Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([Br:14])=[CH:11][CH:12]=2)[C@H:7]([NH2:15])[CH2:6][C@@H:5]1[CH3:16])(=[O:3])[CH3:2].CCN(C(C)C)C(C)C.C1[C:31]([N+]([O-])=O)=[CH:30][CH:29]=[C:28]([O:35][C:36](Cl)=[O:37])C=1.C1(O)CCC1>ClCCl>[CH:28]1([O:35][C:36](=[O:37])[NH:15][C@H:7]2[C:8]3[C:13](=[CH:12][CH:11]=[C:10]([Br:14])[CH:9]=3)[N:4]([C:1](=[O:3])[CH3:2])[C@@H:5]([CH3:16])[CH2:6]2)[CH2:29][CH2:30][CH2:31]1
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](N)C[C@@H]1C
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: OC1CCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(Br)cc2[C@H](NC(=O)OC2CCC2)C[C@@H]1C

Procedure:
(cis)-1-Acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinamine (for a preparation see Intermediate 4) (200 mg, 0.706 mmol) was dissolved in dichloromethane (DCM) (5 mL), mixed with DIPEA (0.370 mL, 2.119 mmol) followed by 4-nitrophenyl chloridocarbonate (157 mg, 0.777 mmol, available from Fluka) and stirred under nitrogen. Cyclobutanol (0.082 mL, 1.059 mmol) was added after 1.75 hours. The reaction was allowed to stir under nitrogen for 17 hours. The reaction was partitioned between distilled water (20 mL) and EtOAc (60 mL). The aqueous layer was extracted with EtOAc (60 mL) and the organic fractions were combined, washed (brine (50 mL)), dried (sodium sulfate) and evaporated to dryness to give a yellow solid (346 mg). The residue was purified by SP4 on a 25+M Biotage silica column, eluting with a gradient of 0 to 50% ethyl acetate in cyclohexane. Product-containing fractions were evaporated to dryness to give a clear, colourless solid (39 mg). LCMS (Method C): Rt=1.05, MH+=383
Reaction SMILES: [Cl:1][CH:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH3:15])=[CH:8][CH:7]=1)C#N.[CH:16]([OH:18])=[O:17].Cl>O>[Cl:1][CH:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH3:15])=[CH:8][CH:7]=1)[C:16]([OH:18])=[O:17]
Reactant: O=CO
Reactant: CCCCc1ccc(CC(Cl)C#N)cc1
Agent: Cl
Solvent: O
Product: CCCCc1ccc(CC(Cl)C(=O)O)cc1
Yield: 77 %

Procedure:
The α-chloro-β-p-butylphenylpropionitrile 2 (166 g, 0.750 moles) was stirred over 240 mL formic acid and 160 mL concentrated HCl at reflux for 16 h. The reaction mixture was cooled, diluted with 300 mL water and washed with ethyl acetate. The ethyl acetate solution was washed with water, saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The bulk oil solidified on standing. The solid was recrystallized twice from hexane, yielding 139.0 g (0.58 moles, 77% yield) of a white solid, mp. 52.7°-53.6° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:27][C:28](Br)=[O:29].[CH3:31][CH:32]([NH2:35])[CH2:33][CH3:34]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:27][C:28]([NH:35][CH:32]([CH2:33][CH3:34])[CH3:31])=[O:29]
Reactant: O=C(Br)CBr
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC)cc32)cc1OC
Reactant: CCC(C)N
Product: CCC(C)NC(=O)CN1CCc2cc(OC)c(OC)cc2C1Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-butylamine
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH2:8][N:9]1[C:15]2[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:14]=2[N:13]([C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:12][CH:11]([NH:27][C:28]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([O:39]CC)=[O:38])[CH:32]=2)=[O:29])[C:10]1=[O:42])=[O:7].O.[OH-].[Li+].O1CCCC1>CO>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH2:8][N:9]1[C:15]2[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:14]=2[N:13]([C:21](=[O:26])[C:22]([CH3:24])([CH3:25])[CH3:23])[CH2:12][CH:11]([NH:27][C:28](=[O:29])[NH:30][C:31]2[CH:32]=[C:33]([CH:34]=[CH:35][CH:36]=2)[C:37]([OH:39])=[O:38])[C:10]1=[O:42])=[O:7]
Reactant: CCOC(=O)c1cccc(NC(=O)NC2CN(C(=O)C(C)(C)C)c3ccc(C)cc3N(CC(=O)c3ccco3)C2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1ccc2c(c1)N(CC(=O)c1ccco1)C(=O)C(NC(=O)Nc1cccc(C(=O)O)c1)CN2C(=O)C(C)(C)C
Yield: 61.8 %

Procedure:
1-[1-(Furan-2-yl)carbonylmethyl-2-oxo-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea (187 mg) was dissolved in methanol (8.8 ml), aqueous lithium hydroxide monohydrate (68.3 mg) solution (4.4 ml) and tetrahydrofuran (4.4 ml) were added, the mixture was refluxed for one hour. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water (50 ml), the solution was washed with diethyl ether, acidified with 1N hydrochloric acid,and extracted with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and diisoproryl ether was added to the residue for trituration, collected by filtration, to thereby obtain 110 mg of the titled compound.
Reaction SMILES: CS(C1C=CC(N2CCCC2)=C(C=1)C(O)=O)(=O)=O.Cl[C:20]1[CH:28]=[CH:27][C:26]([S:29](=[O:34])(=[O:33])[NH:30][CH2:31][CH3:32])=[CH:25][C:21]=1[C:22]([OH:24])=[O:23].[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>>[CH2:31]([NH:30][S:29]([C:26]1[CH:27]=[CH:28][C:20]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)=[C:21]([CH:25]=1)[C:22]([OH:24])=[O:23])(=[O:34])=[O:33])[CH3:32]
Reactant: CCNS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Reactant: C1COCCN1
Agent: CS(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1
Product: CCNS(=O)(=O)c1ccc(N2CCOCC2)c(C(=O)O)c1
Yield: 42 %

Procedure:
The title compound was synthesised according to the procedure described for the synthesis of 5-Methanesulfonyl-2-pyrrolidin-1-yl-benzoic acid from 2-Chloro-5-ethylsulfamoyl-benzoic acid and morpholine and obtained in 42% yield. MS (m/e): 313.2 (MH−, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH2:14][CH3:15])=[C:11]([C:16](Cl)=[O:17])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH:19]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH2:14][CH3:15])=[C:11]([C:16]([NH:25][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:17])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: NC1CCCCC1
Reactant: CCCc1c(C(=O)Cl)cnn1-c1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCc1c(C(=O)NC2CCCCC2)cnn1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 1-(4-chlorophenyl)-5-propyl-pyrazole-4-carbonyl chloride (commercially available, 302 mg, 1.07 mmol) in DCM (5 ml) was added 1 drop of DMF followed by cyclohexylamine (306 μL, 2.68 mmol). The reaction mixture was stirred at room temperature for two hours then stopped.
Reaction SMILES: O=P(Cl)(Cl)Cl.P(Cl)(Cl)(Cl)(Cl)[Cl:7].[CH3:12][C:13]([C:15]([CH3:23])([CH3:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O.[OH-].[NH4+]>C(OCC)C>[CH3:22][C:15]([C:13]([Cl:7])=[CH2:12])([CH3:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(=O)C(C)(C)c1ccccc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O=P(Cl)(Cl)Cl
Product: C=C(Cl)C(C)(C)c1ccccc1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
Into a 250 ml round bottomed flask equipped with magnetic stirring and a reflux condenser was placed 15 g (98 mmol) of POCl3, 30 g (145 mmol) of PCl5, and 19.9 g (123 mmol) of α,α-dimethylbenzyl methyl ketone. The reaction was heated in an oil bath to an external temperature of 110° C. Gas evolution ceased after one hour. The reaction was cooled and carefully poured onto ice and aqueous ammonium hydroxide. Extractive workup with diethyl ether gave a mixture of 1-(α,α-dimethylbenzyl)-1-chloroethylene and 1-(α,α-dimethylbenzyl)-1,1-dichloroethane. Vacuum distillation gave purified 1-(α,α-dimethylbenzyl)-1-chloroethylene bp (23 torr) 110-120° C.
Reaction SMILES: [C:1]1(=[O:28])[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][CH:11]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:21][CH3:22])[O:13][CH2:12]2)[C:4](=[O:23])[C:3]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:2]12.I[CH2:30][CH2:31][CH3:32].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:30]([N:10]([CH:11]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][C:18]=2[O:21][CH3:22])[O:13][CH2:12]1)[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:4](=[O:23])[C:3]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:2]2[C:1]1=[O:28])[CH2:31][CH3:32]
Reactant: CCCI
Reactant: COc1cccc2c1CC(NCCCCN1C(=O)c3ccccc3C1=O)CO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCN(CCCCN1C(=O)c2ccccc2C1=O)C1COc2cccc(OC)c2C1
Temperature: 60 °C
Reaction time: 24 h
Yield: 81 %

Procedure:
1.5 mmol of the compound prepared in Example 1 is dissolved in 10 ml of dimethylformamide in the presence of 4.4 mmol of 1-iodopropane and 4.4 mmol of potassium carbonate. After 24 hours' stirring at 60° C., the solvent is evaporated off and the crude reaction mixture is taken up with 10 ml of water and extracted with dichloromethane. The organic phase is dried and evaporated and the expected product is obtained after purification by chromatography on a silica column (elution solvent: ether/petroleum ether, 1:99).
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][C:18]=1[O:25][CH3:26].[NH2:27][C:28]([NH2:30])=[O:29].Cl>CCO>[OH:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]2[C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[NH:30][C:28](=[O:29])[NH:27]2)=[CH:19][C:18]=1[O:25][CH3:26]
Reactant: COc1cc(C=O)ccc1O
Reactant: O=C(Cc1ccccc1)c1ccccc1
Reactant: NC(N)=O
Agent: Cl
Solvent: CCO
Product: COc1cc(C2NC(=O)NC(c3ccccc3)=C2c2ccccc2)ccc1O
Temperature: 85 °C
Reaction time: 72 h

Procedure:
To a solution of 1,2-diphenylethanone (392 mg, 2.0 mmol), 4-hydroxy-3-methoxybenzaldehyde (274 mg, 1.8 mmol) and urea (324 mg, 5.4 mmol) in EtOH (40 mL) was added concentrated HCl (0.17 mL). The mixture was stirred at 85° C. for 3 days. The volatiles were removed under reduced pressure and the residue was diluted with water (50 mL), extracted with ethyl acetate (100 mL×2), washed with saturated aqueous NaHCO3 (50 mL×2), dried over Na2SO4, concentrated (standard aqueous/EtOAc workup) and purified by silica gel column chromatography (PE:EA=1:1) to afford Compound 87 as an off-white power (100 mg, 15%). 1H NMR (DMSO-d6 500 MHz): δ 8.94 (s, 1H), 8.58 (s, 1H), 7.36 (s, 1H), 7.53 (s, 1H), 7.40 (s, 3H), 7.34 (s, 3H), 7.10 (d, J=5.2 Hz, 1H), 7.20-7.25 (m, 5H), 6.99 (t, J=18 Hz, 3H), 6.90 (s, 1H), 6.80 (t, J=7.0 Hz, 3H), 6.74 (d, J=8.0 Hz, 1H), 4.99 (d, J=2.5 Hz, 1H); MS (ESI): m/z 373.0 [M+1]+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]2[N:32]3[C:27]([CH:28]=[CH:29][CH:30]=[CH:31]3)=[C:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:25]=2[CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:41]=2[CH3:47])=[O:23])[CH2:18][C@@H:17]1[CH2:48][C:49](O)=[O:50])=[O:15])([CH3:12])([CH3:11])[CH3:10].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>O>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]2[N:32]3[C:27]([CH:28]=[CH:29][CH:30]=[CH:31]3)=[C:26]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:25]=2[CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:41]=2[CH3:47])=[O:23])[CH2:18][C@@H:17]1[CH2:48][C:49](=[O:50])[NH:1][CH2:2][CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)=[O:15])([CH3:11])([CH3:12])[CH3:10]
Reactant: NCC1CCOCC1
Reactant: Cc1c(F)cccc1Cc1c(-c2ccccc2)c2ccccn2c1C(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](CC(=O)O)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Product: Cc1c(F)cccc1Cc1c(-c2ccccc2)c2ccccn2c1C(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](CC(=O)NCC2CCOCC2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.5 %

Procedure:
To a stirred, ice-cold solution of 4-aminomethyl-tetrahydropyran (0.047 g, 0.40 mmol), EDIA (0.19 ml, 1.08 mmol) and the compound of step 2 (0.190 g, 0.27 mmol) was added TBTU (0.259 g, 0.81 mmol) in small portions. The solution was stirred at room temperature for 18 h. Then water (8 ml) was added and the mixture was extracted 3 times with EA. The combined organic phases were washed with 1 N hydrochloric acid, water, a saturated solution of sodium hydrogencarbonate and brine, dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure. The residue was purified by chromatography on silica gel (cyclohexane/EA, 100:0, then 50:50) to give 0.117 g of the title compound as an orange gum.
Reaction SMILES: [Cl:1][C:2]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:14][C:15]1[CH:19]=[CH:18][NH:17][N:16]=1.O=[C:21]([CH2:28][CH2:29][CH3:30])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[Cl:1][C:2]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:21]([CH2:28][CH2:29][CH3:30])[NH:14][C:15]2=[N:16][NH:17][CH:18]=[C:19]12
Reactant: Nc1cc[nH]n1
Reactant: O=Cc1cccc(C(F)(F)F)c1Cl
Reactant: CCCC(=O)CC(=O)OCC
Product: CCCC1=C(C(=O)OCC)C(c2cccc(C(F)(F)F)c2Cl)c2c[nH]nc2N1

Procedure:
The title compound was prepared from 2-chloro-3-trifluoromethylbenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:19]([CH2:20][CH2:21][C@:3]12[CH3:4])[C@:16]1([CH2:17][OH:18])[C:11](=[CH:12][C:13](=[O:23])[CH2:14][C@@H:15]1[CH3:22])[CH2:10][C@H:9]3[CH3:24].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH3:22][C@@H:15]1[C@@:16]2([CH:17]=[O:18])[C:11]([CH2:10][C@@H:9]([CH3:24])[C@@H:8]3[C@@H:19]2[CH2:20][CH2:21][C@@:3]2([CH3:4])[C@H:5]3[CH2:6][CH2:7][C:2]2=[O:1])=[CH:12][C:13](=[O:23])[CH2:14]1
Reactant: C[C@@H]1CC2=CC(=O)C[C@H](C)[C@]2(CO)[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: C[C@@H]1CC2=CC(=O)C[C@H](C)[C@]2(C=O)[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Reaction time: 0.5 h

Procedure:
To a solution of 17β,19-dihydroxy-1α,7α-dimethyl-4-androsten-3-one in acetone at 20° C. is added two equivalents of Jones Reagent and the mixture stirred for 30 minutes. The acetone layer is poured onto water with vigorous stirring. The crystals are removed by suction filtration and air dried. Crystallization from an acetone-hexane solution yields 1α,7α-dimethyl-4-androstene-3,17,19-trione.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:39]=[CH:38][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[CH:21]2[CH2:30][CH2:29][C:28]3[CH:27]=[C:26]([O:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])[CH:25]=[CH:24][C:23]=3[CH2:22]2)=[CH:7][CH:6]=1)(O)=[O:2].CN(C)C=O.C(Cl)(=O)C([Cl:48])=O>O1CCCC1>[Cl:48][C:1]([CH2:4][C:5]1[CH:39]=[CH:38][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[CH:21]2[CH2:30][CH2:29][C:28]3[CH:27]=[C:26]([O:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])[CH:25]=[CH:24][C:23]=3[CH2:22]2)=[CH:7][CH:6]=1)=[O:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCc2ccc(CC(=O)O)cc2)c1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCc2ccc(CC(=O)Cl)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of pivalic acid 6-{2-[(4-carboxymethylbenzyl)ethylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydrona phthalen-2-yl ester (54 mg) in tetrahydrofuran (1.5 ml) were sequentially added N,N-dimethylformamide (in catalytic amounts) and oxalyl chloride (0.027 ml) under a nitrogen atmosphere, the solution was stirred for 30 minutes at room temperature, then the solvent was evaporated in vacuo to provide pivalic acid 6-{2-[(4-chlorocarbonylmethylbenzyl)ethylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (74 mg). A solution of this compound (37 mg) and dimethylamine (2.0 M solution in tetrahydrofuran) (0.08 ml) in tetrahydrofuran (0.7 ml) was stirred for 30 minutes at room temperature. To a suspension of lithium aluminum hydride (76 mg) in tetrahydrofuran (2 ml) was added aluminum chloride (267 mg) on an ice bath under a nitrogen atmosphere, and the solution was stirred for 1 hour at room temperature. Among the resulting suspension, 0.5 ml was added dropwise thereto followed by stirring for 2 hours at room temperature. Tetrahydrofuran and concentrated aqueous ammonia were sequentially added thereto, the solution was filtered through celite pad, and concentrated under a nitrogen stream. A solution of the resulting residue in N,N-dimethylformamide was purified by LC-MS, and the title compound (7.1 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([N:11]2[CH2:16][CH2:15][C:14]([CH2:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(O)[CH2:13][CH2:12]2)[CH3:10])=[CH:5][CH:4]=1.C(=O)=O.CC(C)=O.CCN(S(F)(F)[F:40])CC.[Cl:43]CCl>>[ClH:43].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([N:11]2[CH2:16][CH2:15][C:14]([CH2:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([F:40])[CH2:13][CH2:12]2)[CH3:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(C)N2CCC(O)(CC(=O)c3ccccc3)CC2)cc1
Reactant: CCN(CC)S(F)(F)F
Reactant: ClCCl
Agent: O=C=O
Solvent: CC(C)=O
Product: COc1ccc(C(C)N2CCC(F)(CC(=O)c3ccccc3)CC2)cc1
Product: Cl
Temperature: -75 °C
Reaction time: 1 h
Yield: 34.8 %

Procedure:
N-(1-(4-methoxyphenyl)ethyl)-4-benzoylmethyl-4-piperidinol (III-19) is firstly prepared according to the method of synthesis and post-treatment in Example 19. 1.41 g (4.0 mmol) of N-(1-(4-methoxyphenyl)ethyl)-4-benzoylmethyl-4-piperidinol is taken and dissolved into 20 ml of anhydrous dichloromethane and cooled with dry ice-acetone with temperature controlled at below <−70° C. The reaction solution is added dropwise a dichloromethane solution (8 mol, 25 ml) of DAST under protection of nitrogen gas. After completion of addition, the temperature is maintained at −75° C. and reacting for 1 hour, and the temperature is raised slowly and maintained at −10° C. and reacting for 2 hours. Then operating according to the post-treatment method in General Method six obtains 0.57 g of a white crystal, with yield of 34.8%.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:39][CH2:40][C@@H:41]([OH:43])[CH3:42]>>[OH:43][C@@H:41]([CH3:42])[CH2:40][NH:39][C:34](=[O:35])[C:33]1[CH:32]=[CH:31][C:30]([S:27]([CH2:26][C:16]2[C:17]3[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=3[CH:23]=[CH:24][C:15]=2[O:14][C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)(=[O:29])=[O:28])=[CH:38][CH:37]=1
Reactant: C[C@H](O)CN
Reactant: O=C(O)c1ccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Product: C[C@H](O)CNC(=O)c1ccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Yield: 54.5 %

Procedure:
Using the method in Example 172, 4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoic acid (53 mg, 0.10 mmol, 0.20M in DMF) and (S)-1-amino-2-propanol (23 mg, 0.30 mmol, 0.6M in DMF) were combined to give 32 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 588 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:8]=[CH:7][C:6]([C:9](O)=[O:10])=[CH:5][CH:4]=1.Cl.[CH3:15][NH:16][O:17][CH3:18].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.O>[CH3:18][O:17][N:16]([CH3:15])[C:9]([C:6]1[CH:7]=[N:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=1)=[O:10]
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1
Reactant: CNOC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CON(C)C(=O)c1ccc(C(F)(F)F)nc1
Reaction time: 60 h
Yield: 93.2 %

Procedure:
Dissolve 6-(trifluoromethyl)pyridine-3-carboxylic acid (0.949 g, 4.767 mmol) in DMF (10 mL) and add N,O-dimethylhydroxylamine hydrochloride (0.590 g, 5.959 mmol), and DIPEA (1.67 mL, 9.534 mmol), followed by BOP (2.259 g, 5.005 mmol). Stir the resulting mixture for about 60 hours. Pour reaction mixture into water (200 mL). Extract with EtOAc (4×75 mL). Wash the combined organic extracts with a saturated sodium chloride aqueous solution (5×75 mL). Dry the organic extracts over sodium sulfate; filter; collect the filtrate; and concentrate the filtrate under reduced pressure. Dissolve the residue in EtOAc (100 mL). Sequentially wash the residue in EtOAc with a saturated NaHCO3 aqueous solution (50 mL) to remove any residual acid starting material, followed by water (2×50 mL), and then a saturated sodium chloride aqueous solution (2×50 mL). Dry the organic layer over sodium sulfate; filter; collect the filtrate; and concentrate the filtrate under reduced pressure to give the title compound as a clear liquid (1.04 g, 93% yield). 1H NMR (400.43 MHz, d6-DMSO) δ 8.90 (d, J=2.0 Hz, 1H), 8.25-8.23 (m, 1H), 7.96 (dd, J=0.7, 8.1 Hz, 1H), 3.52 (s, 3H), 3.27 (s, 3H).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](=[O:25])[C@@H:11]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:2]2.[Br:26][CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:29].CCOCC>CCOC(C)=O>[Br-:26].[O:29]=[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:27][N+:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[C@@H:3]([O:9][C:10](=[O:25])[C@@H:11]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:2]2
Reactant: O=C(O[C@H]1CN2CCC1CC2)[C@H](Nc1ccccc1)c1ccccc1
Reactant: O=C(CBr)c1ccccc1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)[C@H](Nc1ccccc1)c1ccccc1)C2)c1ccccc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
(R)-quinuclidin-3-yl 2-phenyl-2-(phenylamino)acetate (Diasteroisomer 1 of C2) (20.3 mg, 0.06 mmol) is dissolved in EtOAc (0.60 mL) and 2-bromo-1-phenylethanone (12.0 mg, 0.06 mmol) iss added. The reaction is stirred at room temperature for 2 hours (UPLC-MS: complete and clean conversion). Et2O (0.20 mL) were added and the product is triturated to obtain a white solid which is isolated by filtration and dried under vacuum overnight (31 mg, 96% yield, bromide salt, single diastereoisomer).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[O:10][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)=[CH:8][C:7](=[O:19])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:20]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl.O>[Br:20][CH2:1][C:2]1[C:11]2[O:10][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)=[CH:8][C:7](=[O:19])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2c(=O)cc(-c3cccc(F)c3)oc12
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: O=c1cc(-c2cccc(F)c2)oc2c(CBr)cccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.1 %

Procedure:
A mixture of 14.3 g of 8-methyl-2-(3-fluorophenyl)-4H-benzopyran-4-one, 17.2 g of N-bromosuccinimide and 3.5 g of azobisisobutyronitrile (AIBN) in 700 ml of carbon tetrachloride was refluxed for 6.5 hours, cooled to room temperature and stirred overnight and then diluted with 100 ml of water. The solvents were removed in vacuo and the residue recrystallized from hot ethyl acetate to give 16.5 g of 8-bromomethyl-2-(3-fluorophenyl)-4H-benzopyran-4-one which was used without further purification.