Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7](Cl)=[CH:6][CH:5]=[CH:4][N:3]=1.C[C@@H:10]1[CH2:15][NH:14][CH2:13][CH2:12][NH:11]1.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O.O>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH2:10]1
Reactant: C[C@@H]1CNCCN1
Reactant: Clc1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: c1ccc(N2CCNCC2)nc1
Temperature: 25 °C

Procedure:
Dissolve 2,3-dichloropyridine (8.5 g, 0.057 moles) and (R)-(−)-2-methylpiperazine (5.75 g, 0.057 moles) in DMA(125.0 mL) under nitrogen atmosphere. Add anhydrous powdered K2CO3 (23.75 g, 0.172 moles) to this mixture and stir at 135-140° C. for 48 hours. Cool the reaction mixture to room temperature, dilute with water (400 mL), extract with EtOAc (3×200 mL) and wash the combined organic extract with brine (2×150 mL). Dry over MgSO4, concentrate under vacuum to afford crude product as orange yellow liquid. Distil the crude under high vacuum to afford pyridylpiperazine derivative as yellow viscous oil.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(CC)C(C)C)(C)C>C(#N)C>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([N:15]2[CH2:14][CH2:13][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]2)[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2cc(F)ccc2[N+](=O)[O-])CC1

Procedure:
2,4-Difluoronitrobenzene (10.0 g, 62.9 mmol), t-butyl piperazine-1-carboxylate (11.7 g, 62.9 mmol) and N,N-diisopropylethylamine (8.10 g, 62.9 mmol) were stirred at room temperature in dry acetonitrile (100 mL) for 16 h. The solvent was removed by rotary evaporation and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was removed by rotary evaporation to collect the title compound (19.0 g, 93%). 1H NMR (400 MHz, CDCl3): δ 7.91 (dd, 1H), 6.75 (m, 2H), 3.60 (m, 4H), 3.03 (m, 4H), 1.48 (s, 9H); MS (ESI) m/z: Calculated for C15H20FN3O4: 325.14; Observed: 348.1 (M++Na).
Reaction SMILES: CC(C)=O.[CH3:5][O:6][CH2:7][CH:8]([OH:16])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CC(O)C>[CH3:5][O:6][CH2:7][C:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:16]
Reactant: COCC(O)Cc1ccccc1
Solvent: CC(C)O
Solvent: CC(C)=O
Product: COCC(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
20.4 ml of a Jone's reagent was slowly added dropwise into 200 ml of an acetone solution containing 5.1 g of 1-methoxy-3-phenyl-2-propanol. After stirring for 30 minutes at room temperature, 30 ml of 2-propanol was slowly added to the reaction solution. After removing the solvent, water was added thereto and the mixture was extracted with ethyl acetate. The organic phase was washed with brine and the solvent was removed. The residue was subjected to silica gel column chromatography and elute with hexane/ethyl acetate (6:1), to give 3.7 g of the target compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([Sn:10]([CH3:13])([CH3:12])[CH3:11])[CH:6]=[CH:7][C:8]=1[F:9].Cl[S:15]([CH3:18])(=[O:17])=[O:16].CCN(CC)CC.CCOC(C)=O.O>C(Cl)Cl>[CH3:18][S:15]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]([Sn:10]([CH3:13])([CH3:12])[CH3:11])[CH:6]=[CH:7][C:8]=1[F:9])(=[O:17])=[O:16]
Reactant: C[Sn](C)(C)c1ccc(F)c(CN)c1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CS(=O)(=O)NCc1cc([Sn](C)(C)C)ccc1F
Reaction time: 3 h
Yield: 53.1 %

Procedure:
A mixture of 3-aminomethyl-4-fluoro-1-trimethylstannylbenzene (507.9 mg, 1.76 mmol), ClSO2Me (180.9 μL, 2.29 mmol) and NEt3 (492 μL, 3.52 mmol) was stirred at room temperature in CH2Cl2 (18 mL). After 3 h, extractive EtOAc/H2O workup followed by flash chromatography (EtOAc/Hexanes, 20:80) provided the title compound (342 mg, 53%) as an oil. 1H NMR (CDCl3, 400 MHz.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:33])[CH2:13][CH2:12][N:11]([C:14](=[O:30])[C@H:15]([NH:19][C:20]3[S:21][CH:22]=[C:23]([C:25]([O:27]CC)=[O:26])[N:24]=3)[CH:16]([CH3:18])[CH3:17])[CH2:10][C:9]2([CH3:32])[CH3:31])=[CH:4][CH:3]=1.C1COCC1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:33])[CH2:13][CH2:12][N:11]([C:14](=[O:30])[C@H:15]([NH:19][C:20]3[S:21][CH:22]=[C:23]([C:25]([OH:27])=[O:26])[N:24]=3)[CH:16]([CH3:18])[CH3:17])[CH2:10][C:9]2([CH3:31])[CH3:32])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1csc(N[C@@H](C(=O)N2CC[C@](O)(c3ccc(Cl)cc3)C(C)(C)C2)C(C)C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)[C@@H](Nc1nc(C(=O)O)cs1)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Temperature: 25 °C

Procedure:
To a solution of ethyl 2-((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-ylamino)thiazole-4-carboxylate (69 mg, 0.140 mmol) in MeOH (0.28 ml)/THF (0.280 ml) was added NaOH, IN (0.140 ml, 0.140 mmol) and the reaction stirred at room temperature. The reaction was stirred for 8 h and then neutralized with 1 N HCL. The solvents were removed and water (˜1 mL) was added. The resulting solids were stirred and sonicated briefly, filtered and rinsed with water. HPLC purity of crude solids, ˜90%; MS found: 466.26 (M+)+.
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[C:7]([OH:10])[C:6]([CH3:11])=[CH:5][C:3]=1[OH:4].C(O[CH:16]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])(=O)C.B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[C:26]1([CH:16]([C:5]2[C:3](=[O:4])[C:2]([CH3:1])=[C:8]([CH3:9])[C:7](=[O:10])[C:6]=2[CH3:11])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(=O)OC(CCCCCCC(=O)O)c1ccccc1
Reactant: Cc1cc(O)c(C)c(C)c1O
Agent: FB(F)F
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC1=C(C)C(=O)C(C(CCCCCCC(=O)O)c2ccccc2)=C(C)C1=O
Yield: 78.7 %

Procedure:
2,3,5-Trimethylhydroquinone (3.1 g, 0.02 mole) and 8-acetoxy-8-phenyloctanoic acid (6.0 g, 0.021 mole) were added to toluene (80 ml), and boron trifluoride ethyl etherate (0.3 ml) was added dropwise to the mixture at room temperature, with stirring. The reaction solution was stirred at room temperature for 4 days, and then the solvent was distilled off under reduced pressure. The residue was dissolved in tetrahydrofuran (50 ml), and a 10% aqueous solution of ferric chloride was added to the solution to conduct oxidation to the quinone derivative. The reaction product was extracted twice with ethyl acetate, and the organic layer was washed with water, dried and concentrated under reduced pressure. The resulting crude product was chromatographed on a silica gel column, followed by elution with isopropyl ether, and the quinone derivative was recrystallized from isopropyl ether to give 8-phenyl-8-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)octanoic acid (5.8 g, 78%). Its typical physical properties and nuclear magnetic resonance spectrum data are shown in Table 1. By following the procedure of this Example, the Compound Nos. 10 to 19, 50 and 51 were prepared.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([O:11][CH3:12])=[O:10])[N+:5]([O-:13])=[C:4]([NH:14][C:15]([O:17][CH3:18])=[O:16])[CH:3]=1.[OH:19][CH:20]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]1>C(Cl)Cl>[OH:19][CH:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:2]2[N:7]=[C:6]([NH:8][C:9]([O:11][CH3:12])=[O:10])[N+:5]([O-:13])=[C:4]([NH:14][C:15]([O:17][CH3:18])=[O:16])[CH:3]=2)[CH2:21]1
Reactant: COC(=O)Nc1cc(Cl)nc(NC(=O)OC)[n+]1[O-]
Reactant: OC1CCCNC1
Solvent: ClCCl
Product: COC(=O)Nc1cc(N2CCCC(O)C2)nc(NC(=O)OC)[n+]1[O-]

Procedure:
A suspension of 5.2 g. of dimethyl 6-chloro-2,4-pyrimidine-dicarbamate-3-oxide in 300 ml. of methylene chloride is treated with 12.4 g. of 3-hydroxy-piperidine and stirred for 60 hours under an argon atmosphere. The residue is then filtered off and the filtrate is concentrated, a white precipitate separating out. This precipitate is filtered off and recrystallized from a mixture of methylene chloride and methanol, there being obtained pure dimethyl racemic-6-(3-hydroxy-1-piperidinyl)-2,4-pyrimidine-dicarbamate-3-oxide, having a melting point of 255° C. (decomposition).
Reaction SMILES: C([O:8][C:9]1[CH:51]=[CH:50][C:12]([CH2:13][C:14]([C:40]([O:42]CC2C=CC=CC=2)=[O:41])([CH2:22][CH2:23][C@@H:24]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[C:28]([O:27][C:25](=[O:26])[C@H:24]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:23][CH2:22][C:14]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])([CH2:13][C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:51][CH:50]=1)[C:40]([OH:42])=[O:41])([CH3:29])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)N[C@H](CCC(Cc1ccc(OCc2ccccc2)cc1)(C(=O)OCc1ccccc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H](CCC(Cc1ccc(O)cc1)(C(=O)O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 98.4 %

Procedure:
To a solution of 370 mg di-tert-butyl (5R)-2-[4-(benzyloxy)benzyl]-2-(benzyloxycarbonyl)-5-[(tert-butoxycarbonyl)amino]hexanedioate (0.53 mmol) in methanol (10 mL) was added a 10% palladium on carbon hydrogenation catalyst (50 mg) at room temperature. The suspension was stirred for 2.5 hours at room temperature under an atmosphere of hydrogen. The catalyst was removed by filtration and all volatiles were removed in vacuo. The crude product (273 mg, 99% yield) was used in the next step without further purification.
Reaction SMILES: [C:1]([NH:6][CH2:7][C:8]([NH:10][C@H:11]([C:19]([NH:21][C@H:22]([C:27]([NH:29][CH2:30][C:31]([OH:33])=O)=[O:28])[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:20])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:9])(=[O:5])[C:2]([CH3:4])=[CH2:3].[SH:34][C:35]1[S:36][CH2:37][CH2:38][N:39]=1.CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.ClCCl>[C:1]([NH:6][CH2:7][C:8]([NH:10][C@H:11]([C:19]([NH:21][C@H:22]([C:27]([NH:29][CH2:30][C:31]([N:39]1[CH2:38][CH2:37][S:36][C:35]1=[S:34])=[O:33])=[O:28])[CH2:23][CH:24]([CH3:25])[CH3:26])=[O:20])[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:9])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: SC1=NCCS1
Reactant: C=C(C)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=C(C)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N1CCSC1=S
Temperature: -10 °C
Reaction time: 12 h
Yield: 51.9 %

Procedure:
The synthesis of MA-GFLG-TT followed a published procedure [V. {hacek over (S)}ubr et al., Reactive & Functional Polymers 66 1525-1538 (2006)] with a slight modification. Under nitrogen atmosphere, N-methacryloylglycylphenylalanylleucylglycine (MA-GFLG-OH; 320 mg, 0.7 mmol), 2-mercaptothiazoline (83.5 mg, 0.7 mmol) and DMAP (85.5 mg, 0.7 mmol) were dissolved in dichloromethane (DCM) (20 mL). The solution was stirred for 5 min −10° C., EDCI (134.2 mg, 0.7 mmol) was added and the solution was stirred −10° C. for 3 h and at room temperature for another 12 h. After reaction, 50 mL DCM was added, the solution was washed with NaHCO3 aq. (0.1 M), HCl (0.1 M) and then NaCl aq. The organic layer was dried (MgSO4), solvent removed by rotary evaporation and the crude product was purified by column chromatography (silica gel 60 Å, 200-400 mesh, EtOAc: CH3OH, 15:1) and then recrystallized from DCM to give yellow powder in 51.9% yield. The structure was confirmed by 1H NMR and 13C NMR spectroscopy. 1H NMR (300 MHz, CDCl3, δ in ppm): 0.86 (m, 6 H, CH(CH3)2), 1.51 (m, 2H, CHCH2CH(CH3)2), 1.66 (m, 1H, CH(CH3)2), 1.91 (s, 3 H, CCH3), 3.03 (m, 2 H, Ph-CH2), 3.33 (t, 2 H, SCH2), 4.00 (s, 2 H, NHCH2CO), 4.54 (t, 2 H, NCH2CH2S), 4.63 (m, 1 H, NHCHCO), 4.73 (m, 1 H, NHCHCO), 4.81 (s, 2 H, NHCH2CO), 5.39 (s, 1H, C═CH2), 5.77 (s, 1H, C═CH2), 6.99 (s, 1 H, NH), 7.18 (m, 6 H, NH, Ph-H), 7.56-7.80 (m, 2 H, NH). 13C NMR (75 MHz, CDCl3, δ in ppm): 201.78, 172.6, 170.92, 170.57, 169.33, 168.99, 139.02, 136.46, 129.77, 128.80, 127.21, 121.31, 56.11, 54.89, 51.83, 46.85, 43.61, 41.81, 39.37, 29.37, 24.88, 22.86, 18.21.
Reaction SMILES: [CH:1]1([C:6]([CH2:8][C:9]2[C:10]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])=[C:11]3[C:15](=[C:16]([CH3:20])[C:17]=2[CH2:18][CH3:19])[CH2:14][O:13][C:12]3=[O:21])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1>C1(C)C=CC=CC=1>[Si:23]([O:22][C:10]1[C:9]([CH2:8][C@@H:6]([C:1]2[CH2:5][CH2:4][CH2:3][CH:2]=2)[OH:7])=[C:17]([CH2:18][CH3:19])[C:16]([CH3:20])=[C:15]2[C:11]=1[C:12](=[O:21])[O:13][CH2:14]2)([C:26]([CH3:27])([CH3:28])[CH3:29])([CH3:25])[CH3:24]
Reactant: CCc1c(C)c2c(c(O[Si](C)(C)C(C)(C)C)c1CC(=O)C1CCCC1)C(=O)OC2
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: Cc1ccccc1
Product: CCc1c(C)c2c(c(O[Si](C)(C)C(C)(C)C)c1C[C@H](O)C1=CCCC1)C(=O)OC2
Temperature: -30 °C
Reaction time: 16 h

Procedure:
Cyclopentyl (4-t-butyldimethylsilyloxy-1,3-dihydro-6-ethyl-7-methyl-3-oxoisobenzofuran-5-yl methyl)methanone (4.2 g) was treated with a 1M toluene solution of (R)-tetrahydro-1-methyl-3,3-diphenyl-1H, 3H-pyrrolo[1,2-c][1,3,2]oxazaborole (3 ml). The toluene was evaporated in vacuo and methylene chloride added (2 ml). The reaction mixture was cooled to -30° C. and borane/dimethyl sulfide (0.33 ml) was added three times at 45 minute intervals. The reaction mixture was stirred 16 hours at -30° C. and quenched by addition of 1M hydrogen chloride/ether (3 ml). Toluene was added (10 ml) and the solution filtered, diluted with ether (200 ml), washed with aqueous hydrochloric acid, aqueous sodium bicarbonate and brine. Drying and evaporation gave an oil which was purified by silica gel chromatography to give (S)-2-(4-t-butyldimethylsilyloxy-1,3-dihydro-6-ethyl-7-methyl-3-oxoisobenzofuran-5-yl)-1-cyclopentenyl-1-hydroxyethane. Further purification by crystallization from t-butylmethyl ether gave material with an enantiomeric excess of 97.8% (Chiracel OD-H, 85:15 hexane:i-propanol, 0.8 ml/minute, minor 8.3 minutes, major 9.2 minutes).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH3:35])=[C:6]([C:8]([CH3:33])([CH3:32])[CH2:9][C:10]([C:28]([F:31])([F:30])[F:29])([OH:27])[CH:11]=[N:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][C:17]([C:23]([F:26])([F:25])[F:24])=[N:18]3)[CH:7]=1.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH3:35])=[C:6]([C:8]([CH3:32])([CH3:33])[CH2:9][C:10]([C:28]([F:29])([F:30])[F:31])([OH:27])[CH2:11][NH:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][C:17]([C:23]([F:26])([F:24])[F:25])=[N:18]3)[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(C=Nc1cccc2nc(C(F)(F)F)ccc12)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cccc2nc(C(F)(F)F)ccc12)C(F)(F)F

Procedure:
Analogously to Example 37, 500 mg (0.99 mmol) of 4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-trifluoromethyl-1-(2-(trifluoromethyl)quinolin-5-ylimino)-pentan-2-ol is reacted with 154 mg (4.04 mmol) of sodium borohydride in 5.0 ml of methanol. After purification on silica gel with hexane-ethyl acetate (0–100%), 420 mg (84% of theory) of the product is obtained.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][C:19]2([OH:23])[CH2:22][CH2:21][CH2:20]2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.[OH-].[NH4+:36].S(Cl)(C1C=CC(C)=CC=1)(=O)=O>ClCCl>[NH2:36][C:9]1[C:8]2[N:17]=[C:5]([CH2:4][O:3][CH2:1][CH3:2])[N:6]([CH2:18][C:19]3([OH:23])[CH2:22][CH2:21][CH2:20]3)[C:7]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: [NH4+]
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC1(O)CCC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CC1(O)CCC1
Reaction time: 1 h
Yield: 43 %

Procedure:
To a solution of 1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclobutanol (4.05 g, 13.0 mmol) in dichloromethane (85 mL) at rt was added m-CPBA (55%, 4.08 g, 13.0 mmol). After 1 h, concentrated ammonium hydroxide (85 mL) was added, followed by TsCl (2.73 g, 14.3 mmol). The reaction was stirred rapidly for 2 d. More TsCl (0.25 g) was added and the mixture was stirred one day more. The layers were separated. Water was added to the aqueous layer, which was extracted twice with dichloromethane. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, and concentrated to a pale yellow foam. Acetonitrile was added to the foam, causing a solid to form. The solid was triturated with hot acetonitrile to yield an off white solid that was crystallized from acetonitrile/dichloromethane. Pale yellow crystals were isolated by filtration and dried under vacuum 80° C. to yield 1.81 g (43%) of 1-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclobutanol, mp 174-175° C. 1H NMR (CDCl3, 300 MHz) δ 8.23 (dd, J=8.3, 1.4 Hz, 1H), 7.78 (dd, J=8.4, 1.4 Hz, 1H), 7.50 (ddd, J=8.4, 7.0, 1.4 Hz, 1H), 7.31 (ddd, J=8.4, 7.0, 1.4 Hz, 1H), 5.41 (br s, 2H), 4.893 (s, 2H), 4.886 (s, 2H), 3.64 (q, J=7.0 Hz, 2H), 3.50 (br s, 1H), 2.35-2.27 (m, 2H), 2.10-1.78 (m, 4H), 1.25 (t, J=7.0 Hz, 3H); MS (APCI) m/z 327 (M+H+); Anal. calcd for C18H22N4O2: C, 66.24; H, 6.79; N, 17.16. Found: C, 66.02; H, 6.87; N, 17.09.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:23])[C:11]([C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)([OH:16])[C:12]([F:15])([F:14])[F:13].Br>>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:23])[C:11]([OH:16])([C:17]1[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=1)[C:12]([F:15])([F:13])[F:14]
Reactant: COc1ccc(C(C)C(O)(c2ccncc2)C(F)(F)F)c(Cl)c1
Agent: Br
Product: CC(c1ccc(O)cc1Cl)C(O)(c1ccncc1)C(F)(F)F

Procedure:
The title compound was prepared in analogy to Example 72 from 3-(2-chloro-4-methoxy-phenyl)-1,1,1-trifluoro-2-pyridin-4-yl-butan-2-ol (Example 104) by treatment with aqueous HBr. MS (m/e)=332.1 (MH+).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH:12]=[C:13]([Cl:28])[C:14]=1[CH2:15][C@@H:16]1[CH2:20][CH2:19][N:18]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[C:17]1=[O:27].Cl[C:37]([O:39][CH3:40])=[O:38].C(N(CC)CC)C>C(Cl)Cl>[CH3:40][O:39][C:37]([N:24]1[CH2:25][CH2:26][CH:21]([N:18]2[CH2:19][CH2:20][C@@H:16]([CH2:15][C:14]3[C:13]([Cl:28])=[CH:12][C:11]([C:29]4[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=4)=[CH:10][C:9]=3[Cl:8])[C:17]2=[O:27])[CH2:22][CH2:23]1)=[O:38]
Reactant: O=C1[C@H](Cc2c(Cl)cc(-c3ccc(F)cc3)cc2Cl)CCN1C1CCNCC1
Reactant: COC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N1CCC(N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(F)cc4)cc3Cl)C2=O)CC1
Yield: 93.3 %

Procedure:
Treat a solution of (R)-3-(3,5-Dichloro-4′-fluoro-biphenyl-4-ylmethyl)-1-piperidin-4-yl-pyrrolidin-2-one trifluoroacetic acid (Preparation 29) (0.10 g, 0.19 mmol) in CH2Cl2 (3 mL) with methyl chloroformate (0.03 mL, 0.36 mmol) and triethylamine (0.07 mL, 0.48 mmol). Stir the reaction for 1 hr at room temperature. Quench the reaction with 1N HCl and extract with Et2O. Wash the organic with brine, dry over MgSO4, and filter. Remove the solvent to afford 0.085 g (74%) of product. MS (m/e): 479 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]=[O:12])[CH:10]=1)[NH:7][N:6]=[CH:5]2.[Br:13]Br>C(O)(=O)C.C(Cl)Cl>[Br:13][C:5]1[C:4]2[C:8](=[C:9]([CH:11]=[O:12])[CH:10]=[C:2]([Cl:1])[CH:3]=2)[NH:7][N:6]=1
Reactant: O=Cc1cc(Cl)cc2cn[nH]c12
Reactant: BrBr
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=Cc1cc(Cl)cc2c(Br)n[nH]c12
Reaction time: 1 h

Procedure:
To a mixture of 5-chloro-1H-indazole-7-carbaldehyde (1.0 g, 5.54 mmol) in acetic acid (5 mL) was added bromine (0.43 mL, 8.31 mmol) slowly over 5 min. After 1 h, the reaction mixture was diluted with methylene chloride, washed with water (2×), saturated sodium thiosulfate (2×), saturated sodium bicarbonate (2×), then brine (2×), dried over sodium sulfate, and concentrated to afford 1.4 g (97%) as a yellow powder. LC/MS (HPLC method 1): tR=2.49 min, 261.00(MH)+.
Reaction SMILES: [CH2:1]([OH:21])[C@:2]12[CH2:18][CH2:17][C@H:16]3[C@@H:7]([CH2:8][CH2:9][C:10]4[CH:11]=[C:12]([OH:19])[CH:13]=[CH:14][C:15]=43)[C@@H:6]1[CH2:5][CH2:4][C@@H:3]2[OH:20].[CH:22]1(Br)[CH2:26][CH2:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH:22]1([O:19][C:12]2[CH:13]=[CH:14][C:15]3[C@@H:16]4[C@H:7]([C@H:6]5[C@@:2]([CH2:18][CH2:17]4)([CH2:1][OH:21])[C@@H:3]([OH:20])[CH2:4][CH2:5]5)[CH2:8][CH2:9][C:10]=3[CH:11]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: OC[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: OC[C@]12CC[C@@H]3c4ccc(OC5CCCC5)cc4CC[C@H]3[C@@H]1CC[C@@H]2O

Procedure:
350 mg. of 1,3,5(10)-estratriene-3,17β,18-triol in 10 ml. of ethanol is heated for 5 hours to the boiling point under N2 with 0.5 ml. of cyclopentyl bromide and 0.5 g. of potassium carbonate. After the mixture has been worked up and purified analogously to Example 18, 3-cyclopentyloxy-1,3,5(10)-estratriene-17β,18-diol is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][C:3]=1OS(C(F)(F)F)(=O)=O.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][C:3]=1[C:23]1[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=1
Reactant: O=Cc1ccc(OS(=O)(=O)C(F)(F)F)c(Cl)c1
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2ccc(C=O)cc2Cl)cc1

Procedure:
The title compound was prepared by reacting trifluoro-methanesulfonic acid 2-chloro-4-formyl-phenyl ester (5 g, 17.4 mmol) with 4-methoxyphenylboronic acid (3.44 g, 22.6 mmol) according to Method B to yield 3.83 g (89%) of white solid: mp 85-87° C.; 1H NMR (DMSO-d6): δ 3.82 (3H, s), 7.07 (2H, d, J=8.83 Hz), 7.46 (2H, d, J=8.45 Hz), 7.63 (1H, d, J=7.87 Hz), 7.92 (1H, dd, J=7.87 Hz, J=1.56 Hz), 8.07 (1H, d, J=1.49 Hz); 13C NMR (DMSO-d6): δ 55.14, 113.72, 127.80, 129.72, 130.42, 130.82, 132.15, 132.21, 136.11, 144.90, 159.33, 191.73; IR 1692 cm−1; MS (EI) m/z 246/248 M+.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][N:22]=2)[CH2:14][C@H:13]1[C:27]([OH:29])=O)=[O:10].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][N:22]=2)[CH2:14][C@H:13]1[C:27]([N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)=[O:29])=[O:10]
Reactant: COC(=O)c1cnc(N2CC[C@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@H](C(=O)O)C2)s1
Reactant: C1COCCN1
Product: COC(=O)c1cnc(N2CC[C@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@H](C(=O)N3CCOCC3)C2)s1

Procedure:
The title compound was prepared in a manner analogous to (Intermediate 37) starting from cis(±)4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-1-[5-(methoxycarbonyl)-1,3-thiazol-2-yl]piperidine-3-carboxylic acid (Example 77) and morpholine. MS (ES+): 530, 532 for C21H25Cl2N5O5S.