Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[NH:21][N:22]=[C:23]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([NH:30][CH2:31][C:32]5[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=5)[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)(C)(C)C.Cl>C(O)C>[Cl:38][C:34]1[CH:33]=[C:32]([CH:37]=[CH:36][CH:35]=1)[CH2:31][NH:30][C:26]1[N:25]=[C:24]([C:23]2[C:18]3[C:19](=[N:20][C:15]([NH:14][CH:11]4[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:13][CH2:12]4)=[N:16][CH:17]=3)[NH:21][N:22]=2)[CH:29]=[CH:28][N:27]=1
Reactant: CC(C)(C)OC(=O)NC1CCC(Nc2ncc3c(-c4ccnc(NCc5cccc(Cl)c5)n4)n[nH]c3n2)CC1
Agent: Cl
Solvent: CCO
Product: NC1CCC(Nc2ncc3c(-c4ccnc(NCc5cccc(Cl)c5)n4)n[nH]c3n2)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of (4-{3-[2-(3-chloro-benzylamino)-pyrimidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino}-cyclohexyl)-carbamic acid tert-butyl ester (150 mg, 0.27 mmol) in ethanol (5 mL) was added concentrated hydrochloric acid (3 mL) slowly. The reaction mixture was stirred at room temperature for 15 hours. The solvent was then removed under reduced pressure and the solid was purified by prep-HPLC and concentrated to afford N-{3-[2-(3-chloro-benzylamino)-pyrimidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-6-yl}-cyclohexane-1,4-diamine; hydrochloride. (Yield 25 mg, 20.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[C:5]([NH:7][C:8]([CH3:16])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:9])=[O:6].CN(CCN(C)C)C.CN([CH:33]=[O:34])C>C1COCC1>[Cl:1][C:2]1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[C:4]2[C:3]=1[CH:33]([OH:34])[N:7]([C:8]([CH3:16])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:9])[C:5]2=[O:6]
Reactant: COc1ccc(C(=O)NC(C)(C)c2ccccc2)cc1Cl
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Product: COc1ccc2c(c1Cl)C(O)N(C(C)(C)c1ccccc1)C2=O
Yield: 70.3 %

Procedure:
In a similar manner to Step 2 of Example 16, 3-chloro-4-methoxy-N-(1-methyl-1-phenylethyl)benzamide (500 mg, 1.65 mmol) was dissolved in THF (20 mL), and the solution was treated with TMEDA (0.80 mL, 5.3 mmol), sec-butyl lithium-hexane solution (0.99 mol/L, 5.3 mL, 5.3 mmol) and DMF (0.281 mL, 3.63 mmol), followed by purification by slurry using diisopropylether to obtain 4-chloro-5-methoxy-3-hydroxy-2-(1-methyl-1-phenylethyl)isoindolinone (385 mg, yield 71%).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[Cl:5][CH:6]([CH3:10])[C:7](Cl)=[O:8]>C(OCC)C>[OH:3][CH2:2][CH2:1][O:4][C:7](=[O:8])[CH:6]([Cl:5])[CH3:10]
Reactant: OCCO
Reactant: CC(Cl)C(=O)Cl
Solvent: CCOCC
Product: CC(Cl)C(=O)OCCO
Temperature: 65 °C
Yield: 71.7 %

Procedure:
The compound depicted in FIG. 1E (hereinafter "Compound 1E" was made as follows: ethylene glycol (310.0 g, 5.00 moles) was heated to 60° C. before beginning the dropwise addition of 2-chloropropanoyl chloride (127.0 g, 1.00 mole) dissolved in 300 ml of anhydrous diethyl ether. The reaction was exothermic and the temperature rose to 65° C. The ether was allowed to boil off throughout the reaction. The reaction was heated to maintain 65° C. throughout the latter part of the addition and for 30 minutes after completion. The reaction solution was separated into two 250 ml batches that were added separately to 400 ml of H2O and extracted three times with 200 ml of hexane. The hexane extract was discarded and the aqueous phase was saturated with potassium chloride and extracted three times with 200 ml of ethyl acetate. The ethyl acetate was evaporated in vacuo and the concentrate was diluted with 300 ml of diethyl ether and dried over a mixture of anhydrous potassium carbonate and magnesium sulfate. After removing the solvent, the oil was vacuum distilled to give 109.4 g (71.0% yield) of approximately 95% pure 2-hydroxyethyl-2-chloropropanoate. The colorless, clear liquid had a boiling point of 85°-87° C./0.20 mm Hg. The structure of the compound was in agreement with the following data:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[C:10]([S:13][CH3:14])[CH:11]=[CH:12][C:7]=2[N:6]([C:15]([CH:17]2[CH2:22][CH:21]([CH3:23])[CH2:20][CH2:19][CH:18]2[CH:24]([CH3:26])[CH3:25])=[O:16])[C:5]1=[O:27].C(O)(C(F)(F)F)=[O:29].CS(C)=O>>[NH2:1][CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[C:10]([S:13]([CH3:14])=[O:29])[CH:11]=[CH:12][C:7]=2[N:6]([C:15]([CH:17]2[CH2:22][CH:21]([CH3:23])[CH2:20][CH2:19][CH:18]2[CH:24]([CH3:26])[CH3:25])=[O:16])[C:5]1=[O:27]
Reactant: CSc1ccc2c(c1)n(CCN)c(=O)n2C(=O)C1CC(C)CCC1C(C)C
Reactant: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: CC1CCC(C(C)C)C(C(=O)n2c(=O)n(CCN)c3cc(S(C)=O)ccc32)C1
Reaction time: 18 h

Procedure:
A 10 mL reaction flask was charged with 3-(2-Amino-ethyl)-1-(2-isopropyl-5-methyl-cyclohexanecarbonyl)-5-methylsulfanyl-1,3-dihydro-benzoimidazol-2-one (Compound #42, 300 mg) and 1% TFA/DMSO (1 mL). Oxygen was bubbled through the reaction mixture for 20 min and sealed. The reaction mixture was stirred for 18 h and crude product was purified by preparative HPLC (Ultro 120 (10 um) C18Q) using a 40-60% acetonitrile/H2O (with 0.1% TFA) gradient. The pure fractions were combined, concentrated and lyophilized to give a light fluffy colorless solid (296 mg 94%). MS (ESI) m/z 406 (M++1).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:14]2[CH2:18][CH2:17][C:16]([F:20])([F:19])[CH2:15]2)[C:8]2[N:13]=[N:12][NH:11][C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C@@H:28](O)[CH3:29].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([C:5]1[N:6]=[C:7]([N:14]2[CH2:18][CH2:17][C:16]([F:19])([F:20])[CH2:15]2)[C:8]2[C:9](=[N:11][N:12]([C@@H:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[Cl:21])[CH3:29])[N:13]=2)[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H](O)c1ccccc1Cl
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1Cl)n1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.1 %

Procedure:
To a solution of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (41.3 μmol), (S)-1-(2-chlorophenyl)ethanol (12.9 mg, 82.6 μmol) and PPh3 (21.7 mg, 82.6 μmol) in THF (250 μL) was added DEAD (13.1 μL, 82.6 μmol) at 0° C. After being stirred at the room temperature for 2 h, the reaction mixture was directly purified by preparative HPLC (column: Gemini 5 um C18 110A 75×30 mm. mobile phase: water (0.05% Et3N): acetonitrile 50:50% to 5:95%. WL: 300 nm Flow: 30 mL/min.) to afford the title compound as white solid (3.5 mg, 20%). MS (m/e): 421.4 (MH+).
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=[O:5])C.[CH2:24]([O:26][C:27](=[O:32])[CH2:28][N:29]=[C:30]=[O:31])[CH3:25]>>[CH2:24]([O:26][C:27](=[O:32])[CH2:28][N:29]1[C:4](=[O:5])[C:6]2[CH:7]=[N:8][C:9]3[C:10]([O:22][CH3:23])=[CH:11][CH:12]=[CH:13][C:14]=3[C:15]=2[N:16]([CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21]2)[C:30]1=[O:31])[CH3:25]
Reactant: CCOC(=O)CN=C=O
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Product: CCOC(=O)Cn1c(=O)c2cnc3c(OC)cccc3c2n(C2CCCC2)c1=O
Yield: 60.4 %

Procedure:
(1-Cyclopentyl-7-methoxy-2,4-dioxo-1,4-dihydro-2H-pyrimido[5,4-c]quinolin-3-yl)-acetic acid ethyl ester (24 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.1 mmol) and isocyanato-acetic acid ethyl ester (0.5 mmol) following general procedure C. LCMS: m/z 398 [M+1]+.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20](I)=[CH:19][C:18]=2[F:24])=[C:4]([CH:12]=[CH:13][C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].C([O-])([O-])=O.[K+].[K+].O.[B].[CH2:33]([CH2:36]OC)OC>[Cl-].[Na+].O.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>[CH:33]([C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:3]2[C:2]([F:1])=[C:14]([F:15])[CH:13]=[CH:12][C:4]=2[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6])=[C:18]([F:24])[CH:19]=1)=[CH2:36]
Reactant: O=C(NOCCO)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: COCCOC
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: [B]
Solvent: O
Product: C=Cc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 76 %

Procedure:
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide (1.00 g, 2.21 mmol) was dissolved in dry dimethoxyethane (DME, 18 ml) under a nitrogen atmosphere, Pd(Ph3P)4 (0.13 g, 0.11 mmol) was added and the resulting yellow solution was stirred at ambient temperature for 20 min. K2CO3 (−325 mesh, 0.31 g, 2.21 mmol), water (5.3 ml) and boron complex 2 (0.54 g, 2.21 mmol) were added and the contents of the flask were refluxed for 1 h.1 Water (50 ml) and brine (50 ml) were added and the aqueous phase was extracted with ethyl acetate (3×50 ml). The combined organic extracts were washed with brine (20 ml) and dried over MgSO4. The solvent was removed under vacuum and the residual dark orange oil was chromatographed (ethyl acetate as eluent) to give 0.59 g (76% yield) of 2-[(4-vinyl-2-fluorophenyl)amino]-3,4-difluoro-N-(2-hydroxy-ethoxy)benzamide as a light yellow solid, mp 134–137° C. 1H NMR (d6-DMSO) δ 3.53–3.54 (m, 2 H), 3.82 (s, 2 H), 4.69–4.72 (m, 1 H), 5.14 (d, 1H, J=11 Hz), 5.69–5.77 (m, 1 H), 6.57–6.64 (m, 1 H), 6.77–6.83 (m, 1 H), 7.09–7.18 (m, 2 H), 7.33–7.40 (m, 2 H), 8.74 (bs, 1 H), 11.86 (bs, 1 H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][S:12]([C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[CH:17][CH:16]=1)(=[O:14])=[O:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-]>CO>[CH2:1]([O:8][C:9]([NH:11][S:12]([C:15]1[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:23][CH:24]=1)(=[O:13])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)NC(=O)OCc2ccccc2)cc1
Agent: [OH-]
Solvent: CO
Product: O=C(NS(=O)(=O)c1ccc(C(=O)O)cc1)OCc1ccccc1
Reaction time: 0.58 h

Procedure:
A suspension of methyl 4-({[(benzyloxy)carbonyl]amino}-sulfonyl)benzoate (3.38 g) and 85% pottasium hydroxide (1.28 g) in methanol (40 mL) was stirred for 35 minutes. Methanol was evaporated off, and to the mixture was added 1N hydrochloric acid (20 mL). A white crystal was formed, which was collected by filtration and washed with water and diisopropyl ether, and dried under vacuum. 4-({[(Benzyloxy)carbonyl]amino}sulfonyl)benzoic acid was obtained as a white crystal (2.92 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.CN([C:15]([O:19][N:20]1N=NC2C=CC=N[C:21]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.Cl.CONC>CN(C=O)C>[CH3:15][O:19][N:20]([CH3:21])[C:9]([C:3]1[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([Br:8])[N:4]=1)=[O:11]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Nc1ncc(Br)nc1C(=O)O
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1nc(Br)cnc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-amino-6-bromo-pyrazine-2-carboxylic acid (0.62 g, 2.8 mmol), HATU (1.3 g, 3.4 mmol) and di-isopropylethylamine (1.72 ml, 3.5 mmol) in DMF (20 ml) is stirred at room temperature for 5 minutes. N-Methoxy-N-methylamine hydrochloride (0.33 g, 3.4 mmol) is added and the reaction is stirred at room temperature for 2 hours. The solvent is concentrated in vacuo and the residue dissolved in EtOAc (30 ml), and washed with sat. aq. NaHCO3 (20 ml), 0.1N HCl (20 ml), dried (MgSO4) and concentrated in vacuo to yield a brown oil. Purification by flash chromatography (SiO2, 30% EtOAc in iso-hexane) yields 3-amino-6-bromo-pyrazine-2-carboxylic acid methoxy-methyl-amide as a yellow solid [M+H]+261.
Reaction SMILES: N[C:2]1[C:3]([C:8]2[CH:26]=[CH:25][C:11]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=3)=[O:13])=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.N([O-])=O.[Na+].[H+].[B-](F)(F)(F)[F:33]>O>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:12](=[O:13])[C:11]2[CH:25]=[CH:26][C:8]([C:3]3[C:2]([F:33])=[CH:7][CH:6]=[CH:5][N:4]=3)=[CH:9][CH:10]=2)=[CH:16][CH:17]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: F[B-](F)(F)F
Reactant: CC(C)(C)c1ccc(NC(=O)c2ccc(-c3ncccc3N)cc2)cc1
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)c1ccc(NC(=O)c2ccc(-c3ncccc3F)cc2)cc1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
The product from Example 3 (52.0 mg, 0.145 mmol) in 48% HBF4 (0.75 mL) and water (0.1 mL) was treated with solid NaNO2 (11.9 mg, 0.172 mmol) at 0° C. After stirring for 30 minutes, the layers were allowed to separate and the liquid was layer was removed by pipette. The remaining solid was dried under reduced pressure and slurried in toluene (1.5 mL). The suspension was heated at 100° C. for 2.5 hours, allowed to cool to room temperature, and the toluene was removed by pipette. The residue was treated with 1N NaOH (1 mL) and CHCl3 (1 mL) and stirred for 15 minutes. The phases were allowed to separate and the aqueous layer was extracted with CHCl3 (2×1 mL). The organic layers were combined, dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (20% ethyl acetate in hexanes) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ 8.56 (dt, 1H), 8.12 (d, 2H), 7.98 (d, 2H), 7.84 (br s, 1H), 7.59 (d, 2H), 7.53 (ddd, 1H), 7.40 (d, 2H), 7.33 (ddd, 1H), 1.33 (s, 9H); MS (m/z) 349.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[H][H]>C(O)C.[Ni]>[N:7]1[CH:2]=[CH:3][CH:4]=[C:5]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:12][CH2:11]2)[N:6]=1
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)N1CCC(CNc2ccc(Cl)nn2)CC1
Agent: [Ni]
Solvent: CCO
Product: O=C(OCc1ccccc1)N1CCC(CNc2cccnn2)CC1

Procedure:
Benzyl 4-{[(6-chloro-3-pyridazinyl)amino]methyl}-1-piperidinecarboxylate (EXAMPLE 22) (400 mg, 1.11 mmol) was dissolved in absolute ethanol. Raney nickel (65 mg, 1.11 mmol) was then added and the resulting reaction was stirred under 1 atm hydrogen for 18 h. The catalyst was filtered and the filtrate was concentrated under reduced pressure. The resulting clear oil was purified by silica gel chromatography to give the title compound as a clear oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:22]=1[CH2:23]Cl>CN1CCCC1=O>[CH3:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:22]=1[CH2:23][N:1]1[C:9]2[C:4](=[N:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: COC(=O)c1cnc2cc[nH]c2c1
Reactant: Cc1cccc(C)c1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COC(=O)c1cnc2ccn(Cc3c(C)cccc3C)c2c1
Yield: 25.1 %

Procedure:
To a solution of methyl 1H-pyrrolo[3,2-b]pyridin-6-carboxylate (50 mg) in N-methyl-2-pyrrolidone (1 mL) were added potassium carbonate (158 mg) and 2,6-dimethylbenzyl chloride (91 mg), and then the reaction mixture was subjected to microwave irradiation at 160° C. for 30 minutes. The reaction mixture was quenched with water, and extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the titled compound (21 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][CH:8]([CH3:15])[CH2:7][C:6]2=[O:16].C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl.Cl[C:27]([O:29][CH2:30][CH3:31])=[O:28]>CCCCCC.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:8]([CH3:15])[CH2:7][C:6]2=[O:16]
Reactant: COc1cc2c(cc1OC)C(=O)CC(C)N2
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: CCOC(=O)N1c2cc(OC)c(OC)cc2C(=O)CC1C
Reaction time: 72 h

Procedure:
A mixture of 15 g. of the quinoline product of Example 4, 95 g. of potassium carbonate, and 225 ml. of methylene chloride was stirred for 1 hr., then 14.7 g. of ethyl chloroformate in 20 ml. of methylene chloride was added dropwise and the suspension was allowed to stir for 72 hrs. at room temperature. Additional 7.3 g. portions of ethyl chloroformate were added after 24 and 48 hrs. and 47 g. of potassium carbonate was added after 48 hrs. The reaction mixture was quenched with water and extracted several times with methylene chloride. The combined organic extracts were washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give an oil which solidified upon standing; trituration with 5% ethyl acetate in hexane gave 17 g. of a solid, m.p. 112°-116°. This solid was chromatographed on silica gel, eluting with 1:1 ethyl acetate/hexane, and recrystallized from 1:1 ethyl acetate/hexane to give 13.9 g. of white crystals, m.p. 116.5°-18°.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:16]([C:18]2[CH:19]=[N:20][C:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[N:22][CH:23]=2)O)[CH:13]=[CH:14][CH:15]=1)(C(C)(C)C)(C)C.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>>[N:24]1([C:21]2[N:20]=[CH:19][C:18]([CH2:16][C:12]3[CH:11]=[C:10]([CH2:9][OH:8])[CH:15]=[CH:14][CH:13]=3)=[CH:23][N:22]=2)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(C(O)c2cnc(N3CCOCC3)nc2)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: OCc1cccc(Cc2cnc(N3CCOCC3)nc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.2 %

Procedure:
[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)phenyl][2-(morpholin-4-yl)pyrimidin-5-yl]methanol (400 mg), triethylsilane (364 mg), and TFA (4 ml) were mixed, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and EtOAc and water were added to the obtained residue. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain (3-{[2-(morpholin-4-yl)pyrimidin-5-yl]methyl}phenyl)methanol (39 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10](SC)[CH:9]([CH2:14][CH:15]([CH3:17])[CH3:16])[N:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]=2[CH:24]=1.CO.O.[NH2:28][NH2:29]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:28][NH2:29])[CH:9]([CH2:14][CH:15]([CH3:17])[CH3:16])[N:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]=2[CH:24]=1
Reactant: CSC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1CC(C)C
Reactant: NN
Solvent: CO
Solvent: O
Product: CC(C)CC1N=C(c2ccccc2)c2cc(Cl)ccc2N=C1NN

Procedure:
To a solution of 1.6 parts of 7-chloro-3-isobutyl-2-methylmercapto-5-phenyl-3H-1,4-benzodiazepine in 150 parts by volume of methanol is added 40 parts of 100% hydrazine hydrate. The mixture is refluxed for 4.5 hours and poured into water, followed by extraction with chloroform. The chloroform layer is washed with water, dried over sodium sulfate and the solvent is evaporated. Treatment of the residue with diethyl ether yields 7-chloro-2-hydrazino-3-isobutyl-5-phenyl-3H-1,4-benzodiazepine as crystals. Recrystallization from a mixture of chloroform and n-hexane yields colorless crystals melting at 168° C to 169° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].N1C=CN=C1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].O>C(Cl)Cl>[C:18]([Si:15]([O:9][C:3]1[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])([CH3:17])[CH3:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: Cc1cccc(F)c1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: Cc1cccc(F)c1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2-fluoro-6-methylphenol (176 mg, 1.40 mmol) in DCM (6.3 mL), cooled to 0° Celsius, were added imidazole (142 mg, 2.09 mmol) followed by tert-butyldimethylsilyl chloride (231 mg, 1.54 mmol). The flask was warmed to rt and stirred for 2 hours The reaction mixture was then poured in to water (50 mL) and extracted with DCM (3×50 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated to dryness to provide the title compound that was used without further purification. 1H NMR (500 MHz, CDCl3) δ 6.91-6.85 (m, 2H), 6.80-6.73 (m, 1H), 2.24 (t, J=0.7, 3H), 1.02 (s, 9H), 0.20 (d, J=2.5, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].N1C=CN=C1>CN(C=O)C.C([O-])(O)=O.[Na+]>[O:1]([C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1)[Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: Oc1ccc2c(-c3ccccc3)ccnc2c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c(-c3ccccc3)ccnc2c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 7-hydroxy-4-phenylquinoline (366 mg), tert-butyldimethylsilyl chloride (200 mg) and imidazole (282 mg) in DMF (2 mL) was stirred at r.t. for 17 hr and then diluted with 5% aq. NaHCO3 (20 mL). The mixture was extracted with EtOAc (3×) and the combined organics were washed with H2O (3×), brine, dried (MgSO4) and concentrated. Flash chromatography of the residue (silica gel; EtOAc/hexane (15:85)) provided the title compound as a solid.
Reaction SMILES: [CH2:1]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9](Br)[C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:15][O:16][C:17](=[O:23])[CH2:18][C:19]([O:21][CH3:22])=[O:20].[Na]>CO>[CH3:15][O:16][C:17](=[O:23])[CH:18]([CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1=[O:8])[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)CC(=O)OC
Reactant: O=C1CCCCCCCCCCC1Br
Agent: [Na]
Solvent: CO
Product: COC(=O)C(C(=O)OC)C1CCCCCCCCCCC1=O

Procedure:
reacting α-bromocyclododecanone with sodium malonic acid dimethyl ester in methanol at from about 10° to 40° C. to form 2-(2-oxocyclododec-1-yl)-malonic acid dimethyl ester;
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.C([Mg]Cl)(C)C.CCOCC.[NH2:19][C:20]1[N:31]=[CH:30][C:29]([Br:32])=[CH:28][C:21]=1[C:22](N(OC)C)=[O:23]>O1CCCC1.CCOCC.CO>[NH2:19][C:20]1[C:21]([C:22]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=2)=[O:23])=[CH:28][C:29]([Br:32])=[CH:30][N:31]=1
Reactant: CON(C)C(=O)c1cc(Br)cnc1N
Reactant: Fc1cccc(Br)n1
Agent: CC(C)[Mg]Cl
Solvent: CCOCC
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ncc(Br)cc1C(=O)c1cccc(F)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-bromo-6-fluoropyridine (7.5 g, 42.6 mmol) in tetrahydrofuran (50 ml) at 0° C. was added a 2 M solution of isopropylmagnesium chloride in ether (21.3 ml, 42.6 mmol) over a period of 10 minutes. The ice-bath was removed and the reaction mixture was stirred at room temperature for 2 hours. The resulting solution was added dropwise to a solution of 2-amino-5-bromo-N-methoxy-N-methylnicotinamide (3 g, 11.5 mmol) in tetrahydrofuran (40 ml) at room temperature over a period of 30 minutes. The resulting solution was stirred at room temperature for 18 hours. The solution was quenched by addition of an aqueous saturated solution of ammonium chloride at 0° C. and the mixture was stirred at room temperature for 20 minutes. Water was added and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography (ISCO Companion□, 80 g column, 0-100% EtOAc/Petrol) to give an orange sticky solid which was slurried in ether/MeOH, collected by filtration and dried. The desired compound was obtained as a yellow solid (196 mg, 6% yield).