Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[O:6][CH:7]1[CH2:10][NH:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[S:23](N)([NH2:26])(=[O:25])=[O:24]>O1CCOCC1>[C:1]([Si:5]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[O:6][CH:7]1[CH2:8][N:9]([S:23]([NH2:26])(=[O:25])=[O:24])[CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: NS(N)(=O)=O
Reactant: CC(C)(C)[Si](OC1CNC1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)[Si](OC1CN(S(N)(=O)=O)C1)(c1ccccc1)c1ccccc1

Procedure:
The subtitle compound was prepared according to the procedure outlined in example 15 step (i) using 3-(tert-butyl-diphenyl-silanyloxy)-azetidine (prepared according to patent WO 2003/072557) (0.93 g), dioxane (20 mL) and sulfamide (0.34 g). Isolation was by filtration to remove excess sulfamide, the filtrate was then reduced in vacuo to give the subtitle compound as a brown oil. Yield: 1.2 g
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][C:5]([F:8])([F:7])[F:6].[CH2:9]([NH:16][C:17](=[O:39])[N:18]([C:20]1[CH:21]=[C:22]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:28][C:27]=2[OH:38])[CH:23]=[CH:24][CH:25]=1)[CH3:19])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:9]([NH:16][C:17](=[O:39])[N:18]([C:20]1[CH:21]=[C:22]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:28][C:27]=2[O:38][CH2:2][CH2:3][CH2:4][C:5]([F:8])([F:7])[F:6])[CH:23]=[CH:24][CH:25]=1)[CH3:19])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: FC(F)(F)CCCI
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OCCCC(F)(F)F)c1

Procedure:
In a manner similar to that of Example (25a), by reaction of 500 μL (3.78 mmol, 5.8 eq) of 1-iodo-4,4,4-trifluorobutane and 280 mg (0.65 mmol, 1 eq) of methyl 3-[3′-(3-heptyl-1-methylureido)-2-hydroxybiphenyl-4-yl]propanoate (prepared in Example 15f) in 10 ml of methyl ethyl ketone in the presence of 500 mg (3.61 mmol, 5.5 eq) of potassium carbonate at 80° C. for 12 hours, methyl 3-[3′-(3-heptyl-1-methylureido)-2-(4,4,4-trifluorobutoxy)biphenyl-4-yl]propanoate is obtained in oil form and is used in the following reaction without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:19]2[C:11](=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14]([C:20]([O:22][CH3:23])=[O:21])=[CH:13]3)[CH:10]([CH2:24][O:25]N2C(C)(C)CCCC2(C)C)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O>C1COCC1.CC(O)=O.[Zn]>[C:1]([O:5][C:6]([N:8]1[C:19]2[C:11](=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14]([C:20]([O:22][CH3:23])=[O:21])=[CH:13]3)[CH:10]([CH2:24][OH:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc2c3c(ccc2[nH]1)N(C(=O)OC(C)(C)C)CC3CON1C(C)(C)CCCC1(C)C
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc2c3c(ccc2[nH]1)N(C(=O)OC(C)(C)C)CC3CO
Yield: 79 %

Procedure:
Zinc powder (7.39 g, 113 mmol) was added to a solution of 54 (6.86 g, 14.1 mmol) in THF (150 mL), HOAc (150 mL), and H2O (50 mL). The mixture was stirred at reflux for 40 min, cooled, and filtered through Celite eluting with EtOAc. The filtrate was evaporated and the residue diluted with H2O and extracted with EtOAc (×2). The extracts were washed with H2O, aq NaHCO3, and dried (Na2SO4) and evaporated. Recrystallization from MeOH gave methyl 3-(t-butyloxycarbonyl)-1-hydroxymethyl-1,2-dihydro-3H-pyrrolo[3,2-e]indole-7-carboxylate (55) as a white solid (3.86 g, 79%), mp 189.5-191° C. (dec.). The mother liquor was purified by chromatography (40% EtOAc-petroleum ether) to give more alcohol (0.74 g, 15%). 1H NMR [(CD3)2SO] δ 11.88 (s, 1 H, NH), 7.87 (v br s, 1 H, H-4), 7.29 (d, J=8.9 Hz, 1 H, H-5), 7.11 (d, J=1.4 Hz, 1 H , H-8), 4.95 (t, J=5.2 Hz, 1 H, OH), 4.03 (t, J=10.5 Hz, 1 H), 3.92-3.86 (m, 1 H), 3.87 (s, 3 H, CO2Me), 3.82-3.75 (m, 1 H), 3.67 (br s, 1 H), 3.55-3.48 (m, 1 H), 1.51 (s, 9 H, t-Bu); 13C NMR δ 161.6, 151.8, 136.2, 134.6, 127.8, 123.7, 122.6, 113.3, 113.3, 111.3, 105.5, 79.3, 63.1, 51.7, 51.2, 42.2, 28.1. Anal. Calculated for C18H22N2O5 : C, 62.4; H, 6.4; N, 8.1. Found: C, 62.3; H, 6.6; N, 8.3%.
Reaction SMILES: C(O[C:6]([N:8](C)[C:9]1[CH:14]=[C:13]([O:15]CC2C=CC(OC)=CC=2)[CH:12]=[CH:11][C:10]=1[NH:25][C:26](=O)[CH2:27][O:28][C:29]1[CH:30]=[C:31]([CH:36]=[CH:37][CH:38]=1)[C:32]([O:34][CH3:35])=[O:33])=O)(C)(C)C.[ClH:41].O1CCOCC1>O1CCOCC1>[ClH:41].[OH:15][C:13]1[CH:12]=[CH:11][C:10]2[N:25]=[C:26]([CH2:27][O:28][C:29]3[CH:30]=[C:31]([CH:36]=[CH:37][CH:38]=3)[C:32]([O:34][CH3:35])=[O:33])[N:8]([CH3:6])[C:9]=2[CH:14]=1
Reactant: COC(=O)c1cccc(OCC(=O)Nc2ccc(OCc3ccc(OC)cc3)cc2N(C)C(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1cccc(OCc2nc3ccc(O)cc3n2C)c1

Procedure:
Methyl 3-[2-({2-[(tert-butoxycarbonyl)(methyl)amino]-4-[(4-methoxybenzyl)oxy]phenyl}amino)-2-oxoethoxy]benzoate produced in Example (1d) (296 g, 538 mmol), a 4 M hydrochloric acid/1,4-dioxane solution (500 mL) and 1,4-dioxane (500 mL) was stirred at 60° C. for two hours. After leaving to cool, the precipitated solid was collected by filtration to obtain a hydrochloride of the title compound as a gray solid.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:12][CH3:13])([CH2:10][CH3:11])[CH2:4][CH2:5][S:6]([NH2:9])(=[O:8])=[O:7].CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>C1(C)C=CC=CC=1>[CH3:16][N:17]([CH:19]=[N:9][S:6]([CH2:5][CH2:4][C:3]([CH2:12][CH3:13])([CH2:10][CH3:11])[CH2:2][OH:1])(=[O:7])=[O:8])[CH3:18]
Reactant: CCC(CC)(CO)CCS(N)(=O)=O
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CCC(CC)(CO)CCS(=O)(=O)N=CN(C)C
Temperature: 90 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
To a solution of 2.0 g of the 4-hydroxy-3,3-diethyl-1-butanesulfonamide obtained in Reference Example 33 in 30 ml of toluene was added 1.2 g of N,N-dimethylformamide dimethyl acetal and the mixture was stirred at 90° C. for 1 hour. The solvent was then distilled off under reduced pressure. The residue was subjected to silica gel (70 g) column chromatograhy and elution was carried out with ethyl acetate-chloroform-methanol (20:20:1) to provide 2.43 g of the title compound as oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH2:11][C:12](=O)[C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[C:7]([Br:10])=[CH:8][CH:9]=1)=O.C([O-])(=O)C.[NH4+:28].O>C(O)(=O)C>[Br:10][C:7]1[N:6]2[CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[NH:28][C:3](=[O:2])[C:5]2=[CH:9][CH:8]=1
Reactant: [NH4+]
Reactant: COC(=O)c1ccc(Br)n1CC(=O)c1ccc(C(F)(F)F)cc1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]c(-c2ccc(C(F)(F)F)cc2)cn2c(Br)ccc12
Temperature: 130 °C
Yield: 97.4 %

Procedure:
A mixture of 5-bromo-1-[2-oxo-2-(4-trifluoromethyl-phenyl)-ethyl]-1H-pyrrole-2-carboxylic acid methyl ester (0.09 g, 0.23 mmol) and ammonium acetate (90 mg, 1.17 mmol) in glacial acetic acid (3 mL) were heated to 130° C. overnight. At this time, the reaction was treated with water. The resulting precipitate was collected by filtration, washed with water and dried in vacuo to afford 6-bromo-3-(4-trifluoromethyl-phenyl)-2H-pyrrolo[1,2-a]pyrazin-1-one (80 mg, 97%) as light brown solid. 1H NMR (chloroform-d) δ ppm 7.75-7.83 (m, 7H), 7.68-7.74 (m, 2H), 7.27 (d, J=1.5 Hz, 1H), 7.23 (s, 1H), 7.20 (s, 1H). LC-MS calcd. for C14H7BrF3N2O [(M−H)−] 356, obsd. 354.9.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11]2[CH2:16][CH2:15][CH:14]([CH:17]3[CH2:22][CH2:21][CH:20]([CH2:23][CH2:24][CH2:25]O)[CH2:19][CH2:18]3)[CH2:13][CH2:12]2)=[CH:5][CH:4]=1.C(N(S(F)(F)[F:35])CC)C>C(COC)OC>[F:35][CH2:25][CH2:24][CH2:23][CH:20]1[CH2:21][CH2:22][CH:17]([CH:14]2[CH2:15][CH2:16][CH:11]([CH2:10][CH2:9][C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:28])([F:27])[F:1])=[CH:4][CH:5]=3)[CH2:12][CH2:13]2)[CH2:18][CH2:19]1
Reactant: CCN(CC)S(F)(F)F
Reactant: OCCCC1CCC(C2CCC(CCc3ccc(C(F)(F)F)cc3)CC2)CC1
Solvent: COCCOC
Product: FCCCC1CCC(C2CCC(CCc3ccc(C(F)(F)F)cc3)CC2)CC1
Yield: 49.5 %

Procedure:
Dimethoxyethane (10 ml) was added to the above 3-(4-(4-(2-(4-trifluoromethylphenyl)ethyl)cyclohexyl)cyclohexyl)propanol (1.20 g, 3.03 mmol), followed by dropwise adding thereto diethylaminosulfur trifluoride (DAST) (1.13 g, 7.01 mmol), refluxing the mixture for 5 hours, extracting the resulting product with toluene, washing the organic layer successively with a saturated, aqueous solution of sodium bicarbonate and water, drying over magnesium sulfate, distilling off the solvent, purifying the residue according to column chromatography treatment using heptane as a developing solvent, on silica gel, distilling off the solvent, and recrystallizing the residue from ethanol/heptane (9/1), to isolate only trans-form of 1-(2-(4-(4-(3-fluoropropyl)cyclohexyl)cyclohexyl)ethyl)-4-trifluoromethylbenzene (0.60 g, 1.5 mmol). Yield: 49.5%. SB -I point: 118.9° C.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][C:16](O)=[O:17])=[C:9]([Cl:13])[C:10]=2[Cl:12])[CH2:5][CH2:4][CH:3]1[CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1.S(Cl)(Cl)=O.Cl.[CH2:29]([NH:31][CH2:32][CH3:33])[CH3:30]>C1C=CC=CC=1>[CH2:29]([N:31]([CH2:32][CH3:33])[C:16](=[O:17])[CH2:15][O:14][C:8]1[CH:7]=[C:6]2[C:11](=[C:10]([Cl:12])[C:9]=1[Cl:13])[C:2](=[O:1])[CH:3]([CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[CH2:4][CH2:5]2)[CH3:30]
Reactant: CCNCC
Reactant: O=C(O)COc1cc2c(c(Cl)c1Cl)C(=O)C(C1CCCC1)CC2
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CCN(CC)C(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(C1CCCC1)CC2
Reaction time: 1 h

Procedure:
The product of Example I, Step 5 (4.0 g., 0.02 mole) is added to thionyl chloride (11 g.) and the mixture is refluxed until HCl and SO2 are no longer evolved (about 1 hour). The excess thionyl chloride is evaporated. The residue is dissolved in benzene and a solution of diethylamine (3.6 g., 0.05 mole) in benzene is added. The mixture is kept for 1 hour and then evaporated to dryness. The residue is washed with water, 10% sodium bicarbonate and with water and airdried to obtain N,N-diethyl-(1-oxo-2-cyclopentyl-7,8-dichloro-1,2,3,4-tetrahydro-6-naphthyloxy)acetamide.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([NH:14][C@H:15]3[CH2:19][CH2:18][CH2:17][C@@H:16]3[NH:20][C:21](=[O:33])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N:28]3[N:32]=[CH:31][CH:30]=[N:29]3)=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[N:9]=2)[CH2:3][CH2:2]1.ClC1C(N[C@H]2CCC[C@@H]2NC(=O)C2C=CC=CC=2N2N=CC=N2)=NC=C(C(F)(F)F)N=1.CC1(C)C(C)(C)OB(C(C)=C)O1.[H][H]>CO.[Pd]>[CH3:3][CH:1]([C:4]1[C:5]([NH:14][C@H:15]2[CH2:19][CH2:18][CH2:17][C@@H:16]2[NH:20][C:21](=[O:33])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N:28]2[N:32]=[CH:31][CH:30]=[N:29]2)=[N:6][CH:7]=[C:8]([C:10]([F:12])([F:13])[F:11])[N:9]=1)[CH3:2]
Reactant: O=C(N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)nc1C1CC1)c1ccccc1-n1nccn1
Reactant: [H][H]
Agent: [Pd]
Agent: C=C(C)B1OC(C)(C)C(C)(C)O1
Agent: O=C(N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)nc1Cl)c1ccccc1-n1nccn1
Solvent: CO
Product: CC(C)c1nc(C(F)(F)F)cnc1N[C@H]1CCC[C@@H]1NC(=O)c1ccccc1-n1nccn1

Procedure:
Prepared according to the procedure for N-[(1S,2S)-2-{ [3-cyclopropyl-5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide (Example 109) from N-[(1S,2S)-2-{[3-chloro-5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide (Intermediate 29; 170 mg, 0.38 mmol) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (CAS number 126726-62-3; 190 mg, 1.13 mmol) except this was then dissolved in methanol (1.4 ml) and to this was then added palladium on carbon (10% wt, 50% wet) (15 mg, 0.014 mmol) and the resulting mixture was stirred under a balloon of hydrogen gas for 2 hours. The reaction was filtered through diatomaceous earth (commercially sold under the trade mark “Celite”) and concentrated in vacuo to afford the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:11]([CH3:13])[CH3:12])[C:9]#[N:10])=[CH:4][CH:3]=1.CC(O)C.[OH-].[Na+].Cl[CH:21]([F:23])[F:22]>CCOCC.O>[F:22][CH:21]([F:23])[O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH:11]([CH3:13])[CH3:12])[C:9]#[N:10])=[CH:6][CH:7]=1
Reactant: FC(F)Cl
Reactant: CC(C)C(C#N)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CC(C)O
Product: CC(C)C(C#N)c1ccc(OC(F)F)cc1
Yield: 81.4 %

Procedure:
A mixture of 2-(4-hydroxyphenyl)-3-methylbutyronitrile (25.0 g; 0.1427 mol), 2-propanol (230 ml), and 25.8% aqueous sodium hydroxide (103 ml; 0.857 mol) is stirred in a pressure vessel and chlorodifluoromethane (36.4 g; 0.421 mol) is added over a period of 52 minutes with cooling to control the exotherm and to maintain the temperature of the reaction mixture below 52° C. The reaction mixture is then stirred for an additional 11/2 hours. Water (700 ml) and ether (300 ml) are then added to the reaction mixture and the two phase mixture is separated. The ether solution is washed twice with water (1000 ml+500 ml) and then with saturated brine (300 ml). It is then dried and evaporated under vacuum to yield 30.48 g (94.8%) of a clear, very slightly yellow liquid, shown to be 85.9% pure by gas-liquid chromatography. This corresponds to a yield of 81.4%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:15][C:16]([F:19])([F:18])[F:17])[CH:10]([OH:14])[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][C:21]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:22]=1[NH2:23].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>ClCCl.C(OCC)C>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:15][C:16]([F:19])([F:18])[F:17])[CH:10]([OH:14])[C:11]([NH:23][C:22]1[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:21]=1[CH3:20])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(N)c(C)c1
Reactant: CC(C)(C)OC(=O)NC(CC(F)(F)F)C(O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1ccc(NC(=O)C(O)C(CC(F)(F)F)NC(=O)OC(C)(C)C)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
A mixture of 287 mg (1 mmol) of 3(RS)-(tert-butoxyformamido)-5,5,5-trifluoro-2(RS)-hydroxyvaleric acid, 363 mg (3 mmol) of 2,4-dimethylaniline, 288 mg (1.5 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 150 mg (1.1 mmol) of 1-hydroxybenzotriazole in 10 ml of dichloromethane was stirred at room temperature for 2 hours. The solution was diluted with diethyl ether, washed with 2M hydrochloric acid and saturated sodium bicarbonate solution and then dried over anhydrous magnesium sulphate, filtered and evaporated to give 363 mg of 3(RS)-(tert-butoxyformamido)-5,5,5-trifluoro-2(RS)-hydroxy-2′,4′ dimethylvaleranilide as a white solid, 1H NMR (250 MHz, CDC3) δ: 1.4 (s,4H), 1.45 (s,5H), 2.1 (s,1.5H), 2.15 (s, 1.5H), 2.3 (s,3H), 2.2-2.6 (m,1H), 2.7-3(m,1H), 4.2-4.6 (m,2H), 5.3 (d,0.5H), 5.6 (d,0.5H), 5.9 (d,0.5H), 6.2 (d,0.5H), 7.0 (m,2H), 7.6 (d,0.5H), 7.7 (d,0.5H), 8.6 (s,1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:10])=[N:4][N:5]([CH3:9])[C:6]=1[C:7]#[N:8].[CH:11](OC(=O)C)=[O:12]>>[C:7]([C:6]1[N:5]([CH3:9])[N:4]=[C:3]([CH3:10])[C:2]=1[NH:1][CH:11]=[O:12])#[N:8]
Reactant: CC(=O)OC=O
Reactant: Cc1nn(C)c(C#N)c1N
Product: Cc1nn(C)c(C#N)c1NC=O
Reaction time: 8 h
Yield: 74 %

Procedure:
The starting material is obtained by treating 16 g (0.12 mol) of 4-amino-5-cyano-1,3-dimethyl pyrazole [U.S. Pat. No. 3,121,092: CA 60 2030 (1964)] with acetic-formic anhydride (prepared by adding 45 ml of acetic anhydride to 20 ml of 98% formic acid at 50° C.). After standing at room temperature overnight, the solution is evaporated in vacuo. The residue is stirred in ether to give 14.5 g (74%) of N-(5-cyano-1,3-dimethylpyrazol-4-yl) formamide, mp 135° C.
Reaction SMILES: Br[C:2]1[C:11]2[O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[N:7]3[C:18](=[O:20])[NH:19][C:5]([C:6]=23)=[CH:4][CH:3]=1.[CH3:21][N:22]1[C:26](B2OC(C)(C)C(C)(C)O2)=[C:25]([CH3:36])[CH:24]=[N:23]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.NC1C=CC=CC=1C1C=CC=CC=1[Pd]Cl>[CH3:21][N:22]1[C:26]([C:2]2[C:11]3[O:10][CH2:9][CH:8]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=4)[N:7]4[C:18](=[O:20])[NH:19][C:5]([C:6]=34)=[CH:4][CH:3]=2)=[C:25]([CH3:36])[CH:24]=[N:23]1
Reactant: Cc1cnn(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: O=c1[nH]c2ccc(Br)c3c2n1C(c1ccccn1)CO3
Agent: Nc1ccccc1-c1ccccc1[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cnn(C)c1-c1ccc2[nH]c(=O)n3c2c1OCC3c1ccccn1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
7-Bromo-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (28 mg, 0.084 mmol) was dissolved in 1,4-dioxane (0.67 mL). 1,4-Dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (28 mg, 0.13 mmol) and potassium phosphate (40 mg, 0.2 mmol) in water (0.17 mL) was added. The reaction mixture was deoxygenated with nitrogen. Dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (2 mg, 0.002 mmol) was added and the mixture was again deoxygenated with nitrogen. The reaction mixture was then stirred at 90° C. under nitrogen for 2 h. Product was purified using preparative LCMS (pH 10) to give the title compound. LCMS calc. for C19H17N5O2 (M+H)+: m/z=348.1. found: 348.0.
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.O[NH:28][C:29]([C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[N:37]=[C:36]([NH:41][C@H:42]1[C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[CH2:44][CH2:43]1)[CH:35]=[CH:34]2)=[NH:30]>C(#N)C>[C@H:42]1([NH:41][C:36]2[CH:35]=[CH:34][C:33]3[C:38](=[CH:39][CH:40]=[C:31]([C:29]4[N:28]=[C:1]([CH3:2])[O:4][N:30]=4)[CH:32]=3)[N:37]=2)[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:44][CH2:43]1
Reactant: CC(=O)O
Reactant: N=C(NO)c1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Product: Cc1nc(-c2ccc3nc(N[C@@H]4CCc5ccccc54)ccc3c2)no1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.5 %

Procedure:
To a stirred solution of acetic acid (30 mg, 0.5 mmol) in acetonitrile (2.15 ml) was added at room temperature 1-hydroxy-benzotriazole (95 mg, 0.6 mmol) and N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimid-hydrochloride (110 mg, 0.57 mmol). The mixture was allowed to stir for 3 h at room temperature and N-hydroxy-2-((R)-indan-1-ylamino)-quinoline-6-carboxamidine (107 mg, 0.34 mmol) was added together with acetonitrile (2.15 ml). The mixture was allowed to stir for 2 h at room temperature, evaporated to dryness and diluted with acetic acid (3.5 ml). The reaction mixture was allowed to stir for 2 h at 100° C., evaporated, poured into saturated NaHCO3 solution (40 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (2×50 ml), dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (ethyl acetate/heptane) on silica gel and crystallization (ethyl acetate/heptane) to yield the title compound as light yellow oil (110 mg, 64%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7])#[N:2].[BH4-].[Na+].[CH2:16]1[CH2:20]OC[CH2:17]1.CO>>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH:16]([CH3:20])[CH3:17])[C:6]([O:8][CH3:9])=[O:7])#[N:2]
Reactant: COC(=O)c1ccc(O)c(C#N)c1
Reactant: C1CCOC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(OC(C)C)c(C#N)c1
Reaction time: 0.17 h
Yield: 99 %

Procedure:
To a solution of 3 (3.0 g, 10.8 mmol) in THF/MeOH (10 mL/10 mL) was slowly added NaBH4 (407 mg, 10.8 mmol). The mixture was stirred for 10 min, quenched by saturated NH4Cl and partitioned between EtOAc and H2O. The organic layer was washed with sat NaHCO3 and brine, dried over Na2SO4, filtered and concentrated to give 4 (3.0 g, 99%), which was used without further purification. LRMS (M+H+) m/z 281.0.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.[CH2:10]([O:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1)[CH3:11]>>[CH2:10]([O:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)=[O:9])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1)[CH3:11]
Reactant: CCOc1ccc(N)c([N+](=O)[O-])c1
Reactant: O=C(O)c1cnccn1
Product: CCOc1ccc(NC(=O)c2cnccn2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared from 2-pyrazinecarboxylic acid and 4-ethoxy-2-nitroaniline as a yellow solid as described in Example 15. 1H NMR (CDCl3): 12.34 (s, 1H), 9.50 (d, J=1.2, 1H), 8.91 (d, J=9.0, 1H), 8.84 (d, J=2.4, 1H), 8.72-8.70 (m, 1H), 7.75 (d, J=3.0, 1H), 7.33-7.28 (m, 1H), 4.12 (q, J=6.9, 2H), 1.47 (t, J=6.9, 3H).
Reaction SMILES: [Cl-].[NH4+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])=[CH:6][C:5]=1[N+:18]([O-])=O>[Fe].CC1C=CC=CC=1>[NH2:18][C:5]1[CH:6]=[C:7]([C:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:11])[CH:8]=[CH:9][C:4]=1[Cl:3]
Reactant: O=C(c1ccccc1)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: Nc1cc(C(=O)c2ccccc2)ccc1Cl

Procedure:
To a stirred and refluxing mixture of 11.2 parts of iron, 100 parts of ammonium chloride solution 0.8 N and 20 parts of methylbenzene are added 10.5 parts of (4-chloro-3-nitrophenyl)phenylmethanone and the whole is further stirred at reflux temperature for one hour. Methylbenzene (80 parts) is added and the whole is filtered over Hyflo. The organic layer is separated, dried, filtered and evaporated. The residue is washed with cyclohexane, yielding 8.4 parts of (3-amino-4-chlorophenyl)phenylmethanone; mp. 91.9° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]2[CH2:16][CH:15]2[C:17]([OH:19])=O)=[CH:4][CH:3]=1.[CH3:20][NH:21][C@@H:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:23]>>[CH3:20][N:21]([C@@H:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:23])[C:17]([CH:15]1[CH2:16][CH:14]1[C:9]1[C:10]([CH3:13])=[N:11][O:12][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)=[O:19]
Reactant: CN[C@H](C)c1ccccc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C1CC1C(=O)O
Product: Cc1noc(-c2ccc(Br)cc2)c1C1CC1C(=O)N(C)[C@H](C)c1ccccc1

Procedure:
Prepared according to the procedure described in Example 2, Step 1, using 2-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-cyclopropanecarboxylic acid and methyl-((R)-1-phenyl-ethyl)-amine.
Reaction SMILES: [CH2:1]([Li:5])[CH2:2][CH2:3][CH3:4].[CH3:6][C:7]1[CH:8]=[N:9][C:10]2CCCC[C:15]=2[CH:16]=1>CCCCCC.O1CCCC1>[Li:5][CH:1]1[C:10]2[N:9]=[CH:8][C:7]([CH3:6])=[CH:16][C:15]=2[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cnc2c(c1)CCCC2
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: [Li]C1CCCc2cc(C)cnc21
Reaction time: 0.5 h

Procedure:
A solution of n-butyl-lithium (15% w/w, 36 ml, 0.05 mole) in hexane was added portionwise to a stirred solution of 3-methyl-5,6,7,8-tetrahydroquinoline (7.3 g, 0.05 mole) in dry tetrahydrofuran (50 ml.) at 0° under nitrogen. After the addition the solution was stirred for 0.5 hour to give a dark red solution of 8-lithio-3-methyl-5,6,7,8-tetrahydroquinoline.