Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1]/[C:2](/[C:9]([F:12])([F:11])[F:10])=[CH:3]/[C:4]([O:6]CC)=O.[H-].[Na+].[F:15][C:16]1([F:34])[O:21][C:20]2[CH:22]=[C:23]([F:29])[C:24]([N:26]=[C:27]=[O:28])=[CH:25][C:19]=2[N:18]([CH2:30][C:31]#[CH:32])[C:17]1=[O:33]>CN(C=O)C.C1(C)C=CC=CC=1>[F:12][C:9]([F:10])([F:11])[C:2]1[NH:1][C:27](=[O:28])[N:26]([C:24]2[C:23]([F:29])=[CH:22][C:20]3[O:21][C:16]([F:15])([F:34])[C:17](=[O:33])[N:18]([CH2:30][C:31]#[CH:32])[C:19]=3[CH:25]=2)[C:4](=[O:6])[CH:3]=1
Reactant: C#CCN1C(=O)C(F)(F)Oc2cc(F)c(N=C=O)cc21
Reactant: CCOC(=O)/C=C(/N)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: C#CCN1C(=O)C(F)(F)Oc2cc(F)c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (E)-ethyl 3-amino-4,4,4-trifluorobut-2-enoate (4.24 g, 23.2 mmol) was added dropwise at 5° C. under N2 to a stirred solution of sodium hydride (1.01 g of a 55% suspension in mineral oil, 23.2 mmol) in dry DMF. The light yellow suspension was stirred for 1 hour, while allowing the reaction mixture to warm to room temperature. After that period, a solution of 2,2,7-trifluoro-6-isocyanato-4-(prop-2-ynyl)-2Hbenzo[b][1,4]oxazin-3(4H)-one (6.54 g, 23.2 mmol) in toluene was added dropwise, after which the mixture was heated at 80° C. overnight under nitrogen. As LC/MS indicated that the reaction was not fully complete, heating was continued for a further 3 hours at 100° C., after which the light brown solution was concentrated in vacuo. The dark residue was partitioned between ethyl acetate and aqueous ammonium chloride solution, and the aqueous phase was extracted with additional ethyl acetate. The combined organic fractions were washed with brine and dried over Na2SO4. Filtration and evaporation of the solvent gave 10.68 g crude brown oil. This was purified by column chromatography (EtOAc:heptane, 20-60%) to give three fractions in which the desired product was the major component (present as a mixture of keto and enol tautomers). These three fractions were combined and further purified by column chromatography, eluting with di-isopropyl ether, to give the product (3.0 g) as an offwhite fluffy solid (94% purity according to NMR, with ca. 20% existing as the enol tautomer).
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([NH:19][C:20]1[C:21]2[CH2:29][N:28]([C:30]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][C:31]=3[C:32]#[N:33])[CH2:27][CH2:26][C:22]=2[N:23]=[CH:24][N:25]=1)[C:11]1[CH:12]=[N:13][C:14]([O:17][CH3:18])=[N:15][CH:16]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O.CCOC(C)=O>C1COCC1>[OH:8][CH2:9][C@@H:10]([NH:19][C:20]1[C:21]2[CH2:29][N:28]([C:30]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][C:31]=3[C:32]#[N:33])[CH2:27][CH2:26][C:22]=2[N:23]=[CH:24][N:25]=1)[C:11]1[CH:16]=[N:15][C:14]([O:17][CH3:18])=[N:13][CH:12]=1
Reactant: COc1ncc([C@@H](CO[Si](C)(C)C(C)(C)C)Nc2ncnc3c2CN(c2ccc(C)cc2C#N)CC3)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ncc([C@@H](CO)Nc2ncnc3c2CN(c2ccc(C)cc2C#N)CC3)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of (S)-2-(4-(2-(tert-butyldimethylsilyloxy)-1-(methoxypyrimidin5-yl)ethylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (740 mg, 1.39 mmol) in THF (10 mL) was added 1M TBAF in THF (5 mL). The reaction mixture was stirred at room temperature for 10 minutes, and then treated with water and EtOAc. The organic layer was washed with aq. NaHCO3 and brine, dried (MgSO4), and concentrated. The residue was purified by semi-preparative HPLC to yield a white solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][C:12](=[O:14])[CH3:13].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:3]([NH:11][C:12](=[O:14])[CH3:13])[CH:4]=1)([O-:10])=[O:9]
Reactant: C1CCNC1
Reactant: CC(=O)Nc1cc([N+](=O)[O-])ccc1F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Product: CC(=O)Nc1cc([N+](=O)[O-])ccc1N1CCCC1
Temperature: 90 °C
Reaction time: 2.5 h

Procedure:
0.5 g (2.5 mmol) of N-(2-fluoro-5-nitrophenyl)acetamide was admixed in a pressure reaction vessel with 1 ml (12.6 mmol) of pyrrolidine and stirred at 90° C. for 2.5 hours. After the mixture had been cooled, it was diluted with 20 ml of dichloromethane, adjusted to pH 4 using citric acid solution (10%) and washed four times with water. After the organic phase had been dried, the solvent was removed under reduced pressure. In the aqueous phase, a solid is precipitated out. It was filtered off with suction and washed with water, and combined with the residue from the organic phase (yield 0.58 g, 93%). The product was reacted in stage c without further purification.
Reaction SMILES: Cl[C:2]1[C:7]([I:8])=[C:6]([C:9]([F:12])([F:11])[F:10])[N:5]=[C:4]([S:13][CH:14]([CH3:16])[CH3:15])[N:3]=1.[F:17][C:18]([F:30])([F:29])[C:19]1[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][NH:21][N:20]=1.O>CS(C)=O>[I:8][C:7]1[C:2]([N:21]2[CH:22]=[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:19]([C:18]([F:17])([F:29])[F:30])=[N:20]2)=[N:3][C:4]([S:13][CH:14]([CH3:16])[CH3:15])=[N:5][C:6]=1[C:9]([F:12])([F:11])[F:10]
Reactant: CC(C)Sc1nc(Cl)c(I)c(C(F)(F)F)n1
Reactant: CCOC(=O)c1c[nH]nc1C(F)(F)F
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1cn(-c2nc(SC(C)C)nc(C(F)(F)F)c2I)nc1C(F)(F)F
Temperature: 80 °C
Yield: 70.4 %

Procedure:
4-Chloro-5-iodo-2-isopropylthio-6-trifluoromethylpyrimidine (0.30 g) was dissolved in dimethylsulfoxide (3.0 ml) and ethyl 3-trifluoromethyl-1H-pyrazole-4-carboxylate (0.16 g) and 1,8-diazabicyclo-[5,4,0]-under-7-ene (0.12 g) was added at room temperature with stirring. The mixture was heated to 80° C. and stirred for 2 hr. After cooling to room temperature, the mixture was added water and extracted with benzene. The benzene layer was washed with water and brine, respectively and dried over magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give ethyl 1-(5-iodo-2-isopropylthio-6-trifluoromethylpyrimidin-4-yl)-3-trifluoromethyl-1H-pyrazole-4-carboxylate (0.30 g) as colorless crystalline solid, mp 107-108° C.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:29]3[C:24](=[CH:25][C:26]([C:30](O)=[O:31])=[CH:27][CH:28]=3)[C:23]([CH3:33])=[CH:22]2)=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:34]1([CH:40]([NH2:43])[CH2:41][CH3:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH3:33][C:23]1[C:24]2[C:29](=[CH:28][CH:27]=[C:26]([C:30](=[O:31])[NH:43][CH:40]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:41][CH3:42])[CH:25]=2)[N:21]([CH2:20][C:17]2[CH:18]=[CH:19][C:14]([C:9]3[C:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:15][CH:16]=2)[CH:22]=1
Reactant: CCC(N)c1ccccc1
Reactant: Cc1cn(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: CCC(NC(=O)c1ccc2c(c1)c(C)cn2Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1)c1ccccc1

Procedure:
The title compound was prepared following the same protocol as described in Step 8, Example 1, using the 1-((2′-(tert-Butoxycarbonyl)biphenyl-4-yl)methyl)-3-methyl-1H-indole-5-carboxylic acid instead of the 1-((2′-(tert-Butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid and the 1-phenylpropan-1-amine instead of the (S)-1-(4-bromophenyl)ethanamine.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:30]([CH3:33])([CH3:32])[CH3:31])[N:5]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[N:8]=1.[CH3:34][O:35][C:36]1[C:37]([NH2:51])=[N:38][CH:39]=[C:40](B2OC(C)(C)C(C)(C)O2)N=1.[C:52]([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[NH2:51][C:37]1[N:38]=[CH:39][C:40]([C:2]2[N:3]=[C:4]([C:30]([CH3:33])([CH3:32])[CH3:31])[N:5]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:6]=2[C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([O:20][CH3:21])[CH:15]=3)[N:8]=2)=[CH:52][C:36]=1[O:35][CH3:34]
Reactant: COc1nc(B2OC(C)(C)C(C)(C)O2)cnc1N
Reactant: COc1cc(Nc2nccc(-c3c(Br)nc(C(C)(C)C)n3COCC[Si](C)(C)C)n2)ccn1
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc(Nc2nccc(-c3c(-c4cnc(N)c(OC)c4)nc(C(C)(C)C)n3COCC[Si](C)(C)C)n2)ccn1
Temperature: 100 °C
Yield: 93.1 %

Procedure:
A mixture of 4-(4-bromo-2-tert-butyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-N-(2-methoxypyridin-4-yl)pyrimidin-2-amine (100 mg, 0.19 mmol), 3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazin-2-amine (118 mg, 0.47 mmol, Example 18, Step 2), aqueous 2.0 M Na2CO3 solution (1 ml, 2.0 mmol), and Pd(PPh3)4 (22 mg, 0.019 mmol) in DME (2 mL) was sparged with N2 for 5 min. The reaction was sealed and heated to 100° C. for 2 h. The reaction was allowed to cool to rt, poured into EtOAc and partitioned with water. The layers were separated and the organic portion was washed with water, dried (MgSO4), and concentrated. The resulting residue was purified by flash chromatography (SiO2, 100:0-0:100, hexanes-25% MeOH in EtOAc) to afford 102 mg (69% purity) of 4-(4-(6-amino-5-methoxypyridin-3-yl)-2-tert-butyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-N-(2-methoxypyridin-4-yl)pyrimidin-2-amine: LCMS (m/z): 578.5 (MH+), tR=0.74 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[N:12]1[CH:16]=[N:15][C:14]([CH3:17])=[N:13]1>[Pd].CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:6]=[CH:5][C:4]=1[N:12]1[CH:16]=[N:15][C:14]([CH3:17])=[N:13]1)[NH2:9]
Reactant: COc1cc([N+](=O)[O-])ccc1-n1cnc(C)n1
Agent: [Pd]
Solvent: CO
Product: COc1cc(N)ccc1-n1cnc(C)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.1 %

Procedure:
Step F (2): 10% Palladium on carbon (1.2 g) was added under an atmosphere of nitrogen to a chilled (ice-water bath) solution of 1-(2-methoxy-4-nitrophenyl)-3-methyl-1H-1,2,4-triazole (3.7 g, 12.7 mmol) dissolved in methanol (250 mL). The flask was repeated evacuated and flushed with hydrogen gas (double balloon). The resulting mixture was allowed to warm to rt and left to stir for 18 h under the hydrogen atmosphere. Purged with nitrogen gas. Filtered the crude reaction mixture through a short diatomaceous earth (Celite®) plug. Rinsed reaction vessel and plug with methanol. Concentrated filtrate in vacuo. Dried residue on high vacuum overnight to afford 3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)aniline (2.44 g, 94% yield) as a reddish solid. LC-MS (M+H)+ 205.2. 1H NMR (500 MHz, chloroform-d) δ ppm 8.35 (s, 1 H) 7.36 (d, J=8.55 Hz, 1 H) 6.29-6.34 (m, 2 H) 3.80 (s, 3 H) 2.46 (s, 3 H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][N:9]([CH2:20][C:21]2[CH:22]=[C:23]([CH:35]=[CH:36][CH:37]=2)[CH2:24][N:25]2[CH:29]([C:30](O)=[O:31])[CH2:28][CH2:27][S:26]2(=[O:34])=[O:33])[C@H:10]([CH2:16][N:17]([CH3:19])[CH3:18])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:6]([F:38])[C:5]([O:39][CH3:40])=[CH:4][CH:3]=1.[C:41]12([NH2:51])[CH2:50][CH:45]3[CH2:46][CH:47]([CH2:49][CH:43]([CH2:44]3)[CH2:42]1)[CH2:48]2>>[C:41]12([NH:51][C:30]([C@H:29]3[CH2:28][CH2:27][S:26](=[O:33])(=[O:34])[N:25]3[CH2:24][C:23]3[CH:35]=[CH:36][CH:37]=[C:21]([CH2:20][N:9]([CH2:8][C:7]4[C:2]([Cl:1])=[CH:3][CH:4]=[C:5]([O:39][CH3:40])[C:6]=4[F:38])[C@H:10]([CH2:16][N:17]([CH3:19])[CH3:18])[CH2:11][C:12]([CH3:14])([CH3:15])[CH3:13])[CH:22]=3)=[O:31])[CH2:48][CH:47]3[CH2:46][CH:45]([CH2:44][CH:43]([CH2:49]3)[CH2:42]1)[CH2:50]2
Reactant: COc1ccc(Cl)c(CN(Cc2cccc(CN3C(C(=O)O)CCS3(=O)=O)c2)[C@H](CN(C)C)CC(C)(C)C)c1F
Reactant: NC12CC3CC(CC(C3)C1)C2
Product: COc1ccc(Cl)c(CN(Cc2cccc(CN3[C@@H](C(=O)NC45CC6CC(CC(C6)C4)C5)CCS3(=O)=O)c2)[C@H](CN(C)C)CC(C)(C)C)c1F
Yield: 61.8 %

Procedure:
(R)-2-(3-{[(6-Chloro-2-fluoro-3-methoxy-benzyl)-((S)-1 dimethylaminomethyl-3,3-dimethyl-butyl)-amino]-methyl}-benzyl)-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid (Intermediate 7 (Epimer 2), 0.044 g, 0.073 mmol) was reacted with 1-adamantanamine (0.013 g, 0.089 mmol) to form (R)-2-(3-{[(6-Chloro-2-fluoro-3-methoxy-benzyl)-((S)-1-dimethylaminomethyl-3,3-dimethyl-butyl)-amino]-methyl}-benzyl)-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid adamantan-1-ylamide (Epimer 2) (0.033 g, 61%). m/z=731 (M+1); HRMS: calcd for C39H57ClFN4O4S. Calc [M+H+] 731.3768. found 731.3767.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([O:13]C)=[O:12])[C:5]([OH:7])=[O:6].O[Li].O>C1COCC1.CO.O>[NH2:1][C:2]1[CH:3]=[C:4]([C:5]([OH:7])=[O:6])[CH:8]=[CH:9][C:10]=1[C:11]([OH:13])=[O:12]
Reactant: COC(=O)c1ccc(C(=O)O)cc1N
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Nc1cc(C(=O)O)ccc1C(=O)O
Temperature: 25 °C
Yield: 63 %

Procedure:
3-Amino-4-(methoxylcarbonyl)benzoic acid (2.5 g, 12.8 mmol) was dissolved in a mixture of THF-MeOH—H2O (40 mL, 30:5:5) and then LiOH—H2O (2 g, 64 mmol) was added. The mixture stirred at RT over night. The reaction mixture was concentrated and the residue was dissolved in 5 mL of water and then acidified with 6N HCl to pH˜3. The solid was filtered and dried to give the desired product in 63% yield.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH:23]1[CH2:26][CH:25]([C:27]([OH:30])([CH3:29])[CH3:28])[CH2:24]1>>[Br:1][C:2]1[C:3]([N:23]2[CH2:26][CH:25]([C:27]([OH:30])([CH3:29])[CH3:28])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Reactant: CC(C)(O)C1CNC1
Product: CC(C)(O)C1CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 128.1 using 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2) and 2-azetidin-3-yl-propan-2-ol (WO2010138589) to afford an off-white crystalline product. HPLC (Condition 4) tR=5.84 min, UPLC-MS (Condition 7) m/z=474.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:19]2[NH:28][C:22]3=[N:23][CH:24]=[C:25](Br)[CH:26]=[C:21]3[N:20]=2)[CH:12]=[C:13]([O:15][CH:16]([CH3:18])[CH3:17])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(COC)OC.C(=O)([O-])[O-].[Na+].[Na+]>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.O.C(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:19]2[NH:28][C:22]3=[N:23][CH:24]=[C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:26]=[C:21]3[N:20]=2)[CH:12]=[C:13]([O:15][CH:16]([CH3:18])[CH3:17])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)Oc1cc(OCc2ccccc2)cc(-c2nc3cc(Br)cnc3[nH]2)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: CCO
Solvent: O
Solvent: COCCOC
Product: CC(C)Oc1cc(OCc2ccccc2)cc(-c2nc3cc(-c4ccccc4)cnc3[nH]2)c1
Temperature: 150 °C
Reaction time: 0.07 h
Yield: 100.6 %

Procedure:
To a mixture of 2-(3-(benzyloxy)-5-isopropoxyphenyl)-6-bromo-3H-imidazo[4,5-b]pyridine (0.11 g), phenylboronic acid (0.05 g) and tetrakis(triphenylphosphine)palladium(0) (0.01 g) in a mixed solvent of dimethoxyethane (3.0 ml) and ethanol (1 ml) was 0.5M aqueous sodium carbonate solution (1 ml), and the mixture was subjected to microwave irradiation in a sealed reaction container and stirred at 150° C. for 4 min. After completion of the reaction, water (2 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 ml). The extract was washed successively with water and saturated brine and dried over magnesium sulfate. The solvent was concentrated under reduced pressure, and the obtained crystals were collected by filtration, washed with isopropyl ether and dried to give the title compound (0.11 g). 1H NMR (CDCl3) δ ppm 1.33 (6 H, d, J=6.03 Hz), 4.59-4.71 (1 H, m), 5.19 (2 H, s), 6.70 (1 H, t, J=1.88 Hz), 7.35-7.50 (9 H, m), 7.58 (1 H, s), 7.70 (2 H, d, J=6.97 Hz), 8.37 (1 H, d, J=1.70 Hz), 8.86 (1 H, d, J=1.70 Hz), 14.11 (1 H, s).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11]C.C(Cl)Cl.B(Br)(Br)Br.OP([O-])(O)=O.[K+]>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11]
Reactant: COc1cc([N+](=O)[O-])ccc1Br
Agent: BrB(Br)Br
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(Br)c(O)c1
Temperature: -44 °C
Reaction time: 20 h
Yield: 100 %

Procedure:
A mixture of 29.1 g (125.6 mmol) of 2-bromo-5-nitroanisole and 250 mL CH2Cl2 was stirred at −44° C. in a dry ice acetonitrile bath under a nitrogen atmosphere. Boron tribromide (18 mL) was added dropwise to the reaction mixture. The resulting black reaction was stirred while allowing the cooling bath to slowly rise to room temperature over 20 h. TLC analysis indicated complete reaction, so the reaction mixture was transferred to an addition funnel and added cautiously to a mixture of ice, water and 75 g solid KH2PO4. The layers were separated, the aqueous layer was washed with CH2Cl2, the combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered, concentrated to give 27.4 g (125.6 mmol, 100%) of 2-bromo-5-nitrophenol as a black solid. 1H NMR (400 MHz) CDCl3 7.85 (s, 1H), 7.62-7.70 (m, 2H), 5.88 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[F:10][C:11]([N:14]=[C:15]=[O:16])([F:13])[F:12]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]([NH:5][C:15]([NH:14][C:11]([F:13])([F:12])[F:10])=[O:16])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: O=C=NC(F)(F)F
Reactant: Cc1cc(N)ccc1Cl
Solvent: Cc1ccccc1
Product: Cc1cc(NC(=O)NC(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 3-methyl-4-chloroaniline (70 grams; 0.5 mol) in toluene (150 ml) is placed into a pressure vessel, and is cooled in an acetone-dry ice bath. Trifluoromethyl isocyanate (56 grams; 0.5 mol) is added and the pressure vessel is sealed. The reaction mixture is warmed to about 25° C. and is allowed to stand for about 24 hours. After this time the reaction vessel is opened and its contents are stripped of toluene by evaporation under reduced pressure. The residue is then recrystallized to yield N-(3-methyl-4-chlorophenyl)-N'-trifluoromethyl urea.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:10][C:11]1[S:12][C:13]([NH2:16])=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]([N:30]=[C:31]=[S:32])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CC(C)=O>[C:1]([O:5][C:6]([NH:8][CH:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:10][C:11]1[S:12][C:13]([NH:16][C:31]([NH:30][C:22](=[O:29])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[S:32])=[CH:14][CH:15]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CCOC(=O)C(Cc1ccc(N)s1)NC(=O)OC(C)(C)C
Solvent: CC(C)=O
Product: CCOC(=O)C(Cc1ccc(NC(=S)NC(=O)c2ccccc2)s1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 76.7 %

Procedure:
To a stirred solution of Ethyl N-(tert-butoxycarbonyl)-3-(5-amino-2-thienyl)-DL-alaninate (4.21 g, 13.4 mmol) in acetone (75 ml) at 0° C. was added benzoyl isothiocyanate (2.55 g 15.6 mmol). The mixture was stirred for 5 minutes at 0° C., warmed to room temperature and stirred for 2 hours. The solvent was removed at reduced pressure and the resulting oil dissolved in ethyl acetate, washed with 1N aqueous hydrochloric acid, brine and dried over magnesium sulphate. The solvent was removed at reduced pressure to give a dark green viscous oil. The crude product was purified by chromatography on silica gel eluting with 1:3 ethyl acetate/hexane to yield Ethyl N-(tert-butoxycarbonyl)-3-(5-(3-benzoylthioureido)-2-thienyl)-DL-alaninate (4.91 g, 77%) as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[N:16]=[C:15]2[CH:25]([F:27])[F:26])[N:3]=1.[NH2:28][C@@H:29]1[CH2:34][CH2:33][CH2:32][N:31]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30]1>>[F:26][CH:25]([F:27])[C:15]1[N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([NH:28][C@@H:29]3[CH2:34][CH2:33][CH2:32][N:31]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30]3)[N:3]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=2[N:16]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)nc(N2CCOCC2)n1
Yield: 88 %

Procedure:
Reaction of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole with tert-butyl(3R)-3-amino-1-piperidinecarboxylate as in Example 28 gave tert-butyl(3R)-3-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}-1-piperidinecarboxylate in 88% yield: 1H NMR (DMSO-d6) (rotamers) δ8.11 and 8.00 (2d, J=8.1, 8.2 Hz, 1H), 7.89 and 7.71 (2t, JHF=53.1 Hz, 1H), 7.38 (t, J=8.2 Hz, 1H), 6.95 and 6.94 (2d, J=8.0, 7.8 Hz, 1H), 3.97 (s, 3H), 3.79-3.69 (m, 10H), 3.02-2.80 (m, 2H), 1.97-1.93 (m, 1H), 1.76 (m, 1H), 1.59-1.20 (m, 2H), 1.35 (s, 9H). Anal. Calcd. for C26H34F2N8O4: C, 55.7; H, 6.1; N, 20.0. Found: C, 55.9; H, 6.1; N, 20.1%.
Reaction SMILES: C[Si](C)(C)[N:3]([C@H:8]([B:13]1[O:17][C@@H:16]2[CH2:18][C@@H:19]3[CH2:22][C@H:21]([C@:15]2([CH3:25])[O:14]1)[C:20]3([CH3:24])[CH3:23])[CH2:9][CH:10]([CH3:12])[CH3:11])[Si](C)(C)C.[ClH:28]>O1CCOCC1.C(OCC)C>[ClH:28].[CH3:25][C@:15]12[C@H:21]3[CH2:22][C@H:19]([C:20]3([CH3:23])[CH3:24])[CH2:18][C@H:16]1[O:17][B:13]([C@@H:8]([NH2:3])[CH2:9][CH:10]([CH3:12])[CH3:11])[O:14]2
Reactant: CC(C)C[C@@H](B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1)N([Si](C)(C)C)[Si](C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(C)C[C@H](N)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Temperature: 0 °C
Reaction time: 4 h
Yield: 66 %

Procedure:
To a solution of crude N,N-bis(trimethylsilyl)-(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutylamine of Step 3 (79 g, 0.193 mol) in a mixture of dioxane (100 ml) and diethyl ether (200 ml), a 4 N solution of hydrogen chloride in dioxane (193 ml, 0.772 mol) was added, while cooling at 0° C. The mixture was then stirred at room temperature for 4 hours and concentrated. The residue was taken up with anhydrous hexane (500 ml) and a 2 M solution of hydrogen chloride in diethyl ether (48 ml, 0.096 mol) was added. The mixture was stirred at 0° C. for 1 hour, then concentrated. The residue was taken up with anhydrous hexane and the resulting suspension was stirred at room temperature overnight. The solid was collected by filtration and dried under vacuum affording 38.1 g of product (66% yield). A second crop (4.13 g, 7% yield) was obtained from the mother liquors.