Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC=C)CC1SC(S(N2CCC(NC3C=CC=C(S(C(F)(F)F)(=O)=O)C=3)CC2)(=O)=O)=CC=1)C=C.C[N:38]1[C:45](=[O:46])[CH2:44][C:42](=O)N(C)C1=O.[C:48](O)(=O)[C:49]1[C:50](=[CH:52]C=CC=1)[OH:51].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>C(Cl)Cl.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>[OH:51][C:50]1[CH:52]=[C:44]([CH:42]=[CH:48][CH:49]=1)[C:45]([NH2:38])=[O:46]
Reactant: O=C(O)c1ccccc1O
Reactant: CN1C(=O)CC(=O)N(C)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C=CCN(CC=C)Cc1ccc(S(=O)(=O)N2CCC(Nc3cccc(S(=O)(=O)C(F)(F)F)c3)CC2)s1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: NC(=O)c1cccc(O)c1
Temperature: 23 °C
Reaction time: 72 h

Procedure:
A solution of the bisallylamine 269c (1.15 g, 2.04 mmol), N,N′-dimethylbarbituric acid (NDMBA, 637 mg, 4.08 mmol), and Pd(PPh3)4 (110 mg, 0.096 mmol) in CH2Cl2 (20 mL) was degassed by bubbling argon for 10 min. The reaction was stirred at 23° C. over the week-end (3 d), concentrated, diluted with DMF (12 mL), and treated with salicylic acid (290 mg, 2.10 mmol), 1-hydroxybenzotriazole (HOBt, 283 mg, 2.10 mmol), and N-ethyl-N′-(3-dimethylaminopropyl)-carbodiimide (EDC, 402 mg, 2.10 mmol) for 24 h at 23° C. Dilution with EtOAc, washing (H2O, NaHCO3 sat., brine), drying (MgSO4), and evaporation afforded the crude 3-hydroxybenzamide. Purification by reverse-phase prep. HPLC (C8, H2O:CH3CN 60:40→0:100 over 40 min, r.t=23 min) and freeze-drying afforded 466 mg (38% from 269c) of the title 3-hydroxybenzamide as a white powder: NMR (DMSO-d6) δ 12.1 (s, 1H), 9.48 (t, J=5.9 Hz, 1H), 7.86 (dd, 7.9, 1.5 Hz, 1H), 7.50 (d, J=3.8 Hz, 1H), 7.45 (t, J=8.1 Hz, 1H), 7.41 (dd, J=8.9, 1.5 Hz, 1H), 7.21 (d, J=3.8 Hz, 1H), 7.18-7.10 (m, 3H), 6.93 (d, J=83 Hz, 1H), 6.91 (td, J=8.4, 1.1 Hz, 1H), 6.52 (d, J=7.7 Hz, 1H), 4.73 (d, J=5.8 Hz, 2H), 3.57-3.47 (br. d, 12.1, 2H), 3.52-3.35 (br. m., 1H), 2.62 (t, J=10.4 Hz, 2H), 2.07 (s, 1.2H, residual CH3CN), 2.02-1.92 (br. d, J=10.4 Hz, 2H), 1.47 (qd, 11.2, 3.6 Hz, 2H). 13C NMR (DMSO-d6) δ167.52 (s, C═O), 158.36 (s), 148.98 (s), 147.85 (s), 132.83 (d), 132.74 (s), 131.47 (d), 130.00 (d), 128.98 (s), 127.09 (d), 125.52 (d), 124.83 (s), 118.92 (q, residual CH3CN), 11834 (q, J=326 Hz, CF3), 117.75 (d), 116.24 (d), 115.23 (d), 114.19 (q), 111.33 (d), 45.93 (d), 43.66 (t), 36.66 (t), 29.18 (t), 0.00 (s, residual CH3CN). M/Z APCI: 604 (M+1), 602 (M−1). Anal. HPLC: R.t=6.60 min (method a). C24H24F3N3O6S3. 0.3 CH3CN 1.0 H2O Calc.: C, 47.53%. H, 4.36%. N, 7.44%. Found: C, 47.41%, H, 4.09%, N, 7.49%.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([CH:7]=O)[N:6]=1.[NH2:9][CH2:10][C:11]1[CH:38]=[CH:37][C:14]([CH2:15][N:16]([CH2:27][C:28]2[NH:32][C:31]3[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=3[N:29]=2)[CH:17]2[C:26]3[N:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH2:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1.[BH4-].[Na+]>CO>[NH:32]1[C:31]2[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=2[N:29]=[C:28]1[CH2:27][N:16]([CH2:15][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][NH:9][CH2:7][C:5]2[N:6]=[C:2]([CH3:1])[NH:3][CH:4]=2)=[CH:38][CH:37]=1)[CH:17]1[C:26]2[N:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:20][CH2:19][CH2:18]1
Reactant: Cc1nc(C=O)c[nH]1
Reactant: NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1nc(CNCc2ccc(CN(Cc3nc4ccccc4[nH]3)C3CCCc4cccnc43)cc2)c[nH]1
Yield: 52.9 %

Procedure:
Using General Procedure B: A solution of 2-methyl-1H-imidazole-4-carbaldehyde (27.7 mg, 0.25 mmol) and (4-aminomethyl-benzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (100 mg, 0.25 mmol) in MeOH (2.0 mL) was stirred overnight at room temperature. NaBH4 (18.9 mg, 0.50 mmol) was added and the resultant mixture stirred for an additional 15 minutes. Purification of the crude yellow foam by column chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 200:3:3) afforded the desired amine (65 mg, 53%) as a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18](=[O:27])[C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)[CH:16]=3)[NH:11][C:10](=O)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.P(Cl)(Cl)([Cl:31])=O>>[Cl:31][C:10]1[N:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[O:27])[CH:16]=2)[N:11]=1
Reactant: COc1ccc(C(=O)c2ccc3[nH]c(=O)nc(-c4cccc(Cl)c4)c3c2)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc(C(=O)c2ccc3nc(Cl)nc(-c4cccc(Cl)c4)c3c2)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
Intermediate 13 (0.0432 mol) was added at room temperature to phosphoryl chloride (150 ml). The mixture was stirred at 100° C. for 3 hours then brought to room temperature. The solvent was evaporated till dryness. The residue was taken up in DCM. The solvent was evaporated. The residue was taken up in DCM. The mixture was poured out into ice water, neutralized with K2CO3 solid and extracted with DCM. The organic layer was separated, washed with water, dried (MgSO4), filtered and the solvent was evaporated. The residue was crystallized from CH3CN. The precipitate was filtered off and dried under a vacuo, yielding 15.5 g (87%) of intermediate 14. The mother layer was purified by column chromatography over silica gel (eluent: toluene/EtOAc; 93/7; 15-40 μm). The pure fractions were collected and the solvent was evaporated. The residue (0.7 g, 4%) was crystallized from 2-propanone. The precipitate was filtered off and dried under a vacuo, yielding 0.5 g (3%) of [2-chloro-4-(3-chlorophenyl)-6-quinazolinyl](4-methoxyphenyl)-methanone (intermediate 14), mp. 175° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH2:20])[N:13]=2)=[CH:5][CH:4]=1.[CH2:21]=O>C(O)(=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:13]3[CH2:21][NH:20][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[C:12]3=[CH:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: C=O
Reactant: COc1ccc(-c2nc(-c3ccccc3N)c[nH]2)cc1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ncc3n2CNc2ccccc2-3)cc1
Reaction time: 0.03 h

Procedure:
2-(4-Methoxyphenyl)-4-(2-aminophenyl)imidazole (5 g) is dissolved in acetic acid (20 ml) and formaldehyde (37% in water, 1.53 ml) is added. The reaction is stirred for 2 min., diluted with ethyl acetate (100 ml), and extracted with 5%HCl (250 ml). The aqueous layer is basified with K2 CO3, then extracted with ethyl acetate. The organic layer is evaporated under reduced pressure and the residue is recrystallized from dichloromethane to afford 3-(4-methoxyphenyl)-5,6-dihydroimidazo[1,5-c]quinazoline (3 g) as a light brown solid. m.p. 190°-191° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=O)[C:5]2[NH:6][CH:7]=[N:8][C:9]=2[N:10]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:13]>N1C=CC=CC=1>[CH3:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([SH:13])[N:3]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: Cc1nc2nc[nH]c2c(=O)[nH]1
Solvent: c1ccncc1
Product: Cc1nc(S)c2[nH]cnc2n1
Yield: 53.9 %

Procedure:
To 2-Methylhypoxanthine (1.3 g, 8.6 mmol) and P2S5 (5 g) was added pyridine (50 mL). The mixture was refluxed for 4 h. The pyridine was distilled away and NaOH (50 mL) was added to the residue. A brown precipitate was filtered away. The precipitate was dried in a vacuum oven at 80° C. for 24 h to give the desired product (.77 g, 46.3%) as a light brown solid. mp>300° C. DCI/MC (M+1)=167. (300 MHz) 1H-nmr (DMSO-d6)δ: 8.3 (s, 1H), 2.45 (s, 3H).
Reaction SMILES: [OH-].[K+].[C:3]([NH:8][OH:9])([O:5][CH2:6][CH3:7])=[O:4].[K].[CH3:11][C:12]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[C:13]=1[CH2:14]Cl>>[C:3]([NH:8][O:9][CH2:14][C:13]1[C:16]([CH3:21])=[CH:17][C:18]([CH3:20])=[CH:19][C:12]=1[CH3:11])([O:5][CH2:6][CH3:7])=[O:4]
Reactant: Cc1cc(C)c(CCl)c(C)c1
Reactant: CCOC(=O)NO
Agent: [K+]
Agent: [K]
Agent: [OH-]
Product: CCOC(=O)NOCc1c(C)cc(C)cc1C
Temperature: 0 °C
Yield: 53.8 %

Procedure:
50 ml of a methanolic solution of 12.3 g (0.22 mole) of potassium hydroxide was added to 50 ml of an ice-cooled methanolic solution of 23.1 g (0.22 mole) of N-carboethoxyhydroxylamine to prepare a solution containing a potassium salt of N-carboethoxyhydroxylamine, and 50 ml of a methanolic solution of 33.7 g (0.2 mole) of 2,4,6-trimethylbenzyl chloride was added to the resulting solution at room temperature. The resulting mixture was heated under refluxing for 1 hour, and the solvent was distilled off. 150 ml of diethyl ether and 50 ml of water were then added to the residue and the organic layer was separated, dried over anhydrous sodium sulfate and concentrated under a reduced pressure. The residue thus obtained was distilled under a reduced pressure to obtain 25.5 g (53.8% yield) of substantially pure N-carboethoxy-O-(2,4,6-trimethylbenzyl)hydroxylamine having a boiling point of 148°-153° C/0.9 mmHg.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:12]2[CH:13]=[CH:14][C:15]([NH2:17])=[CH:16][C:11]=2[O:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:18][NH:19][C:20]([C:22]1[S:23][CH:24]=[CH:25][C:26]=1[NH:27][C:28]1[C:33]([Cl:34])=[CH:32][N:31]=[C:30](Cl)[N:29]=1)=[O:21]>>[CH2:1]([O:3][C:4]([N:6]1[C:12]2[CH:13]=[CH:14][C:15]([NH:17][C:30]3[N:29]=[C:28]([NH:27][C:26]4[CH:25]=[CH:24][S:23][C:22]=4[C:20](=[O:21])[NH:19][CH3:18])[C:33]([Cl:34])=[CH:32][N:31]=3)=[CH:16][C:11]=2[O:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCCOc2cc(N)ccc21
Reactant: CNC(=O)c1sccc1Nc1nc(Cl)ncc1Cl
Product: CCOC(=O)N1CCCOc2cc(Nc3ncc(Cl)c(Nc4ccsc4C(=O)NC)n3)ccc21

Procedure:
The title compound was prepared from 3-amino-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid ethyl ester and 3-(2,5-dichloro-pyrimidin-4-ylamino)-thiophene-2-carboxylic acid methylamide in an analogous manner to Example 1410. Product isolated as an orange foam (155 mg, 77%). LCMS (m/e) 503 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 11.32 (bs, 1H), 8.38 (bs, 1H), 8.13 (s, 1H), 7.45-7.27 (m, 2H), 7.21-7.05 (m, 2H), 7.01 (s, 1H), 5.81-5.69 (m, 1H), 4.33-4.05 (m, 4H), 3.90-3.65 (m, 2H), 3.03 (d, 3H, J=4.7 Hz), 2.17-2.02 (m, 2H), 1.42-1.14 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C:4](=[O:12])[C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.FC(F)(F)C(O)=O.[I:30]N1C(=O)CCC1=O.[Al]>O.C(Cl)Cl>[I:30][C:7]1[N:6]=[C:5]([C:8]([O:10][CH3:11])=[O:9])[C:4](=[O:12])[N:3]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[CH:14]=2)[C:2]=1[CH3:1]
Reactant: COC(=O)c1ncc(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Reactant: O=C1CCC(=O)N1I
Agent: [Al]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1nc(I)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Reaction time: 5 h
Yield: 45.9 %

Procedure:
Methyl 5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxylate (1.5 g, 4.8 mmol), dry DCM (7.0 mL), trifluoroacetic acid (3.0 mL) and N-iodosuccinimide (1.0 g, 4.5 mmol) were mixed and stirred at RT in the dark (flask covered with aluminum foil). After 5 h, water (5 mL) was added and the mixture was concentrated by rotary evaporation. Water (3 mL) was added once more and the mixture was concentrated as described above. The resulting mixture was diluted with acetonitrile to a total volume of 50 mL. Purification by preparative HPLC with acetonitrile-water as eluent (neutral eluent) gave methyl 6-iodo-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxylate (0.905 g, 46%) as a yellow crystalline solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]1([S:27]([O-:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Na+].C([O-])([O-])=O.[Cs+].[Cs+].C([O-])(O)=O.[Na+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCOC(C)=O>[C:21]1([S:27]([C:17]2[CH:18]=[CH:19][C:14]([CH:12]3[O:11][CH2:10][CH2:9][N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH2:13]3)=[CH:15][CH:16]=2)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Brc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Reactant: O=S([O-])c1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccccc1)c1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Temperature: 25 °C
Yield: 52.7 %

Procedure:
To a degassed mixture of 4-benzyl-6-(4-bromo-phenyl)-morpholine (0.45 g; 1.35 mmol), sodium benzenesulfinate (0.27 g; 1.63 mmol), Cs2CO3 (0.66 g; 2.03 mmol), and tetrabutylammonium chloride (0.45 g; 1.63 mmol) in toluene (10 mL), was added Pd2dba3 (31.01 mg; 0.03 mmol) and Xantphos (39.19 mg; 0.07 mmol). The resulting mixture was heated under reflux for 2 days. After cooling to RT, EtOAc and a 5% aqueous NaHCO3 solution were added. The layers were separated and the organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Et2O) to afford 2-(4-benzenesulfonyl-phenyl)-4-benzyl-morpholine (0.28 g).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([Si](C)(C)C)=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Li]CCCC.CON(C)[C:23]([C@@H:25]1[CH2:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]1)=[O:24].C([O-])(O)=O.[Na+]>C1COCC1>[O:9]1[C:10]2[C:2]([C:23]([C@@H:25]3[CH2:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]3)=[O:24])=[CH:3][CH:4]=[CH:5][C:6]=2[CH:7]=[CH:8]1
Reactant: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: C[Si](C)(C)c1cc2cccc(Br)c2o1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2cccc3ccoc23)C1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 169.8 %

Procedure:
A stirred solution of 7-bromo-2-(trimethylsilyl)benzofuran (620 mg, 2.3 mmol) in THF (15 mL) was cooled to −70° C. and n-BuLi (2.5 M in hexanes, 0.85 mL, 2.1 mmol) was added dropwise over 2 min. The mixture was stirred at −70° C. for 15 min and a solution of (R)-tert-butyl 3-(N-methoxy-N-methylcarbamoyl)piperidine-1-carboxylate (341 mg, 1.30 mmol) in THF (5 mL) was added dropwise over 2 min. The mixture was stirred at −70° C. for 1 h, poured into satd aq NaHCO3 (100 mL) and extracted with ether (2×100 mL). The combined ether extracts were washed with brine (40 mL) and dried over MgSO4. Removal of the solvent afforded crude (R)-tert-butyl 3-((benzofuran-7-yl)carbonyl)piperidine-1-carboxylate (727 mg) as an oil. This material was dissolved in THF (15 mL) and cooled to −70° C. 4-Methoxybutylmagnesium chloride (1.52 M in THF, 2.0 mL, 3.04 mmol) was added dropwise over 2 min. The mixture was stirred at −70° C. for 2 h and poured into sat'd aq NaHCO3 (100 mL). The mixture was extracted with ether (2×100 mL) and the combined ether extracts were washed with brine (35 mL) and dried over MgSO4. Removal of the solvent left an oil which was purified by chromatography on a 40-g silica cartridge eluted with a gradient from 0 to 100% EtOAc in hexanes to afford (R)-tert-butyl 3-((S)-1-(benzofuran-7-yl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate (240 mg, 44%) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8](I)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH2:15].[CH3:17][N:18]1[C:22]([Sn](CCCC)(CCCC)CCCC)=[CH:21][N:20]=[N:19]1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:22]2[N:18]([CH3:17])[N:19]=[N:20][CH:21]=2)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH2:15]
Reactant: COC(=O)c1cc(I)c(C(F)(F)F)cc1N
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnnn1C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2cnnn2C)c(C(F)(F)F)cc1N
Temperature: 100 °C
Reaction time: 24 h
Yield: 41 %

Procedure:
To a solution of 2-amino-4-trifluoromethyl-5-iodo-benzoic acid methyl ester (1 g, 2.90 mmol) in dioxane (20 mL) were added 1-methyl-5-tributylstannanyl-1H-[1,2,3]triazole (2.02 g, 4.34 mmol) and Pd(dppf)2Cl2 (237 mg, 0.29 mmol) and the resulting mixture was stirred at 100° C. for 24 h. A portion of catalyst (0.1 equiv) was added and the mixture was stirred at 100° C. for an additional 7 h. The solvent was removed in vacuo to afford a dark oil. The residue was purified by flash chromatography (silica gel, EtOAc/hexanes (0:1000 to 40:60)) to provide the title compound as an off-white solid (357 mg, 41% yield). ES-MS: m/z 301.2 [M+H]+, rt 4.49 min.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C(O[C:20]1[CH:37]=[CH:36][C:23]([CH:24]([OH:35])[C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[CH:22][C:21]=1[O:38][CH3:39])C1C=CC=CC=1>>[CH3:39][O:38][C:21]1[CH:22]=[C:23]([CH:36]=[CH:37][CH:20]=1)[C:24]([C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:34])[F:33])=[CH:27][CH:26]=1)=[O:35]
Reactant: COc1cc(C(O)c2ccc(C(F)(F)F)cc2)ccc1OCc1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Product: COc1cccc(C(=O)c2ccc(C(F)(F)F)cc2)c1
Reaction time: 2 h

Procedure:
52.6 g of 4-(benzyloxy)-3-methoxy-4'-(trifluoromethyl)benzhydrol (dissolved in 500 ml of methylene chloride) are treated within 10 minutes at 20° with 30.6 g of pyridinium chlorochromate and stirred at 20° for 2 hours. The precipitate formed is subsequently filtered and washed with methylene chloride. The filtrate is evaporated and the residue is chromatographed on 150 g of silica gel with methylene chloride. After recrystallization from methylene chloride/hexane, there is obtained 4-benzyloxy)-3-methoxy-4'-(trifluoromethyl)benzophenone of melting point 101°.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].C(OC([N:38]1[CH2:43][CH2:42][CH:41]([O:44][C:45]2[CH:50]=[CH:49][C:48]([CH:51]=O)=[CH:47][C:46]=2[F:53])[CH2:40][CH2:39]1)=O)(C)(C)C>>[CH2:1]([N:3]([CH2:51][C:48]1[CH:49]=[CH:50][C:45]([O:44][CH:41]2[CH2:40][CH2:39][NH:38][CH2:43][CH2:42]2)=[C:46]([F:53])[CH:47]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: CCNc1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C=O)cc2F)CC1
Product: CCN(Cc1ccc(OC2CCNCC2)c(F)c1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 29.6 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylamino-4,5-dimethoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 4-(2-fluoro-4-formylphenoxy)piperidine-1-carboxylic acid tert-butyl ester (75 mg) according to an analogous synthetic method to Example 238 and purified by LC-MS, the title compound (7.7 mg) was obtained.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:24][CH2:25][CH3:26])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][C:16]=3[CH3:23])=[O:13])[CH:7]=2)[CH2:3][CH2:2]1.[CH3:27][O:28][CH2:29][CH2:30][NH2:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>C(Cl)Cl>[CH:1]1([CH2:4][N:5]([CH2:24][CH2:25][CH3:26])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][NH:31][CH2:30][CH2:29][O:28][CH3:27])=[CH:17][C:16]=3[CH3:23])=[O:13])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: COCCN
Reactant: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(C=O)cc2C)ncn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: ClCCl
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(CNCCOC)cc2C)ncn1
Reaction time: 15 h

Procedure:
A solution of 6-((cyclopropylmethyl)(propyl)amino)-N-(4-formyl-2-methylphenyl)pyrimidine-4-carboxamide (Intermediate 29, 100 mg; 0.28 mmol) in DCM (5 ml) was treated with 2-methoxyethanamine (Aldrich, 112.7 mg; 0.42 mmol) followed by polymer supported triacetoxy borohydride (150 mg). After stirring for 15 hours the mixture was filtered and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give the title compound as an off-white solid.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19](=[O:21])[CH3:20])=[CH:16][CH:17]=3)[CH2:12][CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br-:22].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.O>C1COCC1>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19](=[O:21])[CH2:20][Br:22])=[CH:16][CH:17]=3)[CH2:12][CH2:11]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc2c(c1)CCN2S(=O)(=O)c1ccccc1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(CBr)c1ccc2c(c1)CCN2S(=O)(=O)c1ccccc1
Reaction time: 1.5 h

Procedure:
The ketone from step 1 (0.310 g, 1.02 mmol) was dissolved in THF (3 ml), and phenyltrimethylammonium tribromide (PTT) (0.386 g, 1.02 mmol) was added as a solid leaving an orange solution which began to deposit a white solid immediately. Stirring for 1.5 hours leaves a colorless mixture to which water (5 ml) was added. THF was then evaporated and the resulting aqueous mixture was extracted with ethyl acetate. Drying over Na2SO4 and evaporation leaves a white crystalline solid (85% desired mono-brominated material by LC-MS, 5% starting material, 10% dibrominated) suitable for the next step. LC-MS (ES+): 381, 379 m/e.
Reaction SMILES: [C@@H:1]1([N:9]2[C:13]3[N:14]=[N:15][N:16]=[C:17]([N:18]=CN(C)C)[C:12]=3[N:11]=[CH:10]2)[O:6][C@H:5]([CH2:7][OH:8])[C@@H:3]([OH:4])[CH2:2]1.CO[CH:25](OC)[N:26]([CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:27][CH:28]([CH3:30])[CH3:29].C(Cl)Cl.CO.CO>O>[C@@H:1]1([N:9]2[C:13]3[N:14]=[N:15][N:16]=[C:17]([N:18]=[CH:25][N:26]([CH2:27][CH:28]([CH3:29])[CH3:30])[CH2:31][CH:32]([CH3:33])[CH3:34])[C:12]=3[N:11]=[CH:10]2)[O:6][C@H:5]([CH2:7][OH:8])[C@@H:3]([OH:4])[CH2:2]1
Reactant: CN(C)C=Nc1nnnc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1
Reactant: COC(OC)N(CC(C)C)CC(C)C
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CC(C)CN(C=Nc1nnnc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1)CC(C)C

Procedure:
As described for 9a but using N,N-di-isobutylformamide dimethylacetal. Colorless crystals (72%). M.p. 138-140°C. TLC (silica gel, CH2Cl2-MeOH, 9:1): Rf 0.40. UV (10% MeOH in water): λmax 236 (10100), 325 nm (25850). 1H-NMR ([D6]DMSO): δ 0.88, 0.94 (2d, 12 H, CH3); 1.95, 2.20 (2m, 2H, CH); 2.80 (2m, 2H, H2—C(2′)); 3.30-3.74 (m, 6H, H2—C(5′) and 2 CH2); 4.00 (m, 1H, H—C(4′)); 4.45 (m, 1H, H—C(3′)); 5.03 (t, 1H, 3J(H,H)=4.9 Hz, 5′—OH); 5.37 (d, 1H, 3J(H,H)=4.0 Hz, 3′—OH); 6.54 (t, 1H, 3J(H,H)=6.4 Hz, H—C(1′)); 8.78 (s, 1H, N═CH); 9.10 (s, 1H, H—C(8)). Anal. calcd. for C18H29N7O3. 1/2 H2O (400.5): C, 53.99; H 7.55; N 24.48; found: C 53.65; H 7.62; N 24.11.