Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([N+:43]([O-:45])=[O:44])[CH:38]=1>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][CH:2]2[O:1][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([N+:43]([O-:45])=[O:44])[CH:38]=2)=[CH:9][CH:10]=1
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2cccc([N+](=O)[O-])c2)cc1

Procedure:
Analogously to Method D, 1.0 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 0.417 g of 1-chloromethyl-3-nitrobenzene are used to obtain the title compound as a slightly yellowish oil. Rf=0.37 (1:2 EtOAc heptane); Rt=6.05.
Reaction SMILES: [OH:1][CH:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>ClCCl>[N:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH:2]([CH:3]1[CH2:7][CH2:6][CH2:5][NH:4]1)[OH:1]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(O)c1ccccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OC(c1ccccn1)C1CCCN1
Reaction time: 1 h

Procedure:
N-Boc-pyrrolidine (5.0 g) is dissolved in diethyl ether (60 mL) and the solution is cooled to −78° C. N,N,N′,N′-Tetramethylenediamine (TMEDA) (4.4 mL) is added to the mixture followed by sec-butyl lithium (27.0 mL, 1.3 M in cyclohexane) maintaining the temperature below −60° C. After 2 h, 2-pyridine carboxaldehyde (3.3 mL) is added and the mixture is stirred at −70° C. for an additional 30 min. The reaction mixture is allowed to warm to room temperature and is then quenched with water (25 mL) and poured into EtOAc (250 mL). The separated organic layer is washed with water (2×50 mL) followed by brine (50 mL), dried (Na2SO4), and concentrated. The crude product is purified by column chromatography (heptane/EtOAc, 4/1; 2/1, 1/1) to afford 4.79 g of tert-butyl 2-(hydroxy(pyridin-2-yl)methyl)pyrrolidine-1-carboxylate as a mixture of diastereomers. The resulting alcohol is dissolved in dichloromethane (10 mL) and trifluoroacetic acid (80 mL) is added with ice bathe cooling. After 1 h, the reaction mixture is concentrated and added to 1 N sodium hydroxide solution (200 mL). The mixture is extracted with CH2Cl2 (3×100 mL). The combined organic layers are dried (Na2SO4) and concentrated. The resulting oil is distilled in a Kugelrohr apparatus (175-200° C., 0.2 Torr) to afford 2.04 g of the title compound as a mixture of diastereomers. Physical characteristics. 1H NMR (400 MHz, DMSO-d6) δ 8.47, 7.76, 7.46, 7.24, 5.27, 4.50, 4.34, 3.32, 3.22, 2.83, 2.68, 1.62-1.36; MS (ESI+) m/z 179 (M+H)+.
Reaction SMILES: [C:1]([CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([CH2:34][CH2:35][CH3:36])[C:9]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH3:29])=[C:24]([OH:30])[C:23]=3[CH2:31][CH2:32][CH3:33])=[CH:10][CH:11]=2)[O:6]1)([O:3]C)=[O:2].[OH-].[Na+]>CO.O>[CH2:31]([C:23]1[C:24]([OH:30])=[C:25]([CH2:28][CH3:29])[CH:26]=[CH:27][C:22]=1[O:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][O:15][C:9]1[C:8]([CH2:34][CH2:35][CH3:36])=[C:7]2[C:12]([CH2:13][CH2:14][CH:5]([C:1]([OH:3])=[O:2])[O:6]2)=[CH:11][CH:10]=1)[CH2:32][CH3:33]
Reactant: CCCc1c(OCCCCCOc2ccc3c(c2CCC)OC(C(=O)OC)CC3)ccc(CC)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCc1c(OCCCCCOc2ccc3c(c2CCC)OC(C(=O)O)CC3)ccc(CC)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
1.26 g (2.5 mmole) of the methyl ester from Example 8 was dissolved in 25 ml of methanol in a single neck 100 ml round bottom flask. Next a solution of 202 mg (5 mmole) of sodium hydroxide in 10 ml water was added. The resulting mixture was stirred with the aid of a magnetic stirring bar for 2 hours at room temperature. The methanol was removed by rotary evaporation and the residue was acidified with dilute hydrochloric acid to pH 2. The acidified solution was extracted three times with 30 ml portions of ethyl acetate. The combined ethyl acetate extracts were dried over anhydrous magnesium sulfate, filtered and the ethyl acetate removed by rotoevaporation to furnish 1.16 g (95%) of the title compound, mp 101°-102°. Calc: C, 71.87; H, 8.32; Found: C, 71.71; H, 8.31.
Reaction SMILES: [CH2:1]([C:3]([OH:8])([CH2:6][CH3:7])[C:4]#[CH:5])[CH3:2].[CH3:9][O:10][C:11](=[O:45])[CH2:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([CH2:43][CH3:44])([C:28]3[CH:33]=[CH:32][C:31](OS(C(F)(F)F)(=O)=O)=[C:30]([CH3:42])[CH:29]=3)[CH2:26][CH3:27])=[CH:21][CH:20]=2)[CH:18]=1.C(=O)(O)[O-].[Na+]>C(N(CC)CC)C.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].[Cu]I>[CH3:9][O:10][C:11](=[O:45])[CH2:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([C:19]2[CH:20]=[CH:21][C:22]([C:25]([CH2:43][CH3:44])([C:28]3[CH:33]=[CH:32][C:31]([C:5]#[C:4][C:3]([CH2:6][CH3:7])([OH:8])[CH2:1][CH3:2])=[C:30]([CH3:42])[CH:29]=3)[CH2:26][CH3:27])=[CH:23][CH:24]=2)[CH:18]=1
Reactant: CCC(CC)(c1ccc(-c2cncc(CC(=O)OC)c2)cc1)c1ccc(OS(=O)(=O)C(F)(F)F)c(C)c1
Reactant: C#CC(O)(CC)CC
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: CCN(CC)CC
Product: CCC(O)(C#Cc1ccc(C(CC)(CC)c2ccc(-c3cncc(CC(=O)OC)c3)cc2)cc1C)CC
Temperature: 160 °C
Yield: 78.3 %

Procedure:
3-Ethyl-1-pentyn-3-ol (0.024 mL, 0.188 mmol), a [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II), dichloromethane complex (1:1) (10.6 mg, 0.013 mmol) and copper (I) iodide (2.5 mg, 0.013 mmol) were added to a solution of (5-{4-[1-ethyl-1-(3-methyl-4-trifluoromethanesulfonyloxy-phenyl)-propyl]-phenyl}-pyridin-3-yl)-acetic acid methyl ester (Example 144-(2); 67 mg, 0.125 mmol) in triethylamine (2 mL), and the mixture was stirred with microwave heating at 160° C. for three minutes. The reaction mixture was then poured into a saturated aqueous sodium bicarbonate solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=1:1) to give the target compound (48.7 mg, 78%).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13].[CH3:16][C:17]1[N:22]=[C:21]([SH:23])[N:20]=[C:19]([OH:24])[CH:18]=1.C(N(CC)CC)C>C(O)C>[Cl:9][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[C:3]=1[CH2:2][S:23][C:21]1[N:20]=[C:19]([OH:24])[CH:18]=[C:17]([CH3:16])[N:22]=1
Reactant: CCN(CC)Cc1cccc(Cl)c1CBr
Reactant: Cc1cc(O)nc(S)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCN(CC)Cc1cccc(Cl)c1CSc1nc(C)cc(O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.3 %

Procedure:
A mixture of {[2-(bromomethyl)-3-chlorophenyl]methyl}diethylamine (13.2 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (1.07 g, 7.5 mmol), and triethylamine (8 mL, 57.4 mmol) in absolute ethanol (50 mL) was stirred at room temperature overnight. The mixture was evaporated and then co-evaporated with EtOAc (20 mL). The solid residue was treated with water (100 mL), and the solution was extracted with dichloromethane (5×100 mL). The organic extracts were combined, dried over MgSO4, filtered, evaporated, and dried in vacuo. The crude product was purified by flash chromatography (0-15% MeOH/CH2Cl2), affording 2-[({2-chloro-6-[(diethylamino)methyl]phenyl}methyl)sulfanyl]-6-methylpyrimidin-4-ol (932 mg, 39% yield); 1H NMR (400 MHz, DMSO-d6): δ 0.96 (t, 6H, J=6.8 Hz), 2.21 (s, 3H), 2.86 (m, 4H), 4.69 (s, 2H), 6.01 (s 1H), 7.35 (m, 1H), 7.42 (m, 1H); M+352.
Reaction SMILES: [O:1]=[C:2]([NH:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])/[C:3](/[CH2:13][S:14][C:15](=[O:17])[CH3:16])=[CH:4]/[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1.B(F)(F)F.CCOCC>C(Cl)Cl>[O:1]=[C:2]([NH:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:22])/[C:3](/[CH2:13][S:14][C:15](=[O:17])[CH3:16])=[CH:4]\[C:5]1[CH:6]=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COc1ccc(/C=C(\CSC(C)=O)C(=O)NCCC(=O)OCc2ccccc2)cc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc(/C=C(/CSC(C)=O)C(=O)NCCC(=O)OCc2ccccc2)cc1
Yield: 52 %

Procedure:
4.93 g (11.5 mmol) of the (Z) diester obtained in Example 17 (step D) are dissolved in 100 ml of methylene chloride which has been passed over basic alumina. The solution is irradiated for 2.5 h using a Hanovia TQ 150 lamp after having added dropwise 1.53 ml of boron trifluoride etherate solution (11.5 mmol). The solution is then washed with 1N hydrochloric acid solution (twice 80 ml), with saturated sodiumhydrogen carbonate solution (twice 80 ml) and is dried over magnesium sulphate. After filtration and evaporation, 2.56 g of (E) isomer are recovered after flash chromatography. Yield=52% (after flash chromatography, eluent: ether/petroleum ether 65/35) m.p.<50° C. IR (nujol): 3290, 1740, 1690, 1630 cm -1 1H NMR (CDCl3): 7.35 to 7.05 (m, 7H; 6.75 (AB, 2H, J=8 Hz); 6.70 (s, 1H); 6.10 (t, 1H, J=5 Hz); 4.95 (s, 2H); 3.80 (s, 3H); 3.40 (q app, 2H, J app.=6 Hz); 2.45 (t, 2H, J=6 Hz); 2.25 (s, 3H). 13C NMR (CDCl3): 194.8, 171.6; 168.6; 159.4; 135.4; 132.0; 131.6; 129.8; 128.5; 128.2; 128.0; 127.2; 113.6; 66.2; 55.0; 34.6; 33.6; 33.2; 30.4 Microanalysis: C23H25O5NS Calc. % C=64.61 H=5.89 N=3.27 Found. % C=64.17 H=5.91 N=3.48
Reaction SMILES: C[C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][C:8]=3[C:9](=[O:11])[CH2:10][C:4]=2[CH:3]=1.[CH2:20](O)C.[BH4-].[Na+].O>CO>[CH3:20][C:19]1[CH:2]=[CH:3][C:4]2[CH2:10][CH:9]([OH:11])[C:8]3[CH:12]=[C:13]([S:16][CH3:17])[CH:14]=[CH:15][C:7]=3[O:6][C:5]=2[CH:18]=1
Reactant: CCO
Reactant: CSc1ccc2c(c1)C(=O)Cc1cc(C)ccc1O2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CSc1ccc2c(c1)C(O)Cc1ccc(C)cc1O2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
8.9 G. of 10,11-dihydro-2-methyl-8-methylthio-dibenz[b,f]oxepin-10-one are suspended in 65 ml. of ethanol and treated with a solution of 1.25 g. of sodium borohydride in 4.3 ml. of water. The mixture is stirred for 2 hours at room temperature. Then, 20 ml. of methanol are added thereto and the resulting mixture is heated at reflux for 15 minutes. Thereafter, the methanol and ethanol are removed by evaporation in vacuo. The residue is extracted with chloroform, the chloroform extracts are washed with water, dried and evaporated in vacuo. The residue is crystallized from diisopropyl ether, and there is obtained 10,11-dihydro-3-methyl-8-methylthio-dibenz[b,f]oxepin-10-ol having a melting point of 67°-69° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:26]=[CH:25][C:16]([CH2:17][S:18]([CH2:21][C:22](O)=[O:23])(=[O:20])=[O:19])=[CH:15][CH:14]=1>C(O)(=O)C>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][S:18]([C:21]2[C:22](=[O:23])[O:10][C:5]3[C:6]([CH:7]=2)=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=3)(=[O:19])=[O:20])=[CH:25][CH:26]=1
Reactant: O=Cc1cc(Br)ccc1O
Reactant: COc1ccc(CS(=O)(=O)CC(=O)O)cc1
Solvent: CC(=O)O
Product: COc1ccc(CS(=O)(=O)c2cc3cc(Br)ccc3oc2=O)cc1
Yield: 78 %

Procedure:
A solution of 5-bromosalicylaldehyde (1 mmol) and 2-(4-methoxybenzylsulfonyl)acetic acid (1 mmol) in acetic acid (10 mL) was subjected to the General Procedure 2, Method A to generate a 78% yield of the title compound; m.p. 231-232° C.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:20])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)=[CH:8][CH:7]=[C:6]([OH:19])[CH:5]=2.BrC1C(=O)C2C(C=1C1C=CC=CC=1)=CC=C(O)C=2.O[CH2:40][CH2:41][CH:42]1[CH2:47][CH2:46][N:45]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:44][CH2:43]1>>[Br:1][C:2]1[C:3](=[O:20])[C:4]2[C:9]([C:10]=1[C:11]1[CH:12]=[C:13]([F:18])[CH:14]=[C:15]([F:17])[CH:16]=1)=[CH:8][CH:7]=[C:6]([O:19][CH2:40][CH2:41][CH:42]1[CH2:43][CH2:44][N:45]([C:48]([O:50][C:51]([CH3:52])([CH3:54])[CH3:53])=[O:49])[CH2:46][CH2:47]1)[CH:5]=2
Reactant: O=C1C(Br)=C(c2cc(F)cc(F)c2)c2ccc(O)cc21
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(O)cc21
Product: CC(C)(C)OC(=O)N1CCC(CCOc2ccc3c(c2)C(=O)C(Br)=C3c2cc(F)cc(F)c2)CC1
Reaction time: 2 h

Procedure:
The procedure of Step 6 of Example 1 was repeated except for using 2-bromo-3-(3,5-difluorophenyl)-6-hydroxy-1H-inden-1-one obtained in Step 5 of Example 36 as a starting material instead of 2-bromo-6-hydroxy-3-phenyl-1H-inden-1-one, t-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate instead of 4-(2-hydroxyethyl)morpholine, being stirred for 2 h, and being purified by silica gel column chromatography (EtOAc/hexanes=1:3) to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([S:9][CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH3:11])[N:3]=1.C(#[N:20])C.[NH4+].[OH-]>O>[NH2:20][C:6]1[CH:7]=[C:2]([Cl:1])[N:3]=[C:4]([S:9][CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH3:11])[N:5]=1
Reactant: CC#N
Reactant: CC(Sc1nc(Cl)cc(Cl)n1)c1ccccn1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CC(Sc1nc(N)cc(Cl)n1)c1ccccn1
Temperature: 35 °C
Reaction time: 15 h
Yield: 94 %

Procedure:
A flask is charged with 4,6-dichloro-2-(1-(2-pyridyl)ethyl)thio-pyrimidine (0.560 g, 1.96 mmol), acetonitrile (6.5 ml) and 13 ml of 29 % NH4OH. The contents are stirred at 35° C. for 15 h, poured into 50 ml of water, extracted once with ethyl acetate. The organic layer is washed with a saturated solution of brine (1×30 ml), dried with anhydrous Na2SO4 and concentrated in vacuo. Chromatography is accomplished with 100 g of silica gel, packed and eluted with ethyl acetate-hexane (2:3), to yield 0.491 g (94%) of 4-amino-6-chloro-2-(1-(2-pyridyl)ethyl)thio-pyrimidine.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([Cl:7])[CH3:6])=[O:3].[N+:8]([O-:22])([O:10][C@@H:11]([C@H:13]([O:18][N+:19]([O-:21])=[O:20])[CH2:14][CH2:15][CH2:16][OH:17])[CH3:12])=[O:9].N1C=CC=CC=1>ClCCl>[C:2](=[O:3])([O:4][CH:5]([Cl:7])[CH3:6])[O:17][CH2:16][CH2:15][CH2:14][C@@H:13]([O:18][N+:19]([O-:21])=[O:20])[C@H:11]([O:10][N+:8]([O-:22])=[O:9])[CH3:12]
Reactant: C[C@@H](O[N+](=O)[O-])[C@@H](CCCO)O[N+](=O)[O-]
Reactant: CC(Cl)OC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(Cl)OC(=O)OCCC[C@@H](O[N+](=O)[O-])[C@@H](C)O[N+](=O)[O-]
Reaction time: 16 h

Procedure:
1-Chloroethyl chloroformate (1.55 mL, 14.2 mmol) was added dropwise to a stirred dichloromethane (50 mL) solution of (2R,3R)-6-hydroxyhexane-2,3-diyl dinitrate (intermediate 1, 2.60 g, 11.6 mmol), followed by pyridine (1.20 mL, 14.8 mmol). After 16 hours, the reaction mixture was concentrated in vacuo, and the residue was purified by column chromatography on silica gel, eluting with 5-25% ethyl acetate/hexanes to give the title compound as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 6.41 (q, J=5.7 Hz, 1H), 5.18-5.28 (m, 2H), 4.18-4.32 (m, 2H), 1.83 (d, J=5.7 Hz, 3H), 1.68-1.90 (m, 4H), 1.42 (d, J=6.4 Hz, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:22][S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1.Cl.[NH2:34][CH2:35][C:36]([NH2:38])=[O:37].C([O-])([O-])=O.[K+].[K+]>C(O)CCC>[F:32][C:28]1[CH:27]=[C:26]([S:23]([NH:22][C:18]2[CH:17]=[C:16]([C:9]3[N:10]=[C:11]([CH:13]([CH3:15])[CH3:14])[S:12][C:8]=3[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:34][CH2:35][C:36]([NH2:38])=[O:37])[N:7]=3)[CH:21]=[CH:20][CH:19]=2)(=[O:25])=[O:24])[CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3cccc(F)c3)c2)c(-c2ccnc(Cl)n2)s1
Reactant: NCC(N)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3cccc(F)c3)c2)c(-c2ccnc(NCC(N)=O)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Example 86, Step B using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]phenyl}-3-fluorobenzenesulfonamide (100 mg, 0.20 mmol) and glycinamide hydrochloride (225 mg, 2.0 mmol) and K2CO3 (566 mg, 4.0 mmol) in 1-butanol (5 mL) the title compound was obtained as a white powder (29 mg, 27.6% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.51 (s, 1H), 8.02 (d, J=5.1 Hz, 1H), 7.57-7.65 (m, 2H), 7.48-7.53 (m, 2H), 7.33 (t, J=7.8 Hz, 1H), 7.19-7.22 (m, 4H), 6.04 (s, 1H), 3.23-3.30 (m, 1H), 2.76 (s, 3H), 1.36 (d, J=6.7 Hz, 6H). MS (ESI): 527.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:15][C@H:14]([NH:16][S:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH2:13][C@H:12]2/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][C:32](OC)=[O:33])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:15][C@H:14]([NH:16][S:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH2:13][C@H:12]2/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][CH2:32][OH:33])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)CCC/C=C\[C@@H]1C[C@@H](NS(=O)(=O)c2ccc(Cl)cc2)CN1S(=O)(=O)c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=S(=O)(N[C@@H]1C[C@@H](/C=C\CCCCO)N(S(=O)(=O)c2ccc(Cl)cc2)C1)c1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 73.7 %

Procedure:
To a solution of (2S,4R)-1-(4-chlorophenylsulfonyl)-4-(4-chlorophenylsulfonylamino)-2-[(Z)-5-methoxycarbonyl-1-pentenyl]pyrrolidine 500 mg) in dry tetrahydrofuran (20 ml) was added lithium aluminum hydride (34 mg) under ice bath cooling. After the mixture was stirred in an ice bath for 30 minutes, aqueous tetrahydrofuran was added thereto and the mixture was filtered through Celite. The filtrate was washed successively with water and brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was solidified with ether to give (2S,4R)-1-(4-chlorophenylsulfonyl)-4-(4-chlorophenylsulfonylamino)-2-[(Z)-6-hydroxy-1-hexenyl]pyrrolidine (350 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[C:7]2[C:12]([C:13]=1[CH:14]=[O:15])=[CH:11][CH:10]=[C:9]([O:16][CH3:17])[CH:8]=2)=[O:4].CC(=CC)C.[O-:30]Cl=O.[Na+]>CC(O)(C)C.O1CCOCC1.O>[CH3:17][O:16][C:9]1[CH:8]=[C:7]2[C:12]([C:13]([C:14]([OH:30])=[O:15])=[C:5]([C:3]([O:2][CH3:1])=[O:4])[N:6]2[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:11][CH:10]=1
Reactant: COC(=O)c1c(C=O)c2ccc(OC)cc2n1Cc1ccccn1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CC(C)(C)O
Product: COC(=O)c1c(C(=O)O)c2ccc(OC)cc2n1Cc1ccccn1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
General Procedure K. To a suspension of methyl3-formyl-6-methoxy-1-(pyridin-2-ylmethyl)-1H-indole-2-carboxylate (Compound 91, 1.64 g, 5.07 mmol) in t-BuOH (120 ml) and dioxane (20 ml) was added 2-methyl-2-butene (25 ml) and a solution of NaH2PO4 (7.3 g, 61 mmol) and NaClO2 (80%, 5.7 g, 50.7 mmol) in H2O (100 ml). The reaction was stirred at room temperature for 6 h, extracted with EtOAc (×2). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→100% EtOAc-hexanes) to yield the title compound as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C@@H:11]([CH2:42][C:43]([OH:45])=O)[CH2:10]2)=[CH:5][CH:4]=1.Cl.[CH3:47][NH:48][O:49][CH3:50]>>[CH3:50][O:49][N:48]([CH3:47])[C:43](=[O:45])[CH2:42][C@H:11]1[CH2:10][C@H:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C@@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]3[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=3[CH:31]=2)[CH2:13][N:12]1[S:32]([C:35]1[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][CH:40]=1)(=[O:34])=[O:33]
Reactant: CNOC
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CC(=O)O)C[C@@H]3c3ccc(OC)cc3)cc21
Agent: Cl
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CC(=O)N(C)OC)C[C@@H]3c3ccc(OC)cc3)cc21

Procedure:
According to general procedure D, 0.79 g of [(2R,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-acetic acid (from example 25f) are reacted with N,O-dimethylhydroxylamine hydrochloride to afford the title compound as a colourless foam. Rf=0.44 (EtOAc-heptane 5:1); Rt=5.00.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[CH:5]2.[CH3:12][O:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:19]1[CH:20]=[CH:21][C:16]([O:15][CH2:14][O:13][CH3:12])=[CH:17][CH:18]=1)[C:6]([CH3:11])=[CH:5]2
Reactant: COCOc1ccc(I)cc1
Reactant: Cc1cc2cc(Br)ccc2[nH]1
Product: COCOc1ccc(-n2c(C)cc3cc(Br)ccc32)cc1
Yield: 8.4 %

Procedure:
5-Bromo-2-methylindole (5.59 g, 23.8 mmol) and 4-methoxymethyloxy iodobenzene (7.47 g, 23.8 mmol), were reacted according to the procedure used in Example 1a above to afford a colorless liquid (8.4%): 1H NMR (DMSO-d6): δ 2.23 (3H, s), 3.43 (2H, s), 5.26 (2H, s), 6.39 (1H, s), 6.94 (1H, d, J=8.7 Hz), 7.01 (1H, dd, J=2.2 Hz, J=8.6 Hz), 7.20 (2H, d, J=8.6 Hz), 7.34 (2H, d, J=8.6 Hz), 7.53 (1H, d, J=2.2 Hz); MS m/z (M+H)+ 346/348 (1 Br). Anal. for C17H16BrN02: Calc'd: C, 58.98; H, 4.66; N, 4.05. Found: C, 58.72; H, 4.53; N, 4.17.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][C:6]=2[CH:14]=1.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[C:19]([F:31])=[CH:18][N:17]=1>>[Cl:30][C:25]1[CH:24]=[C:23]([NH:22][C:20]2[C:19]([F:31])=[CH:18][N:17]=[C:16]([NH:1][C:2]3[CH:3]=[CH:4][C:5]4[O:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][C:6]=4[CH:14]=3)[N:21]=2)[CH:28]=[CH:27][C:26]=1[Cl:29]
Reactant: COC(=O)c1cc2cc(N)ccc2o1
Reactant: Fc1cnc(Cl)nc1Nc1ccc(Cl)c(Cl)c1
Product: COC(=O)c1cc2cc(Nc3ncc(F)c(Nc4ccc(Cl)c(Cl)c4)n3)ccc2o1

Procedure:
In like manner to the preparation of N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine, the reaction of 5-amino-2-methoxycarbonylbenzofuran with 2-chloro-N4-(3,4-dichlorophenyl)-5-fluoro-4-pyrimidineamine gave N4-(3,4-dichlorophenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.70 (bs, 1H), 9.50 (bs, 1H), 8.20 (d, 1H, J=4.5 Hz), 8.09 (m, 1H), 7.80 (m, 3H), 7.62 (m, 2H), 7.53 (m, 1H), 7.38 (m, 1H), 3.88 (s, 3H); LCMS: purity: 94%; MS (m/e): 448 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([CH2:14][OH:15])[C@H:10]([O:16][CH2:17][O:18][CH3:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([CH:14]=[O:15])[C@H:10]([O:16][CH2:17][O:18][CH3:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1C=O
Reaction time: 1 h
Yield: 116.3 %

Procedure:
To a stirred solution of (±)-trans-4-hydroxymethyl-3-methoxymethoxy-piperidine-1-carboxylic acid tert-butyl ester (Example 36, 2.17 mmol, 0.75 g) in anhydrous DCM (5 mL) at room temperature was added 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (4.35 mmol, 1.85 g). The reaction was stirred for 1 hour. The reaction mixture was pre-absorbed on 6.5 g SiO2 and purified on 40 g SiO2 cartridge using a 20-40% ethyl acetate/hexanes gradient to give (±)-trans-4-formyl-3-methoxymethoxy-piperidine-1-carboxylic acid tert-butyl ester (0.69 g).