Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][CH:3]([F:14])[O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][C:6]=1[OH:13].C(N(CC)CC)C.[Br:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[C:29](=O)[NH:28][C:27](=O)/[C:26]/2=[CH:35]/OC>CN(C)C=O>[Br:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[CH:29]=[N:28][CH2:27]/[C:26]/2=[CH:35]\[NH:10][CH2:9][C:8]1[CH:11]=[CH:12][C:5]([O:4][CH:3]([F:14])[F:2])=[C:6]([OH:13])[CH:7]=1
Reactant: NCc1ccc(OC(F)F)c(O)c1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Oc1cc(CN/C=C2\CN=Cc3ccc(Br)cc32)ccc1OC(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
An amount of 90 mg (0.40 mmol) of 4-difluoromethoxy-3-hydroxy benzylamine hydrochloride, is dissolved in N,N-dimethylformamide (4 mL). 50 ul (0.75 mmol) of triethylamine is added followed by 112 mg (0.40 mmol) of (4E)-6-bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione. After the mixture is stirred at room temperature for 30 min, the solvent is removed in-vacuo and the residue dissolved in 7.5% methanol in chloroform and passed thru a short pad of Florisil eluting with 7.5% methanol in chloroform, the eluate is evaporated and the solid triturated with ether, filtered and washed several times with anhydrous ether to give 116 mg of a pink solid (67% yield); mp 256-8° C., MS data ES(−) 437.0, 439.0 (M−1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:12]2[N:13]=[C:14]([CH2:17][CH2:18][CH3:19])[NH:15][CH:16]=2)[OH:11])=[CH:6][CH:5]=1)([O-])=O>CO.C(O)C.[C].[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([C:12]2[N:13]=[C:14]([CH2:17][CH2:18][CH3:19])[NH:15][CH:16]=2)[OH:11])=[CH:8][CH:9]=1
Reactant: CCCc1nc(C(O)c2ccc([N+](=O)[O-])cc2)c[nH]1
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: CCCc1nc(C(O)c2ccc(N)cc2)c[nH]1
Reaction time: 4 h
Yield: 88.4 %

Procedure:
To a mixed solution of (4-nitrophenyl)[2-(1-propyl)imidazolyl]methanol (4.5 g) in methanol (150 ml) and ethanol (100 ml), 10% palladium carbon (450 mg) was added, and the mixture was stirred for 4 hours under hydrogen atmosphere. The insolubles were filtered off, and the residue was purified by basic silica gel column chromatography (methanol-ethyl acetate=1:8) and recrystallized from ethyl acetate-diisopropyl ether, to give (4-aminophenyl)[2-(1-propyl)imidazolyl]methanol (3.52 g) as brown crystals.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1.[Cl:36][C:37]1[CH:45]=[CH:44][C:40]([C:41](Cl)=[O:42])=[CH:39][CH:38]=1>>[Cl:36][C:37]1[CH:45]=[CH:44][C:40]([C:41]([O:1][CH2:2][CH2:3][O:4][C:5]2[CH:10]=[CH:9][C:8]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:13][CH:12]3[O:24][CH2:25][C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)=[CH:7][CH:6]=2)=[O:42])=[CH:39][CH:38]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCO)cc2)C(OCc2ccc3ccccc3c2)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCOC(=O)c3ccc(Cl)cc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 22(k), by acylating tert-butyl (3RS,4RS)-4-[4-(2-hydroxy-ethoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate with 4-chlorobenzoyl chloride there was obtained tert-butyl (3RS,4RS)-4-[4-[2-(4-chloro-benzoyloxy)-ethoxy]-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless oil; MS: 616 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:12][C:13](=O)[C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:25][CH2:24][N:23](C(=O)C(F)(F)F)[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[CH:8]=[C:9]([F:11])[CH:10]=1)=O)C.C([O-])(=O)C.[NH4+:37].O>C(O)(=O)C>[F:11][C:9]1[CH:10]=[C:6]2[C:4](=[O:3])[NH:37][C:13]([C:14]3[CH:15]=[CH:16][C:17]([CH:20]4[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]4)=[CH:18][CH:19]=3)=[CH:12][N:7]2[CH:8]=1
Reactant: CCOC(=O)c1cc(F)cn1CC(=O)c1ccc(C2CCN(C(=O)C(F)(F)F)CC2)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]c(-c2ccc(C3CCNCC3)cc2)cn2cc(F)cc12
Temperature: 110 °C
Reaction time: 8 h

Procedure:
4-Fluoro-1-(2-oxo-2-{4-[1-(2,2,2-trifluoro-acetyl)-piperidin-4-yl]-phenyl}-ethyl)-1H-pyrrole-2-carboxylic acid ethyl ester (1.57 g; 3.42 mmol) is dissolved in acetic acid (10 ml) and ammonium acetate (5.80 g; 75.25 mmol) is added. The reaction mixture is stirred at 110° C. overnight. The reaction mixture is allowed to cool to room temperature, poured into cold water (250 ml) and extracted with ethyl acetate. The organic layers are discarded. The aqueous layer is basified with 2N NaOH (pH11). A precipitate forms. The solid is filtered off by suction, washed with water and a small amount of ethyl acetate. Then the solid is dissolved in 150 ml ethyl acetate, dried over Na2SO4, filtered off by suction and evaporated to dryness. The residue is triturated with diethylether, filtered off and dried under vacuum at 50° C. (overnight). The aqueous filtrate is extracted 3 times with ethyl acetate/MeOH (5%). The combined organic layers are washed with brine, dried over Na2SO4, filtered off and evaporated to dryness. The residue is triturated with diethylether, filtered off by suction and dried under vacuum to afford 7-fluoro-3-(4-piperidin-4-yl-phenyl)-2H-pyrrolo[1,2-a]pyrazin-1-one as beige solid; HPLC/MS 1.37 min (A), [M+H] 312;
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH2:6][C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][N:31]=2)=[CH:25][CH:24]=1)=[O:21].C(NC(C)C)(C)C>CN(C)C=O>[F:38][C:36]([F:37])([F:39])[C:33]1[CH:34]=[CH:35][C:30]([O:29][C:26]2[CH:27]=[CH:28][C:23]([O:22][C:20]([N:16]3[CH2:15][CH2:14][CH:13]([N:5]([CH2:4][CH:1]4[CH2:2][CH2:3]4)[CH2:6][C:7]4[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=4)[CH2:18][CH2:17]3)=[O:21])=[CH:24][CH:25]=2)=[N:31][CH:32]=1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: c1cncc(CN(CC2CC2)C2CCNCC2)c1
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)N1CCC(N(Cc2cccnc2)CC2CC2)CC1

Procedure:
The title product was prepared from cyclopropylmethyl-piperidin-4-yl-pyridin-3-ylmethylamine and 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate, 3 equivalent of diisopropylamine was added, solvent: dimethylformamide. The crude reaction mixture was evaporated without addition of acetic acid, preparative HPLC (method C) (47%, off-white solid. HPLC-MS m/z=(M+1) 513.3, Rt: 2.70 min.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([NH:5][C@@H:6]([CH3:16])[C@H:7]([OH:15])[C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)=[O:4].[N+:19]([O-])([OH:21])=[O:20].C(OCC)(=O)C>C(O)(=O)C>[F:1][C:2]([F:17])([F:18])[C:3]([NH:5][C@@H:6]([CH3:16])[C@H:7]([OH:15])[C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([N+:19]([O-:21])=[O:20])[CH:9]=1)=[O:4]
Reactant: O=[N+]([O-])O
Reactant: C[C@H](NC(=O)C(F)(F)F)[C@H](O)c1ccc(O)cc1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: C[C@H](NC(=O)C(F)(F)F)[C@H](O)c1ccc(O)c([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
To a solution of 2,2,2-trifluoro-N-[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]acetamide (26.9 g) in acetic acid (85 mL) was added dropwise 70% nitric acid (6.78 mL) at room temperature with stirring. The mixture was stirred for 15 minutes at that temperature. The resulting mixture was poured into ice-water (500 g), and ethyl acetate was added. The organic layer was separated, washed successively with saturated aqueous solution of sodium bicarbonate and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by medium-pressure liquid silica gel column chromatography (eluent: n-hexane/ethyl acetate=2/1) to afford the title compound (33.5 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:56]=[CH:55][CH:54]=[CH:53][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32][O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[CH2:40][CH2:41]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:13][CH:12]=1.[O:57]1[CH2:61][CH2:60][NH:59][C:58]1=[O:62]>>[CH3:1][O:2][C:3]1[CH:56]=[CH:55][CH:54]=[CH:53][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32][O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[CH2:40][CH2:41][N:59]2[CH2:60][CH2:61][O:57][C:58]2=[O:62])=[CH:15][CH:16]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: O=C1NCCO1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CCN2CCOC2=O)cc1

Procedure:
Analogously to Example 27a, 020 g of tert-butyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-(2-{2-[2-(toluene-4-sulphonyloxy)ethyl]phenoxy}ethoxy)piperidine-1-carboxylate (Example 26b) and 0.44 g of oxazolidin-2-one are reacted. The title compound is obtained as a colourless oil. Rf=0.27 (2:1 EtOAc-heptane).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH:23]5[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.Br[CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]>>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH:23]5[CH2:28][CH2:27][N:26]([CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:25][CH2:24]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1C1CCNCC1
Product: CC(C)(C)OC(=O)CN1CCC(N2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)CC1

Procedure:
1,1-Dimethylethyl {4-[(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]piperidin-1-yl}acetate was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-piperidin-4-yl-1,3-thiazolidine-2,4-dione (Example 113) and tert-butyl bromoacetate using the same methods as described by Procedure I.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]([CH3:18])([CH3:17])[CH:5]([C:8]([CH3:16])([CH3:15])[O:9][SiH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=C.N#N.CSC.C[OH:26]>ClCCl>[CH3:1][O:2][C:3](=[O:19])[C:4]([CH3:18])([CH3:17])[CH:5]([C:8]([CH3:16])([CH3:15])[O:9][SiH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=[O:26]
Reactant: C=CC(C(C)(C)O[SiH2]C(C)(C)C)C(C)(C)C(=O)OC
Reactant: CO
Agent: N#N
Solvent: ClCCl
Solvent: CSC
Product: COC(=O)C(C)(C)C(C=O)C(C)(C)O[SiH2]C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of Example 2C (3.5 g, 12.2 mmol)in dichloromethane (25 mL) and methanol (2.5 mL) was cooled to −78° C. and O3 was bubbled for twenty-five minutes. The reaction was purged with N2 and DMS (5.29 g, 85.4 mmol) was added. The reaction was stirred at room temperature for three hours. The solvent was evaporated in vacuo and the product purified by flash column chromatography (hexanes:ethyl acetate) 100:0 to 50:50) to provide the title compound as an oil.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:53])[CH:6]([OH:54])[CH2:5][C:4]1=[O:55])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH:60]([CH3:62])[CH3:61].FC(F)(F)S(O)(=O)=O>C(OCC)(=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH:60]([CH3:62])[CH3:61])[CH2:45]2)[CH:7]([CH3:53])[CH:6]([OH:54])[CH2:5][C:4]1=[O:55])[CH3:2]
Reactant: CC(C)OC(=N)C(Cl)(Cl)Cl
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC(C)C)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Yield: 13.3 %

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (300 mg in 4.5 ml 33% methylene chloride in cyclohexane) isopropyl trichloroacetimidate (142 mg neat) was added and the reagents allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (13.4 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 5 days the reaction was diluted with ethyl acetate and quenched with saturated sodium bicarbonate. The layers were separated, and the organic layer was washed with brine then dried over magnesium sulfate. Purification of the concentrate by preparative TLC on silica gel (ethyl acetate:hexane (1:1)+1% methanol) gave the title compound (42 mg). 1H NMR consistent with the desired structure.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[N+:8]([C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([N+]([O-])=O)[C:12]=1[C:13]#[N:14])([O-:10])=[O:9]>>[CH3:1][S:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:15]1[CH:16]=[CH:17][CH:18]=[C:11]([N+:8]([O-:10])=[O:9])[C:12]=1[C:13]#[N:14]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: CSCCCCO
Product: CSCCCCOc1cccc([N+](=O)[O-])c1C#N
Yield: 89 %

Procedure:
Prepared as in Example 215c from 4-(methylthio)butan-1-ol and 2,6-dinitrobenzonitrile in 89% yield. MS 267 (MH+).
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[CH3:5][C:6]1[CH2:11][CH2:10][CH2:9][C:8]([CH3:13])([CH3:12])[C:7]=1[CH:14]=[O:15]>CCOCC>[CH3:5][C:6]1[CH2:11][CH2:10][CH2:9][C:8]([CH3:12])([CH3:13])[C:7]=1[CH:14]([OH:15])[CH2:3][CH:2]=[CH2:1]
Reactant: C=CCBr
Reactant: CC1=C(C=O)C(C)(C)CCC1
Solvent: CCOCC
Product: C=CCC(O)C1=C(C)CCCC1(C)C
Temperature: 0 °C
Yield: 57 %

Procedure:
In a typical experiment 10.7 g. of Mg turnings and 5 g. of allyl bromide were allowed to react in 70 ml. of dry ether. The reaction was exothermic and the temperature of the reaction mixture increased up to the boiling point of the solvent. To this solution allyl bromide (46 g.) and β-cyclocitral (61 6.) in 160 ml. of ether were added with vigorous stirring at such a rate as to maintain the ether at the boiling temperature. The reaction mixture was then kept at reflux during 6 hours and after cooling it was poured into a ice-cold concentrated aqueous solution of NH4C1. The ethereal layer after the usual treatments gave 2,6,6-trimethyl-1-[1-hydroxy-3-butenyl]-1-cyclohexene (44.5 g; 57 % yield): B.p. 60°-2° /0.001 Torr; nD20 = 1.4964; d420 = 0.9398.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C@H:5]([OH:22])[CH2:6][C@H:7]([NH2:21])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH3:2].[C:24]([C:27]1[CH:28]=[C:29]([C:32](O)=[O:33])[NH:30][N:31]=1)(=[O:26])[CH3:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:23])[C@H:5]([OH:22])[CH2:6][C@H:7]([NH:21][C:32]([C:29]1[NH:30][N:31]=[C:27]([C:24](=[O:26])[CH3:25])[CH:28]=1)=[O:33])[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:13][CH:14]=1)[CH3:2]
Reactant: CCOC(=O)[C@H](O)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H](O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(C(C)=O)n[nH]1
Reaction time: 0.03 h
Yield: 66.7 %

Procedure:
(2R,4R)-4-Amino-5-biphenyl-4-yl-2-hydroxypentanoic acid ethyl ester (HCl salt; 500 mg, 1 mmol, 1.0 eq.), 5-acetyl-2H-pyrazole-3-carboxylic acid (330.4 mg, 2.1 mmol, 1.5 eq.), and HATU (820 mg, 2.1 mmol, 1.5 eq.) were combined in DMF (5 mL), and the resulting mixture was stirred for 2 minutes. DIPEA (750 μL) was added and the mixture was stirred for 1 hour. The mixture was dried under vacuum, and the product was purified using reverse phase chromatography (10-70% MeCN/H2O; 0.05% TFA over 70 minutes) to yield the title compound (300 mg, purity 98%) as a TFA salt. MS m/z [M+H]+ calc'd for C25H27N3O5, 450.20. found 450.2.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:17][CH2:18][C:19](Cl)=[O:20]>C(Cl)Cl>[Cl:17][CH2:18][C:19]([NH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)=[O:20]
Reactant: N#Cc1ccc(N)cc1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(NC(=O)CCl)cc1
Temperature: 26 °C
Reaction time: 22 h
Yield: 92.4 %

Procedure:
A mixture of 4-Amino benzonitrile (1.0 g, 0.0084 mol) and triethyl amine (1 ml, 0.010 mol) was taken in DCM (15 ml). Chloro acetyl chloride (0.67 ml, 0.0084 mol) was added slowly and stirred for 22 hours at 25-27° C. Solvent was removed and the residue was dissolved in ethyl acetate (20 ml), washed with water (1×15 ml) followed by brine (2×15 ml). The organic layer was dried over Na2SO4 and the solvent was removed to get pure 2-chloro-N-(4-cyano-phenyl)-acetamide (1.51 g, 92%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][C:13]1[CH:22]=[C:21]2[C:16]([C:17]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]#[C:33][CH2:34][O:35][CH3:36])=[C:28]4[O:37][CH2:38][O:39][C:27]=34)=[C:18]([C:23]#[N:24])[CH:19]=[N:20]2)=[CH:15][C:14]=1[O:40][CH3:41].[I-].[Na+].[ClH:44]>C(OCC)(=O)C.C(OCC)C>[ClH:6].[ClH:44].[C:23]([C:18]1[CH:19]=[N:20][C:21]2[C:16]([C:17]=1[NH:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]#[C:33][CH2:34][O:35][CH3:36])=[C:28]3[O:37][CH2:38][O:39][C:27]=13)=[CH:15][C:14]([O:40][CH3:41])=[C:13]([O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[CH:22]=2)#[N:24]
Reactant: COCC#Cc1ccc(Nc2c(C#N)cnc3cc(OCCOCCCl)c(OC)cc23)c2c1OCO2
Reactant: C1CCNC1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COCC#Cc1ccc(Nc2c(C#N)cnc3cc(OCCOCCN4CCCC4)c(OC)cc23)c2c1OCO2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Pyrrolidine (10 ml) was added to a mixture of 7-[2-(2-chloroethoxy)ethoxy]-3-cyano-6-methoxy-4-[4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyanilino]quinoline (0.225 g) and sodium iodide (0.133 g) and the reaction mixture was stirred at ambient temperature for 24 hours. The reaction mixture was evaporated and the residue was triturated under methylene chloride. The resultant solid was washed with water and dried. The material so obtained was dissolved in the minimum quantity of ethyl acetate and a solution of hydrogen chloride in diethyl ether (1M) was added. The resultant solid was isolated, washed with diethyl ether and dried. There was thus obtained the title compound as a solid (0.145 g); NMR Spectrum: (DMSOd6 and CD3CO2D at 100° C.) 1.84–1.89 (m, 4H), 3.29–3.39 (m, 9H), 3.88 (m, 2H), 3.94 (m, 2H), 3.96 (s, 3H), 4.3 (s, 2H), 4.36 (m, 2H), 6.04 (s, 2H), 6.84 (d, 1H), 6.94 (d, 1H), 7.46 (s, 1H), 7.87 (s, 1H), 8.56 (s, 1H); Mass Spectrum: M+H+ 545.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.CC(C)N=C=NC(C)C.[C:19]([O:23][C:24]([N:26]1[CH2:39][CH2:38][C:37]2[C:36]3[C:35]([Cl:40])=[C:34]([Cl:41])[CH:33]=[CH:32][C:31]=3[N:30]([CH2:42][C:43](O)=[O:44])[C:29]=2[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>CN(C1C=CN=CC=1)C.C1COCC1.CCOC(C)=O>[Cl:41][C:34]1[CH:33]=[CH:32][C:31]2[N:30]([CH2:42][C:43]([NH:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[O:44])[C:29]3[CH2:28][CH2:27][N:26]([C:24]([O:23][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:25])[CH2:39][CH2:38][C:37]=3[C:36]=2[C:35]=1[Cl:40]
Reactant: COc1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CC(=O)O)c3ccc(Cl)c(Cl)c23)CC1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)Cn2c3c(c4c(Cl)c(Cl)ccc42)CCN(C(=O)OC(C)(C)C)CC3)cc1
Reaction time: 4 h
Yield: 37 %

Procedure:
DMAP (89 mg, 0.73 mmol), p-anisidine (0.10 g, 0.81 mmol) and DIC (0.13 mL, 0.81 mmol) were added to the solution of crude [3-(tert-butoxycarbonyl)-9,10-dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl]acetic acid (0.30 g, 0.73 mmol) in dry THF (3.5 mL). After 4 h, additional p-anisidine (45 mg, 0.37 mmol) was added. The reaction was diluted with EtOAc after another 17 h and washed with 10% aqueous citric acid (20 mL), saturated aqueous NaHCO3 (20 mL), and brine (20 mL). The organic layer was then dried over Na2SO4, decanted, and concentrated impure product. It was then crystallized from EtOAc/heptane, triturated with pentane, and recrystallized from EtOAc/heptane to give 0.14 g (36%) of a white solid: mp 143.0-144.0° C.; 1H NMR (300 MHz, DMSO) δ 10.30 (s, 1H), 7.47 (m, 3H), 7.25 (d, J 8.7 Hz, 1H), 6.88 (d, J=9.0 Hz, 2H), 5.04 (br s, 2H), 3.71 (s, 3H), 3.63 (m, 4H), 3.39 (m, 2H), 2.99 (m, 2H), 1.40 (app d, 9H); IR (diffuse reflectance) 2975, 1666, 1545, 1514, 1474, 1451, 1414, 1365, 1253, 1239, 1222, 1173, 1158, 830, 784 cm1; MS (EI) m/z 517 (M+), 377, 375, 227, 224, 212, 134, 124, 121, 55, 53; MS (FAB) m/z 518 (M+H+), 520, 519, 518, 517, 464, 463, 462, 461, 418, 57; HRMS (EI) calcd for C26H29Cl2N3O4 517.1535, found 517.1537; Anal. Calcd for C26H29Cl2N3O4: C, 60.24; H, 5.64; N, 8.10; found: C, 59.86; H, 5.68; N, 7.94.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:18]=[C:19]([CH2:23][CH:24]=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P([O-])(O)(O)=[O:27].[Na+].Cl([O-])=O.[Na+]>O.CS(C)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([C:17]2[CH:18]=[C:19]([CH2:23][C:24]([OH:27])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CCc1cccc(C2CCN(C(=O)OCc3ccccc3)CC2)c1
Reactant: O=P([O-])(O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)Cc1cccc(C2CCN(C(=O)OCc3ccccc3)CC2)c1
Yield: 95.5 %

Procedure:
To a solution of 2.0 g of 3-[1-(benzyloxycarbonyl)-piperidin-4-yl]phenylacetaldehyde and 1.0 g of sodium dihydrogenphosphate in 10 ml of water and 50 ml of dimethyl sulfoxide was added a solution of 2.0 g of sodium chlorite in water (10 ml) and the resulting mixture was reacted at room temperature for 20 minutes. After adding water, the reaction mixture was extracted with ethyl acetate, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, 2.0 g of crude 3-[1-(benzyloxycarbonyl)piperidin-4-yl]phenylacetic acid was obtained as a colorless oily substance. To a solution of 2.0 g of this oily substance in 50 ml of methanol was added 0.47 ml of thionyl chloride at 0° C. and the resulting mixture was reacted at room temperature for 2 hours. The reaction mixture was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 1.2 g of the title compound as a yellow oily substance.