Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:26])[CH2:25][CH2:24][C:5]2([CH2:9][N:8]([C:10](=[O:20])[C@H:11]([CH:17]([CH3:19])[CH3:18])[NH:12][C:13]([O:15][CH3:16])=[O:14])[C@H:7]([C:21]([OH:23])=[O:22])[CH2:6]2)[CH2:4][CH2:3]1.[CH3:27][O:28][C:29]([NH:31][C@H:32]([C:36]([N:38]1[CH2:64][CH2:63][CH2:62][C@H:39]1[C:40]([O:42][CH2:43][C:44]([C:46]1[CH:51]=[CH:50][C:49]([C:52]2[CH:57]=[CH:56][C:55]([C:58](=[O:61])[CH2:59]Br)=[CH:54][CH:53]=2)=[CH:48][CH:47]=1)=[O:45])=[O:41])=[O:37])[CH:33]([CH3:35])[CH3:34])=[O:30].C(N(CC)CC)C>C(#N)C>[F:26][C:2]1([F:1])[CH2:25][CH2:24][C:5]2([CH2:9][N:8]([C:10](=[O:20])[C@@H:11]([NH:12][C:13]([O:15][CH3:16])=[O:14])[CH:17]([CH3:19])[CH3:18])[C@H:7]([C:21]([O:23][CH2:59][C:58]([C:55]3[CH:56]=[CH:57][C:52]([C:49]4[CH:48]=[CH:47][C:46]([C:44](=[O:45])[CH2:43][O:42][C:40]([C@@H:39]5[CH2:62][CH2:63][CH2:64][N:38]5[C:36](=[O:37])[C@@H:32]([NH:31][C:29]([O:28][CH3:27])=[O:30])[CH:33]([CH3:35])[CH3:34])=[O:41])=[CH:51][CH:50]=4)=[CH:53][CH:54]=3)=[O:61])=[O:22])[CH2:6]2)[CH2:4][CH2:3]1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)OCC(=O)c1ccc(-c2ccc(C(=O)CBr)cc2)cc1)C(C)C
Reactant: COC(=O)N[C@H](C(=O)N1CC2(CCC(F)(F)CC2)C[C@H]1C(=O)O)C(C)C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)OCC(=O)c1ccc(-c2ccc(C(=O)COC(=O)[C@@H]3CC4(CCC(F)(F)CC4)CN3C(=O)[C@@H](NC(=O)OC)C(C)C)cc2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (3S)-8,8-difluoro-2-{N-[(methyloxy)carbonyl]-L-valyl}-2-azaspiro[4.5]decane-3-carboxylic acid (116) (168 mg, 0.45 mmol) and 2-[4′-(bromoacetyl)-4-biphenylyl]-2-oxoethyl N-[(methyloxy)carbonyl]-L-valyl-L-prolinate (70) (250 mg, 0.43 mmol) in anhydrous acetonitrile (2 mL) was added triethylamine (0.09 mL, 0.64 mmol) and the reaction stirred at room temperature under nitrogen for 1 h. The reaction was partitioned between EtOAc and 0.1 N HCl (30 mL each), the organic layer was washed with brine and dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 65-100% hexanes/EtOAc to afford the title compound as an off white solid (309 mg, 82% yield).
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][C:14](=[O:16])[CH:15]=2)=[CH:6][CH:5]=1.[OH-].[Na+:25]>CO>[Na+:25].[N:17]1([C:12]2[O:11][C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3]([O-:23])=[O:2])=[CH:5][CH:6]=3)=[CH:15][C:14](=[O:16])[CH:13]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: COC(=O)c1ccc(-c2cc(=O)cc(N3CCOCC3)o2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C([O-])c1ccc(-c2cc(=O)cc(N3CCOCC3)o2)cc1
Yield: 97.5 %

Procedure:
4-(6-Morpholin-4-yl-4-oxo-4H-pyran-2-yl)-benzoic acid methyl ester (3.00 g, 9.52 mmol) was dissolved in methanol (20 ml) and sodium hydroxide (0.381 g, 9.52 mmol) was added. The stirred solution was then refluxed under nitrogen for three hours. The methanol was removed in vacuo and the residue was triturated in ether to give the title compound as a brown solid (3 g, 97%). m/z (LC-MS, ESP): 301 (M++1).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:18]Br>C(O)(=O)C.O>[Br:18][C:9]1[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:6][N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[C:8]=1[NH2:10]
Reactant: Cc1ccccc1-n1nc(C(C)(C)C)cc1N
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccccc1-n1nc(C(C)(C)C)c(Br)c1N
Reaction time: 0.08 h
Yield: 73.3 %

Procedure:
To a solution of 3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-amine (1.00 g, 4.36 mmol) in acetic acid (10 mL) was added bromine (662 mg, 0.21 mL, 4.14 mmol) dropwise. The reaction mixture was stirred for 5 min, and then diluted with water (50 mL), causing a solid to precipitate. The solid was collected by filtration, then dissolved in EtOAc (50 mL). The EtOAc solution was then washed with saturated NaHCO3 and brine, dried (Na2SO4), and concentrated under reduced pressure to afford the product (935 mg, 70%) as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 1.32 (s, 9H), 2.04 (s, 3H) 5.02 (s, 2H), 7.20-7.38 (m, 4H). ES-MS m/z 308.6 (MH+); HPLC RT (min) 3.15.
Reaction SMILES: [CH:1]([NH:3][CH:4]([CH:11]=[C:12]([CH2:21]Br)[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:2].[CH:23]([O:26][P:27]([O:32]C(C)C)[O:28][CH:29]([CH3:31])[CH3:30])([CH3:25])[CH3:24]>>[CH:1]([NH:3][CH:4](/[CH:11]=[C:12](/[CH2:21][P:27]([O:28][CH:29]([CH3:31])[CH3:30])([O:26][CH:23]([CH3:25])[CH3:24])=[O:32])\[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:2]
Reactant: CCOC(=O)CCCC(=CC(CC(=O)OCC)NC=O)CBr
Reactant: CC(C)OP(OC(C)C)OC(C)C
Product: CCOC(=O)CCC/C(=C\C(CC(=O)OCC)NC=O)CP(=O)(OC(C)C)OC(C)C
Reaction time: 19 h

Procedure:
8.7 g (25 mmol) of diethyl 2-formylamino-4-bromomethyl-hept-3-ene-1,7-dicarboxylate and 21 ml (75 mmol) of triisopropylphosphite (90%) are heated to 80°-90° C. and the mixture is stirred for 19 hours under a pressure of ca. 100 mbar. Excess triisopropylphosphite is removed by distillation and the residue obtained after evaporation is chromatographed over 150 g of silica gel first with ethyl acetate and then with ethyl acetate/ethanol (9:1) as eluant, giving diethyl E-2-formylamino-4-diisopropylphosphonomethyl-hept-3-ene-1,7-dicarboxylate as a yellowish oil.
Reaction SMILES: CC[O:3][C:4]([C@@H:6]1[CH2:10][C@@H:9]([CH:11]([CH3:13])[CH3:12])[C@H:8]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH2:23][CH2:24][CH2:25][O:26][CH3:27])[CH:15]=2)[N:7]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=O.[BH4-].[Li+]>O1CCCC1>[C:31]([O:30][C:28]([N:7]1[C@H:6]([CH2:4][OH:3])[CH2:10][C@@H:9]([CH:11]([CH3:13])[CH3:12])[C@@H:8]1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH2:23][CH2:24][CH2:25][O:26][CH3:27])[CH:15]=1)=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: CCOC(=O)[C@@H]1C[C@@H](C(C)C)[C@H](c2ccc(OC)c(OCCCOC)c2)N1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COCCCOc1cc([C@H]2[C@H](C(C)C)C[C@@H](CO)N2C(=O)OC(C)(C)C)ccc1OC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 0.48 g of (2S,4S,5R)-4-Isopropyl-5-[4-methoxy-3-(3-methoxy-propoxy)-phenyl]-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester VIIIa in 10 mL of tetrahydrofuran is cooled to 0° C. and a tetrahydrofuran solution of lithium borohydride (1.0 mL of a 2.0M solution) is added dropwise within 30 minutes. The mixture is stirred for a further 2 hours at 0° C. and quenched by addition of 0.2 mL of glacial acetic acid in 10 mL of tetrahydrofuran. The mixture is diluted with 20 mL of tert-butyl methyl ether and 20 mL of water and the organic phase separated. The organic phase is dried and the solvent removed to give the desired product as an oil. 1H-NMR δ (d6-DMSO/D2O, 300K) 6.90-6.80 (3H), 4.03-3.90 (3H), 3.80 (1H), 3.75 (3H), 3.55-3.45 (3H), 3.23 (3H), 3.05 (1H), 2.00-1.80 (3H), 1.65 (1H), 1.40 (9H), 1.20 (1H), 0.74 (6H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([NH:11]C(C)=O)[CH:5]=[CH:4][CH:3]=1>Cl>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([NH2:11])[C:7]=1[C:8]([OH:10])=[O:9]
Reactant: CC(=O)Nc1cccc(Cl)c1C(=O)O
Agent: Cl
Product: Nc1cccc(Cl)c1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 209.8 %

Procedure:
A mixture of 20.0 grams (0.093 mole) of 6-chloro-2-(methylcarbonylamino)benzoic acid in 150 mL of concentrated hydrochloric acid was stirred at 80° for about 3 hours. The reaction mixture was cooled to ambient temperature and was filtered to collect a solid. The solid was washed with cold diethyl ether and dried to yield 20.3 grams of 6-chloroanthranilic acid hydrochloride; m.p. 194°-195° C. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([N:6]1[CH2:11][CH2:10][CH2:9][CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18]C)[CH:13]=2)[CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].C(=O)=O.B(Br)(Br)Br.C([O-])([O-])=O.[Na+].[Na+].[ClH:33]>C(Cl)Cl>[ClH:33].[CH2:1]([N:6]1[CH2:11][CH2:10][CH2:9][CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)[CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCN1CCCC(c2cccc(OC)c2)C1
Agent: BrB(Br)Br
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: CCCCCN1CCCC(c2cccc(O)c2)C1
Reaction time: 1 h
Yield: 29 %

Procedure:
N-pentyl-3-(3-methoxyphenyl)piperidine (1.3 g, 0.005 mol) in CH2Cl2 (20 ml) was cooled with dry ice and BBr3 (1.6 g, 0.006 mol) was added dropwise. The mixture was then held at -78° C. for 1 h and then allowed to reach r.t. overnight. The solution was made alkaline with aqueous Na2CO3, extracted with CH2Cl2 and the organic phase dried with Na2SO4. Evaporation of the solvent afforded an oily residue which was treated with HCl-saturated ethanol (5 ml). After evaporation of solvent, purification by extractions and recrystallization (ethanol/ether), the desired product (0.40 g, 29%) was obtained, mp. 70°-80° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=3)=[C:20]([C:36]([F:39])([F:38])[F:37])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.Cl>C(O)C>[ClH:34].[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=2)=[C:20]([C:36]([F:39])([F:38])[F:37])[CH:19]=1)([CH2:13][OH:12])[CH2:9][OH:10]
Reactant: CC(C)(C)OC(=O)NC1(CCc2ccc(OCCCc3ccc(Cl)c(Cl)c3)c(C(F)(F)F)c2)COC(C)(C)OC1
Agent: Cl
Solvent: CCO
Product: NC(CO)(CO)CCc1ccc(OCCCc2ccc(Cl)c(Cl)c2)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 180.2 %

Procedure:
Compound 38-4 (790 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (590 mg) as a white powder.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[NH2:13][C:14]1[CH:22]=[C:21]2[C:17]([CH:18]=[CH:19][NH:20]2)=[CH:16][CH:15]=1.C1(C)C=CC=CC=1>CN(C=O)C>[NH:20]1[C:21]2[C:17](=[CH:16][CH:15]=[C:14]([NH:13][C:2](=[O:4])[C:1]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH2:6])[CH:22]=2)[CH:18]=[CH:19]1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: Nc1ccc2cc[nH]c2c1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Nc1ccccc1C(=O)Nc1ccc2cc[nH]c2c1
Yield: 52.7 %

Procedure:
A mixture of isatoic anhydride (5.06 g, 31 mmol), 6-aminoindole (4.103 g, 31 mmol), toluene (300 mL) and DMF (30 mL) was heated to reflux for 18 hours. The reaction was cooled, filtered, and chromatographed to yield 4.103 g (53%) of the title compound as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.I[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2cc[nH]c2c1
Reactant: FC(F)(F)c1ccc(I)cc1
Product: FC(F)(F)c1ccc(-n2ccc3ccc(Cl)cc32)cc1

Procedure:
Prepared by Procedure C and Scheme O using 6-chloro-1H-indole and 1-iodo-4-(trifluoromethyl)benzene ESMS m/e: 295.6 (M+H)+.
Reaction SMILES: C([N:5]1[C:10]2=[N:11][N:12]=[CH:13][N:9]2[C:8]2[CH:14]=[CH:15][CH:16]=[CH:17][C:7]=2[N:6]1[C:18](=[O:21])[CH2:19][CH3:20])(=O)CC.[OH-].[Na+]>>[C:18]([N:6]1[C:7]2[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=2[N:9]2[CH:13]=[N:12][N:11]=[C:10]2[NH:5]1)(=[O:21])[CH2:19][CH3:20]
Reactant: CCC(=O)N1c2ccccc2-n2cnnc2N1C(=O)CC
Agent: [Na+]
Agent: [OH-]
Product: CCC(=O)N1Nc2nncn2-c2ccccc21
Yield: 64.2 %

Procedure:
5.0 g (0.017 mole) of 4,5-dipropionyl-4,5-dihydro-s-triazolo[3,4-c]benzo-as-triazine are treated with 50 ml of a 5% sodium hydroxide solution. The solution which forms within a short time is decolourized, filtered, the filtrate is acidified with acetic acid, and the separated colourless precipitate is filtered off. 2.5 g (63%) of the title compound are obtained; m.p.: 244° C.
Reaction SMILES: O1C=CC=C1C1C=CC(N2CCN(S(CC(C(C)C)C([NH:25][OH:26])=O)(=O)=O)CC2)=CC=1.[Br:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:42][CH2:41][N:40]([S:43]([CH2:46][C:47]3([C:53](O)=[O:54])[CH2:52][CH2:51][O:50][CH2:49][CH2:48]3)(=[O:45])=[O:44])[CH2:39][CH2:38]2)=[CH:33][CH:32]=1>>[OH:26][NH:25][C:53]([C:47]1([CH2:46][S:43]([N:40]2[CH2:39][CH2:38][N:37]([C:34]3[CH:35]=[CH:36][C:31]([Br:30])=[CH:32][CH:33]=3)[CH2:42][CH2:41]2)(=[O:44])=[O:45])[CH2:48][CH2:49][O:50][CH2:51][CH2:52]1)=[O:54]
Reactant: CC(C)C(CS(=O)(=O)N1CCN(c2ccc(-c3ccco3)cc2)CC1)C(=O)NO
Reactant: O=C(O)C1(CS(=O)(=O)N2CCN(c3ccc(Br)cc3)CC2)CCOCC1
Product: O=C(NO)C1(CS(=O)(=O)N2CCN(c3ccc(Br)cc3)CC2)CCOCC1
Yield: 87 %

Procedure:
Prepared according to the method for the preparation of 2-[4-(4-furan-2-yl-phenyl)piperazine-1-sulfonylmethyl]-N-hydroxy-3-methylbutyramide, from 4-[4-(4-bromophenyl)piperazine-1-sulfonylmethyl]tetrahydropyran-4-carboxylic acid (4.54 g), to yield the title compound as a white solid (4.07 g, 87%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:21][C@@H:22]([CH2:27][CH3:28])[CH2:23][CH2:24][CH2:25]Br>CC(=O)CC>[CH3:21][C@@H:22]([CH2:27][CH3:28])[CH2:23][CH2:24][CH2:25][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Reactant: CC[C@H](C)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC[C@H](C)CCCOc1ccc(-c2ccc(Br)cc2)cc1
Reaction time: 10 h
Yield: 91.3 %

Procedure:
A reaction vessel was charged with 1.1 g of 4-hydroxy-4'-bromobiphenyl, 20 ml of 2-butanone, 1.2 g of potassium carbonate and 0.95 g of (S)-4-methylhexyl bromide, and the mixture was refluxed with stirring until TLC showed the disappearance of the starting materials. It took 10 hours for this. The reaction liquid was filtered to remove solids and the filtrate was concentrated. The residue was dried under reduced pressure to obtain 1.4 g (93%) of (S)-4-(4-methylhexyl)oxy-4'-bromobiphenyl.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])=[C:11]([NH:19][C:20]([C:22]2[C:31](=[O:32])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[NH:24][CH:23]=2)=[O:21])[CH:10]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])=[C:11]([NH:19][C:20]([C:22]2[C:31](=[O:32])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[NH:24][CH:23]=2)=[O:21])[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(C)(C)C)c(NC(=O)c2c[nH]c3ccccc3c2=O)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1ccc(N)cc1NC(=O)c1c[nH]c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.9 %

Procedure:
A mixture of [3-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-4-tert-butyl-phenyl]aminoformic acid tert-butyl ester (353) (33 mg, 0.08 mmol), TFA (1 mL) and CH2Cl2 (1 mL) was stirred at room temperature overnight. The solution was concentrated and the residue was dissolved in DMSO (1 mL) and purified by HPLC (10-99% CH3CN/H2O) to yield the product, N-(5-amino-2-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (260) (15 mg, 56%). 1H NMR (400 MHz, DMSO-d6) δ 13.23 (d, J=6.6 Hz, 1H), 12.20 (s, 1H), 10.22 (br s, 2H), 8.88 (d, J=6.8 Hz, 1H), 8.34 (d, J=7.8 Hz, 1H), 7.86-7.80 (m, 3H), 7.56-7.52 (m, 2H), 7.15 (dd, J=8.5, 2.4 Hz, 1H), 1.46 (s, 9H); HPLC ret. time 2.33 min, 10-99% CH3CN, 5 min run; ESI-MS 336.3 m/z (MH+).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([NH:13][C:14]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[N:21]([CH:25]([C:27]2[CH:39]=[CH:38][C:30]([O:31][C@@H:32]([CH3:37])[C:33]([O:35]C)=[O:34])=[CH:29][CH:28]=2)[CH3:26])[C:20]([CH3:40])=[C:19]3[CH3:41])=[O:15])[CH3:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.CN(C=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C@@H:11]([NH:13][C:14]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[N:21]([CH:25]([C:27]2[CH:28]=[CH:29][C:30]([O:31][C@@H:32]([CH3:37])[C:33]([OH:35])=[O:34])=[CH:38][CH:39]=2)[CH3:26])[C:20]([CH3:40])=[C:19]3[CH3:41])=[O:15])[CH3:12])=[CH:9][CH:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: COC(=O)[C@H](C)Oc1ccc(C(C)n2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4ccc(C(C)(C)C)cc4)ccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1c(C)n(C(C)c2ccc(O[C@@H](C)C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3ccc(C(C)(C)C)cc3)cc12

Procedure:
A solution of (2S)-methyl 2-(4-(1-(5-(((S)-1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)ethyl)phenoxy)propanoate (˜0.07 mmol) and NaOH (2 M, 0.2 mL) in MeOH (2 mL) and DMF (1 mL) was stirred at rt for 5 h. It was neutralized and purified by preparative HPLC to yield the title compound as a white solid. ESI-MS (m/z): 541 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][CH:38]=1)[CH2:5][O:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][N:18]2[CH2:22][C@@H:21]([C:23]3[CH:34]=[CH:33][C:26]4[O:27][C:28]([CH3:32])([CH3:31])[O:29][CH2:30][C:25]=4[CH:24]=3)[O:20][C:19]2=[O:35])=[CH:12][CH:11]=1.Cl.[C:40](Cl)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[N:43][CH:42]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:31][C:28]1([CH3:32])[O:27][C:26]2[CH:33]=[CH:34][C:23]([C@H:21]3[O:20][C:19](=[O:35])[N:18]([CH2:17][CH2:16][C:13]4[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][O:6][CH2:5][C:4]5[CH:3]=[C:2]([NH:1][C:40](=[O:47])[C:41]6[CH:46]=[CH:45][CH:44]=[N:43][CH:42]=6)[CH:38]=[CH:37][CH:36]=5)=[CH:15][CH:14]=4)[CH2:22]3)=[CH:24][C:25]=2[CH2:30][O:29]1
Reactant: O=C(Cl)c1cccnc1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCc4ccc(OCCOCc5cccc(N)c5)cc4)C(=O)O3)ccc2O1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)OCc2cc([C@@H]3CN(CCc4ccc(OCCOCc5cccc(NC(=O)c6cccnc6)c5)cc4)C(=O)O3)ccc2O1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of (5R)-3-[2-(4-{2-[(3-aminobenzyl)oxy]ethoxy}phenyl)ethyl]-5(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one {Example 1 xii)} (100 mg), nicotinoyl chloride hydrochloride (38 mg) and N,N-diisopropylethylamine (67 μL) in DCM (2 mL) was stirred at room temperature under nitrogen for 20 h. The solution was then diluted in DCM, washed with 2M HCl, NaHCO3 and brine, dried (MgSO4) and concentrated in vacuo to give the title compound (136 mg). LCMS RT=3.32 min.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]2[NH:16][N:15]=[N:14][N:13]=2)=[C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]2[C:4](=[CH:5][C:6]([F:24])=[C:7]([Cl:23])[CH:8]=2)[N:3]=1.[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26]>>[Cl:23][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[F:24])[N:3]=[C:2]([N:27]([CH2:28][CH3:29])[CH2:25][CH3:26])[C:11]([C:12]1[N:13]=[N:14][NH:15][N:16]=1)=[C:10]2[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCNCC
Reactant: Fc1cc2nc(Cl)c(-c3nnn[nH]3)c(-c3ccccc3)c2cc1Cl
Product: CCN(CC)c1nc2cc(F)c(Cl)cc2c(-c2ccccc2)c1-c1nn[nH]n1

Procedure:
The title compound was prepared in analogy to example 102 step C from 2,6-dichloro-7-fluoro-4-phenyl-3-(1H-tetrazol-5-yl)-quinoline (prepared as described in example 107 step B) and diethylamine. Light brown solid. MS (ESI): 397.4 (M+H)+.
Reaction SMILES: [CH2:1]1[CH:4]2[CH2:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[CH:3]2[C:2]1=[O:12].[OH:13]O.[Na]>C(O)(=O)C.O>[O:13]1[C:2](=[O:12])[CH2:1][CH:4]2[CH2:5][CH:6]3[C:11]([CH:10]=[CH:9][CH:8]=[CH:7]3)=[C:3]12
Reactant: OO
Reactant: O=C1CC2Cc3ccccc3C12
Agent: [Na]
Solvent: O
Solvent: CC(=O)O
Product: O=C1CC2CC3C=CC=CC3=C2O1
Temperature: 0 °C
Reaction time: 3 h
Yield: 92.3 %

Procedure:
A solution of 1,2a,7,7a-tetrahydro-2H-Cyclobut[a]inden-2-one (Example I4, 0.377 mg, 2.383 mmol) in acetic acid (5 mL) and water (0.5 mL) was cooled at 0° C. and hydrogen peroxide (30% in water, 0.810 mL, 7.14 mmol) was added. The solution as stirred for 3 h at 0° C. and the reaction mixture was poured into saturated solution of sodium hydrogenocarbonate. The solution was extracted with ethyl acetate and the combined organic layers were washed with brine, dried and concentrated. The residue was purified by flash chromatography eluting with cyclohexane and ethyl acetate (4/1) to give rac-Tetrahydroindeno[1,2-b]furan-2-one (Colourless oil, 383 mg, 92%), that solidified upon cooling (data match with litt data, CAS 4471-33-4). C11H10O2; MW: 174.20; LCMS (method A) RT 1.32 min; ES: 175 (60%, MH+), 129 (100%); IR: 1769 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.50 (1H, d), 7.25-7.39 (4H, m), 5.91 (1H, d), 3.28-3.45 (2H, m), 2.86-2.97 (2H, m), 2.41 (1H, dd) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:33]=[CH:32][C:5]([O:6][CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([C:16]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[OH:17])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[CH3:34][N:35]=[C:36]=[O:37]>C1C=CC=CC=1>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:16]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)([OH:17])[CH:13]2[CH2:14][CH2:15][N:10]([CH2:9][CH2:8][CH2:7][O:6][C:5]3[CH:32]=[CH:33][C:2]([NH:1][C:36]([NH:35][CH3:34])=[O:37])=[CH:3][CH:4]=3)[CH2:11][CH2:12]2)=[CH:19][CH:20]=1
Reactant: CN=C=O
Reactant: Nc1ccc(OCCCN2CCC(C(O)(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1
Solvent: c1ccccc1
Product: CNC(=O)Nc1ccc(OCCCN2CCC(C(O)(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1
Reaction time: 1 h
Yield: 31.4 %

Procedure:
To a solution of 4.5 g (0.01 mole) of 1-[3-(4-aminophenoxy)propyl]-α,α-bis(4-fluorophenyl)-4-piperidinemethanol in 50 ml of benzene was added dropwise a solution of 0.6 g (0.01 mole) of methylisocyanate in 10 ml of benzene. The mixture was stirred for 1 hr during which time a solid precipitated. The mixture was diluted with 25 ml of cyclohexane, the solid was collected by filtration and recrystallized from 2-propanol to yield 1.6 g (31%) of title compound as a white solid, mp 177°-178° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[N+:30]([O-])=O)[O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[C:19]([OH:26])[CH:18]=3)[CH:12]=2)[CH:7]=1.[K+].[Br-]>>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][C:11]2[CH:10]=[CH:9][C:8]3[C:13](=[CH:14][CH:15]=[C:6]([O:5][C:4]4[CH:27]=[CH:28][C:29]([NH2:30])=[C:2]([OH:1])[CH:3]=4)[CH:7]=3)[CH:12]=2)=[CH:18][C:19]=1[OH:26]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3cc(Oc4ccc([N+](=O)[O-])c(O)c4)ccc3c2)cc1O
Agent: [Br-]
Agent: [K+]
Product: Nc1ccc(Oc2ccc3cc(Oc4ccc(N)c(O)c4)ccc3c2)cc1O
Yield: 85 %

Procedure:
2,6-Bis(4-amino-3-hydroxyphenoxy)naphthalene was synthesized in a manner analogous to Example 2 from 2,6-bis(3-hydroxy-4-nitrophenoxy)naphthalene. Yield 85.0%; mp 239˜241° C.; IR (KBr) 3295, 3367, 1499 cm−1; MS (EI) m/z 374 (M+, 100); Elemental Anal. Calcd. for C22H18N2O4: C, 70.59; H, 4.81; N, 7.49. Found: C, 70.51; H, 4.86; N, 7.462.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].C(OC(=O)[NH:16][CH:17]([CH3:31])[CH2:18][N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([OH:30])[C:26]=2[CH:28]=O)[CH:21]=[N:20]1)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[CH3:6][O:5][C:3]([C:2]1[O:30][C:25]2=[CH:24][CH:23]=[C:22]3[C:27]([N:19]([CH2:18][C@@H:17]([NH2:16])[CH3:31])[N:20]=[CH:21]3)=[C:26]2[CH:28]=1)=[O:4]
Reactant: CC(Cn1ncc2ccc(O)c(C=O)c21)NC(=O)OCc1ccccc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COC(=O)c1cc2c(ccc3cnn(C[C@H](C)N)c32)o1
Temperature: 90 °C

Procedure:
To a 50 mL round bottom flask containing NMP (20 mL), methyl bromoacetate (0.35 g 2.3 mmol), and [2-(7-formyl-6-hydroxy-indazol-1-yl)-1-methyl-ethyl]-carbamic acid benzyl ester (0.751 g, 2.1 mmol) was added K2CO3 (1.4 g, 10 mmol). This mixture was heated to 90° C. for 16 h, then allowed to cool to 23° C., decanted into a saturated aqueous NaHCO3 solution (50 mL), and extracted with ethyl acetate (2×20 mL). The combined extracts were dried (Na2SO4), filtered and concentrated. The crude product was purified by chromatography (silica gel, hexanes: ethyl acetate gradient, 3:1 to 1:1) to provide an oil: LC/MS m/z 408 [M+H]+; 1H NMR (D2O): δ 8.19 (s, 1H), 8.06 (s, 1H), 7.75 (d, J=9.0 Hz, 1H), 7.43 (d, J=9.0 Hz, 1H), 7.30 (bm, 4H), 5.15 (d, 1H), 5.08 (dd, 2H), 4.8 (m, 1H), 4.6 (m, 1H), 4.29 (m, 1H), 4.01 (s, 3H), 1.19 (d, J=6.6 Hz, 3H).