Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[C:16]1C(CCCC2C=CC=CC=2)=C(C)C=[CH:20][C:21]=1S([O-])(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:36]([NH:39][CH:40]([CH3:42])[CH3:41])([CH3:38])[CH3:37]>C(#N)C>[CH:36]([N:39]([CH2:20][CH2:21][CH:16]([C:10]1[CH:11]=[C:12]([Br:15])[CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:40]([CH3:42])[CH3:41])([CH3:38])[CH3:37]
Reactant: Cc1ccc(S(=O)(=O)[O-])c(-c2cc(Br)ccc2OCc2ccccc2)c1CCCc1ccccc1
Reactant: CC(C)NC(C)C
Solvent: CC#N
Product: CC(C)N(CCC(c1ccccc1)c1cc(Br)ccc1OCc1ccccc1)C(C)C
Yield: 163.6 %

Procedure:
3-(2-benzyloxy-5-bromophenyl)-3-phenylpropyl-p-toluenesulfonate (115 g, 0.2 mole) was dissolved in a mixture of acetonitrile (150 g) and diisopropylamine (202 g, 2.0 mole) and the mixture was refluxed for 4 days. The solution was evaporated, and to the resulting syrup was added sodium hydroxide (2M, 200 mL). The mixture was concentrated, cooled and then extracted with diethyl ether. The ethereal layer was extensively washed with water. The amine was extracted with excess sulfuric acid (1M). The aqueous layer was washed with diethyl ether and then basified with sodium hydroxide (11M). The mixture was then extracted with diethyl ether. The organic layer was washed with water, dried over sodium sulfate, filtered and then evaporated to give 78.6 g (78%) of N,N-diisopropyl-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropylamine as a pale yellow oil. The 1-H N.M.R spectrum was in accordance with the above structure.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:14])([CH3:13])[C:11](=[O:15])[N:10]([C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([C:24]([F:27])([F:26])[F:25])[CH:17]=3)[C:9]2=[S:28])=[CH:4][CH:3]=1.[C:29](Cl)(=[O:31])[CH3:30].C(N(CC)CC)C>ClCCl>[C:20]([C:19]1[CH:22]=[CH:23][C:16]([N:10]2[C:11](=[O:15])[C:12]([CH3:14])([CH3:13])[N:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:29](=[O:31])[CH3:30])=[CH:7][CH:6]=3)[C:9]2=[S:28])=[CH:17][C:18]=1[C:24]([F:26])([F:27])[F:25])#[N:21]
Reactant: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=S)N1c1ccc(N)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C2(C)C)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
A mixture of 4-[3-(4-aminophenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-trifluoromethylbenzonitrile (2d) [RD9] (0.008 g, 0.02 mmol), acetyl chloride (0.004 g, 0.03 mmol) and triethylamine (0.003 g, 0.03 mmol) in dichloromethane (1 ml) was stirred at 0° C. for 2 hours. The mixture was concentrated and chromatographed (dichloromethane:acetone, 90:10) to yield N -{4-[3-(4-cyano-3-trifluoromethylphenyl)-5,5-dimethyl-4-oxo-2-thioxo-imidazolidin-1-yl]phenyl}acetamide, 48a, [RD151] (0.007 g, 0.016 mmol, 80%), the structure of which is illustrated in Formula 3, as a white powder.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH3:17])[CH2:11][C:10]2[C:5](=[C:6]([CH3:15])[C:7]([CH:13]=[CH2:14])=[C:8]([CH3:12])[CH:9]=2)[CH:4]1[OH:16].N1C=CN=C1.[Si:23](Cl)([CH2:28][CH3:29])([CH2:26][CH3:27])[CH2:24][CH3:25]>C(Cl)Cl.O>[CH3:17][C:3]1([CH2:2][O:1][Si:23]([CH2:28][CH3:29])([CH2:26][CH3:27])[CH2:24][CH3:25])[CH2:11][C:10]2[C:5](=[C:6]([CH3:15])[C:7]([CH:13]=[CH2:14])=[C:8]([CH3:12])[CH:9]=2)[CH:4]1[OH:16]
Reactant: CC[Si](Cl)(CC)CC
Reactant: C=Cc1c(C)cc2c(c1C)C(O)C(C)(CO)C2
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: C=Cc1c(C)cc2c(c1C)C(O)C(C)(CO[Si](CC)(CC)CC)C2
Reaction time: 6 h
Yield: 67 %

Procedure:
To the stirred solution of starting material 7 (0.85 g, 3.66 mmol) in dry CH2Cl2 added Imidazole (0.5 g, 7.32 mmol) and TESCl (0.6 mL, 3.66 mmol) sequentially at 0° C. under argon atmosphere and stirred the reaction mixture at same temperature for 6 h. Then reaction mixture was diluted with H2O (10 mL) followed by extraction with CH2Cl2 (50 mL), brine (25 mL), dried (Na2SO4) and concentrated in vacuo. Purification by column chromatography (SiO2, 5 to 10% EtOAc in petroleum ether eluant) gave pure compound 8 (0.85 g, 88%) as syrup.
Reaction SMILES: C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[NH2:15][CH:16]([C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:26])[CH2:17][NH2:18].C(=O)(O)[O-].[Na+].[CH3:32][O:33][C:34]([NH:36][C:37](=NC(OC)=O)SC)=[O:35]>C(O)(C)C.C(Cl)(Cl)Cl>[Cl:26][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([Cl:25])[C:19]=1[CH:16]1[CH2:17][NH:18][C:37]([NH:36][C:34]([O:33][CH3:32])=[O:35])=[N:15]1
Reactant: COC(=O)N=C(NC(=O)OC)SC
Reactant: NCC(N)c1c(Cl)cccc1Cl
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: O=C([O-])O
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: COC(=O)NC1=NC(c2c(Cl)cccc2Cl)CN1
Reaction time: 144 h

Procedure:
Three and one-half (3.5) grams (g) of the dihydrochloride salt of β-amino-β-(2,6-dichlorophenyl)ethylamine is added to a suitable reaction vessel containing 30 milliliters (ml) of saturated sodium bicarbonate. The resulting mixture is stirred, diluted with 50 mls of isopropanol and a solution of 2.8 g of a mixture of 1-mono- amd 1,3-bis(methoxycarbonyl)-S-methylisothiourea in 50 ml of chloroform is added. Stirring is continued for six days and the solvents are removed under vacuum. The residue is stirred with 70 ml of 2% hydrochloric acid for 30 minutes and the acidic aqueous solution is washed several times with ether, once with toluene and is then treated with excess of saturated sodium bicarbonate. The resulting precipitate is collected by filtration, stirred with water, collected again and dried at 55° under vacuum affording 2.25 g of 4,5-dihydro-4-(2,6-dichlorophenyl)-2-methoxycarbonylaminoimidazole, melting point (mp) 227°-229° C. A small sample is further purified by recrystallization from toluene to give 4,5-dihydro-4-(2,6-dichlorophenyl)-2-methoxycarbonylaminoimidazole, mp 230°-231° C.
Reaction SMILES: B(O)O.Cl[C:5]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][N:6]=1.C(=O)([O-])[O-].[K+].[K+].O.[C:19](#[N:21])[CH3:20]>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>[Cl:11][C:10]1[C:5]([C:20]2[CH:19]=[N:21][C:9]([CH3:10])=[CH:8][CH:7]=2)=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: Clc1cccnc1Cl
Reactant: CC#N
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: OBO
Solvent: O
Product: Cc1ccc(-c2ncccc2Cl)cn1
Temperature: 160 °C

Procedure:
The above boronic acid (4.2 mmol) was dissolved in acetonitrile (2 ml) and added to a 5 ml microwave vessel. To the solution was 6.9 mmol of 2,3-dichloropyridine (1.01 g), 53 mg of tetrakis(triphenylphosphine)palladium(0). After stirring until dissolution, 13.8 mmol of potassium carbonate (1.90 g) was added, followed by 1 ml of water. The mixture was then heated at 160° C. for 300 seconds. After reaction completion, the solvents were evaporated under vacuum. The target compound was purified by HPLC to give a yellow solid (800 mg; 85%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:18]=[N:19][C:20](Cl)=[C:21]([CH3:24])[C:22]=3[CH3:23])[CH2:13][C@H:12]2[CH3:26])=[N:9][CH:10]=1)=[O:4].CC(C([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1)(O)C(C)C)C.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>[O-]S(C(F)(F)F)(=O)=O.[Pd+2].[O-]S(C(F)(F)F)(=O)=O.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:18]=[N:19][C:20]([CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=4)=[C:21]([CH3:24])[C:22]=3[CH3:23])[CH2:13][C@H:12]2[CH3:26])=[N:9][CH:10]=1)=[O:4]
Reactant: CC(C)C(O)(Cc1ccccn1)C(C)C
Reactant: COC(=O)c1cnc(N2CCN(c3nnc(Cl)c(C)c3C)C[C@H]2C)cn1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)c1cnc(N2CCN(c3nnc(Cc4ccccn4)c(C)c3C)C[C@H]2C)cn1
Temperature: 110 °C
Yield: 5.4 %

Procedure:
(R)-4-(6-Chloro-4,5-dimethyl-pyridazin-3-yl)-2-methyl-3,4,5,6-tetrahydro-2H [1,2′]bipyrazinyl-5′-carboxylic acid methyl ester (250 mg, 0.663 mmol) is combined with 2,4-dimethyl-3-pyridin-2-ylmethyl-pentan-3-ol (114.6 mg, 0.553 mmol), cesium carbonate (216.2 mg, 0.664 mmol), palladium triflate (6.2 mg, 0.028 mmol), tricyclohexyl phosphine (15.5 mg, 0.055), and toluene (2 mL). The reaction mixture is heated to 110° C. for 65 h to reach 10% conversion. Add H2O and extract with EtOAc. Concentrate combined organics in vacuo. The residue is purified by flash chromatography on silica gel (MeOH/CH2Cl2) to afford the title compound (13 mg, 5.4%).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[C:11]([CH3:13])[C:10]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=3)=[N:19][CH:20]=2)=[CH:9][C:4]=1[C:5](OC)=[O:6])=O.Cl.[NH2:29][C@@H:30]1[CH2:35][CH2:34][CH2:33][CH2:32][C@H:31]1[OH:36].C(N(CC)CC)C.S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1>[OH:36][C@@H:31]1[CH2:32][CH2:33][CH2:34][CH2:35][C@H:30]1[N:29]1[CH2:1][C:3]2[C:4](=[CH:9][C:10]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]4[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=4)=[N:19][CH:20]=3)=[C:11]([CH3:13])[CH:12]=2)[C:5]1=[O:6]
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: COC(=O)c1cc(Cc2ccc(-c3ccnc(C)c3)nc2)c(C)cc1C=O
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(Cc3cc4c(cc3C)CN([C@@H]3CCCC[C@H]3O)C4=O)cn2)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.5 %

Procedure:
A solution of methyl 2-formyl-4-methyl-5-((2′-methyl-[2,4′-bipyridine]-5-yl)methyl)benzoate (0.06 g), trans-2-aminocyclohexanol hydrochloride (0.02 g), triethylamine (0.02 mL) and anhydrous magnesium sulfate (0.04 g) in THF (1.20 mL) was stirred at room temperature for 1.5 hr. The insoluble substance was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was diluted with methanol (1.20 mL) and THF (1.20 mL), sodium triacetoxyborohydride (0.06 g) was added thereto, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.02 g).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH2:12]([O:19][C:20]1[CH:37]=[CH:36][C:23]([CH:24]([OH:35])[C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[CH:22][C:21]=1[O:38][CH3:39])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([O:19][C:20]1[CH:37]=[CH:36][C:23]([C:24]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:27][CH:26]=2)=[O:35])=[CH:22][C:21]=1[O:38][CH3:39])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COc1cc(C(O)c2ccc(C(F)(F)F)cc2)ccc1OCc1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Product: COc1cc(C(=O)c2ccc(C(F)(F)F)cc2)ccc1OCc1ccccc1
Reaction time: 2 h

Procedure:
52.6 g of 4-(benzyloxy)-3-methoxy-4'-(trifluoromethyl)benzhydrol (dissolved in 500 ml of methylene chloride) are treated within 10 minutes at 20° with 30.6 g of pyridinium chlorochromate and stirred at 20° for 2 hours. The precipitate formed is subsequently filtered and washed with methylene chloride. The filtrate is evaporated and the residue is chromatographed on 150 g of silica gel with methylene chloride. After recrystallization from methylene chloride/hexane, there is obtained 4-(benzyloxy)-3-methoxy-4'-(trifluoromethyl)benzophenone of melting point 101°.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=O)[CH2:2][C:3](C)=O.Cl.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][NH2:19])=[CH:14][CH:13]=1>C(O)(=O)C>[CH2:8]([O:7][C:1]1[N:18]([C:15]2[CH:16]=[CH:17][C:12]([Br:11])=[CH:13][CH:14]=2)[N:19]=[CH:3][CH:2]=1)[CH3:9]
Reactant: NNc1ccc(Br)cc1
Reactant: CCOC(=O)CC(C)=O
Agent: Cl
Solvent: CC(=O)O
Product: CCOc1ccnn1-c1ccc(Br)cc1
Yield: 34.9 %

Procedure:
Ethyl acetoacetate (3.49 g, 0.02684 mol) and 4-bromophenylhydrazine hydrochloride (6.00 g, 0.02684 mol) were refluxed in acetic acid (50 mL) for 4 hours. The precipitate was removed by filtration, the filtrate concentrated under reduced pressure and the residue purified by flash chromatography on silica using ethyl acetate/n-heptane (7:93) as mobile phase to yield 1-(4-bromophenyl)-1H-5-pyrazolyl ethyl ether (2.63 g, 0.00936 mol) as an off-white solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:17])=[C:4]([NH:9]C(=O)OC(C)(C)C)[C:5]([CH3:8])=[CH:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:9][C:4]1[C:3]([CH3:17])=[C:2]([OH:1])[CH:7]=[CH:6][C:5]=1[CH3:8]
Reactant: Cc1ccc(O)c(C)c1NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(O)c(C)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
To a solution of tert-butyl N-(3-hydroxy-2,6-dimethyl-phenyl)carbamate (657 mg, 2.8 mmol, 1.0 eq) in DCM (5 mL) was added TFA (5 mL) and the reaction stirred at room temperature overnight. The solvent was removed in vacuo. The residue was taken up in water and solution adjusted to pH 7 by addition of aqueous NaHCO3. The aqueous phase was extracted with EtOAc and the organic extract dried (Na2SO4), filtered and evaporated in vacuo to give the title compound as a yellow solid (370 mg, 97%) which was used without further purification.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1.[CH3:13][O:14][C:15](Cl)=[O:16].Cl.O>O>[CH3:13][O:14][C:15]([O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)=[O:16]
Reactant: COC(=O)Cl
Reactant: O=C(O)c1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)Oc1ccc(C(=O)O)cc1
Reaction time: 3 h

Procedure:
A solution of sodium hydroxide (15 g) in water (400 ml) was chilled to 0° C. in ice. To this the 4-hydroxy benzoic acid (17.9 g, 0.130 mol) was added. Methylchloroformate (20 g, 0.212 mol) was added slowly to prevent the temperature from rising above 5° C. The reaction mixture was stirred at 0°-5° C. for 3 h during which time a white suspension gradually formed. The pH was adjusted to 4-5 with addition of HCl/water (1:1). The voluminous precipitate was filtered off, washed with water and recrystallised from ethanol (200 ml).
Reaction SMILES: [CH:1]1([C:4]#[N:5])[CH2:3][CH2:2]1.[CH2:6]([O:8][C:9](=[O:12])[CH2:10]Br)[CH3:7]>C1COCC1.[Zn].[O-2].[Zn+2]>[CH2:6]([O:8][C:9](=[O:12])[CH:10]=[C:4]([NH2:5])[CH:1]1[CH2:3][CH2:2]1)[CH3:7]
Reactant: CCOC(=O)CBr
Reactant: N#CC1CC1
Agent: [O-2]
Agent: [Zn+2]
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)C=C(N)C1CC1
Reaction time: 0.5 h
Yield: 21 %

Procedure:
Cyclopropanecarbonitrile (2.7 g, 40.5 mmol) was dissolved in dry THF (100 mL) and firstly zinc (13.2 g, 202.3 mmol) and then zinc oxide (1.6 g, 20.2 mmol) were added followed by dropwise addition of ethylbromoacetate (6.7 g, 40.5 mmol). The mixture was sonicated in a 35 kHz ultrasonic bath under N2 for 2 hours. After 30 minutes a green colour was observed. The mixture was filtered through celite to remove the zinc and zinc oxide. The filtrate was added to 20 ml of 50% K2CO3 (aq) solution. A thick precipitate formed which was filtered to remove the solid and the aqueous was extracted with 100 ml EtOAc. The extract was washed with 20 ml brine, dried over MgSO4 and concentrated in vacuo to give the crude product (3.8 g). The crude material was purified by column chromatography on silica gel eluting with 90:10 pentane:EtOAc to give the title compound (1.32 g) as a yellow oil.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]([CH3:8])[CH3:7])=[O:3].[C-:9]#[N:10].[Na+]>N(CC(OCC)=O)=[N+]=[N-].CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].C(Cl)Cl>[C:9]([C:2]([O:4][CH2:5][CH:6]([CH3:8])[CH3:7])=[O:3])#[N:10]
Reactant: CC(C)COC(=O)Cl
Reactant: [C-]#N
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: CCOC(=O)CN=[N+]=[N-]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)COC(=O)C#N
Temperature: -5 °C

Procedure:
The solution prepared in part A containing ethyl azidoacetate/Aliquat 336/methylene chloride totaling approximately 120 ml. in volume was cooled to approximately -5° C. in a 500 ml. round bottom 3-neck flask. When the solution reached -5° C., 69 grams (0.50 moles) of 99% pure isobutyl chloroformate (Aldrich) was added to the reaction mixture. The mixture was again allowed to cool to -5° C. whereupon 150 grams of crushed ice was next added to the well stirred reaction mixture. While maintaining the temperature of the reaction mixture at -5° C., 26.91 grams (0.55 moles) of sodium cyanide was added. After 30 minutes the phases were separated and the upper aqueous layer was washed twice with 5 ml. portions of methylene chloride and discarded. The methylene chloride extracts and separated organic phase were combined and stirred with silica gel at 0° C. for approximately 30 minutes. The mixture was filtered and the residue washed three times with 10 ml. aliquots of methylene chloride. The filtrate was returned to a 250 ml. round bottom 3-neck flask and distilled to recover approximately 110 ml. of methylene chloride.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12](O)=O)[CH:10]=2)[O:5][C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.C([O:56][C:57](=[O:72])[C:58]1[CH:63]=[CH:62][C:61]([NH:64][CH:65]2[CH2:70][CH2:69][CH2:68][CH2:67][CH2:66]2)=[C:60]([NH2:71])[CH:59]=1)C.[OH-].[Na+]>CN(C=O)C>[CH:65]1([N:64]2[C:61]3[CH:62]=[CH:63][C:58]([C:57]([OH:56])=[O:72])=[CH:59][C:60]=3[N:71]=[C:12]2[C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[O:5][C:4]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:3][C:2]3=[O:1])[CH2:66][CH2:67][CH2:68][CH2:69][CH2:70]1
Reactant: O=C(O)c1ccc2oc(-c3ccccc3)cc(=O)c2c1
Reactant: CCOC(=O)c1ccc(NC2CCCCC2)c(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3oc(-c4ccccc4)cc(=O)c3c1)n2C1CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-Oxo-2-phenyl-4H-chromene-6-carboxylic acid (280 mg, 1.05 mmol) was dissolved in DMF (5 mL), and HATU (418 mg, 1.1 eq.) and diisopropyl ethylamine (402 μL) were added. After stirring at room temperature for 15 minutes, 3-amino-4-cyclohexylamino-benzoic acid ethyl ester (303 mg, 1.1 eq.) dissolved in 2 mL DMF was added. After stirring overnight, the reaction was evaporated, dissolved in ethyl acetate and washed with water and brine, dried with sodium sulfate, evaporated and dried overnight. The product was then refluxed in acetic acid for 4h, evaporated to dryness, and coevaporated 2 more times with toluene. Saponification proceeds by dissolving the residue in ethanol (10 mL), adding 10 eq. of 1N NaOH solution and stirring at 40° C. for 4 hr. The ethanol was evaporated, water was added and acidified. The resulting precipitate was purified via reverse-phase HPLC. Yield: 58 mg
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:18])[CH3:17])[CH2:12][CH2:11]2)=[N:7][CH:6]=1)=[O:4].Cl.NO.C[O-].[Na+].CO.Cl>O1CCOCC1>[C:16]([N:13]1[CH2:12][CH2:11][N:10]([C:8]2[S:9][C:5]([C:3]([OH:4])=[O:2])=[CH:6][N:7]=2)[CH2:15][CH2:14]1)(=[O:18])[CH3:17]
Reactant: COC(=O)c1cnc(N2CCN(C(C)=O)CC2)s1
Agent: C[O-]
Agent: Cl
Agent: NO
Solvent: CO
Solvent: C1COCCO1
Product: CC(=O)N1CCN(c2ncc(C(=O)O)s2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of compound 22a (100 mg, 0.300 mmol) in 1,4-dioxane (2 mL) were added hydroxylamine hydrochloride (208 mg, 2.991 mmol) and a freshly prepared solution of sodium methoxide in methanol (103 mg, 4.511 mmol of sodium dissolved in 1.5 mL of methanol) under a N2 atmosphere. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was acidified to pH˜6 with 1M HCl and the formed precipitates were filtered off. The filtrate was diluted with ethyl acetate (5 mL) and water (2 mL) and the organic layer was separated. The aqueous layer was washed with ethyl acetate (5 mL) and the combined organic layers were dried on sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 23a. HPLC: Rt=4.42 min.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:46])[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[C:19]([NH:24][C:25]3[N:26]=[CH:27][C:28]4[N:34]([CH3:35])[C:33](=[O:36])[C:32]([F:38])([F:37])[CH2:31][N:30]([CH:39]5[CH2:43][CH2:42][CH2:41][CH2:40]5)[C:29]=4[N:44]=3)=[CH:18][C:17]=2[F:45])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.ClCCl>ClCCl>[CH:39]1([N:30]2[CH2:31][C:32]([F:38])([F:37])[C:33](=[O:36])[N:34]([CH3:35])[C:28]3[CH:27]=[N:26][C:25]([NH:24][C:19]4[C:20]([O:22][CH3:23])=[CH:21][C:16]([C:15]([NH:14][CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)=[O:46])=[C:17]([F:45])[CH:18]=4)=[N:44][C:29]2=3)[CH2:40][CH2:41][CH2:42][CH2:43]1
Reactant: COc1cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C(=O)NC2CCNCC2)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 18 h
Yield: 83 %

Procedure:
To a solution of 0.071 g (0.11 mmole) of 4-[4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxy-benzoyl-amino]-piperidin-1-carboxylic acid tert-butyl ester (I-177) and 3 mL of dichloromethane was added 6 mL of trifluoroacetic acid-dichloromethane (1:1). The mixture was stirred at room temperature for 18 hours, and then concentrated under reduced pressure. The residue was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution, then brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with methanol-dichloromethane (gradient, 0:100-25:75) to give 0.050 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxy-N-piperidin-4-yl-benzamide (I-178).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12](/[C:16](/[C:35]3[CH:42]=[CH:41][C:38]([CH:39]=[O:40])=[CH:37][CH:36]=3)=[C:17](/[C:20]3[CH:25]=[CH:24][C:23](B4OC(C)(C)C(C)(C)O4)=[CH:22][CH:21]=3)\[CH2:18][CH3:19])=[CH:13][CH:14]=2)[CH:9]=[N:8]1.I[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=1.[OH-].[K+].C(Cl)Cl>O1CCOCC1.C(OCC)(=O)C>[N:45]1[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=1[C:23]1[CH:22]=[CH:21][C:20](/[C:17](/[CH2:18][CH3:19])=[C:16](\[C:35]2[CH:42]=[CH:41][C:38]([CH:39]=[O:40])=[CH:37][CH:36]=2)/[C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[N:7]([CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[N:8]=[CH:9]3)=[CH:25][CH:24]=1
Reactant: CC/C(=C(/c1ccc(C=O)cc1)c1ccc2c(cnn2C2CCCCO2)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Ic1ccccn1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC/C(=C(/c1ccc(C=O)cc1)c1ccc2c(cnn2C2CCCCO2)c1)c1ccc(-c2ccccn2)cc1
Temperature: 70 °C
Yield: 40.9 %

Procedure:
A mixture of (E)-4-(1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)but-1-en-1-yl)benzaldehyde (220 mg, 0.39 mmol), 2-iodopyridine (0.062 mL, 0.58 mmol), and KOH (6M aq., 0.40 mL, 2.34 mmol) in 1,4-dioxane was degassed with nitrogen. PdCl2dppf.DCM (31 mg, 0.04 mmol) was added and the resulting mixture was heated to 70° C. overnight. The mixture was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with brine (3×), dried over sodium sulfate, and purified by flash chromatography on silica gel eluting with 0 to 50% ethyl acetate/hexanes to afford 82 mg of the title compound as a yellow foam. LCMS: 514 (M+H)+.