Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([O:18][CH3:19])=[N:4][N:5]([CH3:17])[C:6]=1[CH2:7][N:8](C)[C:9](=O)OC(C)(C)C.Cl>C(Cl)Cl.O1CCOCC1>[Br:1][C:2]1[C:3]([O:18][CH3:19])=[N:4][N:5]([CH3:17])[C:6]=1[CH2:7][NH:8][CH3:9]
Reactant: COc1nn(C)c(CN(C)C(=O)OC(C)(C)C)c1Br
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CNCc1c(Br)c(OC)nn1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 120.1 %

Procedure:
To a solution of compound 91 (1613 mg, 4.826 mmol) in DCM (10 ml) was added 4N HCl in dioxane.(10 ml). The solution was allowed to stir at room temperature for 2 hours, then the reaction mixture was concentrated to give compound 196 (1357 mg, 104%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[N:13]([CH3:14])[CH:12]=[N:11][C:10]=2[C:15]2[CH:20]=[CH:19][C:18]([C@H:21]3[CH2:23][C@@H:22]3[CH2:24][OH:25])=[CH:17][CH:16]=2)=[N:6][CH:7]=1.[H-].[Na+].[F:28][CH2:29][CH2:30]I>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[N:13]([CH3:14])[CH:12]=[N:11][C:10]=2[C:15]2[CH:20]=[CH:19][C:18]([C@H:21]3[CH2:23][C@@H:22]3[CH2:24][O:25][CH2:30][CH2:29][F:28])=[CH:17][CH:16]=2)=[N:6][CH:7]=1
Reactant: Cn1cnc(-c2ccc([C@H]3C[C@@H]3CO)cc2)c1Sc1ccc(Cl)cn1
Reactant: FCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cnc(-c2ccc([C@H]3C[C@@H]3COCCF)cc2)c1Sc1ccc(Cl)cn1
Temperature: 25 °C

Procedure:
[(1S,2S)-2-(4-{5-[(5-Chloropyridin-2-yl)thio]-1-methyl-1H-imidazol-4-yl}phenyl)cyclopropyl]methano 1 (product of Example 23, 20 mg, 0.054 mmol) was dissolved in DMF (1 mL), to which was added NaH (0.25 mmol) and 1-fluoro-2-iodoethane (0.25 mmol) at 0° C. The reaction was warmed to rt and then heated at 55° C. for 2 hours. After it was cooled t rt, the reaction was quenched with 1 mL of aqueous NH4Cl and diluted with 5 mL of EtOAc. The mixture was washed with water (two times) and brine. The organic layer was dried and concentrated to give the crude product that was purified by column (40-100% EtOAc in hexanes) to afford the title compound. 1H NMR (500 MHz, (CDCl3): 9.83 (s, 1H), 8.38 (s, 1H), 7.88 (d, 2H), 7.63 (d, 1H), 7.19 (d, 1H), 7.18 (d, 2H), 4.63 (m, 1H), 4.58 (m, 1H), 4.02 (s, 3H), 3.76 (m, 1H), 4.71 (m, 1H), 3.57 (d, 2H), 1.85 (m, 1H), 1.46 (m, 1H), 1.03 (m, 2H). LCMS: m/z 418 (M+H)+. Human FAAH lysate assay: IC50=69.3 nM.
Reaction SMILES: [O:1]=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.C([O-])(=O)[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Na+].C(OCC)(=O)CCCC>>[C:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:1])[CH3:14]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: O=C([O-])C=Cc1ccccc1
Agent: CCCCC(=O)OCC
Agent: [Na+]
Product: CC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A total of 9 Fernbach flasks, each containing 500 ml. broth, were sterilized for 30 minutes at 121° C. After cooling to room temperature, 5.0 ml. of sterile 50% dextrose solution and 5.0 ml of the 24 hour grown inoculum were added to each flask. The flasks were incubated at 30° C. at 100 rpm for 24 hours. Sterile 10% sodium cinnamate, pH 7.0, was added to each flask as follows, 5 g/l at 24 hours, 9 g/l at 48 hours, and 6 g/l at 72 hours. Samples of broth were analyzed periodically, by GC using ethyl pentanoate as an internal standard. After 44 hours of incubation, all the flasks were combined and product was extracted 3 times with ethyl acetate (approximately ½ volume each time). The combined extracts were washed 2 times with 100 ml. saturated NaHCO3 each time, followed by 2 times 100 ml saturated NaCl washes. The solvent was removed under vacuum and the crude extract was fractionally distilled to recover product. A yield of 2.7 g/L having a purity of 99.4% was obtained.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:12])=[C:10](S(C)=O)[N:9]=[C:8]([NH2:16])[N:7]=1.[CH2:17]([NH2:21])[CH2:18][CH2:19][CH3:20]>C1COCC1>[CH2:17]([NH:21][C:10]1[C:11]([I:12])=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[N:7]=[C:8]([NH2:16])[N:9]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCN
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1I
Solvent: C1CCOC1
Product: CCCCNc1nc(N)nc(-c2ccco2)c1I

Procedure:
From 4-furan-2-yl-5-iodo-6-methanesulfinyl-pyrimidin-2-yl-amine and butylamine in THF. ES-MS m/e (%): 359 (M+H+, 100).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[H-].[Na+].[O:9]1[CH2:14][CH2:13][CH:12](N2C=C(B3OC(C)(C)C(C)(C)O3)C=N2)[CH2:11][CH2:10]1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH:12]2[CH2:13][CH2:14][O:9][CH2:10][CH2:11]2)[CH:6]=1
Reactant: CC1(C)OB(c2cnn(C3CCOCC3)c2)OC1(C)C
Reactant: Brc1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1cnn(C2CCOCC2)c1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
4-bromo-1H-pyrazole (1 eq, 3.92 mmol, 0.5 g) is dissolved in dry DMF (5 ml) under an inert atmosphere of nitrogen. The reaction mixture is cooled down to −10° C. and sodium hydride (1 eq, 3.92 mmol, 0.157 g) is added portionwise. After 15 mins at 0° C., the reaction was warmed to R.T and stirred for 30 mins at R.T. A solution of methane sulfonic acid tetrahydro-pyran-4-yl ester (Intermediate B18, step1) (1 eq, 3.92 mmol, 0.5 g) in DMF (5 ml) is added and the reaction mixture is stirred at 95° C. overnight. The reaction mixture is quenched at 0° C. with water and extracted with DCM. This organic portion is washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting solid is triturated with MeOH and the solid filtered to afford the title compound; [M+H]+ 231/233.
Reaction SMILES: P(Br)(Br)[Br:2].[C:5]([C:9]1[CH:10]=[C:11]([CH:38]=[C:39]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH:40]=1)[CH:12]=[CH:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([CH:22]=[CH:23][C:24]2[CH:29]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:27]=[C:26]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH:25]=2)[CH:21]=1)[CH2:17]O)([CH3:8])([CH3:7])[CH3:6].CC(O)C>ClCCl>[C:5]([C:9]1[CH:10]=[C:11]([CH:38]=[C:39]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH:40]=1)[CH:12]=[CH:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([CH:22]=[CH:23][C:24]2[CH:29]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:27]=[C:26]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH:25]=2)[CH:21]=1)[CH2:17][Br:2])([CH3:8])([CH3:7])[CH3:6]
Reactant: BrP(Br)Br
Reactant: CC(C)(C)c1cc(C=Cc2cc(C=Cc3cc(C(C)(C)C)cc(C(C)(C)C)c3)cc(CO)c2)cc(C(C)(C)C)c1
Solvent: CC(C)O
Solvent: ClCCl
Product: CC(C)(C)c1cc(C=Cc2cc(C=Cc3cc(C(C)(C)C)cc(C(C)(C)C)c3)cc(CBr)c2)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.5 %

Procedure:
Phosphorus tribromide (2.8 cm3, 30 mmol) was added to a solution of 3,5-bis(3′,5′-di-tert-butylstyryl)benzyl alcohol (1.60 g, 3.0 mmol) in dichloromethane (50 cm3) and the mixture stirred at room temperature for 3 h. Propan-2-ol (14 cm3) was added slowly and the solvent was completely removed. The residue was purified by column chromatography over silica, eluting with dichloromethane-light petroleum (40–60) (1:9), giving 3,5-bis(3′,5′-di-tert-butylstyryl)benzyl bromide (1.52 g, 85%). A sample for analysis was recrystallised from a dichloromethane-light petroleum (60–80) mixture, mp 222–223° C. (Found: C, 77.75; H, 8.72. C39H51Br requires C, 78.11; H, 8.57%); vmax(CHCl3)/cm−1 1596s (C═C) and 964s (C═C—H trans); λmax(CHCl3)/nm (log ε) 315 (4.82); δH(400 MHz, CDCl3) 1.38 (36H, s, t-Bu), 4.55 (2H, s, CH2), 712 and 7.24 (4H, d, J 16, 7′, 8′-H), 7.39 (2H, dd, J 1.5, 4′-H), 7.41 (4H, d, J 1.5, 2′, 6′-H), 7.47 (2H, d, J 1, 2, 6-H) and 7.63 (1H, m, 4-H); m/z (APCI+) 521 ((M-Br)+, 100%) and 599 (M+, 40%).
Reaction SMILES: [F:1][CH:2]([F:4])Cl.[NH2:5][C:6]1[N:11]=[C:10]([OH:12])[CH:9]=[C:8]([CH3:13])[N:7]=1>O.[OH-].[Na+].O1CCOCC1>[NH2:5][C:6]1[N:11]=[C:10]([O:12][CH:2]([F:4])[F:1])[CH:9]=[C:8]([CH3:13])[N:7]=1
Reactant: FC(F)Cl
Reactant: Cc1cc(O)nc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(OC(F)F)nc(N)n1

Procedure:
Gaseous difluorochloromethane is introduced, over a period of 12 hours at a temperature of 70° to 75° C., into a solution of 62.5 g of 2-amino-4-hydroxy-6-methyl-pyrimidine in 500 ml of water, 100 ml of 40% sodium hydroxide solution and 100 ml of dioxane. There are added during this time, in each case at intervals of 1 hour and in equal portions, a total of 160 g of solid sodium hydroxide. The organic phase is separated, and concentrated to about 1/10 of its volume; the residue is poured into water, and the solid substance which has precipitated is removed. The yield is 39.9 g of 2-amino-4-difluoromethoxy-6-methyl-pyrimidine, m.p. 136° to 137° C. (compound No. 1.1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:18][CH:19]2[CH2:33][CH:22]3[CH2:23][N:24](C(OC(C)(C)C)=O)[CH2:25][CH:21]3[CH2:20]2)=[N:4][C:5]([NH:8][C:9]2[N:13]([CH3:14])[N:12]=[C:11]([CH:15]3[CH2:17][CH2:16]3)[CH:10]=2)=[N:6][CH:7]=1.Cl.CCOC(C)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([NH:18][CH:19]2[CH2:33][CH:22]3[CH2:23][NH:24][CH2:25][CH:21]3[CH2:20]2)=[N:4][C:5]([NH:8][C:9]2[N:13]([CH3:14])[N:12]=[C:11]([CH:15]3[CH2:17][CH2:16]3)[CH:10]=2)=[N:6][CH:7]=1
Reactant: Cn1nc(C2CC2)cc1Nc1ncc(Cl)c(NC2CC3CN(C(=O)OC(C)(C)C)CC3C2)n1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cn1nc(C2CC2)cc1Nc1ncc(Cl)c(NC2CC3CNCC3C2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.1 %

Procedure:
To a solution of tert-butyl 5-((5-chloro-2-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (751.2 mg, 1.58 mmol) in DCM (15 mL) was added a solution of HCl in EtOAc (15 mL, 60 mmol). The reaction mixture was stirred at rt for 1 h and concentrated in vacuo. The residue was dissolved in water (30 mL) and adjusted to pH=10 with a saturated Na2CO3 aqueous solution, then extracted with DCM (100 mL×3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/10) to give the title compound as a beige solid (0.29 g, 95%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[C:11]2[C:16]([CH3:17])=[CH:15][S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)[C:11]3[C:16]([CH3:17])=[CH:15][S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: COc1ccc(CNc2nc(Cl)nc3scc(C)c23)cc1OC
Product: COc1ccc(CNc2nc(-n3ccnc3C)nc3scc(C)c23)cc1OC

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-5-methyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-5-methyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][NH:5][CH3:6].O=C1CCC(=O)N1O[C:16](=[O:34])[C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24](=[O:33])[N:25]([CH3:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:19][CH:18]=1>>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][N:5]([CH3:6])[C:16]([C:17]1[CH:18]=[CH:19][C:20]([O:23][C:24](=[O:33])[N:25]([CH3:32])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:21][CH:22]=1)=[O:34]
Reactant: CNCCN(C)C
Reactant: CN(C(=O)Oc1ccc(C(=O)ON2C(=O)CCC2=O)cc1)c1ccccc1
Product: CN(C)CCN(C)C(=O)c1ccc(OC(=O)N(C)c2ccccc2)cc1

Procedure:
The title product was prepared from N,N,N′-trimethylethylendiamine and 4-(methyl-phenyl-carbamoyloxy)-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester, preparative HPLC (method C) (2%, colourless oill). HPLC-MS m/z=356.2 (M+1), Rt: 2.17 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]2[CH:12]=[N:13][C:14]([C:17]3[NH:21][C:20]4[CH:22]=[C:23]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)[CH:24]=[CH:25][C:19]=4[N:18]=3)=[CH:15][CH:16]=2)=[N:4][CH:5]=[C:6]([C:8](O)=[O:9])[CH:7]=1.O1CCCC1.[OH-].[Al+3].[Li+].[OH-].[OH-].[OH-]>O>[Cl:1][C:2]1[C:3]([C:11]2[CH:12]=[N:13][C:14]([C:17]3[NH:21][C:20]4[CH:22]=[C:23]([N:26]5[CH2:27][CH2:28][O:29][CH2:30][CH2:31]5)[CH:24]=[CH:25][C:19]=4[N:18]=3)=[CH:15][CH:16]=2)=[N:4][CH:5]=[C:6]([CH2:8][OH:9])[CH:7]=1
Reactant: O=C(O)c1cnc(-c2ccc(-c3nc4ccc(N5CCOCC5)cc4[nH]3)nc2)c(Cl)c1
Agent: [Al+3]
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cnc(-c2ccc(-c3nc4ccc(N5CCOCC5)cc4[nH]3)nc2)c(Cl)c1
Temperature: -80 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
0.49 g of 3-chloro-6′-(6-morpholin-4-yl-1H-benzoimidazol-2-yl)-[2,3′]bipyridinyl-5-carboxylic acid (71) (1.12 mmol) prepared in Example 58 was added to 5 mL of tetrahydrofuran, and cooled to −80° C. 0.09 g of lithium aluminum hydroxide (2.24 mmol) was slowly added thereto. After stirring for 2 hours, the temperature of the reactant was slowly raised to room temperature, and further reacted 2 hours. A small amount of water was added thereto terminate the reaction, and concentrated under reduced pressure. Then, the resultant was dissolved in ethyl acetate and washed with water. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography (eluting solvent: chloroform/methanol=20/1) to obtain 0.44 g of yellow crystal, [3-chloro-6′-(6-morpholin-4-yl-1H-benzoimidazol-2-yl)-[2,3′]bipyridinyl-5-yl]-methanol compound (yield 93%).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[OH:39][C:40]1[CH:41]=[C:42]([NH:55][S:56]([CH3:59])(=[O:58])=[O:57])[CH:43]=[C:44](B2OC(C)(C)C(C)(C)O2)[CH:45]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[OH:39][C:40]1[CH:41]=[C:42]([NH:55][S:56]([CH3:59])(=[O:58])=[O:57])[CH:43]=[C:44]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)[CH:45]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: CC1(C)OB(c2cc(O)cc(NS(C)(=O)=O)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(O)cc(NS(C)(=O)=O)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 37 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (80 mg, 0.13 mmol) was treated with N-(3-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (101 mg, 0.32 mmol), sodium carbonate (34 mg, 0.32 mmols) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (8 mg, 0.01 mmol) using 1,2-dimethoxyethane (0.96 ml) and water (0.24 ml) as solvents according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 80%, hexane-ethyl acetate) to give 46 mg (37% yield, 76% purity) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.[Br:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:21])=[C:17]([CH:20]=1)[CH:18]=O.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>C(#N)C.C(OCC)(=O)C.C=C(C)C>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]2[C:7](=[CH:8][CH:9]=1)[NH:10][CH:18]([C:17]1[CH:20]=[C:13]([Br:12])[CH:14]=[CH:15][C:16]=1[CH3:21])[CH2:3][C:4]2([CH3:9])[CH3:5])=[O:11]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: Cc1ccc(Br)cc1C=O
Agent: C=C(C)C
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(c1)C(C)(C)CC(c1cc(Br)ccc1C)N2
Temperature: 85 °C
Reaction time: 16 h
Yield: 73.1 %

Procedure:
To a stirred solution of 4-amino-benzoic acid methyl ester (8.25 g, 50 mmol) and 5-bromo-2-methyl-benzaldehyde (12 g, 60 mmol) in acetonitrile (200 mL) were added isobutene (14 mL, 0.2 mmol) and ytterbium(III) trifluoromethanesulfonate (Yb(OTf)3) (4.65 g, 7.5 mmol). The resulting mixture was stirred at 85° C. for 16 h in sealed tube. The mixture was diluted with ethyl acetate (300 mL) and washed with water (100 mL×2) and brine (100 mL×2) and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 10-50% ethyl acetate in petroleum ether) to afford 2-(5-bromo-2-methyl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (7.1 g, 35%) as a light yellow solid: MS (ESI) M+1=402.0.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([OH:14])=[CH:9][CH:8]=2)=[O:4].Cl[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][N:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][N:17]=1)=[CH:9][CH:8]=2)=[O:4]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: COC(=O)c1cc2cc(O)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2cc(Oc3ccc([N+](=O)[O-])cn3)ccc2[nH]1
Temperature: 80 °C
Reaction time: 18 h
Yield: 54.4 %

Procedure:
5-Hydroxy-1H-indole-2-carboxylic acid methyl ester (0.845 g, 4.42 mmol) and 2-chloro-5-nitropyridine (0.771 g, 4.86 mmol) were dissolved in DMF (5 mL). To the solution was added anhydrous potassium carbonate (0.611 g, 4.42 mmol) and the resulting solution was stirred for 18 hours at 80° C. Water (80 mL) was added to the reaction solution and the mixture was extracted with ethyl acetate (80 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate and the solvent was removed by evaporation. The residue was purified by silica gel column chromatography (AcOEt:n-hexane=1:3), then the obtained solid was recrystallized from ethyl acetate and n-hexane to yield 0.753 g of the title compound as a yellow powder.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=O.C(N(C(C)C)CC)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH2:44]([O:46][C:47]([C:49]1[N:50]=[C:51]([CH:54]2[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]2)[S:52][CH:53]=1)=[O:48])[CH3:45]>CN(C=O)C>[CH2:44]([O:46][C:47]([C:49]1[N:50]=[C:51]([CH:54]2[CH2:59][CH2:58][N:57]([C:10](=[O:12])[CH2:9][C:3]3[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=3[CH3:1])[CH2:56][CH2:55]2)[S:52][CH:53]=1)=[O:48])[CH3:45]
Reactant: CCOC(=O)c1csc(C2CCNCC2)n1
Reactant: Cc1ccc(C)c(CC(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1csc(C2CCN(C(=O)Cc3cc(C)ccc3C)CC2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.8 %

Procedure:
To a solution of 2,5-dimethylphenylacetic acid (5.45 g, 27.4 mmol) in DMF (80 mL) is added diisopropylethylamine (85.4 mL, 411.32 mmol), followed by O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (12.8 g, 32.9 mmol) at 0° C. After stirring 15 min at RT, 2-piperidin-4-yl-thiazole-4-carboxylic acid ethyl ester (6.59 g, 27.4 mmol) is added to the reaction mixture. After stirring overnight at RT, solvent is evaporated and the resulting yellow oil is dissolved in ethylacetate (500 mL), washed with aqueous saturated sodium bicarbonate solution (500 mL) and the aqueous phase is re-extracted with ethylacetate (100 mL). The combined organic layers are washed with 0.5M HCl solution (400 mL) and brine (400 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure to give 2-{1-[2-(2,5-dimethyl-phenyl)-acetyl]-piperidin-4-yl}-thiazole-4-carboxylic acid ethyl ester (10.46 g, 98%), which can be used in the next step without further purification. 1H-NMR (400 MHz, CDCl3): δ=1.41 (t, 3H), 1.52-1.82 (m, 2H), 2.10-2.22 (m, 2H), 2.25 (s, 3H), 2.30 (s, 3H), 2.73-2.86 (m, 1H), 3.08-3.22 (m, 1H), 3.29-3.40 (m, 1H), 3.68 (s, 2H), 3.8-3.95 (m, 1H), 4.38-4.42 (q, 2H), 4.73-4.88 (m, 1H), 6.96 (s, 1H), 6.98-7.01 (d, 1H), 7.08 (d, 1H), 8.10 (s, 1H). MS: m/z=387 (M+1).
Reaction SMILES: Br[C:2]1[C:3]([NH:11][C:12](=[O:21])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[N:4][N:5]2[CH:10]=[CH:9][CH:8]=[N:7][C:6]=12.[CH3:22][O:23][C:24]1[N:29]=[CH:28][C:27](B(O)O)=[CH:26][N:25]=1>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C:12]([NH:11][C:3]2[C:2]([C:27]3[CH:26]=[N:25][C:24]([O:23][CH3:22])=[N:29][CH:28]=3)=[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][N:5]3[N:4]=2)=[O:21])=[CH:15][CH:16]=1
Reactant: O=C(Cc1ccc(F)cc1)Nc1nn2cccnc2c1Br
Reactant: COc1ncc(B(O)O)cn1
Product: COc1ncc(-c2c(NC(=O)Cc3ccc(F)cc3)nn3cccnc23)cn1

Procedure:
The product from Example 140A and 2-methoxypyrimidine-5-boronic acid were processed using the method analogous to that described in Example 110C to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.69-10.71 (m, 1H), 9.12 (dd, J=6.9, 1.7 Hz, 1H), 8.74 (s, 2H), 8.62 (dd, J=4.1, 1.7 Hz, 1H), 7.30-7.35 (m, 2H), 7.12-7.17 (m, 3H), 3.94 (s, 3H), 3.69 (s, 2H); MS (ESI) m/z 379 (M+H)+.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[NH2:7][C:8]1[C:13]2[C:14]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4[N:27]([CH3:35])[C:28]5[C:33]([CH:34]=4)=[CH:32][CH:31]=[CH:30][CH:29]=5)=[O:25])=[C:19]([O:36][CH3:37])[CH:18]=3)=[CH:15][S:16][C:12]=2[C:11](/[CH:38]=[CH:39]/[C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:10][N:9]=1>CS(C)=O.[H-].[Na+]>[NH2:7][C:8]1[C:13]2[C:14]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4[N:27]([CH3:35])[C:28]5[C:33]([CH:34]=4)=[CH:32][CH:31]=[CH:30][CH:29]=5)=[O:25])=[C:19]([O:36][CH3:37])[CH:18]=3)=[CH:15][S:16][C:12]=2[C:11]([CH:38]2[CH2:2][CH:39]2[C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:10][N:9]=1
Reactant: CCOC(=O)/C=C/c1cnc(N)c2c(-c3ccc(NC(=O)c4cc5ccccc5n4C)c(OC)c3)csc12
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)C1CC1c1cnc(N)c2c(-c3ccc(NC(=O)c4cc5ccccc5n4C)c(OC)c3)csc12
Temperature: 25 °C
Yield: 30.2 %

Procedure:
Trimethylsulfoxonium iodide (45.1 mg, 0.205 mmol) in anhydrous methyl sulfoxide (4 mL) and 60% sodium hydride in mineral oil (16.4 mg, 0.411 mmol) was stirred for 5 minutes at room temperature and treated with a mixture of ethyl (2E)-3-[4-amino-3-(3-methoxy-4-{[(1-methyl-1H-indol-2-yl)carbonyl]amino}phenyl)thieno[3,2-c]pyridin-7-yl]acrylate (108 mg, 0.205 mmol) in methyl sulfoxide (2 mL) was added. After 4 hours the mixture was cooled to room temperature and quenched with saturated ammonium chloride solution (7 mL). The aqueous layer was extracted with dichloromethane (3×10 mL), dried over magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The crude product was purified via HPLC preparative to give the title compound as a white solid (33.6 mg 0.062 mmol): LCMS (Conditions a): MH+=541 Rt =4.20 minutes; 1H NMR (DMSO-d6, 400 MHz) δ 9.51 (1H), 7.99 (1H), 7.69 (2H), 7.58 (2H), 7.35 (2H), 7.18 (1H), 7.15 (1H), 7.06 (1H), 5.49 (1H), 4.18 (2H), 4.04 (3H), 3.91 (3H), 2.45 (1H), 1.86 (1H), 1.56 (1H), 1.47 (1H), 1.26 (3H).
Reaction SMILES: C[O-].[Na+].CO.[NH2:6][C:7]([NH2:9])=[S:8].[F:10][C:11]([F:21])([F:20])[C:12](=O)[CH2:13][C:14](OCC)=[O:15]>C(O)C>[OH:15][C:14]1[CH:13]=[C:12]([C:11]([F:21])([F:20])[F:10])[N:9]=[C:7]([SH:8])[N:6]=1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: NC(N)=S
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: Oc1cc(C(F)(F)F)nc(S)n1
Temperature: 22 °C

Procedure:
To a solution of 25% NaOMe/MeOH (23 ml, 0.10 mol) and ethanol (27 ml) are added thiourea (5.33 g, 0.70 mol) and ethyl 4,4,4-trifluoroacetoacetate (7.3 ml, 50 mmol), then the reaction is heated to reflux for 16 hrs. The mixture is cooled to 22° C., concentrated in vacuo, and the residue dissolved in water (50 ml), acidified with HCl (7 ml), and filtered. The solid is collected, washed with water, and dried: 6.58 g (32.5 mmol, 65%).