Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:41])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:37][CH3:38])([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH:30]([OH:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[C:24]([CH3:36])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:39])=[CH:9][C:8]=1[F:40].[Cl-].[NH4+]>CO>[CH2:20]([C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH:11]=[CH:12][C:7]([CH2:6][C:5]([OH:41])=[O:4])=[C:8]([F:40])[CH:9]=2)=[C:14]([CH3:39])[CH:15]=1)([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH:30]([OH:35])[C:31]([CH3:33])([CH3:34])[CH3:32])=[C:24]([CH3:36])[CH:23]=1)[CH2:37][CH3:38])[CH3:21]
Reactant: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)c(F)c2)c(C)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(CC(=O)O)c(F)c2)c(C)c1
Reaction time: 4 h
Yield: 101.9 %

Procedure:
A 2 N sodium hydroxide aqueous solution (0.21 mL) was added to a solution of (4′-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-fluoro-2′-methyl-biphenyl-4-yl)acetic acid methyl ester (Example 100-(1); 21.1 mg, 0.0394 mmol) in methanol (1.3 mL), and the mixture was stirred for four hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (20.9 mg, 99%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](O)[CH:5]=[C:4]([C:9]2([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=1.C(N(C(C)C)C(C)C)C.P(Cl)(Cl)([Cl:32])=O>C(#N)C>[Cl:32][C:6]1[CH:5]=[C:4]([C:9]2([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: Nc1nc(O)cc(C2(c3ccc(Cl)cc3)CCCC2)n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Nc1nc(Cl)cc(C2(c3ccc(Cl)cc3)CCCC2)n1

Procedure:
360 mg of 2-amino-6-[1-(4-chlorophenyl)cyclopentyl]pyrimidin-4-ol are dissolved in 10 ml of acetonitrile, and 0.8 ml of N-ethyldiisopropylamine is added under nitrogen. 0.5 ml of phosphoryl chloride are subsequently added slowly. The batch is boiled under reflux for 8 h in order to complete the reaction. All volatile constituents are subsequently removed in vacuo, and the batch is added to ice-water and dichloromethane. The organic phase is dried over sodium sulfate, filtered and evaporated. The residue obtained is employed in the subsequent reaction without further purification. (Rt: 2.694 min.; M+H+: 308.2+310.2).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.O>CN(C)C(=O)C>[OH:17][CH:18]1[CH2:23][CH2:22][N:21]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:20][CH2:19]1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=[N+]([O-])c1ccc(N2CCC(O)CC2)cc1
Temperature: 130 °C

Procedure:
4-chloronitrobenzene (31.5 g, 200 mmol) was dissolved in N,N-dimethylacetamide (80 ml), and potassium carbonate (35.9 g, 260 mmol) and 4-hydroxypiperidine (22.3 g, 220 mmol) were added thereto, followed by stirring under heat at 130° C. for 3 hours. After cooling to room temperature, water was added to the mixture, and the precipitate was collected by filtration. The obtained solid was dried under reduced pressure, thereby obtaining 4-hydroxy-N-(4-nitrophenyl)piperidine (41.3 g, 93%) as a yellow solid.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH:12]=O)[CH:10]=[CH:11][C:5]=2[S:4][CH2:3]1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][C:24]1[O:23][CH2:22][CH:21]([N:30]3[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]3)[CH2:20][C:19]2=1.C(O)(=O)C.C([BH3-])#N.[Na+]>ClCCCl.CO>[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][C:24]1[O:23][CH2:22][CH:21]([N:30]3[CH2:31][CH2:32][CH:33]([NH:36][CH2:12][C:9]4[CH:10]=[CH:11][C:5]5[S:4][CH2:3][C:2](=[O:1])[NH:7][C:6]=5[CH:8]=4)[CH2:34][CH2:35]3)[CH2:20][C:19]2=1
Reactant: O=Cc1ccc2c(c1)NC(=O)CS2
Reactant: COc1ccc2ncc3c(c2c1)CC(N1CCC(N)CC1)CO3
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1ccc2ncc3c(c2c1)CC(N1CCC(NCc2ccc4c(c2)NC(=O)CS4)CC1)CO3
Temperature: 25 °C
Reaction time: 15 h

Procedure:
3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbaldehyde (28 mg, 0.14 mmol 1.0 eq) is added at room temperature to a stirred solution of 1-(6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthrene-3-yl)-piperidin-4-ylamine (50 mg, 0.14 mmol, 1.0 eq) in 1,2-dichloroethane (3 mL) and methanol (1.5 mL), followed by acetic acid (9 μL, 0.16 mmol, 1.15 eq) and sodium cyanoborohydride (12 mg, 0.18 mmol, 1.3 eq). After 15 hours stirring at room temperature, the reaction mixture is extracted with dichloromethane (3×10 mL) and a saturated sodium hydrogen carbonate aqueous solution (10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by preparative HPLC to afford 6-{[1-(6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthrene-3-yl)-piperidin-4-ylamino]-methyl}-4H-benzo[1,4]thiazine-3-one as an off-white lyophilizated solid (25 mg, 36% yield).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[CH:4][N:3]=1.[CH2:12]([O:14][C:15](=[O:27])[CH:16]([CH2:22][CH2:23][CH2:24][C:25]#[N:26])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:13]>>[C:25]([CH2:24][CH2:23][CH2:22][C:16]([C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[CH:4][N:3]=1)([C:15]([O:14][CH2:12][CH3:13])=[O:27])[C:17]([O:19][CH2:20][CH3:21])=[O:18])#[N:26]
Reactant: CCOC(=O)C(CCCC#N)C(=O)OCC
Reactant: Cc1cnc(Cl)c([N+](=O)[O-])c1
Product: CCOC(=O)C(CCCC#N)(C(=O)OCC)c1ncc(C)cc1[N+](=O)[O-]

Procedure:
2-Chloro-5-methyl-3-nitro-pyridine (20 g) was reacted with 2-(3-cyanopropyl)malonic acid diethyl ester under conditions analogous to those in Example 1(a). The reaction mixture was partitioned between water and chloroform, the chloroform extract was dried, treated with charcoal and filtered through a silica bed and then evaporated to dryness to give 2-[4-cyano-1,1-dicarbethoxybutyl]-3-nitro-5-methylpyridine (18.3 g) as a yellow oil. N.M.R. (CDCl3) assignment, δ(p.p.m.), multiplicity; CO2CH2CH3 ×2, 1.2, t; --CH2CH2CH2CN, 1.3-2.0, m; --CH2CN, 2.37, m; 5-methylpyridyl, 2.49, s; CO2CH2CH3 ×2, 4.19, q; 4-pyridyl proton 8.17, m; 6-pyridyl proton, 8.57, m;
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH3:13][C:14](=[O:19])[CH2:15][C:16](=[O:18])[CH3:17].O>FC(F)(F)C(O)=O>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[C:15]([C:14](=[O:19])[CH3:13])[C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1
Reactant: CC(=O)CC(C)=O
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)C(=Cc1ccc(C(F)(F)F)cc1)C(C)=O
Temperature: 20 °C

Procedure:
4-Trifluoromethylbenzaldehyde (8,7 g) was condenced with 2,4-pentanedione (5,01 g in trifluoroacetic acid (10 ml) thionylchloride (4 ml) and catalytic amount of water (0,05 ml) were added at room temperature. The solution was stirred over right at 20° C. The solvent was evaporated and the residue was destilled in vacuo, bp 110° C./1,5 mbar. The crude product was crystallized from a mixture of ether-petroleum ether (1:1), mp 46°-48° C., yield 3,8 g (30 %).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.Br[C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=1>COCCOC.C([O-])([O-])=O.[Na+].[Na+].C(OCC)(=O)C.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>[N+:18]([C:13]1[CH:12]=[C:11]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH:16]=[CH:15][C:14]=1[NH2:17])([O-:20])=[O:19]
Reactant: OB(O)c1ccncc1
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Nc1ccc(-c2ccncc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 119.9 %

Procedure:
To a mixture of pyridine-4-boronic acid (3 mmol), 4-bromo-2-nitrophenylamine (2 mmol), and Pd(PPh3)4 (20 mg) in DME (10 mL), 2 M aqueous Na2CO3 was added. The suspension was then refluxed under nitrogen for 36 h. After cooling to the room temperature, the reaction mixture was diluted with ethyl acetate (150 mL). The organic phase was washed with brine (50 mL), dried over sodium sulfate, and concentrated under vacuum. The residue obtained was purified by column chromatography eluting with hexanes/ethyl acetate (1:1) then ethyl acetate/methanol (10:1) to give 516 mg of 2-nitro-4-pyridin-4-ylphenylamine. 1H NMR (DMSO-d6, 400 MHz): LC: Tr 0.44 min, MS: 216.1 (M+1)+. 1H NMR (DMSO-d6, 400 MHz): δ 7.13 (d, 1H), 7.60 (d, 2H), 7.69 (bs, 2H), 7.88 (dd, 1H), 8.37 (d, 1H), 8.55 (d, 2H) ppm.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2[CH2:6][CH2:7][O:8][C:4]=2[CH:3]=1.[Li]CCCC.CN([CH:19]=[O:20])C>C1COCC1>[O:8]1[C:4]2[CH:3]=[C:2]([CH:19]=[O:20])[CH:10]=[CH:9][C:5]=2[CH2:6][CH2:7]1
Reactant: CN(C)C=O
Reactant: Brc1ccc2c(c1)OCC2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccc2c(c1)OCC2
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a solution of 6-bromo-2,3-dihydro-1-benzofuran (190 mg, 0.955 mmol) in THF (4 ml) at −78° C. was added n-BuLi (1.313 ml, 2.100 mmol). The reaction mixture was stirred at −78° C. for 45 min then a solution of DMF (1.109 ml, 1.6 M in hexanes, 14.32 mmol) in THF (2 ml) was added dropwise and the reaction was stirred at −78° C. for 10 min then warmed to rt and stirred for 1 h. LCMS showed no starting material remaining. The reaction was stirred at rt for a further 2.5 h. The reaction mixture was poured cautiously into 2 M HCl (50 ml) and extracted with ethyl acetate (3×50 ml). The combined organic extracts were washed with brine (50 ml), dried over MgSO4, filtered, evaporated and chromatographed (eluting 0-100% EtOAc/Hexane). The relevant fractions were combined and evaporated to deliver the product as a clear, colourless oil (44 mg, 0.297 mmol, 31%).
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][N:9]=[CH:10][CH:11]=2)[N:6]([CH2:13][C:14]([OH:16])=[O:15])[N:5]=1)(=[O:3])[NH2:2].[F:17][C:18]([F:29])([F:28])C1C=C2C=NNC2=CN=1>>[C:1]([C:4]1[C:12]2[C:7](=[CH:8][N:9]=[C:10]([C:18]([F:29])([F:28])[F:17])[CH:11]=2)[N:6]([CH2:13][C:14]([OH:16])=[O:15])[N:5]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)c1nn(CC(=O)O)c2cnccc12
Reactant: FC(F)(F)c1cc2cn[nH]c2cn1
Product: NC(=O)c1nn(CC(=O)O)c2cnc(C(F)(F)F)cc12

Procedure:
was prepared by using the same procedure as described for the preparation of 2-(3-carbamoyl-1H-pyrazolo[3,4-c]pyridin-1-yl)acetic acid and by starting from 5-trifluoromethyl-1H-pyrazolo[3,4-c]pyridine (Scheme A26). MS (LC-MS): 289 [M+H]+, tR (HPLC conditions c): 2.93 min.
Reaction SMILES: [CH:1]1([C:11]([OH:13])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:14]([N:16]1[CH:20]=[C:19]([CH2:21][NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:25][CH:24]=2)[CH:18]=[N:17]1)[CH3:15]>>[CH2:14]([N:16]1[CH:20]=[C:19]([CH2:21][N:22]([C:23]2[CH:24]=[CH:25][C:26]([CH:29]([CH3:30])[CH3:31])=[CH:27][CH:28]=2)[C:11]([CH:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)=[O:13])[CH:18]=[N:17]1)[CH3:15]
Reactant: O=C(O)C1CCCc2ccccc21
Reactant: CCn1cc(CNc2ccc(C(C)C)cc2)cn1
Product: CCn1cc(CN(C(=O)C2CCCc3ccccc32)c2ccc(C(C)C)cc2)cn1
Yield: 12.8 %

Procedure:
By the reaction and treatment in the same manner as in Example 1 using 1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.5 g) and [(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.57 g) as starting materials, N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.12 g) was obtained. melting point: 75-76° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[C:15]([O:16][CH:17]([F:19])[F:18])=[CH:14][N:13]=[C:12]([O:20]C)[CH:11]=2)[CH:3]=1.Br.[NH+]1C=CC=CC=1>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[C:15]([O:16][CH:17]([F:18])[F:19])=[CH:14][NH:13][C:12](=[O:20])[CH:11]=2)[CH:3]=1
Reactant: COc1cc(-c2cc(Cl)ccc2C#N)c(OC(F)F)cn1
Agent: Br
Agent: c1cc[nH+]cc1
Product: N#Cc1ccc(Cl)cc1-c1cc(=O)[nH]cc1OC(F)F

Procedure:
230 mg (purity 80%, 0.59 mmol) of 4-chloro-2-[5-(difluoromethoxy)-2-methoxypyridin-4-yl]benzonitrile and pyridinium hydrobromide were reacted according to General Method 3A. The crude product was purified by flash chromatography (IR-50SI, dichloromethane/methanol 3-25%). Yield: 167 mg (95% of theory)
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:13])=[N+:4]([O-:12])[CH:5]=[C:6]([CH3:11])[C:7]=1[N+]([O-])=O.P(Cl)(Cl)([Cl:16])=O.[OH-].[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[C:3]([CH3:13])=[N+:4]([O-:12])[CH:5]=[C:6]([CH3:11])[C:7]=1[Cl:16]
Reactant: Cc1c[n+]([O-])c(C)c(Cl)c1[N+](=O)[O-]
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1c[n+]([O-])c(C)c(Cl)c1Cl
Temperature: 0 °C

Procedure:
The above 3-chloro-2,5-dimethyl-4-nitropyridine 1-oxide (405 mg) was dissolved in dichloromethane (5 mL), and phosphorus oxychloride (915 μL) was added with stirring under ice-cooling. After stirring at room temperature overnight, the reaction solution was introduced into ice water and neutralized with 5 N sodium hydroxide and a saturated sodium bicarbonate solution with stirring under ice-cooling. The mixture was extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain the title compound (387 mg, quant.) as a solid.
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:8]=1[OH:14].C(N(CC)CC)C>C1COCC1>[CH3:13][C:9]1[C:8]2[O:14][CH2:2][C:3](=[O:4])[NH:6][C:7]=2[CH:12]=[CH:11][CH:10]=1
Reactant: Cc1cccc(N)c1O
Reactant: O=C(Cl)CCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cccc2c1OCC(=O)N2
Reaction time: 24 h
Yield: 78.4 %

Procedure:
A solution of chloroacetyl chloride (0.71 mL, 8.94 mmol) in THF (5 mL) was added dropwise to a solution/suspension of 2-amino-6-methylphenol (1 g, 8.13 mmol) and triethylamine (1.24 mL, 8.94 mmol) in THF (50 mL) which had been pre-cooled in an ice-water bath. After stirring for 5 minutes a further portion of triethylamine (1.24 mL, 8.94 mmol) was added. The mixture was stirred and warmed to r. t. After 24 h the reaction was allowed to stand overnight. The mixture was concentrated in vacuo and the residue was partitioned between water (100 mL) and EtOAc (50 mL). Brine (20 mL) was added to the aqueous phase, and this was further extracted with EtOAc (50 mL). The combined organic fractions were dried (MgSO4), concentrated in vacuo, and purified by column chromatography (SiO2, 20-100% EtOAc/heptane) to give an orange-brown solid (1.04 g), which was dissolved in THF (10 mL) and triethylamine (2 mL), and the mixture left to stand for 3 days. The mixture was concentrated in vacuo and purified by column chromatography (SiO2, 10-50% EtOAc/heptane) to give a cream solid (0.6 g). This was dissolved in DCM (40 mL), and the solution was washed with aqueous NaOH (2M, 10 mL). The organic fraction was dried (MgSO4) and concentrated in vacuo to give the title compound (0.29 g, 22%) as a beige solid. LCMS (ES+) 164 (M+H)+, RT 2.61 minutes (Method 1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([NH:17][C:18](=[O:47])[CH2:19][NH:20][C:21]([C:23]1[CH:46]=[CH:45][C:26]2[N:27]([CH3:44])[C:28]([NH:30][C:31]3[S:32][C:33]4[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:37]=[CH:36][C:34]=4[N:35]=3)=[N:29][C:25]=2[CH:24]=1)=[O:22])[C:14](O)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:48][NH:49][CH3:50].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1.CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C@@H:13]([C:14](=[O:15])[N:49]([CH3:50])[CH3:48])[NH:17][C:18](=[O:47])[CH2:19][NH:20][C:21]([C:23]1[CH:46]=[CH:45][C:26]2[N:27]([CH3:44])[C:28]([NH:30][C:31]3[S:32][C:33]4[CH:39]=[C:38]([C:40]([F:43])([F:41])[F:42])[CH:37]=[CH:36][C:34]=4[N:35]=3)=[N:29][C:25]=2[CH:24]=1)=[O:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC
Reactant: Cn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)NCC(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN(C)C(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)CNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(C(F)(F)F)cc3s1)n2C

Procedure:
[(S)-5-Dimethylcarbamoyl-5-(2-{[1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-acetylamino)-pentyl]-carbamic acid tert-butyl ester (200 mg) was prepared by following General Procedure F starting from (S)-6-tert-butoxycarbonylamino-2-(2-{[1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-acetylamino)-hexanoic acid (260 mg), 2 M dimethylamine in THF (1 mL), HBTU (400 mg), and DIEA (400 uL) in DMF (2 mL).
Reaction SMILES: Br[C:2]1[C:3]([OH:13])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[N:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>COCCOC.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:9][C:6]1[C:7]([CH3:8])=[C:2]([C:17]2[CH:18]=[CH:19][N:14]=[CH:15][CH:16]=2)[C:3]([OH:13])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=1
Reactant: OB(O)c1ccncc1
Reactant: CC(=O)c1cc(Cl)c(C)c(Br)c1O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: CC(=O)c1cc(Cl)c(C)c(-c2ccncc2)c1O
Temperature: 90 °C
Yield: 46.3 %

Procedure:
A solution of 1-(3-bromo-5-chloro-2-hydroxy-4-methylphenyl)ethanone (2.6 g, 9.9 mmol), 4-pyridinylboronic acid (1.6 g, 13 mmol), and potassium carbonate (5.5 g, 40 mmol) in 1,2-dimethoxyethane (48 mL) and water (24 mL) was degassed with nitrogen and treated with triphenylphosphine (260 mg, 0.99 mmol) and palladium acetate (0.22 g, 0.99 mmol). The reaction mixture was degassed with nitrogen for 5 min and heated at 90° C. for 20 hours. The reaction mixture was cooled to room temperature, concentrated to remove most of the DME, diluted with ethyl acetate (200 ml) and water (100 ml), and filtered over celite. The aqueous layer was separated and extracted with ethyl acetate (100 mL). The combined organic layers were washed with brine (100 ml), dried over sodium sulfate, filtered, and concentrated to a crude brown foam. Purification by flash column chromatography using ethyl acetate in hexanes (0%-60%) gave the desired product (1.2 g, 45%). LCMS for C14H13ClNO2 (M+H)+: m/z=262.1. Found: 262.0.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][C:16]([O:25][CH3:26])=[CH:17][C:18]=3[O:23][CH3:24])[N:13]=2)=[CH:7][C:6]=1[CH3:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:48]>CN(C)C=O>[Br:48][CH2:2][CH2:3][CH2:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][C:16]([O:25][CH3:26])=[CH:17][C:18]=3[O:23][CH3:24])[N:13]=2)=[CH:7][C:6]=1[CH3:27]
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(CCCO)c(C)c3)nc2c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(CCCBr)c(C)c3)nc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-[4-(3-hydroxy-propyl)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (1.00 g, 2.70 mmol) in anhydrous N,N-dimethylformamide (15 mL) were added triphenylphosphine (0.78 g, 3.00 mmol) and carbon tetrabromide (1.00 g, 3.00 mmol). The reaction mixture was stirred at room temperature for 16 hours. DMF was removed under reduced pressure. The residue was purified by column chromatography (silica gel 230-400 mesh; 3% methanol in dichloromethane as eluent) to give 2-[4-(3-bromo-propyl)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one as an off-white solid. Yield: 0.60 g (51%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12]3=[N:16][N:17]=[C:18]([CH3:19])[N:11]3[C:10]3[CH:20]=[CH:21][CH:22]=[CH:23][C:9]2=3)=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].I[CH2:35][CH3:36]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH:13]([CH2:35][CH3:36])[C:12]3=[N:16][N:17]=[C:18]([CH3:19])[N:11]3[C:10]3[CH:20]=[CH:21][CH:22]=[CH:23][C:9]2=3)=[CH:4][CH:3]=1
Reactant: Cc1nnc2n1-c1ccccc1N(c1ccc(Cl)cc1)C(=O)C2
Reactant: CCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC1C(=O)N(c2ccc(Cl)cc2)c2ccccc2-n2c(C)nnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.3 %

Procedure:
Into a 50 mL flask evacuated and brimmed with dry nitrogen, was charged with a solution of 6-(4-chlorophenyl)-1-methyl-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-5(6H)-one (Example 1, step 5; 100 mg, 0.31 mmol) in anhydrous tetrahydrofuran (10 mL). To this mixture, was added lithium bis(trimethylsilyl)amide (tetrahydrofuran solution) (0.17 mL, 0.33 mmol) at −78° C. The mixture was stirred at the same temperature for 1 hour, and then warmed to room temperature, maintained at the same temperature for 2 hours. Iodoethane (92.04 mg, 0.59 mmol) was added. The mixture was stirred at room temperature for another 2 hours. The reaction was quenched by ammonium chloride aqueous (5 mL), extracted with ethyl acetate (5 mL*3). The crude product was purified by column chromatography (silica gel, dichloromethane/methanol=25:1) to give 6-(4-chlorophenyl)-4-ethyl-1-methyl-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-5(6H)-one as a light yellow solid (20.0 mg, 18%). LRMS (M+H)+: calcd 352.11. found 352.
Reaction SMILES: [N:1]1[CH2:2][CH:3]=[CH:4][CH:5]=[CH:6][C:7]=1[NH2:8].Cl.C(=O)([O-])[O-].[K+].[K+].[N:16]1[CH:21]=[CH:20][C:19]([C:22](=O)[CH2:23][C:24](OCC)=[O:25])=[N:18][CH:17]=1>C(O)C>[N:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:8]=[C:7]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:1]3[C:24](=[O:25])[CH:23]=2)=[N:18][CH:17]=1
Reactant: NC1=NCC=CC=C1
Reactant: CCOC(=O)CC(=O)c1ccncn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=c1cc(-c2ccncn2)nc2n1CCCCC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 28.7 %

Procedure:
To a suspension of 77.9 g (524.1 mmol) of 2H-azepin-7-amine, 3,4,5,6-tetrahydro, monohydrochloride (synthesis as described in WO96/14844 or in Journal of Medicinal Chemistry (1998), 41(9), 1361-1366) in 390 mL of ethanol was added 72.4 g (524.1 mmol) of potassium carbonate. The reaction mixture was stirred at room temperature for 10 min, 101.7 g (524.1 mmol) of ethyl 3-(4-pyrimidinyl)-3-oxopropionate was added and the resulting mixture was stirred under reflux for 16 h. The cooled solution was evaporated to remove solvent. The mixture was dissolved in dichloromethane, washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and evaporated to dryness. The residue was filtrate through a pad of silica, rinsing with dichloromethane and then ethyl acetate. After evaporation, the resulting solid was triturated in diethyl ether, filtrated to afford 36.4 g (28%) of the desired compound as a white-brown powder.