Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]1=[O:11].[OH:13][C:14]1([CH2:27][SH:28])[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.C(N(CC)CC)C>C(#N)C>[O:11]=[C:2]1[C:1](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([S:28][CH2:27][C:14]2([OH:13])[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:18][CH2:19]2)=[CH:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CS)CC1
Reactant: O=C1C=Cc2ccccc2C1=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(O)(CSC2=CC(=O)C(=O)c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 294.5 %

Procedure:
To a solution of naphthalene-1,2-dione (3.2 g, 2.02 mmol) and tert-butyl 4-hydroxy-4-(mercaptomethyl)piperidine-1-carboxylate (5.0 g, 2.02 mmol) in anhydrous acetonitrile (400 ml) was added triethylamine (2.82 ml, 2.02 mmol). The reaction mixture was allowed to stir for 1 hour at room temperature and the solvents were evaporated under reduced pressure. The crude product was purified by flash column chromatography (SiO2, 40% EtOAc in hexanes to 70% EtOAc in hexanes). Fractions containing the product were concentrated and tritrated with ethyl acetate/ether to afford the desired product as a red solid (2.4 g, 29%). M.p.=156-157° C.; 400 MHz 1H NMR (CDCl3) δ: 8.17-8.12 (m, 1H), 7.87-7.83 (m, 1H), 7.69-7.62 (m, 1H), 7.59-7.52 (m, 1H), 6.49 (s, 1H), 4.0-3.85 (m, 2H), 3.25-3.14 (m, 4H), 1.84-1.78 (m, 2H), 1.76-1.66 (m, 2H), 1.47 (s, 9H); LCMS: 404 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([OH:9])[CH:6]=[C:5]([OH:10])[N:4]=1.S(OCC)(O[CH2:15][CH3:16])(=O)=O>[OH-].[Na+]>[CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH2:15][CH3:16])[CH:6]=[C:5]([OH:10])[N:4]=1
Reactant: CCOS(=O)(=O)OCC
Reactant: COc1nc(O)cc(O)n1
Agent: [Na+]
Agent: [OH-]
Product: CCOc1cc(O)nc(OC)n1

Procedure:
14.2 g (0.1 mol) of 2-methoxy-4,6-dihydroxypyrimidine are added while stirring to 50 cc of 2N sodium hydroxide solution 2N and the mixture is stirred for half an hour with heating to 50°. 17.0 g (0.11 mol) of diethyl sulphate are subsequently added dropwise, over the course of 20 minutes and with stirring; by adding 2N sodium hydroxide solution the pH value should, if possible, be kept at between 8 and 8.2. The mixture is then stirred at 50°, 2N sodium hydroxide solution is added from time to time until the pH remains constant (after approximately 3 hours). The reaction mixture is subsequently cooled to 0°, the precipitate is suction filtered and washed with a small quantity of ethanol. After drying in a high vacuum at 80°, the substance has a M.P. of 192°-194°.
Reaction SMILES: [CH:1]1([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28][CH2:29][C@@H:30]([C:32]3[CH:43]=[CH:42][C:35]4[O:36][C:37](C)([CH3:40])[O:38][CH2:39][C:34]=4[CH:33]=3)[OH:31])[CH:12]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)(=O)C.O>[C:37]([OH:38])(=[O:36])[CH3:40].[C:37]([OH:38])(=[O:36])[CH3:40].[C:37]([OH:38])(=[O:36])[CH3:40].[CH:1]1([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28][CH2:29][C@H:30]([OH:31])[C:32]3[CH:43]=[CH:42][C:35]([OH:36])=[C:34]([CH2:39][OH:38])[CH:33]=3)[CH:12]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC1(C)OCc2cc([C@@H](O)CNCCCCCCOCCOCc3cccc(NC(=O)NC4CCCCC4)c3)ccc2O1
Solvent: O
Solvent: CC(=O)O
Product: O=C(Nc1cccc(COCCOCCCCCCNC[C@H](O)c2ccc(O)c(CO)c2)c1)NC1CCCCC1
Temperature: 25 °C
Yield: 295.9 %

Procedure:
A solution of N-cyclohexyl-N′-[3-({2-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]ethoxy}methyl)phenyl]urea (0.138 g) in acetic acid (4 ml) and water (1 ml) were stirred under nitrogen at 70° C. for 45 min. The reaction mixture was cooled to room temperature before concentrating under vacuum and azeotroping with MeOH (3×10 ml) to give a residue which was purified by Biotage. Elution with 50:8:1 dichloromethane:EtOH:ammonia followed by solvent evaporation in vacuo gave the title compound (0.126 g). LCMS RT=2.65 min, ES+ve 558 (MH)+.
Reaction SMILES: CO[C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[CH3:24][N:25]([CH3:27])[NH2:26]>>[CH3:24][N:25]([CH3:27])[NH:26][C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4]
Reactant: CN(C)N
Reactant: COC(=O)c1cc(OCc2c(-c3ccccc3)noc2C)n[nH]1
Product: Cc1onc(-c2ccccc2)c1COc1cc(C(=O)NN(C)C)[nH]n1
Yield: 24 %

Procedure:
As described for example 1b, 5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.32 mmol) was converted, using N,N-dimethylhydrazine instead of morpholine, to the title compound (26 mg, 24%), which was obtained as a white solid. MS: m/e=342.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:19][C:20]2[CH:25]=[C:24]([CH3:26])[N:23]=[C:22](Cl)[CH:21]=2)([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH2:19][C:20]2[CH:21]=[CH:22][N:23]=[C:24]([CH3:26])[CH:25]=2)([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CCOC(=O)C1(Cc2cc(C)nc(Cl)c2)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)C1(Cc2ccnc(C)c2)CCN(C(=O)OC(C)(C)C)CC1

Procedure:
A mixture of ethyl N-tert-butoxycarbonyl-4-(2-chloro-6-methylpyridin-4-ylmethyl)piperidine-4-carboxylate (0.32 g, 0.81 mmol) and 5% palladium on charcoal (60 mg) in methanol (10 mL) was stirred under a balloon of hydrogen gas at room temp. for 3 h. The resultant mixture was filtered through a plug of Celite. The filtrate was concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 3-5% methanol in chloroform gradient. Collection and concentration of appropriate fractions provided the title compound.
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:17][N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:3]=1.[S:27]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28]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>[Cl:16][C:12]1[CH:11]=[C:10]([S:7]([N:6]2[C:2]([C:29]3[CH:30]=[CH:31][S:27][CH:28]=3)=[CH:3][C:4]([CH2:17][N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:5]2)(=[O:9])=[O:8])[CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)c1ccsc1
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccc(Cl)c2)c1)C(=O)OC(C)(C)C
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+]
Product: CN(Cc1cc(-c2ccsc2)n(S(=O)(=O)c2cccc(Cl)c2)c1)C(=O)OC(C)(C)C
Yield: 70.7 %

Procedure:
Using tert-butyl ({5-bromo-1-[(3-chlorophenyl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (1 g), 3-thienylboronic acid (553 mg), sodium carbonate (687 mg) and tetrakis(triphenylphosphine)palladium (374 mg), a procedure as in Reference Example 56 was performed to give the title compound as a pale-yellow oil (yield 712 mg, 71%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[F:9][C:10]([F:25])([F:24])[CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[CH:23]=[CH:22][CH:21]=[N:20]1)[OH:12].[H-].[Na+]>C1COCC1>[Cl:8][C:6]1[CH:7]=[C:2]([O:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:19]2[CH:23]=[CH:22][CH:21]=[N:20]2)[C:10]([F:9])([F:25])[F:24])[N:3]=[CH:4][N:5]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: OC(c1ccccc1-n1cccn1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: FC(F)(F)C(Oc1cc(Cl)ncn1)c1ccccc1-n1cccn1
Temperature: 42.5 °C
Reaction time: 6 h
Yield: 112.8 %

Procedure:
4,6-Dichloro pyrimidine (0.082 g, 0.55 mmol), 2,2,2-trifluoro-1-(2-pyrazol-1-yl-phenyl)-ethanol (0.121 g, 0.50 mmol), NaH (0.03 g, 0.78 mmol) were added to anhydrous THF (10 ml) under nitrogen atmosphere. The reaction was stirred at 40-45° C. for 6 h, and then was cooled to room temperature, and quenched with water (0.2 ml). The reaction mixture was concentrated to give crude 4-chloro-6-[2,2,2-trifluoro-1-(2-pyrazol-1-yl-phenyl)-ethoxy]-pyrimidine (0.20 g, >90% pure by LCMS), which was directly used in the following step.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[C:12]([N+:14]([O-])=O)[C:11](=[O:17])[N:10]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.[Pd]>[NH2:14][C:12]1[C:11](=[O:17])[N:10]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:9](=[O:23])[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:13]=1
Reactant: [H][H]
Reactant: COC(=O)Cn1c(=O)c([N+](=O)[O-])cn(Cc2ccccc2)c1=O
Agent: [Pd]
Solvent: CO
Product: COC(=O)Cn1c(=O)c(N)cn(Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 63 %

Procedure:
EX-1B) A solution of 1-Benzyl-3-methoxycarbonylmethyl-5-nitro-2,4(1H,3H)pyrimidinedione (EX-1A; 6.30 g, 19.74 mmol) in 100.0 mL methanol was degassed with hydrogen gas. The solution was then added 5% Pd/C (0.737 g) and allowed to stir under an atmosphere of hydrogen at room temperature for 24 hours. The crude reaction was filtered through a pad of Celite 545 and concentrated under reduced pressure. The oil was purified by MPLC (60% Ethyl acetate/hexanes) to give pure 5-amino-1-Benzyl-3-methoxycarbonylmethyl-2,4(1H,3H)-pyrimidinedione (EX-1B) in 63% yield as a tan solid: 1H NMR (300 MHz, DMSO) δ 7.41-7.28 (m, 5H), 6.93 (s, 1H), 4.93 (s, 2H), 4.66 (s, 2H), 4.32 (s, 2H), 3.69 (s, 3H); HRMS (ES) calcd for C14H6N3O4 290.1141, found 290.1138.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[NH:16][C:15](=[O:17])[O:14][C:13]([CH3:19])([CH3:18])[C:12]=2[CH:20]=1.[Cl:21][C:22]1[CH:23]=[C:24]([SH:29])[CH:25]=[CH:26][C:27]=1[Cl:28]>>[Cl:21][C:22]1[CH:23]=[C:24]([S:29][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]3[NH:16][C:15](=[O:17])[O:14][C:13]([CH3:19])([CH3:18])[C:12]=3[CH:20]=2)[CH:25]=[CH:26][C:27]=1[Cl:28]
Reactant: Sc1ccc(Cl)c(Cl)c1
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCCBr)cc21
Product: CC1(C)OC(=O)Nc2ccc(OCCCCCSc3ccc(Cl)c(Cl)c3)cc21

Procedure:
Prepared analogously to Example 1 from 6-(5-bromopentoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 3,4-dichloro-thiophenol.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([N:20]1[CH2:25][CH2:24][CH:23]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[N+:31]([C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH:36]=[O:37])([O-:33])=[O:32]>O1CCCC1>[CH2:13]([N:20]1[CH2:25][CH2:24][CH:23]([CH:26]([CH:36]([OH:37])[C:35]2[CH:38]=[CH:39][CH:40]=[CH:41][C:34]=2[N+:31]([O-:33])=[O:32])[C:27]([O:29][CH3:30])=[O:28])[CH2:22][CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)CC1CCN(Cc2ccccc2)CC1
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C(C1CCN(Cc2ccccc2)CC1)C(O)c1ccccc1[N+](=O)[O-]
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 89 %

Procedure:
Diisopropylamine (3.50 mL, 24.9 mmol) was dissolved in tetrahydrofuran (30 mL). The mixture was cooled to −78° C. Butyllithium (2.5 M in pentane, 9.8 mL, 24.5 mmol) was added to the mixture dropwise, and the reaction stirred at −78° C. for 15 min. A solution of methyl 2-(1-benzylpiperidin-4-yl)acetate (5.50 g, 22.2 mmol) in THF (8 mL) was then added to the mixture dropwise over 20 minutes. The reaction was stirred at −78° C. for 45 minutes. A solution of 2-nitrobenzaldehyde (3.70 g, 24.5 mmol) in THF (5 mL) was then added to the mixture dropwise over 15 minutes. The reaction was stirred at −78° C. for 30 minutes and quenched by the addition of saturated aqueous ammonium chloride. The resulting mixture was warmed to room temperature, extracted with ethyl acetate (2×). The combined organics were dried (magnesium sulfate), filtered, and concentrated. Silica gel chromatography afforded the desired product in 89% yield as light yellow foam. Mass spec.: 399.3 (MH)+.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2].[Br:13]Br.S(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH:1]([C:4]1[C:12]([Br:13])=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2]
Reactant: BrBr
Reactant: CC(C)c1cc2ccccn2n1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)c1nn2ccccc2c1Br

Procedure:
To a solution of 50 g of 2-isopropylpyrazolo[1,5-a]pyridine in 300 ml of chloroform were added about 20 ml of bromine until the solution became faintly yellow under stirring and cooling to 5°-15° C. After the addition was completed, the mixture was stirred at room temperature for 30 minutes, then poured into aqueous 10% sodium bisulfite solution and extracted with chloroform. The chloroform layer was washed with aqueous 10% sodium hydroxide and then water, dried over anhydrous sodium sulfate, and concentrated in vacuo to give 75 g of crude 2-isopropyl-3-bromopyrazolo[1,5-a]pyridine, as colorless needles, mp 51°-52° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7](=[NH:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([Li])CCC.Cl[P:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CCCCC>[C:28]1([P:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:14]=[C:7]([NH:6][C:2]2[S:1][CH:5]=[CH:4][N:3]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: N=C(Nc1nccs1)c1ccccc1
Reactant: ClP(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: CCCCC
Product: c1ccc(C(=NP(c2ccccc2)c2ccccc2)Nc2nccs2)cc1
Yield: 26.8 %

Procedure:
Procedure as described for NP Amidine XVII using the following amounts: 3.06 g of N1-(thiazol-2-yl)benzamidine (Amidine XVI, 15.0 mmol), 7.50 mL of 2.0 M butyllithium (15.0 mmol), 0.93 mL of chlorodiphenylphosphine (15.0 mmol). Following removal of lithium chloride, the solvent was removed from the filtrate to give a sticky residue. The sticky residue was suspended in 100 mL of pentane. Vigorous stirring and scraping eventually yielded an off-white solid after 2 hours. The solid was collected and dried (2.59 g). The lithium chloride solid separated from reaction solution was extracted with 100 mL of diethylether, filtered, taken to dryness, and treated with 100 mL of pentane. Stirring and scraping produced white solid that was collected and dried yielding an additional 1.56 g of solid. Combined yield 4.15 g (71%).
Reaction SMILES: [CH:1]1([C:7]2[O:8][C:9]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[CH:10][C:11]=2[CH2:12][O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:33][NH:34][CH2:35][CH2:36][C:37]([O:39]CC)=[O:38]>>[CH:1]1([C:7]2[O:8][C:9]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:25][CH:24]=3)=[CH:10][C:11]=2[CH2:12][O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([N:34]([CH3:33])[CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:19])=[CH:16][CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(OCc2cc(-c3ccc(C(F)(F)F)cc3)oc2C2CCCCC2)cc1
Reactant: CCOC(=O)CCNC
Product: CN(CCC(=O)O)C(=O)c1ccc(OCc2cc(-c3ccc(C(F)(F)F)cc3)oc2C2CCCCC2)cc1
Yield: 95.3 %

Procedure:
An operation similar to that in Example 1 (4) was performed using 4-({2-cyclohexyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)benzoic acid (133 mg) as well as ethyl 3-(methylamino)propanoate (47 mg) to give the title compound (151 mg, 95%) as an amorphous compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:16]=[CH:15][C:14]2[N:13]3[CH2:17][CH2:18][NH:19][C:20](=O)[C:12]3=[C:11]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:10]=2[CH:9]=1.O>O1CCCC1>[Cl:7][C:8]1[CH:16]=[CH:15][C:14]2[N:13]3[CH2:17][CH2:18][NH:19][CH2:20][C:12]3=[C:11]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:10]=2[CH:9]=1
Reactant: O=C1NCCn2c1c(-c1ccccc1)c1cc(Cl)ccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Clc1ccc2c(c1)c(-c1ccccc1)c1n2CCNC1

Procedure:
To a stirred solution of lithium aluminum hydride (1 gram, 0.026 mole) in 20 ml dry tetrahydrofuran (THF) is added slowly a suspension of 1,2,3,4-tetrahydro-8-chloro-10-phenylpyrazino[1,2-a] indole-1-one (5.2 grams, 0.018 mole) in 40 ml of dry THF. This reaction mixture is stirred and refluxed for 8 hours after which it is cooled and decomposed by the slow addition of 3 ml of water. After stirring 1 hour the suspension is filtered. The filtercake is washed with isopropanol, THF, and acetone. The combined filtrate is taken to dryness and recrystallized from ethanol. The product is filtered off, washed with ether, and dried. The above titled product has a m.p. 163°-64° C. yield 4.5 grams (90%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.CN(C)C=O.[O:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][CH2:30][NH2:31])[CH2:24][CH2:23]1>CCOCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:31][CH2:30][CH2:29][CH2:28][N:25]1[CH2:26][CH2:27][O:22][CH2:23][CH2:24]1
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Reactant: NCCCN1CCOCC1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C1NC(=O)c2ccc(Br)cc2/C1=C/NCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
A mixture of 6-bromo-4-(methoxymethylene)-isoquinoline-1,3(2H,4H)-dione (70.5 mg, 0.25 mmole), dimethylformamide (2 mL) and 3-morpholinopropan-1-amine (36.1 mg, 0.25 mmole) is stirred at room temperature for one hour. The reaction mixture is diluted with ether, filtered and washed with fresh ether and dried to give a cream solid, 53.6 mg, (54% yield) MS (ES+): 394.2, (M+H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[CH:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:12]#[N:13].Cl.Cl[CH2:22][C:23]1[N:24]=[CH:25][NH:26][CH:27]=1>>[NH:26]1[CH:27]=[C:23]([CH2:22][C:11]([C:5]2[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:4]=2[Cl:3])([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:12]#[N:13])[N:24]=[CH:25]1
Reactant: ClCc1c[nH]cn1
Reactant: N#CC(c1ccccc1)c1ccc(Cl)cc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: N#CC(Cc1c[nH]cn1)(c1ccccc1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 64 h

Procedure:
According to the scheme of Example 1, 2.04 g. of 50% sodium hydride, 11.64 g. of 2-(2,4-dichlorophenyl)-2-phenylacetonitrile, and 3.06 g. of 4-chloromethylimidazole hydrochloride were reacted at about 60° C. for 2 hours. The reaction mixture was then allowed to cool to ambient temperature and was stirred for 64 hours. The solvent was then evaporated and the reaction mixture was worked up as described in Example 1. The product was converted to the hydrochloride salt, and crystallized from ethyl acetate/diethyl ether to obtain 6.86 g. of the hydrochloride salt of the product named in the heading above, m.p. 215°-218° C.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([N+:16]([O-:18])=[O:17])[CH:8]=1.O.[C:20](=O)([O-])[O-].[Na+].[Na+]>CO>[Br:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([O:13][CH3:20])=[O:12])=[C:9]([N+:16]([O-:18])=[O:17])[CH:8]=1
Reactant: O=C(O)c1ccc(Br)cc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(Br)cc1[N+](=O)[O-]

Procedure:
Add concentrated sulfuric acid (7 mL) to a solution of commercially available 4-bromo-2-nitrobenzoic acid (25.0 g, 102 mmol) in methanol (150 mL), and heat at reflux for 16 hours. Cool the reaction to room temperature and pour into water (500 mL) and adjust the pH of the suspension to 9 with solid sodium carbonate. Extract the solution with ethyl acetate (2×250 mL), then combine the organic extracts and wash with brine (100 mL), dry over sodium sulfate, filter and remove the solvent under reduced pressure to afford the title compound as a pale amber oil, which crystallizes upon standing (20.5 g, 78%)
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[N:20]=3)[CH:12]=2)[CH2:5][C:6]([O:8]CC)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+]>C1COCC1.CO>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[N:20]=3)[CH:12]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CC(c1cccc(COc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(F)c(-c2ccc(OCc3cccc(C(CC(=O)O)C4CC4)c3)nc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 93.2 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(3-(((5-(2-fluoro-5-methoxyphenyl)-6-neopentylpyridin-2-yl)oxy)methyl)phenyl)propanoate (379 mg) in THF (7.0 mL) and methanol (14 mL) was added 1N aqueous sodium hydroxide solution (7.3 mL), and the mixture was stirred at room temperature for 7 hr. The reaction mixture was concentrated under reduced pressure, and water and 1N hydrochloric acid were added. The reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (334 mg) as a colorless oil.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:6][CH:7]=1)=O.[CH3:13][NH:14][CH3:15].C([BH3-])#N.[Na+].O>CO>[CH3:13][N:14]([CH2:1][C:3]1[CH:4]=[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:6][CH:7]=1)[CH3:15]
Reactant: CCOC(=O)c1cc(C=O)c[nH]1
Reactant: CNC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)c1cc(CN(C)C)c[nH]1
Temperature: 20 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
To a mixture of ethyl 4-formylpyrrole-2-carboxylate (8.8 g, 52.7 mmol) and dimethylamine (2 M in THF, 40 mL, 1.5 equiv) in methanol (60 mL) was added sodium cyanoborohydride (3.3 g, 1 equiv) in portions and the mixture was stirred for 3 h at 20° C. Water was added and the mixture was extracted with EtOAc. The combined organic layer was washed with water and dried over Na2SO4. Evaporation of solvent afforded a crude, which was purified by column chromatography on silica gel, eluted with MeOH-DCM (1:9) to afford ethyl 4-dimethylaminomethyl-pyrrole-2-carboxylate as a solid (7.8 g, 76%). MS (ES): 392 (MH+) 197.