Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[O:7])=[CH:4][CH:3]=1.[CH:20]1[C:28]2[N:23]([CH:24]=[CH:25][C:26](=O)[CH:27]=2)[CH2:22][CH:21]=1>>[F:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=3)[C:10]([C:26]3[CH2:27][CH:28]4[N:23]([CH2:22][CH2:21][CH2:20]4)[CH2:24][CH:25]=3)=[CH:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=c1ccn2c(c1)C=CC2
Reactant: Nc1ccc2c(ccn2C(=O)c2ccc(F)cc2)c1
Product: Nc1ccc2c(c1)c(C1=CCN3CCCC3C1)cn2C(=O)c1ccc(F)cc1

Procedure:
The N-(4-fluorobenzoyl)-5-amino-1H-indole (813 mg, 3.20 mmol) and the 7-indolizinone (560 mg, 4.00 mmol) were converted to product by the procedure of Example 2 to give 818 mg. (68%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]([F:29])([F:28])[C:18]([F:27])([F:26])[C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-:30].[K+]>O1CCCC1>[OH:30][CH2:6][CH2:7][CH2:2][CH2:3][CH2:4][CH2:5][CH2:8][CH2:9][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][C:17]([F:28])([F:29])[C:18]([F:26])([F:27])[C:19]([F:24])([F:25])[C:20]([F:21])([F:22])[F:23])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: Oc1ccc(-c2ccc(OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)cc1
Agent: [K+]
Solvent: C1CCOC1
Product: OCCCCCCCCOc1ccc(-c2ccc(OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)cc1
Yield: 67.2 %

Procedure:
In a flask, 1.7 g of 4-hydroxy-4'-[2-(perfluorobutyl)ethyloxy]biphenyl and 10 ml of tetrahydrofuran were placed. To this solution, 3.9 ml of a 1N aqueous solution of potassium hydroxide was added and stirred for a while. After the solvent was distilled away under a reduced pressure, 15 ml of methanol and 0.85 g of 8-bromooctanol were added to the solution and stirred under reflux for 12 hours. Next, the reaction solution was poured into water, and an organic layer was extracted with ether. The ether layer was washed with dilute hydrochloric acid and water in this order. After the solvent was distilled away, the residue was purified by silica gel column chromatography (eluent: benzene/ethyl acetate=9/1), and recrystallized from toluene to give 1.5 g of 4-(8-hydroxyoctyloxy)-4'-[2-(perfluorobutyl)ethyloxy]biphenyl (Y: 67.2%). The purity of the compound thus obtained was 98.8% by GC.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:32])=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=4)[C:26]([OH:28])=O)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[CH3:33][N:34]1[CH:38]=[C:37]([C:39]2([NH2:42])[CH2:41][CH2:40]2)[N:36]=[CH:35]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:29]=[C:25]([C:26](=[O:28])[NH:42][C:39]5([C:37]6[N:36]=[CH:35][N:34]([CH3:33])[CH:38]=6)[CH2:41][CH2:40]5)[C:24]([O:30][CH3:31])=[CH:23][C:22]=4[CH3:32])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: Cn1cnc(C2(N)CC2)c1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5cn(C)cn5)CC4)c(OC)cc3C)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
5-(2-(4-Fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.2 g, 1 eq), 1-(1-methyl-1H-imidazol-4-yl)cyclopropanamine (0.07 g, 1.1 eq), EDCI.HCl (0.13 g, 1.5 eq), HOBT (0.094 g, 1.5 eq) and TEA (0.19 ml, 3 eq) were dissolved in dichloromethane and the above solution was stirred at room temperature for 18 h. Later water was added and organic layer was separated. The organic layer was washed with water and the crude product was purified by Prep. HPLC. Yield: 24.69 mg (10%) 1HNMR (400 MHz, CDCl3): δ 1.39 (s, 4H), 2.30 (s, 3H), 2.99-3.01 (d, J=4.6 Hz, 3H), 3.81 (s, 3H), 4.04 (s, 3H), 5.90 (s, 1H), 6.87 (s, 1H), 7.16-7.25 (m, 3H), 7.24 (s, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.65 (s, 1H), 7.98-7.99 (m, 3H), 8.29 (s, 1H), 8.95 (s, 1H). LCMS: (ES+) m/z=553.2 (M+H). Method: Column-Ascentis Express C18 (5×2.1 mm-2.7 μm) Mphase A: 2% ACN-98% H2O-10 mM NH4COOH Mphase B: 98% ACN-2% H2O-10 mM NH4COOH Flow: 1 mL/Min
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([NH:11]C(=O)C(F)(F)F)=[C:4]([CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:3]=1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([NH2:11])=[C:4]([CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:3]=1
Reactant: O=C(Nc1c(CN2CCOCC2)cc(Cl)cc1[N+](=O)[O-])C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1c(CN2CCOCC2)cc(Cl)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 8 h
Yield: 76.7 %

Procedure:
To a solution of N-[4-chloro-2-(morpholin-4-ylmethyl)-6-nitrophenyl]-2,2,2-trifluoroacetamide (3.6 g, 9.6 mmol) in ethanol (60 mL) is added a 10% aqueous NaOH solution (60 mL, 150 mmol). The reaction is heated to 80° C. for 3 hours and then left at room temperature overnight. Most of the ethanol is removed under reduced pressure and the resulting solid is isolated by filtration to afford the title compound (2 g, 77%).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][CH:9]=[C:8]2[CH2:15][CH2:16][CH2:17][C@@H:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]#[C:26][C:27]2[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([F:34])[CH:28]=2)[CH2:20][C@@H:19]1[CH2:35][C:36]([O:38]C)=[O:37]>O1CCOCC1.O.C(OCC)C>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][CH:9]=[C:8]2[CH2:15][CH2:16][CH2:17][C@@H:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]#[C:26][C:27]2[CH:28]=[C:29]([F:34])[CH:30]=[C:31]([F:33])[CH:32]=2)[CH2:20][C@@H:19]1[CH2:35][C:36]([OH:38])=[O:37]
Reactant: COC(=O)C[C@H]1CN(CC#Cc2cc(F)cc(F)c2)CC[C@H]1CCCc1ccnc2ccc(OC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc2nccc(CCC[C@@H]3CCN(CC#Cc4cc(F)cc(F)c4)C[C@@H]3CC(=O)O)c2c1
Temperature: 60 °C
Reaction time: 72 h
Yield: 88.2 %

Procedure:
0.83 cm3 of 5N aqueous sodium hydroxide solution was introduced with stirring, at a temperature in the region of 20° C., into a solution of 0.525 g of methyl (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)propyl]-1-[3-(3,5-difluorophenyl)prop-2-ynyl]piperidine-3-acetate in 5 cm3 of dioxane and then the mixture was heated for 3 hours at a temperature in the region of 60° C. After cooling to approximately 20° C., the mixture was stirred for 3 days and then concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained was taken up in 15 cm3 of water and then the solution was extracted with 5 cm3 of ethyl acetate. The aqueous phase was brought to a pH in the region of 5-6 by addition of 4.1 cm3 of 1N aqueous hydrochloric acid and then extracted, first with 30 cm3 of dichloromethane and then with 10 cm3 of the same solvent. The organic extracts were combined, washed with 2 times 5 cm3 of water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained was taken up in diethyl ether and then concentrated under the same conditions as above until a constant weight was obtained. 0.45 g of (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)propyl]-1-[3-(3,5-difluorophenyl)prop-2-ynyl]piperidine-3-acetic acid was obtained in the form of a solid with a light beige color.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[NH:15]1[CH2:20][CH2:19][C:18]2([C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21]2)[CH2:17][CH2:16]1.[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].CO>C(OCC)(=O)C>[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:15]3[CH2:20][CH2:19][C:18]4([C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH:22]=[CH:21]4)[CH2:17][CH2:16]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: C1=CC2(CCNCC2)c2ccccc21
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC2(C=Cc3ccccc32)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and spiro[1H-indene-1,4′-piperidine]. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 80% overall yield. mp 119-120°. FDMS m/e=374 (M+ of free base). α[D]589=−5.51 (c=0.47, methanol).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[OH:25])[NH2:21]>C(#N)C>[NH2:21][C:20]1[CH:22]=[CH:23][C:24]([O:25][C:2]2[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=2[C:4]#[N:5])=[C:18]([Cl:17])[CH:19]=1
Reactant: Nc1ccc(O)c(Cl)c1
Reactant: N#Cc1c(F)cccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1c(F)cccc1Oc1ccc(N)cc1Cl

Procedure:
1.00 g (7.19 mmol) of 2,6-difluorobenzonitrile is initially charged in 10 ml of acetonitrile. 1.99 g (14.4 mmol) of potassium carbonate and 1.03 g (7.19 mmol) of 3-chloro-4-hydroxyaniline are added, and the mixture is heated at reflux for 45 min. The mixture is filtered and the filtercake is washed with ethyl acetate and DCM. The solvent is removed under reduced pressure and the residue is by column chromatography (silica gel 60, gradient column: mobile phase: DCM:petroleum ether=2:1, then DCM).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[F:16][C:17]([F:41])([F:40])[CH2:18][NH:19][C:20]([C:22]1([CH2:35][CH2:36][CH2:37][CH2:38]Br)[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:21]>>[F:16][C:17]([F:40])([F:41])[CH2:18][NH:19][C:20]([C:22]1([CH2:35][CH2:36][CH2:37][CH2:38][N:13]2[CH2:14][CH2:15][N:10]([C:7]3[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=3)[CH2:11][CH2:12]2)[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:21]
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Agent: Cl
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3ccc(Cl)cc3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2 b from 1-(4-chloro-phenyl)-piperazine dihydrochloride and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:9]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([OH:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1)=[CH2:10].N(C(C)(CC(C)C)C#N)=NC(C)(CC(C)C)C#N>C(C(C)=O)C>[CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:3]1([O:19][S:17]([C:14]2[CH:13]=[CH:12][C:11]([CH:9]=[CH2:10])=[CH:16][CH:15]=2)(=[O:20])=[O:18])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: C=Cc1ccc(S(=O)(=O)O)cc1
Agent: CC(C)CC(C)(C#N)N=NC(C)(C#N)CC(C)C
Solvent: C=Cc1ccccc1
Solvent: CCC(C)=O
Product: C=Cc1ccc(S(=O)(=O)OC2CCCCC2)cc1
Temperature: 65 °C
Reaction time: 2 h

Procedure:
A three-necked flask having a capacity of 500 ml was charged with 240 g of methyl ethyl ketone and the content was stirred at 65° C in a nitrogen gas stream. A mixture of 93.74 of styrene, 26.64 g of 4-vinylbenzenesulfonic acid cyclohe ester and 1.99 g of 2,2′-azobis(2,4-dimethylvaleronitrile) was dropwise added thereto over 2 hours. After completion of the dropwise addition, 0.5 g of 2,2′-azobis(2,4-dimethylvaleronitrile) was further added, followed by stirring for further 2 hours, thereby a styrene-4-vinylbenzenesulfonic acid cyclohexyl ester copolymer was obtained. After the reaction mixture was poured into an egg-plant type flask having a capacity of 1 liter and concentrated, 300 g of MFG was added thereto, the reaction mixture was heated for 3 hours with refluxing MFG, thereby sulfonic acid cyclohexyl ester was decomposed to obtain a sulfonic acid. The obtained reaction mixture was cooled to room temperature and poured into a beaker containing 3 liters of water, thus an aqueous solution of a high molecular compound was prepared.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[NH:10][C:4]=2[CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].C1[CH2:31][O:30][CH2:29][CH2:28]1.BrCCOC>CN(C=O)C.C(OCC)(=O)C.C1(C)C=CC=CC=1>[Br:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[N:10]([CH2:28][CH2:29][O:30][CH3:31])[C:4]=2[CH:3]=1
Reactant: Cn1cc(-c2cc3cnc(Br)cc3[nH]2)cn1
Reactant: C1CCOC1
Agent: COCCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COCCn1c(-c2cnn(C)c2)cc2cnc(Br)cc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
6-Bromo-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridine (Preparation 22, 100 mg, 0.36 mmole) was azeotroped with toluene (3 mL) and dissolved in DMF (1 mL). To the solution was added sodium hexamethyldisilazide, 1M in THF (0.4 mL, 0.4 mmole) and the reaction was stirred at room temperature for 20 minutes. Bromoethylmethyl ether (65 uL, 100 mg, 0.8 mmole) was added and the reaction was stirred at room temperature for 18 hours. The reaction was diluted with ethyl acetate (25 mL) and the solution washed with water (3×8 mL) and with brine, dried and evaporated to afford the title compound. 1H-NMR (CDCl3, 500 MHz): δ 3.31 (s, 3H), 3.72 (t, J=5.68 Hz, 2H), 4.01 (s, 3H), 4.28 (t, J=5.68 Hz, 2H), 6.54 (d, J=0.95 Hz, 1H), 7.48 (t, J=0.95 Hz, 1H), 7.71 (s, 1H), 7.74 (d, J=0.95 Hz, 1H), 8.60 (d, J=0.95 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:7](=[O:8])[CH:6]=[CH:5][CH2:4][CH2:3]1.[CH3:16][S:17][CH2:18][CH2:19][C:20](O)=[O:21].OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[Cl:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:2]1([NH:1][C:20](=[O:21])[CH2:19][CH2:18][S:17][CH3:16])[C:7](=[O:8])[CH:6]=[CH:5][CH2:4][CH2:3]1
Reactant: NC1(c2ccccc2Cl)CCC=CC1=O
Reactant: CSCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: CSCCC(=O)NC1(c2ccccc2Cl)CCC=CC1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 65 %

Procedure:
A solution of 6-amino-6-(2-chlorophenyl)-2-cyclohexen-1-one (50 mg, 0.23 mmol), 3-(methylthio)propanoic acid (prepared by the known base hydrolysis from the commercial methyl ester)(33 mg, 0.28 mmol), hydroxybenzotriazole (31 mg, 0.23 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (66 mg, 0.35 mmol) in dimethylformamide (1 ml) was stirred at room temperature for 18 h. The reaction was partitioned between saturated bicarbonate and ethyl acetate, the organic phase was washed with brine, dried (Na2SO4), and the solvent removed by evaporation. Purification was achieved by preparative thin layer chromatography on silica gel eluting with 1:1 ethyl acetate/hexane. Isolation of the UV active band at Rf 0.4 gave 6-(2-chlorophenyl)-6-(3-(methylthio)propanoyl)amino-2-cyclohexen-1-one (60.6 mg, 65%). The title compound was found to be active at 6 μm in the CMK assay.
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].Br[CH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=1[O:24][CH3:25]>C1COCC1>[CH2:10]([O:9][C:3]([CH:4]([C:5](=[O:6])[CH3:7])[CH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=1[O:24][CH3:25])=[O:8])[CH3:11]
Reactant: CCOC(=O)CC(C)=O
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(C(=O)OC)cc1OC)C(C)=O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (60% in mineral oil; 1.45 g) was added portionwise over 10 min to a solution of ethyl acetoacetate (4.4 mL) in THF (60 mL) at 0° C. The resulting suspension was stirred at 0° C. for 10 min and a solution of methyl 4-(bromomethyl)-3-methoxybenzoate (7.5 g) in THF (40 mL) added portionwise over 10 min. The mixture was warmed to 70° C. and stirred for 15 h. The mixture was allowed to cool and then poured cautiously into ice/water (300 mL) and stirred for 30 min. The aqueous phase was extracted with EtOAc and the combined organic phase was dried filtered and evaporated to afford crude product. The reaction was repeated on an identical scale and the two batches of crude product were combined and purified by chromatography eluting with 20-30% EtOAc in isohexane to give the subtitle compound as a colorless oil 14.70 g.
Reaction SMILES: [Cl-:1].[Al+3].[Cl-].[Cl-].[C:5]1(=[O:21])[N:9]([CH2:10][CH2:11][CH2:12][C:13](Cl)=[O:14])[C:8](=[O:16])[C:7]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:6]12.[CH:22]#[CH:23]>ClC(Cl)C(Cl)Cl>[Cl:1][CH:22]=[CH:23][C:13](=[O:14])[CH2:12][CH2:11][CH2:10][N:9]1[C:8](=[O:16])[C:7]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:6]2[C:5]1=[O:21]
Reactant: [Cl-]
Reactant: O=C(Cl)CCCN1C(=O)c2ccccc2C1=O
Reactant: C#C
Agent: [Al+3]
Solvent: ClC(Cl)C(Cl)Cl
Product: O=C(C=CCl)CCCN1C(=O)c2ccccc2C1=O

Procedure:
Aluminum chloride (43 g) is added to a stirred solution of 4-phthalimidobutyryl chloride (36.2 g) in 1,1,2,2-tetrachloroethane (400 ml), previously saturated with acetylene. Acetylene is bubbled through the solution overnight, with stirring, and the reaction mixture is then decomposed by the addition of crushed ice (300 g). The organic layer is separated and the aqueous layer extracted with 1,1,2,2-tetrachloroethane (3 × 100 ml). The combined organic solution is dried over sodium sulphate and concentrated. The residual solid is recrystallized from hexane affording 1-chloro-6-phthalimidohex-1-en-3-one, m.p. 92°C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1O.[C:10](=[O:13])([O-])[O-].[K+].[K+].I[CH3:17]>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:17])[C:3]=1[O:13][CH3:10]
Reactant: CI
Reactant: O=C([O-])[O-]
Reactant: Oc1cccc(F)c1O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cccc(F)c1OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 84.3 %

Procedure:
A mixture of 3-fluorobenzene-1,2-diol (145 g, 1132 mmol), potassium carbonate (313 g, 2264 mmol) and iodomethane (177 mL, 2830 mmol) in N,N-Dimethylformamide (DMF) (300 mL) was stirred at RT for 48 h. LCMS showed the complete consuption of starting material. The mixture was diluted with ethyl acetate (EA), filtered, washed with water, dried and evaporated in vacuo. The crude material was purified by normal phase automatic silica gel column chromatography (Combiflash RF, 220 g column), eluting with EA/Hexane (10%-80%) to afford 1-fluoro-2,3-dimethoxybenzene (149 g, 954 mmol, 84% yield) as a colorless oil. LCMS (M+H)+: 157.0.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[Br:13][CH2:14][CH2:15]O>CO.ClCCl>[Br:13][CH2:14][CH2:15][C:2]([C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4])=[O:1]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: OCCBr
Solvent: ClCCl
Solvent: CO
Product: O=C(CCBr)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 25 °C
Reaction time: 4 h

Procedure:
DOWEX 50Wx4 resin (Alfa Aesar, Ward Hill, Mass.) was washed with deionized water to remove color. A mixture of 225 gm D-glucose (1.25 mol; 1 equiv., Alfa Aesar) and 140 gm DOWEX 50Wx4 was treated with 2.2 L 2-bromoethanol (30.5 mol, 25 equiv.; 124.97 gm/mol; 1.762 gm/mL; BP=150 C; Alfa Aesar) and the stirred mixture heated to 80 C for 4 hours. The reaction was monitored by TLC (20% methanol/dichloromethane (DCM)). Reaction was complete after about four hours, and it was allowed to cool to room temperature. The solution was filtered to remove the resin, and the resin washed with ethyl acetate and DCM. The resulting filtrate was stripped to an amber oil in a rotory evaporator to give a total of 400 g after stripping.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:23])[CH2:3][CH2:2]1.[CH2:24](I)[CH3:25]>>[CH2:24]([N:1]1[CH2:2][CH2:3][CH:4]([N:7]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:23])[CH2:5][CH2:6]1)[CH3:25]
Reactant: CCI
Reactant: O=C1Nc2ccccc2C(c2ccccc2)N1C1CCNCC1
Product: CCN1CCC(N2C(=O)Nc3ccccc3C2c2ccccc2)CC1

Procedure:
In similar way as in Preparation Example 31, the title compound was synthesized from 3-(piperidin-4-yl)-4-phenyl-3,4-dihydro-2(1H)-quinazolinone and ethyl iodide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[N:11][C:12]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[CH:13][CH:14]=2)=[CH:4][C:3]=1[NH:26][C:27]([C:29]1[N:33]([CH3:34])[N:32]=[C:31]([CH3:35])[CH:30]=1)=[O:28].C(N(CC)C(C)C)(C)C.I[CH2:46][C:47]([NH2:49])=[O:48]>CN(C)C=O>[NH2:49][C:47](=[O:48])[CH2:46][N:11]1[C:12](=[N:15][S:16]([C:19]2[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:13]=[CH:14][C:9]([O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([NH:26][C:27]([C:29]3[N:33]([CH3:34])[N:32]=[C:31]([CH3:35])[CH:30]=3)=[O:28])[CH:4]=2)=[CH:10]1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3ccc(F)c(NC(=O)c4cc(C)nn4C)c3)cn2)cc1
Reactant: NC(=O)CI
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)N=c2ccc(Oc3ccc(F)c(NC(=O)c4cc(C)nn4C)c3)cn2CC(N)=O)cc1
Yield: 72.6 %

Procedure:
In the same manner as in Reference Example 5 and using N-{2-fluoro-5-[(6-{[(4-methylphenyl)sulfonyl]amino}pyridin-3-yl)oxy]phenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (7.25 g, 14.6 mmol), N,N-diisopropylethylamine (3.31 mL, 19.0 mmol), N,N-dimethylformamide (30 mL) and iodoacetamide (3.51 g, 19.0 mmol) as starting materials, the title compound (5.86 g, 73%) was obtained as a white solid.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18]([OH:20])=[O:19])=[CH:16][C:3]1=2.C([O-])([O-])=O.[K+].[K+].Br[CH2:28][C:29]([O:31][CH3:32])=[O:30].O>CN(C)C=O>[CH3:32][O:31][C:29](=[O:30])[CH2:28][O:19][C:18](=[O:20])[CH2:17][C:15]1[CH:14]=[CH:13][C:4]2[O:5][CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:2](=[O:1])[C:3]=2[CH:16]=1
Reactant: COC(=O)CBr
Reactant: O=C(O)Cc1ccc2c(c1)C(=O)c1ccccc1CO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COC(=O)Cc1ccc2c(c1)C(=O)c1ccccc1CO2
Temperature: 50 °C
Reaction time: 8 h
Yield: 86.7 %

Procedure:
A mixture of 15 g (0.052 m) of 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetic acid in 100 ml of dimethylformamide and 3.87 g (0.028 m) of K2CO3 was warmed to an internal temperature of 50° C. in an atmosphere of nitrogen for 1.5 hours. To this mixture, 9.41 g (0.062 m) of methyl bromoacetate was added dropwise and the mixture was held at 50° C. overnight. The reaction mixture was poured into water and extracted with ether. The ether extract was washed with 5% NaHCO3 and water, dried over Na2SO4, filtered and evaporated to give 16.5 g (94%) of an oil of methyl(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)acetoxyacetate.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][N:4]([CH3:7])[C:3]1=[N:8][OH:9].[N:10]1[C:17](F)=[N:16][C:14](F)=[N:13][C:11]=1F>N1C=CC=CC=1>[CH3:1][N:2]1[CH2:6][CH2:5][N:4]([CH3:7])[C:3]1=[N:8][O:9][C:11]1[N:13]=[C:14]([O:9][N:8]=[C:3]2[N:4]([CH3:7])[CH2:5][CH2:6][N:2]2[CH3:1])[N:16]=[C:17]([O:9][N:8]=[C:3]2[N:4]([CH3:7])[CH2:5][CH2:6][N:2]2[CH3:1])[N:10]=1
Reactant: CN1CCN(C)C1=NO
Reactant: Fc1nc(F)nc(F)n1
Solvent: c1ccncc1
Product: CN1CCN(C)C1=NOc1nc(ON=C2N(C)CCN2C)nc(ON=C2N(C)CCN2C)n1
Temperature: 42 °C
Reaction time: 15 h

Procedure:
To a cold (0° C.) solution of 1,3-dimethyl-2-imidazolidinone oxime (prepared according Kitamura, Mitsuru; Chiba, Shunsuke; Narasaka, Koichi, Bulletin of the Chemical Society of Japan (2003), 76(5), 1063-1070) (5.3 g, 0.041 mol) in dry pyridine (25 ml) within 15 minutes is dropwise added cyanuric fluoride (1.49 g, 0.011 mol). The mixture is then heated for 2 h at 42° C. and then stirred for 15 h at room temperature. The pyridine is evaporated under reduced pressure, the residue is chromatographed (silica gel, CH2Cl2—CH3OH 20:1 to 10:1) and the pure fractions are crystallized from ethyl acetate hexane to afford 2.4 g of the title compound as white crystalls, mp. 143-145° C. (decomposition).