Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]=[C:2]1[CH2:6][CH2:7][CH:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[CH3:15][O:16][CH:17]([O:21][CH3:22])N(C)C>CO>[CH3:15][O:16][CH:17]([O:21][CH3:22])[N:11]1[CH2:12][CH2:13][CH2:14][CH:8]([CH2:7][CH2:6][C:2]2[NH:3][CH2:4][CH2:5][N:1]=2)[CH2:9][CH2:10]1
Reactant: COC(OC)N(C)C
Reactant: C1CNCCC(CCC2=NCCN2)C1
Solvent: CO
Product: COC(OC)N1CCCC(CCC2=NCCN2)CC1
Temperature: 90 °C

Procedure:
A mixture containing rac-4-[2-(4,5-dihydro-1H-imidazol-2-yl)ethyl]hexahydro-1H-azepine (1.95 g, 0.01M), methanol (50 ml) and dimethylformamide dimethylacetal (36 ml) was heated at 90° C. for 8 hrs. The excess of dimethylformamide dimethylacetal was removed in vacuo to give 4-[2-(4,5-dihydro-1H-imidazol-2-yl)ethyl]hexahydro-1H-azepine-1-carboxaldehyde dimethylacetal to the mixture of 6-aminopenicillanic acid (1.95 g, 0.009M) and diisopropylethylamine (1.52 ml) in dry chloroform (25 ml) was added the solution fo the above hexahydroazepine carboxaldehyde dimethylacetal in dry chloroform (10 ml) at 0° C. The reaction was stirred at 0° C. for 1 hr. and at room temperature for 3 hrs. After the reaction solvent was removed and the residue dissolved in water (30 ml). The aqueous solution, washed with ethylacetate was acidified to pH 3 with dil. HCl and purified on Sephadex LH 20 columns to give [ 2S-(2alpha,5alpha,6beta)]-6-[[[4-[2-(4,5-dihydro-1H-imidazol-2-yl)ethyl]hexahydro-1H-azepin-1-yl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid hyrochloride (1.03 g, 27% yield).
Reaction SMILES: Br.[CH2:2]([O:4][C:5]([N:7]1[CH2:13][CH:12]([NH2:14])[C:11]2=[N:15][C:16]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)=[CH:17][C:18](=[O:19])[N:10]2[CH2:9][CH2:8]1)=[O:6])[CH3:3].[Cl:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[C:29]([O:36][CH3:37])[CH:28]=1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>CN(C)C=O>[CH2:2]([O:4][C:5]([N:7]1[CH2:13][CH:12]([NH:14][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][C:27]([Cl:26])=[CH:28][C:29]=2[O:36][CH3:37])[C:11]2=[N:15][C:16]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)=[CH:17][C:18](=[O:19])[N:10]2[CH2:9][CH2:8]1)=[O:6])[CH3:3]
Reactant: COc1cc(Cl)ccc1C(=O)O
Reactant: CCOC(=O)N1CCn2c(nc(-c3ccncn3)cc2=O)C(N)C1
Agent: Br
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCn2c(nc(-c3ccncn3)cc2=O)C(NC(=O)c2ccc(Cl)cc2OC)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.4 %

Procedure:
To a solution of 0.060 g (0.18 mmol) of (+/−)-9-amino-4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-1,4a,7-triaza-benzocycloheptene-7-carboxylic acid ethyl ester hydrobromide (1:1) dissolved in 1.80 mL of dimethylformamide was added 0.037 g (0.20 mmol) of 4-chloro-2-methoxy-benzoic acid. To the resulting mixture was added 40 μL (0.22 mmol) of diethyl cyanophosphonate and 30 μl (0.20 mmol) of triethylamine at 0° C. The resulting mixture was stirred at room temperature for 2 hours and evaporated to dryness. Water was added and the mixture extracted with dichloromethane. The extracts were washed with a saturated aqueous solution of sodium carbonate, saturated aqueous solution of ammonium chloride, saturated aqueous sodium chloride dried and evaporated. The residue was triturated with a mixture of diethyl ether/ethyl acetate and filtered to afford 0.048 g (53%) of the pure product as a powder.
Reaction SMILES: [CH:1]1([CH2:7][NH:8][CH2:9][CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:20][O:21][C:22]([CH2:24][CH2:25][CH2:26][C:27](Cl)=[O:28])=[O:23]>>[CH:1]1([CH2:7][N:8]([C:27](=[O:28])[CH2:26][CH2:25][CH2:24][C:22]([O:21][CH3:20])=[O:23])[CH2:9][CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)CCCC(=O)Cl
Reactant: c1ccc2c(CCNCC3CCCCC3)c[nH]c2c1
Product: COC(=O)CCCC(=O)N(CCc1c[nH]c2ccccc12)CC1CCCCC1
Yield: 84.5 %

Procedure:
12.0 g of N-cyclohexylmethyl-tryptamine and 8.47 g of 4-methoxycarbonylbutyryl chloride were treated in the same manner as described in Example 1. 15.2 g of N-cyclohexylmethyl-N-(4-methoxycarbonylbutyryl)-tryptamine (i.e., 3-[2-(N-cyclohexylmethyl-4-methoxycarbonylbutanamido)-ethyl]-indole) were thereby obtained. Yield: 84.9%
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][C:8](SC)=[N:7][C:6]=2[C:5]([O:13][CH3:14])=[CH:4][CH:3]=1.[NH:15]1[CH2:18][CH2:17][CH2:16]1>>[N:15]1([C:8]2[O:9][C:10]3[C:2]([Br:1])=[CH:3][CH:4]=[C:5]([O:13][CH3:14])[C:6]=3[N:7]=2)[CH2:18][CH2:17][CH2:16]1
Reactant: C1CNC1
Reactant: COc1ccc(Br)c2oc(SC)nc12
Product: COc1ccc(Br)c2oc(N3CCC3)nc12
Yield: 59.5 %

Procedure:
Starting from 7-bromo-4-methoxy-2-methylsulfanylbenzooxazole (4.8 g) and azetidine (1.0 g). Purification by chromatography on silica eluting with 50% ethyl acetate in heptane afforded the title compound as a pink solid (2.95 g).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1.[Li]CCCC.CN(OC)[C:30](=[O:32])[CH3:31].Cl>C1COCC1.O>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:30](=[O:32])[CH3:31])[N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1
Reactant: Clc1nc(N2CCOCC2)c2ncn(C3CCCCO3)c2n1
Reactant: CON(C)C(C)=O
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1nc2c(N3CCOCC3)nc(Cl)nc2n1C1CCCCO1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 82.9 %

Procedure:
A solution of 2-Chloro-6-morpholin-4-yl-9-(tetrahydro-pyran-2-yl)-9H-purine (0.50 g, 1.55 mmol) and N,N,N′,N-tetramethylethylenediamine (0.35 mL, 2.33 mmol) in dry THF (14 mL) was cooled to −78° C. n-BuLi (2.5M in hexanes, 1.22 mL, 3.05 mmol) was added dropwise and the mixture was stirred at −78° C. for 40 min. N-methyl-N-methoxyacetamide (0.25 mL, 2.33 mmol) was added dropwise and the mixture was stirred at −78° C. for 1.5 h, then allowed to warm to −30° C. Water was added followed by 1M aqueous HCl and the mixture was extracted seven times with ethyl acetate. The combined organic extracts were dried (Na2 SO4), filtered and concentrated in vacuo. The resulting residue was subjected to flash chromatography (SiO2), gradient 0-50% ethyl acetate in cyclohexane to give 1-[2-Chloro-6-morpholin-4-yl-9-(tetrahydro-pyran-2-yl)-9H-purin-8-yl]-ethanone (0.47 g, 83%). LCMS RT=3.57 min, [M+H]+=366/368
Reaction SMILES: [OH:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.C1CCC(N=C=NC2CCCCC2)CC1.C([NH:62][C@H:63]([C:68](O)=[O:69])[CH2:64][CH:65]([CH3:67])[CH3:66])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O>CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[NH2:62][C@H:63]([C:68]([O:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](=[O:26])[NH2:27])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:69])[CH2:64][CH:65]([CH3:67])[CH3:66]
Reactant: NC(=O)c1ccc(C[C@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@@H]2O)cc1
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](N)C(=O)O[C@H]1c2ccccc2C[C@]1(Cc1ccc(C(N)=O)cc1)C1=Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 61.8 %

Procedure:
To a solution of 4-{[(1′R,2′R)-1′-hydroxy-1′,3′-dihydro-1H,2′H-2,2′-biinden-2′-yl]methyl}benzamide (13, 140 mg, 0.36 mmol), DCC (90 mg, 0.44 mmol) and DMAP (4.3 mg, 0.036 mmol) in ethyl acetate (10 mL), was added Fmoc leucine (126 mg, 0.36 mmol) and then stirred at room temperature for 12 h. The solids were filtered, washed with ethyl acetate (25 ml) and the combined filtrate was washed with 1.5 N HCl (25 mL), water (25 mL), brine (10 mL), dried over anhydrous Na2SO4. The organic layer was evaporated under reduced pressure and the residue 1 (250 mg) was dissolved in dry THF (5 mL) and cooled to 0° C. Dimethylamine (5 mL, 20% in THF) was added drop wise and the reaction mixture was slowly allowed to stir at room temperature for 1 h. The reaction mixture was evaporated under reduced pressure and the residue was purified by CombiFlash using 10% methanol in chloroform as an eluent to yield 110 mg (63%) of the title compound as an off white solid.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]([F:38])([F:37])[C:21]1[CH:36]=[CH:35][CH:34]=[CH:33][C:22]=1[CH:23](O)[C:24]1[CH:29]=[CH:28][C:27]([S:30][CH3:31])=[CH:26][CH:25]=1.C(N1CC(OC(C2C=CC(Cl)=CC=2)C2C=CC(Cl)=CC=2Cl)C1)(C1C=CC=CC=1)C1C=CC=CC=1>>[CH:1]([N:14]1[CH2:17][CH:16]([O:18][CH:23]([C:24]2[CH:25]=[CH:26][C:27]([S:30][CH3:31])=[CH:28][CH:29]=2)[C:22]2[CH:33]=[CH:34][CH:35]=[CH:36][C:21]=2[C:20]([F:38])([F:37])[F:19])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CSc1ccc(C(O)c2ccccc2C(F)(F)F)cc1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: Clc1ccc(C(OC2CN(C(c3ccccc3)c3ccccc3)C2)c2ccc(Cl)cc2Cl)cc1
Product: CSc1ccc(C(OC2CN(C(c3ccccc3)c3ccccc3)C2)c2ccccc2C(F)(F)F)cc1

Procedure:
This material was prepared from 1-benzhydryl-3-azetidinol (1) (15 mmol) and 2-(trifluoromethyl)-4′-(methylthio)benzhydrol (116) (30 mmol) using the procedure described for compound (3) (4.68 g, 60%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=3)[N:11]=[CH:10][N:9]=2)=[N:3]1.[CH:19]1([C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=2F)=[O:23])[CH2:21][CH2:20]1.C(O[K])(C)(C)C.O>CN(C)C(=O)C>[CH:19]1([C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=2[O:18][C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[N:11]=[CH:10][N:9]=[C:8]3[NH:7][C:4]2[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=2)=[O:23])[CH2:20][CH2:21]1
Reactant: Cn1ccc(Nc2ncnc3ccc(O)cc23)n1
Reactant: O=C(c1cccc(F)c1F)C1CC1
Agent: CC(C)(C)O[K]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cn1ccc(Nc2ncnc3ccc(Oc4c(F)cccc4C(=O)C4CC4)cc23)n1
Temperature: 110 °C
Reaction time: 1 h
Yield: 30.8 %

Procedure:
4-[(1-Methyl-1H-pyrazol-3-yl)amino]quinazolin-6-ol (70 mg; 0.290 mmol) and 63 mg (0.346 mmol) of cyclopropyl(2,3-difluorophenyl)methanone were added to a solution of 81 mg (0.723 mmol) of tert-butoxy potassium in 6 ml of N,N-dimethylacetamide and the mixture was stirred at 110° C. for 1 hour. Water was added to the reaction solution and the mixture was extracted with chloroform. The organic layer was dried and concentrated and the resulting residue was purified by a silica gel chromatography (chloroform:methanol=10:1) to give 36 mg (yield: 31%) of the title compound as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:37]([F:40])([F:39])[F:38])[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][C:29](=[O:31])[NH:28][C:27](=[O:32])[CH2:26]4)=[O:24])=[C:19]([C:33]([F:36])([F:35])[F:34])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.I[CH2:42][CH2:43][CH3:44].C(=O)([O-])[O-].[K+].[K+].CC#N>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:37]([F:40])([F:38])[F:39])[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:26][C:27](=[O:32])[N:28]([CH2:42][CH2:43][CH3:44])[C:29](=[O:31])[CH2:30]4)=[O:24])=[C:19]([C:33]([F:36])([F:35])[F:34])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: CCCI
Reactant: O=C1CN(C(=O)c2ccc(C3=NOC(c4cc(Cl)cc(C(F)(F)F)c4)(C(F)(F)F)C3)cc2C(F)(F)F)CC(=O)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCCN1C(=O)CN(C(=O)c2ccc(C3=NOC(c4cc(Cl)cc(C(F)(F)F)c4)(C(F)(F)F)C3)cc2C(F)(F)F)CC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 25-mL round-bottom flask, was placed a solution of 4-[(4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-(trifluoromethyl)phenyl)carbonyl]piperazine-2,6-dione (70 mg, 0.12 mmol, 1.00 equiv) in N,N-dimethylformamide (2 mL), 1-iodopropane (32 mg, 0.19 mmol, 2.00 equiv), potassium carbonate (59 mg, 0.43 mmol, 3.00 equiv). The resulting solution was stirred for 2 h at 25° C. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 2×10 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:2). This resulted in 31 mg (41%) of 4-[(4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-(trifluoromethyl)phenyl)carbonyl]-1-propylpiperazine-2,6-dione as a white solid. (ES, m/z): [M+CH3CN]+ 685.0; 1H NMR (300 MHz, CDCl3): δ 7.79-7.84 (m, 2H), 7.73-7.87 (m, 3H), 7.46 (d, J=7.8 Hz, 1H), 4.86 (d, J=19.4 Hz, 1H), 4.56 (d, J=18.3 Hz, 1H), 4.19 (d, J=17.4 Hz, 1H), 4.05 (s, 2H), 3.75-3.81 (m, 3H), 1.52-1.64 (m, 2H), 0.93 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5](OS(C(F)(F)F)(=O)=O)=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.[CH3:21][N:22](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[C:21]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:12])[NH:10]2)#[N:22]
Reactant: CN(C)C=O
Reactant: Cc1ccc(OS(=O)(=O)C(F)(F)F)c2c1NC(=O)CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1ccc(C#N)c2c1NC(=O)CC2
Temperature: 100 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
8-Methyl-5-trifluoromethanesulfonyloxy-3,4-dihydro-1H-quinolin-2-one (4.0 g), zinc cyanide (3.34 g) and tetrakis(triphenylphosphine)palladium (0.299 g) were suspended in DMF (40 ml), and the suspension was stirred at 100° C. for 4 hours. The insoluble matter was filtered off, and ethyl acetate was added to the filtrate, followed by washing with water. After drying over anhydrous magnesium sulfate, the dry product was concentrated, and the residue was recrystallized from a DMF-ethanol mixed solvent to thereby obtain 2.1 g (yield: 87%) of 5-cyano-8-methyl-3,4-dihydro-1H-quinolin-2-one as a light brown powder.
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5]([Cl:6])=[N:4][C:2]=1[Cl:3].CC(C)=O.[OH-].[Na+].[C:16]1([CH:23]=[CH:22][CH:21]=[C:19]([OH:20])[CH:18]=1)[OH:17]>O>[Cl:6][C:5]1([O:17][C:16]2[CH:23]=[CH:22][CH:21]=[C:19]([O:20][C:5]3([Cl:6])[N:4]=[C:2]([Cl:3])[N:1]=[CH:8][NH:7]3)[CH:18]=2)[N:4]=[C:2]([Cl:3])[N:1]=[CH:8][NH:7]1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Oc1cccc(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: ClC1=NC(Cl)(Oc2cccc(OC3(Cl)N=C(Cl)N=CN3)c2)NC=N1
Reaction time: 4 h
Yield: 890.2 %

Procedure:
A 1 L jacketed reaction flask equipped with a gas inlet, a mechanical stirrer, two liquid inlets and a condenser is purged with argon and charged with 37.3 g (0.0200 mol) of cyanuric chloride and 300 mL of acetone. The stirred mixture is cooled below −15° C. and 30 mL of deionized water are added. A 10% aqueous sodium hydroxide solution (88 g) are added over a 66-minute period via a peristaltic pump. Six minutes after the sodium hydroxide addition is started, a resorcinol solution (11.0 g, 0.100 mol in 50 mL of water) addition is begun also via a peristaltic pump. The resorcinol solution is then added over a 60-minute period concurrent with the sodium hydroxide solution. A slight exotherm occurs causing the temperature to rise to −12° C. The mixture is then stirred for an additional four hours at between −15° C. and −20° C. A 200 mL poriton of water is added and the white solids formed are collected by vacuum filtration followed by washing with three 50 mL portions of water. The solids are dried at 60° C. under reduced pressure to afford 36.5 g of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[O:11][CH:12]([C:14]([OH:16])=[O:15])[CH2:13][C:9]=2[C:8]2[CH2:7][CH:6]([CH2:17][CH2:18][CH3:19])[C:5](=[O:20])[C:4]=2[C:3]=1[CH3:21].[Br:22]Br.O.S(=O)(=O)(O)[O-].[Na+]>C(O)(=O)C>[CH3:1][C:2]1[C:10]2[O:11][CH:12]([C:14]([OH:16])=[O:15])[CH2:13][C:9]=2[C:8]2[CH2:7][C:6]([Br:22])([CH2:17][CH2:18][CH3:19])[C:5](=[O:20])[C:4]=2[C:3]=1[CH3:21]
Reactant: CCCC1Cc2c3c(c(C)c(C)c2C1=O)OC(C(=O)O)C3
Reactant: BrBr
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCC1(Br)Cc2c3c(c(C)c(C)c2C1=O)OC(C(=O)O)C3
Yield: 78.4 %

Procedure:
A stirred suspension of 4,5-dimethyl-6-oxo-7-propyl-1,2,7,8-tetrahydro-6H-indeno[5,4-b]furan-2-carboxylic acid (14 g., 0.00486 mole) in acetic acid (15 ml.) is treated with a solution of bromine (0.8 g., 0.005 mole) in acetic acid (5 ml.) during a three minute period. The reaction mixture is poured into water (100 ml.) containing sodium bisulfate (1 g.), extracted with ether, washed with water, dried over magnesium sulfate and the ether distilled at reduced pressure affording an oil which on trituration with cyclohexane affords 4,5-dimethyl-6-oxo-7-bromo-7-propyl-1,2,7,8-tetrahydro-6H-indeno[5,4-b]furan-2-carboxylic acid (1.4 g., 78%) as a white solid which melts at 78°C. and is used in the next step without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[N:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:42]([O:45][CH2:46][O:47][C:48](=[O:69])[C@@:49]([CH2:67][OH:68])([CH3:66])[CH2:50][C@H:51]([NH2:65])[CH2:52][C:53]1[CH:58]=[CH:57][C:56]([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)=[CH:55][CH:54]=1)(=[O:44])[CH3:43]>CN(C=O)C>[C:42]([O:45][CH2:46][O:47][C:48](=[O:69])[C@@:49]([CH2:67][OH:68])([CH3:66])[CH2:50][C@H:51]([NH:65][C:6]([C:4]1[NH:3][N:2]=[N:1][CH:5]=1)=[O:8])[CH2:52][C:53]1[CH:54]=[CH:55][C:56]([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)=[CH:57][CH:58]=1)(=[O:44])[CH3:43]
Reactant: O=C(O)c1c[nH]nn1
Reactant: CC(=O)OCOC(=O)[C@](C)(CO)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)OCOC(=O)[C@](C)(CO)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 5 %

Procedure:
1,2,3-Triazole-4-carboxylic acid (14 mg, 124 μmol), DIPEA (86.3 μL, 496 μmol) and HATU (47.1 mg, 124 μmol) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. This was then combined with (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid acetoxymethyl ester (47.8 mg, 124 μmol). The resulting mixture was stirred for 15 minutes and the reaction was quenched with AcOH. The product purified by preparative HPLC and lyophilized to yield the title compound (3 mg; purity 95%). MS m/z [M+H]+ calc'd for C25H28N4O6, 481.20. found 481.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]Cl)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1.[I-].[K+].[CH3:26][NH:27][CH2:28][CH:29]1[CH2:31][CH2:30]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][N:27]([CH2:28][CH:29]4[CH2:31][CH2:30]4)[CH3:26])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:6]=2[CH:23]=1
Reactant: CNCC1CC1
Reactant: ClCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN(Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2)CC1CC1

Procedure:
A stirred mixture of 8-chloro-1-(chloromethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine (1.37 g., 0.004 mole), potassium iodide (0.67 g., 0.004 mole), methyl(cyclopropylmethyl)amine (1.02 g., 0.012 mole) and tetrahydrofuran (100 ml.) is kept at ambient temperature (25° C.) for 18 hours and concentrated in vacuo. The extract is washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue is crystallized from ethyl acetate and methylene chlorideethyl acetate to give 8-chloro-1-[[(cyclopropylmethyl)methylamino]methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine. Preparation 30 8 -Chloro-1-[[(cyclopropylmethyl)-methylamino]methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine
Reaction SMILES: [C:1]1([C:7]2[C:22](=[O:23])[NH:21][C:10]3=[C:11]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:12]=[N:13][CH:14]=[C:9]3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:31][C:32]1[N:33]([CH3:37])[N:34]=[CH:35][N:36]=1.O>CN(C=O)C>[C:1]1([C:7]2[C:22]([O:23][CH2:31][C:32]3[N:33]([CH3:37])[N:34]=[CH:35][N:36]=3)=[N:21][C:10]3=[C:11]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:12]=[N:13][CH:14]=[C:9]3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=c1[nH]c2c(-c3ccccc3)nncc2cc1-c1ccccc1
Reactant: Cn1ncnc1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ncnc1COc1nc2c(-c3ccccc3)nncc2cc1-c1ccccc1

Procedure:
3,8-Diphenyl-1H-pyrido[2,3-d]pyridazin-2-one (40 mg), cesium carbonate (174 mg) and 3-(chloromethyl)-2-methyl-2H-[1,2,4]triazole (prepared using the conditions described in EP-A-0170073) (27 mg) were stirred together at room temperature in DMF (4 ml) under nitrogen overnight. Water (25 ml) was added and the resultant solution was washed with dichloromethane (3×25 ml). The combined organic washings were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative thin layer chromatography on silica gel, eluting with 5% methanol in dichloromethane. The product was recrystallised froim diethyl ether/ethanol/ethyl acetate, yielding 3,8-diphenyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)pyrido[2,3-d]pyridazine as a white solid (8 mg). Data for the title compound: m.p. 222-223° C. 1H NMR (400 MHz, CDCl3) δ3.62 (3H, s), 5.67 (2H, s), 7.48 (3H, m), 7.56 (3H, m), 7.63 (2H, m), 7.85 (1H, s), 8.13 (2H, m), 8.20 (1H, s), 9.49 (1H, s); MS (ES+) m/e 395 [MH]+.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]#[C:17][C:18]2[CH:19]=[C:20]([NH2:25])[C:21]([NH2:24])=[CH:22][CH:23]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26](C1NC=CN=1)(C1NC=CN=1)=[O:27]>C1COCC1.CCOCC>[CH2:1]([CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][C:16]#[C:17][C:18]2[CH:23]=[CH:22][C:21]3[NH:24][C:26](=[O:27])[NH:25][C:20]=3[CH:19]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(C#CCCN2CCC(Cc3ccccc3)CC2)cc1N
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=c1[nH]c2ccc(C#CCCN3CCC(Cc4ccccc4)CC3)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.8 %

Procedure:
A mixture of 4-[4-(4-benzyl-piperidin-1-yl)-but-1-ynyl]-benzene-1,2-diamine (Example 70) (333 mg, 1 mmol) and carbonyl diimidazole (243 mg, 1.5 mmol) in THF (5 mL) is stirred at room temperature for 1 hr. A precipitate forms; the mixture is diluted with ether (10 mL), filtered and the solid washed with ether to give the title compound as a white powder (233 mg): mp 221-223° C.
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:22])[CH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)C>O.CCO>[C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][CH:9]([CH2:8][CH2:7][C:6]([OH:22])=[O:5])[CH2:10][CH2:11]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: CCOC(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CCC(=O)O)CC1
Reaction time: 2.5 h

Procedure:
A solution of KOH (86%, 0.42 g, 6.4 mmol) in water (1.5 mL) was added to a solution of 3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propionic acid ethyl ester in 95% EtOH (15 mL) at rt. After 2.5 h, the mixture was partitioned between EtOAc (50 mL) and 2 N aq. HCl (50 mL). After extraction of the aqueous layer with EtOAc (50 mL), the organic layers were washed with sat'd NaCl (25 mL), dried (Na2SO4), decanted, and evaporated to give 1.06 g of the title compound as a crystalline solid.