Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[NH:6][C:5]1=[O:24])[CH:2]=[CH2:3].[H-].[Na+].Br[CH2:28][CH2:29][CH3:30]>CN(C=O)C>[CH2:1]([C@@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([CH2:28][CH2:29][CH3:30])[C:5]1=[O:24])[CH:2]=[CH2:3]
Reactant: C=CC[C@@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)NC1=O
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CC[C@@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CCC)C1=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of (3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one (Example 42, Step A) (70 mg, 0.19 mmol) in 430 μL of DMF was added sodium hydride (60% suspension in mineral oil, 20 mg, 0.51 mmol) at 0° C. The reaction was stirred at 0° C. for 15 min and then treated with 1-bromopropane (53 μL, 0.58 mmol). After being stirred at 25° C. for 4 h, the reaction was quenched with sat. aqueous NaHCO3 and extracted (2×EtOAc). The combined organic layers were washed with sat. aq. NaCl and NaHCO3-solutions, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification of the residue by silica gel prep plate (25% EtOAc/hexanes) provided the title compound as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[K+].[Br:10][CH2:11][C:12]1[CH:25]=[C:24]2[C:26]3=[C:27]4[C:17]([CH:18]=[CH:19][CH:20]=[C:21]4[CH:22]=[CH:23]2)=[CH:16][CH:15]=[C:14]3[CH:13]=1>C(#N)C>[Br-:10].[CH:25]1[C:24]2[C:26]3=[C:27]4[C:21](=[CH:22][CH:23]=2)[CH:20]=[CH:19][CH:18]=[C:17]4[CH:16]=[CH:15][C:14]3=[CH:13][C:12]=1[CH2:11][N+:3]1[C:2]([Cl:1])=[C:6]([Cl:7])[N:5]([CH2:11][C:12]2[CH:25]=[C:24]3[C:26]4=[C:27]5[C:17]([CH:18]=[CH:19][CH:20]=[C:21]5[CH:22]=[CH:23]3)=[CH:16][CH:15]=[C:14]4[CH:13]=2)[CH:4]=1
Reactant: BrCc1cc2ccc3cccc4ccc(c1)c2c34
Reactant: Clc1nc[nH]c1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: Clc1c(Cl)[n+](Cc2cc3ccc4cccc5ccc(c2)c3c45)cn1Cc1cc2ccc3cccc4ccc(c1)c2c34
Product: [Br-]

Procedure:
4,5-Dichloroimidazole (0.18 g, 1.33 mmol) and potassium hydroxide (0.08 g, 1.46 mmol) will be dissolved in a minimum volume of acetonitrile and stirred at reflux for 30 min. 2-(Bromomethyl)pyrene (2.95 g, 10.0 mmol) will be added and the mixture will be returned to reflux for 3 h. The mixture will be filtered hot to remove the KBr generated. A second equivalent of 2-(bromomethyl)pyrene will be added to the filtrate and the mixture will be returned to reflux for 6 h. The volatile components will be removed under reduced pressure to yield the product.
Reaction SMILES: [C:1]1([C:7]2[CH:27]=[CH:26][CH:25]=[CH:24][C:8]=2[O:9][C:10]2[CH:11]=[C:12]([NH:16][CH2:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:13]=[CH:14][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:28]([S:30](Cl)(=[O:32])=[O:31])[CH3:29]>>[C:1]1([C:7]2[CH:27]=[CH:26][CH:25]=[CH:24][C:8]=2[O:9][C:10]2[CH:11]=[C:12]([N:16]([CH2:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[S:30]([CH2:28][CH3:29])(=[O:32])=[O:31])[CH:13]=[CH:14][CH:15]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCS(=O)(=O)Cl
Reactant: c1ccc(-c2ccccc2Oc2cccc(NCc3cccnc3)c2)cc1
Product: CCS(=O)(=O)N(Cc1cccnc1)c1cccc(Oc2ccccc2-c2ccccc2)c1

Procedure:
Using the procedure of Example 342 using N-(3-(2-phenylphenoxy)phenyl)pyrid-3-ylmethylamine and ethanesulfonyl chloride (Aldrich) and purifying via preparative HPLC eluting with 99:1 to 97:3 DCM/MeOH gave the title compound. Anal Calcd for C26H24N2O3S: C, 70.25; H, 5.44; N, 6.30. Found: C, 70.13; H, 5.39; N, 6.26. MS found 445.1 [M+H]+
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[CH3:22][C:23]1[O:24][C:25]([CH3:31])=[CH:26][C:27]=1[C:28](Cl)=[O:29]>>[CH3:22][C:23]1[O:24][C:25]([CH3:31])=[CH:26][C:27]=1[C:28]([N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1)=[O:29]
Reactant: Cc1cc(C(=O)Cl)c(C)o1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: Cc1cc(C(=O)N2CCC3(CC2)CSC2=C(O3)c3ccccc3C(=O)C2=O)c(C)o1

Procedure:
Compound 41 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 2,5-dimethyl-3-furoyl chloride and conditions outlined in procedure N. M.p.=234-235° C.; 300 MHz 1H NMR (DMSO-d6) δ 8.15 (d, 1H), 7.81 (d, 1H), 7.63 (t, 1H), 7.54 (t, 1H), 5.92 (s, 1H), 3.40 (m, 2H), 3.05 (s, 2H), 2.40 (s, 3H), 2.21 (s, 3H), 2.18 (m, 2H), 1.90 (m 2H), 1.60 (s, 2H); LCMS: 424 [M+H].
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[C:13]([O:15]COCC[Si](C)(C)C)[C:12]2[C:7](=[C:8]([Br:26])[CH:9]=[C:10]([O:24][CH3:25])[CH:11]=2)[N:6]=1)=[O:4].O1CCCC1.O.O.[OH-].[Li+]>CO>[Br:26][C:8]1[CH:9]=[C:10]([O:24][CH3:25])[CH:11]=[C:12]2[C:7]=1[NH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:14][C:13]2=[O:15]
Reactant: COC(=O)c1cc(OCOCC[Si](C)(C)C)c2cc(OC)cc(Br)c2n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(Br)c2[nH]c(C(=O)O)cc(=O)c2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 79.4 %

Procedure:
To a light brown solution of 8-bromo-6-methoxy-4-(2-trimethylsilanyl-ethoxymethoxy)-quinoline-2-carboxylic acid methyl ester (Reference Example 24c) (4.98 g, 11.3 mmol) in 75 mL 3:1:1 tetrahydrofuran:methanol:water was added lithium hydroxide monohydrate (1.367 g, 32.6 mmol). The reaction was stirred at room temperature for 5 hours. The reaction mixture was concentrated and then poured into water. The solution was acidified to pH 2 with 1 N HCl and the resulting solids were isolated by filtration. The solids were then suspended in methanol and filtered to afford the desired product (2.6732 g, 80%). An additional 0.5768 g (17%) of product was obtained from the methanol filtrates. 1H NMR (300 MHz, DMSO, d6, TFA Shake) δ 7.86 (d, 1 H, Jm=2.7 Hz, ArH5), 7.55 (d, 1 H, Jm=2.7 Hz, ArH7), 7.32 (s, 1 H, C═CH), 3.94 (s, 3 H, OCH3); Mass Spec.: calc. for [C11H8BrNO4+H]+ Theor. m/z=298, 300; Obs.=298, 300.
Reaction SMILES: [OH2:1].[NH2:2][C:3]1[C:4]2[C:9]([N:10]=[C:11]3[C:16]=1[CH2:15][CH2:14][CH2:13][CH2:12]3)=[CH:8][CH:7]=[CH:6][C:5]=2C(C1C=CC=CC=1)C(O)=O.[CH3:27][C:28](C)([O-:30])[CH3:29].[K+].[Cl-].[NH4+]>O1CCCC1>[C:27]1([CH:28]2[C:29](=[O:1])[NH:2][C:3]3=[C:16]4[C:11](=[N:10][C:9]5=[CH:8][CH:7]=[CH:6][C:5](=[C:4]35)[O:30]2)[CH2:12][CH2:13][CH2:14][CH2:15]4)[CH:5]=[CH:4][CH:3]=[CH:16][CH:15]=1
Reactant: CC(C)(C)[O-]
Reactant: O
Reactant: Nc1c2c(nc3cccc(C(C(=O)O)c4ccccc4)c13)CCCC2
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C1Nc2c3c(nc4cccc(c24)OC1c1ccccc1)CCCC3
Reaction time: 1 h
Yield: 148.8 %

Procedure:
Methyl α-[(9-amino-1,2,3,4-tetrahydroacridin-8-yl]phenylacetate hydrate (5.26 g) was dissolved dry tetrahydrofuran (100 ml) and potassium tert-butoxide (1.70 g) was added. After stirring for 1 hr, saturated ammonium chloride solution (100 ml) was added, and stirring was continued for 30 min. The reaction mixture was evaporated and the solid was collected and washed with water. Recrystallization from dimethylformamide-water gave 3.69 g (77.0%) of product, mp 250° (dec).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[Cl:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[S:42]([C@H:45]1[CH2:49][NH:48][C@H:47]([C:50]([O:52][CH3:53])=[O:51])[CH2:46]1)(=[O:44])=[O:43].Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]([N:48]3[CH2:49][C@H:45]([S:42]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=4[Cl:35])(=[O:44])=[O:43])[CH2:46][C@H:47]3[C:50]([O:52][CH3:53])=[O:51])=[O:13])[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CC1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=O)C1(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Under an atmosphere of argon, 1-(4-chlorophenyl)cyclopropanecarboxylic acid (1.57 g, 7.9 mmol, Eq: 1.20) was combined with tetrahydrofuran (70.0 ml) to give a colorless solution. Then EDC (3.09 g, 15.8 mmol, Eq: 2.40), HOBt (2.47 g, 15.8 mmol, Eq: 2.40) and triethylamine (6.66 g, 9.18 ml, 65.8 mmol, Eq: 10.0) was added. (A white suspension was obtained.) The reaction mixture was stirred for 15 min at room temperature. A solution of (2S,4R)-methyl 4-(2-chlorophenylsulfonyl)pyrrolidine-2-carboxylate (2 g, 6.58 mmol, Eq: 1.00) in tetrahydrofuran (14.0 ml) was added dropwise. The reaction was stirred for 3 days at room temperature. The reaction mixture was poured into 75 ml HCl 1M and extracted with 2×100 ml ethyl acetate. The organic layers were washed with 75 ml satd. Na2CO3 solution and 75 ml brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (50 g column, from 0% to 100% ethyl acetate in heptane). The title compound was obtained as a light yellow solid (1.5 g, 47.2%, MS (m/e)=482.3 [M+H+]).
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[CH3:6][C:7]1[CH:12]=[C:11]([S:13][CH3:14])[CH:10]=[CH:9][C:8]=1[OH:15].[CH2:16]([NH2:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>>[CH3:6][C:7]1[CH:12]=[C:11]([S:13][CH3:14])[CH:10]=[CH:9][C:8]=1[O:15][CH2:1][CH:3]([OH:5])[CH2:4][NH:24][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: ClCC1CO1
Reactant: CSc1ccc(O)c(C)c1
Reactant: CCCCCCCCN
Product: CCCCCCCCNCC(O)COc1ccc(SC)cc1C
Yield: 19 %

Procedure:
The epichlorohydrin derivative of 2-methyl-4-(methylthio)phenol (3.14 g., 0.015 mole) is reacted with n-octylamine (1.93 g. 0.015 mole) according to the procedure of Example 1. Concentrating the reaction mixture and crystallization of residual material from ethylacetate-hexane affords a 19% yield of analytically pure 1-[2-methyl-4-(methylthio)phenoxy]-3-(octylamino)-2-propanol, m.p. 59°-60° (corr.).
Reaction SMILES: [CH3:1][NH:2][C:3]([O:5][CH:6]1[CH2:10][NH:9][C@H:8]([C:11]([OH:13])=[O:12])[CH2:7]1)=[O:4].[H][H]>[C].[Pd].CO.O>[CH3:1][NH:2][C:3]([O:5][C@H:6]1[CH2:10][NH:9][C@H:8]([C:11]([OH:13])=[O:12])[CH2:7]1)=[O:4]
Reactant: [H][H]
Reactant: CNC(=O)OC1CN[C@H](C(=O)O)C1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: CNC(=O)O[C@H]1CN[C@H](C(=O)O)C1

Procedure:
A solution of 2.7 g. (0.0084 mole) of trans-N-carbobenzyloxy]-4-[[(methylamino)carbonyl]oxy]-L-proline in 100 ml. of methanol-water (2:1) is treated with 1 g. of 5% palladium-carbon and 45 lb. of hydrogen and shaken on a Parr hydrogenator for 6 hours. The catalyst is filtered off under nitrogen, washed with methanol and the combined filtrates are evaporated, finally at 0.1-0.2 mm, to give 1.5 g. (96%) of a residue which gradually crystallizes to give trans-4-[[(methylamino)carbonyl]oxy]-L-proline as a greyish solid; m.p. 213°-215° (dec.), preceded by gradual darkening and sintering. [α]D26 -12° (c, 0.25% in 1:3 ethanol-methanol).
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([O:13][CH2:14][C@@H:15]2[O:20][C:19]3[C:21]([NH2:26])=[C:22]([NH2:25])[CH:23]=[CH:24][C:18]=3[O:17][CH2:16]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.[F:27][C:28]([F:33])([F:32])[C:29](O)=O>C(Cl)Cl>[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([O:13][CH2:14][CH:15]2[O:20][C:19]3[C:18](=[CH:24][CH:23]=[C:22]4[NH:25][C:29]([C:28]([F:33])([F:32])[F:27])=[N:26][C:21]4=3)[O:17][CH2:16]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc(N)c(N)c3O2)cc1
Reactant: O=C(O)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc4[nH]c(C(F)(F)F)nc4c3O2)cc1

Procedure:
A solution of 3.1 g (7.3 mmole) of [(2R)-7,8-diamino-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate dihydrochloride in 50 mL of trifluoroacetic acid was refluxed under nitrogen for 6 hours. The mixture was diluted to 400 mL with methylene chloride, washed with 400 mL of water and with 400 mL of saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated to a crude foam in vacuum. The crude product was column chromatographed on silica gel with 1% methanol in chloroform and the product fractions combined and concentrated in vacuum to give 3.3 g of the (R)-enantiomer of the title compound as a white solid (m.p. 114-116° C.), which retains one equivalent of chloroform.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:14]=[C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:16]=2)[C:10]([O:12]C)=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[Li+].CO>C1COCC1.O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:14]=[C:15]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:16]=2)[C:10]([OH:12])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(OC2CCCC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(OCc2ccccc2)cc(OC2CCCC2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl 3-(cyclopentyloxy)-5-[(phenylmethyl)oxy]benzoate (9.25 g, 28.34 mmol) was dissolved in THF (120 mL) and a solution of lithium hydroxide mono hydrate (3.49 g, 85.0 mmol) in water (60 mL) added. The bi-phasic solution was stirred at RT for 16 hours (LCMS indicated reaction 80% complete), methanol (15 mL) added and the mixture stirred for a further 4 hours. The THF was removed in vacuo then water (40 mL) added and the pH adjusted to 7 with hydrochloric acid. The solid was collected and washed thoroughly with cold water (8.85 g).
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]2[C:16]([Cl:17])=[CH:15][C:14]([Cl:18])=[CH:13][N:12]=2)[CH:5]=1.[OH-].[Na+]>CO.C1COCC1.O>[Cl:17][C:16]1[C:11]([O:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:19])=[O:2])=[N:12][CH:13]=[C:14]([Cl:18])[CH:15]=1
Reactant: COC(=O)c1cccc(Oc2ncc(Cl)cc2Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc(Oc2ncc(Cl)cc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
A mixture of 3-(3,5-dichloro-pyridin-2-yloxy)-benzoic acid methyl ester (1100 mg, 4.0 mmol) and NaOH (700 mg, 16 mmol) in methanol:THF:water (1:1:1, 6 mL) was stirred at room temperature for 8 h. Solvents were evaporated. Crude mass was taken in water (40 mL), acidified to pH 4.0 and extracted with ethyl acetate. Evaporation of ethyl acetate yielded 3-(3,5-dichloro-pyridin-2-yloxy)-benzoic acid (908 mg).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1.[CH3:10][C:11]([CH3:15])([CH3:14])[C:12]#N.Cl.CC[O:19]CC>>[CH3:10][C:11]([CH3:15])([CH3:14])[C:12]([C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1)=[O:19]
Reactant: Cc1ccc(Br)cc1
Reactant: CCOCC
Reactant: CC(C)(C)C#N
Agent: Cl
Agent: [Mg]
Product: Cc1ccc(C(=O)C(C)(C)C)cc1
Reaction time: 2 h
Yield: 27 %

Procedure:
To a suspension (200 ml) of magnesium (7.14 g, 294 mmol) in ether in a three necked flask was added dropwise a solution of p-bromotoluene (34 ml, 276 mmol) in ether (100 ml), and the mixture was heated under reflux for 1.5 hrs. Thereafter, to the mixture was added a solution of trimethylacetonitrile (25 ml, 226 mmol) in ether (100 ml), and the mixture was stirred for 2 hrs. The mixture was then ice-cooled. To the mixture was added dropwise 6N hydrochloric acid, and the mixture was stirred at room temperature for 30 min. The mixture was diluted with ether, and washed with water and saturated brine. The mixture was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:0, 10:1) to give 2,2-dimethyl-1-(4-methylphenyl)-1-propanone (10.94 g, 27%) as a colorless transparent oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1SC.OO.O1CCC[CH2:23]1.[S:27]([O-:30])([O-])=[O:28].[Na+].[Na+]>C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([CH2:14][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19]2)[C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[S:27]([CH3:23])(=[O:30])=[O:28]
Reactant: O=S([O-])[O-]
Reactant: C1CCOC1
Reactant: CSc1ccc(C(CC2CCCC2)C(=O)O)cc1Cl
Agent: OO
Agent: [Na+]
Solvent: O=CO
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1Cl
Temperature: 0 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
A mixture of 2-(3-chloro-4-methylsulfanyl-phenyl)-3-cyclopentyl-propionic acid (4.14 g, 13.85 mmol) in formic acid (7.08 mL) was cooled to 0° C. and then treated with a 30% aqueous hydrogen peroxide solution (7.85 μL). Tetrahydrofuran (4 mL) was added to help solubilize the starting material. The resulting reaction mixture was allowed to warm to 25° C. where it was stirred overnight. The reaction mixture was then cooled to 0° C. and slowly treated with a saturated aqueous sodium sulfite solution. The product was extracted into ethyl acetate (3×20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to afford 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (4.54 g, 99.1%) as a white solid: mp 123.9–126.2° C.; FAB-HRMS m/e calcd for C15H19ClO4S (M+H)+ 331.0771, found 331.0776.
Reaction SMILES: [Br:1][C:2]1[CH:25]=[C:24]([C:26]([CH3:28])=[CH2:27])[CH:23]=[C:22]([O:29][CH3:30])[C:3]=1[O:4][C:5]1[C:6]2[N:14]=[N:13][N:12]([CH:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[C:7]=2[N:8]=[C:9]([CH3:11])[N:10]=1>C(O)C.[Pt]>[Br:1][C:2]1[CH:25]=[C:24]([CH:26]([CH3:28])[CH3:27])[CH:23]=[C:22]([O:29][CH3:30])[C:3]=1[O:4][C:5]1[C:6]2[N:14]=[N:13][N:12]([CH:15]([CH2:16][CH2:17][CH3:18])[CH2:19][CH2:20][CH3:21])[C:7]=2[N:8]=[C:9]([CH3:11])[N:10]=1
Reactant: C=C(C)c1cc(Br)c(Oc2nc(C)nc3c2nnn3C(CCC)CCC)c(OC)c1
Agent: [Pt]
Solvent: CCO
Product: CCCC(CCC)n1nnc2c(Oc3c(Br)cc(C(C)C)cc3OC)nc(C)nc21
Reaction time: 18 h

Procedure:
Platinum black, 5% (0.19 g) was added to a solution of 7-[2-bromo-6-methoxy-4-(1-methylethenyl)phenoxy]-5-methyl-3-(1-propylbutyl)-3H-1,2,3-triazolo[4, 5-d]pyrimidine (0.17 g) in 50 mL of ethanol. The mixture was hydrogenated at a pressure of 40 psi for 18 hours and filtered through celite. The filtrate was stripped of the solvent under reduced pressure and the residue recrystallized from hexane to yield the title compound as a colorless crystalline solid, mp 129-131° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:11]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)(=[O:13])=[O:12].[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.Cl>O>[ClH:1].[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[S:11]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)(=[O:13])=[O:12])[CH2:22][CH2:21]1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1ccc(Cl)c(S(=O)(=O)N2CCCC2)c1
Agent: Cl
Solvent: O
Product: CN1CCN(c2ccc(C(=O)O)cc2S(=O)(=O)N2CCCC2)CC1

Procedure:
29.0 Grams of 4-chloro-3-pyrrolidinosulfonylbenzoic acid (0.1 mole) were heated with 50 ml of N-methylpiperazine for 4 hours under reflux. Subsequently the reaction solution was introduced into 0.3 l of water, and the pH value of the mixture was adjusted to 3.0 by means of 5N HCl. After having been allowed to stand over night at room temperature, the precipitate was suction-filtered, recrystallized from water and dried at 100° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[I:9]I>CCO.S([O-])([O-])(=O)=O.[Ag+2]>[Cl:8][C:5]1[N:6]=[C:7]([I:9])[C:2]([NH2:1])=[CH:3][CH:4]=1
Reactant: II
Reactant: Nc1ccc(Cl)nc1
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: Nc1ccc(Cl)nc1I
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Amino-2-chloropyridine (5.0 g, 0.039 mol) was dissolved in EtOH (25 mL), and silver sulfate (13.3 g, 0.043 mol) and iodine (10.9 g, 0.043 mol) were added. The reaction was stirred at room temperature overnight, and then the mixture was filtered over Celite to remove solids. The filtrate was concentrated and purified on silica gel (0-50% EtOAc in hexanes) to give the desired product.
Reaction SMILES: C([O:3][C:4](=[O:8])[CH:5]([CH3:7])[OH:6])C.[CH2:9]([CH:11]1[O:13][CH2:12]1)Cl.B(F)(F)F.CC[O:20]CC>>[OH:13][CH:11]([CH2:9][OH:20])[CH2:12][O:6][CH:5]([CH3:7])[C:4]([OH:3])=[O:8]
Reactant: ClCC1CO1
Reactant: CCOCC
Reactant: CCOC(=O)C(C)O
Agent: FB(F)F
Product: CC(OCC(O)CO)C(=O)O

Procedure:
177 g of lactic acid ethylester and 46.2 g of epichlorohydrin are admixed by stirring in the presence of 0.5 ml of borontrifluorideetherate during 4 hours at 80° C. The excess of lactic acid ethyl ester is then distilled off with vacuum (20 mm Hg). The residue is dehalogenated and saponified with diluted sodiumhydroxide.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[Cu](C#N)[C:14]#[N:15].C(=O)([O-])[O-].[K+].[K+].COCCl>CN(C)C=O>[C:14]([C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6])#[N:15]
Reactant: N#C[Cu]C#N
Reactant: COC(=O)c1ccc(O)c(Br)c1
Agent: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(O)c(C#N)c1
Temperature: 150 °C
Reaction time: 16 h
Yield: 22.5 %

Procedure:
Methyl 3-bromo-4-hydroxybenzoate (37.81 g) was dissolved in N,N-dimethylformamide (250 mL), and copper cyanide (22.03 g) was added to the solution. After stirring the mixture at 150° C. for 16 hours, potassium carbonate (68.00 g) and chloromethyl methyl ether (14.8 mL) were added to the solution under ice cooling, and then the mixture was stirred for 2 hours. The reaction solution was filtered and water was added, and then the reaction mixture was extracted with ethyl acetate. After the operation of adding water to the organic layer, stirring the mixture, filtering the mixture and separating the organic layer was repeated three times, the organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was dissolved in chloroform (30 mL). Trifluoroacetic acid (30 mL) was added to the solution, and then the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure and the obtained residue was washed with a mixture of n-hexane and ethyl acetate in a mixing ratio of 2:1 to obtain the title compound (6.53 g) as a pale yellow crystal.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][NH:9][C:10]([NH2:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.Br[CH2:14][C:15]([O:17][CH3:18])=[O:16]>C1(C)C=CC=CC=1>[NH2:12][C:10]([NH:9][N:8]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=1)=[O:11]
Reactant: Cc1cccc(NNC(N)=O)c1
Reactant: COC(=O)CBr
Solvent: Cc1ccccc1
Product: COC(=O)CN(NC(N)=O)c1cccc(C)c1

Procedure:
A mixture of 2-(3-methylphenyl)hydrazinecarboxamide (5 g), DEA (10.5 ml) and methyl bromoacetate (4.5 ml) in toluene (100 ml) was heated under reflux for 20 h, and was then partitioned between ethyl acetate (200 ml) and water (200 ml). The organic layer was washed with water (2×100 ml) and saturated brine (100 ml) before being dried and evaporated in vacuo to leave an oil (6.1 g). This was purified by FCC eluting with ethyl acetate to give the title compound (4.4 g) as a solid, m.p. 68°-70° after recrystallisation from ethyl acetate and trituration with ether.