Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@:2]1([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:6][C:5](=[O:7])[N:4]([C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:9])[CH2:3]1.CI.[H-].[Na+].[C:28](O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[CH3:28][N:16]([C@@:2]1([CH3:1])[CH2:6][C:5](=[O:7])[N:4]([C@@H:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH3:9])[CH2:3]1)[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: C[C@H](c1ccccc1)N1C[C@@](C)(NC(=O)OC(C)(C)C)CC1=O
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: C[C@H](c1ccccc1)N1C[C@@](C)(N(C)C(=O)OC(C)(C)C)CC1=O
Reaction time: 1 h
Yield: 96 %

Procedure:
Tert-Butyl {(3S)-3-methyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidin-3-yl}carbamate (I-343) (4.08 g, 12.8 mmol) and methyl iodide (1.20 ml, 19.2 mmol) were dissolved in N,N-dimethylformamide (120 ml), and with cooling with ice, sodium hydride (55% w/w) (671 mg, 15.4 mmol) was added, followed by stirring for 1 hour with cooling with ice. With cooling with ice, aqueous 10% citric acid solution was added to the reaction liquid, followed by concentration under reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate, then the insoluble was separated by filtration, and the residue obtained by concentration was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=2:1→1:4, v/v) to obtain tert-butyl methyl-{(3S)-3-methyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidin-3-yl}carbamate (4.09 g, 96%) as a colorless oily substance.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[CH:5][CH:4]=[N:3]1.CN1C=CC(C2C=CN=CC=2)=N1.[Br:25]Br.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.ClCCl>[Br:25][C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1
Reactant: Cn1nccc1-c1ccncc1
Reactant: BrBr
Agent: Cn1ccc(-c2ccncc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Cn1ncc(Br)c1-c1ccncc1
Reaction time: 5 h
Yield: 73 %

Procedure:
To a 3.8:1 isomer mix of 4-(1-methyl-1H-pyrazole-5-yl)pyridine and 4-(1-methyl-1-H-pyrazole-3-yl)pyridine (0.30 g) in 5 mL chloroform cooled in ice, was added a solution of 104 μL bromine in 3 mL chloroform. After 5 h, the mixture was treated with excess saturated aqueous sodium bicarbonate and diluted with dichloromethane. The dichloromethane was washed with 3 portions of saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and evaporated to yield 0.39 g crude product as a brown oil. The crude product was purified by chromatography, eluting with 15:1 ethyl acetate-methanol. Fractions containing the major component were combined to afford 0.17 g (73% yield) of a colorless oil. 1H NMR (CDCl3) was consistent with the desired structure. LC/MS indicated one major product with a M+1 molecular ion of m/z 240.3 by positive ESI.
Reaction SMILES: [Si]([O:18][CH2:19][C@@H:20]([N:23]1[C@H:28]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[C@@H:27]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[CH2:26][C@@:25]([CH2:44][C:45]([OH:47])=[O:46])([CH3:43])[C:24]1=[O:48])[CH2:21][CH3:22])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:49][Si](C=[N+]=[N-])(C)C.C(OCC)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CO.C1C=CC=CC=1.C1COCC1>[Cl:42][C:38]1[CH:37]=[C:36]([C@@H:27]2[C@@H:28]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[N:23]([C@@H:20]([CH2:21][CH3:22])[CH2:19][OH:18])[C:24](=[O:48])[C@:25]([CH2:44][C:45]([O:47][CH3:49])=[O:46])([CH3:43])[CH2:26]2)[CH:41]=[CH:40][CH:39]=1
Reactant: CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CO
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CC[C@@H](CO)N1C(=O)[C@@](C)(CC(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1

Procedure:
A solution of 2-((3R,5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid (Example 185) in MeOH (2 mL) and benzene (8 mL) was stirred with (trimethylsilyl)diazomethane, 2.0 M in diethyl ether (2.02 mL, 4.04 mmol) at rt for 0.5 h. After that time the mixture was concentrated to give the crude methyl ester, which was treated with TBAF in THF at rt for 30 h. The mixture was concentrated and purified by chromatography on silica gel (0 to 100% EtOAc in hexanes) to give the title compound. Mass Spectrum (ESI) m/z=478 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1[N:18]=[CH:17][C:16]([C:19]2([CH2:25][NH2:26])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[CH:15][N:14]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:26][CH2:25][C:19]1([C:16]2[CH:17]=[N:18][C:13]([CH3:12])=[N:14][CH:15]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:6]
Reactant: Cc1ncc(C2(CN)CCOCC2)cn1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: Cc1ncc(C2(CNC(=O)c3cccc(Cl)c3Cl)CCOCC2)cn1

Procedure:
From 2,3-dichlorobenzoic acid and (4-(2-methylpyrimidin-5-yl)tetrahydro-2H-pyran-4-yl)methanamine. LCMS (MH+): m/z=380.1, tR (minutes, Method F)=1.80
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[C:19]([NH2:24])[CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:25]#[C:26]Br>CO.C(#N)C>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]3=[N:23][C:26](=[NH:25])[N:24]=[C:19]3[CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(OCCN2CCC(Cc3ccccc3)CC2)cc1N
Reactant: N#CBr
Solvent: CO
Solvent: CC#N
Product: N=C1N=c2ccc(OCCN3CCC(Cc4ccccc4)CC3)cc2=N1
Temperature: 25 °C
Reaction time: 24 h
Yield: 80 %

Procedure:
To a solution of 4-benzyl-1-[(3,4-diaminophenoxy)ethyl]piperidine (202 mg, 0.62 mmol) in MeOH (1.5 mL) was added 130 μL of 5.0 M solution of cyanogen bromide in acetonitrile. The resulting mixture was stirred at r.t. under N2 for 24 h, then evaporated, and the residue was purified by chromatography over silica gel (CHCl3 --MeOH, 4:1) to give 174 mg (80%) of the title compound as a viscous oil. 1H NMR (CDCl3): 1.35-1.46 (m, 2H), 1.50-1.67 (m, 3H), 2.04-2.12 (m, 2H), 2.539 (d, 2H, J=7), 2.773 (t, 2H, J=6), 3.00-3.03 (m, 2H), 3.50 (bs, 1H), 4.035 (t, 2H, J=6), 6.243 (dd, 1H, J=8; 3), 6.317 (d, 1H, J=3), 6.614 (d, 1H, J=8), 7.12-7.30 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([OH:15])=O.[CH3:16][CH:17]1[CH2:22][CH:21]([CH3:23])[CH2:20][NH:19][CH2:18]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([N:19]1[CH2:20][CH:21]([CH3:23])[CH2:22][CH:17]([CH3:16])[CH2:18]1)=[O:15]
Reactant: O=C(O)c1cnoc1-c1ccccc1Cl
Reactant: CC1CNCC(C)C1
Product: CC1CC(C)CN(C(=O)c2cnoc2-c2ccccc2Cl)C1

Procedure:
The title compound was prepared from 5-(2-chlorophenyl)isoxazole-4-carboxylic acid (11.2 mg, 0.050 mmol) and 3,5-dimethylpiperidine (6.8 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (2.1 mg). Calcd for C17H19ClN2O2: 318.1135, found 318.1136.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH2:18])=[S:17])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Br[CH:20]1[C:25](=O)[CH:24]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[C:29]([C:34]([F:37])([F:36])[F:35])[CH:28]=2)[CH2:23][CH2:22][CH2:21]1>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[S:17][C:22]3[CH2:21][CH2:20][CH2:25][CH:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[C:29]([C:34]([F:35])([F:37])[F:36])[CH:28]=4)[C:23]=3[N:18]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: Cc1ccc(C2CCCC(Br)C2=O)cc1C(F)(F)F
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Solvent: CCO
Product: COc1cc(Nc2nc3c(s2)CCCC3c2ccc(C)c(C(F)(F)F)c2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 17 %

Procedure:
A suspension of [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (52 mg, 0.20 mmol) and of crude 6-bromo-2-(4-methyl-3-trifluoromethyl-phenyl)-cyclohexanone (70 mg, 0.21 mmol) in ethanol (2 mL) was heated to reflux under an atmosphere of nitrogen for 2 days. After cooling to room temperature the solvent was evaporated under reduced pressure and the residue was purified by reversed preparative HPLC using acetonitril/water (0.1% formic acid) to yield the title compound (17 mg, 15%) as a pale-brown oil. MS ISP (m/e): 499.0 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.64 (s, 1H), 7.42 (s, 1H), 7.33 (s, 1H), 7.20 (s, 2H), 7.09 (d, 1H), 6.82 (s, 1H), 6.65 (d, 1H), 4.04 (m, 1H), 3.52 (s, 3H), 2.77 (m, 2H), 2.44 (s, 3H), 2.29 (s, 3H), 2.22 (m, 1H), 1.78-2.03 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10](C(=O)C)[CH2:9][CH2:8]2>Cl>[CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH2:9][CH2:8]2
Reactant: COC(=O)Cc1ccc2c(c1)CCN2C(C)=O
Agent: Cl
Product: COC(=O)Cc1ccc2c(c1)CCN2
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.3 %

Procedure:
A suspension of (1-acetyl-2,3-dihydro-1H-indol-5-yl)-acetic acid methyl ester (0.60 g) in 2M hydrochloric acid (15 ml) was heated under reflux for 5 h. The mixture was evaporated to dryness. The residue was dissolved in methanol (20 ml) and treated with concentrated sulphuric acid (5 drops). The solution was stirred at room temperature for one hour, then concentrated. The residue was partitioned between ethyl acetate and sodium carbonate solution. The organic phase was dried and evaporated and the residue purified by chromatography eluting with cyclohexane:ethyl acetate (2:1) to give the title compound as a brown oil (0.40 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]([OH:22])=O)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:25]=[C:26]([S:30]([NH2:33])(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1>>[S:30]([C:26]1[CH:25]=[C:24]([NH:23][C:20]([C:19]2[CH:18]=[N:17][N:11]3[C:12]([CH:14]4[CH2:16][CH2:15]4)=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[N:9][C:10]=23)=[O:22])[CH:29]=[CH:28][CH:27]=1)(=[O:31])(=[O:32])[NH2:33]
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: O=C(O)c1cnn2c(C3CC3)cc(-c3ccc(Cl)cc3)nc12
Product: NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C4CC4)cc(-c4ccc(Cl)cc4)nc23)c1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-cyclopropyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.28) and 3-amino-benzenesulfonamide according to general procedure II. Pale-yellow solid. MS (ISP) 468.5 [(M+H)+].
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:15])([CH3:14])[CH2:4][CH2:5][CH:6]1[CH2:11][C:10]([CH3:12])=[CH:9][C:8](=[O:13])[CH2:7]1.[H][H]>CO.[Pd]>[CH3:1][O:2][C:3]([CH3:14])([CH3:15])[CH2:4][CH2:5][CH:6]1[CH2:11][CH:10]([CH3:12])[CH2:9][C:8](=[O:13])[CH2:7]1
Reactant: COC(C)(C)CCC1CC(=O)C=C(C)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(C)(C)CCC1CC(=O)CC(C)C1

Procedure:
A solution of 3-(3-methoxy-3-methylbut-1-yl)-5-methylcyclohex-5-en-1-one (30.0 g, 0.14 mol) in methanol (150 mL) was placed in a thick walled bottle. Palladium on charcoal (5%, 2.0 g) was added and the mixture was shaken under 53.5 psi of hydrogen. When the theoretical amount of hydrogen had been consumed, workup yielded 3-(3-methoxy-3-methylbut-1-yl)-5-methylcyclohexan-1-one as a mixture of two diastereoisomers bp0.5 104-107~C. (27.6 g, ratio 69:93.1); NMR(CDCl3)δ1.0(d,3H), 1.1(s,6H), 1.3-1.5(m,6H), 1.6-2.0(m,4H), 2.2-2.4(m,2H),3.1(s,3H). IR(neat) 2970, 2925, 1720, 1360, 1090 cm-1 ; MS(m/e) 41, 73, 124, 147, 165, 180, 197.
Reaction SMILES: [O:1]1[CH2:28][CH:2]1[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][C:20]([CH3:25])=[CH:19]4)=[N:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:26][CH3:27].[CH:29]([NH2:32])([CH3:31])[CH3:30]>CN(C=O)C>[OH:1][CH:2]([CH2:28][NH:32][CH:29]([CH3:31])[CH3:30])[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][C:20]([CH3:25])=[CH:19]4)=[N:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:26][CH3:27]
Reactant: CC(C)N
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCC1CO1
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCC(O)CNC(C)C
Temperature: 70 °C
Yield: 15.3 %

Procedure:
A mixture of 7-(2,3-epoxypropoxy)-6-methoxy-4-(2-methylindol-5-yloxy) quinazoline (100 mg, 0.27 mmol), (prepared as described for the starting material in Example 162), and isopropylamine (100 ul, 0.8 mmol) in DMF (4 ml) was heated at 70° C. for 24 hours. The solvent was removed by evaporation and the residue was purified by silica column chromatography eluting with dichloromethane/methanol/0.880 aqueous ammonia (100/8/1) to give 7-(2-hydroxy-3-(isopropylamino)propoxy)-6-methoxy-4(2-methylindol-5-yloxy)quinazoline (18 mg, 16%).
Reaction SMILES: [N+:1]([C:4]1[CH:73]=[CH:72][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3([C:48]4[CH:53]=[CH:52][C:51]([O:54][C:55]5[CH:60]=[CH:59][C:58]([N+:61]([O-])=O)=[C:57]([O:64]CC6C=CC=CC=6)[CH:56]=5)=[CH:50][CH:49]=4)[C:27]4[CH:26]=[C:25]([C:28]56[CH2:37][CH:32]7[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]7)[CH2:29]5)[CH2:35]6)[CH:24]=[CH:23][C:22]=4[C:21]4[C:16]3=[CH:17][C:18]([C:38]35[CH2:47][CH:42]6[CH2:43][CH:44]([CH2:46][CH:40]([CH2:41]6)[CH2:39]3)[CH2:45]5)=[CH:19][CH:20]=4)=[CH:11][CH:10]=2)=[CH:6][C:5]=1[O:74]CC1C=CC=CC=1)([O-])=O>[Pd].CN(C)C=O>[OH:64][C:57]1[CH:56]=[C:55]([CH:60]=[CH:59][C:58]=1[NH2:61])[O:54][C:51]1[CH:52]=[CH:53][C:48]([C:15]2([C:12]3[CH:13]=[CH:14][C:9]([O:8][C:7]4[CH:72]=[CH:73][C:4]([NH2:1])=[C:5]([OH:74])[CH:6]=4)=[CH:10][CH:11]=3)[C:16]3[CH:17]=[C:18]([C:38]45[CH2:45][CH:44]6[CH2:46][CH:40]([CH2:41][CH:42]([CH2:43]6)[CH2:47]4)[CH2:39]5)[CH:19]=[CH:20][C:21]=3[C:22]3[C:27]2=[CH:26][C:25]([C:28]24[CH2:29][CH:30]5[CH2:36][CH:34]([CH2:33][CH:32]([CH2:31]5)[CH2:37]2)[CH2:35]4)=[CH:24][CH:23]=3)=[CH:49][CH:50]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C3(c4ccc(Oc5ccc([N+](=O)[O-])c(OCc6ccccc6)c5)cc4)c4cc(C56CC7CC(CC(C7)C5)C6)ccc4-c4ccc(C56CC7CC(CC(C7)C5)C6)cc43)cc2)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CN(C)C=O
Product: Nc1ccc(Oc2ccc(C3(c4ccc(Oc5ccc(N)c(O)c5)cc4)c4cc(C56CC7CC(CC(C7)C5)C6)ccc4-c4ccc(C56CC7CC(CC(C7)C5)C6)cc43)cc2)cc1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.7 %

Procedure:
Next, 50.2 g of the obtained 9,9-bis[4-(4-nitro-3-benzyloxyphenoxy)-phenyl]-2,7-di(1-adamantyl)-fluorene (46.8 mmol), 1.49 g of 10% palladium-activated carbon (1.40 mmol), 273 mL of N,N-dimethylformamide and a stirrer were charged in a 300 mL recovery flask and agitated at 25° C. for 24 hours under a hydrogen atmosphere. A reaction solution was filtered and then added to in 1 L of ion-exchange water. Solid precipitate was collected by filtration, then agitated in 1 L of ion-exchange water for another one hour and dried under reduced pressure, thus obtaining 34.6 g of 9,9-bis[4-(3-hydroxy-4-amino-phenoxy)-phenyl]-2,7-di(1-adamantyl)-fluorene (41.5 mmol; the yield was 88.7%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C[O:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24]Br>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:24][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[C:17]([OH:26])=[O:16])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: COC(=O)c1ccccc1CBr
Product: Cc1ccc(-c2ccc(OCc3ccccc3C(=O)O)cc2)cc1

Procedure:
2-(4′-Methyl-biphenyl-4-yloxymethyl)-benzoic acid was prepared using general procedure A from 4′-methyl-biphenyl-4-ol (purchased from Maybridge plc, Tintagel, Cornwall, UK or from Intermediate 5) and 2-bromomethyl-benzoic acid methyl ester (Intermediate 1). Yield: 54 mg. Mass spectrum (ES) MH+=319.
Reaction SMILES: [CH2:1]([N:5]1[C:10]([O:11][C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[CH:13]=2)=[C:9]([CH2:20][CH3:21])[C:8](=[O:22])[NH:7][C:6]1=[O:23])[CH:2]=[CH:3]C.C(N1C(OC2C=C(C)C=C(C)C=2)=C(CC)C(=O)NC1=O)/C=C/C1C=CC=CC=1.C(N1C(OC2C=C(C)C=C(C)C=2)=C(CC)C(=O)NC1=O)/C=C\C1C=CC=CC=1.OCC=CCN1C(OC2C=C(C)C=C(C)C=2)=C(CC)C(=O)NC1=O.C(N1C(OC2C=C(C)C=C(C)C=2)=C(CC)C(=O)NC1=O)C#C.C1(C#CCN2C(OC3C=C(C)C=C(C)C=3)=C(CC)C(=O)NC2=O)C=CC=CC=1.C(N1C(OC2C=C(C)C=C(C)C=2)=C(CC)C(=O)NC1=O)C=CCC.COC(C=CCN1C(OC2C=C(C)C=C(C)C=2)=C(CC)C(=O)NC1=O)=O>>[CH2:1]([N:5]1[C:10]([O:11][C:12]2[CH:13]=[C:14]([CH3:19])[CH:15]=[C:16]([CH3:18])[CH:17]=2)=[C:9]([CH2:20][CH3:21])[C:8](=[O:22])[NH:7][C:6]1=[O:23])[CH:2]=[CH2:3]
Reactant: CC=CCn1c(Oc2cc(C)cc(C)c2)c(CC)c(=O)[nH]c1=O
Agent: C#CCn1c(Oc2cc(C)cc(C)c2)c(CC)c(=O)[nH]c1=O
Agent: CCC=CCn1c(Oc2cc(C)cc(C)c2)c(CC)c(=O)[nH]c1=O
Agent: CCc1c(Oc2cc(C)cc(C)c2)n(C/C=C/c2ccccc2)c(=O)[nH]c1=O
Product: C=CCn1c(Oc2cc(C)cc(C)c2)c(CC)c(=O)[nH]c1=O

Procedure:
1-(2-butenyl)-5-ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione; 1-(trans-cinnamyl)-5-ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione; 1-(cis--cinnamyl)-5-ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione; 1-(4-hydroxy-2-butenyl)-5-ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione; 1-propargyl-5-ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione; 1-(3-phenyl-2-propynyl)-5-ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione; 1-(2-pentenyl)-5-ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione; 1-(methoxycarbonylallyl)-5-ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione;
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[CH3:6][S:7]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C@H:17]([OH:27])[CH2:18][NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:13][CH:12]=1)(=[O:9])=[O:8].[OH-].[K+]>[OH-].[Na+].CC(O)C>[CH3:6][S:7]([O:10][C:11]1[CH:12]=[CH:13][C:14]([C@@H:17]2[O:27][CH2:2][C:3](=[O:4])[N:19]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:18]2)=[CH:15][CH:16]=1)(=[O:9])=[O:8]
Reactant: O=C(Cl)CCl
Reactant: CS(=O)(=O)Oc1ccc([C@H](O)CNCc2ccccc2)cc1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CS(=O)(=O)Oc1ccc([C@H]2CN(Cc3ccccc3)C(=O)CO2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
Chloroacetyl chloride (27.5 g, 243 mmol) was dropped to a solution of 4-((1S)-2-benzylamino-1-hydroxyethyl)phenyl methanesulfonate (71 g, 221 mmol) in 1N aqueous sodium hydroxide (330 ml) and stirred for one hour at room temperature. Resulting solution was extracted with chloroform, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. Potassium hydroxide (85%, 17.5 g, 265 mmol) was added to a solution of the resulting pale brown oil in 2-propanol (600 ml), and the mixture was stirred for 10 hours. The solvent was removed in vacuo and the residue was partitioned between water and chloroform. The organic layer was washed with 0.5 M hydrochloric acid, saturated sodium hydrogen carbonate, brine and dried over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure furnished 4-((2S)-4-benzyl-5-oxo-morpholin-2-yl)phenyl methanesulfonate (79.8 g, 100%) as a brown oil.
Reaction SMILES: [C:1]([O-])(=[O:3])[CH3:2].[K+].[CH3:6][O:7][C:8]([C@H:10]1[CH2:13][C@@H:12]([O:14]S(C2C=CC(C)=CC=2)(=O)=O)[CH2:11]1)=[O:9]>CN(C=O)C>[CH3:6][O:7][C:8]([C@H:10]1[CH2:11][C@H:12]([O:14][C:1](=[O:3])[CH3:2])[CH2:13]1)=[O:9]
Reactant: CC(=O)[O-]
Reactant: COC(=O)[C@H]1C[C@@H](OS(=O)(=O)c2ccc(C)cc2)C1
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1C[C@H](OC(C)=O)C1
Temperature: 120 °C

Procedure:
A mixture of potassium acetate (16.9 g, 172 mmol) and cis-3-(toluene-4-sulfonyloxy)-cyclobutanecarboxylic acid methyl ester (9.8 g, 34 mmol; trans/cis=1:5) in dry DMF (50 mL) was heated to 120° C. for 21 h. DMF was partially distilled off (≈4=30 mL), water was added, and the mixture was extracted with EtOAc (6×50 mL). The combined organic layers were washed with water (2×), brine, dried over MgSO4, filtered and concentrated to give the title compound as brown oil, trans/cis=5:1 based on 1H NMR. The material thus obtained was used without further purification.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:12][C:13]1[C:14]([CH2:19]O)=[N:15][CH:16]=[CH:17][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)(O)[O-].[Na+]>ClCCl.O>[CH2:5]([O:12][C:13]1[C:14]([CH2:19][Cl:3])=[N:15][CH:16]=[CH:17][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OCc1ncccc1OCc1ccccc1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: ClCc1ncccc1OCc1ccccc1
Temperature: 25 °C
Yield: 95 %

Procedure:
25.2 ml of thionyl chloride are added to the solution of 40 g (0.19 mol) of 3-(benzyloxy)-2-(hydroxymethyl)pyridine (CAS 6059-29-6; Desideri, N; Sestili, I; Manarini, S; Cerletti, C; Stein; Eur. J. Med. Chem. Chim. Ther.; 26 (4) 1991; 455-460) in 265 ml of dichloromethane. The solution is stirred at ambient temperature under nitrogen, and then concentrated to dryness. The residue obtained is dissolved in water. Sodium bicarbonate is added until a solution at neutral pH is obtained. The aqueous solution is extracted with ethyl acetate. The organic phase is washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulphate, and then concentrated to dryness. 41 g (95%) of a brown oil are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH:18]=2)=[CH:13][C:12]=1[F:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:33][S:34](Cl)(=[O:36])=[O:35].CCOC(C)=O>C(Cl)Cl.CCCCCCC>[CH2:1]([O:8][C:9]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH2:22][CH2:21][CH:20]([O:23][S:34]([CH3:33])(=[O:36])=[O:35])[CH2:19][CH:18]=2)=[CH:13][C:12]=1[F:24])=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(Nc1ccc(C2=CCC(O)CC2)cc1F)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCCC
Product: CS(=O)(=O)OC1CC=C(c2ccc(NC(=O)OCc3ccccc3)c(F)c2)CC1
Reaction time: 1 h
Yield: 88.2 %

Procedure:
To a solution of [2-fluoro-4-(4-hydroxy-cyclohex-1-enyl)-phenyl]-carbamic acid benzyl ester (230 mg. 0.67 mmol) in DCM (5 mL) was added Et3N (0.2 mL, 1.7 mmol, 2 equiv.). The solution was cooled to an ice-water bath and then de-aerated by vacuum/nitrogen exchange. To this solution was transferred a solution of methanesulfonyl chloride (146 mg, 1.2 mmol, 1.5 equiv.) in DCM (2 mL). The clear solution was stirred in an ice-water bath for 1 h. TLC (50% EtOAc in heptane) indicated that the reaction was complete. The reaction was quenched by diluting with DCM (10 mL), followed by addition of NaHCO3 aq. (5 mL). The two layers were separated and the aqueous layer was extracted with DCM (2×5 mL). The combined extracts were washed with NaHCO3 aq. (5 mL), brine (5 mL), and dried (K2CO3). The solution was filtered through a silica gel pad, eluted with 5% MeOH in DCM to afford 248 mg (88%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([CH:26]=[CH:27][CH3:28])=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Se](=O)=[O:30].O>O1CCOCC1.C(OCC)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3[C:19]([CH:26]=[CH:27][CH:28]=[O:30])=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: O=[Se]=O
Reactant: CC=Cc1c([N+](=O)[O-])ccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc([N+](=O)[O-])c(C=CC=O)c3O2)cc1

Procedure:
{(2R)-7-nitro-8-[1-propenyl]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl 4-methylbenzenesulfonate (6.15 g, 15.2 mmole) was dissolved in 180 mL of dioxane. Selenium dioxide (4.20 g, 37.9 mmole) was then added, followed by 0.70 mL of water. The heterogeneous mixture was heated at reflux under nitrogen for 5 hours. Upon cooling, the reaction was filtered and concentrated in vacuum to yield a dark yellow solid. This was dissolved in minimal ethyl acetate and column chromatographed on silica gel using 30% ethyl acetate in hexane as eluant to give 5.75 g of the (R)-enantiomer of the title compound as a light yellow solid (m.p. 138-140° C.).