Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[N:10]=[CH:9][N:8]=[CH:7][C:6]=2[CH:5]=[C:4]2[O:12][CH:13]=[N:14][C:3]=12.[Br:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].Cl>C1COCC1.CC(O)C>[Br:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH:19][C:2]1[C:11]2[N:10]=[CH:9][N:8]=[CH:7][C:6]=2[CH:5]=[C:4]2[O:12][CH:13]=[N:14][C:3]=12
Reactant: Nc1cccc(Br)c1
Reactant: Clc1c2ncncc2cc2ocnc12
Agent: Cl
Solvent: CC(C)O
Solvent: C1CCOC1
Product: Brc1cccc(Nc2c3ncncc3cc3ocnc23)c1
Yield: 45.5 %

Procedure:
A mixture of 4-chlorooxazolo[5,4-g]quinazoline (0.24 g, 1.16 mmol) and 3-bromoaniline (0.25 mL, 2.33 mmol) in a THF/propan-2-ol mixture (1:1, 40 mL) containing a trace of concentrated HCl is heated under reflux for 15 min, then concentration to dryness under reduced pressure. The residue is triturated with EtOAc, and then partitioned between saturated aqueous NaHCO3 and EtOAc. Workup of the organic portion gives 4-(3-bromoanilino)oxazolo[5,4-g]quinazoline (0.18 g, 33%) as a yellow powder, mp (MeOH) 232° C. (dec.).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([N:9]2[C:13](=[N:14][CH:15](Cl)[C:16]([Cl:19])([Cl:18])[Cl:17])[C:12](=[O:21])[N:11]([CH3:22])[C:10]2=[O:23])[CH:6]=[CH:7][CH:8]=1.[F:26][C:27]1[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=1[NH2:29].C(N(CC)CC)C.C(Cl)Cl>C(#N)C>[F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([N:9]2[C:13](=[N:14][CH:15]([NH:29][C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[F:26])[C:16]([Cl:19])([Cl:18])[Cl:17])[C:12](=[O:21])[N:11]([CH3:22])[C:10]2=[O:23])[CH:6]=[CH:7][CH:8]=1
Reactant: CN1C(=O)C(=NC(Cl)C(Cl)(Cl)Cl)N(c2cccc(C(F)(F)F)c2)C1=O
Reactant: Nc1ccccc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC#N
Product: CN1C(=O)C(=NC(Nc2ccccc2F)C(Cl)(Cl)Cl)N(c2cccc(C(F)(F)F)c2)C1=O
Reaction time: 0.08 h

Procedure:
In this Example 1-(3-trifluoromethylphenyl)-3-methyl-5-(1,2,2,2-tetrachloroethyl)imino-1,3-diazolidine-2,4-dione; (0.05 mol) is dissolved in 20 ml of acetonitrile. One equivalent of 2-fluoroaniline (0.05 mol) is added with stirring over a five minute period. Temperature is maintained at 25°-35° C. Triethylamine (0.05 mol) is then added with stirring over a 10-minute period. The temperature is maintained at 25°-35° C. for one hour. Methylene chloride (50 ml) is added and the solution is washed 3 times with 50 ml of water, dried over magnesium sulfate and filtered. The solvent is removed under high vacuum affording 1-(3-trifluoromethylphenyl)-3-methyl-5-(1-2'-fluorophenylamino-2,2,2-trichloroethyl)imino-1,3-diazolidine-2,4-dione.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][C:7]=1[CH3:8].ClC1N=NC(C2C=CC=CC=2)=C(C)C=1C.[CH3:29][N:30](C)[C:31]1N=NC(C2C=CSC=2)=CC=1C>>[CH3:29][N:30]([CH3:31])[C:2]1[N:3]=[N:4][C:5]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc(-c2ccsc2)nnc1N(C)C
Reactant: Cc1cc(-c2cccs2)nnc1Cl
Agent: Cc1c(Cl)nnc(-c2ccccc2)c1C
Product: Cc1cc(-c2cccs2)nnc1N(C)C

Procedure:
The above-named compound is prepared in the same manner as described for the aminopyridazines of Example 38, excepting that 3-chloro-4-methyl-6-(2-thienyl)pyridazine is substituted for 3-chloro-4,5-dimethyl-6-phenylpyridazine. The product obtained has a melting point of 50°-52° C. 3-(Dimethylamino)-4-methyl-6-(3-thienyl)pyridazine, a red oil, (Example 51a) is made in the same manner as described above for the 2-thienyl derivative.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][O:5][CH:4]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[CH2:3]1.CC1CCOC(C2C=CC(OC)=CC=2)C=1>>[CH3:1][C:2]1[CH2:3][CH:4]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)[O:5][CH2:6][CH:7]=1
Reactant: C=C1CCOC(c2ccc(OC)cc2)C1
Agent: COc1ccc(C2C=C(C)CCO2)cc1
Product: COc1ccc(C2CC(C)=CCO2)cc1
Yield: 35 %

Procedure:
The method of claim 9 wherein the mixture comprised of 3-10% tetrahydro-4-methylene-2-(4-methoxyphenyl)-2H-pyran, 35-55% 5,6-dihydro-4-methyl-2-(4-methoxyphenyl)-2H-pyran (II), and 35-55% 3,6-dihydro-4-methyl-2-(4-methoxyphenyl)-2H-pyran is provided at a level of from about 0.5 to about 8 weight percent of the fragranced article.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][Si:9]([C:12]#[CH:13])([CH3:11])[CH3:10].Cl[C:15]1[O:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1>ClC(Cl)C.ClCCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:8][Si:9]([C:12]#[C:13][C:15]1[O:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1)([CH3:11])[CH3:10]
Reactant: Clc1nc2ccccc2o1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: C[Si](C)(C)C#Cc1nc2ccccc2o1
Temperature: 80 °C

Procedure:
A mixture of bis(triphenylphosphine)palladium(II) chloride (0.229 g, 0.326 mmol), triethylamine (1.815 mL, 13.02 mmol), copper(I) iodide (0.124 g, 0.651 mmol), trimethylsilylacetylene (29A, 1.645 mL, 11.72 mmol) and compound 28A (1.0 g, 6.51 mmol) in dichloroethane (10 mL) under an inert atmosphere was heated at 80° C. overnight. After the reaction was complete, the mixture was cooled, diluted with dichloromethane (10 mL), washed with aq. NaHCO3, dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 0-5% EtOAc/hexanes to give a mixture of Compound 29B (575 mg) and Compound 29C (200 mg).
Reaction SMILES: [CH2:1]=[C:2]([Mg]Br)[CH3:3].[Cl:6][C:7]1[C:8]([F:16])=[C:9]([C:12]([F:15])=[CH:13][CH:14]=1)[CH:10]=[O:11]>C1COCC1>[Cl:6][C:7]1[C:8]([F:16])=[C:9]([CH:10]([OH:11])[C:2]([CH3:3])=[CH2:1])[C:12]([F:15])=[CH:13][CH:14]=1
Reactant: O=Cc1c(F)ccc(Cl)c1F
Reactant: C=C(C)[Mg]Br
Solvent: C1CCOC1
Product: C=C(C)C(O)c1c(F)ccc(Cl)c1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 51.7 %

Procedure:
To a solution of prop-1-en-2-ylmagnesium bromide (0.5M in THF) (2 mL, 1.000 mmol) was added 3-chloro-2,6-difluorobenzaldehyde (136 mg, 0.769 mmol) in THF (1 mL) dropwise at 0° C. under Ar and stirred at 0° C. for 15 mins. The reaction mixture was quenched with sat. aq.NH4Cl and extracted with ether. The organic phase was washed with sat. aq.NH4Cl and brine, dried over MgSO4, filtered, and concentrated. Purification by flash chromatography to yield 73A as colorless oil (87 mg, 52%). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.36-7.28 (m, 1H), 6.91-6.83 (m, 1H), 5.48 (d, J=9.2 Hz, 1H), 5.12-5.06 (m, 1H), 5.04-4.99 (m, 1H), 2.56 (dt, J=9.2, 2.2 Hz, 1H), 1.75 (s, 3H).
Reaction SMILES: [CH2:1]([C@H:8]([NH:42][C:43]([C@@H:45]([NH:50][C:51](=[O:54])[O:52][CH3:53])[C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C@@H:9]([OH:41])[CH2:10][C@@H:11]([NH:19][C:20](=[O:40])[C@@H:21]([N:26]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[N:33]=2)[C:27]1=[O:39])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:55][S:56]([CH3:58])=O.C(O)(=O)C.C(OC(=O)C)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>>[CH2:1]([C@H:8]([NH:42][C:43](=[O:44])[C@H:45]([C:46]([CH3:47])([CH3:48])[CH3:49])[NH:50][C:51]([O:52][CH3:53])=[O:54])[C@@H:9]([O:41][CH2:55][S:56][CH3:58])[CH2:10][C@@H:11]([NH:19][C:20](=[O:40])[C@@H:21]([N:26]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[N:33]=2)[C:27]1=[O:39])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(C)=O
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2cccc(C)n2)C1=O)C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@H](C[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2cccc(C)n2)C1=O)C(C)(C)C)OCSC)C(C)(C)C
Yield: 59.6 %

Procedure:
A solution containing the product of Example 10E (1.71 g, 2.3 mmol) in DMSO (3.3 g, 42.3 mmol) was treated with acetic acid (4.1 g, 69 mmol) and acetic anhydride (2.35 g, 23 mmol) at 25° C. for 3 days. Excess ice was added to the mixture which was then made alkaline with 10% sodium carbonate. The mixture was extracted with ethyl acetate, the organic layer was separated, washed with 10% sodium carbonate, water (3×), brine, and dried over sodium sulfate. The solvents were evaporated, and the product was purified by chromatography on silica gel eluting with 30-100% ethyl acetate/dichloromethane to give the title compound (1.1 g, 60% yield).
Reaction SMILES: C[O-].[Na+].[NH:4]([CH2:11][CH2:12][C:13]#[N:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:15][O:16][C:17]1[CH:25]=[C:24]([CH:26]=O)[CH:23]=[C:22]([O:28][CH3:29])[C:18]=1[NH:19][CH:20]=[O:21]>CS(C)=O>[NH:4]([CH:11]=[C:12]([C:13]#[N:14])[CH2:26][C:24]1[CH:23]=[C:22]([O:28][CH3:29])[C:18]([NH:19][CH:20]=[O:21])=[C:17]([O:16][CH3:15])[CH:25]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: N#CCCNc1ccccc1
Reactant: COc1cc(C=O)cc(OC)c1NC=O
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cc(CC(C#N)=CNc2ccccc2)cc(OC)c1NC=O

Procedure:
A mixture of 2.7 g. of sodium methylate, 3.65 g. of β-anilino-propionitrile and 4.2 g. of 2',6'-dimethoxy-4'-formyl-formanilide in 30 ml. of absolute dimethylsulfoxide was stirred at 50° C. for 30 minutes. The solution was poured into 500 ml. of water and the resulting emulsion extracted with two 500 ml. portions of ethyl acetate. The ethyl acetate extract was washed with two 300 ml. portions of water, dried over magnesium sulfate and evaporated under vacuum. The residue was recrystallized from ethyl acetate and there was obtained 4'-(3-anilino-2-cyano-allyl)-2',6'-dimethoxy-formanilide having a melting point of 186°-187° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9](I)=[CH:10]3)[C:6]=2[CH:16]=1.[CH3:17][C:18]1[C:22](B2OC(C)(C)C(C)(C)O2)=[CH:21][NH:20][N:19]=1.C(Cl)Cl.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:22]4[C:18]([CH3:17])=[N:19][NH:20][CH:21]=4)=[CH:10]3)[C:6]=2[CH:16]=1
Reactant: Cc1n[nH]cc1B1OC(C)(C)C(C)(C)O1
Reactant: Brc1ccc2c(c1)-c1nc(I)cn1CCO2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: Cc1n[nH]cc1-c1cn2c(n1)-c1cc(Br)ccc1OCC2
Temperature: 80 °C
Yield: 30.1 %

Procedure:
A mixture of 9-bromo-2-iodo-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (200 mg, 0.51 mmol), 3-methylpyrazole-4-boronic acid pinacol ester (117 mg, 0.56 mmol), PdCl2dppf.DCM (42 mg, 0.05 mmol) and Cs2CO3 (416 mg, 1.28 mmol) in dioxane (4 mL) and H2O (1 mL) was purged with argon and heated at 80° C. for 1 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-3% MeOH in DCM) affording 9-Bromo-2-(3-methyl-1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (53 mg, 30%). LCMS: RT 2.21 min [M+H]+ 345.3
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])=[CH:5][CH:4]=1.[NH2:20][C:21]1[C:25]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=2)=[CH:24][NH:23][N:22]=1>>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:22]3[N:23]=[CH:24][C:25]([C:26]4[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=4)=[C:21]3[N:20]=2)=[CH:5][CH:4]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(C(F)(F)F)cc1
Reactant: Cc1cc(-c2c[nH]nc2N)ccn1
Product: Cc1cc(-c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)ccn1
Yield: 52.6 %

Procedure:
Reaction of 1-(4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (142 mg, 0.5, mmol), prepared from commercially available 4-trifluoromethyl-acetophenone according to general procedure A, and 3-amino-4-(2-methyl-4-pyridinyl)-pyrazole [see part synthesis of amino-pyrazole derivatives] (87 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (111 mg, 53%). MS (ISP) 423.0 [(M+H)+]; mp 243° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:10][C@@H:9]([OH:11])[CH:8]=[C:7]1[CH3:12])=[O:5])[CH3:2].Cl[CH2:14]I>>[OH:11][C@H:9]1[C@@H:8]2[C@@:7]([CH3:14])([CH2:12]2)[C@@H:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:10]1.[OH:11][C@@H:9]1[C@H:8]2[C@:7]([CH3:14])([CH2:12]2)[C@H:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:10]1
Reactant: ClCI
Reactant: CCOC(=O)[C@H]1C[C@@H](O)C=C1C
Product: CCOC(=O)[C@@H]1C[C@H](O)[C@@H]2C[C@]12C
Product: CCOC(=O)[C@H]1C[C@@H](O)[C@H]2C[C@@]12C
Yield: 113.6 %

Procedure:
cis-Ethyl-4-hydroxy-2-methylcyclopent-2-enecarboxylate (0.96 g, 5.64 mmol, Preparation #MM.1) and chloroiodomethane (4.97 g, 28.2 mmol) were reacted according to General Procedure KK to give (1R,2S,4R,5S)-ethyl 4-hydroxy-1-methylbicyclo[3.1.0]hexane-2-carboxylate and (1S,2R,4S,5R)-ethyl 4-hydroxy-1-methylbicyclo[3.1.0]hexane-2-carboxylate (0.59 g, 57%) after purification by flash silica gel chromatography eluting with a gradient of 30-60% EtOAc/heptane: 1H NMR (400 MHz, CDCl3) δ 4.60-4.51 (m, 1H), 4.23-4.10 (m, 2H), 2.74 (dd, J=8.0, 10.9 Hz, 1H), 2.13 (m, 1H), 1.51 (m, 1H), 1.46-1.40 (m, 1H), 1.35-1.29 (m, 1H), 1.28 (m, 6H), 1.09-1.04 (m, 1H), 0.37 (dd, J=5.7, 7.9 Hz, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@@H:6]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:25][C:26](=[O:43])[C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:42][CH2:41][C:36]4([CH2:40][CH2:39][CH2:38][CH2:37]4)[CH2:35][CH2:34]3)=[CH:29][CH:28]=2)(=[O:24])=[O:23])=[CH:18][C:17]=1[N+:44]([O-:46])=[O:45])[CH2:7][S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([N:50]([CH:53](C)C)CC)(C)C.C[N:57](C=O)C>>[NH2:57][C:53]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C@@H:6]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:25][C:26](=[O:43])[C:27]2[CH:28]=[CH:29][C:30]([N:33]3[CH2:34][CH2:35][C:36]4([CH2:37][CH2:38][CH2:39][CH2:40]4)[CH2:41][CH2:42]3)=[CH:31][CH:32]=2)(=[O:24])=[O:23])=[CH:18][C:17]=1[N+:44]([O-:46])=[O:45])[CH2:7][S:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[NH:50]
Reactant: NCCCC[C@H](CSc1ccccc1)Nc1ccc(S(=O)(=O)NC(=O)c2ccc(N3CCC4(CCCC4)CC3)cc2)cc1[N+](=O)[O-]
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(C)C=O
Product: N=C(N)NCCCC[C@H](CSc1ccccc1)Nc1ccc(S(=O)(=O)NC(=O)c2ccc(N3CCC4(CCCC4)CC3)cc2)cc1[N+](=O)[O-]

Procedure:
A solution of Example 287 (30 mg, 0.05 mmol), aminoiminosulfonic acid (7 mg, 0.055 mmol), diisopropylethylamine (0.02 M1), and DMF (0.3 mL) at room temperature was stirred for 24 hours and concentrated. The concentrate was purified by reverse phase chromatography with 0-90% methanol/0.1% aqueous TFA to provide the desired product. MS (ESI(+)) m/e 708 (M+H)′; ′H NMR (500 MHz, DMSO-d6) δ 12.02 (s, 1H), 8.53 (d, 1H) 8.32 (d, 1H), 7.86 (dd, 1H), 7.73 (d, 2H), 7.39 (t, 1H), 7.25-7.10 (m, 6H), 6.93 (d, 2H), 4.12 (m, 1H), 3.35 (m, 6H), 3.05 (m, 2H), 1.75 (m, 2H), 1.59 (m, 4H), 1.42 (m, 8H).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=2[NH:3]1.C1CN([P+](O[N:38]2N=[N:45][C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][C:39]2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C1(N)C=CC=CC=1N.CCN(CC)CC>CN(C=O)C>[NH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[NH:45][C:12](=[O:14])[C:11]1[CH:10]=[CH:9][C:8]([CH2:7][N:6]2[C:5]3[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=3[NH:3][C:2]2=[O:1])=[CH:16][CH:15]=1
Reactant: O=C(O)c1ccc(Cn2c(=O)[nH]c3ccccc32)cc1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1ccccc1N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ccccc1NC(=O)c1ccc(Cn2c(=O)[nH]c3ccccc32)cc1
Temperature: 23 °C
Reaction time: 4 h

Procedure:
A solution of 4-(2-Oxo-2,3-dihydro-benzoimidazol-1 -ylmethyl)-benzoic acid (0.1 mmol) in DMF (1 mL) was sequentially treated with PyBOP (0.12 mmol), 1,2-phenylenediamine (0.12 mmol) and Et3N (0.3 mmol). After stirring at 23° C. for 4 h, the reaction was filtered and the crude material was purified by HPLC to yield N-(2-Amino-phenyl)-4-(2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-benzamide. 1H NMR (400 MHz, DMSO-D6) δ ppm 4.88 (s, 2H), 5.09 (s, 2H), 6.55-6.61 (m, 1H), 6.76 (d, J=8.08 Hz, 1H), 6.93-7.04 (m, 5H), 7.14 (d, J=7.58 Hz, 1H), 7.43 (d, J=8.08 Hz, 2H), 7.93 (d, J=8.08 Hz, 2H), 9.61 (s, 1H), 11.02 (s, 1H). ESI-MS: m/z 359.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH2:8])=[N:4][O:5][C:6]=1[CH3:7].C(N(CC)C(C)C)(C)C.ClC(Cl)(Cl)[C:20](Cl)=[O:21].C([O-])(O)=O.[Na+].[N:30]1([C:37]([CH:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[O:38])[CH2:36][CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH3:1][C:2]1[C:3]([NH:8][C:20]([N:33]2[CH2:34][CH2:35][CH2:36][N:30]([C:37]([CH:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[O:38])[CH2:31][CH2:32]2)=[O:21])=[N:4][O:5][C:6]=1[CH3:7]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Cc1onc(N)c1C
Reactant: O=C(C1CCOCC1)N1CCCNCC1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(NC(=O)N2CCCN(C(=O)C3CCOCC3)CC2)c1C
Temperature: 100 °C
Reaction time: 18 h
Yield: 4.3 %

Procedure:
To a solution of 90 mg (0.8 mmol) of 4,5-dimethyl-isoxazol-3-ylamine in DCM (2 mL) was added N,N-diisopropylethylamine (278 μL, 1.6 mmol), followed by 89 μL (0.8 mmol) of trichloroacetylchloride. The reaction mixture was shaken on an orbital shaker for 18 h. Saturated aqueous NaHCO3 solution (3 mL) was added to the reaction mixture. The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in DMF (3 mL) and added to 487 mg (0.88 mmol) of [1,4]diazepan-1-yl-(tetrahydro-pyran-4-yl)-methanone (triple trifluoroacetic acid salt). To this solution 339 mg (3.2 mmol) of Na2CO3 were added and the mixture was heated in a sealed tube at 100° C. for 18 h. The reaction was cooled to room temperature, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by mass-triggered preparative LC-MS to afford 12 mg of 4-(tetrahydro-pyran-4-carbonyl)-[1,4]diazepane-1-carboxylic acid (4,5-dimethyl-isoxazol-3-yl)-amide.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([NH2:6])=[N:2]1.[CH2:7]([O:10][CH:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1)[CH:8]=[CH2:9].C([BH3-])#N.[Na+].O>C(O)(=O)C>[CH2:7]([O:10][CH:11]1[CH2:16][CH2:15][CH:14]([NH:6][C:3]2[NH:4][CH:5]=[N:1][N:2]=2)[CH2:13][CH2:12]1)[CH:8]=[CH2:9]
Reactant: Nc1nc[nH]n1
Reactant: C=CCOC1CCC(=O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: C=CCOC1CCC(Nc2nnc[nH]2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.4 %

Procedure:
To a solution (100 mL) of 1H-1,2,4-triazol-3-amine (2.4 g) and 4-(prop-2-en-1-yloxy)cyclohexanone (5.3 g) in acetic acid was added sodium cyanoborohydride (9.1 g), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The obtained residue was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with a mixed solvent of ethyl acetate and isopropyl alcohol (3:1). The obtained extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained reaction mixture was purified by silica gel column chromatography to give the title compound as a colorless solid (3.2 g, 50%).
Reaction SMILES: [C:1]([O:9]CC)(=O)[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[H][H].[Cl:16][C:17]1[CH:36]=[CH:35][C:20]2[N:21]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)C(=O)[O:23][C:24](=O)[C:19]=2[CH:18]=1.Cl>CC(N(C)C)=O>[CH2:6]([O:5][C:3]([C:2]1[C:1](=[O:9])[N:21]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[C:20]2[C:19]([C:24]=1[OH:23])=[CH:18][C:17]([Cl:16])=[CH:36][CH:35]=2)=[O:4])[CH3:7]
Reactant: O=c1oc(=O)n(Cc2ccc(F)cc2)c2ccc(Cl)cc12
Reactant: CCOC(=O)CC(=O)OCC
Reactant: [H][H]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1c(O)c2cc(Cl)ccc2n(Cc2ccc(F)cc2)c1=O
Temperature: 90 °C
Yield: 85.2 %

Procedure:
Neat diethyl malonate (3.04 mL, 20 mmol) was added slowly to a suspension of sodium hydride (60% in mineral oil, 0.88 g, 22 mmol) in dimethylacetamide under N2 atmosphere. The mixture was stirred at room temperature until the evolution of hydrogen gas ceased, then the mixture was heated to 90° C. for 30 min and cooled to room temperature. A solution of Compound 60 (6.7 g, 22 mmol) in dimethylacetamide was added slowly and the mixture heated overnight at 110° C. The mixture was cooled to room temperature, poured into ice water, and acidified by cold 10% HCl. The solids formed were filtered, washed several times by water, and dried at room temperature under vacuum to yield 6.4 g (85%) of white solids. 1H NMR (DMSO-d6): δ 1.31 (t, J=6.8 Hz, 3H), 4.34 (q, J=6.8 Hz, 2H), 5.43 (s, 2H), 7.1 (m, 2H), 7.2 (m, 2H), 7.40 (d, J=9.2, 1H), 7.66 (dd, J=2.4, 9.2 Hz, 1H), 8.02 (d, J=2.8 Hz, 1H), 13.00 (b, 1H); EIMS: 376 (M+H).
Reaction SMILES: FC([C:4]([O:10][C:11]([C:14]([C:17]([C:20](F)=[O:21])([F:19])[F:18])([F:16])[F:15])([F:13])[F:12])([C:6]([F:9])([F:8])[F:7])[F:5])=O.[C:23](=O)([O-])[O-:24].[Na+].[Na+].C(=O)=O.S(=O)(=O)(O)O.CO>O.COCCOCCOC>[C:6]([CH:4]([O:10][C:11]([C:14]([C:17]([C:20]([O:24][CH3:23])=[O:21])([F:18])[F:19])([F:16])[F:15])([F:12])[F:13])[F:5])([F:9])([F:7])[F:8]
Reactant: O=C([O-])[O-]
Reactant: O=C(F)C(F)(F)C(F)(F)C(F)(F)OC(F)(C(=O)F)C(F)(F)F
Agent: O=C=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: COCCOCCOC
Solvent: O
Product: COC(=O)C(F)(F)C(F)(F)C(F)(F)OC(F)C(F)(F)F
Temperature: 165 °C
Yield: 56.5 %

Procedure:
FC(O)CF(CF3)—O—(CF2)3COF (503 grams, 1.4 mole), prepared as described in U.S. Pat. App. Pub. No. 2004/0116742, was added over a period of two hours to a stirred mixture of sodium carbonate (387 grams, 3.7 moles) and diglyme (650 grams) at 78° C. The reaction liberated carbon dioxide gas. Distilled water (35 grams, 1.9 mole) was added at 85° C., and then the reaction mixture was heated to 165° C. and maintained at that temperature for 30 minutes. The reaction was allowed to cool, and sulfuric acid (250 grams, 2.6 moles) in 1250 grams of water was added. Two layers formed, and the top layer was washed with 33% sulfuric acid and then esterified at 65° C. with methanol (200 grams, 6.3 moles) and concentrated sulfuric acid (200 grams, 2.0 moles). The reaction mixture was washed with water and distilled at 52° C. at 15 mmHg (2.0×103 Pa) to give 258 grams of CF3CFH—O—(CF2)3COOCH3.