Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[O:4][C:3]1=[O:17].Cl[C:19]1[N:24]=[CH:23][N:22]=[C:21]([O:25][C:26]2[CH:27]=[C:28]([CH3:36])[C:29]3[N:33]=[C:32]([CH3:34])[NH:31][C:30]=3[CH:35]=2)[CH:20]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:34][C:32]1[NH:31][C:30]2[CH:35]=[C:26]([O:25][C:21]3[N:22]=[CH:23][N:24]=[C:19]([N:14]4[CH2:13][CH2:12][C:5]5([O:4][C:3](=[O:17])[NH:2][C:7]6[N:8]=[CH:9][CH:10]=[CH:11][C:6]5=6)[CH2:16][CH2:15]4)[CH:20]=3)[CH:27]=[C:28]([CH3:36])[C:29]=2[N:33]=1
Reactant: O=C1Nc2ncccc2C2(CCNCC2)O1
Reactant: Cc1nc2c(C)cc(Oc3cc(Cl)ncn3)cc2[nH]1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2c(C)cc(Oc3cc(N4CCC5(CC4)OC(=O)Nc4ncccc45)ncn3)cc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.15 g (0.59 mmol) spiro[piperidine-4,4′-pyrido[2,3-d][1,3]oxazin]-2′(1′H)-one hydrochloride, 0.15 g (0.55 mmol) 6-(6-chloro-pyrimidin-4-yloxy)-2,4-dimethyl-1H-benzimidazole and 0.31 mL (1.8 mmol) DIPEA were combined in 1.5 mL DMF and stirred first of all overnight at RT then for 2 h at 50° C. The reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined and the acetonitrile was evaporated down. The residue was made alkaline with 4N aqueous sodium hydroxide solution, the precipitate formed was suction filtered, washed with water and dried under HV.
Reaction SMILES: [CH2:1]([N:5]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:6](=O)[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH2:14][CH2:15][CH2:16][N:17]([CH3:26])[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[C:9]([N+:27]([O-])=O)[CH:8]=1)[CH:2]([CH3:4])[CH3:3].Cl.C(OCC)(=O)C>O1CCCC1>[CH2:1]([N:5]([CH2:6][C:7]1[CH:8]=[C:9]([NH2:27])[C:10]([NH:13][CH2:14][CH2:15][CH2:16][N:17]([CH3:26])[CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=2)=[CH:11][CH:12]=1)[CH2:31][CH:32]([CH3:34])[CH3:33])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CN(CC(C)C)C(=O)c1ccc(NCCCN(C)CCc2ccncc2)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)CN(Cc1ccc(NCCCN(C)CCc2ccncc2)c(N)c1)CC(C)C
Temperature: 0 °C

Procedure:
A molar solution of borane-tetrahydrofuran complex (6.25 ml, 15 eq) is added dropwise to a solution of N,N-diisobutyl-4-({3-[methyl(2-pyridin-4-ylethyl)amino]propyl}amino)-3-nitrobenzamide (200 mg, 1 eq) in tetrahydrofuran (3 ml) cooled down to 0° C. The mixture is heated under reflux for 20 hours then cooled down to 0° C. and hydrolysed with a 6N aqueous solution of hydrochloric acid (12 ml). After 1 hour 30 minutes under reflux, the mixture is cooled down to 0° C. and brought to basic pH by a 6N aqueous solution of soda. After adding ethyl acetate, decanting and extracting, the organic phases are combined, followed by washing with salt water, drying over sodium sulphate and evaporating under reduced pressure. Purification by flash chromatography on silica gel (eluent: 100% dichloromethane to dichloromethane/methanol 8:2) produces the expected compound in the form of an oil (92 mg, 51% yield).
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:24]([CH3:25])[C:13]2=[N:14][CH:15]=[C:16]([CH:18](O)[C:19]([F:22])([F:21])[F:20])[CH:17]=[C:12]2[N:11]=1)[CH3:2].C1(C)C=CC=CC=1.S(Cl)([Cl:35])=O.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[Cl:35][CH:18]([C:16]1[CH:17]=[C:12]2[N:11]=[C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[S:3][CH2:1][CH3:2])[N:24]([CH3:25])[C:13]2=[N:14][CH:15]=1)[C:19]([F:22])([F:21])[F:20]
Reactant: O=S(Cl)Cl
Reactant: CCSc1ccccc1-c1nc2cc(C(O)C(F)(F)F)cnc2n1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCSc1ccccc1-c1nc2cc(C(Cl)C(F)(F)F)cnc2n1C
Temperature: 50 °C

Procedure:
To a mixture of 1-[2-(2-ethylsulfanyl-phenyl)-3-methyl-3H-imidazo[4,5-b]pyridin-6-yl]-2,2,2-trifluoro-ethanol (98 mg), toluene (10 ml), and pyridine (50 μl), thionyl chloride (1 ml) was added. The mixture was stirred with heating at 50° C. for 5 hours, and then saturated aqueous sodium hydrogen carbonate solution was poured, and extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 66 mg of 6-(1-chloro-2,2,2-trifluoro-ethyl)-2-(2-ethylsulfanyl-phenyl)-3-methyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 266).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:41]=[N:42][N:43]([CH3:45])[N:44]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:55])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:41]=[N:42][N:43]([CH3:45])[N:44]=5)=[O:55])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nnn(C)n4)cc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nnn(C)n4)cc2)CCN3CC(C)C)cc1
Reaction time: 0.25 h
Yield: 70.6 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(2-methyl-tetrazol-5-yl)methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.58 g) in methylene chloride (17.4 ml) was added dropwise a solution of m-chloroperbenzoic acid (0.19 g) in methylene chloride (11.6 ml) at −78° C., and the mixture was stirred for 15 minutes. To the reaction mixture was added an aqueous solution of saturated sodium thiosulfate. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(2-methyl-tetrazol-5-yl)methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 234) (420 mg).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:11][C@H:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:19](=[O:21])[CH3:20].[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27](Cl)=[O:28].N1C=CC=CC=1>C1(C)C=CC=CC=1>[C:19]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C@@H:10]([N:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:27]([C:23]2[O:22][CH:26]=[CH:25][CH:24]=2)=[O:28])[CH2:11][C@@H:2]1[CH3:1])(=[O:21])[CH3:20]
Reactant: O=C(Cl)c1ccco1
Reactant: CC(=O)N1c2ccccc2[C@@H](Nc2ccccc2)C[C@@H]1C
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)N1c2ccccc2[C@@H](N(C(=O)c2ccco2)c2ccccc2)C[C@@H]1C
Temperature: 50 °C
Yield: 34 %

Procedure:
A round bottom flask under nitrogen atmosphere was charged with (±)-trans-1-(2-methyl-4-phenylamino-3,4-dihydro-2H-quinolin-1-yl)-ethanone (0.110 g, 0.39 mmol, 1.0 equiv) and 2-furoyl chloride (0.193 mL, 1.9 mmol, 5.0 equ), pyridine (1.0 equ.) and dry toluene (5 mL). The solution was heated to 50° C. for 5 h. The reaction mixture was evaporated in vacuo. The residue was purified by Biotage flash system (30% hexane/70% ethyl acetate to 50% hexane/50% ethyl acetate) to yield the trans isomer 34% yield.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]#[C:16][CH2:17][Cl:18])[CH2:10][C@H:9]1[CH2:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1)=[O:7].[NH2:39][CH2:40][C:41]1[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=1.C(N(CC)CC)C>C(#N)C>[ClH:18].[ClH:18].[ClH:18].[F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]#[C:16][CH2:17][NH:39][CH2:40][C:41]2[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=2)[CH2:10][C@H:9]1[CH2:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1)=[O:7]
Reactant: NCc1cccnc1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(CC#CCCl)C[C@H]1Cc1ccc2ccccc2c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cl
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(CC#CCNCc2cccnc2)C[C@H]1Cc1ccc2ccccc2c1
Yield: 67.8 %

Procedure:
A solution of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(4-chloro-2-butynyl)-2-(2-naphthylmethyl)piperazine (200 mg), 3-(aminomethyl)pyridine (47 mg), and triethylamine (0.08 ml) in acetonitrile (2 ml) was stirred under reflux for 3 hours and evaporated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (10 ml) using dichloromethane-methanol (30:1) as eluent. The obtained oil was dissolved in ethyl acetate and treated with a solution of,4N hydrogen chloride in ethyl acetate. The mixture was evaporated under reduced pressure to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[4-(3-pyridylmethylamino)-2-butynyl]-2-(2-naphthylmethyl)piperazine trihydrochloride (60 mg) as a powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH:10]([NH:13][C:14](=[O:16])[CH3:15])[CH2:9][CH2:8]2.FC(F)(F)C(O)=O.[N+:24]([O-])([O-:26])=[O:25].[Na+].C(=O)(O)[O-].[Na+]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:24]([O-:26])=[O:25])=[C:7]2[C:12]=1[CH2:11][CH:10]([NH:13][C:14](=[O:16])[CH3:15])[CH2:9][CH2:8]2
Reactant: COc1cccc2c1CC(NC(C)=O)CC2
Reactant: O=[N+]([O-])[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc([N+](=O)[O-])c2c1CC(NC(C)=O)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 219 mg. (1 mmol) of N-(1,2,3,4-tetrahydro-8-methoxy-2-naphthalenyl) acetamide in 7.5 ml. of trifluoroacetic acid was treated with 140 mg. of sodium nitrate in one portion. It was stirred for one hour at room temperature, poured into excess sodium bicarbonate solution and extracted well with methylene chloride. The combined extracts were washed with water, dried and evaporated to give crystals. Recrystallization from ethyl acetate gave N-(1,2,3,4-tetrahydro-8-methoxy-5-nitro-2-naphthalenyl) acetamide as white crystals m.p. 205°-206°.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH2:18][CH2:19][CH2:20][Cl:21])[CH:11]=[CH:10]2.CN([CH:25]=[O:26])C>>[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH2:18][CH2:19][CH2:20][Cl:21])[CH:11]=[C:10]2[CH:25]=[O:26]
Reactant: CN(C)C=O
Reactant: O=c1c2ccc(Br)cc2ccn1CCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cn(CCCCl)c(=O)c2ccc(Br)cc12
Temperature: 0 °C

Procedure:
Phosphorousoxychloride (2.37 mL) was added dropwise to DMF (10 mL) stirring at 0° C. The resulting mixture was warmed to room temperature over 2 h before being treated with a solution of 6-bromo-2-(3-chloropropyl)isoquinolin-1(2H)-one (Example 10a, 0.85 g) in DMF (10 mL). The resulting solution was heated at 80° C. for 10 h. The cooled reaction was quenched with iced water and extracted with ethyl acetate. The organics were washed with brine, dried (MgSO4) and concentrated in vacuo to give the subtitle compound (0.91 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([NH2:7])=[O:6].C(Cl)Cl.F[B-](F)(F)F.[CH2:20]([O+](CC)CC)[CH3:21].C(=O)([O-])[O-].[K+].[K+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](=[NH:7])[O:6][CH2:20][CH3:21]
Reactant: NC(=O)c1ccc(Cl)c(Cl)c1
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=N)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3,4-Dichlorobenzamide (139 g.; 0.73 mole) suspended in 600 ml. of methylene chloride is added to 150 g. (0.8 mole) of triethyloxonium fluoroborate in 100 ml. of methylene chloride cooled in an ice-bath to 0° C. over a period of 10-15 min. At the end of the addition, the mixture is allowed to stir at room temperature overnight. The mixture is again cooled in an ice-bath and 141 g. of 50% potassium carbonate in water is added over 30 min. The mixture is stirred for 15 min., the methylene chloride layer separated and the solids washed with methylene chloride. The combined organic layer and washings are dried over sodium sulfate and concentrated in vacuo to a yellow oil which is treated with hexane. A small amount of solids are filtered and the filtrate concentrated to give, after drying in vacuo, 140 g. of the desired imino ether, m.p. 62°-64° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:12]=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:14]([O:18][C:19]([NH:21][C:22]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:23]=1[CH2:24]Cl)=[O:20])([CH3:17])([CH3:16])[CH3:15].[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[C:14]([O:18][C:19]([NH:21][C:22]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:23]=1[CH2:24][NH:1][C:2]1[C:3]2[N:4]([C:8]([CH:12]=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: Cc1cccc(NC(=O)OC(C)(C)C)c1CCl
Reactant: Cc1nc2c(N)cccn2c1C=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1cccc(NC(=O)OC(C)(C)C)c1CNc1cccn2c(C=O)c(C)nc12

Procedure:
The title compound is prepared according to the procedure described for example 7 starting from 8-amino-3-formyl-2-methylimidazo[1,2-a]pyridine (4.0 g), 2-tert-butoxycarbonylamino-6-methylbenzylchloride (7.0 g), sodium iodide (4.1 g) and sodium carbonate (6.1 g) in acetone (250 ml). Purification by chromatography on silica gel (toluene/dioxane 9:1 as eluent) and crystallization from diisopropyl ether yield 7.3 g (81%) of m.p. 210°-212° C.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:10])[NH:4][C:5](=O)[NH:6][C:7]=1[CH3:8].[Cl:11]C1NC(=O)C(C)=C(C)N=1>>[Br:1][C:2]1[C:3](=[O:10])[NH:4][C:5]([Cl:11])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1[nH]c(=O)[nH]c(=O)c1Br
Reactant: Cc1nc(Cl)[nH]c(=O)c1C
Product: Cc1nc(Cl)[nH]c(=O)c1Br
Yield: 63 %

Procedure:
The title compound was prepared in 63% yield from 5-Bromo-6-methyl-1H-pyrimidine-2,4-dione utilizing a method analogous to the preparation of 2-chloro-5,6-dimethyl-3H-pyrimidin-4-one (see Lee, et al., WO 9605177). 1H NMR (400 MHz, DMSO-d6): δ2.38 (s, 3H). MS (ES) [m+H] calc'd for C5H4N2OBrCl, 223, 225, 227; found 223, 225, 227.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[C:23]=1[S:30]([O:33][C:34]1[C:39]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH2:49][CH2:50]OS(C)(=O)=O)=[CH:43][C:42]=2[O:56][CH3:57])=[C:38]([CH3:58])[N:37]=[C:36]([NH2:59])[N:35]=1)(=[O:32])=[O:31]>CC#N.O>[NH2:59][C:36]1[N:35]=[C:34]([O:33][S:30]([C:23]2[C:24]([CH3:29])=[CH:25][C:26]([CH3:28])=[CH:27][C:22]=2[CH3:21])(=[O:32])=[O:31])[C:39]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH2:49][CH2:50][N:1]3[CH2:5][CH2:4][CH2:3][C@@H:2]3[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:43][C:42]=2[O:56][CH3:57])=[C:38]([CH3:58])[N:37]=1
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1
Reactant: COc1cc(OCCCOS(C)(=O)=O)ccc1Cc1c(C)nc(N)nc1OS(=O)(=O)c1c(C)cc(C)cc1C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1cc(OCCCN2CCC[C@@H]2C(=O)OC(C)(C)C)ccc1Cc1c(C)nc(N)nc1OS(=O)(=O)c1c(C)cc(C)cc1C
Temperature: 70 °C
Reaction time: 16 h

Procedure:
(R)-tert-butyl pyrrolidine-2-carboxylate (485 mg) was added to the mixture of potassium carbonate (393 mg), potassium iodide (31 mg) and the crude product from step (viii) in CH3CN (20 mL). After the mixture was stirred at 70° C. for 16 h, the reaction mixture was cooled to RT, diluted with water and extracted with EtOAc. The combined organic layer was washed with water and brine, dried and concentrated under reduced pressure. The residue was purified by flash column chromatography on amino silica gel to afford the sub-title compound (975 mg) as a white amorphous solid; 1H NMR (300 MHz, CDCl3); 6.92 (2H, s), 6.67 (1H, d), 6.39 (1H, d), 6.30 (1H, dd), 4.64 (2H, br s), 4.03-3.90 (2H, m), 3.76 (3H, s), 3.73 (2H, s), 3.20-3.00 (2H, m), 2.96-2.80 (1H, m), 2.66-2.50 (1H, m), 2.57 (6H, s), 2.46-2.30 (1H, m), 2.28 (3H, s), 2.22 (3H, s), 2.21-1.74 (6H, m), 1.43 (9H, s); LC-MS: m/z 655.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:7]Br)[S:5][CH:6]=1.C([O-])([O-])=O.[K+].[K+].[F:15][C:16]1[C:24]([OH:25])=[CH:23][CH:22]=[C:21]([F:26])[C:17]=1[C:18]([NH2:20])=[O:19]>CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]([CH2:7][O:25][C:24]2[C:16]([F:15])=[C:17]([C:21]([F:26])=[CH:22][CH:23]=2)[C:18]([NH2:20])=[O:19])[S:5][CH:6]=1
Reactant: NC(=O)c1c(F)ccc(O)c1F
Reactant: BrCc1nc(Br)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1c(F)ccc(OCc2nc(Br)cs2)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.2 %

Procedure:
To a solution of 4-bromo-2-(bromomethyl)thiazole (1.57 g, 6.10 mmol) in DMF (15 ml) was added dried K2CO3 (2.95 g, 21.38 mmol) followed by addition of 2,6-difluoro-3-hydroxybenzamide (1.05 g, 6.10 mmol). The resulting reaction mass was stirred at room temperature for 2 h. After the completion of the reaction (TLC monitoring), ice-cold water was added (50 ml) followed by extraction with EtOAc (3×100 ml). The combined organics was washed with brine, dried (Na2SO4), filtered and concentrated. The residue was washed with ether and the solid thus obtained was filtered to get the desired product (1.56 g, 74%).
Reaction SMILES: [CH2:1]([C:4]1[N:9]=[C:8]2[S:10][C:11]([CH2:13][O:14][C:15]3[C:16]([F:25])=[C:17]([C:21]([F:24])=[CH:22][CH:23]=3)[C:18]([NH2:20])=[O:19])=[N:12][C:7]2=[CH:6][CH:5]=1)[CH:2]=[CH2:3]>CO.[Pd]>[F:25][C:16]1[C:15]([O:14][CH2:13][C:11]2[S:10][C:8]3[C:7]([N:12]=2)=[CH:6][CH:5]=[C:4]([CH2:1][CH2:2][CH3:3])[N:9]=3)=[CH:23][CH:22]=[C:21]([F:24])[C:17]=1[C:18]([NH2:20])=[O:19]
Reactant: C=CCc1ccc2nc(COc3ccc(F)c(C(N)=O)c3F)sc2n1
Agent: [Pd]
Solvent: CO
Product: CCCc1ccc2nc(COc3ccc(F)c(C(N)=O)c3F)sc2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 43.8 %

Procedure:
To a solution of 3-(5-Allyl-thiazolo[5,4-b]pyridin-2-ylmethoxy)-2,6-difluoro-benzamide (0.018 g, 0.049 mmol) in 5 ml of anhydrous methanol was added Pd—C (10%, 5 mg) and the reaction mixture was stirred at 25° C. for 12 h under hydrogen atmosphere. The reaction mixture was filtered over the bed of celite and the filtrate was evaporated to dryness under reduced pressure to give the title compound as white solid (0.0078 g, 43%). 1H NMR (DMSO-d6, 400 MHz); δ 0.91 (m, 3H), 1.65 (m, 2H), 2.74 (m, 2H), 5.69 (s, 2H), 7.12 (m, 1H), 7.39 (m, 1H), 7.90 (br s, 1H), 8.18 (br s, 1H), 8.27 (br s, 1H) and 8.52 (br s, 1H). MS ES+ (364.11), HPLC (method I) Rt=15.85 min.
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[N:5]([CH3:9])[CH:6]=[CH:7][N:8]=1.F[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19].[Cl-].[Na+]>CN(C)C=O.O.C(O)(=O)C>[F:17][C:14]1[CH:15]=[CH:16][C:11]([S:3][C:4]2[N:5]([CH3:9])[CH:6]=[CH:7][N:8]=2)=[C:12]([N+:18]([O-:20])=[O:19])[CH:13]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: Cn1ccnc1S
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Cn1ccnc1Sc1ccc(F)cc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 27.6 %

Procedure:
To a mixture of 0.6 g of 60% sodium hydride in mineral oil in 25 ml of N,N-dimethylformamide was added 1.1 g (10 mmoles) of 2-mercapto-1-methylimidazole. After stirring for 30 minutes, 1.6 g (10 mmoles) of 2,5-difluoronitrobenzene was added and the mixture stirred at room temperature for 16 hours. After adding 0.5 ml of acetic acid, the mixture was poured into a mixture of ice, water and sodium chloride. After standing for 1 hour the solid was collected by filtration, washed with water and dried. The crude product was purified by chromatography on silica gel using ethyl acetate as the eluent. The fractions containing the product were combined and concentrated to give 0.7 g (28%) of the product as yellow prisms, mp 123°-126° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[CH:10][C:9]2=[O:23])=[CH:4][C:3]=1[NH:24][CH3:25].CN(C(ON1N=N[C:36]2[CH:37]=CC=N[C:35]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:50](O)(=O)CCC.C(N(CC)C(C)C)(C)C.[Cl-].[Cl-].[Ca+2]>CN(C=O)C>[F:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][O:14][C:11]2[CH:12]=[CH:13][N:8]([C:5]3[CH:6]=[CH:7][C:2]4[N:1]=[C:25]([CH2:35][CH2:36][CH3:37])[N:24]([CH3:50])[C:3]=4[CH:4]=3)[C:9](=[O:23])[CH:10]=2)=[CH:17][CH:18]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CNc1cc(-n2ccc(OCc3ccc(F)cc3)cc2=O)ccc1N
Reactant: CCCC(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1nc2ccc(-n3ccc(OCc4ccc(F)cc4)cc3=O)cc2n1C
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A mixture of 1-(4-amino-3-(methylamino)phenyl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one (90 mg), HATU (106 mg), n-butyric acid (0.024 ml), N,N-diisopropylethylamine (0.136 ml) and DMF (2 ml) was stirred at room temperature under a dry atmosphere (CaCl2 tube) for 1 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The resulting residue was dissolved in AcOH (2.0 ml) and stirred at 90° C. for 1 h. After evaporation, the residue was purified by NH silica gel column chromatography (hexane/EtOAc). The resulting solid was recrystallized from EtOAc/MeOH to give the title compound (48.7 mg) as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[Cl:11][C:12]1[C:17]([CH:18]=[O:19])=[C:16]([F:20])[C:15]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:14][CH:13]=1.[OH-].[K+].O>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([CH:18]([C:17]3[C:12]([Cl:11])=[CH:13][CH:14]=[C:15]([O:21][CH2:22][C:23]([F:25])([F:26])[F:24])[C:16]=3[F:20])[OH:19])=[CH:6][NH:7][C:8]2=[N:9][CH:10]=1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: O=Cc1c(Cl)ccc(OCC(F)(F)F)c1F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: OC(c1c(Cl)ccc(OCC(F)(F)F)c1F)c1c[nH]c2ncc(Br)cc12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To 5-bromo-7-azaindole (67, 291 mg, 1.48 mmol) in methanol (22 mL) were added 6-Chloro-2-fluoro-3-(2,2,2-trifluoro-ethoxy)-benzaldehyde (523, 400.0 mg, 1.6 mmol) and potassium hydroxide (1.49 g, 26.6 mmol) under an atmosphere of nitrogen. The reaction was stirred at room temperature for 48 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 25% ethyl acetate in hexane to give the compound (524, 300 mg, 42%). MS (ESI) [M+H+]+=453.1, 455.1.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)=[N:4][O:5][C:6]=1[C:7]([F:10])([F:9])[F:8].[NH:19]1[CH2:24][CH2:23][S:22](=[O:26])(=[O:25])[CH2:21][CH2:20]1>>[O:25]=[S:22]1(=[O:26])[CH2:23][CH2:24][N:19]([C:16]([C:14]2[S:15][C:11]([C:3]3[C:2]([CH3:1])=[C:6]([C:7]([F:8])([F:9])[F:10])[O:5][N:4]=3)=[CH:12][CH:13]=2)=[O:18])[CH2:20][CH2:21]1
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Reactant: O=S1(=O)CCNCC1
Product: Cc1c(-c2ccc(C(=O)N3CCS(=O)(=O)CC3)s2)noc1C(F)(F)F
Yield: 80 %

Procedure:
Prepared from 5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and thiomopholine 1,1-dioxide by the method described in Example 2 Method B. The reaction mixture was evaporated to a solid, triturated and filtered with the aid of water, then washed with a 1 N aqueous hydrochloric acid solution followed by water. The solid was air dried to afford product as a colorless solid (157 mg, 80%). 1H NMR (DMSO-d6) 2.34 (d, J=1.7, 3 H), 3.27 (obs m, 4 H), 4.00 (m, 4 H), 7.58 (d, J=3.5, 1 H), 7.68 (d, J=4.0, 1 H). 13C NMR (incomplete, F-coupled carbons obscured by baseline noise due to poor solubility) 8.0, ˜44 (br), 51.5, 116.6, 128.0, 130.0, 130.8, 139.6, 158.5, 162.7. 19F NMR −62.2. LC/MS 5.80 min, [M+1]+ 395.