Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:30][C:31]2[CH:39]=[CH:38][C:34]3[O:35][CH2:36][O:37][C:33]=3[CH:32]=2)[C:7](=[O:29])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([NH:21]CC1C=CC=CC=1)=[CH:10][CH:9]=2)=[O:4].CO.[H][H]>[C].[Pd].C1COCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:30][C:31]2[CH:39]=[CH:38][C:34]3[O:35][CH2:36][O:37][C:33]=3[CH:32]=2)[C:7](=[O:29])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([NH2:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: [H][H]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(NCc3ccccc3)ccc2c(=O)n1Cc1ccc2c(c1)OCO2
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1c(-c2ccccc2)c2cc(N)ccc2c(=O)n1Cc1ccc2c(c1)OCO2
Yield: 72.3 %

Procedure:
A mixture of 2-(benzo[1,3]dioxol-5-ylmethyl)-6-benzylamino-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (670 mg), 10% palladium carbon (200 mg), methanol (10 ml) and THF (10 ml) was stirred at room temperature at 4-5 atm hydrogen pressure for 48 hrs. Palladium carbon was filtered off and the filtrate was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized (ethyl acetate-hexane) to give the title compound (400 mg).
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([NH:27][CH2:28][C:29]4[CH:30]=[N:31][CH:32]=[C:33]([F:35])[CH:34]=4)=[N:25][CH:26]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[Cl:19][C:17]1[CH:18]=[C:13]2[C:12]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([NH:27][CH2:28][C:29]4[CH:30]=[N:31][CH:32]=[C:33]([F:35])[CH:34]=4)=[N:25][CH:26]=3)=[CH:11][NH:10][C:14]2=[N:15][CH:16]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(Cc2ccc(NCc3cncc(F)c3)nc2)c2cc(Cl)cnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: Fc1cncc(CNc2ccc(Cc3c[nH]c4ncc(Cl)cc34)cn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.6 %

Procedure:
To [5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(5-fluoro-pyridin-3-ylmethyl)-amine (601, 0.060 g, 0.12 mmol) in tetrahydrofuran (10.0 mL) was added tetrabutylammonium fluoride, trihydrate (0.11 g, 0.35 mmol). The reaction was stirred at room temperature overnight, then poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound (P-0324, 13.5 mg, 31%). MS (ESI) [M+H+]+=368.0.
Reaction SMILES: [C:1]([O:9][CH2:10][C:11]#[N:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:13][OH:14]>C(O)C>[C:1]([O:9][CH2:10][C:11]([NH:13][OH:14])=[NH:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCOC(=O)c1ccccc1
Reactant: NO
Solvent: CCO
Product: N=C(COC(=O)c1ccccc1)NO
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.4 %

Procedure:
Cyanomethyl benzoate (22.2 g, 138 mmol) was dissolved in ethanol (250 mL) followed by addition of 50% aqueous hydroxylamine (16.9 mL, 276 mmol) and the mixture was stirred for 15 minutes at room temperature. Concentration followed by addition of water (250 mL) afforded a colorless crystalline solid that was collected by filtration and washed with additional water then dried in vacuo to give 2-(hydroxyamino)-2-iminoethyl benzoate (23.69 g, 88% yield). 1H-NMR (400 MHz; DMSO-d6): 9.37 (s, 1H), 7.98 (m, 2H), 7.65 (m, 1H), 7.54 (tr, 2H), 5.69 (br s, 2H), 4.64 (s, 2H).
Reaction SMILES: N([C@H:4]1[NH:7][C:6](=[O:8])[C@H:5]1[NH:9][C:10]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[N+]=[N-].C(OC)(=O)CC>C1(C)C=CC=CC=1>[C:10]([NH:9][CH:5]1[CH2:4][NH:7][C:6]1=[O:8])([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: [N-]=[N+]=N[C@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCC(=O)OC
Product: O=C1NCC1NC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
To a solution of 2.0 g of (3S,4R)-4-azido-3-tritylamino-2-azetidinone in 35 ml of toluene is added 1.14 g of methyl propionate and the mixture is refluxed for 2 hours. The solvent is then distilled off under reduced pressure and the residue is purified by silica gel column chromatography using n-hexane-ethyl acetate (2:1). The earlier eluate fractions are combined and concentrated under reduced pressure to give 0.818 g of (3S,4R)-[5-methoxycarbonyl)-1,2,3-triazol-1-yl]-3-tritylamino-2-azetidinone (compound A).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[CH:5][NH:6][C:7]=1[CH3:8].C(N(CC)CC)C.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].C(OCC)(=O)C>CN(C=O)C>[Si:16]([O:1][CH2:2][C:3]1[N:4]=[CH:5][NH:6][C:7]=1[CH3:8])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: Cc1[nH]cnc1CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1[nH]cnc1CO[Si](C)(C)C(C)(C)C
Reaction time: 3 h
Yield: 76.7 %

Procedure:
4-(Hydroxymethyl)-5-methyl-1H-imidazole (4 g, 26.9 mmol) was dissolved in DMF (80 mL). Triethylamine (13.5 mL, 96.9 mmol) and tert-butyl(dimethyl)silyl chloride (4.68 g, 31.0 mmol) were added, followed by stirring for three hours. Ethyl acetate was added to the reaction solution, and the organic layer was washed with brine and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=4/1, dichloromethane/methanol=92/8) to obtain 4.67 g of the title compound (77%).
Reaction SMILES: Cl.[O:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH2:4][CH:3]1[CH2:12][NH2:13].[F:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:24][CH2:25][CH2:26]Br.C(N(C(C)C)CC)(C)C>CN(C=O)C>[O:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH2:4][CH:3]1[CH2:12][NH:13][CH2:26][CH2:25][CH2:24][C:18]1[C:17]2[C:21](=[CH:22][CH:23]=[C:15]([F:14])[CH:16]=2)[NH:20][CH:19]=1
Reactant: NCC1COc2ccccc2O1
Reactant: Fc1ccc2[nH]cc(CCCBr)c2c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Fc1ccc2[nH]cc(CCCNCC3COc4ccccc4O3)c2c1
Temperature: 80 °C
Yield: 16 %

Procedure:
2,3-Dihydro-1,4-benzodioxin-2-methanamine hydrochloride (2.0 g, 10.0 mmole) in DMF (100 ml) was slowly added to the mixture of 5-fluoro-3-(3-bromopropyl)indole (2.6 g, 10.0 mmole) and diisopropylethylamine (8.7 ml, 50 mmole) in 100 ml of DMF with stirring and the mixture was heated at 80° C. for 24 hours. Most of DMF was removed and the residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The dichloromethane solution was dried over anhydrous sodium sulfate, filtered, concentrated in vacuum and column chromatographed on silica gel using ethyl acetate as the eluant. The combined fractions of free base of the expected product (0.5 g, 1.6 mmole, 15%) were concentrated, dissolved in 50 ml of ethanol-diethyl ether (1:1). To this was added 0.25M of fumaric acid in ethanol (3.4 ml, 0.85 mmole) and then a minimum amount of hexane to precipitate the title compound as a light tan solid, (2:1) fumarate salt, m.p. 186°-188° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][N:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[C:29]([Cl:34])[CH:30]=4)[CH:25]=3)(=[O:23])=[O:22])[CH2:17][C:16]2=[O:35])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(OCC)(=O)C>[ClH:34].[Cl:34][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([S:21]([N:18]1[CH2:19][CH2:20][N:15]([NH:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[C:16](=[O:35])[CH2:17]1)(=[O:22])=[O:23])[CH:33]=[CH:32]2
Reactant: CC(C)(C)OC(=O)N1CCC(NN2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2=O)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1NC1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-[1-(tert-Butoxycarbonyl)-4-piperidinylamino]-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone (300 mg) was combined with a 4N solution of hydrochloric acid in ethyl acetate (10 ml) and stirred at room temperature for 30 minutes. The reaction mixture was concentrated to obtain a crude crystal of 4-(6-chloronaphthalene-2-sulfonyl)-1-(4-piperidinylamino)-2-piperazinone hydrochloride. A solution of the resultant 4-(6-chloronaphthalene-2-sulfonyl)-1-(4-piperidinylamino)-2-piperazinone hydrochloride and triethylamine (1.16 g) in methanol (15 ml) was combined with ethyl acetoimidate (712 mg) and stirred at room temperature for 15 hours. The reaction mixture was concentrated and the residue was dissolved in dichloromethane, washed with a 1N aqueous solution of sodium hydroxide, dried and concentrated. The resultant residue was dissolved in ethyl acetate, combined with a solution of hydrochloric acid in ethyl acetate to precipitate a hydrochloride, which was collected by filtration and dried to obtain the title compound (243 mg) as a colorless solid.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([O:15][C:16]([NH:18][C@@H:19]([CH2:22][C:23]([CH3:38])([CH3:37])[CH2:24][CH2:25][O:26][Si:27]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29])[CH2:20][OH:21])=[O:17])([CH3:14])([CH3:13])[CH3:12].S([O-])(O)(=O)=O.[K+]>C(Cl)Cl.C(N(CC)CC)C>[C:11]([O:15][C:16]([NH:18][C@@H:19]([CH2:22][C:23]([CH3:37])([CH3:38])[CH2:24][CH2:25][O:26][Si:27]([CH:28]([CH3:30])[CH3:29])([CH:31]([CH3:32])[CH3:33])[CH:34]([CH3:35])[CH3:36])[CH:20]=[O:21])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)[Si](OCCC(C)(C)C[C@@H](CO)NC(=O)OC(C)(C)C)(C(C)C)C(C)C
Agent: O=C(Cl)C(=O)Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)[Si](OCCC(C)(C)C[C@@H](C=O)NC(=O)OC(C)(C)C)(C(C)C)C(C)C
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
14.7 ml of dimethylsulfoxide in 200 ml of methylene chloride are added dropwise to a solution of 13.4 ml of oxalyl chloride in 200 ml of methylene chloride at -60° C. After 15 min, a solution of 43.2 g of 2(S)-tert-butoxycarbonylamino-6-triisopropylsilyloxy-4,4-dimethyl-hexan-1-ol in 320 ml of methylene chloride is added dropwise at -60° C. in the course of 40 min, while stirring vigorously. 58 ml of triethylamine are then added and the reaction mixture is stirred at -60° C. for 90 min. It is allowed to warm to -10° C., 200 ml of a 20% potassium hydrogen sulfate solution are added, the mixture is subsequently stirred briefly and the product is extracted with methylene chloride. This gives 43 g of the title compound, which is reacted further without additional purification: Rf (A)=0.62, Rf (D)=0.3; Rt (II)=34.8 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([C:10]1[NH:11][C:12]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[CH:15][C:13]=2[N:14]=1)=[O:9].[H-].[Na+].[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:41]=[CH:42][C:43]=1[O:44][CH3:45])[C:30]([N:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39]Cl)[CH2:34][CH2:33]1)=[O:31]>CS(C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([C:10]1[N:11]([CH2:39][CH2:38][N:35]2[CH2:36][CH2:37][N:32]([C:30](=[O:31])[C:29]3[CH:41]=[CH:42][C:43]([O:44][CH3:45])=[C:27]([O:26][CH3:25])[CH:28]=3)[CH2:33][CH2:34]2)[C:12]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[CH:15][C:13]=2[N:14]=1)=[O:9]
Reactant: COc1ccc(C(=O)N2CCN(CCCl)CC2)cc1OC
Reactant: COc1cc2nc(C(=O)Nc3ccccn3)[nH]c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(C(=O)N2CCN(CCn3c(C(=O)Nc4ccccn4)nc4cc(OC)c(OC)cc43)CC2)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
In an argon atmosphere, N-(2-pyridyl)-5,6-dimethoxybenzimidazole-2-carboxamide (0.85 g) was dissolved in DMSO (15 ml), and 60% sodium hydride (0.16 g) was added and stirred at room temperature for 1 hr. A solution (5 ml) of 2-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]ethyl chloride (1.25 g) in DMSO was added dropwise and allowed to react overnight at room temperature under agitation. After-treatment and purification in the same manner as described in Example 14 gave the title compound (0.72 g) as amorphous solid.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[C:16]2[N:19]2[CH2:24][CH2:23][N:22]([C:25]([C:27]3[N:31]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[C:35]([F:41])[CH:34]=4)[CH:30]=[N:29][CH:28]=3)=[O:26])[CH2:21][C:20]2=[O:42])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>CO.CCOC(C)=O.[Pd]>[OH:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[C:16]2[N:19]2[CH2:24][CH2:23][N:22]([C:25]([C:27]3[N:31]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[C:35]([F:41])[CH:34]=4)[CH:30]=[N:29][CH:28]=3)=[O:26])[CH2:21][C:20]2=[O:42])=[CH:11][CH:10]=1
Reactant: N#Cc1ccc(Cn2cncc2C(=O)N2CCN(c3cccc4ccc(OCc5ccccc5)cc34)C(=O)C2)cc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: N#Cc1ccc(Cn2cncc2C(=O)N2CCN(c3cccc4ccc(O)cc34)C(=O)C2)cc1F
Reaction time: 18 h

Procedure:
To a solution of the benzyl ether from Step B (430 mg, 0.77 mmol) in 10 mL of 1:1 MeOH/EtOAc was added 10% palladium on carbon (430 mg). The solution was stirred under a balloon atmosphere of hydrogen at room temperature overnight. Another portion of Pd/C was added (400 mg). After another 18 hours, the solution was filtered through celite. Concentration in vacuo provided the titled product which was used in the next reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:26])=[C:4]([C:8]2[C:20]3[C:19]4[C:14](=[CH:15][C:16]([Br:21])=[CH:17][CH:18]=4)[NH:13][C:12]=3[C:11]([C:22]([NH2:24])=[O:23])=[N:10][C:9]=2[CH3:25])[CH:5]=[CH:6][CH:7]=1.[NH:27]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[C:30](=O)[O:29][C:28]1=O.[N+](O[La](O[N+]([O-])=O)O[N+]([O-])=O)([O-])=O.COC(OC)OC>O1CCCC1.C(OCC)(=O)C>[Br:21][C:16]1[CH:15]=[C:14]2[C:19]([C:20]3[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([N:1]5[C:30](=[O:29])[C:31]6[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=6)[N:27]=[CH:28]5)[C:3]=4[CH3:26])=[C:9]([CH3:25])[N:10]=[C:11]([C:22]([NH2:24])=[O:23])[C:12]=3[NH:13]2)=[CH:18][CH:17]=1
Reactant: Cc1nc(C(N)=O)c2[nH]c3cc(Br)ccc3c2c1-c1cccc(N)c1C
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: O=[N+]([O-])O[La](O[N+](=O)[O-])O[N+](=O)[O-]
Solvent: COC(OC)OC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nc(C(N)=O)c2[nH]c3cc(Br)ccc3c2c1-c1cccc(-n2cnc3ccccc3c2=O)c1C
Temperature: 90 °C
Reaction time: 8 h
Yield: 182.5 %

Procedure:
A mixture of 4-(3-amino-2-methylphenyl)-7-bromo-3-methyl-9H-pyrido[3,4-b]indole-1-carboxamide (0.042 g, 0.103 mmol), 1H-benzo[d][1,3]oxazine-2,4-dione (0.042 g, 0.257 mmol), tris(nitrooxy)lanthanum, 6H2O (0.013 g, 0.031 mmol), and trimethoxymethane (0.337 mL, 3.08 mmol) in tetrahydrofuran (0.5 mL) in a sealed vial was heated at 90° C. for 12 h. The reaction mixture was then stirred overnight at room temperature. This reaction was repeated two additional times. The combined reaction mixtures were diluted with ethyl acetate, washed with water, washed with brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure followed by purification by flash silica gel chromatography using a mixture of ethyl acetate and hexane (20%-35%-50%-65%) afforded 7-bromo-3-methyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-1-carboxamide (0.101 g, 0.188 mmol, 59% yield) as a tan solid. LC/MS M+1=538.1 and 540.1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:29]=[CH:28][C:10]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH:20]C(=O)OC(C)(C)C)=[O:12])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH3:30][N:31]1[C:35]([CH3:36])=[C:34]([CH:37]=O)[C:33]([CH3:39])=[N:32]1>>[NH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[NH:13][C:11](=[O:12])[C:10]1[CH:9]=[CH:8][C:7]([CH:4]2[CH2:5][CH2:6][N:1]([CH2:37][C:34]3[C:33]([CH3:39])=[N:32][N:31]([CH3:30])[C:35]=3[CH3:36])[CH2:2][CH2:3]2)=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C2CCNCC2)cc1
Reactant: Cc1nn(C)c(C)c1C=O
Product: Cc1nn(C)c(C)c1CN1CCC(c2ccc(C(=O)Nc3ccccc3N)cc2)CC1
Yield: 32.9 %

Procedure:
Using an analogous procedure to that described in Example 5, tert-butyl 2-[(4-piperidin-4-ylbenzoyl)amino]phenylcarbamate (prepared as described in Method 1 below; 200 mg, 0.51 mmol) was reacted with 1,3,5-trimethyl-1H-pyrazole-4-carbaldehyde (83.5 mg, 0.60 mmol) to give the title compound (70 mg, 56%); NMR Spectrum: (DMSO d6) δ 1.65 (m, 2H), 1.77 (m, 2H), 1.98 (m, 2H), 2.09 (s, 3H), 2.18 (s, 3H), 2.57 (m, 1H), 2.92 (m, 2H), 3.24 (s, 2H), 3.63 (s, 3H), 4.86 (br s, 2H), 6.60 (m, 1H), 6.78 (d, 1H), 6.97 (m, 1H), 7.17 (d, 1H), 7.37 (d, 2H), 7.91 (d, 2H), 9.55 (s, 1H); Mass Spectrum: M+H+ 418.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH2:12])([CH3:11])[CH3:10])=[CH:5][CH:4]=1.[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21](Cl)=[O:22].C(N(CC)CC)C>ClCCl>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([NH:12][C:9]([C:6]1[CH:5]=[CH:4][C:3]([Cl:2])=[CH:8][CH:7]=1)([CH3:10])[CH3:11])=[O:22]
Reactant: O=C(Cl)CCCCCCCBr
Reactant: CC(C)(N)c1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(NC(=O)CCCCCCCBr)c1ccc(Cl)cc1

Procedure:
1-(4-Chlorophenyl)-1-methylethylamine hydrochloride (4.0 g) was reacted with 8-bromooctanoyl chloride (4.7 g) in dichloromethane (50 ml) containing triethylamine (8.1 ml), in a similar manner to Example 52b, to give 8-bromo-N-[1-(4-chlorophenyl)-1-methylethyl]octanamide which was used directly in part c).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[C:14]1([C@@H:20]([CH3:23])[CH2:21][NH2:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CC=CC=1>O>[C:14]1([C@@H:20]([CH3:23])[CH2:21][NH:22][C:11]([C:2]2[CH:3]=[N:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)=[O:12])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1cnc2ccccc2n1
Reactant: C[C@@H](CN)c1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: C[C@@H](CNC(=O)c1cnc2ccccc2n1)c1ccccc1
Yield: 76.4 %

Procedure:
Prepared from 2-quinoxaloyl chloride (0.47 g, 2.4 mmol), (R)-2-phenyl-1-propylamine (0.30 g, 2.2 mmol), pyridine (5 mL), and water (50 mL) yielding 0.49 g (76%) of (172):
Reaction SMILES: [CH:1]1([C:6]([O-:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.OS(O)(=O)=O.C([O-])(O)=O.[Na+].[CH3:19][CH2:20]O>>[CH:1]1([C:6]([O:8][CH2:19][CH3:20])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C([O-])C1CCCC1
Reactant: CCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)C1CCCC1
Temperature: 80 °C
Reaction time: 3.5 h

Procedure:
To a solution of cyclopentanecarboxylate (1.14 g, 10 mmol) in EtOH (5 mL) was added H2SO4 (0.1 mL) at room temperature. The mixture was allowed to warm to 80° C. and stirred at the same temperature for 3.5 h. The reaction mixture was cooled down to room temperature and poured into saturated NaHCO3 aq. (40 mL). The mixture was stirred at room temperature for 30 min and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated under reduced pressure to provide compound A124-1 (1.01 g, 71%) as a pale yellow oil. The crude product was used for next step without purification.
Reaction SMILES: [CH:1]1([C:6]2[N:7]=[C:8]([CH3:25])[N:9]3[C:14](=[O:15])[NH:13][C:12]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[O:22][CH2:23][CH3:24])=[N:11][C:10]=23)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:26][S:27](O)(=[O:29])=[O:28]>ClCCl>[CH2:23]([O:22][C:17]1[CH:18]=[CH:19][C:20]([S:27]([Cl:26])(=[O:29])=[O:28])=[CH:21][C:16]=1[C:12]1[NH:13][C:14](=[O:15])[N:9]2[C:8]([CH3:25])=[N:7][C:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[C:10]2[N:11]=1)[CH3:24]
Reactant: O=S(=O)(O)Cl
Reactant: CCOc1ccccc1-c1nc2c(C3CCCC3)nc(C)n2c(=O)[nH]1
Solvent: ClCCl
Product: CCOc1ccc(S(=O)(=O)Cl)cc1-c1nc2c(C3CCCC3)nc(C)n2c(=O)[nH]1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
372.3 mg (1.1 mmol) of 8-cyclopentyl-2-(2-ethoxy-phenyl)-6-methyl-3H-imidazo [1,5-α][1,3,5]triazin-4-one (example IX) are added in portions to 0.66 ml (9.9 mmol) of ice-cooled chlorosulfonic acid. The mixture is subsequently stirred overnight at room temperature before being diluted with dichloromethane and poured onto ice water. The organic phase is separated off. The aqueous phase is extracted once again with dichloromethane and the organic phases are combined, dried and evaporated.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:28]4[CH:27]=[CH:26][CH:25]=[C:24]([F:23])[CH:29]=4)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Br)c3O2)cc1
Reactant: OB(O)c1cccc(F)c1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4cccc(F)c4)c3O2)cc1
Yield: 75.4 %

Procedure:
Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with 3-fluorophenylboronic acid (0.274 g, 1.96 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.051 g, 0.065 mmol), and potassium carbonate (0.45 g, 3.26 mmol) generally according to the procedure described for Intermediate 37 provided 0.392 g (75%) of (±)-[7-(3-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a light yellow solid. mp 88-90° C.; Anal. calcd. for C22H19FO4S: C, 66.32; H, 4.81. Found: C, 65.63; H, 4.84.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([CH3:9])=[C:6]([CH3:8])[N:7]=1.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([N:20]=[C:21]=[O:22])(=[O:19])=[O:18]>C(#N)C>[CH3:8][C:6]1[N:7]=[C:2]([NH:1][C:21]([NH:20][S:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[Cl:10])(=[O:18])=[O:19])=[O:22])[N:3]=[N:4][C:5]=1[CH3:9]
Reactant: Cc1nnc(N)nc1C
Reactant: O=C=NS(=O)(=O)c1ccccc1Cl
Solvent: CC#N
Product: Cc1nnc(NC(=O)NS(=O)(=O)c2ccccc2Cl)nc1C
Reaction time: 6 h

Procedure:
To a dry, well stirred mixture of 12 g of 3-amino-5,6-dimethyl-1,2,4-triazine in 100 ml of acetonitrile at ambient temperature and pressure was added 21 g of 2-chlorobenzenesulfonyl isocyanate. The mixture was stirred for 6 hours and the precipitated product removed by filtration. After washing with diethyl ether, the product melted at 142°-145°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[N:14]=[C:15]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[S:16][C:17]=1[CH3:18])[CH:6]=[O:7].C(O)C.[BH4-].[Na+].O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][OH:7])[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[N:14]=[C:15]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[S:16][C:17]=1[CH3:18]
Reactant: COc1cc(C=O)ccc1OCc1nc(N2CCOCC2)sc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: COc1cc(CO)ccc1OCc1nc(N2CCOCC2)sc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.3 %

Procedure:
To a solution of 3-methoxy-4-[(5-methyl-2-morpholin-4-yl-1,3-thiazol-4-yl)methoxy]benzaldehyde (7.00 g) in tetrahydrofuran (100 mL)-ethanol (30 mL) was gradually added sodium borohydride (0.76 g) at room temperature. After stirring the reaction mixture at room temperature for 2 hrs, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated to give {3-methoxy-4-[(5-methyl-2-morpholin-4-yl-1,3-thiazol-4-yl)methoxy]phenyl}methanol as colorless crystals (6.29 g, yield 89%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 121-122° C.