Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([N:12]2[CH:16]=[C:15]([C:17]3[C:18]4[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:19]=4[N:20]=[CH:21][N:22]=3)[CH:14]=[N:13]2)[CH2:9][C:10]#[N:11])[CH:5]=[N:6][CH:7]=1.O1CCOCC1.CCN(C(C)C)C(C)C.[C:49]1([SH:55])[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>[C:49]1([S:55][C:2]2[CH:3]=[C:4]([CH:8]([N:12]3[CH:16]=[C:15]([C:17]4[C:18]5[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:19]=5[N:20]=[CH:21][N:22]=4)[CH:14]=[N:13]3)[CH2:9][C:10]#[N:11])[CH:5]=[N:6][CH:7]=2)[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: Sc1ccccc1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)c4cncc(Br)c4)c3)ncnc21
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)c4cncc(Sc5ccccc5)c4)c3)ncnc21
Yield: 80.1 %

Procedure:
To the 3-(5-bromopyridin-3-yl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (0.130 g, 0.000248 mol) from Example 429 Step 2, in dry 1,4-dioxane (1.60 mL, 0.0205 mol) was added DIPEA (0.085 mL, 0.00049 mol). The solution was degassed with nitrogen, followed by addition of (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.007 g, 0.00001 mol), is(dibenzylideneacetone)palladium(0) (0.0036 g, 0.0000062 mol), and benzenethiol (0.025 mL, 0.00025 mol). Again the solution was purged with nitrogen. The reaction mixture in a sealed tube was heated to reflux for 3 h. The reaction mixture was diluted with ethyl acetate, washed with water (2×), brine (1×), dried over magnesium sulfate, filtered, and the solvent was evaporated in vacuo. The crude product was triturated with hexane-ethyl acetate 9:1 to yield 3-[5-(phenylthio)pyridin-3-yl]-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (110 mg, 80%). LC/MS (M+H)+: m/z=554.2.
Reaction SMILES: [O-]CC.[Mg+2].[O-]CC.[C:8]([O:14][CH2:15][CH3:16])(=[O:13])[CH2:9][C:10]([OH:12])=O.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([O:27][CH3:28])=[C:22]([CH:26]=1)C(O)=O.C(N1C=CN=C1)(N1C=CN=C1)=O>C1COCC1>[Cl:17][C:18]1[CH:26]=[CH:22][C:21]([O:27][CH3:28])=[C:20]([C:10](=[O:12])[CH2:9][C:8]([O:14][CH2:15][CH3:16])=[O:13])[CH:19]=1
Reactant: CCOC(=O)CC(=O)O
Reactant: COc1ccc(Cl)cc1C(=O)O
Agent: CC[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Mg+2]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1cc(Cl)ccc1OC
Temperature: 45 °C
Reaction time: 20 h
Yield: 76.3 %

Procedure:
A 3000 mL 3-necked round-bottomed flask flushed with nitrogen was charged with magnesium ethoxide (67.46 g, 589.51 mmoles) and THF (1100 mL), and the resulting mixture was stirred as ethyl hydrogen malonate (162.26 g, 1.18 moles; 145.00 mL diluted in 100 ml of THF) was added and the mixture was heated at 45° C. for 4 hours. Meanwhile, a 2000 mL 3-necked round-bottomed flask flushed with nitrogen was charged with 5-chloro-2-methoxybenzoic acid (100 g, 536 mmoles) and THF (600 mL). To this mixture stirring at room temperature was added 1,1′-carbonyldiimidazole (95.59 g, 589.5 mmoles) in portions to avoid excess foaming. After stirring for 3 hours at room temperature the second solution was added gradually to the first solution. After addition the reaction mixture was heated to 45° C. After 20 hours, the reaction mixture was concentrated under reduced pressure before adding ethyl acetate (1 L) followed by 2 N HCl (500 mL). After mixing, the layers were separated and the organic phase was washed sequentially with 2 N HCl (500 mL), saturated sodium bicarbonate (500 mL), and water (500 mL). The organic phase was concentrated under reduced pressure, the residue taken up in ethyl acetate (1000 mL) and concentrated again to afford the title compound (104.94 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([NH:12][C:13]2[C:18]([NH2:19])=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:7][C:6]=1[Cl:20].[CH:22](OCC)(OCC)OCC>>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([N:12]2[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:18]3[N:19]=[CH:22]2)=[CH:7][C:6]=1[Cl:20]
Reactant: COC(=O)Cc1c(Cl)cc(Nc2ncccc2N)cc1Cl
Reactant: CCOC(OCC)OCC
Product: COC(=O)Cc1c(Cl)cc(-n2cnc3cccnc32)cc1Cl
Temperature: 25 °C
Reaction time: 13.5 h

Procedure:
A mixture of [4-(3-amino-pyridin-2-ylamino)-2,6-dichloro-phenyl]-acetic acid methyl ester (4.5 g, 13.8 mmol) and triethyl orthoformate (60 mL, 361 mmol, 26 equiv) is stirred for 13.5 h at reflux. The resulting mixture is allowed to cool to rt and concentrated in vacuo to provide the title compound as a dark solid: ES-MS: 336.0/338.0 [M+H]+; tR=4.58 min (System 1); Rf=0.28 (Hexane/EtOAc, 1:1).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([OH:8])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[CH2:12]([N:3]1[C:4]([CH3:10])([CH3:9])[CH2:5][CH:6]([OH:8])[CH2:7][C:2]1([CH3:11])[CH3:1])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC1(C)CC(O)CC(C)(C)N1
Reactant: BrCc1ccccc1
Solvent: CCO
Product: CC1(C)CC(O)CC(C)(C)N1Cc1ccccc1

Procedure:
A mixture of 31.4 parts of 2,2,6,6-tetramethylpiperidin-4-ol and 17.1 parts of benzyl bromide in 125 parts of ethyl alcohol was heated under reflux conditions for 96 hours. The cooled reaction mixture was filtered to remove 2,2,6,6-tetramethylpiperidin-4-ol hydrobromide formed during the reaction and the ethyl alcohol solvent was removed by distillation under reduced pressure. Purification of the residue by chromatography on a aluminia column using chloroform as the solvent gave 1-benzyl-2,2,6,6-tetramethylpiperidin-4-ol having a melting point of 151°-2°C and the following elemental analysis by weight
Reaction SMILES: [CH2:1]([NH:5][C:6]1[C:7]([CH3:22])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:24][C:25]1[CH:37]=[CH:36][C:28]([O:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:27]([CH3:38])[CH:26]=1.C(N(CC)C(C)C)(C)C>CC#N>[CH2:1]([N:5]([CH2:24][C:25]1[CH:37]=[CH:36][C:28]([O:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:27]([CH3:38])[CH:26]=1)[C:6]1[C:7]([CH3:22])=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:17]=2)[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)COc1ccc(CBr)cc1C
Reactant: CCCCNc1cccc(-c2ccc(C(F)(F)F)cc2)c1C
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.9 %

Procedure:
To a solution of N-butyl-N-[2-methyl-4′-(trifluoromethyl)-1,1′-biphenyl-3-yl]amine (102 mg, 0.33 mmol) in anhydrous MeCN (8 mL) under nitrogen at room temperature was added ethyl [4-(bromomethyl)-2-methylphenoxy]acetate (95.3 mg, 0.33 mmol) and N,N-diisopropyethylamine (57.8 μL, 0.33 mmol). The resultant solution was heated to reflux and stirred for 3 h. The reaction mixture was allowed to cool to room temperature and the solvent was removed in vacuo. The residue was partitioned between CHCl3 (2×10 mL) and water (10 mL). The organic solution was passed through a hydrophobic frit and the solvent was removed in vacuo. Purification by Biotage™ chromatography (40 g Silica column) eluted with 1:99–1:49 EtOAc:cyclohexane afforded the title compound as a colourless oil (110 mg).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([S:12](Cl)(=[O:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH3:16]>C(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([S:12](=[O:14])(=[O:13])[NH2:16])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)c1cccc2c(Cl)nccc12
Reactant: N
Solvent: ClCCl
Product: NS(=O)(=O)c1cccc2c(Cl)nccc12

Procedure:
A solution of 1-chloro-5-chlorosulphonylisoquinoline (613 mg, 2.34 mmol) in methylene chloride saturated with ammonia gas (20 mL) was stirred at RT for 18 h, concentrated in vacuo to a white solid and purified by column chromatography upon silica gel (preabsorbed) using EtOAc-hexanes (1:1) as eluant to give 1-chloro-5-sulphamoylisoquinoline as a white solid (206 mg, 0.85 mmol).
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[CH:12][C:5]2[N:6]=[C:7]([CH:9]([OH:11])[CH3:10])[O:8][C:4]=2[CH:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>>[C:9]([C:7]1[O:8][C:4]2[CH:3]=[C:2]([CH3:1])[CH:13]=[CH:12][C:5]=2[N:6]=1)(=[O:11])[CH3:10]
Reactant: Cc1ccc2nc(C(C)O)oc2c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Product: CC(=O)c1nc2ccc(C)cc2o1
Yield: 20 %

Procedure:
6-Methyl-2-(1-hydroxyethyl)benzoxazole as the starting material was reacted with pyridinium chlorochromate in the same manner as in Reference Example 1 (4) iii) to obtain 2-acetyl-6-methylbenzoxazole (yield, 20%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.[Cl:10][CH2:11][C:12](Cl)=[O:13].CCN(CC)CC>C(OCC)C>[Cl:10][CH2:11][C:12]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1)=[O:13]
Reactant: C=Cc1ccc(O)cc1
Reactant: O=C(Cl)CCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=Cc1ccc(OC(=O)CCl)cc1
Reaction time: 2 h
Yield: 91.5 %

Procedure:
To a solution of 4-hydroxystyrene (1.22 g, 10 mmol) in ethyl ether 140 mL was added chloroacetic chloride (2.26 g, 20 mmol) and Et3N (1.62 g, 16 mmol). After it was stirred for 2 h, the mixture was washed with brine and water. The ether solution was dried over Na2SO4 and concentrated. After purification by flash column, the 4-chloroacetoxystyrene (1.8 g, 92%) was obtained. Data are: 1H NMR (CDCl3, 300 MHz) δ 7.46 (d, 2H, J=1.8 Hz), 7.11 (d, 2H, J=8.4 Hz), 6.73 (dd, 1H, J=17.7 Hz), 5.74 (d, 1H, J=18 Hz), 5.29 (d, J=11.1 Hz), 4.31 (s, 2H). 13C NMR (CDCl3, 75 MHz) δ166.0, 150.0, 136.0, 135.8, 127.4, 121.3, 114.6, 41.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[F:35])[O:5][C:6]1([C:28]([OH:31])([CH3:30])[CH3:29])[CH2:11][CH2:10][CH2:9][N:8]2[C:12]([C:15]3[CH:16]=[CH:17][C:18]([C:22]4[O:26][C:25]([CH3:27])=[N:24][CH:23]=4)=[C:19]([OH:21])[CH:20]=3)=[N:13][N:14]=[C:7]12.C(=O)([O-])[O-].[K+].[K+].I[CH2:43][CH3:44].C(OCC)(=O)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[F:35])[O:5][C:6]1([C:28]([OH:31])([CH3:30])[CH3:29])[CH2:11][CH2:10][CH2:9][N:8]2[C:12]([C:15]3[CH:16]=[CH:17][C:18]([C:22]4[O:26][C:25]([CH3:27])=[N:24][CH:23]=4)=[C:19]([O:21][CH2:43][CH3:44])[CH:20]=3)=[N:13][N:14]=[C:7]12
Reactant: CCI
Reactant: Cc1ncc(-c2ccc(-c3nnc4n3CCCC4(Oc3ccc(F)c(F)c3)C(C)(C)O)cc2O)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1cc(-c2nnc3n2CCCC3(Oc2ccc(F)c(F)c2)C(C)(C)O)ccc1-c1cnc(C)o1
Reaction time: 8 h

Procedure:
To a mixture of 5-[8-(3,4-difluorophenoxy)-8-(1-hydroxy-1-methylethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-3-yl]-2-(2-methyl-1,3-oxazol-5-yl)phenol (41.1 mg) and potassium carbonate (24 mg) in DMF (0.43 ml) was added iodoethane (60 μL) at room temperature, and the mixture was stirred overnight. To the reaction mixture was added ethyl acetate, the mixture was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (38.1 mg).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:4]=2[CH:3]=[CH:2]1.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CCC(=O)C.O>[C:14]1([S:20]([N:1]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:4]=3[CH:3]=[CH:2]2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)c1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: COC(=O)c1cccc2c1ccn2S(=O)(=O)c1ccccc1
Reaction time: 5 h

Procedure:
A mixture of methyl indole-4-carboxylate (J. Org. Chem. 1980, 45, 3350) (5.0 g, 28.5 mmol), benzenesulphonyl chloride (10.1 g, 57.1 mmol) and anhydrous potassium carbonate (15.78 g, 114 mmol) in butan-3-one (150 ml) was refluxed under nitrogen for 15 hours. Additional benzenesulphonyl chloride (10.1 g) and anhydrous potassium carbonate (10.1 g) were added and refluxing was continued for 5 hours. The mixture was diluted with water (300 ml) and extracted with diethyl ether (3×300 ml). The combined organic solutions were dried (MgSO4) and concentrated to give a white solid which was recrystallised from ethanol (6.35 g, 72%); δH (360 MHz, CDCl3), 8.21 (1H, d, J=8.3 Hz, Ar—H), 7.96 (1H, dd, J=8.1 and 0.7 Hz, Ar—H), 7.87-7.84 (2H, m, Ar—H), 7.69 (1H, d, J=3.7 Hz, Ar—H), 7.56-7.33 (5H, m, Ar—H), 3.94 (3H, s, —OMe); m/z (CI) 316 (M++1).
Reaction SMILES: [CH3:1][C:2](=[O:6])[CH:3]=[CH:4][CH3:5].Cl[Mg][CH2:9][Si:10]([CH3:13])([CH3:12])[CH3:11]>C(OCC)C>[CH3:5][CH:4]([CH2:9][Si:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][C:2](=[O:6])[CH3:1]
Reactant: C[Si](C)(C)C[Mg]Cl
Reactant: CC=CC(C)=O
Solvent: CCOCC
Product: CC(=O)CC(C)C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
A solution of 8.00 g pent-3-en-2-one in 50 mL dry diethyl ether was dropped to a solution of 73.5 mL of chloro[(trimethylsilyl)methyl]magnesium (1.0M in diethyl ether) and 955 mg of CuBr at −5° C. under Argon. The mixture was stirred for 1 hour at room temperature. An aqueous work-up followed by silica gel chromatography yielded 5.20 g (43%) of a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[C:8](=[O:13])[CH2:7][CH2:6][CH2:5]2.[Cl:14]OC(C)(C)C>O1CCCC1>[NH2:1][C:2]1[C:3]([Cl:14])=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[C:8](=[O:13])[CH2:7][CH2:6][CH2:5]2
Reactant: CC(C)(C)OCl
Reactant: Cc1cc2c(cc1N)CCCC2=O
Solvent: C1CCOC1
Product: Cc1cc2c(c(Cl)c1N)CCCC2=O
Yield: 90 %

Procedure:
The product from Example 105 (0.175 g) was dissolved in tetrahydrofuran (5 ml) and was treated with t-butyl hypochlorite (0.12 ml). Following the procedure of Example 95 the desired product was obtained in 90% yield.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[C:21]2[CH2:22][CH2:23][N:24]([CH3:26])[CH2:25][C:20]=2[C:5]2[C:6]([OH:19])=[CH:7][C:8]([CH:10]([CH:12]([CH3:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:11])=[CH:9][C:4]=2[O:3]1.[ClH:28].[O:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][CH2:37][C:38](O)=[O:39])[CH2:31][CH2:30]1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[ClH:28].[CH3:27][C:2]1([CH3:1])[C:21]2[CH2:22][CH2:23][N:24]([CH3:26])[CH2:25][C:20]=2[C:5]2[C:6]([O:19][C:38](=[O:39])[CH2:37][CH2:36][CH2:35][N:32]3[CH2:31][CH2:30][O:29][CH2:34][CH2:33]3)=[CH:7][C:8]([CH:10]([CH:12]([CH3:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:11])=[CH:9][C:4]=2[O:3]1
Reactant: O=C(O)CCCN1CCOCC1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CN(C)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: CCCCCC(C)C(C)c1cc(OC(=O)CCCN2CCOCC2)c2c(c1)OC(C)(C)C1=C2CN(C)CC1

Procedure:
5,5-Dimethyl-10-hydroxy-8-(3-methyl-2-octyl)-2-methyl-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-d]pyridine, γ-morpholinobutyric acid hydrochloride and dicyclohexylcarbodiimide are combined in equimolar amounts in methylene chloride and reacted as in Example 1 to give the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.[C:19](Cl)(=[O:21])[CH3:20]>>[C:19]([N:16]1[CH2:15][CH2:14][N:13]([CH:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH2:7][CH2:8][CH2:9]2)[CH2:18][CH2:17]1)(=[O:21])[CH3:20]
Reactant: COc1ccc2c(c1)C(N1CCNCC1)CCC2
Reactant: CC(=O)Cl
Product: COc1ccc2c(c1)C(N1CCN(C(C)=O)CC1)CCC2

Procedure:
This compound was prepared from (7-methoxytetralin-1-yl)piperazine and acetyl chloride by the method described in Example 11 above (pale yellow oil, 58%). Calc'd for C17H24N2O2 : C, 69.93%; H, 8.43%; N, 9.60%. Found: C, 69.94%; H, 8.18%; N, 9.45%.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:12]([CH:13]([CH3:15])[CH3:14])=[CH:11][CH:10]=[CH:9][C:8]=1[CH:16]([CH3:18])[CH3:17].[CH:19](N1CCCCC1)=[O:20].Cl>CCCCCC.O1CCCC1>[CH:16]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([CH:13]([CH3:15])[CH3:14])[C:7]=1[CH:19]=[O:20])([CH3:18])[CH3:17]
Reactant: O=CN1CCCCC1
Reactant: CC(C)c1cccc(C(C)C)c1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)c1cccc(C(C)C)c1C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.2 %

Procedure:
6.8 ml of a 1.6M solution of butyllithium in hexane was added dropwise at -78° C. while stirring to a solution of 2.6 g of 2-bromo-1,3-diisopropylbenzene in 16 ml of tetrahydrofuran. The mixture was stirred at the same temperature for 30 minutes and thereafter treated with a solution of 1.3 g of N-formylpiperdine in 1.5 ml of tetrahydrofuran. Thereafter, the mixture was left to warm to room temperature over a period of 6 hours. The mixture was cooled to 0° C. and treated with 12 ml of 3N hydrochloric acid. The aqueous solution was extracted four times with diethyl ether and the combined organic extracts were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulphate and evaporated to dryness. The residue was chromatographed on silica gel with dichloromethane as the eluent and yielded 1.07 g of 2,6-diisopropylbenzaldehyde as an oil.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:21][CH:20]=1)[C:13]([C:35]1[CH:40]=[CH:39][C:38]([O:41]CC3C=CC=CC=3)=[CH:37][CH:36]=1)=[C:12]2[CH3:49])C1C=CC=CC=1>C1COCC1.CCO>[N:28]1([CH2:27][CH2:26][O:25][C:22]2[CH:21]=[CH:20][C:19]([CH2:18][N:14]3[C:15]4[C:11](=[CH:10][C:9]([OH:8])=[CH:17][CH:16]=4)[C:12]([CH3:49])=[C:13]3[C:35]3[CH:36]=[CH:37][C:38]([OH:41])=[CH:39][CH:40]=3)=[CH:24][CH:23]=2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Cc1c(-c2ccc(OCc3ccccc3)cc2)n(Cc2ccc(OCCN3CCCCCC3)cc2)c2ccc(OCc3ccccc3)cc12
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(-c2ccc(O)cc2)n(Cc2ccc(OCCN3CCCCCC3)cc2)c2ccc(O)cc12

Procedure:
A solution consisting of indole 44 (17.5g, 26.9 mmol) in THF/EtOH (1:1) was hydrogenated under an atmosphere of H2 using 10% Pd/C as a catalyst. Chromatography on silica gel CH2Cl2/MeOH (gradient from 100/0 to 85/15) yields the desired product as 8.5 g of white foam along with 2.5 g of a fraction containing small impurities. Although the free base is the material used in the next step (bis-glucuronidation), for purposes of characterization and enhancing the compounds shelf life an acid addition salt may be made with HCl by dissolving the compound in MeOH and treating with 1.1 eq of a 2 N aq HCl solution. The compound slowly precipitates out as white crystals. Physical data listed below describes the HCl salt of indole 45:
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.C([O-])(O)=O.[Na+]>C(OCC)(=O)C.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[O:9][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][CH:10]=1
Reactant: C1=COCCC1
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(COC2CCCCO2)cc1
Temperature: 25 °C
Yield: 96.3 %

Procedure:
To a solution of 4-nitrobenzylalcohol (50 g, 0.326 mol) in ethyl acetate (EtOAc) (200 ml) were added 3,4-dihydropyran (35.7 ml, 0.392 mol) and CSA (camphor sulfonic acid) (379 mg, 1.63 mmol) under stirring at room temperature, and the mixture was stirred at room temperature for 1 hour. After the reaction completed, the reaction mixture was neutralized with saturated NaHCO3 solution and separated ethyl acetate layer was dried with MgSO4 and concentrated under reduced pressure. The residue was purified with silica gel column chromatography to give 4-(2-tetrahydro-pyranyloxymethyl)nitrobenzene (74.5 g, 96%) as syrup.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([O:26][CH3:27])[C:23]([OH:25])=[O:24])=[CH:17][CH:16]=1)[CH:2]=[CH2:3]>C(OCC)(=O)C>[CH3:27][O:26][C@@H:22]([CH2:21][C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][CH2:12][CH2:11][O:10][C:9]2[CH:8]=[CH:7][C:6]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:5][C:4]=2[CH2:1][CH2:2][CH3:3])=[CH:20][CH:19]=1)[C:23]([OH:25])=[O:24]
Reactant: C=CCc1cc(-c2ccccc2)ccc1OCCCOc1ccc(CC(OC)C(=O)O)cc1
Solvent: CCOC(C)=O
Product: CCCc1cc(-c2ccccc2)ccc1OCCCOc1ccc(C[C@H](OC)C(=O)O)cc1

Procedure:
3-{4-[3-(3-Allyl-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionic acid from Example 158, Step D dissolved in ethyl acetate was treated with Pd(C) 10% under balloon pressure for 6 hours. Filtered through celite and concentrated to dryness to give the title compound.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[C:12]([OH:18])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:1]([O:18][C:12]1[CH:11]=[C:10]([Br:9])[CH:17]=[CH:16][C:13]=1[CH:14]=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1ccc(Br)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(Br)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
Benzyl bromide (1.35 ml) was added to a mixture of 4-bromo-2-hydroxybenzaldehyde (2.07 g) and potassium carbonate (1.38 g) in DMF (20 ml) and the mixture was stirred at ambient temperature for 10 hours. The reaction mixture was poured into water (50 ml) to give 2-benzyloxy-4-bromobenzaldehyde as a solid which was filtered and dried, yield 2.88 g. The material was used in subsequent reactions without purification.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][C@H:12]([NH2:16])[C:13]([OH:15])=[O:14])[C:4]2=[CH:3][CH:2]=1.[N:17]1([C:23](Cl)=[O:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>[OH-].[Na+].C([O-])([O-])=O.[Na+].[Na+]>[N:17]1([C:23]([NH:16][C@@H:12]([CH2:11][C:10]2[C:4]3[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=3)[CH:7]=[CH:8][CH:9]=2)[C:13]([OH:15])=[O:14])=[O:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: N[C@@H](Cc1cccc2ccccc12)C(=O)O
Reactant: O=C(Cl)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)[C@H](Cc1cccc2ccccc12)NC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.1 %

Procedure:
To a solution of L-1-naphthylalanine (215 mg, 1 mmol) (Peptech Corp.) in 5 mL 1N NaOH and 0.5 mL saturated Na2CO3 (resulting solution at pH 10) was added morpholine-4-carbonyl chloride (150 mg, 1.0 mmol) dissolved in 5 mL. Afterwards, the reaction mixture was stirred at room temperature for 2 h. The alkaline solution was extracted once with ether (10 mL) and the aqueous phase was acidified with 1N HCl. This was extracted twice with 20 mL EtOAc, and the combined organic phases were washed with 50 mL 1N HCl. The organic phase was dried over Na2SO4, filtered and evaporated to an oil, which solidifies to yields 125 mg (38%) of the desired material. This compound was used as such in the next step.
Reaction SMILES: N1C=CC=CC=1.Cl.[NH2:8][OH:9].[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][O:18][C:19]2[CH:33]=[CH:32][C:31]([CH:34]=O)=[CH:30][C:20]=2[C:21]([NH:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[O:22])=[CH:13][CH:12]=1>CO>[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][O:18][C:19]2[CH:33]=[CH:32][C:31](/[CH:34]=[N:8]\[OH:9])=[CH:30][C:20]=2[C:21]([NH:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[O:22])=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(OCc2ccc(F)cc2)c(C(=O)Nc2cccnc2)c1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: O=C(Nc1cccnc1)c1cc(/C=N\O)ccc1OCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Pyridine (0.69 ml, 8.56 mmol) and hydroxylamine hydrochloride (119 mg, 1.71 mmol) were added to a solution of 2-{[(4-fluorophenyl)methyl]oxy}-5-formyl-N-3-pyridinylbenzamide (may be prepared as described in Example 82; 300 mg, 0.86 mmol) in methanol (10 ml) and the mixture was stirred at room temperature for 30 min. The mixture was evaporated under reduced pressure to half volume. The mixture was diluted with water (20 ml) and filtered. The solid was washed with cold water (20 ml)/cold methanol (5 ml) and dried under vacuum to yield the title compound as a white solid. 220 mg.