Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16]4=[C:17]([C@@H:19]5[CH2:24][NH:23][CH2:22][CH2:21][C@@H:20]5[N:15]4[CH2:14][CH2:13][CH2:12]3)[CH:18]=2)=[C:5]([C:25]([F:28])([F:27])[F:26])[CH:4]=1.Br[CH2:30][CH:31]([F:33])[F:32].N>>[F:32][CH:31]([F:33])[CH2:30][N:23]1[CH2:22][CH2:21][C@@H:20]2[N:15]3[C:16]4[C:11](=[CH:10][C:9]([C:6]5[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=5[C:25]([F:28])([F:26])[F:27])=[CH:18][C:17]=4[C@@H:19]2[CH2:24]1)[CH2:12][CH2:13][CH2:14]3
Reactant: FC(F)CBr
Reactant: COc1ccc(-c2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCC3)c(C(F)(F)F)c1
Agent: N
Product: COc1ccc(-c2cc3c4c(c2)[C@@H]2CN(CC(F)F)CC[C@@H]2N4CCC3)c(C(F)(F)F)c1

Procedure:
The title compound was prepared by the method of Example 382 as a yellow oil (27 mg, 77%) from (7aS,11aR)-2-[4-methoxy-2-(trifluoromethyl)phenyl]-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (30 mg, 0.077 mmol) and 2-bromo-1,1-difluoroethane (35 mg, 0.23 mmol). MS (C1, NH3): 453.1 (base, M+H).
Reaction SMILES: [OH:1][CH:2]1CCN(CC#C)C[CH2:3]1.[CH:11](NC(C)C)(C)C.[C:18]([C:22]1[CH:27]=[CH:26][C:25](/[C:28](/[C:44]2[CH:49]=[CH:48][C:47]([C:50]#[C:51][CH2:52][N:53]3[CH2:58]CO[CH2:55][CH2:54]3)=[CH:46][CH:45]=2)=[CH:29]/[CH2:30][O:31][C:32]2[CH:42]=[CH:41][C:35]([O:36][CH2:37][C:38]([OH:40])=[O:39])=[C:34]([CH3:43])[CH:33]=2)=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>O1CCCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:18]([C:22]1[CH:27]=[CH:26][C:25](/[C:28](/[C:44]2[CH:49]=[CH:48][C:47]([C:50]#[C:51][CH2:52][N:53]3[CH2:54][CH2:55][CH:2]([OH:1])[CH2:3][CH2:58]3)=[CH:46][CH:45]=2)=[CH:29]/[CH2:30][O:31][C:32]2[CH:42]=[CH:41][C:35]([O:36][CH2:37][C:38]([O:40][CH3:11])=[O:39])=[C:34]([CH3:43])[CH:33]=2)=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: C#CCN1CCC(O)CC1
Reactant: CC(C)NC(C)C
Reactant: Cc1cc(OC/C=C(\c2ccc(C#CCN3CCOCC3)cc2)c2ccc(C(C)(C)C)cc2)ccc1OCC(=O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCN3CCC(O)CC3)cc2)c2ccc(C(C)(C)C)cc2)cc1C
Temperature: 25 °C

Procedure:
4-Hydroxy-1-propargylpiperidine (171 mg, 1.23 mmol) and diisopropylamine (0.40 mL, 2.85 mmol) were added to a solution of the methyl (Z)-[4-[3-(4-tert-butylphenyl)-3-(4-iodohenyl)allyloxy]-2-methylphenoxy]acetate (350 mg, 0.614 mmol; prepared as described in example 30) in tetrahydrofuran (10 mL). The mixture was degassed and copper(I) iodide (10 mg, 0.053 mmol) and bis(triphenylphosphine)palladium(II) dichloride (22 mg, 0.031 mmol) were added. The reaction mixture was stirred at ambient temperature over night, filtered and the filtrate was evaporated in vacuo. The residue was purified by flash column chromatography (silica gel Fluka 60, dichloromethane/methanol 97:3) yielding methyl (Z)-[4-[3-(4-tert-butyl phenyl]-3-[4-[3-(4-hydroxypiperidin-1-yl)propynyl]phenyl]allyloxy]-2-methylphenoxy]-acetate as white solid.
Reaction SMILES: [C:1]([NH:9][NH:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[Cl:27])[C:21](Cl)=[O:22]>C(Cl)Cl>[C:1]([NH:9][N:10]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:21](=[O:22])[C:20]1[CH:24]=[CH:25][C:26]([Cl:27])=[C:18]([Cl:17])[CH:19]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)NNC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)N(NC(=O)c1ccccc1)C(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 77.8 %

Procedure:
Benzoyl-2-tert-butylhydrazine (4.8 g, 0.025 mole) is stirred vigorously in a two-phase system of 50 mL of methylene chloride and 25 mL of 10% aqueous sodium hydroxide (2.5 g, 0.063 mole) until all dissolves. To this solution is added a solution of 3,4-dichlorobenzoyl chloride (7.3 g, 0.025 mole) in methylene chloride. After stirring the two-phase mixture several hours at ambient temperature, the solid is removed and washed with water and methylene chloride. Recrystallization from 2-propanol gives 7.1 g (78%) of product with mp 234°-235.5° C.
Reaction SMILES: [CH:1]1[C:13]2[N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[C:28](Cl)=[O:29].[Al+3].[Cl-].[Cl-].[Cl-].[C:35](Cl)(=[O:39])/[CH:36]=[CH:37]/[CH3:38]>C(Cl)Cl>[C:20]([C:17]1[CH:16]=[CH:15][C:14]([N:12]2[C:13]3[CH:1]=[CH:2][C:3]([C:35](=[O:39])/[CH:36]=[CH:37]/[CH3:38])=[CH:4][C:5]=3[C:6]3[C:11]2=[CH:10][CH:9]=[C:8]([C:28]([C:24]2[S:23][CH:27]=[CH:26][CH:25]=2)=[O:29])[CH:7]=3)=[CH:19][CH:18]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)c1ccc(-n2c3ccccc3c3ccccc32)cc1
Reactant: C/C=C/C(=O)Cl
Reactant: O=C(Cl)c1cccs1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C/C=C/C(=O)c1ccc2c(c1)c1cc(C(=O)c3cccs3)ccc1n2-c1ccc(C(C)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1-(4-carbazol-9-yl-phenyl)ethanone (30.0 g) in CH2Cl2 (1200 mL) is added thiophenecarbonyl chloride (15.4 g) and AlCl3 (28.4 g) at 0° C. After stirring overnight at room temperature, crotonyl chloride (11.3 g) and AlCl3 (15.5 g) are further added at 0° C. and the mixture is stirred at room temperature overnight. The reaction mixture is poured into ice-water, and the crude product is extracted twice with CH2Cl2. The combined organic layer is washed with H2O and brine, dried over MgSO4, and concentrated to give the residue, which is purified by washing with hot ethyl acetate.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[CH3:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C@@H:32](O)[CH3:33].[CH2:35]([O:42][C:43]1[CH:50]=[CH:49][C:46]([CH2:47]Br)=[CH:45][CH:44]=1)[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41].Cl>C1COCC1.CS(C)=O>[CH2:35]([O:42][C:43]1[CH:50]=[CH:49][C:46]([CH2:47][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:13]=[CH:12][C:11]([O:14][CH:32]([CH3:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH3:26])=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)=[CH:45][CH:44]=1)[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCCCCCOc1ccc(CBr)cc1
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Reactant: CCCCCC[C@H](C)O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CCCCCCCOc1ccc(COc2ccc(-c3ccc(OC(C)CCCCCC)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydride (0.8 g) was decanted twice with n-heptane (20 ml), successively with THF (20 ml) and placed in a flask in the form of a suspension in THF (20 ml), followed by dropwise adding a solution of 4'-hydroxy-4-(1-methylheptyloxy)-biphenyl (IIIa-7) of m.p. 98.1° C. (5.1 g) obtained by reacting 4,4'-dihydroxybiphenyl with a tosylate derived from S-(+)-2-octanol, in THF (30 ml), thereafter dropwise adding DMSO (20 ml), successively dropwise adding a solution of p-heptyloxybenzyl bromide (5.4 g) in DMSO (30 ml), stirring the mixture at room temperature, allowing to stand overnight, adding 6N-HCl (200 ml), extracting with toluene, washing with acid, washing with alkali, washing with water to make it neutral, drying, concentrating, subjecting the concentrate to column chromatography with activated alumina (20 g) to effect separation-concentration using toluene as an elute, and twice recrystallizing from a mixed solvent of ethanol (40 ml) and ethyl acetate (20 ml) to obtain the captioned 4'-(p-(heptyloxy)phenylmethyloxy)-4-(1-methylheptyloxy)biphenyl (3.6 g). Its m.p., etc. are described in Table 2. Further its elementary analysis values accorded well with its calculated values as follows:
Reaction SMILES: [NH:1]([C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[C@H:2]([C:10]([O:12]C1C(F)=C(F)C(F)=C(F)C=1F)=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:34][C@@H:35]([C:37]([OH:39])=[O:38])[CH3:36]>C1COCC1.O>[NH:1]([C:24]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])[C@H:2]([C:10]([NH:34][C@@H:35]([C:37]([OH:39])=[O:38])[CH3:36])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)Oc1c(F)c(F)c(F)c(F)c1F)OCc1ccccc1
Reactant: C[C@@H](N)C(=O)O
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
9.68 g (20.0 mmol) of Z-Phe-OPfp was dissolved in 20 ml of THF and to this was added 2.3 g (25.6 mmol) of H-D-Ala-OH dissolved in 5 ml water, pH 8.5. The reaction mixture was stirred for one day and one night at room temperature. The solvents were removed by evaporation under vacuum, 70 ml ethyl acetate was added, and the mixture was acidified to pH 2-3 by the addition of 70 ml of 2% sulfuric acid. The peptide was extracted twice with 70 ml ethyl acetate, washed with saturated sodium chloride solution to neutral pH, then dried over anhydrous sodium sulfate. The solvent was removed by evaporation under vacuum, leaving a thick oil. The product was crystallized from ether/hexane. The yield was 7.6 g (97.7%), melting point was 153-154° C. Rf=0.40 in chloroform:ethyl acetate:methanol:acetic acid=6:3:1:0.1. Rf=0.53 in acetic acid:chloroform:methanol=0.5:16:1. Rf=0.58 in acetic acid:chloroform:methanol=0.5:9:1. [α]20D=+3.2(C=1, CH3OH).
Reaction SMILES: CN(C(O[N:9]1N=N[C:11]2C=CC=N[C:10]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:25][C:26]1[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][C:27]=1[C:28]([OH:30])=O.C(N(C(C)C)CC)(C)C.C(N)C>C(#N)C.C1COCC1>[Br:25][C:26]1[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][C:27]=1[C:28]([NH:9][CH2:10][CH3:11])=[O:30]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Br
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CCN
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1cc([N+](=O)[O-])ccc1Br
Reaction time: 15 h
Yield: 43 %

Procedure:
To a stirred solution of HATU (501 mg, 1.32 mmol), 2-bromo-5-nitrobenzoic acid (325 mg, 1.32 mmol) and diisopropyl ethylamine (642 μl, 3.90 mmol) in anhydrous acetonitrile (20 ml) at room temperature was added ethylamine (725 μl of a 2.0M solution in THF, 1.45 mmol) and the reaction stirred for 15 hrs. The solvent was evaporated in vacuo and the crude residue purified by flash column chromatography (20% ethyl acetate in petroleum ether) to afford the title compound as a pale yellow solid (155 mg, 43%). HPLC retention time 3.72 min. Mass spectrum (ES+) m/z 273 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12](=[O:14])[CH3:13])[CH:6]=[C:7]([O:10][CH3:11])[C:8]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:34]([O:38][CH2:39][CH3:40])(=[O:37])CO.C[CH2:42][O:43]C(/N=N/C(OCC)=O)=O>O1CCCC1>[CH2:39]([O:38][C:34]([C:8]1[C:7]([O:10][CH3:11])=[CH:6][C:5]([C:12](=[O:14])[CH2:13][O:43][CH3:42])=[CH:4][C:3]=1[O:2][CH3:1])=[O:37])[CH3:40]
Reactant: CCOC(=O)/N=N/C(=O)OCC
Reactant: CCOC(=O)CO
Reactant: COc1cc(C(C)=O)cc(OC)c1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1c(OC)cc(C(=O)COC)cc1OC
Yield: 35.9 %

Procedure:
Ex-61A: 3′,5′-Dimethoxy-4′-hydroxyacetophenone (6.03 g, 31 mmol) and triphenylphosphine (8.05 g, 31 mmol) were stirred in 124 mL of tetrahydrofuran (THF). The mixture was treated with ethyl glycolate (3.2 g, 31 mmol) and diethylazodicarboxylate (4.83 mL, 31 mmol). The reaction mixture was stirred under reflux for about 3.5 h and then evaporated. The residue was crystallized from hexane/ethyl acetate. The mother liquor was concentrated to give a crude product which was purified by recrystallization from EtOH twice to give 3.14 g of 4′-ethoxycarbonyl-methoxy-3′,5′-dimethoxyacetophenone. Solvent removal from the mother liquor provided additional crude product which was purified by silica gel chromatography (hexane/ethyl acetate, 1:1) to give additional product (4.2 g). The total amount of pure material isolated was 7.34 g (90% yield). mp. 81-83° C.; Anal. Calcd. for Cl4H18O6: C, 59.57; H, 6.43; Found: C, 59.60; H, 6.34; MS (direct probe): Calcd for Cl4H18O6: m/z=282, found: m/z=282.
Reaction SMILES: [C:1]([O:4][C:5]1[C:23]([O:24][CH3:25])=[CH:22][C:8]([C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)=[O:10])=[CH:7][C:6]=1[O:26][CH3:27])(=[O:3])[CH3:2].CC(C1C=C(C=C(C(C)(C)C)C=1O)C(NCC1C=CC([N+]([O-])=O)=CC=1)=O)(C)C>>[C:1]([O:4][C:5]1[C:23]([O:24][CH3:25])=[CH:22][C:8]([C:9]([NH:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([NH2:19])=[CH:17][CH:18]=2)=[O:10])=[CH:7][C:6]=1[O:26][CH3:27])(=[O:3])[CH3:2]
Reactant: COc1cc(C(=O)NCc2ccc([N+](=O)[O-])cc2)cc(OC)c1OC(C)=O
Agent: CC(C)(C)c1cc(C(=O)NCc2ccc([N+](=O)[O-])cc2)cc(C(C)(C)C)c1O
Product: COc1cc(C(=O)NCc2ccc(N)cc2)cc(OC)c1OC(C)=O
Yield: 82 %

Procedure:
The experimental protocol used is the same as that described for intermediate 2.2, 4-acetoxy-3,5-dimethoxy-N-[(4-nitrophenyl)methyl]-benzamide replacing the 3,5-bis-(1,1 -dimethylethyl)-4-hydroxy-N-[(4-nitrophenyl)methyl]-benzamide. A colourless oil is obtained with a yield of 82%. The product is used directly in the following stage without additional purification.
Reaction SMILES: [S:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[Cl:13][C:14]1[CH:15]=[C:16]([CH2:21][CH2:22][NH2:23])[CH:17]=[CH:18][C:19]=1[Cl:20].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[Cl:13][C:14]1[CH:15]=[C:16]([CH2:21][CH2:22][NH:23][C:6]([C:5]2[S:1][C:2]3[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=3[CH:4]=2)=[O:8])[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: O=C(O)c1cc2ccccc2s1
Reactant: NCCc1ccc(Cl)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCCc1ccc(Cl)c(Cl)c1)c1cc2ccccc2s1
Temperature: 25 °C
Yield: 87.5 %

Procedure:
To a solution of 300 mg (1.68 mmol) of benzo[b]thiophene-2-carboxylic acid in DMF (8 ml) were added 320 mg (1.68 mmol) of 2-(3,4-dichloro-phenyl)-ethylamine and 595 mg (1.85 mmol) of TBTU. After 10 min 1.47 ml (8.42 mmol) of N,N-diisopropylethyl amine were added and the reaction mixture was stirred over night at RT. Then water was added and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with water, brine, sat. NaHCO3 solution, 1N HCl and again with brine. The organic layer was then dried (MgSO4) and concentrated. The remaining residue was purified by column chromatography (silica gel; ethyl acetate/cyclohexane 9:1) to yield 515 mg (87%) of benzo[b]thiophene-2-carboxylic acid[2-(3,4-dichloro-phenyl)-ethyl]-amide as a white solid. MS (ISP) 350.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]Cl)([O-:15])=[O:14]>CN(C)C=O.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([N:11]([CH3:12])[S:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N+:13]([O-:15])=[O:14])=[O:10])=[CH:6][CH:7]=1
Reactant: CNC(=O)Nc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccccc1SCl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CN(Sc1ccccc1[N+](=O)[O-])C(=O)Nc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 57.9 %

Procedure:
N-4-chlorophenyl-N'-methyl urea (4.1 g) was dissolved in a mixture of dimethylformamide (20 ml) and pyridine (5 ml) and then 2-nitrophenylthiochloride (4.17 g) was added to and dissolved in the solution. After allowing the solution to stand overnight, it was poured into 200 ml of ice-water. The initial product was an oily product which solidified after a while. The solid product was separated by filtration, washed with water and dried. Recrystallization from a mixture of ethyl acetate and n-hexane gave 4.3 g of the object compound. (m.p.: 157°-158° C.)
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24](O)=[O:25])[N:23]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O.CCN(C(C)C)C(C)C.[CH3:58][NH:59][CH:60]1[CH2:65][CH2:64][CH2:63][CH:62]([N:66]2[CH2:71][CH2:70][N:69]([CH3:72])[CH2:68][CH2:67]2)[CH2:61]1>CN(C=O)C>[CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:59]([CH3:58])[CH:60]3[CH2:65][CH2:64][CH2:63][CH:62]([N:66]4[CH2:67][CH2:68][N:69]([CH3:72])[CH2:70][CH2:71]4)[CH2:61]3)=[O:25])[N:23]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:2][CH2:3]1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)O)co2)C2CC2)c(C)c1
Reactant: CNC1CCCC(N2CCN(C)CC2)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N(C)C3CCCC(N4CCN(C)CC4)C3)co2)C2CC2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AH using 2-({cyclopropyl[(4-methoxy-2,6-dimethylphenyl)sulfonyl]amino}methyl)-1,3-oxazole-4-carboxylic acid (50 mg, 0.13 mmol), EDCI (50 mg, 0.26 mmol), HOBt monohydrate (40 mg, 0.26 mmol), DIPEA (90 μL, 0.52 mmol), N-methyl-3-(4-methylpiperazin-1-yl)cyclohexanamine (27 mg, 0.13 mmol) and DMF (1 mL). The resulting crude compound was purified by FCC eluting with 99:1 DCM:7N NH3 in MeOH followed by purification using prep method D.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:22])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1>C(O)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([OH:22])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)CCC(O)c1ccc(-c2ccc(Cl)cc2)cc1
Reaction time: 4 h
Yield: 17.5 %

Procedure:
To a stirred suspension of sodium borohydride (0.0376 g, 0.00099 mol) in absolute ethanol under nitrogen at room temperature was added in one portion 4-(4′-chloro-biphenyl-4-yl)-4-oxo-butyric acid (0.576 g, 0.00199 mol), and the mixture stirred for 4 hours. Additional sodium borohydride (0.013 g, 0.00034 mol) was added, and the mixture stirred for 18 hours. Additional sodium borohydride (0.0144 g, 0.000381 mol) was added and the mixture stirred for 5 hours. Total reaction time was 27 hours. The reaction was quenched with acetone-water and partitioned between 1 M hydrochloric acid and dichloromethane. The organic layer was washed with brine, dried (Na2DO4), and rotary evaporated. The residue was purified by chromatography on silica gel using dichloromethane-methanol (19:1, 1.3 L; 15.1, 1.3 L) to give 0.101 g of (±)-4-(4′-chloro-biphenyl-4-yl)-4-hydroxy-butyric acid as a white solid; mp 133.5-135.0° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[CH:5]=[CH:4][N:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH2:26][CH:25]([NH2:29])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH2:26][CH:25]([NH:29][CH2:11][C:10]2[CH:13]=[CH:14][CH:15]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:9]=2)[CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Reactant: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Product: CC(C)(C)OC(=O)N1CCCC(NCc2cccc(-c3ccnc(Cl)n3)c2)C1

Procedure:
Intermediate 1 was coupled with 3-Amino-piperidine-1-carboxylic acid tert-butyl ester following procedure B. LC-MS showed the product had the expected M+H+ of 403.
Reaction SMILES: [C:1]([Cl:11])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:12][N:13]([CH3:25])[CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1.CCOCC>C(Cl)(Cl)Cl>[ClH:11].[CH3:25][N:13]([CH3:12])[CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([NH:24][C:1](=[O:10])[CH:2]=[CH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:22][CH:23]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: CN(C)CCCOc1ccc(N)cc1
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: CN(C)CCCOc1ccc(NC(=O)C=Cc2ccccc2)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
A solution of 16.6g of cinnamoyl chloride in 125 ml of chloroform is cooled to 15° C and treated dropwise with a solution of 19.4g of 4-[3-(dimethylamino)propoxy]benzenamine in 75 ml of chloroform, keeping the temperature between 15° and 20° C. After stirring for 1 hour, the mixture is heated at reflux for 1 hour, cooled to 25° C and treated with 300 ml of ether to yield 31.6g of material, melting point 253°-257° C, dec.
Reaction SMILES: [OH-].[K+].CS(O[CH2:8][CH2:9][NH:10][S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21])(=[O:13])=[O:12])(=O)=O.C(Cl)Cl.C(OCC)(=O)C>O.C(OCC)(=O)C>[N+:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[S:11]([N:10]1[CH2:8][CH2:9]1)(=[O:13])=[O:12])([O-:22])=[O:21]
Reactant: CS(=O)(=O)OCCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)N1CC1

Procedure:
A solution of KOH (1.73 g, 31 mmol) in water (50 mL) was added to a solution of compound 55 (10 g, 31 mmol) in ethyl acetate (100 mL). The aqueous layer stained in yellow. The mixture was stirred at room temperature for 1 h (TLC monitoring, eluent: CH2Cl2-ethyl acetate, 1:1). If necessary, additional portions of KOH solution (0.5 eq.) were added. The organic layer was separated, washed thoroughly with water, a solution of citric acid (to pH 7), again with water, dried over Na2SO4, and evaporated. Yield of 56: 6.6 g (93%) as a yellowish fluid oil.
Reaction SMILES: C1([C@H]([N:9]2[CH2:14][CH2:13][O:12][C@@H:11]([C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=3)[CH2:10]2)C)C=CC=CC=1.[Cl:23]C(OC(Cl)C)=O>ClCCCl>[ClH:23].[NH:9]1[CH2:14][CH2:13][O:12][C@@H:11]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)[CH2:10]1
Reactant: CC(Cl)OC(=O)Cl
Reactant: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(C#N)cc2)C1
Solvent: ClCCCl
Product: Cl
Product: N#Cc1ccc([C@H]2CNCCO2)cc1
Yield: 78.7 %

Procedure:
To a solution of 4-((2S)-4-((1R)-1-phenylethyl)morpholin-2-yl)benzonitrile (intermediate 15, 45.7 g, 156 mmol) in 1,2-dichloroethane (312 ml) was added 1-chloroethyl chloroformate (66.9 g, 468 mmol) at room temperature. After a reflux for 6 hours, the solution was concentrated under reduced pressure. The residue was dissolved in methanol (312 ml) and the solution was refluxed for 2 hours. After removal of the solvent under reduced pressure, the crude product was washed with acetone and dried under reduced pressure to afford 4-((2S)-morpholin-2-yl)benzonitrile hydrochloride (intermediate 16, 27.6 g, 79%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][C@@H:8]([CH2:22][CH:23]1[C:28](=[O:29])[O:27][C:26]([CH3:31])([CH3:30])[O:25][C:24]1=[O:32])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[C:34]([O-])([O-])=O.[K+].[K+].CI.[Na+].[Cl-]>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6](=[O:33])[NH:7][C@@H:8]([CH2:22][C:23]1([CH3:34])[C:28](=[O:29])[O:27][C:26]([CH3:31])([CH3:30])[O:25][C:24]1=[O:32])[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][CH:15]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)CC1C(=O)OC(C)(C)OC1=O
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)CC1(C)C(=O)OC(C)(C)OC1=O
Temperature: 0 °C
Yield: 75.8 %

Procedure:
[(S)-2-Biphenyl-4-yl-1-(2,2-dimethyl-4,6-dioxo-[1,3]dioxan-5-ylmethyl)-ethyl]carbamic acid t-butyl ester (5.0 g, 11 mmol) and K2CO3 (1.8 g, 13.2 mmol) were dissolved in DMF (33.9 mL) and cooled to 0° C. with stirring under nitrogen. Methyl iodide (892 μL) was added and the resulting mixture was stirred at 0° C. for 1 hour. The mixture was allowed to warm to room temperature. Saturated aqueous NaCl (35 mL) and EtOAc (35 mL) were added, and the resulting mixture was stirred for 2 minutes. The layers were separated and the organic layer was evaporated. The residue was triturated with EtOAc (20 mL). The solid was filtered off and dried under vacuum. The filtrate was concentrated and triturated again with EtOAc to yield the title compound (3.9 g).