Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([OH:11])(=[O:10])([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)=[O:2].CN(CC1C=CC=CC=1)C.[C:22](Cl)(=[O:31])[CH:23]=[CH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CC(C)=O>[S:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:22](=[O:31])[CH:23]=[CH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:7][CH:8]=1)([OH:11])(=[O:10])=[O:2]
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: Nc1ccc(S(=O)(=O)O)cc1
Agent: CN(C)Cc1ccccc1
Solvent: CC(C)=O
Product: O=C(C=Cc1ccccc1)Nc1ccc(S(=O)(=O)O)cc1
Temperature: 30 °C
Reaction time: 0.25 h
Yield: 73.3 %

Procedure:
To a suspension of 86.5 g of anhydrous sulphanilic acid in 120 g of acetone are added dropwise, while stirring at 30° C., 168.8 g of N,N-dimethyl-benzylamine in the course of 15 minutes, followed by a solution of 83.5 g of cinnamoyl chloride in 80 g of acetone in the course of 50 minutes. After the addition is complete, the reaction temperature is increased to the reflux temperature for 1 hour, and the acetone is then removed as completely as possible. The residue which remains is stirred for 1 hour at 80° C., 90 g of 50% strength sodium hydroxide solution in 500 ml of water are then added, and the mixture is again heated to 80° C. and left to stand at this temperature for 15 minutes. The phases are separated and the aqueous phase is washed with 50 g of toluene. The aqueous phase, which is still hot, is diluted with 800 ml of water and neutralized with concentrated sulphuric acid. The cooled aqueous solution is then added dropwise in the course of 20 minutes to 1 kg of 50% strength sulphuric acid, while stirring vigorously. The precipitated crystals are separated off and dissolved in 4 liters of water, the solution is filtered, and again brought to crystallization by the addition of 100 g of concentrated sulphuric acid. 111 g of pure N-(p-sulfophenyl)-cinnamamide (corresponding to 75.9% of theory) with a melting point of 235°-237° C. are obtained. UV spectrum (in methanol):
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[CH2:8]([CH:11]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=[O:18])[CH2:13][CH2:12]1)[C:9]#[CH:10]>CO.ClCCl>[CH2:8]([CH:11]1[CH2:16][CH2:15][CH:14]([C:17]([O:19][CH3:1])=[O:18])[CH2:13][CH2:12]1)[C:9]#[CH:10]
Reactant: C#CCC1CCC(C(=O)O)CC1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Product: C#CCC1CCC(C(=O)OC)CC1

Procedure:
(Trimethylsilyl)diazomethane (2.0 M) solution in hexanes (1 mL, 2 mmol) was added to a solution of 5.4 (0.34 g, 2 mmol) in 15 mL of methanol:dichloromethane (3:7). The solvents were removed under reduced pressure resulting in 100% conversion of starting material to produce. 1H NMR (300 MHz, CDCl3) δ 2.24 (dt, J=3.66, 12.1 Hz, 1 H), 2.10 (dd, J=2.7, 6.5 Hz, 2 H), 2.06 (dd, J=1.54, 6.54 Hz, 1 H), 2.00-1.89 (m, 3 H), 1.76 (d, J=2.3 Hz, 1 H), 1.43 (dq, J=3.28, 13.1 Hz, 2 H), 1.03 (dq, J=3.28, 13.1 Hz, 2 H). 13C NMR (300 MHz, CDCl3) δ 176.8, 83.3, 69.8, 51.9, 43.4, 36.7, 31.9, 29.2, 26.3.
Reaction SMILES: [CH3:1][C@H:2]([OH:5])[C:3]#[CH:4].[F:6][C:7]1[C:8](I)=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])/[C:10]/2=[CH:17]\[C:18]1[NH:22][CH:21]=[N:20][C:19]=1[CH3:23]>CN(C=O)C.CCN(CC)CC.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:6][C:7]1[C:8]([C:4]#[C:3][C@@H:2]([OH:5])[CH3:1])=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])/[C:10]/2=[CH:17]\[C:18]1[NH:22][CH:21]=[N:20][C:19]=1[CH3:23]
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#C[C@H](C)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#C[C@H](C)O)c21

Procedure:
Using Method C above, (S)-but-3-yn-2-ol (38 mg, 0.54 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (50 mg, 0.14 mmol) (Starting Material 3 supra) using (Ph3P)4Pd (16 mg, 0.01 mmol) and Cul (2 mg) in a mixture of DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 5 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4 and concentrated. (S)-(Z)-1,3-Dihydro-5-fluoro-4-(3-hydroxy-1-butynyl)-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one was obtained after silica gel column with a 0-10% MeOH in CH2Cl2 gradient and trituration with Et2O. (Yield 21 mg, 50%).
Reaction SMILES: [F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14]4[N:15]=[C:16]([C:19]5[C:20]([N:39]([CH3:44])[S:40]([CH3:43])(=[O:42])=[O:41])=[CH:21][C:22]6[O:26][C:25]([C:27]7[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=7)=[C:24]([C:34]([NH:36][NH2:37])=[O:35])[C:23]=6[CH:38]=5)[CH:17]=[CH:18][C:13]=4[O:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1.[CH3:45]CN(CC)CC.C(=N)OCC>CC#N>[F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14]4[N:15]=[C:16]([C:19]5[C:20]([N:39]([CH3:44])[S:40]([CH3:43])(=[O:42])=[O:41])=[CH:21][C:22]6[O:26][C:25]([C:27]7[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=7)=[C:24]([C:34]7[O:35][CH:45]=[N:37][N:36]=7)[C:23]=6[CH:38]=5)[CH:17]=[CH:18][C:13]=4[O:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CCN(CC)CC
Reactant: CN(c1cc2oc(-c3ccc(F)cc3)c(C(=O)NN)c2cc1-c1ccc2c(n1)-c1cc3c(F)cccc3n1CO2)S(C)(=O)=O
Agent: CCOC=N
Solvent: CC#N
Product: CN(c1cc2oc(-c3ccc(F)cc3)c(-c3nnco3)c2cc1-c1ccc2c(n1)-c1cc3c(F)cccc3n1CO2)S(C)(=O)=O
Temperature: 110 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
To a solution of N-(5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-3-(hydrazinecarbonyl)benzofuran-6-yl)-N-methylmethanesulfonamide (20 mg, 0.03 mmol) and Et3N (1 mL) in MeCN (5 mL) was added ethyl formimidate (6 mg, 0.05 mmol). Then the mixture was stirred at 110° C. for 2 hours. After the solvent was removed by vacuum, the resulting residue was purified using prep-HPLC to provide Compound 159 (10 mg, yield: 40%). 1H-NMR (CDCl3, 400 MHz) δ 9.01 (s, 1H), 8.35 (s, 1H), 8.10 (t, J=2.8 Hz, 2H), 7.89 (s, 1H), 7.48 (t, J=2.8 Hz, 2H), 7.15˜7.23 (m, 4H), 7.07 (s, 1H), 6.78 (t, J=2.8 Hz, 1H), 5.98 (s, 2H), 3.29 (s, 3H), 2.89 (s, 3H). MS (M+H)+: 626.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[Cl:13][C:14]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][NH2:17].CCN(C(C)C)C(C)C.[CH3:32][NH:33][CH2:34][CH2:35][OH:36]>C1COCC1>[Cl:13][C:14]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][NH:17][C:5](=[O:11])[N:33]([CH2:34][CH2:35][OH:36])[CH3:32]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CNCCO
Reactant: NCc1cccc(Cl)c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(CCO)C(=O)NCc1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.2 %

Procedure:
To a solution of triphosgene (89 mg, 0.3 mmol) in THF were added a solution of 2,3-dichlorobenzylamine (100 mg, 0.59 mmol) in THF dropwise and then DIEA (209 μL, 1.2 mmol). The reaction mixture was stirred at rt for 10 min, and 2-(methylamino)ethanol (90 mg, 1.2 mmol) was added. The reaction mixture was stirred at rt for 15 min and purified on RP-HPLC using a mixture of acetonitrile and H2O to give 3-(2,3-dichlorobenzyl)-1-(2-hydroxyethyl)-1-methylurea (70 mg, 44%). LRMS (M+H+) m/z 277.1.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([OH:5])[CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[C:12](Cl)(=[O:21])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1.O>[OH:5][CH:3]1[CH2:4][N:1]([C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:21])[CH2:2]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OC1CNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CC(O)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.8 %

Procedure:
A solution of azetidin-3-ol (14.7 g) dissolved in THF (170 mL) and water (85 mL) was treated with potassium carbonate (37.1 g) under nitrogen. The mixture was stirred at RT for 30 minutes before cooling to 0° C. and adding benzyl carbonochloridate (20.0 mL) dropwise over 30 minutes at 0° C. The resulting mixture was stirred at 20° C. for 60 hours. The reaction mixture was diluted with water (150 mL), and extracted with ethyl acetate (200 mL). The organic was dried over magnesium sulfate, filtered and evaporated to afford crude product as a colourless oil. The crude product was purified by flash silica chromatography, elution 50% ethyl acetate in isohexane to 100% ethyl acetate. Pure fractions were evaporated to dryness to afford the sub-title product (19.40 g, 69.8%) as a colorless oil.
Reaction SMILES: [F:1][CH:2]([F:30])[CH2:3][N:4]1[CH2:9][C:8]2([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[O:7][CH:6]([C:22](=[O:29])[NH:23][CH2:24][CH:25]([OH:28])CO)[CH2:5]1.O>C1COCC1>[F:30][CH:2]([F:1])[CH2:3][N:4]1[CH2:9][C:8]2([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[CH2:11][CH2:10]2)[O:7][CH:6]([C:22](=[O:29])[NH:23][CH2:24][CH:25]=[O:28])[CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(CC(F)F)CC(C(=O)NCC(O)CO)O2
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN(CC(F)F)CC(C(=O)NCC=O)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.9 %

Procedure:
To tert-butyl 4-(2,2-difluoroethyl)-2-((2,3-dihydroxypropyl)carbamoyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (422 mg, 0.96 mmol) in THF (10 mL) was added NaIO4 (522 mg, 2.44 mmol) followed by H2O (4 mL) the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered and partitioned between sat. aq. sodium bicarbonate/ethyl acetate. The aqueous layer was extracted further with ethyl acetate (3×50 mL). The organics were combined, washed with sat. aq. sodium bicarbonate (50 mL), dried over MgSO4, and concentrated in vacuo to yield tert-butyl 4-(2,2-difluoroethyl)-2-((2-oxoethyl)carbamoyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (377 mg, 96%) as a white solid, which was taken onto the next step without purification. ESI-MS m/z calc. 405.2. Found 406.5 (M+1)+; Retention time: 1.32 minutes (3 min run)
Reaction SMILES: Cl.C[O:3][C:4](=O)[CH2:5][NH2:6].[OH-].[Na+].CO[C:12](=[NH:17])[CH2:13][CH2:14][CH2:15][CH3:16]>CO.ClC1C=CC=CC=1>[CH2:13]([C:12]1[NH:17][C:4](=[O:3])[CH2:5][N:6]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCC(=N)OC
Reactant: COC(=O)CN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Clc1ccccc1
Solvent: CO
Product: CCCCC1=NCC(=O)N1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
31.71 g (0.25 mol) of glycine methyl ester hydrochloride was added to a solution of 10.1 g (0.25 mol) of sodium hydroxide in methanol at 0° C. After 15 minutes, 126.5 g of a 22.8 percent solution of pentanimidic acid methyl ester in chlorobenzene was instilled for 5 minutes in the white suspension. The light yellow suspension was stirred for 4 hours at room temperature and diluted with chlorobenzene (100 ml). The methanol was distilled off at a temperature of 26° C. and a pressure of 30 to 50 mbar, and the orange suspension was diluted with methylene chloride (100 ml) and then filtered. After removal of the solvent from the filtrate, 34.09 g (97 percent) of the title compound (content>95 percent, according to GC and 1H-NMR) was obtained. Data regarding the product was:
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].C(=O)=O.CC(C)=O.[Br:12][C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1.FC(F)(F)S(O)(=O)=O.C(N(CC)CC)C>ClCCl>[Br:12][C:13]1[CH:14]=[C:15]([O:19][C:2]([CH3:3])([CH3:1])[CH3:4])[CH:16]=[CH:17][CH:18]=1
Reactant: Oc1cccc(Br)c1
Reactant: C=C(C)C
Agent: O=C=O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)Oc1cccc(Br)c1
Temperature: -75 °C
Reaction time: 2 h

Procedure:
Condensed isobutylene (100 ml) was added via a dry ice/acetone cold finger, to dichloromethane (70 ml) at −30° C., followed by a solution of 3-bromophenol (21.5 g, 125 mmol) in dichloromethane (30 ml). Trifluoromethanesulphonic acid (1.5 g, 10.0 mmol) was added dropwise, the reaction cooled to −75° C., and stirred for 2 hours. Triethylamine (1.4 ml, 10.0 mmol) was then added, the solution allowed to warm to room temperature and then concentrated in vacuo to remove the isobutylene. The remaining solution was washed with water, dried (Na2SO4), filtered and evaporated to give the desired product as a pale yellow oil, (33 g, slightly impure).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH:8]([CH2:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[C:9]2=[O:12])=[CH:5][C:4]=1[N:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1.CC1C=CC(S(O)(=O)=O)=CC=1.[F:38][C:39]([F:47])([F:46])[C:40]([C:42]([F:45])([F:44])[F:43])=[O:41]>C1(C)C=CC=CC=1.O>[F:38][C:39]([F:47])([F:46])[C:40]([C:18]1[CH:19]=[C:14]([CH2:13][CH:8]2[CH2:7][C:6]3[C:10](=[CH:11][C:3]([O:2][CH3:1])=[C:4]([N:20]4[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]4)[CH:5]=3)[C:9]2=[O:12])[CH:15]=[N:16][CH:17]=1)([OH:41])[C:42]([F:45])([F:44])[F:43]
Reactant: COc1cc2c(cc1N1CCN(C)CC1)CC(Cc1cccnc1)C2=O
Reactant: O=C(C(F)(F)F)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc2c(cc1N1CCN(C)CC1)CC(Cc1cncc(C(O)(C(F)(F)F)C(F)(F)F)c1)C2=O
Temperature: 120 °C

Procedure:
To a stirred solution of 255 (0.05 g, 0.142 mmol) in toluene was added PTSA (0.054 g, 0.284 mmol) and kept stirring at 120° C. Hexafluoroacetone 244 (0.078 g, 0.356 mmol) was added to the reaction and kept at temperature and stirred for 16 h. Reaction was then cooled to RT, diluted with water, and extracted with ethyl acetate twice, The organic layer was dried over sodium sulphate and concentrated to get the crude, which was purified through flash chromatography by using 100-200 mesh silica gel and eluting the compound at 30% ethyl acetate in hexane as thick sticky solid 2-((5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)pyridin-3-yl)methyl)-6-methoxy-5-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-1-one 256.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)[C:3]=1[C:18]([OH:20])=O.Cl.C(N=C=NCCCN(C)C)C.[F:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>ClCCl>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:15])[F:16])=[CH:9][CH:8]=2)[C:3]=1[C:18]([N:43]1[CH2:42][CH2:41][N:40]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[F:33])[CH2:45][CH2:44]1)=[O:20]
Reactant: Fc1ccccc1N1CCNCC1
Reactant: Nc1onc(-c2ccc(OC(F)(F)F)cc2)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Nc1onc(-c2ccc(OC(F)(F)F)cc2)c1C(=O)N1CCN(c2ccccc2F)CC1
Yield: 64.1 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-amino-3-(4-(trifluoromethoxy)phenyl)isoxazol-4-carboxylic acid (530 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(2-fluorophenyl)piperazine (332 mg, 1.84 mmol), a white solid required compound (533 mg, 1.18 mmol, 64%) was obtained.
Reaction SMILES: [C:1]([N:20]1[C:24]([CH2:25][C:26]([O:28]CC)=[O:27])=[N:23][N:22]=[N:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([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.O1CCCC1.[OH-].[Na+].Cl>C(O)C.C(OCC)(=O)C>[C:1]([N:20]1[C:24]([CH2:25][C:26]([OH:28])=[O:27])=[N:23][N:22]=[N:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)Cc1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(O)Cc1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 117.4 %

Procedure:
To a stirred solution of 1.21 g of ethyl (1-trityl-1H-tetrazol-5-yl)acetate in ethanol (6mL)-tetrahydrofuran (6 mL) was added 1.67 mL of 2 mol/L sodium hydroxide solution under ice-cooling, and the mixture was stirred at room temperature for an hour. To the reaction mixture were added ethyl acetate and 10 mL of 1 mol/L hydrochloric acid, and the mixture was separated. After being washed with water, and brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 1.32 g of (1-trityl-1H-tetrazol-5-yl)acetic acid.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][C:13]3[C:18]([N:19]=2)=[CH:17][CH:16]=[C:15]([C:20]2([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:22][CH2:21]2)[N:14]=3)=[C:7]([F:29])[CH:6]=1)[OH:4].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.CCOC(C)=O.CCCCCC>C(Cl)Cl>[F:31][C:2]([F:1])([F:30])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][C:13]3[C:18]([N:19]=2)=[CH:17][CH:16]=[C:15]([C:20]2([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:21][CH2:22]2)[N:14]=3)=[C:7]([F:29])[CH:6]=1)=[O:4]
Reactant: OC(c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1)C(F)(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1)C(F)(F)F
Reaction time: 3 h

Procedure:
To a solution of 2,2,2-trifluoro-1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo-[5,4-b]pyridine-2-yl)phenyl)ethanol (1.15 g, 2.6 mmol) in 25 mL DCM under nitrogen was added Dess-Martin Periodinane (2.0 g, 4.7 mmol) in one portion. The reaction mixture was allowed to stir for 3 h. The reaction mixture was quenched with sat'd aq. Sodium thiosulfate (2 mL) and 25 mL sat'd aq. Sodium bicarbonate and allowed to stir rapidly for 30 min. The organic layer was separated and the aq. Layer was extracted with DCM, combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo to give a yellow foam. The material was treated with DCM and passed through a Redi-Sep® pre-packed silica gel column (40 g) using 0-60% EtOAc/hexane. The product-containing fractions were concentrated to afford 2,2,2-trifluoro-1-(3-fluoro-4-(5-(1-phenylcyclopropyl)-thiazolo[5,4-b]pyridine-2-yl)phenyl)ethanone as a yellowish foam. The foam was treated with hexanes and concentrated in vacuo a few times to give a nice light yellow solid. MS (ESI) m/z: calculated: 442.1; Observed: 461.0 (M++H2O+1).
Reaction SMILES: [C:1]([O:5][CH2:6][CH:7]([O:9][C:10](=[O:17])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]Br)[CH3:8])(=[O:4])[CH:2]=[CH2:3].[OH:18][C:19]1[CH:44]=[CH:43][C:22]([C:23]([O:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33](=[O:41])[C:34]3[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=3)=[CH:28][C:27]=2[CH3:42])=[O:24])=[CH:21][CH:20]=1.[C:45]([O-:48])([O-:47])=O.[K+].[K+].Cl>CC(=O)CC>[C:1]([O:5][CH2:6][CH:7]([CH3:8])[O:9][C:10](=[O:17])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([O:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33](=[O:41])[C:34]3[CH:39]=[CH:38][C:37]([O:40][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:45]([O:48][CH:7]([CH3:8])[CH2:6][O:5][C:1](=[O:4])[CH:2]=[CH2:3])=[O:47])=[CH:36][CH:35]=3)=[CH:28][C:27]=2[CH3:42])=[O:24])=[CH:43][CH:44]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: O=C([O-])[O-]
Reactant: C=CC(=O)OCC(C)OC(=O)CCCCCBr
Reactant: Cc1cc(OC(=O)c2ccc(O)cc2)ccc1OC(=O)c1ccc(O)cc1
Agent: Cl
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CC(=O)OCC(C)OC(=O)CCCCCOc1ccc(C(=O)Oc2ccc(OC(=O)c3ccc(OCCCCCC(=O)OC(C)COC(=O)C=C)cc3)c(C)c2)cc1
Temperature: 100 °C

Procedure:
A mixture of 2-[(6-bromohexanoyl)oxy]propyl acrylate (4.15 g), 4-[(4-hydroxybenzoyl)oxy]-2-methylphenyl 4-hydroxybenzoate (2.24 g) and K2CO3 (2.55 g) in 2-butanone (40 ml) was heated at 100° C. overnight. The reaction mixture was poured into HCl 1N (50 ml) and extracted twice with 80 ml of diethylether. The etheral extracts were dried over Na2SO4 and evaporated to dryness. The obtained pasty residue was purified by silica column chromatography to give nearly pure 4-{[4-({6-[2-(acryloyloxy)-1-methylethoxy]-6-oxohexyl}oxy)benzoyl]oxy}-2-methylphenyl 4-({6-[2-(acryloyloxy)-1-methylethoxy]-6-oxohexyl}oxy)benzoate as slightly yellow oil.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.N(OCCC(C)C)=O.[ClH:19]>C(O)(=O)C.S(=O)(=O)(O)O.[Cu]Cl>[Cl:19][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12
Reactant: Nc1ccnc2[nH]ccc12
Reactant: Cl
Agent: Cl[Cu]
Agent: CC(C)CCON=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Clc1ccnc2[nH]ccc12
Temperature: 12 °C
Reaction time: 3 h

Procedure:
750 mg (5.63 mmol) of 4-amino-1H-pyrrolo[2,3-b]pyridine (from example XVII) are dissolved in a mixture of 67.5 ml of glacial acetic acid and 0.67 ml of concentrated sulfuric acid. The mixture is cooled to 12° C. 3.67 ml (3.20 g, 117 mmol) of isopentyl nitrite are slowly added dropwise, and the mixture is stirred at 12° C. for 3 hours. This solution is then added to a suspension (temperature: 50° C.) of 6.07 g (61.4 mmol) of copper(I) chloride in 34 ml of concentrated hydrochloric acid, and the mixture is then heated at 80-90° C. for 30 min. The mixture is cooled to RT and stirred overnight. For work-up, the reaction solution is concentrated and made alkaline using 1N aqueous sodium hydroxide solution, the precipitated copper salts are filtered off with suction through kieselguhr and the mixture is extracted 3× with ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated using a rotary evaporator.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[F:15][C:16]([F:31])([F:30])[O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH:28]=[N:27][NH:26][C:25]2=[O:29])=[CH:20][CH:19]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:26]1[C:25](=[O:29])[N:24]([C:21]2[CH:20]=[CH:19][C:18]([O:17][C:16]([F:15])([F:31])[F:30])=[CH:23][CH:22]=2)[CH:28]=[N:27]1)[CH3:13]
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: O=c1[nH]ncn1-c1ccc(OC(F)(F)F)cc1
Product: C[C@@H](n1ncn(-c2ccc(OC(F)(F)F)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 62.5 %

Procedure:
In the same manner as in Reference Example 5, starting from 1.36 g of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 1.33 g of 4-(4-trifluoromethoxyphenyl)-3(2H,4H)-1,2,4-triazolone, 2-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-4-(4-trifluoromethoxyphenyl)-3(2H,4H)-1,2,4-triazolone (1.45 g) was obtained as colorless prisms.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([C:14]#[N:15])([CH3:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:27][C:28]1[CH:29]=[C:30]([CH:49]=[CH:50][CH:51]=1)[O:31][C:32]1[CH:46]=[CH:45][C:35]2[N:36]=[C:37]([NH:39][C:40]([CH:42]3[CH2:44][CH2:43]3)=[O:41])[S:38][C:34]=2[C:33]=1[C:47]#[N:48]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]([C:11]([C:14]#[N:15])([CH3:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:27][C:28]1[CH:51]=[CH:50][CH:49]=[C:30]([O:31][C:32]2[CH:46]=[CH:45][C:35]3[N:36]=[C:37]([NH:39][C:40]([CH:42]4[CH2:44][CH2:43]4)=[O:41])[S:38][C:34]=3[C:33]=2[C:47]#[N:48])[CH:29]=1)=[O:6]
Reactant: N#Cc1c(Oc2cccc(N)c2)ccc2nc(NC(=O)C3CC3)sc12
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)sc4c3C#N)c2)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of 2-chloro-3-(1-cyano-1-methylethyl)benzoic acid (76 mg, 0.339 mmol) in tetrahydrofuran (2 mL) were added oxalyl chloride (36 μL, 0.420 mmol) and N,N-dimethylformamide (20 μL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in N,N-dimethylacetamide (2 mL). N-[6-(3-Aminophenoxy)-7-cyano-1,3-benzothiazol-2-yl]cyclopropanecarboxamide (100 mg, 0.29 mmol) was added to the solution, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate (15 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (10 mL) and saturated brine (10 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=30/70→80/20), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (129 mg, 81%) as a white powder.