Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[C:17]2[C:12](=[N:13][CH:14]=[N:15][C:16]=2[NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[C:21]([CH2:33][CH3:34])[CH:20]=2)[NH:11][N:10]=1)(=O)=O.[OH:35][CH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[CH2:33]([C:21]1[CH:20]=[C:19]([NH:18][C:16]2[N:15]=[CH:14][N:13]=[C:12]3[NH:11][N:10]=[C:9]([O:8][CH2:7][CH2:6][N:39]4[CH2:40][CH2:41][CH:36]([OH:35])[CH2:37][CH2:38]4)[C:17]=23)[CH:24]=[CH:23][C:22]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[CH3:34]
Reactant: CCc1cc(Nc2ncnc3[nH]nc(OCCOS(C)(=O)=O)c23)ccc1OCc1ccccn1
Reactant: OC1CCNCC1
Product: CCc1cc(Nc2ncnc3[nH]nc(OCCN4CCC(O)CC4)c23)ccc1OCc1ccccn1
Yield: 46 %

Procedure:
The procedure described in Example 55 was repeated using 2-[(4-{[3-ethyl-4-(pyridin-2-ylmethoxy)phenyl]amino}-1H-pyrazolo[3,4-d]pyrimidin-3-yl)oxy]ethyl methanesulfonate (prepared as described in Example 19) and 4-hydroxypiperidine to give the title compound in 46% yield; NMR Spectrum: 1.20 (t, 3H), 1.32-1.39 (m, 2H), 1.66-1.69 (m, 2H), 2.16 (t, 2H), 2.67 (q, 2H), 2.75-2.81 (m, 4H), 4.39 (t, 2H), 4.52 (d, 1H), 5.20 (s, 2H), 7.01 (d, 1H), 7.34-7.40 (m, 1H), 7.44 (d, 1H), 7.50-7.55 (m, 2H), 7.85 (td, 1H), 8.24 (s, 1H), 8.25 (s, 1H), 8.59 (d, 1H); Mass Spectrum: 490 (MH+).
Reaction SMILES: O([CH2:8][CH2:9][N:10]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([C:19]([OH:21])=[O:20])[C:13]=2[CH:12]=[CH:11]1)C1C=CC=CC=1.[CH3:22][O:23][C:24]([O:31][CH3:32])([O:29][CH3:30])[CH2:25]CCBr>>[CH3:22][O:23][C:24]([O:31][CH3:32])([O:29][CH3:30])[CH2:25][CH2:8][CH2:9][N:10]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([C:19]([OH:21])=[O:20])[C:13]=2[CH:12]=[CH:11]1
Reactant: O=C(O)c1cccc2c1ccn2CCOc1ccccc1
Reactant: COC(CCCBr)(OC)OC
Product: COC(CCCn1ccc2c(C(=O)O)cccc21)(OC)OC

Procedure:
This compound is prepared analogously to Intermediate AO 1-(2-Phenoxy-ethyl)-1H-indole-4-carboxylic acid replacing (2-bromoethoxy)benzene with trimethyl 4-bromoorthobutyrate.
Reaction SMILES: [C:1]([N:9]1[CH2:15][CH2:14][CH2:13][CH:12]([Cl:16])[CH2:11][C:10]1=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:18](C1C=CC(C(Cl)=O)=CC=1)([O-:20])=[O:19]>>[N+:18]([C:5]1[CH:4]=[CH:3][C:2]([C:1]([N:9]2[CH2:15][CH2:14][CH2:13][CH:12]([Cl:16])[CH2:11][C:10]2=[O:17])=[O:8])=[CH:7][CH:6]=1)([O-:20])=[O:19]
Reactant: O=C1CC(Cl)CCCN1C(=O)c1ccccc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Product: O=C1CC(Cl)CCCN1C(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
Synthesized as in the alternative preparation for N-benzoyl-3-chlorocaprolactam (Example VI) using 4-nitrobenzoyl chloride in place of benzoyl chloride.
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][S:26]([C:29]2C=CC(C3C=C(C=CC=3)C(OC)=O)=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[C:15]1[CH2:45][CH2:46][NH:47][S:48]([CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1[Cl:58])(=[O:50])=[O:49])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:59]1[CH2:63][O:62][CH2:61][CH2:60]1.[OH-:64].[Na+]>CO>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][S:26]([C:29]2[CH:30]=[CH:31][C:60]([C:61]([OH:64])=[O:62])=[CH:59][CH:63]=2)(=[O:28])=[O:27])=[C:15]1[CH2:45][CH2:46][NH:47][S:48]([CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1[Cl:58])(=[O:50])=[O:49])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: COC(=O)c1cccc(-c2ccc(S(=O)(=O)CCc3c(CCNS(=O)(=O)Cc4ccccc4Cl)n(C(c4ccccc4)c4ccccc4)c4ccc(Cl)cc34)cc2)c1
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)c1ccc(S(=O)(=O)CCc2c(CCNS(=O)(=O)Cc3ccccc3Cl)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 80 %

Procedure:
Methyl 3-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate (1 eq), THF (0.1M), MeOH (1 mL/1 mL THF), and NaOH (1N) (11 eq) were stirred together overnight. Solvents were removed and the resulting residue was taken up in water. The solution was acidified with 1N HCl and collected resulting precipitate by filtration. Obtained 4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoic acid (red-orange solid) in 80% yield. HRMS calc for [C39H34Cl2N2O6S2+H] 761.13081 found 761.13146.
Reaction SMILES: ClC1C=C2C(=O)OC(=[O:7])C2=CC=1.C([O-])(=O)C1C=CC=CC=1.[K+].[C:23](=[O:26])([O-:25])[O-].[K+].[K+].[CH:29]1[C:34]([O:35][C:36]2[CH:41]=[CH:40][C:39]3C([O:44][C:45](=[O:46])[C:38]=3[CH:37]=2)=O)=[CH:33][C:32]2[C:47]([O:49][C:50](=[O:51])[C:31]=2[CH:30]=1)=[O:48]>CN1CCCC1=O>[O:35]([C:36]1[CH:37]=[C:38]([C:45]([OH:44])=[O:46])[C:39](=[CH:40][CH:41]=1)[C:23]([OH:25])=[O:26])[C:34]1[CH:33]=[C:32]([C:47]([OH:49])=[O:48])[C:31](=[CH:30][CH:29]=1)[C:50]([OH:51])=[O:7]
Reactant: O=C([O-])[O-]
Reactant: O=C1OC(=O)c2cc(Oc3ccc4c(c3)C(=O)OC4=O)ccc21
Reactant: O=C1OC(=O)c2cc(Cl)ccc21
Agent: O=C([O-])c1ccccc1
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=C(O)c1ccc(Oc2ccc(C(=O)O)c(C(=O)O)c2)cc1C(=O)O
Reaction time: 2 h

Procedure:
4-Chlorophthalic anhydride (10 g, 55 mmol), potassium benzoate (1.0 g, 6.2 mmol), and N-methylpyrrolidinone (25 g) were heated to about 175.C. Potassium carbonate (3.87 g, 28 mmol) was added and the suspension was heated to about 175.C. After 2 hours, GC analysis indicated a greater than 97% conversion to 4,4'-oxydiphthalic anhydride. The solvent was removed under reduced pressure and the residue treated with an aqueous 25% sodium hydroxide solution. The solution was acidified with concentrated HCl. The solid was collected and dried to give 4,4'-oxydiphthalic acid (4.85 g) mixed with some sodium chloride. The tetra acid was cyclized and recrystallized from hot acetic anhydride (2.4 mL) and filtered to remove salts to give 4,4'-oxydiphthalic anhydride, 4.2 g.
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].Br[C:18]1[CH:19]=[N:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[C:23]([CH3:28])[CH:22]=2.[CH3:29]S(C)=O>[Cu]I>[CH2:13]([O:12][C:10](=[O:11])[C:9]1[CH:15]=[CH:16][C:6]([CH:2]([NH:1][C:18]2[CH:19]=[N:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[C:23]([CH3:28])[CH:22]=3)[CH2:3][CH:4]([CH3:29])[CH3:5])=[CH:7][CH:8]=1)[CH3:14]
Reactant: Cc1ccc2cc(Br)cnc2c1
Reactant: CCCC(N)c1ccc(C(=O)OCC)cc1
Reactant: CS(C)=O
Agent: [Cu]I
Product: CCOC(=O)c1ccc(C(CC(C)C)Nc2cnc3cc(C)ccc3c2)cc1
Yield: 15 %

Procedure:
To a reaction vial with 4-(1-Amino-3-methyl-butyryl)-benzoic acid ethyl ester (2) (440 mg, 1.9 mM) was added DMSO (6.33 mL), 3-bromo-7-methylquinoline (9) (420 mg, 1.9 mM), followed by CuI catalyst (36 mg, 0.19 mM) and CsOAc (726 mg, 3.78 mM). The mixture was purged with argon gas and then the tube was sealed. The reaction mixture was heated to 100° for 48 h. The reaction mixture was cooled, diluted with EtOAc (10 mL), washed with water (3×5 mL), dried (Na2SO4) and concentrated. The crude material was separated by a 40 g silica gel with 0-80% EtOAc in heptane to give a yellow color product (108 mg, 15%). 1H NMR (500 MHz, CDCl3) δ ppm 0.98 (d, J=6.34 Hz, 3 H) 1.04 (d, J=6.34 Hz, 3 H) 1.39 (t, 3 H) 1.61-1.71 (m, 1 H) 1.71-1.86 (m, 2 H) 2.46 (s, 3 H) 4.36 (q, 2 H) 4.38-4.43 (m, 1 H) 4.47-4.56 (m, 1 H) 6.75 (d, J=1.95 Hz, 1 H) 7.20 (d, J=8.29 Hz, 1 H) 7.36 (d, J=8.05 Hz, 1 H) 7.47 (d, J=8.29 Hz, 2 H) 7.69 (s, 1 H) 8.03 (d, 2 H) 8.47 (br. s., 1 H). LC-MS: m/z 377.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16](O)=[O:17])=[N:14][CH:15]=1.[NH2:33][CH2:34][CH2:35][OH:36].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:25][N:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([NH:33][CH2:34][CH2:35][OH:36])=[O:17])=[N:14][CH:15]=1
Reactant: NCCO
Reactant: Cc1cc(C(=O)O)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(C(F)(F)F)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cc1cc(C(=O)NCCO)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 72 %

Procedure:
To a solution of 5-[(2,5-difluorophenyl)[[5-(trifluoromethyl)pyridin-2-yl]sulfonyl]methyl]-4-methylpyridine-2-carboxylic acid (118 mg, 0.25 mmol) in methylene chloride (3 ml), 2-aminoethanol (0.017 ml, 0.28 mmol), 1-hydroxybenzotriazole (37 mg, 0.28 mmol), 4-methylmorpholine (0.030 ml, 0.28 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (53 mg, 0.28 mmol) were added at room temperature. After stirring for 5 hours at room temperature, the reaction mixture was washed with water and then with saturated brine. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the obtained residue was subjected to flash silica gel chromatography. The fraction obtained from an elution with hexane:ethyl acetate=1:1 was concentrated under reduced pressure, and the resulting residue was washed with hexane, and was dried under reduced pressure to obtain the title compound (91 mg, 0.18 mmol, 71%) as a colorless foamy substance.
Reaction SMILES: F[C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5].O.[NH3:13]>C(#N)C>[NH2:13][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(F)ccc(F)c1F
Reactant: N
Solvent: O
Solvent: CC#N
Product: N#Cc1c(F)ccc(F)c1N

Procedure:
2,3,6-Trifluorobenzonitrile (1.76 ml, 15.2 mmol) in aqueous ammonia (20 ml) and acetonitrile (10 ml) was stirred for 7 days. Water was added. The whole was extracted with ether, the ether was dried (sodium sulphate) and evaporated. Flash column chromatography on silica gel, eluting with dichloromethane, gave the product (1.2 g), MS (+EI) 154 (M+), 1H NMR (CDCl3) 7.07-7.16 (1H, m), 6.36-6.43 (1H, m), 4.62 (2H, s).
Reaction SMILES: COC([C:5]1[C:10]([O:11][CH3:12])=[CH:9][N:8]=[CH:7][N:6]=1)=O.ClC1C([C:20](OCC)=[O:21])=NC=NC=1.[CH3:25][O-:26].[Na+]>CO>[CH3:12][O:11][C:10]1[C:5]([O:26][CH3:25])=[N:6][C:7](=[C:20]=[O:21])[NH:8][CH:9]=1
Reactant: C[O-]
Reactant: COC(=O)c1ncncc1OC
Reactant: CCOC(=O)c1ncncc1Cl
Agent: [Na+]
Solvent: CO
Product: COC1=CNC(=C=O)N=C1OC

Procedure:
4-Methoxycarbonyl-5-methoxypyrimidine can be prepared by heating 5-chloro-4-ethoxycarbonylpyrimidine (23 g) with sodium methoxide (15 g) in methanol (230 cc) for 8 hours. The solvent is evaporated off and the residue is suspended in diethyl ether (1000 cc). The suspension is washed with water (50 cc). The organic phase is dried over sodium sulphate, filtered and concentrated to dryness to give 5-methoxy-4-methoxy-carbonylpyrimidine (6 g) melting at 75° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][OH:7].[N:8]#[C:9][Br:10]>>[BrH:10].[OH:7][CH2:6][CH2:5][N:4]1[CH2:3][CH2:2][N:1]=[C:9]1[NH2:8]
Reactant: N#CBr
Reactant: NCCNCCO
Product: Br
Product: NC1=NCCN1CCO
Yield: 82.3 %

Procedure:
Reaction of 2-(2-aminoethylamino)ethanol (8.0 g, 76.8 mmol) with cyanogen bromide (8.13 g, 76.8 mmol) as described in the preparation of intermediate 6 gave 13.27 g (82% yield) of the title product as large white prisms (ethanol); mp 112-115° C. 1HNMR 400.1HNMR 400 MHz (DMSO-d6) δ (ppm): 3.36 (2H, t, J=5.3 Hz, CH2), 3.50-3.58 (4H, m, 2×CH2), 3.69 (2H, m, CH2), 4.97 (1H, t, J=5.0 Hz, OH), 7.73 and 7.85 (broad s, NH). Anal. Calcd for C5H11N30.HBr: C, 28.58; H, 5.75, N 20.00. Found: C, 28.79; H, 5.58; N, 20.12.
Reaction SMILES: [C:1]([CH:4]([O:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:17])[C:9](=O)[CH:8]=1)[CH3:5])([OH:3])=[O:2].[NH:19]([C:21]1[C:26]([O:27][CH3:28])=[CH:25][C:24]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:23][N:22]=1)[NH2:20]>Cl.C(O)(=O)C>[CH3:28][O:27][C:26]1[C:21]([N:19]=[N:20][C:9]2[CH:8]=[C:7]([O:6][CH:4]([C:1]([OH:3])=[O:2])[CH3:5])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[OH:17])=[N:22][CH:23]=[C:24]([S:29](=[O:32])(=[O:31])[NH2:30])[CH:25]=1
Reactant: COc1cc(S(N)(=O)=O)cnc1NN
Reactant: CC(OC1=CC(=O)C(=O)c2ccccc21)C(=O)O
Agent: Cl
Solvent: CC(=O)O
Product: COc1cc(S(N)(=O)=O)cnc1N=Nc1cc(OC(C)C(=O)O)c2ccccc2c1O
Reaction time: 8 h

Procedure:
4-(1-Carboxyethoxy)-1,2-naphthoquinone (0.22 g, 9×10-4) and 2-hydrazino-3-methoxy-5-sulfamoylpyridine (0.2 g, 9×10-4 mole) were added to acetic acid (15 ml), along with 2 to 3 drops of concentrated hydrochloric acid. After stirring overnight, the resulting precipitate was collected by filtration, air dried, slurried twice with boiling acetic acid (5 ml) and isolated again by filtration; yield, 80 mg (20 percent).
Reaction SMILES: [CH3:1][C:2]1[N:3]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:4]=[CH:5][C:6]=1[CH:7]=[O:8].[Br:18]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:18][C:4]1[N:3]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:10])=[O:11])[C:2]([CH3:1])=[C:6]([CH:7]=[O:8])[CH:5]=1
Reactant: Cc1c(C=O)ccn1S(=O)(=O)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C=O)cc(Br)n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
To a solution of 2-methyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde (2.00 g) in N,N-dimethylformamide (20 mL) was added N-bromosuccinimide (1.56 g) at 0° C., and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=3:1) to give the title compound as a white solid (yield 2.28 g, 86%).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([O:12][CH2:13][CH:14]=[CH2:15])[CH:6]=1)=[S:3].[S:16]1[CH2:20][CH2:19][NH:18][CH2:17]1.C(N(CC)CC)C>C(OCC)C>[S:16]1[CH2:20][CH2:19][N:18]([C:2](=[S:3])[O:4][C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([O:12][CH2:13][CH:14]=[CH2:15])[CH:6]=2)[CH2:17]1
Reactant: C=CCOc1cc(OC(=S)Cl)ccc1Cl
Reactant: C1CSCN1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=CCOc1cc(OC(=S)N2CCSC2)ccc1Cl
Reaction time: 4 h
Yield: 66.5 %

Procedure:
O-(3-Allyloxy-4-chlorophenyl) chlorothioformate (2.63 g) was dissolved in 60 ml of diethyl ether. To this solution were added with stirring 1.01 g of thiazolidine and 1.42 ml of triethylamine. The resulting mixture was stirred for 4 hours and then washed with water. The solvent was distilled off from the ether layer. The residue was recrystallized from methanol to give 2.1 g of O-(3-allyloxy-4-chlorophenyl) 3-thiazolidinecarbothioate [Compound (33)]. The product had a melting point of 103.6°-105.6° C.
Reaction SMILES: [C:1]([C:5]([C:8]([C:11]([C:14]([C:17]([C:20](C(F)=O)([F:22])[F:21])([F:19])[F:18])([F:16])[F:15])([F:13])[F:12])([F:10])[F:9])([F:7])[F:6])([F:4])([F:3])[F:2].FF.[C:28]([O:32][C:33]([C:36]([Cl:39])([F:38])[F:37])([Cl:35])[F:34])([F:31])([F:30])F>>[C:1]([C:5]([C:8]([C:11]([C:14]([C:17]([C:20]([C:28]([O:32][C:33]([C:36]([Cl:39])([F:37])[F:38])([Cl:35])[F:34])([F:30])[F:31])([F:22])[F:21])([F:18])[F:19])([F:16])[F:15])([F:13])[F:12])([F:10])[F:9])([F:7])[F:6])([F:4])([F:3])[F:2]
Reactant: O=C(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: FC(F)(F)OC(F)(Cl)C(F)(F)Cl
Agent: FF
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)OC(F)(Cl)C(F)(F)Cl
Reaction time: 1.83 h

Procedure:
19.65 g of CF3—OCFCl—CF2Cl as solvent, 23.07 g of CFCl═C—FCl (CFC 1112) and 7.57 g of CF3—(CF2)6—COF are introduced into the equipment described in the Example 1. The reaction mixture is maintained at the temperature of −55° C. and 1.5 Nl/h of fluorine diluted with nitrogen (molar ratio fluorine/nitrogen 1/5) are fed therein for 110 minutes.
Reaction SMILES: [CH:1]([Si:4]([CH:13]([CH3:15])[CH3:14])([CH:10]([CH3:12])[CH3:11])[C:5]1[O:6][CH:7]=[CH:8][N:9]=1)([CH3:3])[CH3:2].CCCCCC.C([Li])CCC.C(O[B:31]([O:36][CH:37]([CH3:39])[CH3:38])[O:32][CH:33]([CH3:35])[CH3:34])(C)C.CC(O)(C(C)(O)C)C>C1COCC1.C(O)(=O)C>[CH3:39][C:37]1([CH3:38])[C:33]([CH3:34])([CH3:35])[O:32][B:31]([C:7]2[O:6][C:5]([Si:4]([CH:1]([CH3:3])[CH3:2])([CH:10]([CH3:12])[CH3:11])[CH:13]([CH3:15])[CH3:14])=[N:9][CH:8]=2)[O:36]1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)[Si](c1ncco1)(C(C)C)C(C)C
Agent: CC(C)(O)C(C)(C)O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)[Si](c1ncc(B2OC(C)(C)C(C)(C)O2)o1)(C(C)C)C(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(triisopropylsilyl)oxazole (6.7 g) in THF (200 mL) was added dropwise n-butyllithium hexane solution (1.6M, 22.3 mL) at −78° C. The reaction mixture was stirred at −78° C. for 1 hr under nitrogen atmosphere, triisopropylborate (8.2 mL) was added thereto, and mixture was stirred at −78° C. for 2 hr. The mixture was allowed to be warmed to room temperature, and stirred overnight. To the reaction mixture was added a solution of 2,3-dimethylbutane-2,3-diol (3.51 g) in THF (20 mL) and acetic acid (2.3 mL), and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure, water was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (8.8 g).
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]3)[N:12]=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)=[O:30])=[CH:24][CH:23]=3)[N:10]=1)[CH2:2]2.[C:38]([OH:44])([C:40](F)(F)F)=O.[NH2:45][CH2:46][CH2:47]N1CCCC1>>[N:45]1([CH:18]2[CH2:17][CH2:16][N:15]([C:13]3[N:14]=[C:9]([N:3]4[CH2:2][CH:1]5[O:8][CH:5]([CH2:6][CH2:7]5)[CH2:4]4)[N:10]=[C:11]([C:22]4[CH:23]=[CH:24][C:25]([NH:28][C:29]([NH:31][C:32]5[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=5)=[O:30])=[CH:26][CH:27]=4)[N:12]=3)[CH2:20][CH2:19]2)[CH2:40][CH2:38][O:44][CH2:47][CH2:46]1
Reactant: O=C(O)C(F)(F)F
Reactant: O=C1CCN(c2nc(-c3ccc(NC(=O)Nc4ccncc4)cc3)nc(N3CC4CCC(C3)O4)n2)CC1
Reactant: NCCN1CCCC1
Product: O=C(Nc1ccncc1)Nc1ccc(-c2nc(N3CCC(N4CCOCC4)CC3)nc(N3CC4CCC(C3)O4)n2)cc1

Procedure:
By reacting 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea.TFA (50 mg) with 1-(2-aminoethyl)pyrrolidine (0.030 mL) and following the procedure as mentioned in Experimental 118, the title product was isolated as its tri-TFA salt; MS (ES+) 599.8 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH2:18][CH3:19])([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[CH:20]=1.Br[C:22]1[S:26][C:25]([C:27]#[N:28])=[CH:24][C:23]=1[CH3:29]>>[CH2:18]([C:7]1([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[C:6]2[CH:20]=[C:2]([C:22]3[S:26][C:25]([C:27]#[N:28])=[CH:24][C:23]=3[CH3:29])[CH:3]=[CH:4][C:5]=2[NH:11][C:10](=[O:12])[CH2:9][O:8]1)[CH3:19]
Reactant: Cc1cc(C#N)sc1Br
Reactant: CCC1(c2cccs2)OCC(=O)Nc2ccc(Br)cc21
Product: CCC1(c2cccs2)OCC(=O)Nc2ccc(-c3sc(C#N)cc3C)cc21

Procedure:
Prepared from 7-bromo-5-ethyl-5-thien-2-yl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 5-bromo-4-methyl-thiophene-2-carbonitrile generally according to the procedures described in examples 82 and 1. An off-white solid: mp 182-184° C.; 1H NMR (DMSO-d6): δ 10.19 (s, 1H), 7.83 (s, 1H), 7.57 (dd, J=4.88, 0.98 Hz, 1H), 7.46 (dd, J=8.3, 1.95 Hz, 1H), 7.33 (d, J=1.95 Hz, 1H), 7.29 (d, J=8.3 Hz, 1H), 7.07 (dd, J=4.88, 3.42 Hz, 1H), 6.98 (dd, J=3.42, 0.98 Hz, 1H), 4.14 (d, J=15.6 Hz, 1H), 3.98 (d, J=15.13 Hz, 1H), 2.47 (m, 1H), 2.35 (m, 1H), 2.21 (s, 3H), 0.77 (t, J=6.84 Hz, 3H); MS (ESI) m/z 395 ([M+H]+); MS (ESI) m/z 393 ([M−H]−); Anal. calcd for C21H18N2O2S2: C, 63.93; H, 4.60; N, 7.10. Found: C, 60.33; H, 4.13; N, 6.65.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH:13]=O)[CH2:11][O:10][C:9]1([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17]C(C)([O-])C.[K+].C(OP(C=[N+]=[N-])(=O)OCC)C>CCOCC>[C:6]([N:8]1[C@@H:12]([C:13]#[CH:17])[CH2:11][O:10][C:9]1([CH3:16])[CH3:15])([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CC(C)(C)OC(=O)N1[C@@H](C=O)COC1(C)C
Reactant: CC(C)(C)[O-]
Agent: CCOP(=O)(C=[N+]=[N-])OCC
Agent: [K+]
Solvent: CCOCC
Product: C#C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
(S)-N-Boc-2,2-dimethyl-4-ethynyl-oxazolidine was prepared according to Method X above by the treatment of tert-butyl-(R)-4-formyl-2,2-dimethyl-3-oxazolidine-carboxylate (1.00 g, 4.36 mmol) (Aldrich) with potassium tert-butoxide (730 mg, 6.54 mmol) and diazomethyl-phosphonic-acid-diethylester (1.20 g, 6.54 mmol) (Method X above). The reaction was allowed slowly to warm up to room temperature and stirred for a total of 12 hrs. (S)-N-Boc-2,2-dimethyl-4-ethynyl-oxazolidine was obtained after silica gel column chromatography with 20% Et2O in hexanes. (Yield 420 mg, 43%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[C:8](/[CH2:30][CH3:31])=[C:9](\[C:19]1[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28])=[CH:21][CH:20]=1)/[C:10]1[CH:11]=[C:12]2C(=[CH:17][CH:18]=1)N[N:14]=[CH:13]2.[C:32]([O-])([O-])=O.[Cs+].[Cs+].IC.C[N:41]([CH:43]=O)[CH3:42]>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[C:8](/[CH2:30][CH3:31])=[C:9](\[C:19]1[CH:20]=[CH:21][C:22](/[CH:25]=[CH:26]/[C:27]([O:29][CH3:32])=[O:28])=[CH:23][CH:24]=1)/[C:10]1[CH:11]=[C:12]2[C:43](=[CH:17][CH:18]=1)[N:41]([CH3:42])[N:14]=[CH:13]2
Reactant: O=C([O-])[O-]
Reactant: CN(C)C=O
Reactant: CC/C(=C(/c1ccc(/C=C/C(=O)O)cc1)c1ccc2[nH]ncc2c1)c1ccccc1Cl
Agent: [Cs+]
Solvent: CI
Solvent: O
Product: CC/C(=C(/c1ccc(/C=C/C(=O)OC)cc1)c1ccc2c(cnn2C)c1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (E)-3-(4-((E)-2-(2-chlorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid (80 mg, 0.19 mmol; Compound 14) and Cs2CO3 (0.15 g, 0.46 mmol) in DMF (3.8 mL) at room temperature, iodomethane (65 mg, 0.46 mmol) was added. The mixture was stirred at room temperature overnight, diluted with water, extracted with EtOAc, and concentrated to give the (E)-methyl 3-(4-((E)-2-(2-chlorophenyl)-1-(1-methyl-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylate. This residue was redissolved in THF-MeOH (3.8 mL) and an aqueous solution of LiOH (89 mg, 3.7 mmol; dissolved in a minimum amount of water) was added at room temperature. The reaction mixture was stirred overnight, quenched with 1N HCl, extracted with EtOAc, dried over sodium sulfate, filtered and concentrated to give the crude material. This crude product was purified on a RP-C18 column using 50-100% acetonitrile in water in the presence of 0.1% TFA to afford the title compound. 1H NMR (300 MHz, DMSO-d6): δ 12.28 (s, 1H), 8.07 (s, 1H), 7.67-7.64 (m, 2H), 7.48-7.11 (m, 8H), 6.95 (d, 2H), 6.35 (d, 1H), 4.05 (s, 3H), 2.36 (q, 2H), 0.90 (t, 3H). LCMS: 443 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]2[S:6][C:7]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([OH:17])=[O:16])[C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl.[CH2:21](O)[CH3:22]>C(OCC)(=O)C.C1C=CC=CC=1>[OH:1][C:2]1[CH:19]=[CH:18][C:5]2[S:6][C:7]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([O:17][CH2:21][CH3:22])=[O:16])[C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: O=C(O)c1cccc2c1CCc1cc(O)ccc1S2
Reactant: CCO
Agent: Cl
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cccc2c1CCc1cc(O)ccc1S2
Yield: 85 %

Procedure:
An amount of 1.7 g of 2-hydroxy-9-carboxy-10,11-dihydrodibenzo[b,f]thiepin was dissolved in 50ml of anhydrous ethanol and the mixture was refluxed for 3 hours, while hydrogen chloride gas was bubbled into the mixture. The solvent was distilled off to obtain the residue which was dissolved in the mixed solvent of ethyl acetate-benzene. The solution was washed with saturated sodium chloride solution and freed of solvent by distillation to obtain 1.6 g (85%) of 2-hydroxy-9-ethoxycarbonyl-10,11-dihydrodibenzo[b,f]thiepin as brown crystals having a melting point of 125°-129° C.