Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[OH:12].[F:13][C:14]([F:29])([F:28])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[O:25][C:24]([CH:26]=O)=[CH:23][CH:22]=1>>[C:8]([C:6]1[CH:5]=[CH:4][C:3]([OH:12])=[C:2]([N:1]=[CH:26][C:24]2[O:25][C:21]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:14]([F:28])([F:13])[F:29])=[CH:22][CH:23]=2)[CH:7]=1)([CH3:9])([CH3:11])[CH3:10]
Reactant: CC(C)(C)c1ccc(O)c(N)c1
Reactant: O=Cc1ccc(-c2ccccc2C(F)(F)F)o1
Product: CC(C)(C)c1ccc(O)c(N=Cc2ccc(-c3ccccc3C(F)(F)F)o2)c1

Procedure:
Using 2-amino-4-tert-butylphenol and 5-(2-(trifluoromethyl)phenyl)furan-2-carbaldehyde, 4.25 g of 4-tert-butyl-2-{[5-(2-(trifluoromethyl)phenyl)furan-2-yl]methyleneamino}phenol were obtained as a yellow powder (yield 91%).
Reaction SMILES: [C:1]1(=[N:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:9]([C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=1)([O-:11])=[O:10].O.CCOCC>C(Cl)Cl>[N:7]([C:1]1([O:17][CH2:16][C:15]2[CH:14]=[CH:13][C:12]([N+:9]([O-:11])=[O:10])=[CH:20][CH:19]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:8]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: ON=C1CCCCC1
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: O=NC1(OCc2ccc([N+](=O)[O-])cc2)CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
A solution of cyclohexanone oxime (2.66 g, 23.51 mmol) in methylene chloride (50 mL) was added dropwise with stirring to a solution of LTA (10.42 g, 23.51 mmol) and 4-nitrobenzoic acid (39.29 g, 235.1 mmol) in methylene chloride (300 mL) at 0° C. A blue color gradually appeared with the addition of the oxime. After 1 h at 0° C., the reaction mixture was warmed to room temperature. After 3 h at room temperature, water (50 mL) was added and the organic layer was extracted with water (2×50 mL) and 3% sodium bicarbonate solution (2×50 mL). The organic layer was dried over Na2SO4, the solvent evaporated and the residue was recrystalized in diethyl ether/petroleum, ether (1:1) in a −5° C. freezer to give 1-Nitroso-1-para-nitrobenzoxycyclohexane as bright blue crystals (20-25% yield): Rf 0.55 (pentane/ethyl acetate=20:1); 1H NMR (300 MHz, Benzene-d6) δ 1.17-2.04 (m, 10H), 7.38-7.98 (d, 4H); 13C NMR (300 MHz, Benzene-d6) δ 22.1 (2CH2), 25.0 (CH2), 29.7 (2CH2), 123.8 (2Ph-CH), 125.3 (O—C—N), 131.1 (2Ph-CH), 135.3 (Ph-C), 151.1 (Ph-C), 162.6 (C═O).
Reaction SMILES: [CH2:1]([C:15]1[CH:20]=[C:19]([CH2:21]C)[CH:18]=[C:17]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:16]=1[OH:27])[C:2]1[CH:7]=[C:6]([CH2:8]C)[CH:5]=[C:4]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:3]=1[OH:14].C(C1C=C(C)C=C(C2CCCCC2)C=1O)C1C=C(C)C=C(C2CCCCC2)C=1O.C(C1C=C(C)C=C(CCCCCCCCC)C=1O)C1C=C(C)C=C(CCCCCCCCC)C=1O.C(C1C=C(C(C)(C)C)C=C(C(C)(C)C)C=1O)C1C=C(C(C)(C)C)C=C(C(C)(C)C)C=1O.C(C1C=C(C(C)(C)C)C=C(C(C)(C)C)C=1O)(C1C=C(C(C)(C)C)C=C(C(C)(C)C)C=1O)C.C(C1C=C(CC(C)C)C=C(C(C)(C)C)C=1O)(C1C=C(CC(C)C)C=C(C(C)(C)C)C=1O)C.C(C1C=C(CCCCCCCCC)C=C(C(C)C2C=CC=CC=2)C=1O)C1C=C(CCCCCCCCC)C=C(C(C)C2C=CC=CC=2)C=1O.C(C1C=C(CCCCCCCCC)C=C(C(C)C2C=CC=CC=2C)C=1O)C1C=C(CCCCCCCCC)C=C(C(C)C2C=CC=CC=2C)C=1O.C(C1C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=1)C1C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=1.C(C1C=C(C(C)(C)C)C(O)=C(C)C=1)C1C=C(C(C)(C)C)C(O)=C(C)C=1.C(C1C(O)=CC(C)=C(C(C2C=C(C(C)(C)C)C(O)=CC=2C)CCC)C=1)(C)(C)C.C(C1C(O)=C(C=C(C)C=1)CC1C=C(C)C=C(CC2C=C(C)C=C(C(C)(C)C)C=2O)C=1O)(C)(C)C>>[CH2:1]([C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:3]=1[OH:14])[C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:16]=1[OH:27]
Reactant: CCc1cc(Cc2cc(CC)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Agent: CC(C)(C)c1cc(Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Agent: CC(C)(C)c1cc(Cc2cc(C(C)(C)C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Agent: CC(C)Cc1cc(C(C)c2cc(CC(C)C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Product: Cc1cc(Cc2cc(C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1

Procedure:
2,2'-methylenebis (6-tert-butyl-4-ethylphenol); 2,2'-methylenebis [4-methyl-6-(α-methylcyclohexyl) -phenol]; 2,2'-methylenebis (4-methyl-6-cyclohexylphenol); 2,2'-methylenebis (6-nonyl-4-methylphenol); 2,2'-methylenebis (4,6-di-tert-butylphenol); 2,2'-ethylidenebis (4,6-di-tert-butylphenol); 2,2'-ethylidenebis (6-tert-butyl-4-isobutylphenol); 2,2'-methylenebis [6-(α-methylbenzyl)-4-nonylphenol]; 2,2'-methylenebis [6- (2, α-dimethylbenzyl)-4-nonyl-phenol]; 4,4'-methylenebis (2,6-di-tert-butylphenol); 4,4'-methylenebis (6-tert-butyl-2-methylphenol); 1,1-bis (5-tert-butyl-4-hydroxy-2-methylphenyl) butane; 2,6-di (3-tert-butyl-5-methyl-2-hydroxybenzyl) -4-methylphenol; 1,1,3-tris (5-tert-butyl-4-hydroxy-2-methylphenyl)-3-n-dodecylmercapobutane; ethylene glycol bis [3,3-bis (3'-tert-butyl-4'-hydroxylphenyl) butyrate]; di(3-tert-butyl-4-hydroxy-5-methylphenyl) dicyclopentadiene; di[2-(3'-tert-butyl-2'-hydroxy-5'-methylbenzyl)-6-tertbutyl -4-methyl pheny] terephthalate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:22]([O-])=O)=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:7]=1.O.NN>C(O)C.[Ni]>[NH2:22][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=1[NH:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)ccc2[N+](=O)[O-])CC1
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)ccc2N)CC1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
1,1-Dimethylethyl 4-[(5-chloro-2-nitrophenyl)amino]-piperidinecarboxylate D27 (6.3 g) was dissolved in ethanol (100 mL) and Raney nickel (50% aqueous suspension, 5 mL) was added at room temperature; the mixture was heated to 40° C. and hydrazine monohydrate (3.0 mL) was added over 30 min. After 30 min more, the reaction mixture was cooled to room temperature, filtered through Celite and the solvent was evaporated to yield the title compound, 5.8 g.
Reaction SMILES: [Mg].[CH3:2]I.[CH3:4][C:5]1([CH3:12])[CH2:10][CH2:9][C:8](=[O:11])[CH:7]=[CH:6]1.[Cl-].[NH4+]>C(OCC)C.Cl[Cu]>[CH3:2][CH:6]1[C:5]([CH3:12])([CH3:4])[CH2:10][CH2:9][C:8](=[O:11])[CH2:7]1
Reactant: CC1(C)C=CC(=O)CC1
Reactant: CI
Agent: Cl[Cu]
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Product: CC1CC(=O)CCC1(C)C
Yield: 62.8 %

Procedure:
109 g of CuCl were added in small portions to a Grignard solution prepared from 26.4 g of magnesium turnings and 156.2 g of methyliodide in 200 ml diethylether under a nitrogen atmosphere. To the reaction mixture there were then added 124 g of 4,4-dimethyl-cyclohex-2-en-1-one in ether solution and the whole was refluxed for 2 h. The mixture was then hydrolysed with a saturated aqueous solution of ammonium chloride and subjected to the usual treatments to afford on distillation 88 g (63% yield) of 3,4,4-trimethyl-cyclohexanone; B.p. 80°-85°/12 Torr.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:14]([CH:18]=2)[C:15](O)=[O:16])=[O:9])[CH2:4][CH2:3]1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([NH2:33])[CH:28]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O.O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:14]([CH:18]=2)[C:15]([NH:33][C:29]2[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=2)=[O:16])=[O:9])[CH2:4][CH2:3]1
Reactant: Nc1cccnc1
Reactant: CN1CCN(C(=O)c2ccc(OCc3ccccc3)c(C(=O)O)c2)CC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)c2ccc(OCc3ccccc3)c(C(=O)Nc3cccnc3)c2)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 5-[(4-methyl-1-piperazinyl)carbonyl]-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 51; 166 mg, 0.47 mmol), 3-pyridinamine (44.1 mg, 0.47 mmol), and EDC (90 mg, 0.47 mmol) in N,N-dimethylformamide (DMF) (4 mL) stirred under nitrogen at room temperature was added neat HOBT (71.7 mg, 0.47 mmol) in one charge. The reaction mixture was stirred at room temperature for 6 h. The mixture was diluted with water (50 ml), extracted with ethyl acetate (3×50 ml). The organic phase was washed with saturated brine (25 ml), dried over sodium sulfate, and evaporated in vacuo to give the crude product. The crude product was purified by Prep-HPLC (Gilson GX-281; Durashell 10 μm, 21.5*250 nm n; A: 10 mmol/water, B: MeCN, O-7.2 min, 35%-35%; 7.2-7.5 min, 35%-95%; 7.5-11.5 min, 95%; RT: 7.0 min) to yield the title compound as a white solid. 30 mg.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[CH:2]=1.[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[C:24]1[N:25]=[C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[S:27][CH:28]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[C:24]1[N:25]=[C:26]([N:29]2[CH2:30][CH2:31][N:32]([C:8]([NH:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[O:15])[CH2:33][CH2:34]2)[S:27][CH:28]=1
Reactant: O=C(Nc1cccnc1)OCC(Cl)(Cl)Cl
Reactant: Clc1ccc(-c2csc(N3CCNCC3)n2)c(Cl)c1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccnc1)N1CCN(c2nc(-c3ccc(Cl)cc3Cl)cs2)CC1
Temperature: 70 °C
Reaction time: 72 h
Yield: 45.6 %

Procedure:
A mixture of 2,2,2-trichloroethyl pyridin-3-ylcarbamate (189 mg, 0.700 mmol), 1-[4-(2,4-dichlorophenyl)-1,3-thiazol-2-yl]piperazine (200 mg, 0.636 mmol) and diisopropylethylamine (0.222 ml, 1.27 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 3 days. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate), and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 126 mg (45.5%) of the desired product as a solid.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:10](=O)[C:9]2[CH:19]=[CH:20][CH:21]=[N:22][C:8]1=2)=[O:6])[CH3:3].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:24]>N1C=CC=CC=1>[CH3:1][N:2]([CH2:4][C:5]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:10](=[S:24])[C:9]2[CH:19]=[CH:20][CH:21]=[N:22][C:8]1=2)=[O:6])[CH3:3]
Reactant: CN(C)CC(=O)N1c2ccccc2NC(=O)c2cccnc21
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: CN(C)CC(=O)N1c2ccccc2NC(=S)c2cccnc21

Procedure:
A mixture of 6,11-dihydro-11-[(dimethylamino)acetyl]-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one (0.14 mole), phosphorus pentasulfide (0.155 mole) and 1200 ml. of pyridine is heated at reflux temperature for 24 hours and the pyridine is then evaporated. Methylene chloride and water are added, and the organic layer is separated (some solid is present), washed with aqueous sodium bicarbonate until only a trace of solid is present, then with saturated salt solution, dried over anhydrous magnesium sulfate and evaporated. Trituration of the residue with methanol gives a solid which after crystallization from methylene chloride-methanol gives the product 6,11-dihydro-11-[(dimethylamino)acetyl]-5H-pyrido[2,3-b][1,5]benzodiazepin-5-thione.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[O:9])=[CH:6][CH:5]=[C:4]([NH:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[N:3]=1.[CH3:24][N:25]=[C:26]=[O:27]>>[CH3:24][NH:25][C:26]([N:21]1[CH2:20][CH2:19][CH:18]([NH:17][C:4]2[CH:5]=[CH:6][C:7]([C:8](=[O:9])[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])=[C:2]([NH2:1])[N:3]=2)[CH2:23][CH2:22]1)=[O:27]
Reactant: CN=C=O
Reactant: Nc1nc(NC2CCNCC2)ccc1C(=O)c1ccccc1F
Product: CNC(=O)N1CCC(Nc2ccc(C(=O)c3ccccc3F)c(N)n2)CC1

Procedure:
The title compound was prepared from [2-Amino-6-(piperidin-4-ylamino)-pyridin-3-yl]-(2-fluoro-phenyl)-methanone (Example 9) and methyl isocyanate (Aldrich 98%) using the procedure described in Example 12. HRMS, observed: 371.1756, calcd for M+: 371.1758.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][CH3:17])[C:11]([C:18]([F:21])([F:20])[F:19])=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].C([O:28][C:29](=O)[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[CH:40]=[N:41][C:42]([CH:45]3[CH2:47][CH2:46]3)=[CH:43][CH:44]=2)[CH:34]=1)=[O:32])(C)(C)C>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][CH3:17])[C:11]([C:18]([F:21])([F:20])[F:19])=[CH:10][C:9]=1[NH:22][C:29](=[O:28])[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[CH:40]=[N:41][C:42]([CH:45]3[CH2:46][CH2:47]3)=[CH:43][CH:44]=2)[CH:34]=1)=[O:32])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccc(C3CC3)nc2)c1
Reactant: CCCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CCCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccc(C4CC4)nc3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-propoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J35) (251 mg, 0.75 mmol) and 3-[3-(6-cyclo-propyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K21) (253 mg, 0.75 mmol) according to the general procedure M. Obtained as a yellow foam (372 mg, 83%).
Reaction SMILES: C1C2C(CO[C:16]([NH:18][C@H:19]([C:36]([O:38][CH3:39])=[O:37])[CH2:20][S:21][CH2:22][CH:23]([C:28](=[O:35])[C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)[CH2:24][C:25]([OH:27])=[O:26])=[O:17])C3C(=CC=CC=3)C=2C=CC=1.[CH3:40][O:41][C:42]1[CH:43]=[C:44]([N:52]=C=O)[CH:45]=[C:46]([O:50][CH3:51])[C:47]=1[O:48][CH3:49]>>[CH3:51][O:50][C:46]1[CH:45]=[C:44]([NH:52][C:16]([NH:18][C@H:19]([C:36]([O:38][CH3:39])=[O:37])[CH2:20][S:21][CH2:22][CH:23]([C:28](=[O:35])[C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[CH2:24][C:25]([OH:27])=[O:26])=[O:17])[CH:43]=[C:42]([O:41][CH3:40])[C:47]=1[O:48][CH3:49]
Reactant: COC(=O)[C@H](CSCC(CC(=O)O)C(=O)c1cccnc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: COc1cc(N=C=O)cc(OC)c1OC
Product: COC(=O)[C@H](CSCC(CC(=O)O)C(=O)c1cccnc1)NC(=O)Nc1cc(OC)c(OC)c(OC)c1
Yield: 7.2 %

Procedure:
The title compound was prepared from 3-({(2R)-2-[(fluoren-9-ylmethoxy)carbonylamino]-2-(methoxycarbonyl)ethylthio}methyl)-4-oxo-4-(3-pyridyl)butanoic acid and 3,4,5-trimethoxyphenyl isocyanate as described in Example 16 in a 7.2% yield; ESMS, (M+1)+536.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([CH3:8])([CH3:7])[C:4](O)=[O:5].C(Cl)(=O)C(Cl)=O.[NH4+:17].[OH-]>C(Cl)Cl.CN(C=O)C.C1COCC1>[F:1][C:2]([F:10])([F:9])[C:3]([CH3:8])([CH3:7])[C:4]([NH2:17])=[O:5]
Reactant: CC(C)(C(=O)O)C(F)(F)F
Reactant: [NH4+]
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C(N)=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
A solution of 3,3,3-trifluoro-2,2-dimethylpropionic acid (0.5 g, 3.20 mmol) in DCM (5 mL) was treated with oxalyl chloride (0.350 mL, 4.00 mmol) and 1 drop of DMF, stirred at RT for 1 h, added drop-wise to a solution of NH4OH (˜15M, 5 mL, ˜75 mmol) in THF (5 mL) and stirred at RT overnight. Solids were removed via filtration through diatomaceous earth, rinsed well with 4:1 DCM/THF, the filtrate saturated with solid NaCl, extracted with 4:1 DCM/THF (3×) and the combined organics were dried over Na2SO4 and concentrated to dryness to afford 3,3,3-trifluoro-2,2-dimethylpropanamide (370 mg, 74%). 1H NMR (400 MHz, DMSO-d6): δ 7.42 (s, 1H), 7.35 (s, 1H), 1.29 (s, 6H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH2:36]([O:38][C:39]1[CH:45]=[C:44]([N:46]2[CH2:51][CH2:50][CH:49]([N:52]3[CH2:57][CH2:56][N:55]([S:58]([CH3:61])(=[O:60])=[O:59])[CH2:54][CH2:53]3)[CH2:48][CH2:47]2)[CH:43]=[CH:42][C:40]=1[NH2:41])[CH3:37].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:41][C:40]3[CH:42]=[CH:43][C:44]([N:46]4[CH2:51][CH2:50][CH:49]([N:52]5[CH2:57][CH2:56][N:55]([S:58]([CH3:61])(=[O:60])=[O:59])[CH2:54][CH2:53]5)[CH2:48][CH2:47]4)=[CH:45][C:39]=3[O:38][CH2:36][CH3:37])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: CCOc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)ccc1N
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: CCOc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)ccc1Nc1nccc(-c2c(-c3ccc(OC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 175 °C
Yield: 53.7 %

Procedure:
A mixture of 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (0.10 g, 0.20 mmol), 2-(ethyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}aniline (Example 222, Step D) (0.078 g, 0.20 mmol) and para-toluenesulfonic acid (0.093 g, 0.49 mmol) in i-PrOH (5 mL) was heated in a microwave at 175° C. for 25 min. The reaction mixture was concentrated onto silica gel and purified by flash chromatography. Recrystallization from DCM and diethyl ether afforded N-(2,6-difluorophenyl)-5-(3-{2-[(2-(ethyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}phenyl)amino]-4-pyrimidinyl}imidazo[1,2-a]pyridin-2-yl)-2-(methyloxy)benzamide (0.090 g, 53%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.80 (s, 1H), 9.35 (br. s., 1H), 8.36 (s, 1H), 8.24 (d, J=5.3 Hz, 1H), 8.12 (d, J=1.7 Hz, 1H), 7.75-7.83 (m, 1H), 7.71 (d, J=9.0 Hz, 1H), 7.36-7.49 (m, 3H), 7.29 (d, J=8.7 Hz, 1H), 7.15-7.25 (m, 2H), 6.88-7.01 (m, 1H), 6.67 (d, J=2.3 Hz, 1H), 6.56 (d, J=5.1 Hz, 1H), 6.49 (dd, J=8.7, 2.4 Hz, 1H), 4.07 (q, J=6.9 Hz, 2H), 4.00 (s, 3H), 3.68-3.80 (m, 2H), 3.04-3.17 (m, 4H), 2.87 (s, 3H), 2.57-2.73 (m, 6H), 2.38-2.46 (m, 1H), 1.79-1.89 (m, 2H), 1.47-1.61 (m, 2H), 1.25 (t, J=6.9 Hz, 3H). MS (M−H, ES−) 836.
Reaction SMILES: [CH:1]1([C:7]([C:9]2[NH:10][CH:11]=[CH:12][CH:13]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:16]I>CN(C=O)C>[CH:1]1([C:7]([C:9]2[N:10]([CH3:16])[CH:11]=[CH:12][CH:13]=2)=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CI
Reactant: O=C(c1ccc[nH]1)C1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cccc1C(=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
Compound 25a (2.0 g, 11.3 mmol dissolved dry DMF) was added portionwise to the mixture of NaH (60%; 0.904 g, 22.6 mmol) and dry DMF (200 mL) and the mixture was stirred for 30 min at rt, then MeI (1.9 g, 11.6 mmol) was added at 0° C. The stirred mixture was allowed to stand at rt for 2 h, poured slowly into ice-water and extracted with EA. The organic phase was dried (MgSO4), evaporated and purified by CC to give compound 25b (1.73 g, 80%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]([S:13][CH3:14])[C:6](=[O:12])[NH:7]2.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].N1C=CN=C1>CN(C=O)C.CCCCCC.CCOC(C)=O>[CH3:14][S:13][CH:5]1[C:4]2[C:8](=[CH:9][CH:10]=[CH:11][C:3]=2[CH2:2][O:1][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[NH:7][C:6]1=[O:12]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CSC1C(=O)Nc2cccc(CO)c21
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CSC1C(=O)Nc2cccc(CO[Si](C)(C)C(C)(C)C)c21
Reaction time: 24 h
Yield: 95.1 %

Procedure:
A solution of 0.82 g (3.9 mmol) of 4-hydroxymethyl-3-methylsulfanyl-1,3-dihydro-indol-2-one in DMF (20 mL) was treated with 0.65 g (4.3 mmol) of t-butyidimethylsilyl chloride and 0.3 g (4.4 mmol) of imidazole and stirred for 24 h. The solution was diluted with 75 mL of hexane and 75 mL of EtOAc. The organic phase was washed with brine, dried over MgSO4 and concentrated to give 1.2 g (95%) of 3-methylsulfanyl-4-(t-butyldimethylsilyloxy)methyl-1,3-dihydro-indol-2-one as a clear oil which crystallised upon storage at rt: 1H NMR (DMSO-d6): δ 0.051 (s, 3H), 0.064 (s, 3H), 0.881 (s, 9H), 1.87 (s, 3H), 4.43 (s, 1H), 4.79 (d, J=14.2 Hz, 1H), 4.88 (d, J=14.2 Hz, 1H), 6.70 (d, J=7.9 Hz, 1H), 7.00 (d, J=7.9 Hz, 1H), 7.19 (t, J=7.9 Hz, 1H), 10.48 (s, 1H); APCI-MS m/z 346 (M+23)+.
Reaction SMILES: [N+:1]([C:4]1[NH:8][N:7]=[C:6]([CH2:9][C:10]([OH:12])=O)[N:5]=1)([O-:3])=[O:2].[CH2:13]([C@@H:20]1[NH:25][CH2:24][CH2:23][N:22]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH:35]3[CH2:38][CH2:37][CH2:36]3)[CH:27]=2)[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([C@H:20]1[CH2:21][N:22]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH:35]3[CH2:38][CH2:37][CH2:36]3)[CH:27]=2)[CH2:23][CH2:24][N:25]1[C:10](=[O:12])[CH2:9][C:6]1[N:5]=[C:4]([N+:1]([O-:3])=[O:2])[NH:8][N:7]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)Cc1n[nH]c([N+](=O)[O-])n1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCC1
Product: COc1ccc(N2CCN(C(=O)Cc3n[nH]c([N+](=O)[O-])n3)[C@@H](Cc3ccccc3)C2)cc1OC1CCC1

Procedure:
Prepared by the method outlined for Example 189 using (5-Nitro-1H-[1,2,4]triazol-3-yl)-acetic acid and 3(S)-benzyl-1-(3-cyclobutoxy-4-methoxy-phenyl)-piperazine (Example 7, Compound 95) as starting materials to afford product as an oil. LC/MS (Method B) 3.18 min, [M+1]+ 507. Potency class B.
Reaction SMILES: [F:1][C:2]1([F:44])[CH2:7][CH2:6][C@H:5]([O:8][C:9]2[CH:14]=[C:13]([F:15])[C:12]([S:16]([N:19](CC3C=CC(OC)=CC=3OC)[C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)(=[O:18])=[O:17])=[C:11]([F:37])[CH:10]=2)[C@@H:4]([C:38]2[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=2)[CH2:3]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:44][C:2]1([F:1])[CH2:7][CH2:6][C@H:5]([O:8][C:9]2[CH:14]=[C:13]([F:15])[C:12]([S:16]([NH:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)(=[O:17])=[O:18])=[C:11]([F:37])[CH:10]=2)[C@@H:4]([C:38]2[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=2)[CH2:3]1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2c(F)cc(O[C@H]3CCC(F)(F)C[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1[C@H]1CC(F)(F)CC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)c(F)c1
Yield: 85.3 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 4-{[(1S*,2R*)-4,4-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide (85.9 mg, 0.14 mmol) prepared in Example 129a, triethylsilane (0.10 mL), trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield the title compound (58.0 mg, 88%) as a colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.[C:18](Cl)(=[O:22])[C:19](Cl)=[O:20]>>[CH2:9]([O:8][C:6]([C:5]1[CH:16]=[CH:17][C:2]([O:1][C:18](=[O:22])[C:19]([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:7])=[CH:16][CH:17]=2)=[O:20])=[CH:3][CH:4]=1)=[O:7])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Reactant: O=C(Cl)C(=O)Cl
Product: O=C(Oc1ccc(C(=O)OCc2ccccc2)cc1)C(=O)Oc1ccc(C(=O)OCc2ccccc2)cc1

Procedure:
A similar procedure to Example 1 is carried out by using 22.8 g of benzyl p-hydroxybenzoate and 6.4 g of oxalic acid dichloride to yield di(p-benzyloxycarbonylphenyl)oxalate, m.p. 106°-108° C., as white crystals.
Reaction SMILES: [CH2:1]([C:12]1[C:16]2[S:17][C:18]([C:20]([NH2:22])=O)=[CH:19][C:15]=2[S:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]>O=P(Cl)(Cl)Cl>[CH2:1]([C:12]1[C:16]2[S:17][C:18]([C:20]#[N:22])=[CH:19][C:15]=2[S:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCCc1csc2cc(C(N)=O)sc12
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCCCCCCc1csc2cc(C#N)sc12
Yield: 57.8 %

Procedure:
To 6-undecyl-thieno[3,2-b]thiophene-2-carboxylic acid amide (4.2 g) was added 30 mL of POCl3 and the mixture was heated to reflux for 2 hours before POCl3 was removed by a rotary evaporator. Dichloromethane (50 mL) was added and then 100 mL of ice water was added dropwise. The organic layer was further washed with 30 mL of water twice and then dried over anhydrous Na2SO4 before the solvent was removed. The obtained brown oil was passed through a column of silica gel with hexane/dichloromethane (v/v, 3/2) as the eluent. The solvent was removed to give a yellow oil (2.3 g, 75.7% yield).