Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3][C:4]1[NH:5][C:6]2[C:7](=[C:9]([C:13]([O:15][CH3:16])=[O:14])[S:10][C:11]=2[CH3:12])[N:8]=1)[CH3:2].[H-].[Na+].[Cl:19][C:20]([Cl:41])([Cl:40])[C:21]1[O:25][N:24]=[C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]2[CH:37]=[CH:36][C:35]([CH2:38]Br)=[CH:34][CH:33]=2)[N:22]=1.O>CN(C=O)C>[CH2:1]([S:3][C:4]1[N:8]([CH2:38][C:35]2[CH:36]=[CH:37][C:32]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[C:23]3[N:22]=[C:21]([C:20]([Cl:40])([Cl:19])[Cl:41])[O:25][N:24]=3)=[CH:33][CH:34]=2)[C:7]2=[C:9]([C:13]([O:15][CH3:16])=[O:14])[S:10][C:11]([CH3:12])=[C:6]2[N:5]=1)[CH3:2]
Reactant: CCSc1nc2c(C(=O)OC)sc(C)c2[nH]1
Reactant: ClC(Cl)(Cl)c1nc(-c2ccccc2-c2ccc(CBr)cc2)no1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1nc2c(C)sc(C(=O)OC)c2n1Cc1ccc(-c2ccccc2-c2noc(C(Cl)(Cl)Cl)n2)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To an ice-cooling solution of methyl 2-ethylthio-4-methylthieno[3,4-d]imidazole-6-carboxylate (3 g) in DMF (20 ml) was added sodium hydride (60%, oil) (0.56 g), and the mixture was stirred for 10 minutes. To the ice-cooling mixture was added [2'-(5-trichloromethyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl bromide (6.1 g), and the mixture was stirred for two hours at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous saline solution. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel to afford the title compound as a pale yellow syrupy product (4.15 g, 58%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]#[C:10][C:11]#[CH:12])[CH:6]=[CH:7][CH:8]=1.[F:13][C:14]([F:27])([F:26])[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=1I.C1C=CC=CC=1>C(N(CC)CC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]#[C:10][C:11]#[C:12][C:16]2[CH:17]=[C:18]([C:21]([F:24])([F:23])[F:22])[CH:19]=[CH:20][C:15]=2[C:14]([F:13])([F:26])[F:27])[CH:6]=[CH:7][CH:8]=1
Reactant: C#CC#Cc1cccc(OC)c1
Reactant: FC(F)(F)c1ccc(C(F)(F)F)c(I)c1
Agent: Cl[Cu]
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COc1cccc(C#CC#Cc2cc(C(F)(F)F)ccc2C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 13 h
Yield: 29.6 %

Procedure:
430 mg of the thus-obtained 1-(3-methoxyphenyl)-1,3-butadiyne and 1200 mg of 2,5-bis(trifluoromethyl) iodobenzene were dissolved in 20 ml of triethylamine in an atmosphere of argon, and 21 mg of bis(triphenylphosphine) palladium (II) chloride and 6 mg of copper (I) chloride were rapidly added to the reaction mixture. After the solution had been stirring at room temperature for 13 hours, 30 ml of benzene were added thereto, and the precipitates produced were filtered off. After the solvent had been evaporated, the residue was neutralized by 1N hydrochloric acid and then subjected to extraction with 50 ml benzene three times. The organic layer was dried over magnesium sulfate, and the solvent was then evaporated. The residue was then purified by silica-gel column chromatography using hexane as an eluent to obtain 300 mg of 1-(3-methoxyphenyl)-4-[2,5-bis(trifluoromethyl)phenyl]-1,3-butadiyne. This compound was a slightly yellowish white crystal having a melting point of 37° C.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([OH:26])=O)=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH:4]=[CH2:5].C(N(CC)CC)C.ClC(OCC)=O.[N-:40]=[N+:41]=[N-:42].[Na+]>CC(C)=O.O>[CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([N:40]=[N+:41]=[N-:42])=[O:26])=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH:4]=[CH2:5]
Reactant: [N-]=[N+]=[N-]
Reactant: C=CCCC[C@H]1CC[C@H](c2ccc(-c3ccc(C(=O)O)cc3)cc2)CC1
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: O
Product: C=CCCC[C@H]1CC[C@H](c2ccc(-c3ccc(C(=O)N=[N+]=[N-])cc3)cc2)CC1
Temperature: 2 °C

Procedure:
A mixture of 10.3 g of 4'-[trans-4-(4-pentenyl)cyclohexyl]-4-biphenylcarboxylic acid and 300 ml of acetone was cooled to 2° C. while stirring and gassing with nitrogen, treated dropwise within 10 minutes with a solution of 8.2 ml of triethylamine in 58 ml of acetone and stirred for a further 5 minutes. Thereafter, the mixture was treated dropwise at 0°-2° C. within 10 minutes with a solution of 7.1 ml of ethyl chloroformate in 29 ml of acetone. The mixture was stirred for a further 30 minutes at 0°-2° C. and treated dropwise within 10 minutes with a solution of 5.25 g of sodium azide in 29 ml of water. The reaction mixture was stirred for a further 2.25 hours while cooling with an ice-bath, then poured into 1 l of water and extracted once with 1 l of diethyl ether and once with 500 ml of diethyl ether. The ether phases were washed with water, dried over sodium sulphate, filtered and concentrated. The beige crystalline residue (12.2 g) was separated by chromatography on silica gel with methylene chloride, whereby 9.9 g (89.5%) of 4'(trans-4-(4-pentenyl)cyclohexyl]-4-biphenylcarboxylic acid azide were obtained as colourless crystals.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[N+:13]1([O-:22])[C:14]([C:19]([OH:21])=O)=[CH:15][CH:16]=[CH:17][CH:18]=1.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1>CN(C)C=O>[N:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[NH:23][C:19]([C:14]1[N+:13]([O-:22])=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:21]
Reactant: Nc1ccccn1
Reactant: O=C(O)c1cccc[n+]1[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C(Nc1ccccn1)c1cccc[n+]1[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 0.1 %

Procedure:
1,1'-Carbonyldiimidazole (4.254 g, 26.2 mol) was added to a solution of picolinic acid N-oxide (3.318g, 23.9 mol) in dry dimethylformamide (50 ml). After 4 hours, 2-aminopyridine (2.466 g, 26.2 mol) was added. After 1 hour, the solution was warmed to 100° for 80 minutes and cooled to room temperature. After 18 hours the solution was subjected to evaporation in vacuo to give an oil which slowly crystallised. The solid was recrystallised from EtOH to give the title compound (3.775 g) as needles, m.p. 140°-5°.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].NCCCOC1C=CN2C(C=1)=CC(C(NC[C@H](NS(C1C=CC=CC=1)(=O)=O)C(O)=O)=O)=CC2=O.C([O:46][C:47](=[O:88])[C@@H:48]([NH:78][S:79]([C:82]1[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=1)(=[O:81])=[O:80])[CH2:49][NH:50][C:51]([C:53]1[CH:54]=[C:55]2[N:60]([C:61](=[O:63])[CH:62]=1)[CH:59]=[CH:58][C:57]([O:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][NH:70]C(OC(C)(C)C)=O)=[CH:56]2)=[O:52])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:70][CH2:69][CH2:68][CH2:67][CH2:66][CH2:65][O:64][C:57]1[CH:58]=[CH:59][N:60]2[C:55]([CH:56]=1)=[CH:54][C:53]([C:51]([NH:50][CH2:49][C@H:48]([NH:78][S:79]([C:82]1[CH:83]=[CH:84][CH:85]=[CH:86][CH:87]=1)(=[O:81])=[O:80])[C:47]([OH:88])=[O:46])=[O:52])=[CH:62][C:61]2=[O:63]
Reactant: CC(C)(C)OC(=O)NCCCCCOc1ccn2c(=O)cc(C(=O)NC[C@H](NS(=O)(=O)c3ccccc3)C(=O)OC(C)(C)C)cc2c1
Agent: NCCCOc1ccn2c(=O)cc(C(=O)NC[C@H](NS(=O)(=O)c3ccccc3)C(=O)O)cc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCCCCOc1ccn2c(=O)cc(C(=O)NC[C@H](NS(=O)(=O)c3ccccc3)C(=O)O)cc2c1
Yield: 86 %

Procedure:
Using the procedure described for the preparation of compound XXX (step E), (S)-2-benzenesulfonylamino-3-{[8-(5-tert-butoxycarbonylamino-pentyloxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionic acid tert-butyl ester (42 mg, 0.063 mmol) was treated with trifluoroacetic acid in dichloromethane to afford compound XXXIV (34 mg, 86%) as a yellow solid which was characterized by 1HNMR (400 MHz, CD3OD) δ: 9.04 (1H, d, J=7.9 Hz), 7.86 (2H, dd, J=1.2, 7.7 Hz), 7.46-7.54 (3H, m), 7.21 (1H, d, J=2.5 Hz), 7.06 (1H, d, J=1.1 Hz), 7.02 (1H, dd, J=2.7, 8.0 Hz), 6.58 (1H, d, J=1.6 Hz), 4.21-4.25 (3H, m), 3.79 (1H,dd, J=5.0, 13.5 Hz), 3.52 (1H, dd, J=8.5, 13.4 Hz), 2.99 (2H, t, J=7.4 Hz), 1.92-1.99, 1.74-1.82, 1.61-1.68 (6H, 3 multiplets).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].C[O:7][C:8](=[O:28])[CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13](S(=O)(=O)NC2C=CC=C(Br)C=2)[CH:12]=1.Cl>>[Cl:1][S:2]([C:14]1[CH:15]=[CH:16][C:11]([CH:10]=[CH:9][C:8]([OH:28])=[O:7])=[CH:12][CH:13]=1)(=[O:5])=[O:3]
Reactant: COC(=O)C=Cc1cccc(S(=O)(=O)Nc2cccc(Br)c2)c1
Reactant: O=S(=O)(O)Cl
Agent: Cl
Product: O=C(O)C=Cc1ccc(S(=O)(=O)Cl)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 20.3 %

Procedure:
To neat chlorosulfonic acid (5.3 ml, 80 mmol) at 0–5° C. temperature slowly cinnamic acid (41) (1.47 g, 10 mmol) was added. As the reaction proceeded hydrogen chloride gas evolved. The reaction mixture was stirred successively at 0° C. for 1 hour, at ambient temperature for 2 hours and at 40–42° C. for 2 hours. The dark, viscous syrup was poured onto ice, the precipitated solid was filtered and washed with water. The title compound (0.5 g, 20%) as a white solid was obtained. 1H NMR (DMSO-d6, HMDSO), δ 6.55 (1H, d, J=16 Hz); 7.58 (1H, d, J=16.0 Hz); 7.65 (4H, s); 8.15 (1H, br s).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][C:16](O)=[O:17])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.S(Cl)(Cl)=O>C1C=CC=CC=1>[F:29][C:2]([F:28])([F:1])[C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14]3[CH2:19][C:20]4[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:16](=[O:17])[CH2:15]3)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: O=C(O)CC(Cc1ccccc1)c1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: O=C1CC(c2ccc(Oc3ccc(C(F)(F)F)cc3)cc2)Cc2ccccc21

Procedure:
3-(4(p-trifluoromethylphenoxy)phenyl)-4-phenylbutyric acid (23 g) was refluxed in benzene with thionyl chloride (46 ml) for one hour. The solution was then evaporated to dryness and the residue dissolved in benzene (23 ml). A solution of stannic chloride (23 g) in benzene (46 ml) was added at 0° with stirring. The solution was allowed to stir at 0° for 0.5 hr. Ice; water, diethylether and dilute HCl were then added sequentially. The ether extracts were further washed with aqueous potassium hydroxide and evaporated to give 3-(4-(p-trifluoromethylphenoxy)phenyl)tetralone m.p. 136°-137° (ethanol).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([C:21]4[CH:22]=[CH:23][C:24]([N:27]5[C@H:31]([CH2:32][OH:33])[CH2:30][O:29][C:28]5=[O:34])=[N:25][CH:26]=4)=[O:20])[CH2:15][CH2:14]3)=[N:6][CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:3][CH2:2]1.[CH3:35]I>>[CH:1]1([C:4]2[C:5]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([C:21]4[CH:22]=[CH:23][C:24]([N:27]5[C@H:31]([CH2:32][O:33][CH3:35])[CH2:30][O:29][C:28]5=[O:34])=[N:25][CH:26]=4)=[O:20])[CH2:15][CH2:14]3)=[N:6][CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:2][CH2:3]1
Reactant: O=C(c1ccc(N2C(=O)OC[C@H]2CO)nc1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Reactant: CI
Product: COC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C4CC4)cc3C3CC3)CC2)cn1

Procedure:
By reaction and treatment in the same manner as in Example 73 and using (R)-3-{5-[4-(3,5-dicyclopropylpyridin-2-yl)piperazine-1-carbonyl]pyridin-2-yl}-4-hydroxymethyloxazolidin-2-one (310 mg) described in Example 252 and methyl iodide (50 μL), the title compound (85 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][O:16][C:17]3[NH:22][C:21](=[O:23])[N:20]=[CH:19][CH:18]=3)=[N:13][CH:14]=2)=[CH:4][C:3]=1[C:24]([F:27])([F:26])[F:25].Cl.Cl[CH2:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][O:16][C:17]3[CH:18]=[CH:19][N:20]([CH2:30][C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)[C:21](=[O:23])[N:22]=3)=[N:13][CH:14]=2)=[CH:4][C:3]=1[C:24]([F:25])([F:26])[F:27]
Reactant: O=c1nccc(OCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cn2)[nH]1
Reactant: ClCc1cccnc1
Agent: Cl
Product: O=c1nc(OCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cn2)ccn1Cc1cccnc1

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 6-{[(5-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-2-pyridinyl)methyl]oxy}-2(1H)-pyrimidinone and 3-(chloromethyl)pyridine hydrochloride. LC-MS (ESI): m/z 489 [M+H]+; 2.67 min (ret time).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:6]2[NH:7][C:8](=[O:10])[NH:9][C:5]=2[CH:4]=1.[OH-].[Na+]>I>[OH:2][C:3]1[CH:12]=[CH:11][C:6]2[NH:7][C:8](=[O:10])[NH:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2[nH]c(=O)[nH]c2c1
Agent: I
Agent: [Na+]
Agent: [OH-]
Product: O=c1[nH]c2ccc(O)cc2[nH]1
Temperature: 130 °C
Reaction time: 12 h
Yield: 511.7 %

Procedure:
A mixture of intermediate 37 (3.6 g, 22 mmol) and 48% hydrogen iodide (30 mL) was heated to reflux (130° C.) and stirred for 12 h. The reaction mixture was neutralized to pH=8 with aq NaOH and then extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, concentrated under vacuum and purified by flash chromatography on silica gel column (elution with DCM/MeOH=80:1) to give 5-hydroxy-1H-benzo[d]imidazol-2(3H)-one (intermediate 38) (16.9 g, 80%). HPLC: 99%, RT 1.377 min. MS (ESI) m/z 151.0 [M+H]+. mp: 186-187° C.
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](OCC)=[O:29])[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][O:34][CH:35]1[CH2:38][NH:37][CH2:36]1.C[Al](C)C.C(O)(=O)C.C(OCC)(=O)C>C1(C)C=CC=CC=1.C1C=CC=CC=1>[Si:1]([O:18][CH:19]1[CH2:20][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28]([N:37]3[CH2:38][CH:35]([O:34][CH3:33])[CH2:36]3)=[O:29])[N:27]=2)[CH2:22]1)([C:14]([CH3:15])([CH3:17])[CH3:16])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC1CNC1
Reactant: CCOC(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Agent: C[Al](C)C
Solvent: c1ccccc1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC1CN(C(=O)c2csc(N3CC(O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)C3)n2)C1
Temperature: 80 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
Subsequently, to a solution of 3-t-butyldiphenylsilyloxy-1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)azetidine (500 mg, 1.07 mmol) in toluene (25 ml) was added a solution of 0.67M 3-methoxyazetidine-trimethylaluminium in benzene (3.21 ml) at room temperature under an atmosphere of nitrogen. The mixture was stirred in a water bath (80° C.) for 1 hour. After checking the completion of the reaction, 10% aqueous acetic acid solution (20 ml) and ethyl acetate (50 ml) were added to the reaction mixture in an ice bath, and the resulting mixture was stirred at room temperature for 1 hour. After adding ethyl acetate thereto, the reaction mixture was partitioned between ethyl acetate and water. The obtained organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate as the eluant to afford 3-t-butyldiphenylsilyloxy-1-[4-(3-methoxyazetidine-1-carbonyl)-1,3-thiazol-2-yl]azetidine (366 mg, yield 67%) as a pale brown solid.
Reaction SMILES: CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1.C([O:19][C:20](=O)/[CH:21]=[C:22](/[C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)=[CH:26][CH:25]=1)\[CH3:23])C.Cl>C1COCC1.CO>[Cl:36][C:33]1[CH:32]=[CH:31][C:30]([C:27]2[CH:28]=[CH:29][C:24](/[C:22](/[CH3:23])=[CH:21]/[CH2:20][OH:19])=[CH:25][CH:26]=2)=[CH:35][CH:34]=1
Reactant: CCOC(=O)/C=C(\C)c1ccc(-c2ccc(Cl)cc2)cc1
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CO
Solvent: C1CCOC1
Product: C/C(=C\CO)c1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 25 °C

Procedure:
A 1M solution of DIBAL-H in toluene (10 ml, 10 mmol) was added dropwise, at −70° C. over 10 min, to a stirred solution of (E)-ethyl-3-(4′-chloro-biphenyl-4-yl)-but-2-enoate (1.0 g, 3.32 mmol) in dry THF (25 ml), and the mixture warmed to room temperature over 4 h. Methanol (1 ml) was carefully added, followed by 1N HCl (50 ml) and the resulting mixture extracted with ethyl acetate (2×50 ml). The combined organic extracts were washed with brine, dried (MgSO4), and evaporated to give the product, (E)-3-(4′-chloro-biphenyl-4-yl)-but-2-en-1-ol as a colourless solid: 0.86 g (100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([CH:18]=1)[CH2:7][C:8]1[CH:17]=[CH:16][C:11]([O:12][CH2:13][CH2:14][OH:15])=[CH:10][CH:9]=1.N1C=CC=CC=1.[S:26](Cl)([C:29]1[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=1)(=[O:28])=[O:27].CC(=O)OCC>C(Cl)Cl.O>[CH3:33][C:32]1[CH:34]=[CH:35][C:29]([S:26]([O:15][CH2:14][CH2:13][O:12][C:11]2[CH:16]=[CH:17][C:8]([CH2:7][C:6]3[CH:18]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=3[Cl:19])=[CH:9][CH:10]=2)(=[O:28])=[O:27])=[CH:30][CH:31]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCOc1ccc(Cc2cc(Br)ccc2Cl)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCCOc2ccc(Cc3cc(Br)ccc3Cl)cc2)cc1
Temperature: 0 °C
Yield: 81.7 %

Procedure:
To a solution of 2-(4-(5-bromo-2-chlorobenzyl)phenoxy)ethanol (intermediate I) (3.41 g) in anhydrous DCM (20 mL), pyridine (2.0 eq) was added, and then the mixture was stirred and cooled to 0° C. Then TsCl (1.3 eq) was added in portions, and the mixture was allowed to warmed to room temperature and stirred overnight. TLC (PE:EA=4:1) showed the reaction was complete. Then the mixture was poured into water and extracted with DCM, washed with water and brine, and dried with anhydrous Na2SO4. The solvent was then evaporated under reduced pressure, and the solid crude product was purified by column chromatography (PE:EA=30:1) to obtain intermediate AB (4.05 g, yield 81.7%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:1]([O:5][C:6]([N:8]1[C@@H:9]([CH2:10][CH:11]([CH3:12])[CH3:13])[C:14](=[O:16])[O:15][CH2:17]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: CC(C)C[C@H]1C(=O)OCN1C(=O)OC(C)(C)C

Procedure:
(4S)-N-tert-Butyloxycarbonyl 4-isobutyl-1,3-oxazolidin-5-one (4) was prepared from N-tert-butyloxycarbonyl-(L)-leucine (2.31 g, 10.0 mM) and para-toluenesulfonic acid (30 mg) following general procedure A and obtained as a colourless, slowly solidifying oil after purification by flash column chromatography, using 30% chloroform/petroleum ether as eluant (1.91 g, 79%): [α] D20 +88.5 (c 0.9, CHCl3); IR (CHCl3): 1790, 1720 cm-1 ; 1H NMR (200 MHz, CDCl3): δ 5.48 (d, J=5 Hz, 1H), 5.09 (d, J=5 Hz, 1H), 4.22 (t, J=6 Hz, 1H), 1.43 (s, 9H), 1.23-1.16 (m, 3H), 0.92 (d, J=5 Hz, 3H), 0.90 (d, J=5 Hz, 3H); 13C NMR (50.3 MHz, CDCl3): δ 172.9, 152.2, 81.5, 77.8, 53.2, 39.4, 27.9, 24.2, 22.4,22.2; LRMS (NH3): 244 (MH+).
Reaction SMILES: [CH3:1][C:2]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10](=[O:11])[C:9]2[C:4](=[CH:5][C:6]([OH:14])=[C:7]([Cl:13])[C:8]=2[Cl:12])[C:3]1=[O:15].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]([O:32]CC)=[O:31].[OH-].[K+].Cl>CN(C)C=O.O.CO>[O:15]=[C:3]1[C:4]2[C:9](=[C:8]([Cl:12])[C:7]([Cl:13])=[C:6]([O:14][CH2:29][C:30]([OH:32])=[O:31])[CH:5]=2)[C:10](=[O:11])[C:2]1([CH3:1])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC1(c2ccccc2)C(=O)c2cc(O)c(Cl)c(Cl)c2C1=O
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: CC1(c2ccccc2)C(=O)c2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O

Procedure:
A stirred mixture of 2-methyl-2-phenyl-4,5-dichloro-6-hydroxyindan-1,3-dione (2.14 g., 0.0067 mole), potassium carbonate (1.85 g., 0.0134 mole) and ethyl bromoacetate (2.32 g., 0.0134 mole) in dimethylformamide (30 ml.) is warmed at 55°-60°C. for 3 hours, then treated with potassium hydroxide (0.97 g., 0.0147 mole) dissolved in a minimum amount of water in methanol (30 ml.) and heated on a steam bath for 21/2 hrs. The reaction mixture is poured into water (500 ml.), acidified with 6 N hydrochloric acid and the precipitate collected after trituration with ether-petroleum ether and dried to give (1,3-dioxo-2-methyl-2-phenyl-4,5-dichloro-6-indanyloxy)acetic acid.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH2:7][NH2:8])=[CH:4][CH:3]=1.F[C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]>>[CH3:1][C:2]1[S:6][C:5]([CH2:7][NH:8][C:15]2[CH:16]=[N:17][CH:18]=[CH:10][C:11]=2[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccncc1F
Reactant: Cc1ccc(CN)s1
Product: Cc1ccc(CNc2cnccc2C(=O)O)s1
Yield: 7 %

Procedure:
The title compound was prepared in 7% yield from 5-methylthiophen-2-ylmethylamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. 1H NMR (400 MHz, DMSO-d6): δ 8.27 (br s, 1H), 7.84 (br s, 1H), 7.57 (d, 1H, J=4.8 Hz), 6.87 (d, 1H, 3.2 Hz), 6.65 (d, 1H, J=2.3 Hz), 4.65 (s, 2H), 2.38 (s, 3H). [M+H] calc'd for C12H12N2O2S, 249; found 249.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][C:18]3[C:23]([CH3:24])=[CH:22][C:21]([N+:25]([O-])=O)=[CH:20][C:19]=3[CH3:28])=[CH:14][CH:15]=2)[C:10]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][C:18]3[C:19]([CH3:28])=[CH:20][C:21]([NH2:25])=[CH:22][C:23]=3[CH3:24])=[CH:14][CH:15]=2)[C:10]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCc1nn(C(=O)OC(C)(C)C)c2ccc(Oc3c(C)cc([N+](=O)[O-])cc3C)cc12
Agent: [Pd]
Solvent: CCO
Product: CCCCCc1nn(C(=O)OC(C)(C)C)c2ccc(Oc3c(C)cc(N)cc3C)cc12
Reaction time: 2 h
Yield: 104.9 %

Procedure:
A suspension of 1.570 g (3.116 mmol) of 1-tert-butoxycarbonyl-5-(2,6-dimethyl-4-nitrophenoxy)-3-pentylindazole (Example XXII) and 250 mg (2.349 mmol) of palladium/carbon (10%) in 25 ml of ethanol are hydrogenated under a hydrogen atmosphere for 2 h. The reaction mixture is filtered off through kieselguhr, and the filtrate is concentrated in vacuo and dried. 1.385 g (95% or theory) of 1-tert-butoxycarbonyl-5-(4-amino-2,6-dimethylphenoxy)-3-pentyl-1H-indazole are obtained.
Reaction SMILES: [Na+:1].C(NC([N:12]1[CH2:18][CH2:17][C@@H:16]2[C@H:13]1[C:14](=O)[N:15]2[S:19]([O-:22])(=[O:21])=[O:20])=O)C1C=CC=CC=1.C(N(CC)CC)C.[C:31](Cl)(=[O:40])[CH:32]=[CH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>ClCCl>[Na+:1].[C:34]1(/[CH:33]=[CH:32]/[C:31]([C@:13]23[CH2:14][N:15]([S:19]([O-:22])(=[O:20])=[O:21])[C@@H:16]2[CH2:17][CH2:18][NH:12]3)=[O:40])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(NCc1ccccc1)N1CC[C@@H]2[C@H]1C(=O)N2S(=O)(=O)[O-]
Reactant: O=C(Cl)C=Cc1ccccc1
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(/C=C/c1ccccc1)[C@]12CN(S(=O)(=O)[O-])[C@@H]1CCN2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(1S,5R)-2,6-Diazabicyclo[3.2.0]heptan-7-one (Example 2) (500 mg, 4.5 mmol) were suspended in 50 ml of dichloromethane. 0.75 ml (5.4 mmol) of triethylamine and subsequently 890 mg (5.4 mmol) of cinnamoyl chloride were added dropwise thereto while cooling with ice and the mixture was left to stir for 30 minutes while cooling and for 3.5 hours at room temperature. Thereafter, it was extracted once each time with saturated aqueous sodium carbonate solution, 2% aqueous citric acid solution, water and saturated aqueous sodium chloride solution. The combined organic phases were dried over magnesium sulphate and concentrated. Purification was effected by flash chromatography over silica gel with ethyl acetate. Yield: 560 mg (52%).