Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([NH:12][C:13]([C:15]3[CH:16]=[C:17]([CH:51]=[CH:52][CH:53]=3)[CH2:18][NH:19][C:20]([C:22]3[S:23][C:24]([C:27]4[CH:28]=[N:29][N:30](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[CH:31]=4)=[CH:25][CH:26]=3)=[O:21])=[O:14])=[CH:7][CH:8]=2)[CH2:3]1>N1C=CC=CC=1.Cl.CO>[CH3:1][N:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([NH:12][C:13]([C:15]3[CH:16]=[C:17]([CH:51]=[CH:52][CH:53]=3)[CH2:18][NH:19][C:20]([C:22]3[S:23][C:24]([C:27]4[CH:28]=[N:29][NH:30][CH:31]=4)=[CH:25][CH:26]=3)=[O:21])=[O:14])=[CH:7][CH:8]=2)[CH2:3]1
Reactant: CN1CCc2ccc(NC(=O)c3cccc(CNC(=O)c4ccc(-c5cnn(C(c6ccccc6)(c6ccccc6)c6ccccc6)c5)s4)c3)cc2C1
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CN1CCc2ccc(NC(=O)c3cccc(CNC(=O)c4ccc(-c5cn[nH]c5)s4)c3)cc2C1
Yield: 41.5 %

Procedure:
Heat a solution of 5-(1-trityl-1H-pyrazol-4-yl)-thiophene-2-carboxylic acid 3-(2-methyl-1,2,3,4-tetrahydro-isoquinolin-7-ylcarbamoyl)-benzylamide (167 mg, 0.234 mmol) in 10% pyridine/HCl in MeOH (50 mL) at 50° C. overnight. Cool the reaction to rt, concentrate, and purify the residue by prep-HPLC (10% to 90%, CH3CN/water). Further purify the residue through a short silica plug to remove baseline impurity affording desired product 5-(1H-pyrazol-4-yl)-thiophene-2-carboxylic acid 3-(2-methyl-1,2,3,4-tetrahydro-isoquinolin-7-ylcarbamoyl)-benzylamide (68 mg, 0.097 mmol). MS, electrospray 472.2 (M+H), rt 0.94 min.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=O)[C:7]([OH:9])=[O:8].Cl.[CH3:12][O:13][NH2:14].C([O-])([O-])=O.[Na+].[Na+].Cl>CO>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[N:14][O:13][CH3:12])[C:7]([OH:9])=[O:8]
Reactant: O=C(O)C(=O)c1ccco1
Reactant: CON
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CON=C(C(=O)O)c1ccco1
Temperature: 25 °C
Yield: 109 %

Procedure:
A magnetically stirred mixture of 2-(furan-2-yl)-2-oxoacetic acid (5.0 g, 35.7 mmol), O-methylhydroxylamine hydrochloride (5.96 g, 71.4 mmol) and Na2CO3 (15.13 g, 143 mmol) in 100 mL of MeOH was refluxed for 2 hr. The reaction mixture was cooled to room temperature and concentrated HCl was added slowly until a pH of 2-3 was obtained. Most of the solvent was removed on the rotary evaporator and the residue was diluted with 50 mL of water and 100 mL of ether. Concentrated HCl was again added to give a pH of 2-3. The aqueous layer was extracted with 2×50 mL of ether. The combined organic layers were washed with 50 mL of a saturated solution of NaCl, dried (MgSO4) and solvent removed to give 6.58 g of crude 2-(furan-2-yl)-2-(methoxyimino)acetic acid as a viscous oil (crystals formed upon standing).
Reaction SMILES: C(N)(=O)[C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:4]([NH2:6])=[O:5].[C:13]([NH2:26])(=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([NH2:24])=[O:23].[C:27]([NH2:36])(=[O:35])[CH2:28][CH2:29][CH2:30][CH2:31][C:32]([NH2:34])=[O:33]>>[C:4]([NH2:6])(=[O:5])[C:3]1[CH:2]=[CH:10][C:9]([C:22]([NH2:24])=[O:23])=[CH:8][CH:7]=1.[C:13]([NH2:26])(=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([NH2:24])=[O:23].[C:27]([NH2:36])(=[O:35])[CH2:28][CH2:29][CH2:30][CH2:31][C:32]([NH2:34])=[O:33]
Reactant: NC(=O)c1ccccc1C(N)=O
Agent: NC(=O)CCCCC(N)=O
Agent: NC(=O)CCCCCCCCC(N)=O
Product: NC(=O)c1ccc(C(N)=O)cc1

Procedure:
A series of films were prepared using these above four bisamides at an equivalent molar replacement, that is, normalizing to the molecular weights of 396.5, 432.6 and 376.5 for the phthalamide, sebacamide and adipamide replacements of 390.5 m.w. hexamethoxymethyl-melamine. Removal of 1.5 g melamine from a nominal ten g solids formulation therefore resulted in replacement by 1.52 g iso- or terephthalamide, 1.66 g sebacamide and 1.43 g adipamide. Removal of drawn films after curing for 20 minutes at 300° F. as described above allowed the following dynamic mechanical analysis of crosslinking as described in Journal of Coatings Technology, 46, no. 808, 29-42 (1992) by L. W. Hill in the article `Structure/Property Relationships of Thermoset Coatings.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[CH3:14][NH:15][S:16]([C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[CH2:22]2)(=[O:18])=[O:17].N1CCCCC1>C(O)C>[CH3:13][C:7]1[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])=[CH:10][NH:9][C:8]=1[CH:11]=[C:22]1[C:21]2[C:25](=[CH:26][CH:27]=[C:19]([S:16](=[O:17])(=[O:18])[NH:15][CH3:14])[CH:20]=2)[NH:24][C:23]1=[O:28]
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Solvent: C1CCNCC1
Solvent: CCO
Product: CNS(=O)(=O)c1ccc2c(c1)C(=Cc1[nH]cc(CCC(=O)O)c1C)C(=O)N2
Yield: 83.8 %

Procedure:
4-(2-Carboxyethyl)-2-formyl-3-methylpyrrole (90.6 mg), 113 mg 5-methylaminosulfonyl-2-oxindole, and 75 μL piperidine in 2 mL of ethanol were heated at 95° C. for 5 hours. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven to give 163 mg (83%) of the title compound as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SC)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[NH:34]1[CH2:39][CH2:38][CH2:37][C@H:36]([C:40]([OH:42])=[O:41])[CH2:35]1>>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:29])([F:31])[F:30])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:34]4[CH2:39][CH2:38][CH2:37][C@H:36]([C:40]([OH:42])=[O:41])[CH2:35]4)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: O=C(O)[C@H]1CCCNC1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: O=C1N=C(N2CCC[C@H](C(=O)O)C2)SC1=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1

Procedure:
1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidine-3-(S)-carboxylic acid was prepared from 5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and piperidine-3-(S)-carboxylic acid following General Procedure C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:10][CH:9]([CH3:11])[O:8][C:7]([CH3:13])([CH3:12])[C:6]=2[CH:14]=1.[Cl:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][C:21]=1[F:22].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>COCCOC.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>[Cl:15][C:16]1[CH:17]=[C:18]([C:2]2[CH:3]=[CH:4][C:5]3[NH:10][CH:9]([CH3:11])[O:8][C:7]([CH3:13])([CH3:12])[C:6]=3[CH:14]=2)[CH:19]=[CH:20][C:21]=1[F:22]
Reactant: CC1Nc2ccc(Br)cc2C(C)(C)O1
Reactant: OB(O)c1ccc(F)c(Cl)c1
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: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC1Nc2ccc(-c3ccc(F)c(Cl)c3)cc2C(C)(C)O1
Temperature: 85 °C
Reaction time: 0.25 h
Yield: 52.3 %

Procedure:
A mixture of 6-bromo-2,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazine (3.0 g, 11.7 mmol), 3-chloro-4-fluorobenzeneboronic acid (3.1 g, 17.6 mmol), tetrakis(triphenylphosphine)palladium (0) (0.67 g, 0.59 mmol), and sodium carbonate (3.72 g, 35.1 mmol) in DME (80 mL) and water (40 mL) was subject to a blanket of nitrogen flow for 15 minutes at 50° C. and then was heated at 85° C. under nitrogen for 1 hour. The reaction was cooled to room temperature and ethyl acetate (200 mL) was added. The organic layer was washed twice with aqueous ammonium chloride (50 mL) and once with brine (50 mL), dried over sodium sulfate and concentrated to a yellow solid. The solid was triturated with ether (25 mL) and hexane (25 mL), collected on a filter, and dried to give 6-(3-chloro-4-fluorophenyl)-2,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazine (1.87 g, 35%) as a yellow solid: mp 173-175° C.; 1H-NMR (DMSO-d6) δ 7.79 (dd, 1H, J=6.84, 2.14 Hz), 7.60-7.57 (m, 1H), 7.43-7.39 (m, 2H), 7.29 (dd, 1H, J=8.12, 2.14 Hz), 6.62 (d, 1H, J=8.54 Hz), 6.40 (s, 1H), 4.79 (q, 1H, J=5.55 Hz), 1.53 (s, 3H), 1.48 (s, 3H), 1.28 (d, 3H, J=5.55 Hz); MS (ES) m/z 306/308([M+H]+).
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[N:17]([CH2:29][CH3:30])[C:18]3[C:23]([C:24]=2[C:25]#[N:26])=[CH:22][CH:21]=[C:20]([O:27][CH3:28])[CH:19]=3)=[CH:10][CH:9]=1)=[O:6].C([O-])([O-])=O.[K+].[K+].CN(C=O)C>CCOC(C)=O>[CH2:29]([N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[C:20]([O:27][CH3:28])[CH:19]=2)[C:24]([C:25]#[N:26])=[C:16]1[C:15]#[C:14][C:11]1[CH:12]=[CH:13][C:8]([N:7]2[CH2:2][CH2:3][NH:4][C:5]2=[O:6])=[CH:9][CH:10]=1)[CH3:30]
Reactant: CCn1c(C#Cc2ccc(NC(=O)NCCCl)cc2)c(C#N)c2ccc(OC)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCn1c(C#Cc2ccc(N3CCNC3=O)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
1-(2-Chloroethyl)-3-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl] urea (55 mg, 0.13 mmol), prepared as in Example 1AC, was combined with K2CO3 (50 mg, 0.36 mmol) and DMF (550 μL). This mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted in EtOAc, and was washed with H2O, and then with brine. The organic layer was dried and concentrated. Purification by silica chromatography (10-50%, EtOAc/CH2Cl2) yielded 1-ethyl-6-methoxy-2-[4-(2-oxo-imidazolidin-1-yl)-phenylethynyl]-1H-indole-3-carbonitrile (47 mg, 94%) as a white solid.
Reaction SMILES: O.Cl.[OH:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[C:14](=O)[CH3:15]>[Zn].Cl[Hg]Cl.C1(C)C=CC=CC=1>[CH2:14]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][C:4]=1[OH:3])[CH3:15]
Reactant: CC(=O)c1c(O)ccc2ccccc12
Agent: Cl
Agent: Cl[Hg]Cl
Agent: [Zn]
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1c(O)ccc2ccccc12
Temperature: 110 °C
Reaction time: 0.08 h
Yield: 84.3 %

Procedure:
A single neck round-bottom flask was charged with 2.3 g of zinc, 0.23 g of HgCl2 and 4 mL of water. Then 37% HCl (0.1 mL) was added and the mixture stirred for 5 minutes. After this, 3 mL of toluene and 3.4 mL of 37% HCl were added and finally 1 g (5.37 mmol) of 1-(2-hydroxynaphthalen-1-yl)ethanone was added portion wise. The resulting mixture was heated at 110° C. for 18 h. The phases were separated and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford 780 mg (84% yield) of 1-ethylnaphthalen-2-ol as brown solid.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C@:12]3([CH2:17][CH2:16][NH:15][C@@H:14]([CH3:18])[CH2:13]3)[N:11]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)[C:10](=[O:26])[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27][C:28]1([CH3:41])[CH:37]=[CH:36][C:35]2[C:30](=[C:31]([C:38](O)=[O:39])[CH:32]=[CH:33][CH:34]=2)[NH:29]1.C(N(C(C)C)CC)(C)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH:1]1([NH:7][C:8]2[C@:12]3([CH2:17][CH2:16][N:15]([C:38]([C:31]4[CH:32]=[CH:33][CH:34]=[C:35]5[C:30]=4[NH:29][C:28]([CH3:41])([CH3:27])[CH:37]=[CH:36]5)=[O:39])[C@@H:14]([CH3:18])[CH2:13]3)[N:11]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)[C:10](=[O:26])[N:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[C@H]1C[C@]2(CCN1)C(NC1CCCCC1)=NC(=O)N2c1cccc(F)c1
Reactant: CC1(C)C=Cc2cccc(C(=O)O)c2N1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H]1C[C@]2(CCN1C(=O)c1cccc3c1NC(C)(C)C=C3)C(NC1CCCCC1)=NC(=O)N2c1cccc(F)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 11-9 (0.309 g, 0.861 mmol) in DMF (10 mL) was added: 2,2-dimethyl-1,2-dihydroquinoline-8-carboxylic acid (0.175 g, 0.861 mmol), diisopropyethylamine (0.334 g, 2.58 mmol) and BOP reagent (0.381 g, 0.861 mmol). After stirring at 50° C. overnight the reaction mixture was diluted with water and extracted using chloroform (three times). The combined organic layer were dried over MgSO4 and concentrated under vacuum. Purification by silica gel chromatography (4% methanol/chloroform/1% triethylamine) afforded the desired product.
Reaction SMILES: [N:1]([C:4](=[CH:10][C:11]1[C:12]2[N:13]([CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:19]=2)[CH:14]=[CH:15][CH:16]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+]=[N-].[K+].[Br-]>>[C:20]1([C:18]2[CH2:17][N:13]3[CH:14]=[CH:15][C:16]4[C:11]([CH:10]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:1]=4)=[C:12]3[N:19]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)C(=Cc1cccn2cc(-c3ccccc3)nc12)N=[N+]=[N-]
Agent: [Br-]
Agent: [K+]
Product: CCOC(=O)c1cc2c3n(ccc-2n1)CC(c1ccccc1)=N3

Procedure:
From 6c (yield: 90%); mp 255-257° C.; IR (KBr) 3266, 1676, 1253 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 1.39 (t, 3H, J=7 Hz), 4.39 (q, 2H, J=7 Hz), 7.07 (d, 1H, J=7.5 Hz), 7.32 (t, 1H, J=7.5 Hz), 7.47 (m, 3H), 7.99 (d, 2H, J=7.5 Hz), 8.31 (d, 1H, J=7.5 Hz), 8.33 (s, 1H), 12.6 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 14.3, 60.4, 101.7, 106.7, 109.6, 113.2, 124.3, 125.2, 125.8, 127.1, 128.6, 133.2, 134.2, 141.1, 142.0, 160.5; MS m/z 305 (M+, 40), 259 (100), 102 (48). Anal. Calcd for C18H15N3O2: C, 70.81; H, 4.95; N, 13.76. Found: C, 71.02; H, 4.88; N, 13.87.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([CH:7]([NH:12][C:13]1[N:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)=[CH:21][CH:20]=2)=[CH:15][N:14]=1)[CH2:8][CH:9]([CH3:11])[CH3:10])=[O:6])#[N:2].CS(O)(=O)=O.C([O-])(O)=O.[Na+]>C1COCC1>[C:1]([CH2:3][NH:4][C:5](=[O:6])[CH:7]([NH:12][C:13]1[N:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:26][CH2:27][NH:28][CH2:29][CH2:30]3)=[CH:21][CH:20]=2)=[CH:15][N:14]=1)[CH2:8][CH:9]([CH3:11])[CH3:10])#[N:2]
Reactant: CC(C)CC(Nc1ncc(-c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)cn1)C(=O)NCC#N
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)CC(Nc1ncc(-c2ccc(N3CCNCC3)cc2)cn1)C(=O)NCC#N

Procedure:
To tert-butyl 4-(4-{2-[(1-{[(cyanomethyl)amino]carbonyl}-3-methylbutyl)amino]-5-pyrimidinyl}phenyl)-1-piperazinecarboxylate (108 mg, 0.213 mmol) in dry THF (5 mL) under dry nitrogen was gradually added a total of 9 equivalents of MeSO3H (total of 125 μL, 1.92 mmol) over a period of 3 days in portions of 1–2 equivalents at a time. Aqueous sat. NaHCO3 was added carefully and the product extracted with EtOAc (3×), dried over Na2SO4, concentrated in vacuo, and purified by flash chromatography over silica gel (NH4OH/MeOH/CH2Cl2, 1/9/90) to afford N-(cyanomethyl)-4-methyl-2-({5-[4-(1-piperazinyl)phenyl]-2-pyrimidinyl}amino)pentanamide. MS (−ESI): 406.4 [M−1]−.
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl[C:11]([CH3:26])([CH3:25])[CH:12](N=O)[CH2:13][CH2:14][N:15]1[CH:19]=[CH:18][N:17]=[C:16]1[N+:20]([O-:22])=[O:21]>>[CH3:25][C:11]([CH3:26])=[CH:12][CH2:13][CH2:14][N:15]1[CH:19]=[CH:18][N:17]=[C:16]1[N+:20]([O-:22])=[O:21]
Reactant: CC(C)(Cl)C(CCn1ccnc1[N+](=O)[O-])N=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)=CCCn1ccnc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of 7-amino-4-aza-3,3-dimethyl-5-oxaheptan-2-one oxime (Example 7(E), 0.875 g, 0.005 mol) and diisopropylethylamine (0.7 g, 0.0055 mol) was added 4-chloro-4-methyl-1-(2-nitro-1H-imidazol-1-yl)-3-nitrosopentane (Example 10(A), 1.3 g, 0.05 mol) and the mixture was stirred at room temperature for 24 hrs. The white solid formed was filtered and dried. This was purified by column chromatography (silica gel, CH2Cl2 :CH3OH) followed by recrystallization from acetonitrile. mp 122°-123° C. 1H NMR (D2O)ε 1.16 [s, 6H, C(CH3)2 ], 1.36 [s, 6H, C(CH3)2 ], 1.81 (s, 3H, CH3), 2.87 (t, 2H, CH2CH2CN<), 3.11 (m, 2H, OCH2CH2NH), 3.86 (m, 2H,OCH2CH2NH), 4.69 (t, 2H, CH2CH2CN<), 7.10 and 7.36 (s, 2H, imiH). Anal. Calcd. for C16H29N7O5 : Found: C, 48.47; H, 7.39; N, 24.12. Calcd.: C, 48.11; H, 7.32; N, 24.55.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:12]2[NH:16][C:15](=[O:17])[N:14]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[N:13]=2)[C:6]([CH:9]([F:11])[F:10])=[N:7][CH:8]=1.[CH:28]1([C:32](Cl)=[O:33])[CH2:31][CH2:30][CH2:29]1>C(Cl)Cl>[F:10][CH:9]([F:11])[C:6]1[N:7]=[CH:8][C:3]([CH2:2][NH:1][C:32]([CH:28]2[CH2:31][CH2:30][CH2:29]2)=[O:33])=[CH:4][C:5]=1[C:12]1[NH:16][C:15](=[O:17])[N:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:26])([F:25])[F:27])=[CH:20][CH:19]=2)[N:13]=1
Reactant: O=C(Cl)C1CCC1
Reactant: NCc1cnc(C(F)F)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Solvent: ClCCl
Product: O=C(NCc1cnc(C(F)F)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1)C1CCC1
Yield: 22.5 %

Procedure:
The title compound was prepared by following the procedure as described in Example-108 by using 3-(5-(aminomethyl)-2-(difluoromethyl)pyridin-3-yl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one (step-1 of Example-186, 0.75 g, 0.19 mmol), cyclobutane carbonyl chloride (0.035 g, 0.29 mmol), TEA (0.059 g, 0.58 mmol) and DCM (10 mL) to afford 0.020 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.89-2.29 (m, 7H), 4.45 (s, 2H), 7.31-7.52 (m, 1H), 7.72 (d, J=8.4 Hz, 2H), 8.05 (s, 1H), 8.18 (d, J=8.4 Hz, 2H), 8.66 (s, 1H); MS (m/z): 468.26 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26](O)=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C1CN([P+](ON2N=[N:56][C:51]3C=[CH:53][CH:54]=[CH:55][C:50]2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.N1CCCCC1>C(Cl)Cl.CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([N:56]4[CH2:53][CH2:54][CH2:55][CH2:50][CH2:51]4)=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: O=C(O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: O=C(COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1)N1CCCCC1
Reaction time: 0.5 h

Procedure:
A suspension of 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (70 mg, 0.14 mmol), PyBOP® (40 mg, 0.077 mmol), DIEA (24 μL, 0.14 mmol) in dry CH2Cl2:DMF (2:0.1 mL) was stirred at RT for 15 minutes. To this solution of activated acid was added piperidine (7.7 mg, 0.091 mmol). After 30 minutes, 1.0 equivalent of DIEA and 0.55 equivalents of PyBOP® were added. After stirring the solution for 15 minutes, 0.65 equivalents of piperidine were added and the mixture was stirred for an additional 30 minutes. The solvent was removed in vacuo and the crude product was purified using prep HPLC (25-55—90 mins) to afford 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-1-(piperidin-1-yl)ethanone. (29 mg, 0.061 mmol, 43%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][CH:4]=[C:3]1[CH2:8][NH2:9].[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][N:21]([C:24]2[S:25][C:26]([C:30](O)=[O:31])=[C:27]([CH3:29])[N:28]=2)[C:20](=[O:33])[CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][N:21]([C:24]2[S:25][C:26]([C:30]([NH:9][CH2:8][C:3]3[N:2]([CH3:1])[C:6]([CH3:7])=[CH:5][CH:4]=3)=[O:31])=[C:27]([CH3:29])[N:28]=2)[C:20](=[O:33])[CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)O
Reactant: Cc1ccc(CN)n1C
Product: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)NCc1ccc(C)n1C
Yield: 33 %

Procedure:
Following the procedure as described in Example 22, making variation only as required to use (1,5-dimethyl-1H-pyrrol-2-yl)methanamine in place of benzo[b]thiophen-2-ylmethanamine to react with 2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 33% yield: 1H NMR (300 MHz, DMSO-d6) δ 8.60 (d, J=8.1 Hz, 1H), 8.53 (t, J=5.4 Hz, 1H), 7.44-7.33 (m, 5H), 6.37 (dd, J=8.1, 2.7 Hz, 1H), 6.21 (d, J=2.7 Hz, 1H), 5.91 (d, J=3.3 Hz, 1H), 5.64-5.63 (m, 1H), 5.15 (s, 2H), 4.32 (d, J=5.4 Hz, 2H), 3.39 (s, 3H), 2.51 (s, 3H), 2.10 (s, 3H); MS (ES+) m/z 449.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:16][C:17]([OH:20])([CH3:19])[CH3:18])=[C:11]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[C:31](OC(=O)C)(=[O:33])[CH3:32].C(N(CC)CC)C>CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:16][C:17]([OH:20])([CH3:19])[CH3:18])=[C:11]([C:21]3[CH:22]=[CH:23][C:24]([S:27]([NH:30][C:31](=[O:33])[CH3:32])(=[O:28])=[O:29])=[CH:25][CH:26]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(O)COc1c(-c2ccc(S(N)(=O)=O)cc2)cnn(-c2cccc(Cl)c2)c1=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: CC(=O)NS(=O)(=O)c1ccc(-c2cnn(-c3cccc(Cl)c3)c(=O)c2OCC(C)(C)O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-(3-chlorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone (Example 482, 1 equivalent), acetic anhydride (3 equivalents), 4-(dimethylamino)pyridine (0.3 equivalents), and triethylamine (1.2 equivalents) is stirred at room temperature for 16 hours. The reaction mixture is partitioned between ethyl acetate and water. The organic layer is washed with brine then dried over MgSO4 and filtered. The filtrate is concentrated in vacuo to give the title compound.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([N+:13]([O-])=O)[CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1>CO.[Pd]>[OH:1][CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([NH2:13])[CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1
Reactant: O=[N+]([O-])c1ccc2c(c1)OC(CO)CO2
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1)OC(CO)CO2
Yield: 86.9 %

Procedure:
4.2 g of the nitro compound from example k in 120 ml MeOH were hydrogenated at atmospheric pressure with 10% Pd—C at room temperature for 3 hrs. The mixture was filtered and the filtrate evaporated to yield 3.13 g of the title compound.
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]([CH2:41]OS(C)(=O)=O)[CH2:20][O:21][C:22]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[F-:47].C([N+](CCCC)(CCCC)CCCC)CCC>CN(C)C=O>[CH2:1]([O:17][CH2:18][CH:19]([CH2:41][F:47])[CH2:20][O:21][C:22]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCOCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)COS(C)(=O)=O
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCOCC(CF)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 18 h
Yield: 89.1 %

Procedure:
A solution of 9 (1.10 g, 1.70 mmol) and tetrabutylammonium fluoride (2.00 g, 7.60 mmol) in dry N,N-dimethylformamide was stirred under N2 at 60°. After 18 hours, the solution was concentrated and the residue was partitioned between hexane and water. The hexane layer was washed 3 times with water, dried over Na2SO4 and concentrated. Chromatography on silica gel using hexane-CH2Cl2 (1:1, v/v) afforded 0.871 g (87%) of the title compound (10) as a colorless wax, m.p. 32°. NMR (CDCl3, --(CH3)4Si); δ0.90 (t, 3H, J=6 Hz, --CH3), 1.25 (s, 26H, --CH2 --), 1.55 (m, 2H, --OCH2CH2R), 2.32 (d of septets, 1H, JH--H =6 Hz, JH--F =23.5 Hz, --CH), 3.19 (d, 2H, J=6.0 Hz, --CH2OTr), 3.36 (t, 2H, J=6.5 Hz, --OCH2R), 3.49 (d, 2H, J=6.0 Hz, --CH2OR), 4.59 (d of d, 2H, JHH =6.0 Hz, JH--F =47.5 Hz, --CH2F), 7.2-7.52 (m, 15H, --C(C6H5)3)