Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:27]=1[B:28]1[O:32]C(C)(C)[C:30](C)(C)[O:29]1)[O:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[C:9]([O:15][CH2:16][CH2:17][O:18]C2CCCCO2)[N:8]=1)=O.[BH4-].[Na+].Cl>CO>[OH:32][B:28]1[C:27]2[CH:26]=[CH:25][C:5]([O:6][C:7]3[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[C:9]([O:15][CH2:16][CH2:17][OH:18])[N:8]=3)=[CH:4][C:3]=2[CH2:30][O:29]1
Reactant: CC1(C)OB(c2ccc(Oc3ccc(C#N)c(OCCOC4CCCCO4)n3)cc2C=O)OC1(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1ccc(Oc2ccc3c(c2)COB3O)nc1OCCO
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 6-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-2-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-nicotinonitrile (2.5 g, 5.15 mmol) in methanol (15 mL) at 0° C. was added sodium borohydride (0.38 g, 10.32 mmol). After 1 h at rt, the solution was cooled in an ice bath and 2M HCl was added until pH reached to 3-4. The resulting mixture was stirred at 0° C. for 2 h and then at room temperature for 30 min. The solvent was removed under reduced pressure purification was accomplished by reverse phase prep HPLC using CH3CN/H2O (0.1% AcOH) as the eluent to yield the title compound D99 (1.0 g, 40%) as white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.23 (s, 1H), 8.22 (d, J=8.2 Hz, 1H), 7.77 (d, J=8.2 Hz, 1H), 7.27 (s, 1H), 7.18 (d, J=8.2 Hz, 1H), 6.66 (d, J=8.6 Hz, 1H), 4.97 (s, 2H), 4.82 (t, 1H), 4.12 (t, J=4.9 Hz, 2H), 3.73-3.50 (m, 2H); MS (ES) m/z: 313 (M+1)+; HPLC purity 98.78% (Maxplot), 98.58% (220 nm).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([S:33][CH2:34][CH:35]3[O:39][CH2:38][CH2:37][O:36]3)[NH:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:16][CH:15]=1>ClCCl>[CH3:32][O:31][C:28]1[CH:27]=[CH:26][C:25]([C:24]2[N:23]=[C:22]([S:33]([CH2:34][CH:35]3[O:39][CH2:38][CH2:37][O:36]3)=[O:9])[NH:21][C:20]=2[C:17]2[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)=[CH:30][CH:29]=1
Reactant: COc1ccc(-c2nc(SCC3OCCO3)[nH]c2-c2ccc(OC)cc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(-c2nc(S(=O)CC3OCCO3)[nH]c2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.19 g (80%) of 3-chloroperbenzoic acid in 100 ml. of dichloromethane is added dropwise to a solution of 1.99 g. of [4,5-bis(4-methoxyphenyl)-2-imidazolyl]-(1,3-dioxolan-2-ylmethyl)sulfide in 150 ml. of dichloromethane. The mixture is stirred for 4 hours at room temperature, then washed with sodium bicarbonate solution; the organic solution is dried over sodium sulfate and concentrated under vacuum. The residue is crystallized from ethyl acetate/hexane. After recrystallization from ethyl acetate/hexane, 1.43 g. of [4,5-bis-(4-methoxyphenyl)-2-imidazolyl]-(1,3-dioxolan-2-ylmethyl)sulfoxide is obtained, m.p. 203°-204°.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(S(O[CH2:21][CH2:22][Cl:23])(=O)=O)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:21][CH2:22][Cl:23])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=S(=O)(OCCCl)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=[N+]([O-])c1ccc(OCCCl)cc1
Yield: 82.2 %

Procedure:
A mixture of 4-nitrophenol (139 g, 1 mole), 2-(benzenesulphonyloxy)ethyl chloride (220.5 g, 1 mole--see Ber. (1920), 53, 1836) and anhydrous potassium carbonate (138 g, 1 mole) in methyl ethyl ketone ("MEK"--1000 ml) was stirred at reflux for 16 hours. After cooling, the mixture was poured onto water and the organic layer was separated. Following two further extractions with methyl ethyl ketone, the combined organic fractions were dried (MgSO4), filtered and evaporated. The resultant solid was crystallised from ethanol to give the title compound, (165.8 g), m.p. 60°.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])=[CH:4][C:5]([O:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])=[C:6]([CH:8]=1)[NH2:7].C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[Br:1][C:2]1[C:3]([O:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])=[CH:4][C:5]([O:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])=[C:6]([NH:7][S:35]([CH3:34])(=[O:37])=[O:36])[CH:8]=1
Reactant: Nc1cc(Br)c(Oc2ccc(F)cc2F)cc1Oc1ccc(F)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cc(Br)c(Oc2ccc(F)cc2F)cc1Oc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.4 %

Procedure:
To the product from Example 13B (0.52 g, 1.214 mmol) and triethylamine (0.423 mL, 3.04 mmol) in dichloromethane (12.14 mL) was added dropwise methanesulfonyl chloride (0.207 mL, 2.67 mmol). The mixture was stirred for 2 hours at ambient temperature, and concentrated. The residue was dissolved in a mixture of dioxane (4 mL) and 1 M sodium hydroxide (1 mL) and heated for 1 hour at 90° C. The mixture was cooled and diluted with ethyl acetate, brought to pH 7 with 1 M HCl and the organic layer was separated, dried (anhydrous Na2SO4), filtered, and concentrated. Purification by chromatography (silica gel, 20-60% ethyl acetate in heptanes) afforded the title compound (0.5 g, 81%).
Reaction SMILES: [F:1][C@:2]12[C@@H:22]([OH:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][C@H:14]([CH3:26])[C@:15]3([OH:25])[C:16](=[O:19])[CH2:17][SH:18])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:28])[CH:4]=[CH:5][C:6](=[O:27])[CH:7]=1.[CH:29]([NH:31][C@H:32]([C:37](O)=[O:38])[CH2:33][CH2:34]SC)=[O:30]>>[F:1][C@:2]12[C@@H:22]([OH:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][C@H:14]([CH3:26])[C@:15]3([OH:25])[C:16](=[O:19])[CH2:17][S:18][C:37](=[O:38])[CH:32]([NH:31][CH:29]=[O:30])[CH2:33][CH3:34])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:28])[CH:4]=[CH:5][C:6](=[O:27])[CH:7]=1
Reactant: CSCC[C@H](NC=O)C(=O)O
Reactant: C[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CS
Product: CCC(NC=O)C(=O)SCC(=O)[C@@]1(O)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C
Yield: 43.9 %

Procedure:
The title compound (0.28 gm) was prepared from 9-fluoro-11β,17-dihydroxy-16β-methylpregna-1,4-diene-3,20-dione-21-thiol (0.5 gm) and N-formyl-L-methionine (0.76 gm) in the same manner as in Synthetic Example 1.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=O)[CH:4]=[C:3]1[S:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[S:25]([NH2:28])(=[O:27])=[O:26]>Cl[Ti](Cl)(Cl)Cl.C(N(CC)CC)C>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[N:28][S:25]([C:21]2[S:20][CH:24]=[CH:23][CH:22]=2)(=[O:27])=[O:26])[CH:4]=[C:3]1[S:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)CSC1=CC(=O)c2ccccc2C1=O
Reactant: NS(=O)(=O)c1cccs1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)CSC1=CC(=NS(=O)(=O)c2cccs2)c2ccccc2C1=O
Yield: 60.4 %

Procedure:
63 mg (0.228 mmoles) ethyl 2-(1,4-dioxo-1,4-dihydronaphthalen-2-ylthio)acetate (7a) was mixed with 37 mg (0.228 mmoles) thiophene-2-sulfonamide in 2.5 ml dichloromethylene, to which at 0° C. was added 76 mg TiCl4.2THF followed by 70 μl triethylamine. The mixture was heated at 60° C. with microwave synthesizer (Initiator 8, Biotage) for 20 min. Diluted with dichloromethylene to 60 ml, the reaction mixture was washed with H2O and brine and dried over Na2SO4. After removal of Na2SO4, the filtrate was concentrated and the residue was purified with flash column (EtOAc/Hexane) affording title compound 58 mg (60.4%) as orange oil which was solidified on standing, m.p.: 110-112° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[SH:10].[CH:11]1[C:16]([Cl:17])=[CH:15][C:14]([Cl:18])=[C:13]([CH2:19]Cl)[CH:12]=1.Cl>N1C=CC=CC=1>[Cl:18][C:14]1[CH:15]=[C:16]([Cl:17])[CH:11]=[CH:12][C:13]=1[CH2:19][S:10][C:3]1[C:4](=[O:9])[O:5][C:6]([CH3:8])=[CH:7][C:2]=1[OH:1]
Reactant: Cc1cc(O)c(S)c(=O)o1
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: Cl
Solvent: c1ccncc1
Product: Cc1cc(O)c(SCc2ccc(Cl)cc2Cl)c(=O)o1
Temperature: 90 °C
Yield: 56 %

Procedure:
4-Hydroxy-3-mercapto-6-methyl-2-pyrone (47.5 g., 0.300 mole) and α2,4-trichlorotoluene (58.6 g., 0.300 mole) were dissolved in pyridine (250 ml.). The temperature rose from 20° to 43°C. The solution was then heated at 90°C. for two hours, cooled and poured onto ice and 500 ml. of concd. hydrochloric acid. The resulting mixture was extracted with methylene chloride. The extract was dried (MgSO4) and the solvent removed by evaporation. The residue was mixed with hexane, filtered and dried, giving 53.3 g. (56 percent) of the desired product. Recrystallization from benzene gave the pure product as a white solid, m.p. 163°-164°C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:13]OS(C)(=O)=O)[CH2:10][CH:11]=[CH2:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:13][N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)[CH2:10][CH:11]=[CH2:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C=CCC(COS(C)(=O)=O)c1ccc(Cl)c(Cl)c1
Reactant: c1c[nH]cn1
Solvent: CC#N
Product: C=CCC(Cn1ccnc1)c1ccc(Cl)c(Cl)c1
Yield: 70.3 %

Procedure:
4-(3,4-Dichlorophenyl)-5-(methanesulphonyloxy)pent-1-ene (5.4 g) (see Preparation 23) and imidazole (3.6 g) were dissolved in anhydrous acetonitrile (40 ml) and the mixture heated under reflux for 100 hours. The solvent was removed under reduced pressure, the residue dissolved in dichloromethane and the solvent removed under reduced pressure. The residue was dissolved in dichloromethane (100 ml) and washed with sufficient aqueous sodium carbonate solution to ensure that the aqueous phase reached pH14. The two phases were separated and the aqueous phase extracted with dichloromethane (100 ml). The organic phases were combined and the solvent removed under reduced pressure to give a residue which was chromatographed on silica gel eluting with a solvent gradient of 100:0 changing to 98:2, by volume, dichloromethane:methanol, to give 4-(3,4-dichlorophenyl)-5-(imidazol-1-yl)pent-1-ene (3.45 g) as an orange oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[CH3:19][O:20][C:21]1[C:26]([O:27][CH3:28])=[C:25]([O:29][CH3:30])[CH:24]=[CH:23][C:22]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:22]3[CH:23]=[CH:24][C:25]([O:29][CH3:30])=[C:26]([O:27][CH3:28])[C:21]=3[O:20][CH3:19])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Reactant: COc1ccc(B(O)O)c(OC)c1OC
Product: CCCNC(=O)c1nnc2c(-c3ccc(OC)c(OC)c3OC)cccc2c1N
Yield: 92 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (106 mg, 0.34 mmol) and 2,3,4-trimethoxyphenyl boronic acid (206 mg, 0.97 mmol) were reacted to afford the title compound (124 mg, 92.1% yield) as a pale-yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.56 (br, 1H), 7.88 (dd, J=8.2 Hz, J′=1.5 Hz, 1H), 7.76 d, J=6.3 Hz, 1H), 7.69 (t, J=7.6 Hz, 1H), 7.09 (d, J=8.6 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 3.94 (s, 3H), 3.92 (s, 3H), 3.62 (s, 3H), 3.45 (q, J=6.7 Hz, 2H), 1.65 (m, J=7.2 Hz, 2H), 0.99 (t, J=7.4 Hz, 3H) MS APCI, m/z=397 (M+H) HPLC 1.70 min.
Reaction SMILES: [CH3:1][C@H:2]1[C:10]2[C:9]([N:11]3[C:31]4[C:26](=[C:27]([CH2:32][NH:33][C:34]5[N:39]=[CH:38][CH:37]=[CH:36][N:35]=5)[CH:28]=[CH:29][CH:30]=4)[C:13]4([CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]4)[CH2:12]3)=[N:8][CH:7]=[N:6][C:5]=2[CH2:4][CH2:3]1.[ClH:40]>>[ClH:40].[ClH:40].[CH3:1][C@H:2]1[C:10]2[C:9]([N:11]3[C:31]4[C:26](=[C:27]([CH2:32][NH:33][C:34]5[N:35]=[CH:36][CH:37]=[CH:38][N:39]=5)[CH:28]=[CH:29][CH:30]=4)[C:13]4([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]4)[CH2:12]3)=[N:8][CH:7]=[N:6][C:5]=2[CH2:4][CH2:3]1
Reactant: C[C@@H]1CCc2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4c(CNc5ncccn5)cccc43)c21
Agent: Cl
Product: C[C@@H]1CCc2ncnc(N3CC4(CCNCC4)c4c(CNc5ncccn5)cccc43)c21
Yield: 99 %

Procedure:
A solution of (R)-tert-butyl 1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-4-((pyrimidin-2-ylamino)methyl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (4 mg, 7.58 μmol) and HCl (50.0 μL; 4N in dioxane) was stirred at ambient temperature overnight. The solvent was removed to yield (R)—N-((1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methyl)pyrimidin-2-amine bishydrochloride as a solid (4.0 mg, 7.6 mmol, >99%). 1H NMR (400 MHz, CD3OD) δ 8.77 (s, 1H), 8.59 (br s, 2H), 7.99 (br d, J=6.6 Hz, 1H), 7.35 (t, J=8.2 Hz, 1H), 7.27 (d, J=7.8 Hz, 1H), 6.98 (t, J=5.1 Hz, 1H), 4.95 (d, J=3.12 Hz, 2H), 4.69 (d, J=10.2 Hz, 1H), 4.26 (d, J=10.5 Hz, 1H), 3.96-3.91 (m, 1H), 3.74-3.71 (m, 1H), 3.64-3.58 (m, 4H), 3.60-3.52 (m, 2H), 3.46 (m, 2H), 3.14-3.10 (m, 2H), 2.95-2.85 (m, 1H), 2.65-2.55 (m, 2H), 1.92 (d, J=12.9 Hz, 1H), 1.95-1.88 (m, 2H), 1.27 (m, 6H), 1.13 (d, J=5.9 Hz, 1H). LCMS (APCI+) M+H+ 428 (100%); Rt=2.49 min. HPLC purity at 254 nm >99%, Rt=1.84 min.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[Cl:8][C:9]1[C:10]([O:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([C:34]([F:37])([F:36])[F:35])[CH:28]=2)=[CH:11][C:12]([F:25])=[C:13]([CH:24]=1)[C:14](OC1C=CC(C)=CC=1)=[O:15].O>CC1CCCO1>[Cl:8][C:9]1[C:10]([O:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([C:34]([F:37])([F:35])[F:36])[CH:28]=2)=[CH:11][C:12]([F:25])=[C:13]([CH:24]=1)[C:14]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[O:15]
Reactant: Cc1ccc(OC(=O)c2cc(Cl)c(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2F)cc1
Reactant: CS(N)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CC1CCCO1
Solvent: O
Product: CS(=O)(=O)NC(=O)c1cc(Cl)c(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1F
Temperature: 65 °C
Reaction time: 1 h
Yield: 53.4 %

Procedure:
To a suspension of sodium hydride (7.39 g, 184.66 mmol) in 2-methyltetrahydrofuran (400 mL) at 0-5° C. was added methanesulphonamide (16.47 g, 173.12 mmol) and the mixture stirred for 1 hour and allowed to reach room temperature. 4-Methylphenyl 5-chloro-4-[4-chloro-3-(trifluoromethyl)phenoxy]-2-fluorobenzoate (Preparation 163, 53 g, 115.41 mmol) in 2-methyltetrahydrofuran (100 mL) was added and the reaction mixture heated at 65° C. for 6 hours and cooled. Water (250 mL) was charged to the stirred reaction mixture and the layers separated. The organic layer was further washed with 1M citric acid solution (200 mL) and concentrated under reduced pressure at 45° C. The resulting solid was stirred in tert butyl methyl ether (250 mL) at 50° C. for 1 hour, cooled to 0-5° C., filtered and dried to give the title compound as an off-white solid (27.5 g, 53%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[CH:12][CH:11]=1.[CH3:27][OH:28]>>[CH3:27][O:28][C:10]1([C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[CH:11]=[CH:12][C:13](=[N:16][S:17]([C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)(=[O:18])=[O:19])[CH:14]=[CH:15]1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(-c3nc4ccccc4s3)cc2)cc1
Reactant: CO
Product: COC1(c2nc3ccccc3s2)C=CC(=NS(=O)(=O)c2ccc(C)cc2)C=C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 73 %

Procedure:
To the the sulfonamide (0.1 g) dissolved in methanol (2 mL) was added BTIB (1.1 eq.) in one portion as a solid. The resulting suspension was stirred at room temperature for 5 hours. The precipitate formed was collected on a filter, washed with ice cold methanol (2 mL) and dried under vacuum to give the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH:10]=[C:9]([C:20]([O:22][CH3:23])=[O:21])[C:8]=2[C:24]([O:26][CH3:27])=[O:25])=[CH:3][CH:2]=1.[CH:28](I)([CH3:30])[CH3:29]>>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH:28]([CH3:30])[CH3:29])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH:10]=[C:9]([C:20]([O:22][CH3:23])=[O:21])[C:8]=2[C:24]([O:26][CH3:27])=[O:25])=[CH:3][CH:2]=1
Reactant: COC(=O)c1cc2cc(O)c(OC)cc2c(-c2ccncc2)c1C(=O)OC
Reactant: CC(C)I
Product: COC(=O)c1cc2cc(OC(C)C)c(OC)cc2c(-c2ccncc2)c1C(=O)OC

Procedure:
1-(4-Pyridyl)-2,3-bis(methoxycarbonyl)-6-hydroxy-7-methoxynaphthalene and isopropyl iodide are treated in the same manner as in Reference Example 117-(2) to give 1-(4-pyridyl)-2,3-bis(methoxycarbonyl)-6-isopropyloxy-7-methoxynaphthalene.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][C:9]#[N:10].Cl.[NH2:12][OH:13].C([O-])(=O)C.[Na+]>C(O)C.O>[OH:13][N:12]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][C:9]#[N:10]
Reactant: NO
Reactant: N#CCC1CCCCC1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#CCC1CCCCC1=NO

Procedure:
The product of Example 149 is reacted with hydroxylamine hydrochloride and sodium acetate in ethanol/water by the method of Example 1 to generate the title compound.
Reaction SMILES: Cl.[NH:2]1[CH:6]=[C:5]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16](=[O:20])[CH2:15][CH2:14][CH2:13]3)[N:4]=[CH:3]1.[CH3:21][C:22]1[S:26][C:25]([CH:27]=O)=[CH:24][CH:23]=1>[OH-].[K+].CCO>[NH:2]1[CH:6]=[C:5]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16](=[O:20])[C:15](=[CH:27][C:25]2[S:26][C:22]([CH3:21])=[CH:23][CH:24]=2)[CH2:14][CH2:13]3)[N:4]=[CH:3]1
Reactant: Cc1ccc(C=O)s1
Reactant: O=C1CCCc2cc(OCCc3c[nH]cn3)ccc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(C=C2CCc3cc(OCCc4c[nH]cn4)ccc3C2=O)s1
Yield: 53.1 %

Procedure:
According to the method of Example 34, 6-[2-(1H-imidazole-4-yl)-ethoxy]-3,4-dihydro-2H-naphthalen-1-one, monohydrochloride (0.313 g, 1.07 mmol) was reacted with 5-methyl-2-thiophene carboxaldehyde (0.142 g, 1.13 mmol) in 5 mL of 4% KOH in EtOH overnight to afford 0.207 g (44%) of the title compound as a bright orange solid, mp 69-70° C.: CI-MS m/e 364 (M+), 365 (M++1).
Reaction SMILES: C(OC([N:7]1[C@:11]2([C@@H:16]([F:17])[CH2:15][C@@H:14]3[C@H:12]2[C@H:13]3[C:18]([OH:20])=[O:19])[C:10](=[O:21])[O:9]C1)=O)C=C.[C:22]([O:30][CH2:31]Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[NH2:7][C@@:11]1([C:10]([OH:9])=[O:21])[C@@H:16]([F:17])[CH2:15][C@@H:14]2[C@H:12]1[C@H:13]2[C:18]([O:20][CH2:31][O:30][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:19]
Reactant: C=CCOC(=O)N1COC(=O)[C@]12[C@H]1[C@@H](C[C@@H]2F)[C@@H]1C(=O)O
Reactant: O=C(OCCl)c1ccccc1
Product: N[C@]1(C(=O)O)[C@H]2[C@@H](C[C@@H]1F)[C@@H]2C(=O)OCOC(=O)c1ccccc1
Yield: 35.1 %

Procedure:
(1S,2S,3S,5R,6S)-3′-((Allyloxy)carbonyl)-3-fluoro-5′-oxospiro[bicyclo[3.1.0]hexan-2,4′-oxazolidine]-6-carboxylic acid (A-1-2, 500 mg) and chloromethyl benzoate (712 mg) were treated in the same manner as in Example A-1 (3) and (4) to give the title compound (A-9, 198 mg) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4](Cl)[N:3]=1.[CH3:12][C@H:13]1[CH2:18][O:17][CH2:16][CH2:15][NH:14]1.CCN(C(C)C)C(C)C>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][C@@H:13]2[CH3:12])[N:3]=1
Reactant: Clc1nc(Cl)c2nc[nH]c2n1
Reactant: C[C@H]1COCCN1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1COCCN1c1nc(Cl)nc2[nH]cnc12
Temperature: 80 °C
Reaction time: 17 h
Yield: 75.9 %

Procedure:
A mixture of 2,6-dichloro-9H-purine (5.2 g, 27.51 mmol), (S)-3-methylmorpholine (3.30 g, 32.62 mmol) and DIPEA (5.0 mL, 28.71 mmol) in IMS (130 mL) were heated at 80° C. for 3 h then stirred at r.t. for 17 h. The resulting white precipitate was collected by filtration and the filtrate concentrated in vacuo to a reduced volume and the resulting precipitate also collected by filtration. Both batches of solid were combined in DCM and the organic phase washed with H2O and brine, then dried (MgSO4) and concentrated in vacuo affording the title compound as a white powder (5.3 g, 76%). LCMS (method H): RT 2.54 min [M+H]+ 254.1
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:9][CH2:8]1.C(=O)([O-])[O-].[K+].[K+].O>C(=O)([O-])[O-].[K+].[K+].ClCCl>[Cl:1][CH2:2][C:3]([NH:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:9][CH2:8]1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: NC1CCN(CCc2c[nH]c3ccccc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: O=C(CCl)NC1CCN(CCc2c[nH]c3ccccc23)CC1
Yield: 121.1 %

Procedure:
Chloroacetyl chloride (4.0 cm3, 50.18 mmol) was added dropwise to a vigorously stirred mixture of 4-amino-1-(2-[indol-3-yl]ethyl)piperidine (12.10 g, 49.8 mmol), potassium carbonate (7.0 g 50.72 mmol) water (100 cm3) and dichloromethane (300 cm3). After 3/4 hour more chloroacetyl chloride (0.5 cm3, 6.27 mmol) and potassium carbonate (0.5 g, 3.62 mmol) were added and stirring continued for a further 3/4 hour. The organic phase was separated, washed with water, dried over magnesium sulphate and evaporated to give 2-chloro-N-[1-[2-(1H-indol-3-yl)ethyl]-4-piperidinyl]acetamide (19.29 g crude)
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]1([C:18]([OH:20])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[Na+].[Na+]>CCOCC.O>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][C:12]2([C:18]([OH:20])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:7])=[CH:4][CH:3]=1
Reactant: NC1(C(=O)O)CCCCC1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: O=C(NC1(C(=O)O)CCCCC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 660.9 %

Procedure:
A solution of 25.0 g (15.8 mmol) of 4-fluorobenzoyl chloride in 30 ml of ether was added dropwise to a mixture solution of 22.6 g (15.8 mmol) of 1-aminocyclohexanecarboxylic acid and 25.0 g (23.7 mmol) of sodium carbonate in 100 ml of ether and 300 ml of water under ice-cooling, and the mixture was stirred at room temperature overnight. After the ether layer was separated, the aqueous layer was neutralized with concentrated hydrochloric acid under ice-cooling and the precipitated crystal was collected by filtration to obtain 27.7 g (66%) of the title compound.
Reaction SMILES: C([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3([OH:25])[CH2:22][C@@H:21]([CH3:23])[O:20][C@@H:19]([CH3:24])[CH2:18]3)[CH:14]=2)[CH2:9]1)C1C=CC=CC=1.[H][H]>>[CH2:9]1[C:10]2[C:15](=[CH:14][C:13]([C:17]3([OH:25])[CH2:22][C@@H:21]([CH3:23])[O:20][C@@H:19]([CH3:24])[CH2:18]3)=[CH:12][CH:11]=2)[CH2:16][NH:8]1
Reactant: C[C@@H]1CC(O)(c2ccc3c(c2)CN(Cc2ccccc2)C3)C[C@H](C)O1
Reactant: [H][H]
Product: C[C@@H]1CC(O)(c2ccc3c(c2)CNC3)C[C@H](C)O1

Procedure:
Prepared in analogy to Example A62(c) from (2S,6R)-4-(2-benzyl-2,3-dihydro-1H-isoindol-5-yl)-2,6-dimethyl-tetrahydro-pyran-4-ol and hydrogen. Brown oil. MS (m/e): 248.3 ([M+H]+, 100%).
Reaction SMILES: [C:1]1([C:7]2[C:12](=[O:13])[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:10][N:9]([OH:20])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NO.N1C=CC=[CH:25][C:24]1=[O:29].C(OC(=O)C)(=O)C>>[C:24]([O:20][N:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:12](=[O:13])[C:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:10]1)(=[O:29])[CH3:25]
Reactant: O=c1c(-c2ccccc2)cn(O)cc1-c1ccccc1
Reactant: O=c1cccc[nH]1
Agent: NO
Solvent: CC(=O)OC(C)=O
Product: CC(=O)On1cc(-c2ccccc2)c(=O)c(-c2ccccc2)c1

Procedure:
A 2.4 g. portion of 3,5-diphenyl-1-hydroxy-4(1H)-pyridone was made by the process of Example 23, using hydroxylamine as the aminating agent. The pyridone was added to 25 ml. of acetic anhydride and the mixture was heated on the steam bath for about 1 hour. The volatiles were then evaporated under vacuum, and the residue was washed with benzene and then recrystallized, first from benzene and then from chloroform-hexane. The yield was 2.1 g. of 1-acetoxy-3,5-diphenyl-4(1H)-pyridone, m.p. 197°-199° C.