Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH:18]([OH:19])[CH2:17][N:16]([C:20]4[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[C:23]([C:30]([OH:32])=O)=[CH:22][N:21]=4)[CH2:15]3)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C[N:36](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.[NH4+].[Cl-]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:34]=[CH:33][C:5]([C:6]([N:8]2[CH2:9][CH2:10][N:11]([CH:14]3[CH:18]([OH:19])[CH2:17][N:16]([C:20]4[N:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[C:23]([C:30]([NH2:36])=[O:32])=[CH:22][N:21]=4)[CH2:15]3)[CH2:12][CH2:13]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1cnc(N2CC(O)C(N3CCN(C(=O)c4ccc(Cl)cc4)CC3)C2)nc1C(F)(F)F
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: NC(=O)c1cnc(N2CC(O)C(N3CCN(C(=O)c4ccc(Cl)cc4)CC3)C2)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 35 %

Procedure:
To a solution of 2-{3-[4-(4-Chloro-benzoyl)-piperazin-1-yl]-4-hydroxy-pyrrolidin-1-yl}-4-trifluoromethyl-pyrimidine-5-carboxylic acid (1 eq) in DMF (1 mL), was added HATU (1.5 eq), DIPEA (4 eq) and HOBt (1.5 eq). The mixture was stirred at RT for 5 min. Then NH4Cl (2 eq) was added. The final reaction mixture was stirred at RT for overnight. EtOAc (2 mL) was added. The organic layer was washed with H2O (2×1 mL), dried over Na2SO4, and concentrated. The residue was purified by column chromatography (Ethyl acetate) to give the desired product as a white solid (35% yield). MS: (ESI), M/Z, 499 (M+1). Retention time: 1.56 min (FA-polar).
Reaction SMILES: C1([C:7]([N:9]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH2:11][CH2:10]2)=[O:8])CCCCC1.N1C2C(=CC(S(N)(=O)=O)=CC=2)CC1.[N:35]1(C(Cl)=O)[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>>[N:35]1([C:7]([N:9]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH2:21])(=[O:19])=[O:20])=[CH:15][CH:16]=3)[CH2:11][CH2:10]2)=[O:8])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: NS(=O)(=O)c1ccc2c(c1)CCN2C(=O)C1CCCCC1
Agent: NS(=O)(=O)c1ccc2c(c1)CCN2
Product: NS(=O)(=O)c1ccc2c(c1)CCN2C(=O)N1CCOCC1
Yield: 59 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 55, indoline-5-sulfonamide (Intermediate 54A, 250 mg, 1.26 mmol) and morpholine-4-carbonyl chloride (206 μL, 1.77 mmol) were converted to the title compound (230 mg, 59%) after purification using preparative HPLC. 1H NMR (DMSO-d6) δ 7.61-7.58 (m, 2H), 7.15-7.12 (m, 3H), 3.92 (t, J=6.5 Hz, 2H), 3.78-3.75 (m, 2H), 3.66-3.63 (m, 4H), 3.10-3.07 (m, 4H); MS(ESI+) m/z 312.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([OH:15])[CH2:10]2)[C:5]([C:16]#[N:17])=[CH:4][N:3]=1.[OH-].[NH4+].C(O)(C(F)(F)F)=O.C(=O)(O)[O-]>C(O)C.[Ni]>[NH2:17][CH2:16][C:5]1[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([OH:15])[CH2:10]2)=[N:7][CH:2]=[N:3][CH:4]=1
Reactant: N#Cc1cnc(Cl)nc1N[C@@H]1CCC[C@H](O)C1
Agent: [Ni]
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: NCc1cncnc1N[C@@H]1CCC[C@H](O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-chloro-4-((1R,3S)-3-hydroxycyclohexyl-amino)pyrimidine-5-carbonitrile (70 mg, 0.277 mmol) and ammonium hydroxide (500 μl, 12.84 mmol) in ethanol (4 mL) was added Raney nickel (16.26 mg, 0.277 mmol). The resulting mixture was evacuated and then stirred under a balloon of hydrogen at atmospheric pressure and ambient temperature overnight. Ethanol was removed in vacuo and the remaining residue was purified using reverse-phased preparative HPLC (5-80% acetonitrile+0.1% TFA in water+0.1% TFA, over 30 min). Fractions containing product were concentrated under reduced pressure. The resulting residue was redissolved in methanol (5 mL), passed over a Varian StratoSpheres HCO3 resin SPE tube for TFA removal (0.9 mmol bicarbonate equiv.), and then concentrated under reduced pressure to afford the title compound as an oil that was used for NMR purposes only. The regiochemistry was confirmed by the presence of two distinct aromatic peaks in the 1H NMR spectrum and the observation of an NOE signal between the C5 methylene hydrogens and only one of these aromatic peaks in the NOISY spectrum. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.32 (s, 1H), 7.92 (s, 1H), 7.32 (d, J=7.48 Hz, 1H), 4.67 (d, J=3.87 Hz, 1H), 3.88-4.01 (m, 1H), 3.59 (s, 2H), 3.49 (d, J=3.61 Hz, 1H), 2.06-2.16 (m, 1H), 1.99 (br. s., 2H), 1.81 (t, J=13.28 Hz, 2H), 1.69 (dt, J=13.35, 3.51 Hz, 1H), 1.01-1.35 (m, 4H). MS (ESI) m/z 223.5 [M+1]+.
Reaction SMILES: [NH2:1][C@H:2]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)[CH2:3][CH2:4][OH:5].[C:13]([O:17][C:18]([NH:20][C:21]1([C:36](O)=[O:37])[CH2:26][CH2:25][N:24]([C:27]2[C:28]3[CH:35]=[CH:34][NH:33][C:29]=3[N:30]=[CH:31][N:32]=2)[CH2:23][CH2:22]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC(N(C)C)=O>[Cl:12][C:9]1[CH:8]=[CH:7][C:6]([C@@H:2]([NH:1][C:36]([C:21]2([NH:20][C:18](=[O:19])[O:17][C:13]([CH3:15])([CH3:14])[CH3:16])[CH2:22][CH2:23][N:24]([C:27]3[C:28]4[CH:35]=[CH:34][NH:33][C:29]=4[N:30]=[CH:31][N:32]=3)[CH2:25][CH2:26]2)=[O:37])[CH2:3][CH2:4][OH:5])=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Reactant: N[C@@H](CCO)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](CCO)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 20 °C
Reaction time: 24 h
Yield: 82.3 %

Procedure:
(S)-3-Amino-3-(4-chlorophenyl)propan-1-ol (Intermediate 47) (2.055 g, 11.07 mmol) was added in one portion to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (4 g, 11.07 mmol) and DIPEA (5.80 ml, 33.20 mmol) in DMA (40 ml). HATU (4.63 g, 12.18 mmol) was added and the resulting solution was stirred at 20° C. for 24 hours. The reaction mixture was evaporated to dryness then diluted with EtOAc (300 mL), and washed sequentially with water (50 mL) and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 2 to 6% MeOH with ammonia in DCM. Pure fractions were evaporated to dryness and triturated with dioxane (40 ml) to afford (S)-tert-butyl 4-(1-(4-chlorophenyl)-3-hydroxypropylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (Intermediate 22) (4.82 g, 82%) as a white solid. (S)-tert-butyl 4-(1-(4-chlorophenyl)-3-hydroxypropylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (Intermediate 22) (4.82 g, 82%) was suspended in dioxane (40.0 ml) and 4M hydrogen chloride in dioxane (7.69 ml, 221.36 mmol) added. The reaction was stirred at ambient temperature for 2 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 3.5M NH3/MeOH and pure fractions were evaporated to dryness. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 μm silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford (S)-4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (1.200 g, 25.3%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][N:8]=[C:7]2O)([O-:3])=[O:2].C(N(C(C)C)C(C)C)C.P(Cl)(Cl)([Cl:26])=O>ClC(Cl)C>[Cl:26][C:7]1[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:10]=[CH:9][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1ccc2ncnc(O)c2c1
Solvent: CC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc2ncnc(Cl)c2c1
Temperature: 80 °C

Procedure:
To a solution of 6-nitroquinazolin-4-ol (4.40 g, 23.01 mmol) and N-ethyl-N-isopropylpropan-2-amine (11.89 g, 92.04 mmol) in dichloroethane (50 mL) was added phosphoryl trichloride (7.06 g, 46.02 mmol). After heating to 80° C. for 16 hours, the mixture was concentrated under reduced pressure. The residue was concentrated again with toluene (2×100 mL) to provide the product.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[N:26]1([C:32]([NH2:34])=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:2]([NH:34][C:32]([N:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)=[O:33])=[CH:3][CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]2)[N:15]=1
Reactant: CN1CCN(c2cc(N3CCc4ccc(Br)cc4C3)nc(N)n2)CC1
Reactant: NC(=O)N1CCCCC1
Product: CN1CCN(c2cc(N3CCc4ccc(NC(=O)N5CCCCC5)cc4C3)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 34 starting from 4-(7-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine and 1-piperidinecarboxamide (Aldrich Cat. No. 344753). LCMS (M+H)+: m/z=451.2.
Reaction SMILES: [CH2:1]([N:8](C)[C:9]([CH3:29])([CH3:28])[CH:10]([C:12]1[CH:17]=[CH:16][C:15]([C@@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:19])=[CH:14][CH:13]=1)[OH:11])C1C=CC=CC=1>CO.[Pd]>[C:23]([O:22][C:21](=[O:27])[NH:20][C@H:18]([C:15]1[CH:14]=[CH:13][C:12]([CH:10]([OH:11])[C:9]([CH3:29])([NH:8][CH3:1])[CH3:28])=[CH:17][CH:16]=1)[CH3:19])([CH3:25])([CH3:24])[CH3:26]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C(O)C(C)(C)N(C)Cc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: CNC(C)(C)C(O)c1ccc([C@H](C)NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 106 %

Procedure:
227 mg of the compound [86-3] was dissolved in 7 mL of methanol, and 114 mg of a 20% palladium/carbon catalyst was added thereto. The mixture was stirred at room temperature for 1 hour under hydrogen atmosphere. The catalyst was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain 188 mg of tert-butyl((1S)-1-{4-[1-hydroxy-2-methyl-2-(methylamino)propyl]phenyl}ethyl)carbamate [86-4] (hereinafter, referred to as the compound [86-4]).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([N:11]2[C:15](=[O:16])[C:14]3([CH2:21][CH2:20][N:19](C(OCC4C=CC=CC=4)=O)[CH2:18][CH2:17]3)[N:13]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:12]2)[CH:8]=[CH:9][CH:10]=1)=[O:4]>CO.[Pd]>[O:16]=[C:15]1[C:14]2([CH2:17][CH2:18][NH:19][CH2:20][CH2:21]2)[N:13]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:12][N:11]1[C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)c1cccc(N2CN(c3ccccc3)C3(CCN(C(=O)OCc4ccccc4)CC3)C2=O)c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cccc(N2CN(c3ccccc3)C3(CCNCC3)C2=O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.2 %

Procedure:
To a solution of benzyl 3-(3-(methoxycarbonyl)phenyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.18 g, 0.36 mmol) in methanol (4 mL), was added 10 wt % palladium on carbon (0.036 g). After stirring under hydrogen at room temperature and atmospheric pressure for 18 hours, the reaction mixture was filtered, washed with methanol, concentrated in vacuo to obtain methyl 3-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)benzoate (0.12 g).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][N:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[S:22]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[NH:25][CH2:24][CH2:23]1.CC(C)([O-])C.[Na+]>O1CCOCC1.C(Cl)Cl.[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[S:22]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]([C:2]2[C:7]([CH2:8][N:9]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:24][CH2:23]1
Reactant: Clc1ncccc1CN(c1cccnc1)c1cccnc1
Reactant: c1ccc2c(c1)NCCS2
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: c1cncc(N(Cc2cccnc2N2CCSc3ccccc32)c2cccnc2)c1
Yield: 74.9 %

Procedure:
To a solution of N-[(2-chloropyridin-3-yl)methyl]-N-pyridin-3-ylpyridin-3-amine (110 mg, 0.37 mmol) and 3,4-dihydro-2H-1,4-benzothiazine (85 mg, 0.56 mmol) (prepared according to procedure described in patent WO 0220498) in dry dioxane (1.25 mnL) was added sodium t-butoxide (48 mg, 0.50 mmol), and bis(tri-t-butylphosphine) palladium(0) (34 mg, 0.066 mmol). The vessel was sealed with a septum cap, degassed (3×), and heated at 100 C for 3 hours. The cooled reaction was diluted with methylene chloride and washed with NaHCO3 solution, and water and the organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent evaporated. The residue was subjected to silica gel chromatography eluting with a 20-90% acetone/hexane gradient to give the title compound as a colorless glass(114 mg, 75% yield). 1H-NMR (500 MHz, CDCl3): δ 8.41 (1H, d, J=4.9 Hz), 8.28 (2H, d, J=3.7 Hz), 8.23 (2H, d, J=4.6 Hz), 7.70 (1H, d, J=6.1 Hz), 7.21-7.26 (4H, m), 7.17 (1H, d, J=3.7 Hz), 7.16 (1H, d, J=4.6 Hz), 7.06 (1H, dd, J=4.9, 7.6 Hz), 6.91 (1H, t, J=7.8 Hz), 6.84 (1H, t, J=7.6 Hz), 6.32 (1H, d, J=8.0 Hz), 4.56 (2H,s), 4.13 (2H, br s), 3.32 (2H, t, J=5.6 Hz). m/e (m+1): 412.2.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:9](=[O:22])[N:10]([C:13]3[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=3[Cl:21])[CH:11]([CH3:12])[C:5]2=[CH:4][N:3]=1.[NH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[Cl:21][C:14]1[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:13]=1[N:10]1[CH:11]([CH3:12])[C:5]2[C:6](=[N:7][C:2]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:3][CH:4]=2)[N:8]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:9]1=[O:22]
Reactant: Nc1ccccc1
Reactant: COc1ccc(Cl)c(N2C(=O)N(c3ccccc3)c3nc(Cl)ncc3C2C)c1
Product: COc1ccc(Cl)c(N2C(=O)N(c3ccccc3)c3nc(Nc4ccccc4)ncc3C2C)c1
Temperature: 100 °C

Procedure:
(±)-7-Chloro-3-(2-chloro-5-methoxy-phenyl)-4-methyl-1-phenyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (0.20 g; 0.49 mmol) (from Example 12b supra) was combined with aniline (150 μL; 1.65 mmol) (Aldrich) and heated in an oil bath at 100° C. for about 70 minutes. Upon cooling, the residue was triturated with hexanes and then partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography (Biotage, 40M; 40:60 ethyl acetate-hexanes) to give (±)-3-(2-chloro-5-methoxy-phenyl)-4-methyl-1-phenyl-7-phenylamino-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one as a light yellow solid. (Yield 0.15 g; 63.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][NH:11][C:12]([C:14]2[S:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[CH:15]=2)=O)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[OH-].[Na+]>C1COCC1>[S:18]1[C:14]([CH2:12][NH:11][CH2:10][CH2:9][C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)=[CH:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]1=2
Reactant: O=C(NCCc1ccc(Cl)c(Cl)c1)c1cc2ccccc2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Clc1ccc(CCNCc2cc3ccccc3s2)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32.3 %

Procedure:
A solution of 364 mg (1.04 mmol) of benzo[b]thiophene-2-carboxylic acid[2-(3,4-di-chloro-phenyl)-ethyl]-amide in 10 ml of THF was added dropwise to 5.2 ml of a 1 molar solution of BH3-THF complex in THF at 0° C. The reaction mixture was stirred for 30 min at RT and then heated to reflux over night. Then 2 ml of 6 N HCl were added very carefully at ambient temperature and the mixture was heated again to reflux for 2 hours. After cooling to RT, the pH was adjusted to 8-9 by addition of 1 N sodium hydroxide solution and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried with magnesium sulfate, filtered and concentrated. Final purification of the residue (silica gel; dichloromethane/methanol 95:5) yielded 113 mg (32%) of benzo[b]thiophen-2-ylmethyl-[2-(3,4-dichloro-phenyl)-ethyl]-amine as off-white solid. MS (ISP) 336.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[O:23]([C:30]1[CH:35]=[CH:34][C:33]([N:36]=[C:37]=[O:38])=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:37]([NH:36][C:33]2[CH:34]=[CH:35][C:30]([O:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:31][CH:32]=2)=[O:38])=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C=Nc1ccc(Oc2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(Oc5ccccc5)cc4)cc3)c2cc1OC
Yield: 60 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (53 mg) was dissolved in toluene (3 ml) with heat, 4-phenoxyphenyl isocyanate (0.2 ml) was added, and the admixture was refluxed with heat for 30 minutes. The resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 55 mg of the title compound (yield: 60%).
Reaction SMILES: FC(F)(F)S(O)(=O)=O.[Br:9][C:10]1[CH:11]=[C:12]([CH2:16][CH:17]([CH3:22])[CH2:18][C:19]([OH:21])=O)[CH:13]=[CH:14][CH:15]=1>C(Cl)Cl.C(Cl)(Cl)Cl>[Br:9][C:10]1[CH:11]=[C:12]2[C:13](=[CH:14][CH:15]=1)[C:19](=[O:21])[CH2:18][CH:17]([CH3:22])[CH2:16]2
Reactant: CC(CC(=O)O)Cc1cccc(Br)c1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC1CC(=O)c2ccc(Br)cc2C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A flask was charged with trifluoromethane sulfonic acid (450 g, 3 mol) and cooled to 0° C. with an ice-water bath. 4-(3-bromophenyl)-3-methylbutanoic acid, prepared in a similar manner as described in Example 32 (15.5 g, 60 mmol), was added as a solution in DCM (30 mL) slowly to produce a clear dark brown solution. After 15 min, the reaction was diluted with 500 mL of CHCl3 and poured slowly onto approximately 1 L of crushed ice. The resulting slurry was allowed to stir until the solution warms to room temperature and became biphasic. Following separation of layers, the aqueous layer was extracted with CHCl3. The combined organics were washed with brine and dried over anhydrous MgSO4 prior to concentration in vacuo. Purification via Isco column chromatography (50% DCM/hex isocratic) provided a quantitative yield of the named compound as a pale yellow amorphous solid. LCMS-ESI+ (m/z): [M]+ calcd for C11H11BrO: 239.11; found: 239.20.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:10][CH2:11][O:12][CH2:13][CH:14]=2)[CH:5]=[C:6]([F:8])[CH:7]=1>CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Fc1cc(F)cc(C2=CCOCC2)c1
Agent: [Pd]
Solvent: CO
Product: Fc1cc(F)cc(C2CCOCC2)c1
Reaction time: 18 h
Yield: 71 %

Procedure:
To a solution of 4-(3,5-difluorophenyl)-3,6-dihydro-2H-pyran (1.0 equiv.) in methanol (0.2 M) was added 10% Pd/C (0.05 equiv.). The reaction was placed under an atmosphere of hydrogen and stirred for 18 hours. Upon completion, the solution was filtered over a pad of Celite, the pad was washed with DCM, the filtrate was concentrated in vacuo to give 4-(3,5-difluorophenyl)tetrahydro-2H-pyran in 71% yield. 1H NMR (400 MHz, <cdcl3>) δ ppm 1.76 (br. s., 4 H), 2.75 (br. s., 1 H), 3.50 (br. s., 2 H), 4.08 (d, J=9.78 Hz, 2 H), 6.56-6.94 (m, 3 H). cl Synthesis of 2-(2,6-difluoro-4-(tetrahydro-2H-pyran-4-yl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
Reaction SMILES: [CH2:1]([OH:5])[CH:2]=[CH:3][CH3:4].Cl.O.[CH:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:8]1([CH:3]([CH3:4])[CH2:2][CH2:1][OH:5])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC=CCO
Reactant: c1ccccc1
Agent: Cl
Solvent: O
Product: CC(CCO)c1ccccc1
Temperature: 5 °C

Procedure:
A reaction vessel was fitted with a mechanical stirrer, thermometer and a reflux condenser capped with an additional funnel. While under a positive flow of dry nitrogen, the system was flame dried. The vessel was charged 250 ml of benzene and then 25 gm of aluminum chloride was added as quickly as possible. This mixture was cooled with stirring to 5° C. in an ice/salt bath and a solution of 7.2 gm (0.1 mol) of crotyl alcohol in 45 ml of benzene was added dropwise while maintaining the temperature below 5° C. Next, 50 ml of concentrated hydrochloric acid was added cautiously. After warming to room temperature, 50 ml of water was added and the lower organic phase removed. The aqueous portion was then extracted with benzene. The combined organics were washed with aqueous 10% sodium bicarbonate and water. After drying over anhydrous magnesium sulfate, filtering and evaporating, a dark oil was recovered. This was vacuum distilled to give 8.2 gm of colorless 3-phenyl butanol (ND25 = 1.5210).
Reaction SMILES: OC1C=CC=CN=1.[C:8]([O:12][C:13](=[O:41])[NH:14][C@H:15]([C@@H:34]1[CH2:38][C@@H:37]([CH3:39])[C:36](=[O:40])[O:35]1)[CH2:16][N:17]1[CH2:22][C:21](=[O:23])[N:20]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[CH3:31])[CH2:19][C:18]1([CH3:33])[CH3:32])([CH3:11])([CH3:10])[CH3:9].[CH3:42][C:43]([CH3:47])([CH3:46])[CH2:44][NH2:45]>O>[C:8]([O:12][C:13](=[O:41])[NH:14][C@@H:15]([CH2:16][N:17]1[CH2:22][C:21](=[O:23])[N:20]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[CH3:31])[CH2:19][C:18]1([CH3:33])[CH3:32])[C@@H:34]([OH:35])[CH2:38][C@H:37]([C:36](=[O:40])[NH:45][CH2:44][C:43]([CH3:47])([CH3:46])[CH3:42])[CH3:39])([CH3:10])([CH3:11])[CH3:9]
Reactant: CC(C)(C)CN
Reactant: Cc1ccc(F)cc1N1CC(C)(C)N(C[C@H](NC(=O)OC(C)(C)C)[C@@H]2C[C@@H](C)C(=O)O2)CC1=O
Agent: Oc1ccccn1
Solvent: O
Product: Cc1ccc(F)cc1N1CC(C)(C)N(C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C[C@@H](C)C(=O)NCC(C)(C)C)CC1=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
25 mg of 2-hydroxypyridine (0.26 mmol) was added to a solution of 250 mg of {(S)-2-[2,2-dimethyl-4-(5-fluoro-2-methylphenyl)-5-oxopiperazin-1-yl]-1-[(2S,4R)-4-methyl-5-oxotetrahydrofuran-2-yl]ethyl}carbamic acid t-butyl ester obtained in Example (101b) (0.52 mmol) in 1.22 ml of (2,2-dimethylpropyl)amine (10.4 mmol), and the mixture was stirred at 80° C. for two hours. The reaction mixture was cooled and then water was added, followed by extraction with methylene chloride. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: methylene chloride/acetone=2/1) to obtain 228 mg of the title compound (yield: 78%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH:20]([CH3:22])[CH3:21].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH:20]([CH3:22])[CH3:21])[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)Br
Reactant: Cc1c(C(=O)OC(C)(C)C)oc2cccc(O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(C(=O)OC(C)(C)C)oc2cccc(OC(C)C)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 4-hydroxy-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester (200 mg, 0.8 mmol) in 4 mL of DMF was added 2-bromopropane (0.5 mL), and K2CO3 (200 mg). The mixture was stirred at room temperature overnight. The mixture was washed with brine and extracted with ethyl acetate. The combined ethyl acetate layers were washed with brine. Removal of the solvent gave 176 mg of 3-methyl-4-isopropoxy-benzofuran-2-carboxylic acid tert-butyl ester as colorless crystals.