Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([C:12]([N:14]3[CH2:17][CH:16]([O:18][C:19]4[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=4)[CH2:15]3)=[O:13])=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:28]1[C:31]2([CH2:35][CH2:34][CH2:33][O:32]2)[CH2:30][NH:29]1.C(N(CC)CC)C.[Na].C([O-])(O)=O.[Na+]>ClCCl>[CH2:30]1[C:31]2([CH2:35][CH2:34][CH2:33][O:32]2)[CH2:28][N:29]1[CH2:23][C:22]1[CH:21]=[CH:20][C:19]([O:18][CH:16]2[CH2:15][N:14]([C:12]([C:10]3[O:11][C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[N:8][N:9]=3)=[O:13])[CH2:17]2)=[CH:26][CH:25]=1
Reactant: C1COC2(C1)CNC2
Reactant: O=Cc1ccc(OC2CN(C(=O)c3nnc(-c4ccccc4)o3)C2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1nnc(-c2ccccc2)o1)N1CC(Oc2ccc(CN3CC4(CCCO4)C3)cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
To a solution of 4-(1-(5-phenyl-1,3,4-oxadiazole-2-carbonyl)azetidin-3-yloxy)benzaldehyde (70 mg, 0.20 mmol) in dichloromethane (2 mL) was added 5-oxa-2-azaspiro[3.4]octane hydrochloride (80 mg, 0.53 mmol) and triethylamine (0.100 mL, 0.72 mmol). After stirring at ambient temperature for 30 minutes, sodium triacetoxyhydroborate (70 mg, 0.33 mmol) was added. Stirring was continued at ambient temperature overnight, after which NaHCO3 (aq, sat, 5 ml) was added. The phases were separated with the aid of a phase separator. The aqueous phase was extracted twice with dichloromethane and dried with the aid of a phase separator. The combined organic phases were concentrated in vacuo to afford 88 mg of a colourless residue.
Reaction SMILES: [CH2:1]([C:8]1[C:9]([O:21][CH3:22])=[N:10][CH:11]=[C:12]([CH:14]=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[C].[Pd].C(O)C>[CH2:1]([C:8]1[C:9]([O:21][CH3:22])=[N:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C=Cc1cnc(OC)c(Cc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1cnc(OC)c(Cc2ccccc2)c1
Yield: 99.3 %

Procedure:
A mixture of 950 mg of 3-benzyl-5-(2-ethoxycarbonylethenyl)-2-methoxypyridine, 90 mg of 10% palladium carbon and 10 ml of ethanol was stirred at room temperature for one hour in a hydrogen atmosphere. After the atmosphere in the system was replaced by nitrogen, the mixture was filtered through Celite. The solvent was removed, to give 950 mg of the target compound.
Reaction SMILES: CCO.Cl.[CH2:5]([NH:12]/[C:13](/[C:21]1[CH:26]=[C:25]([Br:27])[CH:24]=[CH:23][C:22]=1[OH:28])=[CH:14]\[C:15](=O)[C:16]([F:19])([F:18])[F:17])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O.N.CCOC(C)=O>[Br:27][C:25]1[CH:26]=[C:21]2[C:22](=[CH:23][CH:24]=1)[O:28][C:15]([C:16]([F:18])([F:19])[F:17])=[CH:14]/[C:13]/2=[N:12]/[CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(/C=C(\NCc1ccccc1)c1cc(Br)ccc1O)C(F)(F)F
Agent: Cl
Agent: N
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: FC(F)(F)c1c/c(=N/Cc2ccccc2)c2cc(Br)ccc2o1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
To a cooled (ice bath) EtOH (96 ml) was bubbled through hydrogen chloride gas for 30 min. (Z)-4-(benzylamino)-4-(5-bromo-2-hydroxyphenyl)-1,1,1-trifluorobut-3-en-2-one (24.0 g, 60 mmol) was then added in one portion to this solution. The reaction was stirred at RT for 36 h. The resulted mixture was diluted with 900 ml of cool water, 28% aq NH3 (96 ml) was then added. The precipitate formed was filtered and washed with water to give a brown sticky solid. The solid was dissolved in EtOAc, washed with 1N HCl and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was crystallized from hexane to give the title compound as a brown solid. MS m/z: 382.
Reaction SMILES: C(N1C2C(=CC(S(N)(=O)=O)=CC=2)CC1)C.[CH:16]1([C:22]([N:24]2[C:32]3[C:27](=[CH:28][C:29]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:30][CH:31]=3)[CH2:26][CH2:25]2)=O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH:16]1([CH2:22][N:24]2[C:32]3[C:27](=[CH:28][C:29]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:30][CH:31]=3)[CH2:26][CH2:25]2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: NS(=O)(=O)c1ccc2c(c1)CCN2C(=O)C1CCCCC1
Agent: CCN1CCc2cc(S(N)(=O)=O)ccc21
Product: NS(=O)(=O)c1ccc2c(c1)CCN2CC1CCCCC1
Yield: 56.6 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 53, 1-(cyclohexanecarbonyl)indoline-5-sulfonamide (Intermediate 55, 120 mg, 0.39 mmol) was converted to the title compound (65 mg, 57%) after purification using preparative HPLC. 1H NMR (CD3OD) δ 7.54 (dd, J=8.4, 2.0 Hz, 1H), 7.45 (d, J=1.5 Hz, 1H), 6.38 (d, J=8.4 Hz, 2H), 3.54 (d, J=8.7 Hz, 2H), 3.04-2.96 (m, 4H), 1.80-1.68 (m, 6H), 1.31-1.23 (m, 3H), 1.05-0.96 (m, 2H); MS(ESI+) m/z 295.1 (M+H)+.
Reaction SMILES: CC1(C)[O:6][C:5](=[O:7])[CH:4]([CH:8]([CH2:12][CH2:13][CH2:14][CH3:15])[C:9]([OH:11])=O)[O:3]1.[NH:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1>>[OH:3][C@@H:4]([C@H:8]([C:9]([N:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)=[O:11])[CH2:12][CH2:13][CH2:14][CH3:15])[C:5]([OH:6])=[O:7]
Reactant: CCCCC(C(=O)O)C1OC(C)(C)OC1=O
Reactant: c1ccc(C2CCCN2)nc1
Product: CCCC[C@@H](C(=O)N1CCCC1c1ccccn1)[C@H](O)C(=O)O

Procedure:
The title compound is prepared from 2-(2,2-dimethyl-4-oxo-1,3-dioxolan-5-yl)hexanoic acid B-5 and commercially available 2-pyrrolidin-2-yl-pyridine A-5 according to General Procedure B.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[CH:11][C:10]=1[Cl:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:18][C:19]1[N:24]=[C:23]2[N:25]=[C:26]([CH2:28][CH3:29])[NH:27][C:22]2=[C:21]([CH3:30])[CH:20]=1>>[Si:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][N:25]2[C:23]3=[N:24][C:19]([CH3:18])=[CH:20][C:21]([CH3:30])=[C:22]3[N:27]=[C:26]2[CH2:28][CH3:29])=[CH:11][C:10]=1[Cl:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCc1nc2nc(C)cc(C)c2[nH]1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CBr)cc1Cl
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(O[Si](C)(C)C(C)(C)C)c(Cl)c1
Yield: 15.9 %

Procedure:
The product of Step C (1.79 g, 5.15 mmol) was used to alkylate 0.750 g (4.29 mmol) of 5,7-dimethyl-2-ethylimidazo[4,5-b]-pyridine (prepared as described in EP 400,974 published Dec. 5, 1990) according to the procedure described for Step B of Example 2, which after purification afforded 0.294 g (15%) of the title compound.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[N:12][CH:13](Cl)[C:14]([Cl:17])([Cl:16])[Cl:15])[C:10](=[O:19])[N:9]([CH3:20])[C:8]2=[O:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.C(OCC)C>C(#N)C>[C:1]1([N:7]2[C:11](=[N:12][CH:13]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:14]([Cl:17])([Cl:16])[Cl:15])[C:10](=[O:19])[N:9]([CH3:20])[C:8]2=[O:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN1C(=O)C(=NC(Cl)C(Cl)(Cl)Cl)N(c2ccccc2)C1=O
Reactant: Nc1ccccc1
Solvent: CC#N
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CN1C(=O)C(=NC(Nc2ccccc2)C(Cl)(Cl)Cl)N(c2ccccc2)C1=O
Reaction time: 5 h

Procedure:
In this Example 1-phenyl-3-methyl-5-(1,2,2,2-tetrachloroethyl)imino-1,3-diazolidine-2,4-dione (0.02 mol) was dissolved in 20 ml of acetonitrile and 0.02 mol of aniline then added. A mild exothermic reaction was observed. After ten minutes, triethylamine was added causing a very exothetmic reaction, which subsided within an hour to occur. The mixture was stirred for five hours and then 20 ml of ethyl ether added to assist precipitation of salts. The mixture was filtered and the filtrate evaporated off under high vacuum affording 1-phenyl-3-methyl-5-(1-phenylamino-2,2,2-trichloroethyl)imino-1,3-diazolidine-2,4-dione oil (Anal. calcd. for C18H15Cl3N4O2 --C50.79, H3.55, Cl24.98, N13.16 found C51.6, H3.8, Cl26.54, N12.2.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)O1.[Br:16][C:17]1[C:22]([CH3:23])=[CH:21][C:20](I)=[CH:19][C:18]=1[CH3:25]>>[Br:16][C:17]1[C:22]([CH3:23])=[CH:21][C:20]([C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)=[CH:19][C:18]=1[CH3:25]
Reactant: Cc1cc(I)cc(C)c1Br
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Product: Cc1cc(-c2ccncc2)cc(C)c1Br

Procedure:
The title compound is prepared from 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine and 2-bromo-5-iodo-1,3-dimethyl-benzene following a procedure analogous to that described in Step 1 of Intermediate 56. LC (method 9): tR=0.90 min; Mass spectrum (ESI+): m/z=262/264 (Br) [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:16])[N:7]([CH2:13][CH2:14]O)[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O>ClC(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:16])[N:7]([CH2:13][CH2:14][Cl:19])[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=c1[nH]c2cc(Cl)ccc2c(=O)n1CCO
Solvent: ClC(Cl)Cl
Product: O=c1[nH]c2cc(Cl)ccc2c(=O)n1CCCl
Yield: 88 %

Procedure:
A mixture of 23 parts of 7-chloro-3-(2-hydroxyethyl)-2,4(1H,3H)-quinazolinedione, 32 parts of thionyl chloride and 150 parts of trichloromethane is stirred and refluxed for 4 hours. The reaction mixture is cooled. The precipitated product is filtered off, washed with trichloromethane and with petroleumether, and dried, yielding 22 parts (88%) of 7-chloro-3-(2-chloroethyl)-2,4(1H,3H)-quinazolinedione.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]2[OH:16].[CH2:17](O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C(Cl)Cl.C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]2[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1[nH]c2ccc(Br)cc2c1O
Reactant: OCc1ccccc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)c1[nH]c2ccc(Br)cc2c1OCc1ccccc1
Temperature: 0 °C
Yield: 79.3 %

Procedure:
To a solution containing 2.04 g of ethyl 5-bromo-3-hydroxyindole-2-carboxylate, 3.94 g of benzyl alcohol and 3.34 g of di-tert-butyl azodicarboxylate in 30 mL of THF and 15 mL of CH2Cl2 at −78° C. was treated dropwise with a solution containing 3.81 g of triphenylphosphine in 15 mL of CH2Cl2. The resulting reaction mixture was warmed slowly to 0° C. upon consumption of the starting material (monitored by TLC). 800 μL of acetic acid was added and after 30 min the solvents were removed under vacuum and the excess of acetic acid was removed by coevaporation with toluene. The crude product was filtered over a pad of silica gel eluting with CH2Cl2. The organic phase was concentrated to dryness and the solid was swished with hexane to give 2.13 g of the title compound as a white solid.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:19]=[CH:18][C:8]([CH2:9][NH:10][C:11](=[O:17])[C@H:12](Br)[C@H:13]([OH:15])[CH3:14])=[CH:7][CH:6]=1>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(Cl)Cl>[CH3:3][O:4][C:5]1[CH:19]=[CH:18][C:8]([CH2:9][NH:10][C:11](=[O:17])[C@@H:12]2[O:15][C@@H:13]2[CH3:14])=[CH:7][CH:6]=1
Reactant: COc1ccc(CNC(=O)[C@H](Br)[C@@H](C)O)cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(CNC(=O)[C@@H]2O[C@@H]2C)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
50 ml of 50% NaOH solution and 456 mg (2 mmol) of benzyltriethylammonium chloride are added to a solution of 6.04 g (20 mmol) of (2R,3R)-2-bromo-3-hydroxybutyric acid p-methoxybenzylamide in 150 ml of methylene chloride. The two phase mixture is vigorously stirred for 20 hours at room temperature. The organic layer is separated off and the aqueous phase is subsequently extracted with methylene chloride. The combined methylene chloride solutions are dried and concentrated by evaporation. The crude product that forms is chromatographed over 40 times the amount by weight of silica gel in a methylene chloride/methanol - 99:1 system. After crystallisation of the pure fractions from methylene chloride/ether/petroleum ether, the title compound is obtained, melting point 75°-76°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19].[Br:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[C:27](I)=[CH:26][C:25]=1[CH3:33].C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C1(C)C=CC=CC=1>[CH2:9]([S:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:27]2[CH:26]=[C:25]([CH3:33])[C:24]([Br:23])=[CH:29][C:28]=2[O:30][CH3:31])=[C:3](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:4]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COc1cc(Br)c(C)cc1I
Reactant: CCOC(=O)/C=C/c1cc(SCc2ccccc2)ccc1N
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C/c1cc(SCc2ccccc2)ccc1Nc1cc(C)c(Br)cc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.4 %

Procedure:
A RBF was charged with (E)-ethyl 3-(2-amino-5-(benzylthio)phenyl)acrylate (4.729 g, 15.09 mmol, made via Method 42, Steps 1-2), 1-bromo-4-iodo-5-methoxy-2-methylbenzene (5.18 g, 15.84 mmol, Oakwood), Xantphos (0.437 g, 0.754 mmol), Pd2(dba)3 (0.345 g, 0.377 mmol), cesium carbonate (9.83 g, 30.2 mmol), and toluene (30 mL) were added. A reflux condenser was attached, and the mixture was heated to reflux. After 4 h, additional portions of Pd2(dba)3 (172 mg) and Xantphos (213 mg) were added. After 2 h, additional portions of cesium carbonate (ca. 2 g) and 1-bromo-4-iodo-5-methoxy-2-methylbenzene (600 mg) were added. Following an additional 30 min of reflux, mixture was cooled and filtered through celite. The filter pad was washed with EtOAc (3×). The filtrate was concentrated. The residue was concentrated from MeOH, and taken up in MeOH. The resulting suspension was heated to boiling, then sonicated and cooled to RT. The mixture was filtered, and the collected solid was washed with MeOH (3×) and dried under a stream of N2 (g) for 48 hrs to give (E)-ethyl 3-(5-(benzylthio)-2-((4-bromo-2-methoxy-5-methylphenyl)amino)phenyl)acrylate (5.21 g, 10.17 mmol, 67.4% yield) as a bright-yellow solid. 1H NMR (400 MHz, DMSO-d6) □=7.75 (d, J=15.9 Hz, 1 H), 7.66 (d, J=2.1 Hz, 1H), 7.42 (s, 1 H), 7.37-7.20 (m, 6 H), 7.14 (s, 1 H), 6.85 (d, J=8.5 Hz, 1 H), 6.62 (s, 1 H), 6.51 (d, J=15.9 Hz, 1 H), 4.23 (s, 2 H), 4.15 (q, J=7.0 Hz, 2 H), 3.78 (s, 3 H), 2.14 (s, 2 H), 1.23 (t, J=7.1 Hz, 3 H). m/z (ESI) 512.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:19][C:20]1[CH:25]=[CH:24][C:23](I)=[CH:22][CH:21]=1.CC(C)([O-])C.[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OCC)(=O)C.O1CCOCC1>[F:19][C:20]1[CH:25]=[CH:24][C:23]([NH:1][C:2]2[CH:11]=[C:10]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(Oc2ccccc2)cc1N
Reactant: Fc1ccc(I)cc1
Agent: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Oc2ccccc2)cc1Nc1ccc(F)cc1
Temperature: 25 °C
Yield: 51.5 %

Procedure:
To dioxane 5.0 mL solution of methyl 2-amino-4-phenoxybenzoate 0.34 g were added 1-fluoro-4-iodobenzene 0.18 mL,1,1′-bis(diphenylphosphino)ferrocene 93 mg,1,1′-bis(diphenylphosphino)ferrocene palladium(II) dichloride dichloromethane complex 46 mg and sodium tert-butoxide 0.15 g at room temperature, and it was heated and refluxed under nitrogen atmosphere for 3 hours. After the reaction mixture was cooled to room temperature,10% citric acid aqueous solution and ethyl acetate were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [eluent; hexane:ethyl acetate=20:1] to give methyl 2-(4-fluoroanilino)-4-phenoxybenzoate 0.036 g of colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].[CH2:12]([NH:19][C:20]([C:22]1[S:26][C:25]([NH2:27])=[N:24][C:23]=1[CH3:28])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([NH:19][C:20]([C:22]1[S:26][C:25]([NH:27][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][C:10]([Cl:11])=[C:2]([Cl:1])[CH:3]=2)=[N:24][C:23]=1[CH3:28])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Product: Cc1nc(NC(=O)c2ccc(Cl)c(Cl)c2)sc1C(=O)NCc1ccccc1
Yield: 15 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 3,4-dichlorobenzoyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 15% yield; m.p. 212-214° C.; 1H NMR (CD3OD, 300 MHz) δ 8.21 (d, J=2.0 Hz, 1H), 7.93 (dd, J=2.0, 8.4 Hz, 1H), 7.68 (d, J=8.4 Hz, 1H), 7.33-7.23 (m, 5H), 4.50 (s, 2H), 2.54 (s, 3H); MS (ES+) m/z 420.0 (M+1).
Reaction SMILES: [C:1]([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C@H:7]([CH2:23][O:24][CH2:25][CH2:26][OH:27])[CH2:6]1)(=[O:3])[CH3:2].ClS([N:32]=[C:33]=[O:34])(=O)=O.O>C(#N)C>[C:1]([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C@H:7]([CH2:23][O:24][CH2:25][CH2:26][O:27][C:33](=[O:34])[NH2:32])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(=O)S[C@H]1C[C@@H](COCCO)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Solvent: CC#N
Solvent: O
Product: CC(=O)S[C@H]1C[C@@H](COCCOC(N)=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 1 h

Procedure:
To a solution of (2S,4S)-4-acetylthio-2-(2-hydroxy-ethyloxymethyl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.1 g) in acetonitrile (20 ml) was added chlorosulfonyl isocyanate(0.32 ml) at 0°-5° C. and the mixture was stirred at 20°-25° C. for 1 hour. Water (3 ml) was added to the solution at the same temperature and the mixture was stirred for 20 hours. After the solvent was evaporated, the residue was dissolved in ethyl acetate, washed with water, saturated sodium bicarbonate and brine successively. The dried organic layer was evaporated to give (2S,4S)-4-acetylthio-2-(2-carbamoyloxyethyloxymethyl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.19 g).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CCCCCCC.CCOC(C)=O>CC(C)=O>[CH2:15]([O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[I:1])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Oc1ccccc1I
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Ic1ccccc1OCc1ccccc1
Reaction time: 0.25 h
Yield: 82.3 %

Procedure:
In a 25 mI ovendried flask 2-iodophenol (1.03 g, 4.7 mmol) and potassium carbonate (0.71 g, 5.2 mmol) were dissolved in dry acetone (10 mL). The mixture was stirred for 15 min followed by addition of benzylbromide (0.61 mL, 5.2 mmol) and left over-night at rt. Addition of H20 (50 mL) followed by extraction with ethyl acetate (3×50 mL) and the combined organic phases were dried (MgSO4) and evaporated to dryness, to produce 1.7 g of crude 25. The crude product was subjected to CC [eluent:Heptane: EtOAc (9:1)] to give pure 25 (1.2 g, 81%). LC-MS [M+H]+ 310 (cald. 310.0).
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([N:15]3[CH2:20][CH2:19][CH:18]([NH:21][CH3:22])[CH2:17][CH2:16]3)=[O:14])[N:10]=[C:9]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[CH:8]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:38][CH:39]([CH3:43])[C:40](Cl)=[O:41]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([N:15]3[CH2:16][CH2:17][CH:18]([N:21]([CH3:22])[C:40](=[O:41])[CH:39]([CH3:43])[CH3:38])[CH2:19][CH2:20]3)=[O:14])[N:10]=[C:9]([C:23]3[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=3)[CH:8]=2)=[CH:29][CH:30]=1
Reactant: CNC1CCN(C(=O)Cn2nc(-c3ccncc3)cc2Cc2ccc(F)cc2)CC1
Reactant: CC(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(=O)N(C)C1CCN(C(=O)Cn2nc(-c3ccncc3)cc2Cc2ccc(F)cc2)CC1
Reaction time: 0.17 h

Procedure:
To a solution of 1-{[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetyl}-N-methylpiperidin-4-amine (150 mg, 0.37 mmol) in DCM (3 mL) at room temperature was added triethylamine (56 μL, 0.40 mmol) followed by 2-methylpropanoyl chloride (32 μL, 0.37 mmol) and the solution stirred for 10 minutes. The solution was then loaded directly onto a pre-wetted Biotage 25M column for flash chromatography and eluted with 2-8% MeOH/DCM to yield the title compound as a white solid, 147 mg, 83%. 1H NMR (mix of rotomers, 400 MHz, DMSO-D6) δ ppm 8.47-8.60 (2 H, m) 7.62-7.72 (2 H, m) 7.31 (2 H, dd, J=8.46, 5.68 Hz) 7.15 (2 H, t, J=8.97 Hz) 6.53 (1 H, s) 5.07-5.35 (2 H, m) 4.43-4.61 (0.5 H, m) 4.38 (1 H, d, J=12.88 Hz) 3.95 (3.5 H, s) 3.05-3.29 (1 H, m) 2.88-3.04 (0.5 H, m) 2.53-2.89 (4.5 H, m) 1.39-1.86 (4 H, m) 0.91-1.08 (6 H, m); m/z (APCI+) for C27H32N5O2F 478.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]=[C:8]([CH2:12][C:13]([CH3:15])=O)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[C:26]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[CH:27]=1)[N:24]=[CH:23][CH:22]=[CH:21]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(O)(=O)C>[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[C:26]([N:28]3[CH2:29][CH2:30][N:31]([CH:13]([CH3:15])[CH2:12][C:8]4[C:7]5[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:11]=5[O:10][CH:9]=4)[CH2:32][CH2:33]3)[CH:27]=1)[N:24]=[CH:23][CH:22]=[CH:21]2
Reactant: COc1cccc2c(CC(C)=O)coc12
Reactant: COc1cc(N2CCNCC2)c2ncccc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1cc(N2CCN(C(C)Cc3coc4c(OC)cccc34)CC2)c2ncccc2c1

Procedure:
6-methoxy-8-{4-[2-(7-methoxy-1-benzofuran-3-yl)-1-methylethyl)piperazin-1-yl]quinoline was prepared by generally following the procedure outlined in example 35, step 2, starting from the 1-(7-methoxy-1-benzofuran-3-yl)acetone (204 mg, 1 mmol) and 6-methoxy-8-piperazino quinoline (243.0 mg, 1 mmol) in 1,2-dichloroethane (100 ml) and acetic acid (1 ml), sodium triacetoxyborohydride (422 mg, 2 mmol). The product was purified by silica-gel column chromatography by eluting it initially with 80% ethyl acetate:hexane and then with 5% methanol:ethyl acetate, yielding a brown semi-solid. Yield: 75 mg (17%); (M+H): 432.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.[NH2:28][CH:29]1[C:35](=[O:36])[NH:34][C:33]2[N:37]=[CH:38][CH:39]=[CH:40][C:32]=2[CH2:31][CH2:30]1>CN(C=O)C>[CH3:14][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])([CH3:15])[CH2:10][C:11](=[O:13])[NH:28][CH:29]1[C:35](=[O:36])[NH:34][C:33]2[N:37]=[CH:38][CH:39]=[CH:40][C:32]=2[CH2:31][CH2:30]1
Reactant: NC1CCc2cccnc2NC1=O
Reactant: CC(C)(CC(=O)O)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(CC(=O)NC1CCc2cccnc2NC1=O)NC(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 49 %

Procedure:
To 68 mg of 3-t-butoxycarbonylamino-3-methylbutanoic acid in 1 mL of DMF was added 60 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC). The mixture was stirred at 20° C. for 2 h before 50 mg of 7-amino-5,6,7,9-tetrahydro-8H-pyrido[2,3-b]azepin-8-one was added and the reaction was stirred an additional 18 h. The DMF was removed in vacuo and the residue was purified by preparative silica gel layer chromatography to yield 52 mg of the product characterized by its NMR and mass spectra.