Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl.Cl.[CH3:12][Si:13]([CH3:40])([CH3:39])[CH2:14][CH2:15][O:16][CH2:17][N:18]1[C:22]2[N:23]=[CH:24][N:25]=[C:26]([C:27]3[CH:28]=[N:29][N:30]([C:32]4([CH2:36][C:37]#[N:38])[CH2:35][NH:34][CH2:33]4)[CH:31]=3)[C:21]=2[CH:20]=[CH:19]1.Cl[C:42]1[N:43]=[CH:44][C:45]([C:48]([NH:50][C@@H:51]([CH3:56])[C:52]([F:55])([F:54])[F:53])=[O:49])=[N:46][CH:47]=1.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[C:37]([CH2:36][C:32]1([N:30]2[CH:31]=[C:27]([C:26]3[C:21]4[CH:20]=[CH:19][N:18]([CH2:17][O:16][CH2:15][CH2:14][Si:13]([CH3:39])([CH3:12])[CH3:40])[C:22]=4[N:23]=[CH:24][N:25]=3)[CH:28]=[N:29]2)[CH2:33][N:34]([C:42]2[N:43]=[CH:44][C:45]([C:48]([NH:50][C@@H:51]([CH3:56])[C:52]([F:55])([F:54])[F:53])=[O:49])=[N:46][CH:47]=2)[CH2:35]1)#[N:38]
Reactant: C[C@H](NC(=O)c1cnc(Cl)cn1)C(F)(F)F
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ncnc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)c1cnc(N2CC(CC#N)(n3cc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)cn1)C(F)(F)F
Temperature: 120 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
N,N-Diisopropylethylamine (0.11 mL, 0.62 mmol) was added to a mixture of {3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile dihydrochloride (110 mg, 0.22 mmol) and 5-chloro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]pyrazine-2-carboxamide (52 mg, 0.21 mmol) in NMP (3.0 mL). The reaction mixture was stirred at 120° C. for 2 h. The reaction mixture was worked up with saturated aqueous NaHCO3, and extracted with dichloromethylene (3×20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in dichloromethylene (0-65%) to afford the desired product (100 mg, 73%). LCMS (M+H)+: m/z=627.2.
Reaction SMILES: [N:1]12[CH2:7][C:4]([C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[OH:9])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[C:22]1([CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][Br:34])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC#N>[Br-:34].[OH:9][C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]12[CH2:7][N+:1]([CH2:33][CH2:32][CH2:31][CH2:30][O:29][CH2:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([CH2:6][CH2:5]1)[CH2:2][CH2:3]2
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)C2
Reactant: BrCCCCOCc1ccccc1
Solvent: CC#N
Product: OC(c1ccccc1)(c1ccccc1)C12CC[N+](CCCCOCc3ccccc3)(CC1)C2
Product: [Br-]
Yield: 7.3 %

Procedure:
Following the general procedure outlined in Example 1, 1-azabicyclo[2.2.1]hept-4-yl(diphenyl)methanol (33.1 mg, 0.118 mmol) and 4-bromobutyl phenylmethyl ether (0.04 mL, 0.21 mmol) in 2 CH3CN/3 CHCl3 (2.5 mL) were reacted to give the desired product (4.5 mg, 7%). EI-MS m/z 442 (M+) Rt (2.01 min).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Si](C)(C)[N:14]1[C:18]2=[N:19][CH:20]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[CH:22]=[C:17]2[C:16]([C:30](O)=[O:31])=[CH:15]1)(C)(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:1]([NH:8][C:30]([C:16]1[C:17]2[C:18](=[N:19][CH:20]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[CH:22]=2)[NH:14][CH:15]=1)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)n1cc(C(=O)O)c2cc(-c3cccc(F)c3)cnc21
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCc1ccccc1)c1c[nH]c2ncc(-c3cccc(F)c3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.7 %

Procedure:
To a solution of benzylamine (4.4 μL, 40.3 μmol) in dry CH2Cl2 (0.5 mL) was added carboxylic acid 10 (15 mg, 40.5 μmol), WSCHCl (9.32 mg, 44.86 μmol), HOBT (5.5 mg, 40.5 μmol) and i-Pr2NEt (7.1 μL, 40.8 μmol) and the reaction mixture left to stir at r.t. overnight Separation by LCMS (CombiPrep ODS-AM column) using water—acetonitrile as eluent (in gradient) afforded amide 11 (2.33 mg, 17%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 4.70 (d, J=5.5 Hz, 2H), 6.18 (t, J=5.5 Hz, 1H), 7.29-7.44 (m, 8H), 7.80 (s, 1H), 8.57 (d, J=1.8 Hz, 1H), 8.66 (d, J=2.1 Hz, 1H).
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]([CH3:51])[C:36]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)=[C:37]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[N:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=[O:55]>>[OH2:23].[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][CH:15]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]([CH3:51])[C:36]([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)=[C:37]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[N:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[OH2:55].[OH2:23].[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][CH:15]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]([CH3:51])[C:36]([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)=[C:37]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[N:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3nc(-c4ccccc4)c(-c4ccccc4)n3C)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reactant: O=C(O)C(F)(F)F
Product: CCCc1nc2c(C)cc(-c3nc(-c4ccccc4)c(-c4ccccc4)n3C)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Product: O

Procedure:
Prepared analogously to Example 151 from tert.butyl 4'-[[2-n-propyl-4-methyl-6-(1-methyl-4,5-diphenyl-imidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:4]=2[N:5]=[CH:6][N:7]=1.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[N:29][NH:30][CH:31]=2)O1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C>[NH:29]1[CH:28]=[C:27]([C:2]2[C:3]3[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH:31]=[N:30]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cl)ncnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Temperature: 125 °C

Procedure:
To a mixture of 4-chloro-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (1.4 g, 0.0049 mol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.4 g, 0.0074 mol) in DMF (40 mL, 0.5 mol) was added potassium carbonate (2.0 g, 0.015 mol) in 15 mL of water. The mixture was purged with a steady stream of nitrogen for 15 minutes. Tetrakis(triphenyl-phosphine)palladium(0) (0.41 g, 0.00036 mol) was added and the reaction was heated to 125° C. for 30 min. The mixture was allowed to cool then diluted with ethyl acetate. The diluted reaction mixture was washed with water, brine, dried over Na2SO4 and concentrated to give a solution in a small volume of DMF (about 2-3 mL). Water was added, causing the material to form a gum on the walls of the flask. Then water was decanted, and the solids were dissolved in ethyl acetate. The solution was dried over Na2SO4, and concentrated in vacuo to afford a yellow solid. The product was triturated with ethyl ether to yield 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine as a white powder which was dried under vacuum (1 g, 60%). 1H NMR (300 MHz, CDCl3): δ 10.80 (br s, 1H), 8.93 (s, 1H), 8.46 (s, 2H), 7.46 (d, 1H), 6.88 (d, 1H), 5.73 (s, 2H), 3.61 (dd, 2H), 0.98 (dd, 2H), 0.00 (s, 9H); MS(ES): 316 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][CH2:7][CH2:6]2.Br[CH2:16][C:17](Cl)=[O:18].C([O-])([O-])=O.[K+].[K+].[NH:26]([CH2:29][CH3:30])[CH2:27][CH3:28]>C1COCC1.CCOC(C)=O>[CH2:27]([N:26]([CH2:29][CH3:30])[CH2:16][C:17]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:11]([N+:12]([O-:14])=[O:13])[CH:10]=2)[CH2:6][CH2:7]1)=[O:18])[CH3:28]
Reactant: COc1cc2c(cc1[N+](=O)[O-])NCC2
Reactant: O=C(Cl)CBr
Reactant: CCNCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCN(CC)CC(=O)N1CCc2cc(OC)c([N+](=O)[O-])cc21
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 91.2 %

Procedure:
A mixture of 5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole (Intermediate B99, 433 mg, 2.23 mol), bromoacetyl chloride (386 mg, 2.45 mmol) and K2CO3 (924 mg, 6.69 mmol) in THF (50 mL) was stirred for 40 min and then Et2NH (326 mg, 4.46 mmol) was added. The reaction mixture was stirred for 1 day, additional Et2NH (0.3 mL) was added, stirring was continued for an additional 24 h, then the reaction was heated at 60° C. for 2 h. The resulting mixture was diluted with EtOAc (200 mL), washed with water (150 mL) and a saturated NaCl solution (100 mL), and back extracted with EtOAc (100 mL). The organic layers were combined, dried (Na2SO4), and concentrated to obtain N,N-diethyl-2-[5-(methyloxy)-6-nitro-2,3-dihydro-1H-indol-1-yl]-2-oxoethanamine (687 mg, 100%). ESIMS (M+H)+=307.97.
Reaction SMILES: FC(F)(F)S(O)(=O)=[O:4].N[C:10]1[C:11]([S:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[N:12][CH:13]=[CH:14][CH:15]=1.ClCCl.N([O:27][C:28]([CH3:31])(C)C)=O>COCCOC.CCCCC>[C:28]([O:27][C:10]1[C:11]([S:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[N:12][CH:13]=[CH:14][CH:15]=1)(=[O:4])[CH3:31]
Reactant: COC(=O)CSc1ncccc1N
Reactant: CC(C)(C)ON=O
Reactant: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: COCCOC
Solvent: CCCCC
Product: COC(=O)CSc1ncccc1OC(C)=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 15.6 %

Procedure:
First, 1.92 g of trifluoromethanesulfonic acid was added dropwise to a mixture of 2.54 g of 3-amino-2-(methoxycarbonyl)methylthiopyridine, 6 ml of 1,2-dimethoxyethane, and 2 ml of dichloromethane at −10° C. After stirring at the same temperature for 10 minutes, a solution of 1.59 g of t-butyl nitrite in 1 ml of 1,2-dimethoxyethane was added dropwise to the reaction mixture at −5° C. or lower. After stirring at the same temperature for 30 minutes, n-pentane was poured into the mixture. The lower one of the two layers separated was dissolved in 3 ml of acetic anhydride, and the solution was stirred at 50° C. to 70° C. for 1 hour. The reaction mixture was cooled to room temperature and then poured into water, and the mixture was extracted with t-butyl methyl ether. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel chromatography to give 0.48 g of 3-acetoxy-2-(methoxycarbonyl)methylthiopyridine.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:9]([CH3:16])([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11].C([O-])([O-])=O.[Cs+].[Cs+].O>CC#N>[CH3:15][C:9]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH3:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: Oc1ccccc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)C(C)(C)Oc1ccccc1
Yield: 47.5 %

Procedure:
To a solution of phenol (2 g, 21.25 mmol) in CH3CN (50 mL) was added ethyl 2-bromo-2-methylpropanoate (5 g, 25.5 mmol) and Cs2CO3 (20 g, 63.75 mmol) at 25° C. The mixture was heated at reflux for 16 h then water (100 mL) added and extracted with ethyl acetate (2×50 mL). The organic layer was washed with brine (30 mL), dried over Na2SO4 and concentrated to give the title compound (2.1 g, 47.7%) as colorless oil which was used in next step without further purification.
Reaction SMILES: [Cl-].[CH3:2][C:3]1[S:4][CH:5]=[CH:6][C:7]=1[C:8]([O-:10])=O.C1COCC1.[CH3:16][NH2:17]>C(OCC)(=O)C>[CH3:16][NH:17][C:8]([C:7]1[CH:6]=[CH:5][S:4][C:3]=1[CH3:2])=[O:10]
Reactant: Cc1sccc1C(=O)[O-]
Reactant: CN
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccsc1C
Yield: 71.8 %

Procedure:
2-Methyl-3-thiophenecarboxylate chloride (60.5 g)/THF (300 ml) solution was added dropwise to a 40% aqueous solution of methylamine (400 ml) at 0° C. Ethyl acetate (21) was added thereto, and then the organic layer was washed sequentially with water, a 5N aqueous solution of hydrochloric acid, an aqueous solution of saturated sodium bicarbonate, water and brine, dried and evaporated. The resulting residue was crystallized from n-hexane, to give the title compound as awhite powder (43.5 g, yield; 71.8%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[C:17]([CH3:19])[CH:18]=2)[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1.[C:26](Cl)(=[O:29])[CH2:27][CH3:28]>>[CH3:19][C:17]1[CH:18]=[C:13]([CH:11]([NH:10][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:26](=[O:29])[CH2:27][CH3:28])[N:7]=2)=[O:9])[CH3:12])[CH:14]=[N:15][C:16]=1[O:20][CH2:21][C:22]([F:24])([F:25])[F:23]
Reactant: CCC(=O)Cl
Reactant: Cc1cc(C(C)NC(=O)c2ccnc(N)n2)cnc1OCC(F)(F)F
Product: CCC(=O)Nc1nccc(C(=O)NC(C)c2cnc(OCC(F)(F)F)c(C)c2)n1

Procedure:
The title compound is prepared from 2-amino-N-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)pyrimidine-4-carb oxamide (20 mg, 0.06 mmol, Step-1, single enantiomer) and propionyl chloride (26 mg, 0.28 mmol) according to the procedure similar to that described in Step-2 of Example 8.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]#[N:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:12]1([C:18]2[S:19][CH2:20][CH:21]([C:23]([OH:25])=[O:24])[N:22]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(#N)C1C=CC=CC=1.N[C@H](C(O)=O)CS.P([O-])([O-])([O-])=O>CO>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[S:19][CH2:20][C@@H:21]([C:23]([OH:25])=[O:24])[N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:12]1([C:18]2[S:19][CH2:20][CH:21]([C:23]([OH:25])=[O:24])[N:22]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: N#Cc1ccc2[nH]ccc2c1
Agent: N[C@@H](CS)C(=O)O
Agent: O=C(O)C1CSC(c2ccccc2)=N1
Agent: O=P([O-])([O-])[O-]
Solvent: CO
Solvent: N#Cc1ccccc1
Product: O=C(O)[C@@H]1CSC(c2ccc3[nH]ccc3c2)=N1
Temperature: 40 °C
Reaction time: 72 h

Procedure:
(R)-2-(1H-Indol-5-yl)-4,5-dihydrothiazole-4-carboxylic acid 63a was synthesized from 1H-indole-5-carbonitrile using the same method as used for 42a of U.S. application Ser. No. 12/981,233 (now US2011/0257196) and U.S. application Ser. No. 1/216,927 (now US2012/0071524), incorporated herein by reference in their entirety. Briefly, benzonitrile (40 mmol) was combined with L-cysteine (45 mmol) in 100 mL of 1:1 MeOH/pH 6.4 phosphate buffer solution. The reaction was stirred at 40° C. for 3 days. The precipitate was removed by filtration, and MeOH was removed using rotary evaporation. To the remaining solution was added 1 M HCl to adjust to pH=2 under 0° C. The resulting precipitate was filtered to yield a white solid 2-phenyl-4,5-dihydrothiazole-4-carboxylic acid 42a, which was used directly to next step without purification. To a vigorously stirring solution of 63a (1 mmol) and tetrabutylammonium hydrogen sulfate (0.15 mmol) in toluene (10 mL) at 0° C. was added 50% aqueous sodium hydroxide (10 mL) and sulfonyl chloride (2 mmol). The resultant solution was stirred at RT for 6 h. Then 1 N HCl was added to acidify the mixture to pH=2 and extracted with CH2Cl2, the organic layer was separated and dried (MgSO4); then evaporated to dryness to yield 64a, which were used in subsequent steps without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[C:4]#[N:5].[Br:11]Br.C(Cl)(Cl)Cl.[Al+3].[Cl-].[Cl-].[Cl-]>O>[Br:11][C:9]1[C:2]([CH3:1])=[C:3]([C:6]([CH3:10])=[CH:7][CH:8]=1)[C:4]#[N:5]
Reactant: BrBr
Reactant: Cc1cccc(C)c1C#N
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1ccc(Br)c(C)c1C#N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 2,6-dimethylbenzonitrile (5.0 g, 38.0 mmol), bromine (1.9 ml, 38.0 mmol) and chloroform (10 ml) is stirred at room temperature for 24 hours and subsequently heated to 60° C. for 6 hours. Upon cooling down to 0° C., 10 g of AlCl3 are added and the mixture is stirred for 4 hours at 0° C. The reaction mixture is poured into water and extracted with toluene. The organic phase is separated and concentrated and the residue is purified by column chromatography yielding the pure product as brown crystals, 6.2 g, mp. 60° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:10].C([O-])([O-])=O.[K+].[K+].Cl[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][N:19]=1.O>CN(C=O)C>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][N:19]=2)=[C:3]([CH3:10])[CH:4]=1)=[O:7]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: Cc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C=O)ccc1Oc1ccc(C#N)cn1
Temperature: 25 °C
Yield: 97.1 %

Procedure:
Combine 4-hydroxy-3-methyl-benzaldehyde (401 mg, 2.94 mmol), K2CO3 (570 mg, 4.12 mmol) and 6-chloronicotinonitrile (408 mg, 2.94 mmol) in DMF (6 ml), heat at 100° C. After 4 h cool to ambient temperature and pour into water. Extract the aqueous layer with EtOAc. Dry the organic layer over Na2SO4 and eliminate the solvent. Dry under vacuum at 45° C. overnight to get the title compound (680 mg, 97%). 1H-NMR (CDCl3, 400 MHz): 9.99 (s, 1H), 8.43 (d, 1H, J=2.5 Hz), 7.97 (dd, 1H, J=2.5 and 8.8 Hz), 7.84 (bs, 1H), 7.80 (dd, 1H, J=2.5 and 8.8 Hz), 7.22 (d, 1H, J=8.4 Hz), 7.11 (d, 1H, J=8.4 Hz), 2.24 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]C(C)(C)C.[F:13][C:14]1[CH:15]=[CH:16][C:17]([O:36][CH3:37])=[C:18]([C:20]([CH3:35])([CH3:34])[CH2:21]/[C:22](=[N:27]/S(C(C)(C)C)=O)/[C:23]([F:26])([F:25])[F:24])[CH:19]=1>C1COCC1.CCCCC>[F:13][C:14]1[CH:15]=[CH:16][C:17]([O:36][CH3:37])=[C:18]([C:20]([CH3:34])([CH3:35])[CH2:21][C:22]([NH2:27])([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[C:23]([F:26])([F:25])[F:24])[CH:19]=1
Reactant: COc1ccc(F)cc1C(C)(C)C/C(=N/S(=O)C(C)(C)C)C(F)(F)F
Reactant: Cc1ccccn1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: COc1ccc(F)cc1C(C)(C)CC(N)(Cc1ccccn1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 25.2 %

Procedure:
To a chilled (−78 C.) solution of 0.05 mL (0.514 mmol) of 2-methylpyridine in 3 mL of dry THF was added 0.23 mL (0.4 mmol) of a 1.7 M solution of t-BuLi in pentane. The mixture turned a bright orange. After 10 min, a solution of 98 mg (0.257 mmol) of 2-methyl-propane-2-sulfinic acid [3-(5-fluoro-2-methoxy-phenyl)-3-methyl-1-trifluoromethyl-but-(Z)-ylidene]-amide in 0.5 mL of anhydrous THF was added. The reaction was then warmed to room temperature, quenched with aqueous ammonium chloride, stirred for 30 min and extracted with diethyl ether.(3×) The combined organic layers were dried (MgSO4), filtered and concentrated. The residue was dissolved in 2 mL of methanol, 3 drops of concentrated HCl were added and the reaction was warmed at 75° C. in a sealed tube. After 1 h, the reaction was cooled to room temperature, concentrated in vacuo, neutralized with aqueous sodium bicarbonate and extracted with EtOAc (3×). The combined organic layers were dried over (MgSO4), filtered and concentrated to afford an oil. The residue was purified by preparative thin layer chromatography eluting with hexanes-EtOAc (95:5) to afford 24 mg (25%) of the title compound.
Reaction SMILES: I[C:2]1[C:3]([NH2:22])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][CH:10]=1.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[C:33]([NH:37][C:38](=[O:41])[CH2:39][CH3:40])[CH:34]=[CH:35][CH:36]=2)O1>>[NH2:22][C:3]1[C:2]([C:35]2[CH:34]=[C:33]([NH:37][C:38](=[O:41])[CH2:39][CH3:40])[CH:32]=[CH:31][CH:36]=2)=[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1
Reactant: CCC(=O)Nc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Nc1nccc(Oc2ccc(Oc3ccccc3)cc2)c1I
Product: CCC(=O)Nc1cccc(-c2c(Oc3ccc(Oc4ccccc4)cc3)ccnc2N)c1
Yield: 49 %

Procedure:
N-(3-(2-amino-4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)propionamide was prepared from 3-iodo-4-(4-phenoxyphenoxy)pyridin-2-amine and N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propionamide using Method C (49% yield). HPLC: 98%, RT=4.186 min. MS: m/z=426 [M+H]+, RT=4.18 min. 1H-NMR (DMSO-d6) δ 10.01 (s, 1H), 7.94 (d, 1H), 7.73 (s, 1H), 7.63 (d, 1H), 7.44 (t, 1H), 7.39 (t, 2H), 7.24 (s, 2H), 7.16-7.01 (m, 8H), 6.35 (d, 1H), 2.32 (q, 2H), 1.07 (t, 3H).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:19]([CH2:24][C:25]4[CH:26]=[C:27]([NH2:31])[CH:28]=[CH:29][CH:30]=4)[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:32]([N:40]=[C:41]=[O:42])(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.CCCCCC>C(Cl)Cl>[C:32]([NH:40][C:41]([NH:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([CH2:24][CH:19]2[CH2:20][CH2:21][CH2:22][CH:23]=[C:18]2[C:9]2[O:10][C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)[CH:26]=1)=[O:42])(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Nc1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reactant: O=C=NC(=O)c1ccccc1
Solvent: CCCCCC
Solvent: ClCCl
Product: O=C(NC(=O)c1ccccc1)Nc1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.9 %

Procedure:
To a solution of (±)-3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}phenylamine (110 mg, 0.27 mmol) in methylene chloride (3 ml) was added benzoylisocyanate (0.038 ml, 0.27 mmol) at 5° C., and the mixture was stirred at room temperature for 16 hours. To the mixture was added hexane (9 ml), and the resulting precipitate was collected, washed with hexane to give (±)-1-benzoyl-3-{3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}phenyl}urea (114.9 mg, 77%).
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=O)[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:17][CH2:18][C:19]([NH:21][C@H:22]([C:27]([NH:29][C@H:30]([C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[CH3:31])=[O:28])[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:20]>>[NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([NH:17][CH2:18][C:19]([NH:21][C@H:22]([C:27]([NH:29][C@H:30]([C:32]([O:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:33])[CH3:31])=[O:28])[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:20])=[O:9])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CC(C)C[C@H](NC(=O)CN)C(=O)N[C@@H](C)C(=O)OCc1ccccc1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: CC(C)C[C@H](NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)OCc1ccccc1

Procedure:
Boc-Leu-Gly-Leu-Ala-OBzl was prepared by coupling Boc-Leu-OH (2.62 g, 10.5 mmoles) to H-Gly-Leu-Ala-OBzl using the mixed anhydride procedure described in Example 2. The resulting product was crystallized from ethyl acetate:hexane to yield 2.7 g (mp 95°-96°) in the first crop.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:25]=[CH:24][C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH:12]=2)=[O:9])=[CH:6][CH:5]=1.[NH:26]1[CH2:30][CH2:29][N:28]=[C:27]1N1C(C)=CC(C)=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:8](=[O:9])[C:7]2[CH:6]=[CH:5][C:4]([CH2:3][NH:2][C:27]3[NH:28][CH2:29][CH2:30][N:26]=3)=[CH:25][CH:24]=2)=[CH:12][C:13]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: NCc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Reactant: Cc1cc(C)n(C2=NCCN2)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(CNC2=NCCN2)cc1

Procedure:
100 mg of the crude HCl salt of 4-(aminomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide was reacted with 80 mg of 1-(4,5-dihydro-1H-imidazol-2-yl)-3,5-dimethyl-1H-pyrazole and 110 of DIPEA in 1 mL of DMF in the microwave at 150° C. for 5 minutes. The crude product was concentrated to dryness and purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((4,5-dihydro-1H-imidazol-2-ylamino)methyl)benzamide. MS (Q1) 406 (M)+.