Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([OH:12])=[C:7]([C:9](=[O:11])[CH3:10])[CH:8]=1.CN(C)C=O.[Na].[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1>>[C:9]([C:7]1[CH:8]=[C:3]([CH2:2][N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)[CH:4]=[CH:5][C:6]=1[OH:12])(=[O:11])[CH3:10]
Reactant: CC(=O)c1cc(CCl)ccc1O
Reactant: c1c[nH]cn1
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(=O)c1cc(Cn2ccnc2)ccc1O
Reaction time: 4 h
Yield: 32.8 %

Procedure:
To a mixture of 5'-(chloromethyl)-2'-hydroxyacetophenone (1.85 g, 10.0 mmol), sodium dimethylformamide was added imidazole (0.75 g, 11.0 mmol). The mixture was stirred four hours and concentrated in vacuo. The residue was stirred under 50 mL ethanol, filtered, and the filtrate concentrated in vacuo to give a residue. The residue was stirred under 30 mL chloroform, filtered, and the filtrate concentrated in vacuo to give crude product. The crude product was purified by flash chromatography eluting with 5:95 methanol:chloroform to give a solid. The solid was recrystallized from n-butlychloride to give 0.71 g (33%) product as a yellow crystalline solid, mp 106°-107° C.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C@H:6]([CH2:14][CH3:15])[N:5]([CH:16]([CH3:18])[CH3:17])[C:4]=2[N:3]=1.C[CH:20]1[CH2:24][C:23]2=[C:25]([C:30]([OH:32])=[O:31])[CH:26]=[CH:27][C:28]([NH2:29])=[C:22]2[O:21]1.Cl>C(O)C.O>[CH:16]([N:5]1[C:4]2[N:3]=[C:2]([NH:29][C:28]3[CH:27]=[CH:26][C:25]([C:30]([OH:32])=[O:31])=[C:23]4[C:22]=3[O:21][CH2:20][CH2:24]4)[N:11]=[CH:10][C:9]=2[N:8]([CH3:12])[C:7](=[O:13])[C@@H:6]1[CH2:14][CH3:15])([CH3:18])[CH3:17]
Reactant: CC[C@H]1C(=O)N(C)c2cnc(Cl)nc2N1C(C)C
Reactant: CC1Cc2c(C(=O)O)ccc(N)c2O1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC[C@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)O)c4c3OCC4)nc2N1C(C)C
Yield: 57.9 %

Procedure:
(7S)-2-Chloro-8-isopropyl-7-ethyl-5-methyl-7H-pteridin-6-one 43d (2.50 g, 9.24 mmol) and methyl 7-amino-2,3-dihydrobenzofuran-4-carboxylateic acid 1g (1.50 g, 8.40 mmol) were dissolved in 120 mL of the mixture solvent of ethanol and water (V/V=1:2) followed by the addition of 1.5 mL of concentrated hydrochloric acid. The reaction mixture was heated to reflux for 24 hours with stirring and the precipitate was filtered. The filter cake was washed with dichloromethane (50 mL×3) and dried by heating to obtain the crude compound 7-[[(7S)-8-isopropyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carboxylic acid 43e (2 g) as a gray solid, which was used in the next step without further furification.
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH2:4][C:5]([O:7]CC)=O.[CH:11]([NH2:13])=[S:12].O.[NH3:15]>C(O)C>[CH3:2][C:3]1[N:13]=[CH:11][S:12][C:4]=1[C:5]([NH2:15])=[O:7]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: N
Reactant: NC=S
Solvent: CCO
Solvent: O
Product: Cc1ncsc1C(N)=O
Yield: 82 %

Procedure:
3.3 g (20 mmol) ethyl chloroacetoacetate and 1.8 g (30 mmol) thioformamide were dissolved in 40 ml ethanol, and reacted under reflux for 8 hr, followed by removing the solvent by rotation drying; and then, ethyl acetate and water were added to separate the layers. The resultant organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a red oily liquid. 60 ml ammonia water was directly added to the red oily liquid without purification, to carry out reaction in closed state for 24 hr. The reaction product was extracted with ethyl acetate, dried with sodium sulfate, filtered and concentrated to obtain 2.3 g of a solid (yield 82%).
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH:18]=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:21]([F:26])([F:25])C([O-])=O.[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O.CCOCC>[CH2:1]([O:8][C:9]([CH:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH:18]=[C:21]([F:26])[F:25])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])C(F)(F)Cl
Reactant: O=CCC1CCC(C(=O)OCc2ccccc2)CC1
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)C1CCC(CC=C(F)F)CC1
Temperature: 130 °C
Reaction time: 4 h
Yield: 58 %

Procedure:
A solution of 4-(2-oxo-ethyl)-cyclohexanecarboxylic acid benzyl ester (trans:cis=4:1) (21.4 mg, 0.082 mmol) in dimethylformamide (0.3 ml) was added to a solution of sodium chlorodifluoroacetate (34.1 mg, 0.224 mmol) and triphenylphosphine (59.9 mg, 0.228 mmol) in dimethylformamide (0.41 ml) at 90 to 95° C. over five minutes, and the mixture was stirred at 130° C. for four hours. Sodium chlorodifluoroacetate (34.0 mg, 0.22 mmol) was then added to the reaction mixture at the same temperature, and the mixture was further stirred for two hours. The reaction mixture was diluted with ether, and the organic layer was washed with water, dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 4-(3,3-difluoro-allyl)-cyclohexanecarboxylic acid benzyl ester (trans:cis=4:1) (14.1 m, 58%).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][OH:8])[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18]>>[C:17]([OH:19])(=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][O:8][CH2:7][CH2:6][O:5][CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)CCCCCBr
Reactant: CCCCOCCO
Agent: [H-]
Agent: [Na+]
Product: CCCCOCCOCCCCCC(=O)O

Procedure:
Illustratively, 2-butoxyethanol can be reacted with sodium hydride and the resulting alcoholate reacted with 6-bromohexanoic acid to give 7,10-dioxatetradecanoic acid. So also, 2-ethoxyethanol can be reacted with sodium hydride and the resulting alcoholate reacted with 8-bromooctanoic acid to provide 9,12-dioxatetradecanoic acid.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][N:3]1[C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH3:21])[C:18]([OH:20])=[O:19])=[CH:13][CH:12]=1.C(N(CC)CC)C.Br[CH:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:32](=[O:33])[O:31]1>C(Cl)(Cl)Cl>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][N:3]1[C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH3:21])[C:18]([O:20][CH:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:32](=[O:33])[O:31]2)=[O:19])=[CH:13][CH:12]=1
Reactant: O=C1OC(Br)c2ccccc21
Reactant: CC(C(=O)O)c1ccc(N2Cc3ccccc3C2=O)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C(=O)OC1OC(=O)c2ccccc21)c1ccc(N2Cc3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 75 %

Procedure:
To a solution of 8.4 g of 2-[4-(1-oxo-2-isoindolinyl)phenyl]propionic acid in 40 ml of chloroform and 3.4 of triethylamine is added a solution of 6.2 g of 3-bromophthalide in 20 ml of chloroform. The solution thus obtained is stirred 24 hours at room temperature, the organic phase is washed with an aqueous solution of sodium bicarbonate, then with water and finally it is dried on anhydrous sodium sulfate and evaporated to dryness to yield the phthalidyl 2-[4-(1-oxo-2-isoindolinyl)phenyl]propionate; yield 75%.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].O=[C:16]([NH:22][CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(Cl)(Cl)Cl>[C:25]1([C:24]2[S:2][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:22][CH:23]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCOC(=O)C(=O)NCC(=O)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ncc(-c2ccccc2)s1
Yield: 74.7 %

Procedure:
P2S5 (25.5 g, 114.7 mmol) was added to a solution of ethyl 2-oxo-2-((2-oxo-2-phenylethyl)amino)acetate (13.5 g, 57.39 mmol) in dry CHCl3 (150 mL), and the resulting reaction mixture was heated to reflux for 5 h. The reaction mixture was quenched with water and the organic product was extracted with CHCl3. The combined extracts were washed with H2O and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 10-15% EtOAc in petroleum ether) to afford ethyl 5-phenylthiazole-2-carboxylate (10 g, yield 75%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.16 (s, 1H), 7.64-7.62 (m, 2H), 7.48-7.39 (m, 3H), 4.53-4.47 (q, J=7.0 Hz, 2H), 1.49-1.45 (t, J=7.2 Hz, 3H). MS (ESI) m/z: Calculated for C12H11NO2S: 233.05. found: 234.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[I:13].[CH:14](OCC)(OCC)OCC.[N-:24]=[N+:25]=[N-:26].[Na+]>CC(O)=O>[I:13][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:7][C:2]=1[N:1]1[CH:14]=[N:26][N:25]=[N:24]1
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)Cc1ccc(N)c(I)c1
Reactant: CCOC(OCC)OCC
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)Cc1ccc(-n2cnnn2)c(I)c1
Temperature: 100 °C

Procedure:
A solution of methyl (4-amino-3-iodophenyl)acetate (5 g, 17.2 mmol) and triethyl orthoformate (7.6 mg, 51.5 mmol) in 40 mL of HOAc was added sodium azide (1.2 g, 17.2 mmol), and the mixture was heated to 100° C. for 3 hours. The reaction mixture was cooled to ambient temperature. The solvent was removed under vacuum. The residue was dissolved in EtOAc, washed with water, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatograph to afford methyl [3-iodo-4-(1H-tetrazol-1-yl)phenyl]acetate. 1H-NMR (300 MHz, CDCl3) δ ppm 8.90 (s, 1H), 7.96 (s, 1H), 7.47 (d, J=8.2 Hz, 1H), 7.38 (d, J=7.9 Hz, 1H), 3.74 (s, 3H), 3.70 (s, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[CH2:7][N:8]1[C:14](=[O:15])[CH:13]([N:16]2C(=O)C3=CC=CC=C3C2=O)[CH2:12][S:11][CH:10]([C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29][CH:28]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].CNN>C(Cl)Cl.CO>[NH2:16][CH:13]1[CH2:12][S:11][CH:10]([C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29][CH:28]=2)[CH2:9][N:8]([CH2:7][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:37])[C:14]1=[O:15]
Reactant: CC(C)(C)OC(=O)CN1CC(c2cccc3ccccc23)SCC(N2C(=O)c3ccccc3C2=O)C1=O
Agent: CNN
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CN1CC(c2cccc3ccccc23)SCC(N)C1=O
Reaction time: 48 h
Yield: 102.7 %

Procedure:
To a solution of 2.5 g of t-butyl[2-(1-naphthyl)-5-oxo-6-phthalimidoperhydro-1,4-thiazepin-4-yl]acetate [prepared as described in step (f) above] in a mixture of 20 ml of methylene chloride and 2 ml of methanol was added 0.77 ml of methylhydrazine, and the reaction mixture was allowed to stand for 2 days at room temperature. The reaction mixture was then concentrated by evaporation under reduced pressure, 15 ml of methylene chloride were added to the residue and the mixture was stirred. The resulting precipitate was filtered off and the filtrate was concentrated by evaporation under reduced pressure. The residue was subjected to silica gel column chromatography using a 1:20 by volume mixture of methanol and ethyl acetate as eluent, to give 1.92 g of the title compound as an amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([OH:15])=[O:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH2:20]([N:22]([CH2:29][CH3:30])[CH2:23][C:24]([CH3:28])([CH3:27])[CH2:25]O)[CH3:21]>C1C=CC=CC=1>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][C:11]([C:13]([O:15][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][N:22]([CH2:29][CH3:30])[CH2:20][CH3:21])=[O:14])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCN(CC)CC(C)(C)CO
Reactant: O=C(O)c1ccc(-c2ccc(Cl)cc2)o1
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: CCN(CC)CC(C)(C)COC(=O)c1ccc(-c2ccc(Cl)cc2)o1
Product: Cl
Reaction time: 18 h

Procedure:
5-(p-Chlorophenyl)-2-furoic acid (33.5 g., 0.15 mole) is added with rapid stirring to thionyl chloride (58 ml.) at room temperature, heated until solution occurs (about 20 min.) and then refluxed for 2 hr. The mixture is stripped of excess thionyl chloride in vacuo, benzene (100 ml.) is added, and again stripped of solvent. The residue is treated with a solution of 3-diethylamino-2,2 dimethylpropanol (24.1 g., 0.15 mole) in benzene (700 ml.), refluxed for 4 hr., cooled, diluted with petroleum ether (450 ml.) and stored for 18 hours at room temperature. The benzene-petroleum ether solution is decanted, the residue is dissolved in H2O (1000 ml.), and the solution is adjusted to pH 8 with saturated aqueous Na2CO3 (70 ml.). The product is extracted from the aqueous phase with benzene (1000 ml.) in portions and the extract is dried overnight with MgSO4 and activated charcoal. The solution is filtered and the filtrate is adjusted to pH 3 with ether-HCl (cooled in ice bath). Petroleum ether (300 ml.) is added and the product oiled out of solution. The benzene-petroleum ether solution is decanted and the product is washed twice with anhydrous ether (scratching induced crystallization). The solid is recrystallized from ethanol (200 ml.) to yield: 32 g. (53%). A sample is recrystallized twice from isopropanol, m.p. 139°-143°.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19]4[S:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=[C:13]3[C:12]([C:24]3[CH:25]=[C:26]([CH:47]=[CH:48][CH:49]=3)[CH2:27][NH:28][C:29]([C:31]3[C:32](=[O:46])[N:33]([CH2:37][C:38]4[CH:43]=[CH:42][C:41]([F:44])=[C:40]([F:45])[CH:39]=4)[CH:34]=[CH:35][CH:36]=3)=[O:30])=[CH:11]2)(=O)=O)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[S:20]1[CH:21]=[CH:22][CH:23]=[C:19]1[C:17]1[CH:18]=[C:13]2[C:12]([C:24]3[CH:25]=[C:26]([CH:47]=[CH:48][CH:49]=3)[CH2:27][NH:28][C:29]([C:31]3[C:32](=[O:46])[N:33]([CH2:37][C:38]4[CH:43]=[CH:42][C:41]([F:44])=[C:40]([F:45])[CH:39]=4)[CH:34]=[CH:35][CH:36]=3)=[O:30])=[CH:11][NH:10][C:14]2=[N:15][CH:16]=1
Reactant: O=C(NCc1cccc(-c2cn(S(=O)(=O)c3ccccc3)c3ncc(-c4cccs4)cc23)c1)c1cccn(Cc2ccc(F)c(F)c2)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(NCc1cccc(-c2c[nH]c3ncc(-c4cccs4)cc23)c1)c1cccn(Cc2ccc(F)c(F)c2)c1=O

Procedure:
1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid 3-(1-benzenesulfonyl-5-thiophen-2-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-benzylamide (0.079 mmol, 0.000079 mol) was dissolved in methanol (1.8 mL, Fisher;) and water (0.60 mL, Fisher). To this was added potassium carbonate (46 mg, 0.00033 mol; Fisher) and the reaction was heated at reflux for 1 hour. The reaction was evaporated, taken up in N,N-dimethylformamide, neutralized with TFA (100 uL) and purified by preparative HPLC chromatography to yield the product in 3.4 mg yield. 1H NMR (500 MHz, CDCl3-MeOH-d4) d ppm 10.244 (s, 1H) 8.734 (s, 1H) 8.550-8.480 (m, 2H) 7.677 (s, 1H) 7.604 (s, 1H) 7.537 (s, 1H) 7.506-7.393 (m, 3H) 7.390-7.326 (m, 2H) 7.144-7.035 (m, 3H) 6.999-6.938 (m, 1H) 6.442 (m, 1H) 5.070 (s, 2H) 4.689 (m, 2H); MS m/z=552.95 M+H.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][O:9][N:10]=[C:11]([C:18]2[N:22]([CH3:23])[N:21]=[N:20][N:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[CH:4][CH:3]=1.[CH:24]1(/[CH:30]=[CH:31]/B(O)O)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1.C(O)C.O>[CH:24]1(/[CH:30]=[CH:31]/[C:2]2[N:7]=[C:6]([CH2:8][O:9][N:10]=[C:11]([C:18]3[N:22]([CH3:23])[N:21]=[N:20][N:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:5]=[CH:4][CH:3]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: OB(O)/C=C/C1CCCCC1
Reactant: Cn1nnnc1C(=NOCc1cccc(Br)n1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: Cn1nnnc1C(=NOCc1cccc(/C=C/C2CCCCC2)n1)c1ccccc1
Temperature: 90 °C
Yield: 71.8 %

Procedure:
In a dried and purged vessel were added N-[(6-bromopyridin-2-yl)methoxy]-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (0.2 g, 0.536 mmol, 1 eq.), [(E)-2-cyclohexylvinyl]boronic acid (0.090 g, 0.58 mmol, 1.1 eq.), Na2CO3 (0.119 g, 1.12 mmol, 2.1 eq.) and Tetrakis(triphenylphosphine)palladium (0.030 g, 0.027 mmol, 0.05 eq.). A mixture of solvent was added toluene/ethanol/water (4/1/1) was added and the vessel purged with argon and sealed. The reaction was heated to 90° C. for 6 hrs. After cooling, 10 ml of EtOAc were added and the solids were filtered through a “Celite” plug and washed with EtOAc. The organics were separated, dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel to give N-({6-[(E)-2-cyclohexylvinyl]pyridin-2-yl}methoxy)-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (0.155 g, 68% yield) as a colorless gum.
Reaction SMILES: [C:1]([C:4]12CCC(C(O)=O)([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=O.C([N:17]([CH2:20][CH3:21])CC)C.C1(P([N:36]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[ClH:39]>C1(C)C=CC=CC=1>[ClH:39].[ClH:39].[NH2:36][C:4]12[CH2:1][CH2:21][C:20]([NH2:17])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2
Reactant: O=C(O)C12CCC(C(=O)O)(CC1)CC2
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCN(CC)CC
Agent: Cl
Solvent: Cc1ccccc1
Product: NC12CCC(N)(CC1)CC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.4 %

Procedure:
A suspension of 1,4-dicarboxybicyclo[2.2.2]octane (9.91 g, 50 mmol) in toluene (225 mL) was azeotroped under a Dean-Stark trap to dryness, then cooled to room temperature under nitrogen and treated with triethylamine (20 mL, 143 mmol) and diphenylphosphoryl azide (33.0 g, 120 mmol). The solution was slowly and cautiously warmed to 80° C. (some exotherm and much evolution of gas observed) and stirred at 80°-90° C. for 3 h, then concentrated in vacuo to remove toluene and the residue cooled on an ice bath and treated with 6N hydrochloric acid (150 mL, 900 mmol). The bath was removed and the mixture stirred at room temperature for 3 h, then partially concentrated to remove most water. Acetonitrile (600 mL) was added, and the suspension was cooled for an hour in a refrigerator, filtered, and the solid rinsed with acetonitrile and dried in vacuo to afford 9.31 g (87%) of subject material as a white solid. [M+H]+=141.3. 1H NMR (d6-DMSO) δ 8.24 (br s, 6H), 1.81 (s, 12H).
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5](=[O:15])[CH:4]=1)[NH2:2].[C:16]1([CH:26]=O)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.[CH3:28][C:29]1[CH:33]=[CH:32][S:31][C:30]=1[CH:34]=O>>[CH2:9]([N:8]1[C:3]2=[N:1][N:2]([CH2:26][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=[CH:18][CH:17]=3)[C:34]([C:30]3[S:31][CH:32]=[CH:33][C:29]=3[CH3:28])=[C:4]2[C:5](=[O:15])[N:6]([CH3:14])[C:7]1=[O:13])[CH:10]([CH3:11])[CH3:12]
Reactant: CC(C)Cn1c(NN)cc(=O)n(C)c1=O
Reactant: Cc1ccsc1C=O
Reactant: O=Cc1cccc2ccccc12
Product: Cc1ccsc1-c1c2c(=O)n(C)c(=O)n(CC(C)C)c2nn1Cc1cccc2ccccc12

Procedure:
This compound was made following the procedure described above, starting with 6-hydrazino-1-isobutyl-3-methylpyrimidine-2,4(1H,3H)-dione, and condensing first with 1-naphthaldehyde, followed by 3-methylthiophene-2-carbaldehyde. Mass: 458.87 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH2:24][CH2:23][C:5]2[N:6]([CH2:14][CH:15]([NH2:22])[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH3:25][C:26]([CH3:28])=O.C(O)(=O)C.C([BH3-])#N.[Na+]>C(Cl)Cl>[CH3:1][N:2]1[CH2:24][CH2:23][C:5]2[N:6]([CH2:14][CH:15]([NH:22][CH:26]([CH3:28])[CH3:25])[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(N)c2ccncc2)CCN(C)C1
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(n2CC(NC(C)C)c2ccncc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.4 %

Procedure:
2-(2,8-Dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethylamine (200 mg, 0.62 mmol) was dissolved in 15 mL DCM, acetone (108 mg, 1.87 mmol), acetic acid (0.5 mL) was added and the reaction mixture was stirred at RT overnight. Sodiumcyanoborohydride (117 mg, 1.87 mmol) was added and stirred at for 1 h. The reaction mixture was diluted with DCM (300 mL) and washed with saturated bicarbonate solution (200 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by reverse phase chromatography to obtain 120 mg of [2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethyl]-isopropyl-amine as the TFA salt. 1H NMR (CD3OD, TFA salt): δ (ppm): 8.52 (m, 2H), 7.42 b(s, 2H), 7.30 b(s, 1H), 7.22 (s, 1H), 7.02 (m, 1H), 4.8 (m, 1H), 4.58 (m, 2H), 4.23 (t, 1H), 3.72 (m, 1H), 3.4 (m, 3H), 3.13 (m, 2H), 2.99 (d, 3H), 2.39 (s, 3H), 1.43 (d, 3H), 1.34 (d, 3H). Chiral HPLC separates the racemate into enantiomers II-10a-b.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][CH:5]=1.[CH2:13]([Mg]Cl)[CH:14]([CH3:16])[CH3:15]>O1CCCC1>[OH:11][CH:10]([C:7]1[CH:8]=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:12])=[CH:5][CH:6]=1)[CH2:13][CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)C[Mg]Cl
Reactant: COC(=O)c1ccc(C=O)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(O)CC(C)C)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 19 %

Procedure:
A solution of 4-formyl-benzoic acid methyl ester (1.56 g, 9.50 mmol) in tetrahydrofuran (53 mL) was cooled to 0° C. Isobutylmagnesium chloride (4.75 mL, 2M in THF) was then added dropwise over 15 minutes. The reaction was stirred at 0° C. for 1 hour. The ice bath was removed and the reaction was allowed to warm to room temperature and stir for 1 hour. The reaction was quenched by carefully adding 1N HCl. The reaction was diluted with water and diethylether and the layers were separated. The aqueous was extracted three more times with diethyl ether. The combined organics were dried over magnesium sulfate, filtered, and concentrated. Purification by column chromatography (0-40% ethyl acetate in heptane) gave (+/−)-methyl 4-(1-hydroxy-3-methylbutyl)benzoate (404.6 mg, 19%) as a clear, colorless oil. 1H NMR (400 MHz, CDCl3, δ): 7.99 (d, J=8.2 Hz, 2H), 7.40 (d, J=8.2 Hz, 2H), 4.79 (br. s., 1H), 3.89 (s, 3H), 1.94 (d, J=2.73, 1H), 1.65-1.78 (m, 2H), 1.42-1.52 (m, 1H), 0.91-0.97 (m, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[N+:9]([O-:12])(O)=[O:10].[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:12])=[O:10])[C:3]=1[NH:4][C:13](=[O:15])[CH3:14]
Reactant: O=[N+]([O-])O
Reactant: Nc1ccccc1Br
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1c(Br)cccc1[N+](=O)[O-]
Yield: 16.7 %

Procedure:
To a solution of 2-bromoaniline (XC) (50 g, 0.29 mol, 1 eq) in acetic anhydride (265 mL) was added dropwise nitric acid (fuming) (36.75 mL, 0.93 mol, 3.2 eq) at 0° C. and then stirred at that temperature, when the starting material was consumed, the mixture was filtered, the filtrate was poured into ice water. The aqueous phase was basified with aqueous solution of sodium bicarbonate to pH=7, then the mixture was extracted with EtOAc (30 mL×3). The organic layers were combined, dried and concentrated in vacuo to give the N-(2-bromo-6-nitrophenyl)acetamide (XCI) (12.6 g, 48.6 mmol, 16.7% yield) as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ ppm 2.06 (s, 3H), 7.43 (t, J=8 Hz, 1H), 7.94 (d, J=8 Hz, 1H), 8.05 (d, J=8 Hz, 1H); ESIMS found for C8H7BrN2O3 m/z 259 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([NH2:10])[CH:9]=1)[C:5]#[N:6].[Cl:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=2)[N:15]=[CH:14][CH:13]=1>C(O)C>[ClH:11].[NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([NH:10][C:12]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]=[CH:14][CH:13]=2)[CH:9]=1)[C:5]#[N:6]
Reactant: N#Cc1cc(N)cc(N)c1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Solvent: CCO
Product: Cl
Product: N#Cc1cc(N)cc(Nc2ccnc3cc(Cl)ccc23)c1
Yield: 74.3 %

Procedure:
3,5-Diaminobenzonitrile (500 mg, 3.76 mmol) and 4,7-dichloroquinoline (744 mg, 1 eq) were stirred at room temperature in 50 mL of ethanol for 18 h. The precipitate was removed by filtration to yield expected compound as a yellow powder (925 mg, 74% yield).