Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3](C(OCC(C)C)=O)[C:4]2[C:5]([N:21]=1)=[N:6][CH:7]=[C:8]([C:10]1[CH:11]=[CH:12][C:13]3[O:19][CH2:18][CH2:17][NH:16][CH2:15][C:14]=3[CH:20]=1)[CH:9]=2.[C@@H:29]([N:33]([CH2:44][C:45]1[N:54]=[C:53](Cl)[C:52]2[CH2:51][C:50]([CH3:57])([CH3:56])[CH2:49][CH2:48][C:47]=2[N:46]=1)C(=O)OCC1C=CC=CC=1)([CH2:31][CH3:32])[CH3:30]>>[CH3:57][C:50]1([CH3:56])[CH2:49][CH2:48][C:47]2[N:46]=[C:45]([CH2:44][NH:33][C@H:29]([CH2:31][CH3:32])[CH3:30])[N:54]=[C:53]([N:16]3[CH2:15][C:14]4[CH:20]=[C:10]([C:8]5[CH:9]=[C:4]6[NH:3][C:2]([CH3:1])=[N:21][C:5]6=[N:6][CH:7]=5)[CH:11]=[CH:12][C:13]=4[O:19][CH2:18][CH2:17]3)[C:52]=2[CH2:51]1
Reactant: CC[C@H](C)N(Cc1nc(Cl)c2c(n1)CCC(C)(C)C2)C(=O)OCc1ccccc1
Reactant: Cc1nc2ncc(-c3ccc4c(c3)CNCCO4)cc2n1C(=O)OCC(C)C
Product: CC[C@H](C)NCc1nc2c(c(N3CCOc4ccc(-c5cnc6nc(C)[nH]c6c5)cc4C3)n1)CC(C)(C)CC2

Procedure:
Prepared according to the method of example 6 by using 2-methylpropyl 2-methyl-6-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-imidazo[4,5-b]pyridine-1-carboxylate and (S)-benzyl sec-butyl((4-chloro-6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-2-yl)methyl)carbamate (reagent preparation 17) in step 3 followed by Cbz deprotection. 1H NMR (400 MHz, DMSO-d6) δ 8.61-8.44 (m, 1H), 8.12-7.93 (m, 1H), 7.71 (d, 1H), 7.54 (dd, 1H), 7.03 (d, 1H), 4.67 (s, 2H), 4.35-4.27 (m, 2H), 3.92-3.84 (m, 2H), 3.56 (q, 2H), 2.69 (t, 3H), 2.54 (s, 2H), 2.45 (s, 3H), 2.42-2.30 (m, 1H), 1.59 (t, 2H), 1.27 (dd, 2H), 1.18-1.04 (m, 1H), 0.87 (s, 6H), 0.83 (d, 3H), 0.70 (t, 3H); MS (EI) for C31H39N7O: 526 (MH+).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([Br:13])[CH:10]=[C:9]([Br:14])[CH:8]=1.[C:15]1([CH3:34])[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:16]=1[B:23]([C:25]1[C:30]([CH3:31])=[CH:29][C:28]([CH3:32])=[CH:27][C:26]=1[CH3:33])F>CCCCCC.C(OCC)C>[Br:13][C:11]1[CH:12]=[C:7]([B:23]([C:25]2[C:26]([CH3:33])=[CH:27][C:28]([CH3:32])=[CH:29][C:30]=2[CH3:31])[C:16]2[C:17]([CH3:22])=[CH:18][C:19]([CH3:21])=[CH:20][C:15]=2[CH3:34])[CH:8]=[C:9]([Br:14])[CH:10]=1
Reactant: Brc1cc(Br)cc(Br)c1
Reactant: Cc1cc(C)c(B(F)c2c(C)cc(C)cc2C)c(C)c1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: Cc1cc(C)c(B(c2cc(Br)cc(Br)c2)c2c(C)cc(C)cc2C)c(C)c1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
6.25 ml (0.01 mol) of 1.6M butyllithium in hexane are added over 5 minutes at -78° C. to a suspension of 3.14 g (0.01 mol) of 1,3,5-tribromobenzene in 50 ml of diethyl ether. The reaction mixture is stirred at -78° C. for 2 hours, during which a yellow-orange suspension is produced. 2.68 g (0.01 mol) of solid dimesitylfluoroborane are added, and the reaction mixure is warmed to room temperature over about one hour. The mixture is then diluted with 50 ml of hexane and cooled to 0° C. The solid produced is filtered, washed several times with cold hexane and then washed with water and, finally, with methanol, until the solid is colourless. Drying gives 3.54 g (0.0073 mol; i.e. 73% of theory) of a white solid (1,3-dibromo-5-dimesitylborylbenzene). Following purification by chromatography (hexane; SiO2) a melting point of 190°-191° C. is obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[S:3]([N:6]1[C:10]2[CH:11]=[C:12]([O:17][CH3:18])[C:13]([O:15][CH3:16])=[CH:14][C:9]=2[N:8]=[CH:7]1)(=[O:5])=[O:4].C([Li])CCC.Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27]>C1COCC1.CCCCCC>[CH3:19][N:2]([CH3:1])[S:3]([N:6]1[C:10]2[CH:11]=[C:12]([O:17][CH3:18])[C:13]([O:15][CH3:16])=[CH:14][C:9]=2[N:8]=[C:7]1[C:26]([O:28][CH2:29][CH3:30])=[O:27])(=[O:4])=[O:5]
Reactant: COc1cc2ncn(S(=O)(=O)N(C)C)c2cc1OC
Reactant: CCOC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)c1nc2cc(OC)c(OC)cc2n1S(=O)(=O)N(C)C
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
1-(N,N-dimethylsulfamoyl)-5,6-dimethoxybenzimidazole (5.70 g) was dissolved in dry THF (170 ml) in a dry argon atmosphere, cooled to -60° C. and a solution of n-butyl lithium (1.58M) in hexane (15.2 ml) was added dropwise and stirred for 30 minutes. After ethyl chloroformate (2.60 g) was added dropwise, the mixture was slowly returned to room temperature and allowed to react overnight. THF was distilled off, the residue was dissolved in ethyl acetate, washed with water and dried over anhydrous Na2SO4, and the solvent was distilled off. Purification of the residue by column chromatography on silica gel gave the title compound (5.13 g) as an oily product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5]([OH:7])=O.[NH2:27][C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:27][C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)=[O:7])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Reactant: Nc1ccncc1
Product: O=C(Nc1ccncc1)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 4-aminopyridine via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(pyridin-4-yl)terephthalamide. MS (Q1) 463 (M)+.
Reaction SMILES: [Cl:1][C:2]1[N:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:3]=1[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[Li+].CC([N-]C(C)C)C.[I:27]I>C1COCC1>[Cl:1][C:2]1[N:17]=[CH:16][C:15]([I:27])=[C:14]([Cl:18])[C:3]=1[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5]
Reactant: O=C(OCc1ccccc1)c1c(Cl)ccnc1Cl
Reactant: II
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)c1c(Cl)ncc(I)c1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 60.5 %

Procedure:
Into a solution of benzyl 2,4-dichloronicotinate (4.35 g, 15.4 mmol) in THF (40 mL) at −78° C. was added LDA (1.5 M×11.8 mL, 17.7 mmol) dropwise. The mixture was stirred at −78° C. for 30 min. Iodine (4.7 g, 18.5 mmol) was added portionwise. The temperature was then allowed to rise to room temperature slowly and the reaction was quenched with saturated NH4Cl solution. The mixture was extracted with ethyl acetate. The organic layers were combined and washed with brine, dried over sodium sulfate, evaporated and purified by silica chromatography (0-7% ethyl acetate in hexanes) to give benzyl 2,4-dichloro-5-iodonicotinate (3.8 g, 60%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[NH2:32][CH2:33][CH2:34][OH:35]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:32][CH2:33][CH2:34][OH:35])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: NCCO
Product: Cc1cc(F)ccc1-c1nc(NCCO)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
The product of Example 48, and 2-aminoethanol were reacted by the procedure of Example 60 to afford the title compound 8-(2,6-difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-(2-hydroxy-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR (CDCl3) δ 2.26 (s, 3H), 3.18 (m, 2H), 3.53 (m, 2H), 3.70 (br s, 1H), 6.21 (br s, 1H), 6.40 (d, 1H, J=9.7 Hz), 7.09 (m, 4H), 7.21-7.65 (m, 3H). LC MS (m/e)=427 (MH+). Rt=1.96 min
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14](B3OC(C)(C)C(C)(C)O3)=[CH:13][C:12]=2[O:26][CH3:27])=[O:9])[N:5]([CH3:7])[CH:6]=1.Br[C:29]1[N:30]=[C:31]([C@H:39]2[CH2:44][CH2:43][C@H:42]([N:45]3[CH2:50][CH2:49][N:48]([CH3:51])[CH2:47][CH2:46]3)[CH2:41][CH2:40]2)[N:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[C:33]=12>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:29]3[N:30]=[C:31]([C@H:39]4[CH2:40][CH2:41][C@H:42]([N:45]5[CH2:46][CH2:47][N:48]([CH3:51])[CH2:49][CH2:50]5)[CH2:43][CH2:44]4)[N:32]4[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[C:33]=34)=[CH:13][C:12]=2[O:26][CH3:27])=[O:9])[N:5]([CH3:7])[CH:6]=1
Reactant: Cc1nccn2c1c(Br)nc2[C@H]1CC[C@H](N2CCN(C)CC2)CC1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)c1cc(Cl)cn1C
Product: COc1cc(-c2nc([C@H]3CC[C@H](N4CCN(C)CC4)CC3)n3ccnc(C)c23)ccc1NC(=O)c1cc(Cl)cn1C

Procedure:
Reaction of 4-chloro-N-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methyl-1H-pyrrole-2-carboxamide (30 mg) and 1-bromo-8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazine (30 mg) according to the procedure described in example 4 step 4c and purification by column chromatography (silica gel; dichloromethane with gradient 0 to 20% of methanol) gave 4-chloro-N-(2-methoxy-4-(8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-1-methyl-1H-pyrrole-2-carboxamide (21 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:10]=[C:11]([NH2:14])[S:12][CH:13]=1.[CH3:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:10]=[C:11]([NH:14][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][C:16]([CH3:15])=[CH:17][CH:18]=2)[S:12][CH:13]=1
Reactant: COc1ccccc1-c1csc(N)n1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Product: COc1ccccc1-c1csc(NC(=O)c2ccc(C)cc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(2-Methoxy-phenyl)-thiazol-2-ylamine (41.3 mg, 0.200 mmol) and 4-methyl-benzoyl chloride (30.9 mg, 0.200 mmol) were dissolved in 1 mL of pyridine. The reaction mixture was stirred at room temperature overnight and then purified by reverse-phase preparative liquid chromatography (7.32 mg, 0.0226 mmol, 11.3%). ESI-MS m/z calc. 324.1, found 325.2 (M+1)+ Retention time 3.75 minutes.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8].C(=O)(O)[O-].[Na+].Br[CH2:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>C(#N)C>[C:7]([C:6]1[CH:5]=[C:4]([CH:11]=[CH:10][CH:9]=1)[CH2:3][N:2]([CH3:1])[CH2:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])#[N:8]
Reactant: CC(C)(C)OC(=O)CCBr
Reactant: CNCc1cccc(C#N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CN(CCC(=O)OC(C)(C)C)Cc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred mixture of 3-[(methylamino)methyl]benzonitrile (6.1 g, 41.7 mmol) and sodium bicarbonate (7.0 g, 83.4 mmol) in ACN (70 mL) was added dropwise tert-butyl 3-bromo-propanoate (7 mL, 41.7 mol). After being stirred at RT for 12 hours, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (silica, pet ether/EtOAc) to afford the title compound as a pale yellow liquid. 1H NMR (DMSO-d6, 400 MHz) δ 7.70 (s, 2H), 7.60 (m, 1H), 7.51 (m, 1H), 3.49 (s, 2H), 2.58 (m, 2H), 2.36 (m, 2H), 2.09 (s, 3H), 1.38 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14](=[O:24])[N:15]3[CH2:18][C:17]4([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)[CH2:16]3)[C:9]2=[O:25])=[CH:4][CH:3]=1.Br[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=1.C(N(C(C)C)C(C)C)C>ClCCl>[F:32][C:29]1[CH:28]=[CH:27][C:26]([C:8]2([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14](=[O:24])[N:15]3[CH2:18][C:17]4([CH2:19][CH2:20][N:21]([CH2:34][C:35]5[CH:36]=[CH:37][C:38]([C:41]([F:42])([F:43])[F:44])=[CH:39][CH:40]=5)[CH2:22][CH2:23]4)[CH2:16]3)[C:9]2=[O:25])=[CH:31][CH:30]=1
Reactant: O=C(CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O)N1CC2(CCNCC2)C1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O)N1CC2(CCN(Cc3ccc(C(F)(F)F)cc3)CC2)C1
Temperature: 40 °C

Procedure:
To 3,3-bis(4-fluorophenyl)-1-(2-oxo-2-(2,7-diazaspiro[3.5]nonan-2-yl)ethyl)pyrrolidin-2-one (0.050 g, 0.114 mmol; Example 153A) and 1-(bromomethyl)-4-(trifluoromethyl)benzene (0.030 g, 0.125 mmol) in dichloromethane (0.5 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.030 mL, 0.171 mmol), and the reaction was heated to 40° C. for 1 hour. The reaction was cooled, loaded onto a GraceResolv™ 12 g silica gel column (Grace Davison Discovery Sciences), and the title compound eluted with a gradient of 0.8% methanol/dichloromethane containing 0.2 N NH3 to 5.6% methanol/dichloromethane containing 0.2 N NH3(Flow=25 mL/minute) over 30 minutes. 1H NMR (300 MHz, CDCl3) δ 7.57 (d, J=8.1, 2H), 7.42 (d, J=8.0, 2H), 7.34-7.27 (m, 4H), 7.04-6.94 (m, 4H), 3.97 (s, 2H), 3.72 (d, J=19.3, 4H), 3.52 (dd, J=5.5, 12.0, 4H), 2.75 (t, J=6.5, 2H), 2.31 (s, 4H), 1.74 (d, J=4.9, 4H); MS (ESI+) m/z 598.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:18])[CH:8]=2)[N:3]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[C:19]([NH:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:18])[CH:8]=2)[N:3]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc(-c2ccccc2)c2cc(Cl)ccc2n1
Product: CC(=O)Nc1cc(-c2ccccc2)c2cc(Cl)ccc2n1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A mixture of 0.1 g of 2-amino-6-chloro-4-phenylquinoline and 8 ml of acetic anhydride was stirred at 70° C. for 1 hour, the solvent was removed by distillation, the solid residue was stirred with water, and the crystalline substance was filtered off.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[NH2:11][C:12]([CH3:17])([CH2:15]O)[CH2:13][OH:14]>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]2[O:8][CH2:15][C:12]([CH2:13][OH:14])([CH3:17])[N:11]=2)=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CC(N)(CO)CO
Product: CC1(CO)COC(c2ccc(Cl)nc2)=N1
Temperature: 25 °C
Yield: 39.7 %

Procedure:
A suspension of 6-chloronicotinic acid (3.2 g, 20.4 mmol) and 2-amino-2-methyl-1,3-propanediol (2.1 g, 20 mmol) in xylenes (mixture of isomers, 80 ml) is heated at reflux under Dean-Stark conditions for 24 h, during which the mixture clarifies. Upon cooling to room temperature, a solid settles down. The mixture is filtered through a silicagel column, eluting first with hexane to remove the xylenes and then with ethyl acetate to afford 1.8 g of [2-(6-chloropyridin-3-yl)-4-methyl-4,5-dihydro-1,3-oxazol-4-yl]methanol ax55.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:12]=[C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]#[N:22])=[CH:16][CH:15]=3)[C:10]([CH2:23][CH3:24])=[C:9]([CH3:25])[N:8]=2)=[CH:4][CH:3]=1.[NH2:26][OH:27].Cl.C([O-])([O-])=O.[K+].[K+].CCO>O>[Cl:1][C:2]1[S:6][C:5]([C:7]2[N:12]=[C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([NH:26][OH:27])=[NH:22])=[CH:16][CH:15]=3)[C:10]([CH2:23][CH3:24])=[C:9]([CH3:25])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CCc1c(C)nc(-c2ccc(Cl)s2)nc1Nc1ccc(CC#N)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCc1c(C)nc(-c2ccc(Cl)s2)nc1Nc1ccc(CC(=N)NO)cc1
Temperature: 25 °C
Yield: 46.7 %

Procedure:
A 50-mL round bottomed flask was charged with 2-[4-[[2-(5-Chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]amino]phenyl]acetonitrile (120 mg, 0.325 mmol, 1 eq.), NH2OH/HCl (160 mg, 2.3 mmol, 7 eq), K2CO3 (320 mg, 2.3 mol, 7 eq.), EtOH (10 ml) and water (1 ml). The mixture was stirred under reflux overnight. After cooling to room temperature, the volatile material was removed under reduced pressure. The residue was purified by chromatography on silica gel using 1.5˜4% of methanol in dichloromethane as eluent to give the title compound (61 mg, 47% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([C:8]([CH3:26])([CH3:25])[CH2:9][C:10]([OH:24])([C:20]([F:23])([F:22])[F:21])[CH2:11][C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[C:15]#[N:16])[CH:7]=1.[OH-:29].[K+].OO.Cl>CCO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([C:8]([CH3:26])([CH3:25])[CH2:9][C:10]([OH:24])([C:20]([F:23])([F:22])[F:21])[CH2:11][C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[C:15]([NH2:16])=[O:29])[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(Cc1cccc(C#N)c1)C(F)(F)F
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COc1ccc(F)cc1C(C)(C)CC(O)(Cc1cccc(C(N)=O)c1)C(F)(F)F
Reaction time: 24 h
Yield: 67.4 %

Procedure:
To a solution of 24 mg (0.061 mmol) of 3-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]benzonitrile in EtOH was added 15 mg (0.23 mmol) of potassium hydroxide followed by 0.2 mL of 30% aqueous hydrogen peroxide. The mixture was stirred for 24 hours and then diluted with water, made acidic with 1 N aqueous HCl, and extracted with three 5 mL portions of EtOAc. The combined organic layers were washed with two 5 mL portions of saturated aqueous sodium bicarbonate, two 5 mL portion of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford crude product which was purified on silica gel using dichloromethane-hexanes (1:1) to load the sample and then eluting with EtOAc-hexanes (1:99, then 3:97, then 6:93, then 1:9, then 2:8, then 3:7, then 4:6, then 1:1) to afford 17 mg (67%) of the title compound as a clear resin, m.p. 70° C.-75° C.
Reaction SMILES: C([NH:20][C@@H:21]([CH2:25][O:26][CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1)[CH:22]([CH3:24])[CH3:23])(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(O)=O>[N:30]1[CH:31]=[CH:32][CH:33]=[C:28]([CH2:27][O:26][CH2:25][C@@H:21]([CH:22]([CH3:24])[CH3:23])[NH2:20])[CH:29]=1
Reactant: CC(C)[C@H](COCc1cccnc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O=CO
Product: CC(C)[C@@H](N)COCc1cccnc1
Yield: 82 %

Procedure:
A solution of N-trityl-O-(3-pyridyl)methyl-(D)-valinol (3.63 g, 8.3 mmol) in formic acid (30 ml) was kept for 5.5 hours at room temperature. After removal of the formic acid in vacuo, the residue was dissolved in water (100 ml) and extracted twice with ethyl acetate (100 ml, 50 ml) in order to remove trityl alcohol. The aqueous phase was basified with a saturated solution of sodium carbonate (50 ml) and 4N sodium hydroxyde (3 ml) and extracted with ethyl acetate (4×50 ml). After washing with brine until neutral (2×50 ml), the combined organic layers were dried over sodium sulfate. After usual work-up, the resulting amine was used without further purification (1.32 g, 82% yield). Rf.: 0.12 (silica gel, dichloromethane/methanol: 8/2).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Mg+2].[Cl-].[Cl-].[Br:15][C:16]1[CH:17]=[C:18]([C:24]2([C:30](O)=[O:31])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23].S(Cl)(Cl)=O>C(#N)C>[Br:15][C:16]1[CH:17]=[C:18]([C:24]2([C:30]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[O:31])[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: COc1ccc(C2(C(=O)O)CCOCC2)cc1Br
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Cl-]
Agent: [Mg+2]
Solvent: O=S(Cl)Cl
Solvent: CC#N
Product: CCOC(=O)C(C(=O)OCC)C(=O)C1(c2ccc(OC)c(Br)c2)CCOCC1
Temperature: 0 °C
Yield: 16.1 %

Procedure:
A mixture of diethyl malonate (2.8 g, 17 mmol) in 50 mL ACN was stirred at 0° C. This mixture was treated with MgCl2 (1.7 g, 17 mmol) in one portion and dropwise with TEA (3.9 g, 38 mmol). The resulting mixture was then stirred at room temperature for 2.5 hours. A mixture of 4-(3-bromo-4-methoxyphenyl)-tetrahydro-2H-pyran-4-carboxylic acid (5.5 g, 17 mmol) in thionyl chloride (21 g, 175 mmol) was refluxed for 2 hours and then concentrated in vacuo. The residue was diluted with 10 mL ACN and added dropwise to the above mixture. The mixture was stirred at 50° C. for 15 hours, M−1=455/457. The mixture was cooled to room temperature, diluted with 100 mL ether, washed with H2O (2×50 mL) and brine (20 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was purified by column chromatography eluting with 10-20% EtOAc/hexane to give 1.25 g of the intermediate as a pale yellow oil. MS m/e=455/457 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:14]=[C:13]([O:15][C:16]3[C:21]([CH3:22])=[CH:20][C:19]([N+:23]([O-:25])=[O:24])=[CH:18][C:17]=3[CH3:26])[CH:12]=[CH:11][C:10]=2[O:27]C)=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:14]=[C:13]([O:15][C:16]3[C:21]([CH3:22])=[CH:20][C:19]([N+:23]([O-:25])=[O:24])=[CH:18][C:17]=3[CH3:26])[CH:12]=[CH:11][C:10]=2[OH:27])=[CH:6][CH:7]=1
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1Cc1ccc(F)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ccc(O)c(Cc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.7 g (4.5 mmol) of 1-[(4-fluorophenyl)methyl]-2-methoxy-5-(2,6-dimethyl -4-nitrophenoxy)benzene in 100 ml methylene chloride is added 13.5 ml (13.5 mmol) 1.0 N boron tribromide in methylene chloride. The solution is stirred overnight at room temperature, poured into ice water (300 ml) and stirred 1 hour. The organic layer is separated, washed with water, dried (CaSO4) and evaporated. Flash chromatography of the residue gives 2-[(4-fluorophenyl)methyl]-4-(2,6-dimethyl-4-nitrophenoxy)phenol, m.p. 127°-132°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH:25]3[CH2:27][O:26]3)=[CH:19][CH:18]=2)=[C:12]([C:14]([NH2:16])=[O:15])[N:13]=1.[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>CO>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[O:10][C:11]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH:25]([OH:26])[CH2:27][N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:21][CH:22]=2)=[C:12]([C:14]([NH2:16])=[O:15])[N:13]=1
Reactant: C1CCNCC1
Reactant: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(OCC2CO2)cc1
Solvent: CO
Product: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(OCC(O)CN2CCCCC2)cc1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 11.8 %

Procedure:
To a solution of 2-(2,6-difluorophenyl)-5-(4-(oxiran-2-ylmethoxy)phenyl)oxazole-4-carboxamide (0.025 g, 0.0671 mmol) in MeOH (1 ml) was added piperidine (0.017 g, 0.201 mmol). The reaction was heated to 100° C. via microwave irradiation and held at this temperature for 15 minutes. The crude reaction was then purified by preparative HPLC to give 2-(2,6-difluorophenyl)-5-(4-(2-hydroxy-3-(piperidin-1-yl)propoxy)phenyl)oxazole-4-carboxamide (0.0036 g, 0.0079 mmol, 12%) as an off white powder. 1H NMR (DMSO) δ 1.34-1.41 (2H, m), 1.46-1.54 (4H, m), 2.35-2.48 (6H, m), 3.92-4.01 (2H, m), 4.04-4.08 (1H, m), 7.08-7.12 (2H, m), 7.34-7.41 (2H, m), 7.66 (1H, br. s), 7.68 (1H, br, s), 7.69-7.76 (1H, m), 8.20-8.24 (2H, m). LCMS (2) 3.06 min; m/z (ES+) 458.
Reaction SMILES: [OH:1][C:2]1[C:15]2[C@:14]34[CH2:16][CH2:17][NH:18][C@@H:8]([C@@H:9]3[CH2:10][C@H:11]([CH3:20])[C:12](=[O:19])[CH2:13]4)[CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[O:21][CH3:22].[CH:23]1([CH2:27]Br)[CH2:26][CH2:25][CH2:24]1.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH:23]1([CH2:27][N:18]2[CH2:17][CH2:16][C@@:14]34[C:15]5[C:2]([OH:1])=[C:3]([O:21][CH3:22])[CH:4]=[CH:5][C:6]=5[CH2:7][C@@H:8]2[C@@H:9]3[CH2:10][C@H:11]([CH3:20])[C:12](=[O:19])[CH2:13]4)[CH2:26][CH2:25][CH2:24]1
Reactant: BrCC1CCC1
Reactant: COc1ccc2c(c1O)[C@]13CCN[C@H](C2)[C@@H]1C[C@H](C)C(=O)C3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1O)[C@]13CCN(CC4CCC4)[C@H](C2)[C@@H]1C[C@H](C)C(=O)C3

Procedure:
Prepared by reaction of 18a (3.70 g, 12.3 mmole) with cyclobutylmethyl bromide (2.24 g, 14.7 mmole) in the presence of NaHCO3 (2.00 g, 25 mmole) in DMF (50 ml) at 100° under argon for 6 hours to give, after processing in the usual manner, 4.50 g (99%) of 19a-CBM as a foam. NMR: δ 6.60; 2H, s (aromatic); 5.5, 1H, broad (hydroxyl), 4.24, 1H, d (H-5α, J=13 Hz); 3.76 (CH3O--), 0.86, 3H, d(7α-CH3, J=6.5 Hz).