Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[NH:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=O)[CH:5]=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=O.O=P(Cl)(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:24]2[N:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]=2)[CH:5]=[C:6]([C:7]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=2)[CH:23]=1
Reactant: O=C(Nc1ccccc1Nc1ccccc1)c1cc(Br)cc(C(=O)Nc2ccccc2Nc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O=P(Cl)(Cl)Cl
Product: Brc1cc(-c2nc3ccccc3n2-c2ccccc2)cc(-c2nc3ccccc3n2-c2ccccc2)c1
Temperature: 100 °C
Yield: 67.1 %

Procedure:
To a suspension of Compound 6 (30 g, 52 mmol) in anhydrous 1,4-dioxane (300 mL), POCl3 (30.6 g, 18.6 mL, 200 mmol) was added slowly with water bath cooling. The resulting mixture was then maintained at 100° C. After cooling to room temperature, the mixture was poured into ice (ca. 300 g) and neutralized with Na2CO3, followed by extraction with CH2Cl2 (2×300 mL). The organic phase was then washed with brine, dried over Na2SO4 and concentrated in vacuo. To the mixture, acetonitrile (300 mL) was added and stirred, then filtered. The solid was collected and recrystallized in CH2Cl2/hexane to afford a white solid (18.9 g). The filtrant was purified by flash chromatography (SiO2, 100% hexanes to 9:1 to 4:1-hexanes/ethyl acetate). The main fraction was collected and concentrated to give additional product, white solid (5.17 g). Total amount is 24.1 g (86%): confirmed by LCMS (APCI): calculated for C32H21BrN4 (M+): 541; Found: 541.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24]>CN1CCCC1=O>[O:24]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1=[O:25]
Reactant: O=C(O)CCCCC/C=C\CCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: O=C1CCCCC/C=C\CCCCCCCCO1
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=C1CCCCCC=CCCCCCCCCO1

Procedure:
41 g of potassium carbonate were suspended in 600 ml of N-methyl-pyrrolidone. A solution of 51 g (0.15 mol) of 7Z-16-bromohexadec-7-enoic acid in 400 ml of N-methylpyrrolidone was added dropwise at 90° C. within 8 hours. After usual work up and chromatography 30 g (77%) of 8Z-oxacycloheptadec-8-en-2-one were obtained having the following characteristics: Z/E=90/10;
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=2)=[CH:3][CH:2]=1.CCN(CC)CC.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[C:54]1([S:60]([NH:63][C@@H:64]([CH2:68][NH2:69])[C:65]([OH:67])=[O:66])(=[O:62])=[O:61])[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>CN(C=O)C>[N:1]1[CH:2]=[CH:3][C:4]([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([C:15]([NH:69][CH2:68][C@H:64]([NH:63][S:60]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)(=[O:62])=[O:61])[C:65]([OH:67])=[O:66])=[O:17])=[CH:18][CH:19]=2)=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccc(OCCCc2ccncc2)cc1
Reactant: NC[C@H](NS(=O)(=O)c1ccccc1)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NC[C@H](NS(=O)(=O)c1ccccc1)C(=O)O)c1ccc(OCCCc2ccncc2)cc1
Reaction time: 3 h
Yield: 106.1 %

Procedure:
A solution of 19-5 (200 mg, 0.78 mmol), NEt3 (0.22 mL, 1.5 mmol), and DMF (4 mL) at ambient temperature was treated with BOP (345 mg, 0.78 mmol). After 3.0 h, NEt3 (0.22 mL, 1.5 mmol) and 19-2 (190 mg, 0.78 mmol) were added. After 20 h, the reaction mixture was concentrated and subjected to flash chromatography (silica, 10/1/1 CH2Cl2 /CH3OH/AcOH) to give impure 19-6 (400 mg). Prep HPLC purification (Delta Pak C-18Å column, 0 to 100% CH3CN/H2O containing 0.1% trifluoroacetic acid) gave pure 19-6 as a whim solid after lyophilization. Rf 0.74 (silica, 10/1/1 CH2Cl2 /CH3OH/AcOH).
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:11]([S:21][CH3:22])=[N:12][N:13]3[C:18](=O)[NH:17][C:16]([CH3:20])=[N:15][C:14]=23)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26][CH2:27][NH2:28]>>[C:1]1([S:7]([C:10]2[C:11]([S:21][CH3:22])=[N:12][N:13]3[C:18]([CH:27]([NH2:28])[CH2:26][CH2:25][N:24]([CH3:29])[CH3:23])=[N:17][C:16]([CH3:20])=[N:15][C:14]=23)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CSc1nn2c(=O)[nH]c(C)nc2c1S(=O)(=O)c1ccccc1
Reactant: CN(C)CCCN
Product: CSc1nn2c(C(N)CCN(C)C)nc(C)nc2c1S(=O)(=O)c1ccccc1

Procedure:
In an analogous manner to that described in Example 123 b), from 8-benzenesulphonyl-2-methyl-7-methylsulphanyl-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one and 3-dimethylamino-1-propylamine there was obtained (8-benzenesulphonyl-2-methyl-7-methylsulphanyl-pyrazolo[1,5-a][1,3,5]triazin-4-yl)-N′,N′-dimethyl-propan-1,3-diamine which was converted with HCl/diethyl ether into the corresponding hydrochloride (1:1.75), m.p. 249-250°.
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[C:20]3[N:19]=[CH:18][N:17]=[C:15]([NH2:16])[C:14]=3[N:13]=[CH:12]2)[C@H:8]([OH:21])[C@@H:7]1Br)(=[O:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.[Pd]>[C:1]([O:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[C:20]3[N:19]=[CH:18][N:17]=[C:15]([NH2:16])[C:14]=3[N:13]=[CH:12]2)[C@H:8]([OH:21])[CH2:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1Br
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)OC[C@@H]1C[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.5 %

Procedure:
After 5 g of 5'-O-acetyl-3'-deoxy-3'-bromoadenosine (X) was dissolved in 100 ml of acetonitrile, 1.71 g of sodium carbonate (dissolved in 10 ml of water) and 1.5 g of Pd/C were added to the solution. The mixture was stirred at room temperature for 2 hours under hydrogen atmosphere of 3.5 atms. The reaction solution was filtered and the residue was washed with ethyl acetate. The filtrate was combined with the washing liquid. After the organic solvent was distilled off under reduced pressure, the formed crystals were taken out by filtration. The crystals were dissolved in 200 ml of ethyl acetate. The solution was dried over magnesium sulfate and the drying agent was removed. The system was concentrated to give 2.7 g (yield, 69%) of 3'-deoxy-5'-O-acetyladenosine (XII).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[CH3:17])=[C:6]([NH:18][C:19](=O)[CH2:20][C:21]2[S:25][CH:24]=[N:23][CH:22]=2)[CH:5]=1.Cl>O1CCOCC1>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:10]([C@@H:11]3[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]3[CH3:17])[C:19]([CH2:20][C:21]3[S:25][CH:24]=[N:23][CH:22]=3)=[N:18][C:6]=2[CH:5]=1)=[O:27]
Reactant: COC(=O)c1ccc(N[C@@H]2CCCC[C@H]2C)c(NC(=O)Cc2cncs2)c1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(c1)nc(Cc1cncs1)n2[C@@H]1CCCC[C@H]1C
Yield: 30.8 %

Procedure:
To 1.26 g 4-((1R,2R)-2-Methyl-cyclohexylamino)-3-(2-thiazol-5-yl-acetylamino)-benzoic acid methyl ester in 10 ml dioxane were added 12 ml of 4M hydrochloric acid in dioxane and the mixture was heated to reflux for 2 h. The reaction was concentrated and the residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and brine. The organic layers were dried over sodium sulphate and concentrated. The resulting residue was purified by HPLC to yield 0.37 g (31%) of 1-((1R,2R)-2-Methyl-cyclohexyl)-2-thiazol-5-ylmethyl-1H-benzoimidazole-5-carboxylic acid methyl ester.
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[N:13]([OH:18])[C:12]([CH3:20])([CH3:19])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([O:25][CH:26]1[CH2:31][C:30]([CH3:33])([CH3:32])[N:29]([O:34][CH3:35])[C:28]([CH3:37])([CH3:36])[CH2:27]1)(=[O:24])[CH:22]=[CH2:23]>>[C:1]([O:9][CH:10]1[CH2:11][C:12]([CH3:20])([CH3:19])[N:13]([O:18][CH2:23][CH2:22][C:21]([O:25][CH:26]2[CH2:27][C:28]([CH3:36])([CH3:37])[N:29]([O:34][CH3:35])[C:30]([CH3:32])([CH3:33])[CH2:31]2)=[O:24])[C:14]([CH3:16])([CH3:17])[CH2:15]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Reactant: C=CC(=O)OC1CC(C)(C)N(OC)C(C)(C)C1
Product: CON1C(C)(C)CC(OC(=O)CCON2C(C)(C)CC(OC(=O)c3ccccc3)CC2(C)C)CC1(C)C
Yield: 50 %

Procedure:
The title compound is prepared in 50% yield as a colorless syrup from 4-benzoyloxy-1-oxyl-2,2,6,6-tetramethylpiperidine and 1-methoxy-2,2,6,6-tetramethylpiperidin-4-yl acrylate following the general procedure of Example 12.
Reaction SMILES: Cl.Cl.[C:3]([N:6]1[CH2:11][CH2:10][N:9]([NH2:12])[CH2:8][CH2:7]1)(=[O:5])[CH3:4].[F:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.C(N(CC)CC)C>ClCCl>[C:3]([N:6]1[CH2:11][CH2:10][N:9]([NH:12][S:20]([C:17]2[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=2)(=[O:22])=[O:21])[CH2:8][CH2:7]1)(=[O:5])[CH3:4]
Reactant: CC(=O)N1CCN(N)CC1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(NS(=O)(=O)c2ccc(F)cc2)CC1
Yield: 47.8 %

Procedure:
To a mixture of 1-acetyl-4-aminopiperazine dihydrochloride (540 mg) and 4-fluorobenzenesulfonyl chloride (535 mg) in dichloromethane (5 ml) was added triethylamine (1.2 ml) in a few minutes with stirring in an ice bath. After stirring for half an hour at the same temperature, the mixture was washed with brine, dried, and concentrated in vacuo. The residue was crystallized from ethanol and recrystallized from a mixture of ethanol and diethyl ether to Yield N-(4-acetyl-1-piperazinyl)-4-fluorobenzenesulfonamide (360 mg) as white crystals.
Reaction SMILES: Cl[CH:2]([C:13]1[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1)=O.[NH2:21][C:22]1[CH2:26][CH2:25][CH2:24][N:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH3:12][S:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:21]=[C:22]3[CH2:26][CH2:25][CH2:24][N:23]3[C:2]=2[C:13]2[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: CSc1ccc(C(=O)C(Cl)c2ccc(SC)cc2)cc1
Reactant: NC1=NCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ccc(-c2nc3n(c2-c2ccc(SC)cc2)CCC3)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To 9.0 g (0.028 mol) of 2-chloro-1,2-di(4-methylthiophenyl)ethanone in 50 ml of dry N,N-dimethylformamide was added 7.0 g (0.084 mol) of 2-amino-4,5-dihydro-3H-pyrrole. The mixture was stirred for 48 hours at ambient temperature, then poured into 1 liter of ice containing 300 ml of 5% aqueous sodium carbonate solution. The precipitate was collected by filtration and dissolved in methylene chloride. The solution was washed with water, dried (K2CO3) and evaporated to give a residue which was chromatographed on alumina and eluted with methylene chloride-methanol (95:5) to give the title compound, m.p. 127°-128°.
Reaction SMILES: [CH2:1]([C:4]1[C:19]([OH:20])=[C:18]([N+:21]([O-:23])=[O:22])[CH:17]=[CH:16][C:5]=1[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[CH:2]=[CH2:3].ClC1C=CC=C(C(OO)=[O:32])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCCl>[OH:32][CH2:3][CH:2]1[CH2:1][C:4]2=[C:5]([C:6]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:7])[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[C:19]2[O:20]1
Reactant: C=CCc1c(C(=O)OCc2ccccc2)ccc([N+](=O)[O-])c1O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCCl
Product: O=C(OCc1ccccc1)c1ccc([N+](=O)[O-])c2c1CC(CO)O2
Temperature: 70 °C
Reaction time: 3 h
Yield: 30.4 %

Procedure:
Benzyl 2-allyl-3-hydroxy-4-nitro-benzoate 29c (1.36 g, 4.30 mmol) was dissolved in 100 mL of 1,2-dichloroethane followed by the addition of m-chloroperbenzoic acid (1.18 g, 4.77 mmol). The reaction solution was heated to 70° C. and stirred for 3 hours. The resulting solution was cooled down to room temperature, added with 20 mL of saturated sodium thiosulfate solution, stirred for 30 minutes and extracted with ethyl acetate (20 mL×3). The combined organic phase was washed with water (20 mL), saturated sodium chloride solution (20 mL) successively, then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound benzyl 2-(hydroxymethyl)-7-nitro-2,3-dihydrobenzofuran-4-carboxylate 29d (430 mg, yield: 30.1%) as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]([CH3:12])=[N:7][CH:6]=[CH:5][C:4]=2[C:3]=1[NH2:13].[F:14][C:15]([F:27])([F:26])[C:16]1[CH:25]=[CH:24][C:19]([CH2:20][N:21]=[C:22]=[O:23])=[CH:18][CH:17]=1>>[F:1][C:2]1[C:3]([NH:13][C:22]([NH:21][CH2:20][C:19]2[CH:18]=[CH:17][C:16]([C:15]([F:14])([F:27])[F:26])=[CH:25][CH:24]=2)=[O:23])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:12])=[N:7][CH:6]=[CH:5]2
Reactant: Cc1nccc2c(N)c(F)ccc12
Reactant: O=C=NCc1ccc(C(F)(F)F)cc1
Product: Cc1nccc2c(NC(=O)NCc3ccc(C(F)(F)F)cc3)c(F)ccc12

Procedure:
Prepared from 6-fluoro-1-methylisoquinolin-5-amine (Description 103) and [4-(trifluoromethyl)benzyl]isocyanate (description 58) according to the procedure of description 61. m/z (ES+) 378 (M+H)+.
Reaction SMILES: [O:1]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:22][C:23]([CH3:29])([CH2:27][CH3:28])[C:24](Cl)=[O:25]>>[CH3:22][C:23]([CH3:29])([CH2:27][CH3:28])[C:24]([N:4]1[CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][N:16]([C:24](=[O:25])[C:23]([CH3:29])([CH3:22])[CH2:27][CH3:28])[CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:1][CH2:2][CH2:3]1)=[O:25]
Reactant: C1COCCOCCNCCOCCOCCOCCN1
Reactant: CCC(C)(C)C(=O)Cl
Product: CCC(C)(C)C(=O)N1CCOCCOCCOCCN(C(=O)C(C)(C)CC)CCOCCOCC1

Procedure:
Analogously to Example 2 from 1,7,10,13,19-pentaoxa-4,16-diazacycloheneicosane and 2,2-dimethylbutyryl chloride. Example 30
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([C:16]#[C:17][C:18]3[CH:19]=[N:20][C:21]([NH2:24])=[CH:22][CH:23]=3)=[C:14]([CH2:25][CH3:26])[N:13]=[C:12]([NH2:27])[N:11]=2)=[CH:6][C:5]=1[Cl:28]>C1COCC1>[NH2:27][C:12]1[N:11]=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:29])=[O:2])=[C:5]([Cl:28])[CH:6]=2)[C:15]([C:16]#[C:17][C:18]2[CH:19]=[N:20][C:21]([NH2:24])=[CH:22][CH:23]=2)=[C:14]([CH2:25][CH3:26])[N:13]=1
Reactant: CCc1nc(N)nc(-c2ccc(C(=O)OC)c(Cl)c2)c1C#Cc1ccc(N)nc1
Solvent: C1CCOC1
Product: CCc1nc(N)nc(-c2ccc(C(=O)O)c(Cl)c2)c1C#Cc1ccc(N)nc1

Procedure:
The title compound is synthesized according to general procedure GP8 starting from 951 mg (2.3 mmol) 4-[2-amino-5-(6-amino-pyridin-3-ylethynyl)-6-ethyl-pyrimidin-4-yl]-2-chloro-benzoic acid methyl ester using 3.5 mL (3.5 mmol) 1 N NaOH in 16 mL THF. The product precipitates from the reaction mixture and is isolated by filtration. The product is washed with THF and diethylether. Yield: 345 mg (38%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([OH:20])=[O:19].[CH2:21](I)[CH3:22]>CN(C)C=O>[NH2:1][C:2]1[C:7]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: Nc1c(CC(=O)O)cccc1C(=O)c1ccc(Br)cc1
Reactant: CCI
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cccc(C(=O)c2ccc(Br)cc2)c1N
Temperature: 25 °C
Reaction time: 24 h
Yield: 74 %

Procedure:
A slurry of 35.6 g (0.1 mole) of 2-amino-3-(4-bromobenzoyl)benzeneacetic acid in 500 ml of dimethylformamide was treated with 32.0 g (0.2 mole) of ethyl iodide and stirred at ambient temperature for 24 hours. The mixture was filtered and the filtrate was poured into 3.5 liters of water. The solid which precipitated was collected by filtration, washed with water and recrystallized from absolute ethanol to give 26.8 g (74%) of title compound, gold needles, m.p. 107°-109° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]#[C:9][CH3:10])[CH:7]=1.[B:11](OC(C)C)([O:16]C(C)C)[O:12]C(C)C.[Li]CCCC.Cl>C1(C)C=CC=CC=1>[C:8]([C:6]1[CH:7]=[C:2]([B:11]([OH:16])[OH:12])[CH:3]=[N:4][CH:5]=1)#[C:9][CH3:10]
Reactant: CC#Cc1cncc(Br)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: CC#Cc1cncc(B(O)O)c1
Temperature: -50 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
3-Bromo-5-(prop-1-ynyl)pyridine (Intermediate 24, 25 g, 117 mmol), 2-Me THF (60 mL), toluene (200 mL) and triisopropyl borate (33.2 mL, 140.78 mmol) were mixed. The mixture was cooled to −50° C. To the cold mixture was added n-BuLi (59.8 mL, 149.5 mmol) dropwise during 30 min. The mixture was stirred for 60 min. at −50° C. 2M HCl aq. (100 mL) was added. The mixture was then allowed to reach r.t. and stirred for 20 min. The organic and water phase were separated. The organic phase was extracted with NaOH (2M aq.) (2×100 mL). The water phases were combined and the pH was adjusted to pH 5. The product was extracted with 2-methyl-THF (2×100 mL). The organic phase was dried with Na2SO4, filtered and concentrated to give the title compound (16.47 g, 87% yield): 1H NMR (500 MHz, CD3OD) δ ppm 2.11 (s, 3 H) 8.21 (br. s., 1 H) 8.53 (m, 2 H); MS (APCI+) m/z 162.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:11][CH:12]=O)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[CH3:14][C:15]1[C:20]([NH2:21])=[CH:19][CH:18]=[C:17]([N:22]2[CH2:26][CH2:25][C@@H:24]([N:27]3[CH2:31][CH2:30][CH2:29][C@@H:28]3[CH3:32])[CH2:23]2)[N:16]=1>>[CH3:1][O:2][C:3]([C:5]1([CH2:11][CH2:12][NH:21][C:20]2[C:15]([CH3:14])=[N:16][C:17]([N:22]3[CH2:26][CH2:25][C@@H:24]([N:27]4[CH2:31][CH2:30][CH2:29][C@@H:28]4[CH3:32])[CH2:23]3)=[CH:18][CH:19]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(CC=O)CCCCC1
Reactant: Cc1nc(N2CC[C@@H](N3CCC[C@@H]3C)C2)ccc1N
Product: COC(=O)C1(CCNc2ccc(N3CC[C@@H](N4CCC[C@@H]4C)C3)nc2C)CCCCC1

Procedure:
The title compound was synthesized in essentially the same manner using the procedures as set forth in Step 1 of Example 1, by condensing 1-(2-oxo-ethyl)-cyclohexanecarboxylic acid methyl ester (41 mg, 0.22 mmol) and 2-methyl-6-((2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-ylamine to obtain 94 mg of a crude solid, which was used in the next step of the reaction without further purification.
Reaction SMILES: [NH:1]1[C:8](=[O:9])[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].S(=O)(=O)(O)O.[CH3:15]O>>[OH:3][C:2]1[N:4]=[C:5]([OH:6])[CH:7]=[C:8]([O:9][CH3:15])[N:1]=1
Reactant: O=C1CC(=O)NC(=O)N1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COc1cc(O)nc(O)n1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a suspension of barbituric acid (51.2 g) in methanol (1 L) was added concentrated sulfuric acid (80 mL) in a dropwise manner over 20 minutes, and the mixture was stirred at room temperature for 22 hours. The crystals were collected by filtration. The collected crystals were washed with methanol, cold water and diethyl ether successively, and dried under reduced pressure to give 2,4-dihydroxy-6-methoxypyrimidine (52.9 g). To a mixture of fuming nitric acid (20 mL) and concentrated sulfuric acid (10 mL) was added 2,4-dihydroxy-6-methoxypyrimidine (14.2 g) slowly at around 15° C., and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added ice water (150 mL), and the mixture was stirred at room temperature for 30 minutes. The crystals were collected by filtration. The collected crystals were washed with water, and dried under reduced pressure to give the title compound (7.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([CH2:12][N:13]3[CH2:17][CH2:16][C@H:15]([NH:18][S:19]([C:22]4[CH:31]=[CH:30][C:29]5[C:24](=[CH:25][C:26]([O:32][CH3:33])=[CH:27][CH:28]=5)[CH:23]=4)(=[O:21])=[O:20])[C:14]3=[O:34])=[CH:7][CH:8]=2)[N:3]=1.[CH3:35]I.[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([CH2:12][N:13]3[CH2:17][CH2:16][C@H:15]([N:18]([CH3:35])[S:19]([C:22]4[CH:31]=[CH:30][C:29]5[C:24](=[CH:25][C:26]([O:32][CH3:33])=[CH:27][CH:28]=5)[CH:23]=4)(=[O:20])=[O:21])[C:14]3=[O:34])=[CH:7][CH:8]=2)[N:3]=1
Reactant: CI
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4ccc5ccc(Cl)nc5c4)C3=O)cc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2ccc(S(=O)(=O)N(C)[C@H]3CCN(Cc4ccc5ccc(Cl)nc5c4)C3=O)cc2c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 87.7 %

Procedure:
7-Methoxynaphthalene-2-sulfonic acid [1-(2-chloro-quinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide (0.4 g, 0.81 mmol), prepared as in EXAMPLE 15, Part F, is dissolved in DMF (20 mL) and cooled to 0° C. To the solution is added methyl iodide (0.28 g, 2.01 mmol) and sodium hydride (34 mg, 0.85 mmol, 60% mineral oil dispersion). The ice water bath is removed and the mixture is stirred at room temperature for 3 hours. The resulting solution is poured into a separatory funnel and diluted with EtOAc (100 mL). The organic layer is washed with 1N HCl, H2O and saturated NaCl. The organic phase is then dried over MgSO4, filtered and concentrated. The crude residue is purified by column chromatography eluting with 10% EtOAc/CH2Cl2 to give the title compound (0.36 g, 0.71 mmol) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1.BrC1C=CC=C2C=1C=CN=C2.[ClH:23].BrC1C=CC=C2C=1C=C[N+]([O-:35])=C2>>[ClH:23].[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N+:8]([O-:35])=[CH:9]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc2ccncc2c1
Reactant: [O-][n+]1ccc2c(Br)cccc2c1
Agent: Brc1cccc2cnccc12
Agent: Cl
Product: [O-][n+]1ccc2ccc(Br)cc2c1

Procedure:
Compound 37a was prepared from 7-bromoisoquinoline (Tyson, F. L., J. Am. Chem. Soc. 61, 183 (1939), this procedure gave a mixture of 7-bromoisoquinoline and 5-bromoisoquinoline) using the procedure described for 1a. The title compound was contaminated with the 5-bromoisoquinoline N-oxide hydrochloride. M.p. 107.0-112.5° C.
Reaction SMILES: [CH2:1]([CH:4]([CH2:14][CH2:15][CH3:16])[CH2:5][CH2:6][CH2:7][CH:8]1[CH2:13][O:12][CH2:11][CH2:10][NH:9]1)[CH2:2][CH3:3].[CH2:17]1[O:20][CH2:19][CH2:18]1>C(O)C>[CH2:14]([CH:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH:8]1[CH2:13][O:12][CH2:11][CH2:10][N:9]1[CH2:17][CH2:18][CH2:19][OH:20])[CH2:15][CH3:16]
Reactant: CCCC(CCC)CCCC1COCCN1
Reactant: C1COC1
Solvent: CCO
Product: CCCC(CCC)CCCC1COCCN1CCCO
Yield: 86.2 %

Procedure:
A mixture of 22.7 grams (0.1 mole) of 3-(4-propyl-heptyl)morpholine, 6.4 grams (0.11 moles) trimethyleneoxide and 150 ml. 96% ethanol was kept at 150°-200° C. for 15 hours in an autoclave. Distillation of the reaction mixture gave 24.6 g (86%) of 3-(4-propyl-heptyl)-4-(3-hydroxypropyl)morpholine), boiling point 122°-124° C./0.01 mm Hg.
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH2:7][C:8](=[O:14])[NH:9][C:10]3[CH:11]=[CH:12][CH:13]=[C:4]([C:5]=32)[N:3]1[CH2:15][C:16]([O:18]C)=[O:17].[OH-].[Na+:21].Cl>CO.CC#N>[O:1]=[C:2]1[N:6]2[CH2:7][C:8](=[O:14])[NH:9][C:10]3[CH:11]=[CH:12][CH:13]=[C:4]([C:5]=32)[N:3]1[CH2:15][C:16]([O-:18])=[O:17].[Na+:21]
Reactant: COC(=O)Cn1c(=O)n2c3c(cccc31)NC(=O)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC#N
Product: O=C([O-])Cn1c(=O)n2c3c(cccc31)NC(=O)C2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl (2,5-dioxo-5,6-dihydro-4H-imidazo[1,5,4-de]quinoxalin-1(2H)-yl)acetate from Step C (367 mg, 1.40 mmol) in MeOH (40 mL) and CH3CN (5 mL) was added 1.0 N sodium hydroxide (2.82 mL, 2.82 mmol) and the reaction mixture was stirred at room temperature for 18 h. The mixture was neutralized with 1 N aqueous HCl and concentrated in vacuo to give the title compound. MS: m/z=248 (M+1).