Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:36]=[CH:35][C:14]([C:15]([NH:17][CH2:18][CH:19]4[CH2:24][CH2:23][N:22]([C:25]5[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=5)[CH2:21][CH2:20]4)=[O:16])=[CH:13][CH:12]=3)=[N:7][C:6]=2[CH:5]=[C:4]([C:37]#[N:38])[CH:3]=1.[CH3:39]/[C:40](/B(O)O)=[CH:41]/[CH3:42]>>[C:37]([C:4]1[CH:3]=[C:2](/[C:40](/[CH3:39])=[CH:41]\[CH3:42])[C:10]2[O:9][C:8]([C:11]3[CH:36]=[CH:35][C:14]([C:15]([NH:17][CH2:18][CH:19]4[CH2:20][CH2:21][N:22]([C:25]5[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:27][N:26]=5)[CH2:23][CH2:24]4)=[O:16])=[CH:13][CH:12]=3)=[N:7][C:6]=2[CH:5]=1)#[N:38]
Reactant: C/C=C(/C)B(O)O
Reactant: N#Cc1cc(Br)c2oc(-c3ccc(C(=O)NCC4CCN(c5ccc(C(F)(F)F)cn5)CC4)cc3)nc2c1
Product: C/C=C(/C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4CCN(c5ccc(C(F)(F)F)cn5)CC4)cc3)oc12

Procedure:
The title compound was prepared from 4-(7-bromo-5-cyano-1,3-benzoxazol-2-yl)-N-({1-[5-(trifluoromethyl)pyridin-2-yl]piperidin-4-yl}methyl)benzamide and [(1E)-1-methylprop-1-en-1-yl]boronic acid by a procedure analogous to that described in EXAMPLE 113, Step B. Mass spectrum (ESI) 560.2 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]1[C:11]([N+:12]([O-])=O)=[C:10]([NH:15][CH3:16])[N:9](C)[N:8]=1.O.NN>[Ni].C(O)C>[NH2:12][C:11]1[C:7]([CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])=[N:8][NH:9][C:10]=1[NH:15][CH3:16]
Reactant: CNc1c([N+](=O)[O-])c(COCCOC)nn1C
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: CNc1[nH]nc(COCCOC)c1N
Yield: 106.5 %

Procedure:
3-(2-Methoxyethoxy)methyl-1-methyl-5-methylamino-4-nitropyrazole (0.73 g, 3 mmoles), hydrazine hydrate (0.5 ml) and Raney nickel (200 mg) were stirred in ethanol (12 ml) at 50° C. for 1.5 hours. The Raney Nickel was filtered off and the ethanol removed under reduced pressure yielding the title compound (0.64 g, 100%).
Reaction SMILES: [O:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:2]1=[O:3].[N+:12]([O-])([OH:14])=[O:13]>>[N+:12]([C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[O:1][C:2](=[O:3])[CH:4]=[CH:5]2)([O-:14])=[O:13]
Reactant: O=c1ccc2ccccc2o1
Reactant: O=[N+]([O-])O
Product: O=c1ccc2cc([N+](=O)[O-])ccc2o1
Yield: 85 %

Procedure:
In greater detail, coumarin (10 g, 68 mmol) was nitrated as described in the literature with an excess of fuming nitric acid overnight at room temperature to give 6-nitrocoumarin as the only major product. The 6-nitrocoumarin exhibited the following characteristics: Yield 85%. 1H NMR (DMSO-d6): 8.74 (d, J=3Hz, 1H), 8.42 (dd, J=3, 9Hz, 1H), 8.24 (d, J=10Hz, 1H), 7.63 (d, J=9Hz, 1H), 6.70 (d, J=10Hz, 1H).
Reaction SMILES: Cl.[CH:2]([N:5]1[C:9]([C:10]2[N:19]=[C:18]3[N:12]([CH2:13][CH2:14][O:15][C:16]4[CH:23]=[C:22]([CH:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[CH:21]=[CH:20][C:17]=43)[CH:11]=2)=[N:8][C:7]([CH3:30])=[N:6]1)([CH3:4])[CH3:3].C(N(CC)CC)C.Cl[CH2:39][C:40]([NH:42][CH:43]([CH3:45])[CH3:44])=[O:41]>C(Cl)Cl.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH:43]([NH:42][C:40](=[O:41])[CH2:39][N:27]1[CH2:28][CH2:29][CH:24]([C:22]2[CH:21]=[CH:20][C:17]3[C:18]4[N:12]([CH:11]=[C:10]([C:9]5[N:5]([CH:2]([CH3:4])[CH3:3])[N:6]=[C:7]([CH3:30])[N:8]=5)[N:19]=4)[CH2:13][CH2:14][O:15][C:16]=3[CH:23]=2)[CH2:25][CH2:26]1)([CH3:45])[CH3:44]
Reactant: CC(C)NC(=O)CCl
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(C4CCNCC4)cc2OCC3)n(C(C)C)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(-c2cn3c(n2)-c2ccc(C4CCN(CC(=O)NC(C)C)CC4)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 96 h
Yield: 51.4 %

Procedure:
To a suspension of 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene hydrochloride (150 mg, 0.35 mmol) in DCM (2 mL) was added triethylamine (107 μL, 0.77 mmol). The resultant mixture was stirred for 10 minutes before the addition of 2-chloro-N-isopropyl-acetamide (52 mg, 0.38 mmol) and tetrabutylammonium iodide (13 mg, 0.04 mmol). The reaction was stirred at RT for 4 days before the reaction was washed with sodium hydrogen carbonate solution (sat. aq.). The aqueous phase was extracted with 10% MeOH in DCM (×3) and the combined organic layers dried (Na2SO4) then concentrated in vacuo. The resultant residue was purified by flash column chromatography (SiO2, gradient 0-10% MeOH in DCM) affording 277 (88 mg, 0.18 mmol, 51%). LCMS: RT=2.85 min, [M+H]+=492. 1H NMR δ (ppm) (CDCl3): 8.43 (1 H, d, J=8.29 Hz), 7.59 (1 H, s), 7.01 (1 H, dd, J=8.34, 1.82 Hz), 6.97 (1 H, s), 6.89 (1 H, d, J=1.76 Hz), 5.92-5.82 (1 H, m), 4.48-4.44 (2 H, m), 4.42-4.38 (2 H, m), 4.13-4.02 (1 H, m), 3.10-2.85 (4 H, m), 2.58-2.46 (1 H, m), 2.38 (3 H, s), 2.35-2.20 (2 H, m), 1.94-1.84 (2 H, s), 1.81-1.68 (2 H, m), 1.54 (6 H, d, J=6.64 Hz), 1.16 (6 H, d, J=6.55 Hz)
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].I.[CH3:16][N:17]1[CH2:21][C:20](=[O:22])[N:19]=[C:18]1SC.C(N(CC)CC)C>C(O)C>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:18]2[N:17]([CH3:16])[CH2:21][C:20](=[O:22])[N:19]=2)=[CH:7][CH:6]=1)[CH3:1]
Reactant: CSC1=NC(=O)CN1C
Reactant: CN(C)Cc1ccc(CSCCN)o1
Agent: I
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(C)Cc1ccc(CSCCNC2=NC(=O)CN2C)o1

Procedure:
2-(5-Dimethylaminomethylfuran-2-ylmethylthio)ethylamine (2.25 g), 1-methyl-2-methylthio-imidazolin-4-one hydroiodide (2.85 g) and triethylamine (3.635 g) were refluxed in ethanol (25 ml) for 4 hours.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][N:16]=2)[C:11]([F:24])=[CH:10][C:9]=1[F:25])([CH3:4])([CH3:3])[CH3:2].O1CCCC1>CO.[C].[Pd]>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][N:16]=2)[C:11]([F:24])=[CH:10][C:9]=1[F:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])cn2)c(F)cc1F
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cc(Oc2ccc(N)cn2)c(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
A suspension of tert-butyl{2,4-difluoro-5-[(5-nitropyridin-2-yl)oxy]phenyl}carbamate (10.10 g, 27.5 mmol) and 10% palladium-carbon (5.0 g) in methanol (50 mL)-tetrahydrofuran (50 mL) was vigorously stirred at room temperature under a hydrogen atmosphere overnight. The insoluble material was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was poured into water (200 mL), and the mixture was extracted with ethyl acetate (100 mL×2). The ethyl acetate layers were combined dried over anhydrous sodium sulfate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the residue was crystallized from acetonitrile to give the title compound (8.70 g, 94%) as a white powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.[Cu](C#N)[C:19]#[N:20]>CN(C)C=O>[C:19]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)#[N:20]
Reactant: Brc1ccc2[nH]cc(Cc3cccnc3)c2c1
Reactant: N#C[Cu]C#N
Solvent: CN(C)C=O
Product: N#Cc1ccc2[nH]cc(Cc3cccnc3)c2c1

Procedure:
A mixture of compound of Description 3 [5-Bromo-3-(pyridin-3-ylmethyl)-1H-indole] (1.1 g; 0.0038 mol) and copper cyanide (0.86 g; 0.0096 mol) in dimethylformamide (35 ml) was treated at 140° C. for 8 hours. The reaction mixture was poured into an ice ammonium hydroxide solution and the product was extracted with ethyl acetate. The organic extract was dried (MgSO4) and evaporated under vacuum. After purification by Flash Chromatography on silica gel using as eluent methylene chloride/methanol (97/3), the desired compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:30])[C:4](=[O:29])[C:5]([C:20]2[CH:21]=[C:22]([CH:27]=[O:28])[N:23]([CH2:25][CH3:26])[CH:24]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[C:14]([F:19])=[N:15][CH:16]=[CH:17][CH:18]=3)[CH:8]=2)[N:6]=1.[BH4-].[Na+]>C1COCC1.CO>[NH2:1][C:2]1[N:3]([CH3:30])[C:4](=[O:29])[C:5]([C:20]2[CH:21]=[C:22]([CH2:27][OH:28])[N:23]([CH2:25][CH3:26])[CH:24]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[C:14]([F:19])=[N:15][CH:16]=[CH:17][CH:18]=3)[CH:8]=2)[N:6]=1
Reactant: CCn1cc(C2(c3cccc(-c4cccnc4F)c3)N=C(N)N(C)C2=O)cc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCn1cc(C2(c3cccc(-c4cccnc4F)c3)N=C(N)N(C)C2=O)cc1CO

Procedure:
A solution of 4-{2-amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}-1-ethyl-1H-pyrrole-2-carbaldehyde (0.071 g; 0.25 mmol) in THF (20 mL) and methanol (5 mL) was stirred at ambient temperature as an excess of NaBH4 (0.071 g; 1.88 mmol) was added. After one hour the solvents were evaporated and the residue was taken up into dichloromethane and washed with water. The dichloromethane phase was dried over MgSO4, filtered, and evaporated. The resultant residue was crystallized from ethyl acetate and hexane to obtain the title product as a white solid, mp 170-172° C.; MS (ES) m/z 406.1; [M−H]
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:26]=[CH:25][C:24]([OH:27])=[C:6]([C:7]([NH:9][C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)=[O:8])[CH:5]=1.CO.[OH-].[Na+].Cl>O1CCCC1>[F:17][C:16]([F:18])([F:19])[C:14]1[CH:15]=[C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:5]=[C:4]([CH:26]=[CH:25][C:24]=2[OH:27])[C:3]([OH:28])=[O:2])[CH:11]=[C:12]([C:20]([F:23])([F:21])[F:22])[CH:13]=1
Reactant: COC(=O)c1ccc(O)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(O)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Yield: 97.4 %

Procedure:
N-[3,5-Bis(trifluoromethyl)phenyl]-4-hydroxyisophthalamic acid methyl ester (2.85 g, 7 mmol) was suspended in a mixed solvent of methanol (14 mL) and tetrahydrofuran (14 mL). 2 N aqueous sodium hydroxide (14 mL) was added, and the mixture was refluxed for 2 hours. After cooling, the reaction mixture was added 2 N hydrochloric acid (20 ml) and the separated solid was filtered, washed with water, dried to give the title compound (2.68 g, 97.4%) as a white crystal.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:4]([OH:5])[C:3]=1[OH:10].[CH3:11]S(C)=O.ClCCl.[OH-].[Na+]>O>[CH3:1][C:2]1[C:3]2[O:10][CH2:11][O:5][C:4]=2[CH:6]=[C:7]([CH3:9])[CH:8]=1
Reactant: CS(C)=O
Reactant: Cc1cc(C)c(O)c(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Cc1cc(C)c2c(c1)OCO2
Yield: 93 %

Procedure:
3,5-Dimethylcatechol (13.8 g) in a vigorously stirred mixture of dimethylsulphoxide (150 ml), dichloromethane (10 g) and sodium hydroxide (8.3 g) under nitrogen atmosphere was heated over an oil bath (120°-130° C.) for 2 hours. The mixture was poured into water (600 ml) and extracted (×4) with ether. The ethereal solution was dried and evaporated to afford 3,5-dimethyl-l,2-(methylenedioxy)benzene (14.0 g, 93%) as an oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15](=[O:46])[CH2:16][C:17]3[NH:18][C:19]([CH2:39][CH2:40][C:41]4[S:42][CH:43]=[CH:44][N:45]=4)=[C:20]([C:35]([O:37][CH3:38])=[O:36])[CH:21]([C:27]4[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:28]=4[Cl:34])[C:22]=3[C:23]([O:25][CH3:26])=[O:24])[CH2:11][CH2:10]2)[CH2:7][CH2:6][CH2:5][CH2:4]1.[C:47]1(=O)[CH2:51][CH2:50][CH2:49][CH2:48]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl.CC(O)=O>[CH:47]1([NH:1][CH2:2][C:3]2([CH2:8][N:9]3[CH2:10][CH2:11][N:12]([C:15](=[O:46])[CH2:16][C:17]4[NH:18][C:19]([CH2:39][CH2:40][C:41]5[S:42][CH:43]=[CH:44][N:45]=5)=[C:20]([C:35]([O:37][CH3:38])=[O:36])[CH:21]([C:27]5[C:28]([Cl:34])=[CH:29][CH:30]=[CH:31][C:32]=5[Cl:33])[C:22]=4[C:23]([O:25][CH3:26])=[O:24])[CH2:13][CH2:14]3)[CH2:4][CH2:5][CH2:6][CH2:7]2)[CH2:51][CH2:50][CH2:49][CH2:48]1
Reactant: COC(=O)C1=C(CCc2nccs2)NC(CC(=O)N2CCN(CC3(CN)CCCC3)CC2)=C(C(=O)OC)C1c1c(Cl)cccc1Cl
Reactant: O=C1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)C1=C(CCc2nccs2)NC(CC(=O)N2CCN(CC3(CNC4CCCC4)CCCC3)CC2)=C(C(=O)OC)C1c1c(Cl)cccc1Cl
Reaction time: 0.08 h

Procedure:
To a suspension of dimethyl 2-[2-[4-[[1-(aminomethyl)cyclopentyl]methyl]-1-piperazinyl]-2-oxoethyl]-4-(2,6-dichlorophenyl)-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate (205 mg/0.298 mmol) and cyclopentanone (0.032 ml/0.36 mmol) in dichloromethane (2 ml) was added AcOH (1 drop) and the resulting mixture was stirred for 5 minutes. NaBH(OAc)3 (80 mg/0.36 mmol) was added to the mixture and the resulting mixture was stirred for 5 hours. The mixture was diluted with dichloromethane (50 ml) and the resulting solution was washed with water (10 ml) and brine (10 ml) successively. The solution was dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (NH2 gel/dichloromethane:methanol=100:0-100:2) to give a yellow film (220 mg/98%).
Reaction SMILES: [CH3:1][C:2]([CH3:35])([CH3:34])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[CH:15]=3)[N:12]=2)[N:7]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:6]=1)=[O:4].C(N(C(C)C)CC)(C)C.Br[CH2:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48]>CN(C)C=O>[C:50]([O:49][C:47](=[O:48])[CH2:46][N:23]1[CH2:24][CH2:25][N:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:11]3[N:12]=[C:13]4[C:5]([C:3](=[O:4])[C:2]([CH3:35])([CH3:34])[CH3:1])=[CH:6][N:7]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:31])([CH3:33])[CH3:32])[C:8]4=[N:9][CH:10]=3)[CH:15]=2)[CH2:21][CH2:22]1)([CH3:53])([CH3:52])[CH3:51]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cccc(N4CCNCC4)c3)nc12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CN1CCN(c2cccc(-c3cnc4c(n3)c(C(=O)C(C)(C)C)cn4COCC[Si](C)(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.2 %

Procedure:
To a solution of 2,2-Dimethyl-1-[2-(3-piperazin-1-yl-phenyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-propan-1-one (0.233 g, 0.473 mmol) in 2 mL of dimethyl formamide was added 0.074 mL of diisopropylethylamine (0.055 g, 0.425 mmol) and 0.629 mL of tert-butyl bromoacetate (0.083 g, 0.425 mmol). The reaction was stirred at room temperature overnight before quenching with water and extracting with dichloromethane. The combined organics were washed with water, dried over MgSO4, filtered and concentrated in vacuo. Silica gel chromatography (10→60% EtOAc/hexanes over 30 minutes) afforded 0.1582 g (61% yield) of (4-{3-[7-(2,2-Dimethyl-propionyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-phenyl}-piperazin-1-yl)-acetic acid tert-butyl ester as a yellow oil. MS (E/I): 608 (M+H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH2:9][C:10]([OH:12])=[O:11])[C:3]1=[O:13].[OH-].[Na+].O.[C:17]1([CH2:23][C:24](=O)[C:25]([O-:27])=[O:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Na+].C([BH3-])#N.[Na+]>O>[C:10]([CH2:9][N:4]1[CH2:5][CH2:6][CH2:7][CH2:8][C@H:2]([NH:1][CH:24]([C:25]([OH:27])=[O:26])[CH2:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:3]1=[O:13])([OH:12])=[O:11]
Reactant: O=C([O-])C(=O)Cc1ccccc1
Reactant: N[C@H]1CCCCN(CC(=O)O)C1=O
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CN1CCCC[C@H](NC(Cc2ccccc2)C(=O)O)C1=O

Procedure:
Prepare an aqueous solution of 500 mg 3-(S)-amino-1-carboxymethylperhydroazepin-2-one in 5 ml water. Adjust the pH to 6 with 1N sodium hydroxide solution and add 15 ml water. React this amine with 2.24 g sodium phenylpyruvate monohydrate and 400 mg sodium cyanoborohydride as described in Example 1. Purify 370 mg of the crude product on an LH-20 column and isoalte 240 mg of 1-carboxymethyl-3-(S)-[(1-carboxy-2-phenylethyl)amino]perhydroazepin-2-one.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[CH:18][C:19]([F:34])=[C:20]([NH:22][S:23]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])[CH:21]=2)[CH:5]=[CH:4][N:3]=1.[CH2:35]([NH2:37])[CH3:36].C1COCC1>>[CH2:35]([NH:37][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[CH:18][C:19]([F:34])=[C:20]([NH:22][S:23]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])(=[O:24])=[O:25])[CH:21]=2)[CH:5]=[CH:4][N:3]=1)[CH3:36]
Reactant: CC(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Reactant: CCN
Solvent: C1CCOC1
Product: CCNc1nccc(-c2sc(C(C)C)nc2-c2ccc(F)c(NS(=O)(=O)c3c(F)cccc3F)c2)n1

Procedure:
Following a procedure analogous to the procedure described in Example 1 using N-{5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (0.150 g, 0.286 mmol) and ethyl amine 2.0 M in THF (2 mL, 4.00 mmol), the title compound was obtained as an off-white solid (74 mg, 49% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.92 (s, 1H), 8.07 (d, J=5.0 Hz, 1H), 7.65-7.80 (m, 1H), 7.44 (dd, J=7.5, 1.8 Hz, 1H), 7.36-7.42 (m, 1H), 7.21-7.33 (m, 4H), 6.17 (br. s., 1H), 3.16-3.31 (m, 3H), 1.36 (d, J=6.9 Hz, 6H), 1.10 (t, J=7.1 Hz, 3H). MS (ESI): 534.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12](=[O:17])[N:11]([CH3:18])[C:10]=3[N:9]=[C:8]2[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)=[CH:4][CH:3]=1.I[CH2:33][CH3:34].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:33][CH3:34])[C:12](=[O:17])[N:11]([CH3:18])[C:10]=3[N:9]=[C:8]2[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:27])[F:28])[CH:21]=2)=[CH:30][CH:31]=1
Reactant: Cn1c(=O)[nH]c(=O)c2c1nc(Oc1cccc(C(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCn1c(=O)c2c(nc(Oc3cccc(C(F)(F)F)c3)n2Cc2ccc(Cl)cc2)n(C)c1=O
Temperature: 50 °C
Reaction time: 3 h
Yield: 28.5 %

Procedure:
To a solution of 7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethyl)phenoxy)-1H-purine-2,6(3H,7H)-dione (50 mg, 0.11 mmol, example 1) in DMF (1 mL) was added iodoethane (18.7 mg, 0.12 mmol) followed by potassium carbonate (23 mg, 0.16 mmol). Then the mixture was stirred at 50° C. for 3 h. The mixture was diluted with ethyl acetate and extracted with brine and saturated aqueous ammonium chloride solution. The organic phase was dried and concentrated to give crude solid product which was collected and washed with ethanol to give 7-(4-chlorobenzyl)-1-ethyl-3-methyl-8-(3-(trifluoromethyl)phenoxy)-1H-purine-2,6(3H,7H)-dione (15 mg, 26.7% yield) as white solid. 1H-NMR (DMSO-d6) δ 7.77 (s, 1H), 7.69-7.73 (m, 3H), 7.43 (s, 4H), 5.46 (s, 2H), 3.91-3.93 (q, 2H), 3.29 (s, 3H), 1.11-1.14 (t, 3H). LCMS retention time 3.109 min; LCMS MH+ 479.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[OH:12].CS([Cl:17])(=O)=O>CO>[Cl:17][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[OH:12]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cccc(CCCO)c1O
Solvent: CO
Product: Cc1cccc(CCCCl)c1O
Temperature: 110 °C
Reaction time: 1.5 h

Procedure:
A solution of N,N-dimethylaniline (24.0 mL) in toluene (20.0 mL) was bubbled with hydrochloride gas to prepare the corresponding hydrochloride. To the mixture were added 2-(3-hydroxypropyl)-6-methylphenol (20.0 g) and methanesulfonyl chloride (10.2 mL), and the resulting mixture was stirred at 110° C. for 1.5 hours. After cooling, methanol (2.4 mL) was added to the reaction mixture. The mixture was washed with distilled water, an aqueous sodium bicarbonate solution, distilled water and brine successively and then evaporated to give a solution of 2-(3-chloropropyl)-6-methylphenol (19.9 g) in toluene (21 g). NMR spectrum of this compound was identical with that of Reference Example 12.
Reaction SMILES: [CH:1]1[C:11]2[C:10](=[O:12])[NH:9][C:8]3[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][N:29]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.[ClH:36]>O.C(#N)C>[ClH:36].[N:29]1([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][N:6]2[C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[C:10](=[O:12])[NH:9][C:8]3[CH:13]=[CH:14][CH:15]=[CH:16][C:7]2=3)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: O=C1Nc2ccccc2Nc2ccccc21
Reactant: BrCCCCCCN1CCCCCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CC#N
Product: O=C1Nc2ccccc2N(CCCCCCN2CCCCCC2)c2ccccc21
Yield: 15 %

Procedure:
Prepared analogously to Example 6 from 5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one, n-butyl-lithium and 1-bromo-6-(hexahydro-1H-1-azepinyl)hexane in a yield of 15% of theory. The monohydrochloride, which is sparingly soluble in water, melted at 103°-105° C. (from acetonitrile using activated charcoal).
Reaction SMILES: C[O:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([CH3:11])[CH:4]=1.B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([CH3:11])[CH:4]=1
Reactant: COc1ccc(C#N)c(C)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(O)ccc1C#N
Temperature: 0 °C
Reaction time: 120 h
Yield: 103.9 %

Procedure:
A solution of 4-methoxy-2-methylbenzonitrile (5.0 g, 33.97 mmol) in DCM (150 mL) is cooled down to 0° C. before adding dropwise a 1M BBr3 in DCM solution (136 mL, 136 mmol). The reaction mixture is allowed to reach rt and stirring is then continued at 45° C. for 5 days. Ice water (500 mL) is then added and the reaction mixture is stirred for 1 h before sat. aq. NaHCO3 (250 mL) is added. The mixture is extracted with DCM (200 mL then 4×100 mL) and the combined organic extracts are dried over MgSO4, filtered and evaporated to give the title compound as a brown solid (4.7 g); LC-MS: tR=0.76 min. 1H NMR (D6-DMSO): δ 2.38 (s, 3H), 6.73 (dd, J=8.5, 2.0 Hz, 1H), 6.79 (d, J=2.0 Hz, 1H), 7.55 (d, J=8.5 Hz, 1H), 10.49 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[SH:10].[CH2:11](Br)[C:12]#[CH:13].[Br-].[NH+]1C=CC=CC=1>N1C=CC=CC=1>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[S:10][CH2:13][C:12]#[CH:11]
Reactant: C#CCBr
Reactant: Cc1cc(O)c(S)c(=O)o1
Agent: [Br-]
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Product: C#CCSc1c(O)cc(C)oc1=O
Reaction time: 1 h

Procedure:
A solution of 39.5 g. (0.250 mole) of 4-hydroxy-3-mercapto-6-methyl-2-pyrone in 250 ml. of pyridine was cooled to 15°C. in an ice bath. Propargyl bromide (29.7 g., 0.250 mole) was then added in one portion, causing the temperature of the reaction mixture to rise to 53°C. When the temperature began to subside, the flask was placed on the steam bath and heated at 80°C. for one hour, during which pyridinium bromide by-product precipitated. The reaction mixture was then cooled and poured into a mixture of ice and 500 ml. of concentrated hydrochloric acid. After this mixture had been kept cold in an ice bath for one hour, the crystalline product, which formed, was collected on a filter and dried; m.p. 143.5°-146°C., weight 27.2 g. More product was obtained by extraction of the filtrate with methylene chloride, giving a total yield of 41.9 g., (85 percent). Two recrystallizations (Darco) from ethanol afforded the pure 4-hydroxy-6-methyl-3-propargylthio- 2-pyrone as light tan crystals, m.p. 148°-149°C. (dec.).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:26]1([N:32]=[C:33]=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[N:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:25]=[CH:24][C:22]([NH:23][C:33]([NH:32][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:34])=[CH:21][CH:20]=3)[N:8]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Product: O=C(Nc1ccccc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1

Procedure:
Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (140 mg, 0.40 mmoles) and phenyl isocyanate (72 mg, 0.61 mmoles), the title compound was isolated as a white solid. The product was purified by Silica gel column chromatography by eluting it with ethyl acetate. Yield: 0.128 g (68%) (M+H)=462.3