Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[O:16])[CH:10]=1.[BH4-].[Na+].Cl>COCCOC.O1CCCC1>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][OH:16])[CH:10]=1
Reactant: Cc1cccc(C)c1-c1cccc(C=O)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOC
Solvent: C1CCOC1
Product: Cc1cccc(C)c1-c1cccc(CO)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.5 %

Procedure:
2′,6′-Dimethylbiphenyl-3-carbaldehyde (18.5 g, 88.0 mmol) was dissolved in a mixed solvent of 1,2-dimethoxyethane (100 mL) and tetrahydrofuran (100 mL), and sodium borohydride (1.66 g, 44.0 mmol) was added under ice-cooling, and the mixture was stirred at the same temperature for 3 hr, further at room temperature for 3 hr. Diluted hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10%-50% ethyl acetate/hexane) to give the title compound (15.6 g, yield 83%) as a colorless oil.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([C:14]([OH:16])=[O:15])=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:18](O)[CH3:19]>>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([C:14]([O:16][CH2:18][CH3:19])=[O:15])=[N:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(Cc2ccccc2)cn1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1ccc(Cc2ccccc2)cn1

Procedure:
2.0 Grams of 5-benzylpicolinic acid were suspended in 25 ml. of ethanol. The resulting suspension was saturated with hydrogen chloride gas under ice-cooling. After reflux for three hours, the reaction solution was concentrated under reduced pressure. Ether was added thereto to form crystals. The crystals were then recrystallized from a solvent comprising a mixture of acetone/ether to obtain 1.7 g of ethyl 5-benzylpicolinate of a melting point of 109°~111° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=[O:14])[CH2:11][C:10](=O)[CH2:9]1.Cl.[NH2:17][CH2:18][C:19]#[C:20][CH3:21].O1CCCC1>C(N(CC)CC)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:9][C:10]2[N:17]=[CH:18][CH:19]=[C:20]([CH3:21])[C:11]=2[C:12](=[O:14])[CH2:13]1
Reactant: O=C1CC(=O)CC(c2ccccc2F)C1
Reactant: CC#CCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccnc2c1C(=O)CC(c1ccccc1F)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.9 %

Procedure:
To a mixture of 5-(2-fluorophenyl)cyclohexane-1,3-dione (0.98 g), 1-amino-2-butyne hydrochloride (0.5 g), molecular sieves 4A (2 g) and tetrahydrofuran (20 ml) was added triethylamine (0.48 g), and the mixture was stirred at room temperature for 1 hour, refluxed for 12 hours and cooled. Insoluble materials were filtered off. Under reduced pressure, the solvent was evaporated, and the residue was stirred for 6 hours at 220° C. and cooled, to which were added ethyl acetate and sodium hydrogen carbonate solution. The organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was purified with silica gel column chromatography (EtOAc/hexane) to give oil of 7-(2-fluorophenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.35 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:5]([CH3:15])=[CH:4][N:3]=1.[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=2)[CH2:19][CH2:18]1>C(Cl)Cl.CO>[Cl:14][C:10]1[CH:9]=[C:8]([C:6]2[C:5]([CH3:15])=[CH:4][N:3]=[C:2]([NH:28][C:27]3[CH:26]=[CH:25][C:24]([CH2:23][N:20]4[CH2:19][CH2:18][N:17]([CH3:16])[CH2:22][CH2:21]4)=[CH:30][CH:29]=3)[N:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Reactant: Cc1cnc(Cl)nc1-c1cccc(Cl)c1
Solvent: CO
Solvent: ClCCl
Product: Cc1cnc(Nc2ccc(CN3CCN(C)CC3)cc2)nc1-c1cccc(Cl)c1
Yield: 77 %

Procedure:
The title compound was prepared according to synthesis procedure B described above from 2-chloro-4-(3-chlorophenyl)-5-methylpyrimidine and 4-((4-methylpiperazin-1-yl)methyl)aniline in 77% yield (yellow solid) after flash chromatography (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). 1H NMR (400 MHz, CDCl3): δ 8.31 (s, 1H), 7.61 (s, 1H), 7.56 (d, 2H, J=8.2 Hz), 7.48 (m, 1H), 7.40 (m, 2H), 7.25 (d, 2H, J: not calculated due to overlapping peaks), 3.45 (s, 2H), 2.45 (bs, 8H), 2.27 (s, 3H), 2.24 (s, 3H); MS (ESI): 408.4 [M+H]+, 204.7 [M+2H]2+.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:9]=1[CH3:17])(=O)=O.[Br-:18].[Li+]>CC(C)=O>[Br:18][CH2:6][CH2:7][C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:9]=1[CH3:17]
Reactant: Cc1ccc([N+](=O)[O-])cc1CCOS(C)(=O)=O
Reactant: [Br-]
Agent: [Li+]
Solvent: CC(C)=O
Product: Cc1ccc([N+](=O)[O-])cc1CCBr
Yield: 98.3 %

Procedure:
A mixture of 2-(2-methanesulfonyloxyethyl)-1-methyl-4-nitrobenzene (4.0 g) and lithium bromide (6.6 g) in acetone (250 mL) was boiled under reflux for 3½ h. The resulting mixture was cooled and filtered. The residue was purified by flash chromatography on silicagel (eluent:ethyl acetate/heptane 1:2) to give the title compound (3.7 g). 1H NMR (DMSO-d6): 2.45 (s, 3H); 3.25 (t, 2H); 3.80 (t, 2H); 7.50 (d, 1H); 8.05 (dd, 1H); 8.15 (d, 1H).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1.[F:11][C:12]1[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([F:19])[C:13]=1B(O)O.[F-].[K+]>O1CCCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[F:11][C:12]1[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([F:19])[C:13]=1[C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1
Reactant: OB(O)c1c(F)cc(O)cc1F
Reactant: COC(=O)c1csc(Br)n1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1csc(-c2c(F)cc(O)cc2F)n1
Temperature: 120 °C
Yield: 41.1 %

Procedure:
To a suspension of methyl 2-bromothiazole-4-carboxylate (500 mg, 2.16 mmol), 2,6-difluoro-4-hydroxyphenylboronic acid (2 equiv., 767 mg) and potassium fluoride (3.3 equiv., 414 mg) in tetrahydrofuran (10 mL) and water (1 mL) was added bis(tri-tert-butylphosphine)palladium(0) (0.1 equiv., 110 mg) and the mixture was heated to 120° C. for 15 min in the microwave reactor. After in vacuo concentration, the reaction mixture was purified by CombiFlash (0 to 100% EtOAc in heptane) to provide 241 mg of the title compound as a ˜1:1 mixture with methyl 2-bromothiazole-4-carboxylate, which was used directly without further purification.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:20][C:21]([CH:23]1[CH2:28][CH2:27][CH2:26][O:25][CH2:24]1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH:29](=[O:31])[CH3:30]>O1CCCC1>[CH2:13]([O:20][C:21]([C:23]1([CH:29]([OH:31])[CH3:30])[CH2:28][CH2:27][CH2:26][O:25][CH2:24]1)=[O:22])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(OCc1ccccc1)C1CCCOC1
Reactant: CC=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(O)C1(C(=O)OCc2ccccc2)CCCOC1
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 40.2 %

Procedure:
A cooled (−78° C.) solution of N,N-diisopropylamine (4.7 mL, 33.316 mmol, dried over calcium hydride) in anhydrous tetrahydrofuran (60 mL) was treated with a solution of n-butyllithium in hexanes (12.5 mL, 31.234 mmol, 2.5 M). After stirring at −78° C. for 25 minutes, the mixture was treated with a solution of tetrahydro-pyran-3-carboxylic acid benzyl ester (4.587 g, 20.823 mmol) in anhydrous tetrahydrofuran (20 mL). After stirring at −78° C. for 15 minutes, the mixture was treated with acetaldehyde (3.5 mL, 62.469 mmol). After stirring at room temperature for 45 minutes, the reaction was quenched at 0° C. with hydrochloric acid (2 M, 50 mL). The aqueous layer was saturated with sodium chloride, extracted with dichloromethane (2 x). The organics were combined, filtered through a phase separator and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 100 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 3:2 to afford the title compound (2.212 g, 40%) as a yellow oil and as a 3:1 mixture of diastereoisomers. LCMS (m/z) 287.0 [M+Na], Tr=2.00 min.
Reaction SMILES: C(OC1C([N+]([O-])=O)=C([NH:13][C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=2[F:21])C(F)=C(F)C=1)C=C.C[O-].[Na+]>C1COCC1>[F:21][C:15]1[CH:16]=[C:17]([I:20])[CH:18]=[CH:19][C:14]=1[NH2:13]
Reactant: C=CCOc1cc(F)c(F)c(Nc2ccc(I)cc2F)c1[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 155.8 %

Procedure:
To a solution of (3-allyloxy-5,6-difluoro-2-nitro-phenyl)-(2-fluoro-4-iodo-phenyl)-amine (Intermediate 7, 1.0 g, 2.22 mmol) in THF (8 mL) was drop wise added NaOMe solution [prepared by dissolving Na metal (51 mg, 2.2 mmol) in methanol (5 mL)] at −78° C. After complete addition, the reaction mixture was warmed to room temperature and stirred for 16 h. The progress of reaction was monitored by TLC. After completion, reaction mixture was concentrated under reduced pressure. The residue was dissolved in water and extracted with ethyl acetate (20 mL×3). The combined organic layer was washed with water (20 mL×2), dried over anhydrous sodium sulfate and concentrated to yield 3-allyloxy-6-fluoro-5-methoxy-2-nitro-phenyl)-(2-fluoro-4-iodo-phenyl)-amine (820 mg). A suspension of (3-allyloxy-6-fluoro-5-methoxy-2-nitro-phenyl)-(2-fluoro-4-iodo-phenyl)-amine (800 mg, 1.73 mmol) in ethanol (10 mL) was stirred at 70° C. to obtain a clear solution. To this hot solution, a freshly prepared solution of Na2S2O4 (900 mg, 5.2 mmol) in water (1.8 mL) was added drop wise and stirred the reaction mixture at 90° C. for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water and brine. The combined organic layer was dried over anhydrous sodium sulfate and concentrated to yield 6-allyloxy-3-fluoro-N2-(2-fluoro-4-iodo-phenyl)-4-methoxy-benzene-1,2-diamine (720 mg). 1H-NMR (400 MHz, CDCl3): δ3.74 (2H, bs), 3.83 (3H, s), 4.56 (2H, d, J=5.6), 5.32 (1H, d, J=10.8), 5.40-5.45 (2H, m), 6.04-6.09 (1H, m), 6.24 (1H, t), 6.52 (1H, d, J=7.6), 7.21 (1H, d, J=8.4), 7.36 (1H, d, J=10.4).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8]CC=C)[C:5]([O:12][CH3:13])=[CH:4][N:3]=1.N1CCOCC1>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>[Cl:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([O:12][CH3:13])=[CH:4][N:3]=1
Reactant: C=CCOc1nc(Cl)ncc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: ClCCl
Product: COc1cnc(Cl)[nH]c1=O
Yield: 68.2 %

Procedure:
To a solution of 2-chloro-5-methoxy-4-(prop-2-en-1-yloxy)pyrimidine (95.0 g, 475 mmol) in anhydrous DCM (2 L) under nitrogen atmosphere was added morpholine (124 mL, 1.425 moL) and then Pd(Ph3P)4 (13.7 g, 11.9 mmol) and the reaction mixture was stirred at room temperature for 15 min. The reaction mixture was concentrated until thick, then poured into EtOAc. The precipitate was collected and dried to give 52 g of a mixture of 2-chloro-5-methoxypyrimidin-4(3H)-one and morpholine (1:1). 1H-NMR (CDC3, 400 MHz) δ 7.45 (s, 1H), 3.67 (s, 3H). MS (ESI) m/z (M+H)+ 161.0.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]([F:15])([F:14])[F:13])=[CH:7][CH:6]=1)[CH2:3][OH:4].[N:16]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[N:29]=[CH:28][N:27]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=3)[N:26]=2)=[CH:21][CH:20]=1)=[C:17]=[S:18]>>[OH:4][CH2:3][CH:2]([NH:1][C:17]([NH:16][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[N:29]=[CH:28][N:27]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:37])[F:38])=[CH:32][CH:31]=3)[N:26]=2)=[CH:21][CH:20]=1)=[S:18])[C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]([F:13])([F:14])[F:15])=[CH:9][CH:10]=1
Reactant: FC(F)(F)c1ccc(-n2cnc(-c3ccc(N=C=S)cc3)n2)cc1
Reactant: NC(CO)c1ccc(OC(F)(F)F)cc1
Product: OCC(NC(=S)Nc1ccc(-c2ncn(-c3ccc(C(F)(F)F)cc3)n2)cc1)c1ccc(OC(F)(F)F)cc1

Procedure:
The title compound was prepared with 2-amino-2-(4-(trifluoromethoxy)phenyl)ethanol and 3-(4-isothiocyanatophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazole and isolated as a white solid (1.58 g, 99%): 1H NMR (300 MHz, CDCl3) δ 8.07 (s, 1H), 7.67 (d, J=8.5 Hz, 2H), 7.37-7.26 (m, 3H), 7.21 (d, J=8.6 Hz, 2H), 6.76 (dd, J=11.6, 8.6 Hz, 4H), 6.64-6.56 (m, 3H), 6.43 (d, J=7.9 Hz, 1H), 5.13 (s, 1H), 3.45 (dd, J=11.2, 4.0 Hz, 1H), 3.33 (dd, J=11.2, 4.5 Hz, 1H); ESIMS m/z 568 ([M+H]+).
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[NH:26][N:25]=[CH:24][CH:23]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[CH3:27][N:28]([CH3:35])[C@H:29]1[CH2:33][NH:32][CH2:31][C@@H:30]1[OH:34].CCN(C(C)C)C(C)C.C([O-])([O-])=O.[Na+].[Na+]>CC(O)C>[Cl:19][C:16]([F:18])([F:17])[O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:20]=[C:21]([C:22]3[NH:26][N:25]=[CH:24][CH:23]=3)[C:2]([N:32]3[CH2:31][C@H:30]([OH:34])[C@@H:29]([N:28]([CH3:35])[CH3:27])[CH2:33]3)=[N:3][CH:4]=2)=[CH:10][CH:11]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2ccn[nH]2)c1
Reactant: CN(C)[C@H]1CNC[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CN(C)[C@H]1CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cc2-c2ccn[nH]2)C[C@@H]1O
Temperature: 110 °C

Procedure:
A mixture of 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1H-pyrazol-5-yl)nicotinamide (Stage 48.1, 63 mg, 0.156 mmol), (3S,4S)-4-(dimethylamino) pyrrolidin-3-ol (50.8 mg, 0.250 mmol) and DIPEA (0.191 mL, 1.094 mmol) and iPrOH (1 mL) in a sealed vial was heated at 110° C. for 4 h The RM was treated with sat. aq. Na2CO3 (20 mL) and extracted with EtOAc. The combined extracts were washed with brine (10 mL), dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a crude product which was purified by preparative SFC (Column 4-EP, isocratic 25% in 15 min) followed by preparative HPLC (Condition 10). Fractions containing product were combined, treated with sat. aq. Na2CO3 and the MeCN was evaporated off under reduced pressure to give an aq. residue which was extracted with DCM. The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the title product as a white foam. HPLC (Condition 7) tR=5.71 min, UPLC-MS (Condition 3) tR=0.78 min, m/z=493 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.14 (s, 6H) 2.95-3.03 (m, 1H) 3.16-3.26 (m, 2H) 3.34-3.46 (m, 2H) 4.00-4.13 (m, 1H) 4.97-5.13 (m, 1H) 6.33-6.45 (m, 1H) 7.34 (d, J=8.99 Hz, 2H) 7.80-7.91 (m, J=9.40 Hz, 3H) 8.04 (s, 1H) 8.68-8.81 (m, 1H) 10.20 (s, 1H) 12.88-13.16 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[S:7][CH2:6][CH2:5][NH:4][C@H:3]1[C:8]([OH:10])=[O:9].[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[S:22](Cl)(=[O:24])=[O:23]>>[CH3:1][C:2]1([CH3:11])[S:7][CH2:6][CH2:5][N:4]([S:22]([C:13]2[CH:14]=[CH:15][C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:12]=2)(=[O:24])=[O:23])[CH:3]1[C:8]([OH:10])=[O:9]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: CC1(C)SCCN[C@H]1C(=O)O
Product: CC1(C)SCCN(S(=O)(=O)c2ccc3ccccc3c2)C1C(=O)O

Procedure:
Following typical sulfonylation conditions and method L, the title compound is prepared from (S)-2,2-dimethyl-thiomorpholine-3-carboxylic acid and naphthalene-2-sulfonyl chloride. LCMS (m/z): 381.2 (M+1), 379.3 (M−1), CHN: Calc CHN: 53.66, 5.30, 7.36. Found CHN: 593.51, 5.20, 7.07.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Br>CN(C)C=O>[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][N:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1
Reactant: Clc1ccccc1CBr
Reactant: OC1CCNCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: OC1CCN(Cc2ccccc2Cl)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
0.202 g (0.002 mol) of 4-hydroxypiperidine, 1.22 ml (0.0088 mol) of triethylamine and 0.43 g (0.0021 mol) of 2-chlorobenzyl bromide were dissolved in 5 ml of dimethylform-amide and stirred at room temperature for 2 hrs. The solvent was distilled off and the residue was taken up in dichloromethane and washed with saturated bicarbonate solution and sodium chloride solution. The organic phase was dried over sodium sulfate and concentrated. 0.28 g (62%) 1-(2-chloro-benzyl)-piperidin-4-ol was obtained as a colorless oil.
Reaction SMILES: C([O:8][C:9]1[C:10]([O:27][CH3:28])=[CH:11][C:12]([C:21]2[N:25]=[C:24]([CH3:26])[O:23][N:22]=2)=[C:13]([S:15]([N:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[CH:14]=1)C1C=CC=CC=1.Cl>[Ti](Cl)(Cl)(Cl)Cl.C(Cl)Cl>[OH:8][C:9]1[C:10]([O:27][CH3:28])=[CH:11][C:12]([C:21]2[N:25]=[C:24]([CH3:26])[O:23][N:22]=2)=[C:13]([S:15]([N:18]([CH3:20])[CH3:19])(=[O:16])=[O:17])[CH:14]=1
Reactant: COc1cc(-c2noc(C)n2)c(S(=O)(=O)N(C)C)cc1OCc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: COc1cc(-c2noc(C)n2)c(S(=O)(=O)N(C)C)cc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-benzyloxy-4-methoxy-N,N-dimethyl-2-(5-methyl-[1,2,4]oxadiazol-3-yl)benzenesulfonamide and methylene chloride (20 mL) was added titanium(IV) chloride (0.472 g) under ice-bath cooling. After stirring at room temperature overnight, 2 mol/L hydrochloric acid and methylene chloride were added to the mixture. The separated organic layer was washed with 2 mol/L hydrochloric acid and brine successively, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 10%-100% ethyl acetate/hexane, gradient elution) to give the title compound (121 mg).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[C:20]([C:26]([C:29]([NH:31]C(C)(C3C=CC=CC=3)C)=[O:30])=[CH:27][N:28]=2)[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:14][C@H:13]1[O:41][CH3:42])=[O:10]>C(O)(C(F)(F)F)=O>[NH2:31][C:29]([C:26]1[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][C:18]([N:15]2[CH2:16][CH2:17][C@H:12]([NH:11][C:9]([C:3]3[NH:4][C:5]([CH3:8])=[C:6]([Cl:7])[C:2]=3[Cl:1])=[O:10])[C@H:13]([O:41][CH3:42])[CH2:14]2)=[N:28][CH:27]=1)=[O:30]
Reactant: CCOC(=O)c1cc(N2CC[C@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@H](OC)C2)ncc1C(=O)NC(C)(C)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc(N2CC[C@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@H](OC)C2)ncc1C(N)=O
Yield: 73.2 %

Procedure:
A solution of 103 mg (0.17 mmol) of Cis(±)-ethyl 2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-5-{[(1-methyl-1-phenylethyl)amino]carbonyl} isonicotinate (Example 198) in 10 ml TFA was heated at 40° C. overnight and at 50° C. for 6 h. Solvent was removed and the residue was triturated with MeOH to give 62 mg of a white solid. MS (ES) MH+: 498 for C21H25Cl2N5O5.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1)(=[O:10])=[O:9].[C:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)#[N:19]>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([C:23]2[CH:24]=[CH:25][C:20]([C:18]#[N:19])=[CH:21][CH:22]=2)=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(NCCCCCO)c1ccc(Br)cc1
Reactant: N#Cc1ccc(B(O)O)cc1
Product: N#Cc1ccc(-c2ccc(S(=O)(=O)NCCCCCO)cc2)cc1

Procedure:
Using a method analogous to that described in Example 40, 4-bromophenyl-sulfonic acid-(5-hydroxypentyl)-amide and 4-cyanophenyl boronic acid were reacted to give the title compound as a white solid. δC (DMSO, 62.9 MHz): 22.6, 28.9, 32.0, 42.6, 60.5, 111.0, 118.7, 127.3 127.0, 127.9, 128.1, 133.0, 140.6, 141.9 and 143.1.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:12]([SH:28])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[O-]CC.[Na+].C(Br)C1C=CC=CC=1>C(O)C>[CH2:12]([S:28][CH2:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCCCCCCCCS
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: BrCc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCSCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89.5 %

Procedure:
A solution of 4-nitrobenzyl bromide in ethanol (150.0 g, 0.694 mol in 1.5 L) was brought to reflux. Separately, a solution of 1-hexadecanethiol in ethanol (231 mL, 0.691 mol in 1.5 L) was treated with sodium ethoxide in ethanol (258 mL, 0.691 mol of a 21% solution) over ten minutes, stirred at room temperature for 15 minutes, then warmed to dissolve the precipitate. This was then added to the benzyl bromide solution over twenty minutes, stirred at room temperature for two hours, then allowed to sit undisturbed overnight. The crystallized thioether was collected and combined with the product from a 230 mmol run. This light yellow solid was dissolved in CH2Cl2 (3 L), washed with water (1 L), then dried (Na2SO4), filtered, and spin-evaporated to give 324.5 g of 1 (89.5% yield). The material was a single spot by TLC (19:1 hexanes/EtOAc), and was suitable for further transformation.
Reaction SMILES: C1(O[C:8](=[O:19])[NH:9][C:10]2[S:11][C:12]([CH:15]3[CH2:18][CH2:17][CH2:16]3)=[CH:13][N:14]=2)C=CC=CC=1.[NH2:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]=[C:26]([CH3:31])[CH:25]=[CH:24]2>O1CCOCC1>[CH:15]1([C:12]2[S:11][C:10]([NH:9][C:8]([NH:20][C:21]3[CH:22]=[C:23]4[C:28](=[CH:29][CH:30]=3)[N:27]=[C:26]([CH3:31])[CH:25]=[CH:24]4)=[O:19])=[N:14][CH:13]=2)[CH2:16][CH2:17][CH2:18]1
Reactant: O=C(Nc1ncc(C2CCC2)s1)Oc1ccccc1
Reactant: Cc1ccc2cc(N)ccc2n1
Solvent: C1COCCO1
Product: Cc1ccc2cc(NC(=O)Nc3ncc(C4CCC4)s3)ccc2n1
Yield: 92.3 %

Procedure:
A solution of (5-cyclobutyl-thiazol-2-yl)-carbamic acid phenyl ester (Example 2; 35 mg, 0.128 mmol) and 6-amino-2-methyl-quinoline (50 mg, 0.128 mmol) in 1,4-dioxane (500 μl) were heated at about 70° C. for 24 hours. Purification by silica gel chromatography (1:3 hexanes-ethylacetate; 40:1→20:1 chloroform-methanol) and subsequent conversion to the HCl salt afforded 40 mg of the title compound. 1HNMR (400 MHz, CDCl3) δ 8.11(s,1H), 7.87 (s,7.88,1H), 7.85 (s,1H), 7.45 (d, J=7.6 Hz,1H), 7.16 (d, J=8.4 Hz, 1H), 6.94 (s,1H), 3.55 (m,1 H), 2.67 (s,3H), 2.35 (m,2H), 2.15-1.80 (m,4H). LRMS m/z (APCl+) 339.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([F:32])=[C:16]([N:19]4[CH2:23][CH2:22][CH:21]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]4)[CH:17]=3)[C:12](=[O:33])[N:11]([O:34]CC3C=CC=CC=3)[C:10]2=[O:42])=[CH:5][CH:4]=1>[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([F:32])=[C:16]([N:19]4[CH2:23][CH2:22][CH:21]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:29])[CH3:30])=[O:26])[CH2:20]4)[CH:17]=3)[C:12](=[O:33])[N:11]([OH:34])[C:10]2=[O:42])=[CH:5][CH:4]=1
Reactant: COc1ccc(-n2c(=O)n(OCc3ccccc3)c(=O)c3cc(F)c(N4CCC(NC(=O)OC(C)(C)C)C4)cc32)cc1
Agent: [Pd]
Product: COc1ccc(-n2c(=O)n(O)c(=O)c3cc(F)c(N4CCC(NC(=O)OC(C)(C)C)C4)cc32)cc1
Yield: 100.1 %

Procedure:
Using the General Method 6A, the reaction of 10% Pd/C (0.074 g) with 1-(4-methoxy phenyl)-6-fluoro-3-benzyloxy-7-(3-t-butoxycarbonylamino-pyrrolidin-1-yl)-1H-quinazoline-2,4-dione (Example Q-1, 0.222 g, 0.38 mmol) afforded 0.185 g of 1-(4-methoxyphenyl)-6fluoro-3-hydroxy-7-(3-t-butoxycarbonylamino-pyrrolidin-1-yl)-1H-quinazoline-2,4-dione as a solid.