1H), 7.7 (m, 1H), 7.5 (m, 2H), 7.3 (m, 1H), 3.7 (m, 2H), 2.9 (t, 2H), 1.9 ppm (m, 2H).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Br:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([OH:31])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:54]1[CH2:59][CH2:58][N:57]([CH2:60][CH2:61][O:62][CH2:63][CH2:64]O)[CH2:56][CH2:55]1.C(Cl)[Cl:67]>>[ClH:67].[Br:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH2:64][CH2:63][O:62][CH2:61][CH2:60][N:57]4[CH2:58][CH2:59][O:54][CH2:55][CH2:56]4)=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1
Reactant: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1O
Reactant: OCCOCCN1CCOCC1
Reactant: ClCCl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1OCCOCCN1CCOCC1
Product: Cl
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 49 %

Procedure:
Diethyl azodicarboxylate (378 μl, 2.4 mmol) was added dropwise to a mixture of 4-(4-bromo-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (292 mg, 0.8 mmol), (prepared as described for the starting material in Example 48), triphenylphosphine (629 mg, 2.4 mmol) and 2-(2-morpholinoethoxy)ethanol (196 mg, 1.12 mmol), (prepared as described for the starting material in Example 53), in methylene chloride (10 ml) under nitrogen. The mixture was stirred for 3.5 hours at ambient temperature and the mixture was purified by pouring it directly on to a column of silica and eluting with methylene chloride/acetonitrile/methanol (6/3/1). The purified product was dissolved in methylene chloride/methanol and the insolubles were removed by filtration. 2M Ethereal hydrogen chloride (1 ml) was added to the filtrate and the volatiles were removed by evaporation. The residue was triturated with ether, collected by filtration, washed with ether and dried under vacuum to give 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(2-(2-morpholinoethoxy)ethoxy)quinazoline hydrochloride (232 mg, 49%).
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[CH3:6][C:7]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:8]=1[CH:9]=[O:10].CC1C=C(CC2OC2)C=CC=1C=O>[OH-].[Na+]>[CH3:6][C:7]1[CH:14]=[C:13]([O:15][CH2:1][CH:3]2[O:5][CH2:4]2)[CH:12]=[CH:11][C:8]=1[CH:9]=[O:10]
Reactant: Cc1cc(O)ccc1C=O
Reactant: ClCC1CO1
Agent: Cc1cc(CC2CO2)ccc1C=O
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(OCC2CO2)ccc1C=O
Temperature: 55 °C
Reaction time: 3 h

Procedure:
To epichlorohydrin (20 g., 0.216 mole) heated at 55° C. is added dropwise a solution of 2-methyl-4-hydroxybenzaldehyde (9.0 g., 0.006 mole) in 2.5 N sodium hydroxide solution (40 ml.). After the addition, the solution is allowed to stir an additional 3 hours at 55° C. and then at room temperature overnight. the oil is distilled to give 8.3 g. of 2-methyl-4-(2,3-epoxypropyl)benzaldehyde, m.p. 160°-170° C. at 1 mm. Hg.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:17]=[CH:16][C:6]2[NH:7][C:8]3[S:9][CH:10]=[CH:11][C:12]=3[C:13]([NH2:15])=[N:14][C:5]=2[CH:4]=1.[CH3:18][O:19][CH2:20][CH2:21][C@H:22]1[CH2:27]N[CH2:25][CH2:24][NH:23]1.CS(C)=O.C1(C)C=CC=CC=1>C(OCC)(=O)C>[Cl:2][C:3]1[CH:17]=[CH:16][C:6]2[NH:7][C:8]3[S:9][CH:10]=[CH:11][C:12]=3[C:13]([N:15]3[CH2:25][CH2:24][NH:23][C@@H:22]([CH2:21][CH2:20][O:19][CH3:18])[CH2:27]3)=[N:14][C:5]=2[CH:4]=1
Reactant: COCC[C@H]1CNCCN1
Reactant: NC1=Nc2cc(Cl)ccc2Nc2sccc21
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COCC[C@H]1CN(C2=Nc3cc(Cl)ccc3Nc3sccc32)CCN1
Temperature: 105 °C
Reaction time: 24 h
Yield: 36.2 %

Procedure:
Combine 7-Chloro-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine hydrochloride (1.20 g, 4.19 mmol), (S)-2-(2-methoxy-ethyl)-piperazine (1.51 g, 10.48 mmol), DMSO (4.0 ml), and toluene (16.0 ml). Stir and heat the mixture at 105° C. After 24 hours, cool the mixture to ambient temperature and stir it for 16 hours. Dilute the mixture with ethyl acetate and wash the organic layer with 0.1N NaOH and brine. Dry (sodium sulfate) and concentrate the organic layer to residue. Purify the residue on silica gel using a gradient of dichloromethane to dichloromethane/methanol (90:10) to give 571.5 mg (36%) of an brown solid: mass spectrum (ion spray): m/z=377.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[S:10][C:11]2[C:12]([NH2:18])=[N:13][CH:14]=[CH:15][C:16]=2[N:17]=1.[CH:19]12[CH2:24][CH:23]1[C:22](=[O:25])[O:21][C:20]2=O>O1CCOCC1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[S:10][C:11]2[C:12]([N:18]3[C:20](=[O:21])[CH:19]4[CH:23]([CH2:24]4)[C:22]3=[O:25])=[N:13][CH:14]=[CH:15][C:16]=2[N:17]=1
Reactant: O=C1OC(=O)C2CC12
Reactant: Nc1nccc2nc(-c3c(Cl)cccc3Cl)sc12
Solvent: C1COCCO1
Product: O=C1C2CC2C(=O)N1c1nccc2nc(-c3c(Cl)cccc3Cl)sc12
Temperature: 25 °C
Yield: 78.8 %

Procedure:
A solution of 2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridin-4-amine (550 mg, 1.86 mmol) and 3-oxabicyclo[3.1.0]hexane-2,4-dione (835 mg, 7.46 mmol) in 1,4-dioxane (10 mL) was heated at 90° C. for 2 hours. The reaction mixture was then cooled to room temperature and concentrated. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (1:10 to 1:2) to give the desired product as a solid. (570 mg, 78.8% yield). LCMS (ESI) m/z: 390.0 [M+H+].
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2N=NN(CC)C=2N=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C:38]([F:42])([F:41])[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].Br[CH2:44][C:45]([C:47]1[CH:52]=[CH:51][CH:50]=[C:49]([Cl:53])[CH:48]=1)=[O:46]>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C:38]([F:41])([F:42])[CH2:37]2)[C:30]2[N:35]=[N:34][N:33]([CH2:44][C:45]([C:47]3[CH:52]=[CH:51][CH:50]=[C:49]([Cl:53])[CH:48]=3)=[O:46])[C:31]=2[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: O=C(CBr)c1cccc(Cl)c1
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Agent: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(CC(=O)c3cccc(Cl)c3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-bromo-1-(3-chlorophenyl)ethanone and isolated as white solid. MS(m/e): 435.3 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=3)[C:18]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10][CH2:9]2)=[O:7])=[C:4]([O:30][CH3:31])[CH:3]=1.Cl[C:33](OC1C=CC([N+]([O-])=O)=CC=1)=[O:34].[CH2:45]([NH2:49])[CH:46]([CH3:48])[CH3:47]>ClCCl.O>[C:21]([NH:20][C:18](=[O:19])[C:17]1[CH:25]=[CH:26][CH:27]=[C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:5]3[CH:28]=[CH:29][C:2]([NH:1][C:33]([NH:49][CH2:45][CH:46]([CH3:48])[CH3:47])=[O:34])=[CH:3][C:4]=3[O:30][CH3:31])[CH2:9][CH2:10]2)[CH:16]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)CN
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COc1cc(N)ccc1C(=O)N1CCN(Cc2cccc(C(=O)NC(C)(C)C)c2)CC1
Solvent: O
Solvent: ClCCl
Product: COc1cc(NC(=O)NCC(C)C)ccc1C(=O)N1CCN(Cc2cccc(C(=O)NC(C)(C)C)c2)CC1
Reaction time: 0.5 h
Yield: 26.7 %

Procedure:
3-((4-(4-Amino-2-methoxybenzoyl)piperazin-1-yl)methyl)-N-tert-butylbenzamide (200 mg, 0.48 mmol) and 4-nitrophenol chloroformate (475 mg, 0.48 mmol) were combined and stirred in dichloromethane for 1 hour. Isobutylamine (102.4 mg, 1.4 mmol, 0.14 mL) was added and the reaction mixture was stirred for 30 minutes. The reaction mixture was diluted with water and flushed through a hydrophobic fret. The organic phase was concentrated under reduced pressure and purified by acidic reverse phase HPLC to afford the title compound (67 mg). MS (ESI) m/z 524.5 [M+H]+
Reaction SMILES: [ClH:1].Cl.[CH:3]1[CH:12]=[CH:11][C:10]2[CH2:13][CH2:14][CH2:15][N:8]3[C:9]=2[C:4]=1[C@@H:5]1[CH2:18][NH:17][CH2:16][C@H:6]1[CH2:7]3.C=O.[C:21](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.Cl>ClCCCl.CCOCC>[ClH:1].[ClH:1].[CH3:21][N:17]1[CH2:18][C@@H:5]2[C@H:6]([CH2:7][N:8]3[CH2:15][CH2:14][CH2:13][C:10]4[CH:11]=[CH:12][CH:3]=[C:4]2[C:9]3=4)[CH2:16]1
Reactant: c1cc2c3c(c1)[C@@H]1CNC[C@H]1CN3CCC2
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN1C[C@H]2CN3CCCc4cccc(c43)[C@@H]2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.8 %

Procedure:
To a solution of (±)-trans-5,6,8,8a,9,10,11,11a-octahydro-4H-pyrido[3,2,1-ij]pyrrolo[3,4-c]quinoline from EXAMPLE 4 (95 mg, 0.44 mmol) in 5 mL of 1,2-dichloroethane was added 37% aqueous formaldehyde (0.043 mL, 0.53 mmol), sodium triacetoxyborohydride (168 mg, 0.79 mmol) and glacial acetic acid (0.027 mL, 0.48 mmol). The resulting mixture was stirred at ambient temperature for 1 h and then the reaction was quenched with water. The mixture was partitioned between chloroform and saturated aqueous sodium carbonate. The organics were washed with brine, dried (K2CO3) and concentrated in vacuo. The residue was dissolved in 1 mL ethanol and 5 mL of ether and then there was added 2M HCl in ether (0.44 mL, 0.88 mmol). A solid precipitated out of solution. The solvents were decanted and the solid was triturated twice with ether and dried in vacuo to afford 35 mg (27%) of the title compound of EXAMPLE 6 as an off white powder. 1H NMR (d6-dmso): δ 11.22 (broad s, 1H), 6.76 (d, 1H, J=7.7 Hz), 6.57 (dd, 1H, J=7.3, 12.5 Hz), 6.38 (t, 1H, J=7.3 Hz), 4.17-4.08 (m, 1H), 3.81-3.72 (m, 1H), 3.68-3.60 (m, 1H), 3.42-3.18 (m, 5H), 2.98-2.80 (m, 4H), 2.66-2.60 (m, 2H), 2.10-1.98 (m, 1H), 1.95-1.83 (m, 1H), 1.82-1.72 (m, 1H). LRMS (ES)+: 229.4 (M+H)+.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[C@@H:10]1[CH2:14][NH:13][CH2:12][C@H:11]1[C:15]([O:17][CH3:18])=[O:16].[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22](Cl)[N:21]=1.C(N(C(C)C)CC)(C)C.O>CN1C(=O)CCC1>[Cl:19][C:20]1[N:21]=[C:22]([N:13]2[CH2:14][C@@H:10]([C:4]3[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:3]=3[F:2])[C@H:11]([C:15]([O:17][CH3:18])=[O:16])[CH2:12]2)[CH:23]=[CH:24][CH:25]=1
Reactant: Clc1cccc(Cl)n1
Reactant: COC(=O)[C@@H]1CNC[C@H]1c1ccc(F)cc1F
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COC(=O)[C@@H]1CN(c2cccc(Cl)n2)C[C@H]1c1ccc(F)cc1F
Temperature: 25 °C

Procedure:
Methyl (3S,4R)-4-(2,4-difluorophenyl)pyrrolidine-3-carboxylate hydrochloride (prepared according to Young, J. R. et. al. Bioorganic and Medicinal Chemistry Letters 2007, 17, 5310-5315; 100 mg, 0.360 mmol), 2,6-dichloropyridine (107 mg, 0.720 mmol) and N,N-diisopropyl-N-ethylamine (0.189 ml, 1.080 mmol) in NMP (2.0 ml) was heated by microwave (150° C., 30 min). The mixture was cooled to rt, poured into water and extracted with MTBE. Purification on SiO2 (0 to 30% EtOAc, hexanes) afforded the title compound. HPLC/MS: 353.1/354.9 (M+1); Rt=1.22 min (LC2).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].Br[CH2:10][CH:11]([OH:15])[CH2:12][CH2:13]Br.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[N:4]1[CH2:13][CH2:12][CH:11]([OH:15])[CH2:10]1
Reactant: OC(CBr)CCBr
Reactant: Nc1ccccc1Br
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: OC1CCN(c2ccccc2Br)C1

Procedure:
2-Bromoaniline (2 g) was heated with 1,4-dibromo-2-butanol (1.58 ml) and diisopropylethylamine (4.9 ml) in toluene (10 ml) at reflux for 20 h. The reaction mixture was allowed to cool, diluted with water (60 ml) and the aqueous phase extracted with ethyl acetate (3×30 ml). The combined extracts were washed with water, brine, dried (MgSO4), filtered and evaporated. The residue was adsorbed onto silica and purified by column chromatography, eluting with a gradient of 0–20% ethyl acetate in isohexane, to afford the product as a yellow oil (2.30 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([CH3:18])=[C:5]2[CH2:19][C:20]([OH:22])=[O:21].[H-].[Na+].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].Cl>C1COCC1.CS(C)=O>[C:27]([CH2:26][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([CH3:18])=[C:5]2[CH2:19][C:20]([OH:22])=[O:21])([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)CBr
Reactant: Cc1c(CC(=O)O)c2cc(O)ccc2n1Cc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CCOC(=O)COc1ccc2c(c1)c(CC(=O)O)c(C)n2Cc1ccccc1
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
A solution of 590 mg (2.0 mmol) of 5-hydroxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetic acid (Example 2, Part C) in 30 mL of THF and 10 mL of DMSO was treated with 180 mg (4.5 mmol) of 60% NaH/mineral oil and after 10 minutes, 0.25 mL (2.25 mmol) of ethyl 2-bromoacetate was added. The mixture was stirred for 0.5 hour, acidified with 1N HCl and extracted with EtOAc. The EtOAc solution was washed with water, saturated NaCl solution, dried (Na2SO4) and concentrated at reduced pressure. After chromatography on silica (eluted with a gradient, CH2Cl2 →3% MeOH/CH2Cl2) there was obtained 590 mg (77% yield) of 5-(carbethoxymethoxy)-2-methyl-1-(phenylmethyl)-1H-indole-3-acetic acid.
Reaction SMILES: [CH:1](=[C:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9])[CH2:2][CH3:3].B(F)(F)F.[CH2:14]=[CH:15][C:16](=C)[CH3:17].[C:19]1(C)C=CC=CC=1>>[CH2:15]([CH:16]1[C:4]2([C:5](=[O:9])[CH2:6][CH2:7][CH2:8]2)[CH2:1][CH:2]=[C:3]([CH3:19])[CH2:17]1)[CH3:14]
Reactant: C=CC(=C)C
Reactant: Cc1ccccc1
Reactant: CCC=C1CCCC1=O
Agent: FB(F)F
Product: CCC1CC(C)=CCC12CCCC2=O
Reaction time: 3.5 h
Yield: 103 %

Procedure:
A solution of propylidene cyclopentanone (124 g; 1 mol) in toluene (124 g) was cooled to 0° C. BF3 etherate (10 ml) were added at 0° C. over 10 minutes. Isoprene (168 g; 2.47 mol), dissolved in toluene (168 g) was then added dropwise over 3 hours at 0° C. Stirring was continued at 0° C. for 3.5 hours. Usual work-up (see above) afforded 198 g of a crude product as a mixture of isomer (ratio 5/4/91). Distillation through a Vigreux column afforded 165 g of 96% pure cycloadduct (yield: 86%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9](O)(=[O:27])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1.O>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:9](=[O:27])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:3][CH:4]=1
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: Nc1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: CCCCCCCCCCCCCCCCCC(=O)Nc1ccc(O)cc1
Temperature: 110 °C

Procedure:
A 3-liter flask was charged with 218 grams (2 moles) of 4-aminophenol, 538 grams (1.9 moles) of stearic acid, 20 grams of p-toluenesulfonic acid, 300 ml of xylene and swept with nitrogen. The flask was fitted with a Dean-Stark trap for water removal and the contents heated with stirring to 220° C. with water and xylene removal for 2 hours. Twenty-eight milliliters of water were removed. The contents of the flask were cooled to 110° C. and poured into a polyethylene container, which was stripped of volatiles at 125-130° C. at 29 inches of Hg vacuum to give 737 grams of a waxy solid with an infrared spectroscopic spectra showing phenolic and amide functional groups.