Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].[OH:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=1)[C:14](OC)=O.[NH3:21]>>[NH2:21][C:1]1[CH:3]=[CH:14][C:13]2[C:12](=[C:11]([O:10][CH:5]([CH3:4])[CH2:6][CH2:7][CH2:8][O:9][C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[CH:20]=[CH:19][CH:18]=2)[N:2]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: COC(=O)c1cccc(O)c1
Reactant: N
Product: CC(CCCOc1ccc(C#N)cc1)Oc1cccc2ccc(N)nc12

Procedure:
The title compound was prepared according to the procedure described in Example 92 substituting 4-cyanophenol for methyl 3-hydroxybenzoate. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.36 (d, 1H), 7.70 (m, 2H), 7.44 (m, 3H), 7.12 (d, 1H), 7.00 (m, 2H), 4.84 (m, 1H), 4.12 (m, 2H), 1.74–2.05 (m, 4H), 1.40 (d, 3H); MS (DCI/NH3) m/z 348 [M+H]+.
Reaction SMILES: [Br-].C(OC([N:8]1[C@H:12]([CH2:13][C:14]2[S:18][C:17]3=[CH:19][N:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:21]([CH3:22])=[N+:16]3[CH:15]=2)[CH2:11][C@H:10]([S:29][C:30]2[C@H:31]([CH3:47])[C@@H:32]3[C@@H:42]([C@H:43]([OH:45])[CH3:44])[C:41](=[O:46])[N:33]3[C:34]=2[C:35]([O:37]CC=C)=[O:36])[CH2:9]1)=O)C=C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1.C(O)C>[CH2:27]([O:26][C:24]([CH2:23][N:20]1[CH:19]=[C:17]2[S:18][C:14]([CH2:13][C@H:12]3[NH:8][CH2:9][C@@H:10]([S:29][C:30]4[C@H:31]([CH3:47])[C@@H:32]5[C@@H:42]([C@H:43]([OH:45])[CH3:44])[C:41](=[O:46])[N:33]5[C:34]=4[C:35]([O-:37])=[O:36])[CH2:11]3)=[CH:15][N+:16]2=[C:21]1[CH3:22])=[O:25])[CH3:28]
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](Cc3c[n+]4c(C)n(CC(=O)OCC)cc4s3)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: CCOC(=O)Cn1cc2sc(C[C@@H]3C[C@H](SC4=C(C(=O)[O-])N5C(=O)[C@H]([C@@H](C)O)[C@H]5[C@H]4C)CN3)c[n+]2c1C
Temperature: 25 °C
Reaction time: 0.92 h
Yield: 4.4 %

Procedure:
Anhydrous THF (0.6 ml) and 0.6 ml of dry ethanol are added to 49.7 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-[6-ethoxycarbonylmethyl-5-methylimidazo[5,1-b]thiazolium-2-yl]methylpyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate bromide. Triphenylphosphine (6.9 mg), 0.014 ml of morpholine, and 3.8 mg of tetrakis(triphenylphosphine)palladium(0) are successively added thereto, and the mixture is stirred in an argon atmosphere at room temperature for 55 min. THF (10 ml) is added, the resultant precipitate is further washed twice with 3 ml of THF and dried in vacuo to give a yellow powder which is then purified by column chromatography on Cosmosil 40C18-PREP (water-methanol) to give 1.6 mg of the title compound as a colorless flocculent material.
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C@@H:15]2[C@:10]([CH3:23])([CH2:11][CH2:12][C:13]3[C:20]([Cl:21])=[C:19](Br)[CH:18]=[CH:17][C:14]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].[C:27](OCC)(=[O:29])C>CO.[Cu]Br>[CH2:1]([N:8]1[CH2:16][C@@H:15]2[C@:10]([CH3:23])([CH2:11][CH2:12][C:13]3[C:20]([Cl:21])=[C:19]([O:29][CH3:27])[CH:18]=[CH:17][C:14]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@]12CCc3c(ccc(Br)c3Cl)[C@@H]1CN(Cc1ccccc1)C2
Reactant: CCOC(C)=O
Agent: [Cu]Br
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(c1Cl)CC[C@]1(C)CN(Cc3ccccc3)C[C@@H]21
Temperature: 120 °C
Yield: 11 %

Procedure:
A mixture of trans-2-benzyl-7-bromo-6-chloro-3a-methyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole (0.704 mmol, 275 mg), sodium methoxide (8.75 mmol, 2 ml, 1890 mg), copper(I) bromide (0.352 mmol, 51.5 mg) and ethyl acetate (0.699 mmol, 69 μl, 62.2 mg) in MeOH (2 ml) was heated in a microwave reactor at 120° C. for 0.5 h. The reaction mixture was partitioned between DCM and water and the aqueous was further extracted with DCM. The combined organic extracts were dried over Na2SO4 and concentrated in vacuo before being purified by silica column chromatography (eluting with neat DCM—5% MeOH in DCM) to afford the trans-2-benzyl-6-chloro-7-methoxy-3a-methyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole (26.4 mg), m/z=342.2, 344.2 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]2[CH:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:7][N:8]([CH3:11])[CH2:9][CH2:10][C:4]=2[C:3]=1[N+:20]([O-])=O>C(O)C.[Pd]>[NH2:20][C:3]1[C:4]2[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH:6]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:5]=2[CH:18]=[CH:19][C:2]=1[OH:1]
Reactant: CN1CCc2c(ccc(O)c2[N+](=O)[O-])C(c2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Product: CN1CCc2c(ccc(O)c2N)C(c2ccccc2)C1
Reaction time: 2 h

Procedure:
0.16 g (0.00053 mol) 7-hydroxy-3-methyl-6-nitro-1 -phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine was dissolved in 15 ml ethanol. 0.05 g 10%Pd/C-catalyst were added and hydrogenation was carried out at a burette apparatus for 2h. The catalyst was filtered off and the solution was concentrated in vacuo. The compound was obtained as a light brown powder.
Reaction SMILES: [CH:1]12[CH2:10][CH:6]([CH2:7][CH2:8][CH2:9]1)[CH:5]1[CH2:11][CH:2]2[CH2:3][CH2:4]1.[Br:12]Br.S([O-])(O)=O.[Na+]>>[Br:12][C:1]12[CH2:10][CH:6]([CH2:7][CH2:8][CH2:9]1)[CH:5]1[CH2:11][CH:2]2[CH2:3][CH2:4]1
Reactant: C1CC2CC(C1)C1CCC2C1
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Product: BrC12CCCC(C1)C1CCC2C1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
1.0 Gram (4.8 millimoles) of tricyclo [4.3.1.12,5 ] undecane is added to 2 ml (38.7 millimoles) of liquid bromine and the entirety is stirred at room temperature for 17 hours. The reaction mixture is added slowly to a cooled, saturated solution of sodium hydrogensulfite under stirring to decompose excess bromine. The aqueous solution is subjected to two extractions each with 20 ml of carbon tetrachloride and the combined extracts are dried with magnesium sulfate. Carbon tetrachloride is distilled out and the residue (1.9 g) is distilled under reduced pressure to collect a fraction boiling at 96°-8° C./2mmHg. Colorless crystals having a melting point of 57.5°-58.5° C. are thus obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[CH:3]=1.C([O:13][B:14](OC(C)C)[O:15]C(C)C)(C)C.C([Li])CCC.Cl>O1CCCC1.CCCCCC>[Cl:9][C:4]1[CH:3]=[C:2]([B:14]([OH:15])[OH:13])[CH:7]=[C:6]([Cl:8])[CH:5]=1
Reactant: Clc1cc(Cl)cc(Br)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1cc(Cl)cc(Cl)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cold (-78° C.) solution of 1-bromo-3,5-dichlorobenzene (14 g) and triisopropoxyborane (20.8 ml) in tetrahydrofuran (140 ml) was added dropwise n-butyllithium in hexane (1.66 M, 52.3 ml). The mixture was stirred at -78° C. for one hour and warmed to room temperature over two hours. The reaction mixture was poured onto 2M hydrochloric acid solution (120 ml) and stirred for 10 minutes. The product was extracted with ether (200 ml) 3 times, and the organic layers were combined, washed with brine, dried over magnesium sulfate and evaporated in vacuo. To the residue was added petroleum ether and the crystalline was collected, washed with petroleum ether and dried to give 3,5-dichlorophenyl-dihydroxyborane.
Reaction SMILES: [F:1][C:2]([F:42])([C@H:35]1[CH2:40][CH2:39][C@H:38]([OH:41])[CH2:37][CH2:36]1)[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][N:13]([CH2:16][CH2:17][C@@:18]([CH3:33])([S:29]([CH3:32])(=[O:31])=[O:30])[C:19]([NH:21][O:22]C3CCCCO3)=[O:20])[C:12](=[O:34])[CH:11]=2)=[CH:6][CH:5]=1.Cl.CO>ClCCl.O1CCOCC1>[F:42][C:2]([F:1])([C@H:35]1[CH2:36][CH2:37][C@H:38]([OH:41])[CH2:39][CH2:40]1)[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][N:13]([CH2:16][CH2:17][C@@:18]([CH3:33])([S:29]([CH3:32])(=[O:31])=[O:30])[C:19]([NH:21][OH:22])=[O:20])[C:12](=[O:34])[CH:11]=2)=[CH:6][CH:5]=1
Reactant: C[C@@](CCn1ccc(-c2ccc(OC(F)(F)[C@H]3CC[C@H](O)CC3)cc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@@](CCn1ccc(-c2ccc(OC(F)(F)[C@H]3CC[C@H](O)CC3)cc2)cc1=O)(C(=O)NO)S(C)(=O)=O
Reaction time: 0.33 h

Procedure:
To a stirred solution of (2R)-4-[4-{-4-[difluoro(trans-4-hydroxycyclohexyl)methoxy]phenyl}-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (280 mg, 0.473 mM) in 2.3 mL of dichloromethane was added a solution of 4 M HCl in dioxane (0.120 mL, 0.473 mM). The reaction mixture was allowed to stir for 20 minutes before being treated with 0.5 mL of MeOH. Reaction was concentrated in vacuo and purified by reverse phase (Shimadzu) prep HPLC 35 mg, (14%). LCMS 529.1 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.30 (br. s., 2H) 1.40-1.54 (m, 2H) 1.64-1.74 (m, 3H) 1.99-2.14 (m, 4H) 2.31-2.42 (m, 1H) 2.51-2.67 (m, 1H) 3.09 (s, 3H) 3.45-3.62 (m, 1H) 3.87-4.02 (m, 1H) 4.23-4.34 (m, 1H) 6.70-6.75 (m, 1H) 6.78 (s, 1H) 7.21-7.33 (m, 2H) 7.65-7.74 (m, 3H)
Reaction SMILES: [N:1]1[C:10]2[C:5](=[C:6]([CH2:11][CH2:12][OH:13])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:33]([O:37][C:38](=[O:57])[CH2:39][CH:40]([NH:45][S:46]([C:49]1[CH:54]=[CH:53][C:52]([NH2:55])=[CH:51][C:50]=1O)(=[O:48])=[O:47])[C:41]([NH:43][CH3:44])=[O:42])([CH3:36])([CH3:35])[CH3:34].N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:33]([O:37][C:38](=[O:57])[CH2:39][CH:40]([NH:45][S:46]([C:49]1[CH:54]=[CH:53][C:52]([NH2:55])=[CH:51][C:50]=1[O:13][CH2:12][CH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[CH:3][CH:2]=[N:1]2)(=[O:48])=[O:47])[C:41]([NH:43][CH3:44])=[O:42])([CH3:36])([CH3:34])[CH3:35]
Reactant: OCCc1cccc2ncccc12
Reactant: CNC(=O)C(CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(N)cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CNC(=O)C(CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(N)cc1OCCc1cccc2ncccc12
Reaction time: 18 h

Procedure:
A mixture of 0.167 g (0.972 mmol) 2-quinolin-5-yl-ethanol, 0.48 g (1.94 mmol) triphenyl phosphine, and 0.392 g (0.972 mmol) 3-(4-amino-2-hydroxy-benzenesulfonylamino)-N-methyl-succinamic acid tert-butyl ester was stirred in 25 mL THF at room temperature under a nitrogen atmosphere. 0.31 mL (1.94 mmol) diethyl azodicarboxylate was added dropwise and the mixture stirred 18 h. TLC anaylsis indicated complete reaction. The solvent was evaporated under reduced pressure and the residue purified on silica eluting with 1:1 hexanes:EtOAc to EtOAc yielding 0.23 g (43%) of 3-(4-amino-2-(2-quinolin-5-yl-ethoxy)-benzenesulfonylamino)-N-methyl-succinamic acid tert-butyl ester as a colorless foam. MS (APCI) m/z 559 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]#[N:17])=[CH:7][CH:6]=2)[CH3:2].Br[CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21]>>[CH2:1]([C:3]1[N:4]([CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]([F:15])([F:13])[F:14])[C:8]([C:16]#[N:17])=[CH:7][CH:6]=2)[CH3:2]
Reactant: CCc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: CCC(Br)CC
Product: CCc1cc2c(C(F)(F)F)c(C#N)ccc2n1C(CC)CC

Procedure:
Synthesized as described in Example 145B from 2-ethyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile and 3-bromopentane: MS (ESI): m/z 309 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][C@@H:7]([C:9]([OH:11])=[O:10])[NH2:8])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:18]O>>[ClH:1].[NH2:8][CH:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=1)[C:9]([O:11][CH3:18])=[O:10]
Reactant: N[C@@H](Cc1ccc(Cl)cc1)C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C(N)Cc1ccc(Cl)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99 %

Procedure:
While under nitrogen, a stirred suspension of 4-chlorophenylalanine (2.50 g, 12.5 mmol) in anhydrous methanol (18 mL) was cooled in an ice-water bath and carefully treated with thionyl chloride (1.00 mL, 13.8 mmol). After stirring for 10 min, and the cooling bath was removed and the mixture was allowed to warm to room temperature. A reflux condenser was attached, and the slurry was warmed to 55° C. After stirring overnight, the mixture was cooled to room temperature, concentrated and dried under reduced pressure to give methyl 2-amino-3-(4-chlorophenyl)propanoate hydrochloride (3.13 g, 99%) as a white solid. ESI+ MS found for C10H12ClNO2 m/z 214.0 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([N+:13]([O-:15])=[O:14])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:23][CH2:24][O:25][CH3:26].C(OCC)(=O)C>C(#N)C.O>[CH3:26][O:25][CH2:24][CH2:23][O:1][C:2]1[CH:3]=[C:4]([N+:13]([O-:15])=[O:14])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(O)cc([N+](=O)[O-])c1C
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: COCCOc1cc(C(=O)OC)c(C)c([N+](=O)[O-])c1
Temperature: 80 °C
Yield: 63.4 %

Procedure:
To stirred solution of methyl 5-hydroxy-2-methyl-3-nitrobenzoate (1.50 g, 7.61 mmol) in ACN (15 mL) was added cesium carbonate (4.96 g, 15.2 mmol) and 1-bromo-2-methoxyethane (1.57 g, 11.4 mmol). The resulting reaction mixture was heated at 80° C. overnight. On completion, the reaction mixture was diluted with water and extraction was carried out using ethyl acetate. The combined organic layers were washed with water, dried, and concentrated under reduced pressure. The crude material was purified by column chromatography to afford the title compound (1.3 g, 68).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6].[Br:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([Br:27])[C:20]=1[N:28]=[C:29]=[S:30]>CN(C)C1C=CN=CC=1>[Cl:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])[C:2]=1[NH:1][C:29](=[S:30])[NH:28][C:20]1[C:21]([Br:27])=[CH:22][C:23]([O:25][CH3:26])=[CH:24][C:19]=1[Br:18]
Reactant: COc1cc(Br)c(N=C=S)c(Br)c1
Reactant: COC(=O)c1ccc(Cl)c(N)c1NCCCO
Agent: CN(C)c1ccncc1
Product: COC(=O)c1ccc(Cl)c(NC(=S)Nc2c(Br)cc(OC)cc2Br)c1NCCCO
Temperature: 80 °C
Reaction time: 16 h
Yield: 24.9 %

Procedure:
A mixture of methyl 3-amino-4-chloro-2-[(3-hydroxypropyl)amino]benzoate (1.00 g, 3.87 mmol), 1,3-dibromo-2-isothiocyanato-5-methoxybenzene (1.50 g, 4.64 mmol) and catalytic amount of 4-dimethylaminopyridine was stirred at 80° C. for 16 h and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 30-70% ethyl acetate/n-hexane gradient mixture to give the title compound as a brown oil (560 mg, 0.963 mmol, 25%).
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][C:7]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].O1CCCC1.B(Cl)([C@H]1[C@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1)[C@H]1[C@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1.N(CCO)CCO>CCCCCC>[OH:3][C@H:1]([C:4]1[CH:16]=[CH:15][C:7]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC(=O)c1ccc(C(=O)OC(C)(C)C)cc1
Agent: C[C@@H]1[C@H]2C[C@@H](C[C@H]1B(Cl)[C@@H]1C[C@@H]3C[C@H]([C@H]1C)C3(C)C)C2(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: OCCNCCO
Product: C[C@H](O)c1ccc(C(=O)OC(C)(C)C)cc1
Reaction time: 1.5 h
Yield: 103.3 %

Procedure:
To tert-butyl 4-acetylbenzoate (3.33 g) in a tetrahydrofuran (23 ml) solution, (−)-B-chlorodiisopinocampheylborane in a 65% hexane solution (11.2 ml) was added dropwise under ice cooling, then the mixture was stirred at that temperature for 1.5 hours. The reaction solution was concentrated, and the residue was diluted by diethyl ether. To the thus solution obtained, diethanolamine (4.3 ml) was added under ice cooling, and the mixture was stirred at room temperature for 2 hours. The precipitates were removed by filtration, and the filtrate was concentrated. The residue was purified by flash column chromatography (silica gel, hexane/ethyl acetate=9/1 to 4/1) to obtain the title compound (3.47 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:15]([CH3:16])=[CH:14][C:13]([O:17]CC3C=CC(F)=CC=3F)=[C:12](Br)[C:11]2=[O:28])=[C:6]([Cl:29])[CH:5]=1.Cl>C1COCC1.O>[Cl:29][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[N:10]1[C:15]([CH3:16])=[CH:14][C:13]([OH:17])=[CH:12][C:11]1=[O:28])[C:3]([O:2][CH3:1])=[O:30]
Reactant: COC(=O)c1ccc(-n2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c(Cl)c1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-n2c(C)cc(O)cc2=O)c(Cl)c1
Reaction time: 8 h
Yield: 110.8 %

Procedure:
Methyl-4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-3-chlorobenzoate (2.30 g, 4.61 mmol) was taken up in THF (20 ml) and H2O (4 ml). 2.5 N NAOH (9.2 ml) was added to the vessel and the reaction stirred overnight to completion. Concentrated HCl was added dropwise until reaction was made acidic (pH=1). H2O (100 ml) and THF (100 ml) were added to the mixture. The contents were poured into a separatory funnel and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over Na2SO4, the solvent removed in vacuo, and the residue was taken up in a 50% mixture of ethyl acetate/hexane. The precipitate was collected on a filter pad to yield a white powder (1.5 g, 67%). 1H NMR (300 MHz, DMSO) δ 13.59 (1H), 8.16 (d, J=1.81 Hz, 1H), 8.06 (dd, J=6.24, 1.81 Hz, 1H), 7.73 (app q, J=8.46, 1H), 7.68 (d, J=8.26 Hz, 1H), 7.38 (dt, J=9.48, 2.62 Hz, 1H), 7.26-7.18 (m, 1H), 6.80 (s, 1H), 5.39 (s, 2H), 3.93 (s, 3H), 1.96 (s, 3H); ES-MS m/z 483 (M+H). ES-HRMS m/z 483.9749 (M+H calcd for C20H14BrClF2NO4 requires 483.9757).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[C:18]([O:22][C:23]([NH:25][C@@H:26]([C:31]([OH:33])=O)[CH2:27][CH:28]([CH3:30])[CH3:29])=[O:24])([CH3:21])([CH3:20])[CH3:19].C(Cl)CCl.Cl.[CH2:39]([O:46][C:47](=[O:54])[C@H:48]([CH2:50][CH:51]([CH3:53])[CH3:52])[NH2:49])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>ClCCl>[CH2:39]([O:46][C:47](=[O:54])[C@H:48]([CH2:50][CH:51]([CH3:52])[CH3:53])[NH:49][C:31](=[O:33])[C@@H:26]([CH2:27][CH:28]([CH3:29])[CH3:30])[NH:25][C:23]([O:22][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:24])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)C[C@H](N)C(=O)OCc1ccccc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)C[C@H](NC(=O)[C@@H](CC(C)C)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1

Procedure:
HOBt (4 equivalents, 540 mg, 4 mmol), N-methylmorpholine (3 equivalents, 3 mmol), N-tert-butoxycarbonyl-D-leucine (1.0 equivalent, 230 mg, 1 mmol; Bachem), EDC (2 equivalents, 380 mg, 2 mmol) and again N-methylmorpholine (2 equivalents, 2 mmol) are added successively at −10° C. to a solution of L-leucine benzyl ester hydrochloride (1.1 equivalents, 300 mg, 1.1 mmol; cf. T. Wakamiya, M. Kamata, S. Kusumoto, H. Kobayashi, Y. Sai, et al., Bull. Chem. Soc. Jpn., 1998, 71, 699-710) in dichloromethane p.a. (30 ml). The reaction mixture warms slowly (about 12 h) to RT, whereby complete conversion of the amine component is observed by means of HPLC. The reaction mixture is concentrated in vacuo, taken up in acetonitrile and purified by means of preparative HPLC (Method 13). 362 mg (80% of theory) of the title compound are obtained.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([N:22]4[CH2:27][CH2:26][CH:25]([C:28]([O:30]CC)=[O:29])[CH2:24][CH2:23]4)=[O:21])=[C:14]([Cl:33])[C:13]=3[Cl:34])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[OH-].[K+].[OH-].[Na+]>CCOCC>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([N:22]4[CH2:27][CH2:26][CH:25]([C:28]([OH:30])=[O:29])[CH2:24][CH2:23]4)=[O:21])=[C:14]([Cl:33])[C:13]=3[Cl:34])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C1CCN(C(=O)/C=C/c2ccc(Sc3ccc4c(c3)OCCO4)c(Cl)c2Cl)CC1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: O=C(O)C1CCN(C(=O)/C=C/c2ccc(Sc3ccc4c(c3)OCCO4)c(Cl)c2Cl)CC1

Procedure:
The title compound was prepared by the procedures described in Example 155, substituting the ethyl ester from Example 137 with the ethyl ester from Example 328, and KOH with NaOH, to produce a white solid. 1 H NMR (d6-DMSO, 300 MHz) δ 1.33-1.55 (m, 2H), 1.62-1.78 (m, 2H), 1.93-2.07 (m, 1H), 2.90 (brt, J=10.5 Hz, 1H), 3.16 (brt, J=10.5 Hz, 1H), 3.96 (br d, J=13.5 Hz, 1H), 4.09 (br d, J=13.5 Hz, 1H), 4.26-4.42 (m, 4H), 6.60 (d, J=9.0 Hz, 1H), 7.04-7.08 (m, 2H), 7.13 (d, J=1.5 Hz, 1H), 7.22 (d, J=15.3 Hz, 1H), 7.70 (d, J=15.3 Hz, 1H), 7.86 (d, J=9.0 Hz, 1H). MS (ESI+) (M+H)+ at m/z 516, 518, 520. Anal. Calcd for C23H20Cl2N1NaO5S.0.36 Et2O: C, 54.06; H, 4.38; N, 2.58. Found: C, 53.99; H, 4.37; N, 2.22.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]=[C:10]([C:13]#[N:14])[C:11]#[N:12])=[CH:4][CH:3]=1.BrC1C=CC(N)=CC=1.C(#N)CC#N.O.[NH2:29][NH2:30]>>[NH2:14][C:13]1[C:10](=[N:9][NH:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[C:11]([NH2:12])=[N:30][N:29]=1
Reactant: N#CC(C#N)=NNc1ccc(Br)cc1
Reactant: NN
Agent: Nc1ccc(Br)cc1
Solvent: O
Solvent: N#CCC#N
Product: NC1=NN=C(N)C1=NNc1ccc(Br)cc1
Yield: 78 %

Procedure:
This compound was prepared using 125 mg (0.5 mmol) of 2-[(4-bromophenyl)-hydrazono]malononitrile, which was derived from 4-bromoaniline (172 mg, 1.0 mmol) and malononitrile (1.5 mmol) as described in Example 8, and hydrazine hydrate. The hydrazine hydrate was added to the solution at a temperature of 75° C. despite the fact that the starting material had not fully dissolved. The solution cleared briefly and then a precipitate formed. The resulting solid was isolated by filtration, washed with ethanol, and dried to yield 109 mg (78%) of the title compound as a yellow solid. 1H NMR (ppm, DMSO-d6): 6.15 (br s, 4H), 7.52 (d, 2H), 7.61 (d, 2H), 10.71 (s, 1H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20](OCC)=[O:21])=[CH:15][CH:14]=1.[OH:25]C(C)(C)C(OC)=O.[CH3:33][C:34]([O-:37])([CH3:36])[CH3:35].[K+].Cl>C1COCC1.O>[OH:25][C:33]1[C:34]([CH3:36])([CH3:35])[O:37][C:20](=[O:21])[C:19]=1[C:16]1[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)=[CH:18][CH:17]=1
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)C(C)(C)O
Reactant: CCOC(=O)Cc1ccc(OCc2ccc3ccccc3n2)cc1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)OC(=O)C(c2ccc(OCc3ccc4ccccc4n3)cc2)=C1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 45 %

Procedure:
To a solution of ethyl 2-(4-(quinolin-2-ylmethoxy)phenyl)acetate (2.0 g, 0.006 mol) in THF (10 mL), were added methyl 2-hydroxy-2-methylpropanoate (1.4 g, 0.012 mol) and t-BuOK (1 N, 50 mL) at RT under an inert atmosphere. The mixture was then stirred for 16 h at RT. The reaction mixture was diluted with water, acidified with HCl (1N), and extracted with EtOAc (2×200 mL). The combined organic layers were washed with water, dried over Na2SO4 and concentrated in vacuo to afford 4-hydroxy-5,5-dimethyl-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one (1.0 g, 45%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[NH:11][CH2:12][CH3:13].[ClH:14].Cl[CH2:16][C:17](N)=N>C(#N)C>[Cl:14][CH2:13][C:12]1[N:11]([CH2:16][CH3:17])[C:3]2[CH:4]=[C:5]([C:8](=[O:10])[CH3:9])[CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: CCNc1cc(C(C)=O)ccc1N
Reactant: Cl
Reactant: N=C(N)CCl
Solvent: CC#N
Product: CCn1c(CCl)nc2ccc(C(C)=O)cc21

Procedure:
A mixture of 1-(4-amino-3-ethylamino-phenyl)-ethanone (300 mg, 1.69 mmol) and 2-chloroacetamidine hydrochloride (804 mg, 5.1 mmol) in acetonitrile (20 mL) is refluxed for 3 hours. Solvent is removed and the residue is treated with NaHCO3 (5%, 20 mL) and DCM (50 mL). The organic layer is separated and the aqueous layer is extracted with DCM (2×40 mL). The combined organic layers are dried and solvent removed to give 1-(2-Chloromethyl-3-ethyl-3H-benzoimidazol-5-yl)-ethanone.