Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)[N:5]2[N:12]=[CH:13][C:14]([CH:15]=[C:16]3[S:20][C:19](=[O:21])[NH:18][C:17]3=[O:22])=[C:4]2[N:3]=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27].C1(C)C=CC(S(O)(=O)=O)=CC=1.CO.ClCCl>CN1C(=O)CCC1>[Cl:23][C:24]1[CH:25]=[C:26]([NH:27][C:2]2[CH:7]=[C:6]([NH:8][CH:9]3[CH2:11][CH2:10]3)[N:5]3[N:12]=[CH:13][C:14]([CH:15]=[C:16]4[S:20][C:19](=[O:21])[NH:18][C:17]4=[O:22])=[C:4]3[N:3]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: O=C1NC(=O)C(=Cc2cnn3c(NC4CC4)cc(Cl)nc23)S1
Reactant: Nc1cccc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: O=C1NC(=O)C(=Cc2cnn3c(NC4CC4)cc(Nc4cccc(Cl)c4)nc23)S1
Temperature: 180 °C

Procedure:
To 5-((5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)thiazolidine-2,4-dione (20 mg, 0.06 mmol) in NMP was added 3-chloroaniline (38 μL, 0.36 mmol) and few granules p-toluenesulfonic acid. The reaction was heated in microwave at 180° C. for 1.5 hours. Mixture was filtered and prepared by HPLC then preparative TLC (1% methanol/dichloromethane) to yield 5-((5-(3-chlorophenylamino)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)thiazolidine-2,4-dione as a yellow solid. LCMS (M+1=427)
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][N:2]1[C:11]([C:13]1[CH:21]=[C:20]2[C:16]([CH2:17][CH2:18][CH:19]2[NH:22][C:23](=[O:31])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])=[CH:15][CH:14]=1)=[O:12].CCN(C(C)C)C(C)C.Cl[C:42]1[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=1.CC[OH:50]>>[Cl:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:23]([NH:22][CH:19]1[C:20]2[C:16](=[CH:15][CH:14]=[C:13]([C:11]([N:2]3[CH2:1][C:5]4([CH2:10][CH2:9][N:8]([C:42]5[CH:47]=[CH:46][N+:45]([O-:50])=[CH:44][CH:43]=5)[CH2:7][CH2:6]4)[CH2:4][CH2:3]3)=[O:12])[CH:21]=2)[CH2:17][CH2:18]1)=[O:31]
Reactant: CCO
Reactant: O=C(NC1CCc2ccc(C(=O)N3CCC4(CCNCC4)C3)cc21)c1ccccc1Cl
Reactant: Clc1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CCc2ccc(C(=O)N3CCC4(CCN(c5cc[n+]([O-])cc5)CC4)C3)cc21)c1ccccc1Cl
Temperature: 130 °C
Yield: 23 %

Procedure:
A stirred mixture of N-(6-(2,8-diazaspiro[4.5]decane-2-carbonyl)-2,3-dihydro-1H-inden-1-yl)-2-chlorobenzamide (350 mg, 0.799 mmol, 1 eq.), DIPEA (0.34 ml, 1.99 mmol, 2.5 eq.) and 4-chloropyridine (103 mg, 0.799 mmol, 1 eq.) in EtOH (7 ml) was heated at 130° C. for 72 h. The solvent was removed and the crude material was purified by column chromatography (silica gel, 3-5% MeOH/MC) to afford the final product as a light brown solid. Yield: 23% (100 mg, 0.19 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH:17]([C@H:19]4[CH2:24][CH2:23][C@H:22]([CH3:25])[CH2:21][CH2:20]4)[CH3:18])[CH:15]=[N:16][C:12]=3[CH:11]=[C:10]([C:26]#[N:27])[N:9]=2)[CH:5]=[N:6][CH:7]=1.P([O-])([O-])(O)=O.[Na+].[Na+].[Br:35]N1C(C)(C)C(=O)N(Br)C1=O>C1COCC1>[Br:35][C:15]1[N:14]([C@H:17]([C@H:19]2[CH2:24][CH2:23][C@H:22]([CH3:25])[CH2:21][CH2:20]2)[CH3:18])[C:13]2[C:8]([C:4]3[CH:5]=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)=[N:9][C:10]([C:26]#[N:27])=[CH:11][C:12]=2[N:16]=1.[Br:35][C:15]1[N:14]([C@@H:17]([C@H:19]2[CH2:24][CH2:23][C@H:22]([CH3:25])[CH2:21][CH2:20]2)[CH3:18])[C:13]2[C:8]([C:4]3[CH:5]=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)=[N:9][C:10]([C:26]#[N:27])=[CH:11][C:12]=2[N:16]=1
Reactant: CC([C@H]1CC[C@H](C)CC1)n1cnc2cc(C#N)nc(-c3cncc(Cl)c3)c21
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H]([C@H]1CC[C@H](C)CC1)n1c(Br)nc2cc(C#N)nc(-c3cncc(Cl)c3)c21
Product: C[C@H]([C@H]1CC[C@H](C)CC1)n1c(Br)nc2cc(C#N)nc(-c3cncc(Cl)c3)c21

Procedure:
Alternatively, racemic 4-(5-chloropyridin-3-yl)-3-[1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (Step 2) was resolved into its enantiomers as described in Preparative Example 15.1 and brominated using the conditions described above or using the alternative conditions (disodium hydrogen phosphate and 1,3-dibromo-5,5-dimethylhydantoin in THF at 35° C., described in Example 2.1, Step 1 and Preparative Example 3.1, Step 3) to afford 2-bromo-4-(5-chloropyridin-3-yl)-3-[(1S)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile and 2-bromo-4-(5-chloropyridin-3-yl)-3-[(1R)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile.
Reaction SMILES: CO[CH:3]([O:14]C)[C:4]1[CH:9]=[C:8]2[O:10][CH2:11][O:12][C:7]2=[CH:6][C:5]=1Br.[CH:16]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[O:28][CH:29]([CH3:31])[CH3:30])[CH:23]=O)([CH3:18])[CH3:17].[C:32]([C:39]([O:41][CH2:42][CH3:43])=[O:40])#[C:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]>>[CH:16]([O:19][C:20]1[CH:21]=[C:22]([C:23]2[C:5]3[C:4](=[CH:9][C:8]4[O:10][CH2:11][O:12][C:7]=4[CH:6]=3)[C:3]([OH:14])=[C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:32]=2[C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH:25]=[CH:26][C:27]=1[O:28][CH:29]([CH3:31])[CH3:30])([CH3:18])[CH3:17]
Reactant: COC(OC)c1cc2c(cc1Br)OCO2
Reactant: CC(C)Oc1ccc(C=O)cc1OC(C)C
Reactant: CCOC(=O)C#CC(=O)OCC
Product: CCOC(=O)c1c(C(=O)OCC)c(-c2ccc(OC(C)C)c(OC(C)C)c2)c2cc3c(cc2c1O)OCO3
Yield: 51 %

Procedure:
2-Bromo-4,5-methylenedioxybenzaldehyde dimethyl-acetal, 3,4-diisopropoxybenzaldehyde and diethyl acetylene-dicarboxylate are treated in the same manner as described in Example 1, whereby 1-(3,4-diisopropoxyphenyl)-2,3-bis(ethoxycarbonyl)-4-hydroxy-6,7-methylenedioxynaphthalene is obtained.
Reaction SMILES: Cl[CH:2]([O:4][CH2:5][CH3:6])[CH3:3].[CH2:7]([NH:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([O-:30])=[O:29])=[CH:26][CH:25]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[Na+].CN(C)P(N(C)C)(N(C)C)=O>O>[CH2:7]([NH:23][C:24]1[CH:25]=[CH:26][C:27]([C:28]([O:30][CH:2]([O:4][CH2:5][CH3:6])[CH3:3])=[O:29])=[CH:31][CH:32]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)[O-])cc1
Reactant: CCOC(C)Cl
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OC(C)OCC)cc1
Reaction time: 3 h

Procedure:
A mixture of 22.0 g. of ethyl 1-chloroethyl ether, 77.0 g. of sodium 4-(hexadecylamino)benzoate and 250 ml. of hexamethylphosphoramide is stirred at 20° C. for 24 hours. After slow addition of water to the crystallization point and standing for 3 hours, the acetal ester is collected on a filter.
Reaction SMILES: C(OC([NH:8][CH:9]([C:14]([CH3:18])([CH3:17])[CH:15]=[CH2:16])[C:10]([O:12][CH3:13])=[O:11])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][CH:9]([C:14]([CH3:18])([CH3:17])[CH:15]=[CH2:16])[C:10]([O:12][CH3:13])=[O:11]
Reactant: C=CC(C)(C)C(NC(=O)OC(C)(C)C)C(=O)OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CC(C)(C)C(N)C(=O)OC
Reaction time: 2 h
Yield: 75.8 %

Procedure:
To a solution of methyl 2(R/S)-(tert-butoxycarbonyl)amino-3,3-dimethyl-4-pentenoate (4.97 g, 19.3 mmol) in 50 mL of dichloromethane at 0° C. was added 16.5 mL of trifluoroacetic acid. After 2 hours, the solution was concentrated and the residue was dissolved in 100 mL of dichloromethane and washed with sat. aq. sodium bicarbonate (50 mL). The organic layer was dried over sodium sulfate and concentrated to give methyl 2(R/S)-amino-3,3-dimethyl-4-pentenoate (2.30 g), which was dissolved in 50 mL of dichloromethane and cooled to 0° C. Triethylamine (8.1 mL, 58 mmol) was added, followed by addition of 4-(4-fluorophenoxy)benzenesulfonyl chloride (6.71 g, 21.3 mmol). The reaction was allowed to warm to room temperature and stirred for 18 hours and then washed 3 N hydrochloric acid (125 mL), dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel, eluting with 20% ethyl acetate in hexane, to yield 4.41 g (61%) of methyl 2(R/S)-[4-(4-fluorophenoxy)benzenesulfonyl]amino-3,3-dimethyl4-pentenoate as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1.CC(O)=O.[CH2:11]=O.[BH3-][C:14]#[N:15].[Na+]>CO>[CH3:1][N:2]1[CH2:6][CH:5]([N:15]([CH3:14])[CH3:11])[CH2:4][CH2:3]1
Reactant: [BH3-]C#N
Reactant: CN1CCCC1
Reactant: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN1CCC(N(C)C)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 78 %

Procedure:
To a stirred solution of trans-4-amino-1-tert-butoxycarbonyl-(2S)-tert-butyldiphenylsilyloxy) methylpyrrolidine (400 mg, 0.88 mmol), AcOH (120 ml, 2.0 mmol), and 37% HCHO aq (500 ml) in MeOH (10 ml) was added NaBH3CN (111 mg, 1.76 mmol) at 0° C. The reaction mixture was stirred at room temperature for 18 hr. After concentrated in vacuo, water was added and extracted with CH2Cl2. The extract was dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel with MeOH—CH2Cl2 (3:97, v/v) as eluent to give trans-1-tert-butoxycarbonyl-(2S)-tert-butyldiphenylsilyloxy)methyl-4-dimethylaminopyrrolidine (330 mg, 78%) as a pale yellow oil. 1H-NMR (CDCl3) δ1.06 (s, 9H), 1.33 and 1.45 (each s total 9H), 1.80-2.25 (m, 2H), 2.23 (br s, 6H), 2.95-4.05 (m, 6H), 7.36-7.39 (m, 6H), 7.63-7.65 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:11]([O-])(=O)C.[Na+].[OH-:16].[Na+]>C(O)=O>[Br:10][C:8]1[CH:9]=[C:2]2[C:3]([C:4](=[O:16])[NH:5][CH:11]=[N:1]2)=[CH:6][CH:7]=1
Reactant: CC(=O)[O-]
Reactant: N#Cc1ccc(Br)cc1N
Reactant: [OH-]
Agent: [Na+]
Solvent: O=CO
Product: O=c1[nH]cnc2cc(Br)ccc12
Reaction time: 1 h

Procedure:
To a solution of 2-amino-4-bromo-benzonitrile (550 mg, 2.79 mmol) in formic acid, add sodium acetate (435 mg, 5.30 mmol) in one portion. Reflux the reaction mixture for 16 h then remove the formic acid under reduced pressure to give a solid. Add 20% aqueous NaOH and stir for 1 hour. Remove the undissolved solids via filtration and acidify the filtrate with 12N HCl to produce a white solid. Collect the solid via filtration and wash it with water (5×) and ether (1×) to give 7-bromo-3H-quinazolin-4-one as an off-white solid.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[C:11]#[CH:12]>C1(C)C=CC=CC=1.C(OCC)(=O)C.[Au+].ClP(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:9]/[CH:12]=[CH:11]\[C:10]([O:14][CH2:15][CH3:16])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#CC(=O)OCC
Reactant: O=C(O)c1ccccc1
Agent: [Au+]
Agent: Cl[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C\OC(=O)c1ccccc1
Temperature: 60 °C
Yield: 99.5 %

Procedure:
To a suspension of benzoic acid (24.4 g, 200 mmol), silver hexafluorophosphate(V) (253 mg, 1 mmol), chlorotriphenylphosphine gold(I) (495 mg, 1 mmol) in toluene (125 mL) was added ethyl prop-2-ynoate (5.1 mL, 50 mmol). The reaction mixture was stirred and heated at 60° C. for 16 hrs. The volatiles were removed to give a residue, which was dissolved in ethyl acetate (200 mL) with some trace insoluble material being removed by filtration. The filtrate was washed with saturated aqueous NaHCO3 (with gas evolved—CAUTION) until there was no further gas evolution, and evaporated to give a light brown oil. This oil was purified via flash chromatography (eluting with a gradient of 0%-100% EtOAc in heptanes) to give the title compound (10.96 g, 99% yield) as a colorless oil, which solidified to afford needle-liked crystals. 1H NMR (400 MHz, chloroform-d) δ ppm 8.24-8.32 (m, 2H) 7.85 (d, J=7.09 Hz, 1H) 7.63-7.72 (m, 1H) 7.48-7.58 (m, 2H) 5.44 (d, J=7.21 Hz, 1H) 4.29 (q, J=7.21 Hz, 2H) 1.38 (t, J=7.15 Hz, 3H). 13C NMR (101 MHz, chloroform-d) δ ppm 164.15 (s, 1C) 162.55 (s, 1C) 144.54 (s, 1C) 134.31 (s, 1C) 130.66 (s, 2C) 128.74 (s, 2C) 127.90 (s, 1C) 103.38 (s, 1C) 60.30 (s, 1C) 14.28 (s, 1C).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:11])[C:9]=1[OH:10])[CH:5]=[O:6].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:18]([O:20][C:21](=[O:26])[C:22](Br)([CH3:24])[CH3:23])[CH3:19]>CC(C)C(=O)C>[CH2:18]([O:20][C:21](=[O:26])[C:22]([O:10][C:9]1[C:8]([CH3:11])=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[CH3:1])([CH3:24])[CH3:23])[CH3:19]
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)C(C)C
Product: CCOC(=O)C(C)(C)Oc1c(C)cc(C=O)cc1C
Temperature: 25 °C
Yield: 90 %

Procedure:
A solution of 3,5-Dimethyl-4-hydroxybenzaldehyde (20 g, 0.133 mol) in 3-Methyl-2-butanone (400 mL) was treated with Cs2CO3 (86.9 g, 2 eq.) and Ethyl-2-bromoisobutyrate (39.2 L, 2 eq.). The resulting mixture was stirred at reflux for 36 hours. After cooling to rt the reaction mixture was filtered off. The cake was washed with ethyl acetate. The filtrate was evaporated off and the residue was diluted with ethyl acetate (1 L), washed with water (500 mL) and then with NaOH 1N (500 mL). The organic layer was drying over Na2SO4 and filtration evaporation gave the title compound (31.8 g, 0.12 mol) as a brown oil in a 90% yield.
Reaction SMILES: C(Cl)Cl.[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:10]([C:13]1([CH2:24][C@H:25]2[C@:27]([CH3:34])([CH2:28][CH2:29][CH:30]=[C:31]([CH3:33])[CH3:32])[O:26]2)[C:18]([O:19][CH3:20])=[CH:17][C:16](=O)[CH:15]=[C:14]1[O:22][CH3:23])[CH:11]=[CH2:12].CCCCCC>CCOC(C)=O>[CH2:10]([C:13]1([CH2:24][C@@H:25]2[O:26][C@@:27]2([CH3:34])[CH2:28][CH2:29][CH:30]=[C:31]([CH3:33])[CH3:32])[C:14]([O:22][CH3:23])=[CH:15][CH2:16][CH:17]=[C:18]1[O:19][CH3:20])[CH:11]=[CH2:12]
Reactant: C=CCC1(C[C@@H]2O[C@@]2(C)CCC=C(C)C)C(OC)=CC(=O)C=C1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=CCC1(C[C@@H]2O[C@@]2(C)CCC=C(C)C)C(OC)=CCC=C1OC
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 45.2 %

Procedure:
A DCM (0.5 mL) slurry of lithium aluminum hydride (23 mg, 0.61 mmol, 2 equiv.) was cooled to −78° C. in a 10-mL recovery flask, and a DCM (0.5 mL) solution of 7 (106 mg, 0.31 mmol, 1 equiv.) was added via cannula, followed by a DCM (0.5 mL) rinse. The slurry was stirred at −78° C. for 25 min, Et2O (0.5 mL), and the reaction was warmed to 0° C. After stirring for 75 min, the reaction was quenched sequentially with H2O (23 μL), 15 wt % NaOHaq (23 μL), and H2O (63 μL). The reaction was then warmed to room temperature, diluted with H2O, and extracted four times with EtOAc. The organic extracts were combined, washed with H2O and brine, dried over Na2SO4, filtered, and concentrated in vacuo to a brown residue. Flash column chromatography (30 mL SiO2, 19:1 hexane:EtOAc) afforded 45 mg (0.14 mmol, 44% yield) of 8 as a clear, colorless oil. TLC Rf 0.74 (1:1 hexane:EtOAc). 1H NMR (600 MHz; CDCl3): δ 5.57 (ddt, J=17.1, 10.1, 7.1 Hz, 1H), 5.05 (t, J=7.2 Hz, 1H), 4.94-4.88 (m, 2H), 4.80 (t, J=3.5 Hz, 1H), 4.76 (t, J=3.5 Hz, 1H), 3.54 (s, 3H), 3.49 (s, 3H), 2.78 (app q, J=3.5 Hz, 2H), 2.64 (dd, J=8.0, 4.0 Hz, 1H), 2.39 (qd, J=12.7, 7.2 Hz, 2H), 2.03 (dd, J=13.7, 4.0 Hz, 1H), 1.97 (q, J=7.9 Hz, 2H), 1.76 (dd, J=13.7, 8.0 Hz, 1H), 1.67 (s, 3H), 1.58 (s, 3H), 1.57-1.54 (m, 1H), 1.29 (dt, J=13.5, 8.4 Hz, 1H), 1.18 (s, 3H). 13C NMR (125 MHz; CDCl3): δ 153.80, 153.73, 135.3, 131.8, 124.2, 116.1, 93.23, 93.17, 61.25, 61.09, 54.6, 54.2, 46.2, 40.2, 39.4, 34.2, 25.8, 24.2, 24.0, 17.8, 16.8. IR (NaCl, thin film, cm−1) 2932, 2831, 1694, 1659, 1451, 1381, 1223, 1206, 1139, 908. HRMS-ESI (m/z): [M+H]+ calculated for C21H32O3, 333.2424. found, 333.2425.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[CH:10]=2)[O:5][CH:4]([C:19]2[CH:28]=[CH:27][C:22]([O:23][CH2:24][CH2:25][OH:26])=[CH:21][CH:20]=2)[C:3]=1[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][O:37]2)[CH:30]=1.C(N(CC)CC)C.[CH3:49][S:50](Cl)(=[O:52])=[O:51].[Cl-].[NH4+]>C(Cl)Cl.O>[CH3:49][S:50]([O:26][CH2:25][CH2:24][O:23][C:22]1[CH:27]=[CH:28][C:19]([CH:4]2[C:3]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH:36]4[CH2:41][CH2:40][CH2:39][CH2:38][O:37]4)[CH:30]=3)=[C:2]([CH3:1])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH:13]4[CH2:18][CH2:17][CH2:16][CH2:15][O:14]4)[CH:10]=3)[O:5]2)=[CH:20][CH:21]=1)(=[O:52])=[O:51]
Reactant: CS(=O)(=O)Cl
Reactant: CC1=C(c2cccc(OC3CCCCO3)c2)C(c2ccc(OCCO)cc2)Oc2ccc(OC3CCCCO3)cc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC1=C(c2cccc(OC3CCCCO3)c2)C(c2ccc(OCCOS(C)(=O)=O)cc2)Oc2ccc(OC3CCCCO3)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
To a solution of 2-(4-(4-methyl-6-((tetrahydro-2H-pyran-2-yl)oxy)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2H-chromen-2-yl)phenoxy)ethanol (Intermediate 4, 0.7 g, 1.25 mmol) in DCM (25 mL) at 0° C., triethylamine (0.26 mL, 1.87 mmol) and methanesulfonyl chloride (0.146 mL, 1.87 mmol) were added respectively. The reaction mixture was stirred at 0° C. for 1 h, and then diluted with DCM. To this mixture, water (20 mL), and sat'd ammonium chloride (20 mL) were added. The layers were separated and the organic layer was washed with water, washed with saturated NaHCO3, washed with brine, dried over Na2SO4, and concentrated to give 2-(4-(4-methyl-6-((tetrahydro-2H-pyran-2-yl)oxy)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2H-chromen-2-yl)phenoxy)ethyl methanesulfonate (0.7 g). 1H NMR (DMSO-d6): δ 7.25 (d, 3H), 6.99-6.98 (m, 1H), 6.93-6.87 (m, 3H), 6.85-6.78 (m, 2H), 6.77-6.75 (dd, 1H), 6.61 (d, 1H), 5.98 (d, 1H), 5.43 (d, 1H), 5.34 (br, 1H), 4.47-4.45 (m, 2H), 4.16 (br, 2H), 3.83-3.70 (m, 2H), 3.56-3.47 (m, 2H), 3.18 (s, 3H), 2.05 (s, 3H), 1.92-1.65 (m, 6H), 1.60-1.40 (m, 6H).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH:18]([CH3:22])[C:19]([OH:21])=[O:20])=[CH:10][C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[C:26](=O)(O)[O-].[Na+]>S(=O)(=O)(O)O.O>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH:18]([CH3:22])[C:19]([O:21][CH3:26])=[O:20])=[CH:10][C:9]1=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C(=O)O)c1cc(=O)n(Cc2ccccc2)c2ccccc12
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)C(C)c1cc(=O)n(Cc2ccccc2)c2ccccc12
Yield: 74 %

Procedure:
A mixture of α-(1-benzyl-1,2-dihydro-2-oxoquinol-4-yl)propionic acid (0.5g.), methanol (5ml.) and concentrated sulphuric acid (4 drops) was heated under reflux for six hours. The mixture was then poured into water (10 ml.), and the resulting mixture was neutralised with sodium bicarbonate solution. The mixture was extracted with ethyl acetate (3 × 5 ml.) and the combined extracts were washed successively with sodium bicarbonate solution (5 ml.) and water (5 ml.), and then dried with sodium sulphate. The solvent was evaporated in vacuo and the residue crystallised from cyclohexane to give methyl α-(1-benzyl-1,2-dihydro-2-oxoquinol-4-yl)propionate m.p. 90°-92.5° C., in 74% yield.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:5][C:6]1[CH:15]=[CH:14][C:9]2[N:10]=[C:11]([SH:13])[S:12][C:8]=2[CH:7]=1)[CH3:4].[N+:16]([C:19]1[CH:25]=[CH:24][C:23](Cl)=[CH:22][C:20]=1[NH2:21])([O-:18])=[O:17]>O.CN(C)C=O>[N+:16]([C:19]1[CH:25]=[CH:24][C:23]([S:13][C:11]2[S:12][C:8]3[CH:7]=[C:6]([O:5][CH2:3][CH3:4])[CH:15]=[CH:14][C:9]=3[N:10]=2)=[CH:22][C:20]=1[NH2:21])([O-:18])=[O:17]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CCOc1ccc2nc(S)sc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc2nc(Sc3ccc([N+](=O)[O-])c(N)c3)sc2c1
Reaction time: 16 h

Procedure:
To a stirred solution of 0.15 moles of potassium hydroxide in a mixture of 15 ml of water and 300 ml of dimethylformamide add 0.15 moles of 6-ethoxybenzothiazole-2-thiol (L. B. Sebrell and C. E. Boord, J. Am. Chem. Soc., 45, 2390 (1923)) under a nitrogen atmosphere. After complete dissolution, add 2-nitro-5-chloroaniline (R. C. Fuson, R. A. Dauman, E. Howard, Jr., and E. N. Marvell, J. Org. Chem., 12, 084 (1947)) and heat the mixture under reflux and a positive nitrogen pressure for about 16 hours. Pour the mixture into 1000 ml of water and remove the resulting precipitate. Wash the precipitate with water and crystallize from acetonitrile to give the title compound having a melting point of 126°-129° C.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[CH:17][C:16]([C:19](=[O:25])[CH:20](OCC)O)=[CH:15][C:10]=1[C:11]([O:13]C)=O)C1C=CC=CC=1.[CH2:26]([C:33]1([NH2:36])[CH2:35][CH2:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.FC(F)(F)C([O-])=O>>[CH2:26]([C:33]1([NH:36][CH2:20][CH:19]([C:16]2[CH:17]=[CH:18][C:9]([OH:8])=[C:10]([CH2:11][OH:13])[CH:15]=2)[OH:25])[CH2:35][CH2:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(O)C(=O)c1ccc(OCc2ccccc2)c(C(=O)OC)c1
Reactant: NC1(Cc2ccccc2)CC1
Agent: O=C([O-])C(F)(F)F
Product: OCc1cc(C(O)CNC2(Cc3ccccc3)CC2)ccc1O

Procedure:
Prepared according to general method 5 from 344 mg (1 mmol) methyl 2-benzyloxy-5-(2-ethoxy-2-hydroxy-acetyl)-benzoate and 147 mg (1 mmol) 1-benzyl-cyclopropylamine. Yield: 184 mg (43%, trifluoroacetate); mass spectroscopy: [M+H]+=314.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([O:16]C)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[OH-].[K+].CO>O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([OH:16])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccccc1-c1ccc(C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(-c2ccccc2C(=O)O)cc1
Reaction time: 5 h
Yield: 92.8 %

Procedure:
Methyl 4'-methylbiphenyl-2-carboxylate (10.0 g, 44.2 mmol, 1 eq), 0.5N KOH in methanol (265.5 mL, 133 mmol, 3 eq), and water (50 mL) were mixed and refluxed under N2. After 5 hours, the solvent was removed in vacuo and water (200 mL) and ethyl acetate (200 mL) added. The aqueous layer was acidified with concentrated hydrochloric acid to a pH of 3 and the layers were separated. The aqueous phase was extracted with ethyl acetate (2×200 mL), the organic layers collected, dried (MgSO4) and the solvent removed in vacuo to yield 8.71 g of a white solid; m.p. 140.0°-145.0°. NMR (200 MHz, DMSO-d6) δ 7.72 (d, 1H, J=7Hz); 7.56 (t, 1H, J=7 Hz); 7.45 (d, 1H, J=7 Hz); 7.40 (t, 1H, J=7 Hz); 7.25 (s, 4H); 2.36 (s, 3H). Anal Calcd. for C14H12O2 ; C, 79.23; H, 5.70. Found: C, 79.22; H, 5.47.
Reaction SMILES: [Cl:1]Cl.[CH3:3][C:4]([CH3:45])([CH3:44])[C:5](=[O:43])[CH:6]([N:20]1[CH:23](SC)[CH:22]([CH:26]([O:28][C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=2)=[O:30])[CH3:27])[C:21]1=[O:42])[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)=[O:8]>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Cl:1][CH:23]1[N:20]([CH:6]([C:5](=[O:43])[C:4]([CH3:45])([CH3:44])[CH3:3])[C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[C:21](=[O:42])[CH:22]1[CH:26]([O:28][C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=1)=[O:30])[CH3:27]
Reactant: ClCl
Reactant: CSC1C(C(C)OC(=O)OCc2ccc([N+](=O)[O-])cc2)C(=O)N1C(C(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)C(C)(C)C
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(OC(=O)OCc1ccc([N+](=O)[O-])cc1)C1C(=O)N(C(C(=O)OCc2ccc([N+](=O)[O-])cc2)C(=O)C(C)(C)C)C1Cl
Temperature: -60 °C
Reaction time: 2 h

Procedure:
660 μl of a solution containing 850 mg of chlorine in 10 ml of carbon tetrachloride is added to a solution of 244 mg (0.395 mmol) of p-nitrobenzyl 4,4-dimethyl-2-[4-methylthio-3-(1-(p-nitrobenzyloxycarbonyloxy)-ethyl)-2-oxoazetidinyl]-3-oxopentanoate in 16 ml of methylene chloride at -60° C. The pale yellow solution is stirred at -60° C. for 2 hours, and the solvent is removed in vacuo, to give 236 mg of a colourless, non-crystalline solid. IR spectrum in CH2Cl2 : 2930, 2850, 1795, 1765, 1725, 1620, 1530, 1355 cm-1.