Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:59])[CH:5]=[C:6]([Cl:58])[C:7]=1[CH2:8][C@@H:9]([C:43]1[CH:48]=[CH:47][C:46]([O:49][CH:50]([F:52])[F:51])=[C:45]([O:53][CH2:54][CH:55]2[CH2:57][CH2:56]2)[CH:44]=1)[O:10][C:11]([C@H:13]1[N:17]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27](=[O:42])[NH:28][CH2:29][CH2:30][NH:31][C:32](=[O:41])[C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([CH:39]=O)[CH:34]=3)[CH:22]=2)(=[O:20])=[O:19])[CH2:16][CH2:15][S:14]1)=[O:12].[NH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:59])[CH:5]=[C:6]([Cl:58])[C:7]=1[CH2:8][C@@H:9]([C:43]1[CH:48]=[CH:47][C:46]([O:49][CH:50]([F:51])[F:52])=[C:45]([O:53][CH2:54][CH:55]2[CH2:57][CH2:56]2)[CH:44]=1)[O:10][C:11]([C@H:13]1[N:17]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27](=[O:42])[NH:28][CH2:29][CH2:30][NH:31][C:32](=[O:41])[C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][NH:60][C:61]4[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=4)[CH:34]=3)[CH:22]=2)(=[O:20])=[O:19])[CH2:16][CH2:15][S:14]1)=[O:12]
Reactant: O=Cc1cccc(C(=O)NCCNC(=O)c2cccc(S(=O)(=O)N3CCS[C@H]3C(=O)O[C@@H](Cc3c(Cl)c[n+]([O-])cc3Cl)c3ccc(OC(F)F)c(OCC4CC4)c3)c2)c1
Reactant: Nc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(NCCNC(=O)c1cccc(S(=O)(=O)N2CCS[C@H]2C(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)c1)c1cccc(CNc2ccccc2)c1
Temperature: 25 °C
Yield: 105.9 %

Procedure:
3,5-Dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(((S)-3-((3-((2-(3-formylbenzamido)ethyl)carbamoyl)phenyl)sulfonyl)thiazolidine-2-carbonyl)oxy)ethyl)pyridine 1-oxide (30 mg, 0.034 mmol) was dissolved in DCM (300 μl, 4.66 mmol). Aniline (3.75 mg, 0.040 mmol) and acetic Acid (2.306 μl, 0.040 mmol) were added, and the mixture was stirred at RT for 30′. Sodium triacetoxyborohydride (8.54 mg, 0.040 mmol) was added, and the mixture was stirred at room temperature for 8 hrs to achieve completion. The reaction mixture was diluted with DCM and extracted with water. The organic phase was dried over Na2SO4 and concentrated under vacuum to give 3,5-dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(((S)-3-((3-((2-(3-((phenylamino)methyl)benzamido)ethyl)carbamoyl)phenyl)-sulfonyl)thiazolidine-2-carbonyl)oxy)ethyl)pyridine 1-oxide (35 mg, 0.036 mmol, 107% yield).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])#[N:2].[C:14]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O.CCOC(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][CH3:14])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])#[N:2]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(C#N)ccc1O
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COC(=O)c1cc(C#N)ccc1OC
Temperature: 65 °C
Reaction time: 10 h
Yield: 28 %

Procedure:
A solution of acid methyl 5-cyano-2-hydroxybenzoate (2 g, 11.2 mmol) in dry acetone (50 mL) was cooled to 0° C. and K2CO3 (2.34 g, 16.9 mmol) followed by MeI (1.1 mL, 16.9 mmol) were added dropwise. The reaction mixture was allowed to stir at 65° C. for 10 h and then diluted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield methyl 5-cyano-2-methoxybenzoate (600 mg, crude), which was carried through without further purification. 1H NMR (300 MHz, CDCl3) δ 8.11 (d, J=2.2 Hz, 1H), 7.78-7.74 (dd, J=8.8 Hz, 2.2 Hz, 1H), 7.08-7.05 (d, J=8.8 Hz, 1H), 3.98 (s, 3H), 3.92 (s, 3H). MS (ESI) m/z: Calculated for C10H9NO3: 191.06. found: 191.8 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[N:16](C(OC(C)(C)C)=O)[C:15]3[C:10](=[N:11][C:12]([O:24][CH3:25])=[CH:13][CH:14]=3)[CH:9]=2)[C:5]([OH:26])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>ClCCl.O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[NH:16][C:15]3[C:10](=[N:11][C:12]([O:24][CH3:25])=[CH:13][CH:14]=3)[CH:9]=2)[C:5]([OH:26])=[CH:4][CH:3]=1
Reactant: COc1ccc2c(cc(-c3nc(Cl)ccc3O)n2C(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: COc1ccc2[nH]c(-c3nc(Cl)ccc3O)cc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
To a stirred solution of tert-butyl 2-(6-chloro-3-hydroxypyridin-2-yl)-5-methoxy-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (260 mg, 0.69 mmol) in dichloromethane (6.0 mL) was added TFA (118 mg, 1.04 mmol). The mixture was stirred at room temperature for 8 hours. The mixture was diluted with H2O and extract with EtOAc. The organics were washed with brine and dried over Na2SO4. After concentrated, the crude product of 6-chloro-2-(5-methoxy-1H-pyrrolo[3,2-b]pyridin-2-yl)pyridin-3-ol (128 mg, yield: 67%). MS (M+H)+: 276/278.
Reaction SMILES: ClC1C=CC2SC=C(CN3CCN(C4SC(C(O)=O)=C(C)N=4)C3=O)C=2C=1.[F:27][C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[CH2:37][CH2:36][N:35]([C:38]3[S:39][C:40]([C:44]([OH:46])=O)=[C:41]([CH3:43])[N:42]=3)[C:34]2=[O:47])=[CH:30][CH:29]=1.[N:50]1[CH:55]=[CH:54][N:53]=[CH:52][C:51]=1[CH2:56][NH2:57]>>[F:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:32][N:33]2[CH2:37][CH2:36][N:35]([C:38]3[S:39][C:40]([C:44]([NH:57][CH2:56][C:51]4[CH:52]=[N:53][CH:54]=[CH:55][N:50]=4)=[O:46])=[C:41]([CH3:43])[N:42]=3)[C:34]2=[O:47])=[CH:48][CH:49]=1
Reactant: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: NCc1cnccn1
Agent: Cc1nc(N2CCN(Cc3csc4ccc(Cl)cc34)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1cnccn1
Yield: 42 %

Procedure:
Following the procedure as described in Example 32, making variations as required to replace 2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with pyrazin-2-ylmethanamine, the title compound was obtained as a colorless solid in 42% yield: mp 185-187° C.; 1H NMR (300 MHz, CDCl3) δ 8.65 (s, 1H), 8.53-8.51 (m, 2H), 7.30-7.25 (m, 2H), 7.07-7.01 (m, 2H), 6.83 (br s, 1H), 4.76 (d, J=6.0 Hz, 2H), 4.46 (s, 2H), 4.09 (t, J=9.0 Hz, 2H), 3.46 (t, J=9.0 Hz, 2H), 2.63 (s, 3H); MS (ES+) m/z 427.2 (M+1).
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH3:32])[CH2:14][C:15]2[C:16]([CH3:31])=[N:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)=[CH:19][CH:20]=2)=[CH:9][C:8]=1[CH2:33][CH2:34][CH2:35][O:36][CH3:37])C.[OH-].[Na+]>C1COCC1.CCO>[CH3:37][O:36][CH2:35][CH2:34][CH2:33][C:8]1[CH:9]=[C:10]([N:13]([CH3:32])[CH2:14][C:15]2[C:16]([CH3:31])=[N:17][C:18]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=3)=[CH:19][CH:20]=2)[CH:11]=[CH:12][C:7]=1[O:6][CH2:5][C:4]([OH:38])=[O:3]
Reactant: CCOC(=O)COc1ccc(N(C)Cc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1CCCOC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COCCCc1cc(N(C)Cc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1OCC(=O)O
Reaction time: 0.5 h

Procedure:
0.125 g (0.24 mmol) of the above prepared (2-(3-methoxy-propyl)-4-{methyl-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethyl]-amino}-phenoxy)-acetic acid ethyl ester was dissolved in 1.44 ml of THF/EtOH=1/1, treated with 0.72 ml (3 eq.) of 1N NaOH, and kept at ambient temperature for 0.5 h. The reaction mixture was then poured onto crashed ice/AcOEt/HCl dil., the organic layer washed with water, dried over sodium sulfate, and evaporated to dryness. Crystallization from hexane/AcOEt produced finally 0.102 g of the title compound as off-white crystals of mp. 72–73° C.
Reaction SMILES: C(OC[N:10]1[C:15](=[O:16])[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])=[CH:28][CH:27]=2)[CH3:22])=[C:13]([Cl:37])[CH:12]=[N:11]1)C1C=CC=CC=1.B(Br)(Br)Br.CO.O>C1C=CC=CC=1>[Cl:37][C:13]1[CH:12]=[N:11][NH:10][C:15](=[O:16])[C:14]=1[NH:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:23][CH2:24][O:25][C:26]1[CH:27]=[CH:28][C:29]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])=[CH:30][CH:31]=1)[CH3:22]
Reactant: CN(CCCNc1c(Cl)cnn(COCc2ccccc2)c1=O)CCOc1ccc(NS(C)(=O)=O)cc1
Agent: BrB(Br)Br
Solvent: c1ccccc1
Solvent: O
Solvent: CO
Product: CN(CCCNc1c(Cl)cn[nH]c1=O)CCOc1ccc(NS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.1 %

Procedure:
2.69 g (4.88 mmoles) of the compound of Example 44 are dissolved in 53 ml of anhydrous benzene. 2.92 ml of boron tribromide are dropped to the solution so that the temperature of the reaction mixture should not exceed 20° C. The suspension thus obtained is stirred at room temperature for half an hour. Then 40 ml of methanol are dropped under stirring and cooling with icy water at such a rate that the inner temperature should not exceed 25° C. The reaction mixture is evaporated, the residue is boiled with 68 ml of distilled water for 1 hour, the solution is cooled, diluted with 100 ml of distilled water, the pH is adjusted with solid potassium hydrogen carbonate to neutral and the solution is extracted with chloroform. The organic phase is dried and evaporated, then the residue is purified by column chromatography. Thus 1.01 g (48%) of the desired compound are obtained. Rf =0.45. Its monohydrochloride salt melts at 181°-183° C.
Reaction SMILES: C(OC[O:6][C:7](=[O:31])[C:8]([NH:29][NH2:30])([CH3:28])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:12]([O:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:11]=1)(=O)C.[C:32]([O:38][CH2:39]I)(=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34]>>[CH3:34][C:33]([CH3:36])([CH3:35])[C:32]([O:38][CH2:39][O:31][C:7](=[O:6])[C:8]([NH:29][NH2:30])([CH3:28])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:12]([O:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:11]=1)=[O:37]
Reactant: CCOC(=O)Oc1ccc(CC(C)(NN)C(=O)OCOC(C)=O)cc1OC(=O)OCC
Reactant: CC(C)(C)C(=O)OCI
Product: CCOC(=O)Oc1ccc(CC(C)(NN)C(=O)OCOC(=O)C(C)(C)C)cc1OC(=O)OCC

Procedure:
Following the procedure for preparation of compound 101, and substituting bromomethyl acetate with iodomethyl pivalate, provided the title compound. 1H NMR (CD3OD, 400 MHz): 1.24 (s, 9H), 1.34 (t, 6H), 1.44 (s, 3H), 3.08 (dd, 2H), 4.29 (q, 4H), 5.88 (dd, 2H), 7.19–7.25 (m, 3H). MS (ESI) m/z 485.32 (M+H+)
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[C:14]([CH2:15][CH3:16])=[CH:13][C:12]([CH2:17][CH3:18])=[CH:11][C:10]=2[CH2:19][CH3:20])=[C:5]([O:21][CH2:22]SC)[C:4]([CH3:25])=[N:3]1.Cl[C:27]1C=CC=C(C(OO)=O)C=1.[S:37]([O-:41])([O-])(=[O:39])=S.[Na+].[Na+]>ClCCl>[CH3:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[C:10]([CH2:19][CH3:20])=[CH:11][C:12]([CH2:17][CH3:18])=[CH:13][C:14]=2[CH2:15][CH3:16])=[C:5]([O:21][CH2:22][S:37]([CH3:27])(=[O:41])=[O:39])[C:4]([CH3:25])=[N:3]1
Reactant: O=S([O-])([O-])=S
Reactant: CCc1cc(CC)c(-c2c(OCSC)c(C)nn(C)c2=O)c(CC)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CCc1cc(CC)c(-c2c(OCS(C)(=O)=O)c(C)nn(C)c2=O)c(CC)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 0.30 g of 2,6-dimethyl-5-methylthiomethoxy-4-(2,4,6-triethylphenyl)-3(2H)-pyridazinone [compound (I-2-2)] and 4 mL Of dichloromethane, 205 mg of m-chloroperbenzoic acid was added, followed by stirring at room temperature for 16 hours. To the reaction mixture, an aqueous saturated sodium thiosulfate solution (10 mL) was added, followed by extraction with chloroform (10 mL×2). The organic layer was washed with an aqueous saturated sodium bicarbonate solution (10 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:1) to obtain 0.23 g of 2,6-dimethyl-5-methylsulfonylmethoxy-4-(2,4,6-triethylphenyl)-3(2H)-pyridazinone [compound (I-4-1)]. Melting point: 142 to 143° C.
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]=[C:7]([C:9]3[CH:10]=[C:11]([CH:21]=[CH:22][CH:23]=3)[O:12][CH2:13][C:14]([O:16]C(C)(C)C)=[O:15])[O:8][C:4]=2[CH:3]=1.Cl.C(OCC)(=O)C.O>O1CCCC1>[Br:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]=[C:7]([C:9]3[CH:10]=[C:11]([CH:21]=[CH:22][CH:23]=3)[O:12][CH2:13][C:14]([OH:16])=[O:15])[O:8][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)COc1cccc(-c2nc3ccc(Br)cc3o2)c1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)COc1cccc(-c2nc3ccc(Br)cc3o2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.4 %

Procedure:
To a solution of tert-butyl [3-(6-bromobenzoxazol-2-yl)phenoxy]acetate (Compound of Example 279) (2.22 g) in tetrahydrofuran (10 ml) was added 4 N hydrochloric acid-ethyl acetate (50 ml), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate-tetrahydrofuran (3:1, v/v). The organic layer was washed with water and dried over MgSO4. The solvent was distilled off under reduced pressure, and the resulting crystals were collected by filtration to obtain [3-(6-bromobenzoxazol-2-yl)phenoxy]acetic acid (1.27 g, 66%). The crystals were recrystallized from tetrahydrofuran-ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([C:21]([OH:23])=O)[C:6](=[O:20])[N:7]2[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1.C(Cl)(=O)C(Cl)=O.[C:30]1(=[O:37])[CH2:35][CH2:34][CH2:33][C:32](=[O:36])[CH2:31]1.C(N(CC)CC)C.CC(C)(O)C#N>C(Cl)(Cl)Cl.CN(C)C=O>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([C:21]([C:31]1[C:32](=[O:36])[CH2:33][CH2:34][CH2:35][C:30]=1[OH:37])=[O:23])[C:6](=[O:20])[N:7]2[C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1
Reactant: COc1ccc(-n2c(=O)c(C(=O)O)nc3c(Cl)cccc32)cc1
Reactant: O=C1CCCC(=O)C1
Agent: CC(C)(O)C#N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(-n2c(=O)c(C(=O)C3=C(O)CCCC3=O)nc3c(Cl)cccc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
6.7 g (20 mmol) of 5-chloro-1-(4-methoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid was dissolved in chloroform (300 mL), and to this solution, N,N-dimethylformamide (0.5 mL) and 5.2 g (41 mmol) of oxalyl chloride were added sequentially. The mixture was stirred for one hour at room temperature. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure. The residue thus obtained was dissolved in chloroform (70 mL), and this solution was added dropwise at 0° C. over 5 minutes to a solution prepared by dissolving 2.5 g (22 mmol) of 1,3-cyclohexanedione and 2.5 g (25 mmol) of triethylamine in chloroform (70 mL). The reaction solution was returned to room temperature and stirred for 3 hours, and then 0.86 g (10 mmol) of acetone cyanohydrin and 2.5 g (25 mmol) of triethylamine were added thereto. The mixture was stirred for 12 hours at room temperature. The reaction solution was washed with 10% hydrochloric acid and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue thus obtained was washed with ethyl acetate, to obtain 6.0 g (yield: 70%) of 5-chloro-3-(2-hydroxy-6-oxo-1-cyclohexenecarbonyl)-1-(4-methoxyphenyl)quinoxalin-2(1H)-one as a pale orange-colored powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]([OH:33])([CH2:31][OH:32])[C@H:9]([N:11]1[CH:15]=[CH:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])=[CH:18][CH:17]=2)[C:12]1=[O:30])[CH3:10].[CH3:34][S:35](Cl)(=[O:37])=[O:36].C(N(CC)CC)C>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]([OH:33])([CH2:31][O:32][S:35]([CH3:34])(=[O:37])=[O:36])[C@H:9]([N:11]1[CH:15]=[CH:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:29])([F:28])[CH:25]([F:26])[F:27])=[CH:18][CH:17]=2)[C:12]1=[O:30])[CH3:10]
Reactant: C[C@@H](n1ccn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O)[C@](O)(CO)c1ccccc1F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[C@@H](n1ccn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O)[C@](O)(COS(C)(=O)=O)c1ccccc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
1-[(1R,2S)-2-(2-Fluorophenyl)-2,3-dihydroxy-1-methylpropyl]-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2(1H,3H)-imidazolone (1.90 g) was dissolved in 30 ml of ethyl acetate, to which 0.69 g of methanesulfonyl chloride and 0.61 g of triethylamine were added dropwise with ice cooling. After stirring at 0° C. for 30 minutes, the reaction solution was washed with water (20 ml×2) and 10 ml of an aqueous solution of sodium chloride successively. The organic layer was dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give 2.2 g of 1-[(1R,2S)-2-(2-fluorophenyl)-2-hydroxy-3-methanesulfonyloxy-1-methylpropyl]-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2(1H,3H)-imidazolone as a colorless oil.
Reaction SMILES: COC(=O)[CH:4]([N+:19]([O-])=O)[CH:5]1[C:14]2[C:9]3[C:10](=[CH:15][CH:16]=[CH:17][C:8]=3[C:7](=O)O1)[CH:11]=[CH:12][CH:13]=2.C(O)(=[O:25])C.[C:27]([O:30][CH2:31]C)(=[O:29])C>CCO.[Fe]>[CH3:31][O:30][C:27]([C:17]1[CH2:16][C:15](=[O:25])[C:10]2[C:9]3[C:8]=1[CH:7]=[N:19][CH:4]=[CH:5][C:14]=3[CH:13]=[CH:12][CH:11]=2)=[O:29]
Reactant: CCOC(C)=O
Reactant: CC(=O)O
Reactant: COC(=O)C(C1OC(=O)c2cccc3cccc1c23)[N+](=O)[O-]
Agent: [Fe]
Solvent: CCO
Product: COC(=O)C1=C2C=NC=Cc3cccc(c32)C(=O)C1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
To a solution of nitro-(3-oxo-1H,3H-benzo[de]isochromen-1-yl)-acetic acid methyl ester (1.05 g, 3.33 mmol) in EtOH (12 mL) is added acetic acid (4 mL) followed by Fe (560 mg, 10 mmol) and the mixture is stirred at 100° C. for 90 min. Ethyl acetate is added to the mixture and any insoluble material is filtered. The filtrate is washed with water and the organic phase is dried over magnesium sulfate. The solvent is removed under reduced pressure and the residue purified by flash chromatography using a gradient of 0-50% EtOAc/hexane as eluent to give the title compound.
Reaction SMILES: [OH-].[K+].[CH3:3][C@@:4]12[C:20](=[O:21])[CH2:19][CH2:18][C@H:17]1[C@H:16]1[C@@H:7]([C:8]3[CH:9]=[CH:10][C:11]([OH:22])=[CH:12][C:13]=3[CH2:14][CH2:15]1)[CH2:6][CH2:5]2.[C:23]([C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1)#[N:24].C(O)(=O)C>C(O)C.O>[OH:22][C:11]1[CH:10]=[CH:9][C:8]2[CH:7]3[CH:16]([CH2:15][CH2:14][C:13]=2[CH:12]=1)[CH:17]1[C:4]([CH3:3])([C:20](=[O:21])[C:19](=[CH:29][C:28]2[CH:31]=[CH:32][C:25]([C:23]#[N:24])=[CH:26][CH:27]=2)[CH2:18]1)[CH2:5][CH2:6]3
Reactant: N#Cc1ccc(C=O)cc1
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CC12CCC3c4ccc(O)cc4CCC3C1CC(=Cc1ccc(C#N)cc1)C2=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Potassium hydroxide (2.0 g) was added to a suspension of estrone (1:352 g, 5.0 mmol) and 4-cyano-benzaldehyde (655 mg, 5.0 mmol) in ethanol (40 mL). The resulting orange solution was stirred for 4 hours at room temperature, then acetic acid (5 mL) and water (5 ml) were added (colour changes to yellow). The product precipitated and was filtered off, washed with water (50 mL), ethanol (50 mL) and diethyl ether (50 mL) and dried under high vacuum. Yield: 1.795 g (94%) pale yellow solid. 1H-NMR (DMSO-d6, 400 MHz). δ: 0.91 (s, 3H, —CH3), 1.30-1.66 (m, 5H), 1.82-1.90 (m, 1H), 1.94-2.02 (m, 1H), 2.14-2.22 (m, 1H), 2.30-2.38 (m, 1H), 2.58-2.92 (m, 3H), 6.45 (d, J=2.3 Hz, 1H), 6.51 (dd, J=8.6, 2.3 Hz, 1H), 7.04 (d, J=8.6 Hz, 1H), 7.36 (s, 1H), 7.82 (d, J=8.6 Hz, 2H), 7.90 (d, J=8.6 Hz, 2H), 9.03 (s, 1H, —OH). LRMS (FAB+): 384.1 (100, [M+H]+). LRMS (FAB−): 383.2 (100, [M]−).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][C:3]=1[OH:9].[F:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21]([OH:23])=O)[CH:17]=[CH:18][CH:19]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:30]N(C=O)C>>[Cl:1][C:2]1[CH:8]=[C:7]2[C:5](=[CH:4][C:3]=1[OH:9])[O:6][CH:30]=[C:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH2:12][CH2:11][F:10])[CH:15]=1)[C:21]2=[O:23]
Reactant: O=C(O)Cc1cccc(OCCF)c1
Reactant: CN(C)C=O
Reactant: Oc1ccc(Cl)c(O)c1
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: O=c1c(-c2cccc(OCCF)c2)coc2cc(O)c(Cl)cc12

Procedure:
This compounds was synthesised in the same manner as described above. 4-Chlororesorcinol (0.36 g, 2.5 mmol), [3-(2-Fluoro-ethoxy)-phenyl]-acetic acid (0.5 g, 2.5 mmol), BF3Et2O (5 ml), PCl5 (0.79 g, 3.79 mmol), DMF (8 ml and 5 ml). 6-Chloro-3-[3-(2-fluoro-ethoxy)-phenyl]-7-hydroxy-chromen-4-one precipitated out as a white solid (0.49 g, 58.6%). This was taken onto the next stage without further purification. Rf 0.6 ethyl acetate/hexane (70/30)].
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[C:32]([O:36][C:37](=[O:45])[NH:38][CH:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)([CH3:35])([CH3:34])[CH3:33]>>[C:32]([O:36][C:37](=[O:45])[NH:38][CH:39]1[CH2:44][CH2:43][N:42]([C:20]2[S:21][C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:26]=[CH:27][C:2]([Cl:1])=[CH:3][C:4]=3[C:28]([F:30])([F:31])[F:29])[N:8]=[CH:9]4)[C:18](=[O:25])[N:19]=2)[CH2:41][CH2:40]1)([CH3:35])([CH3:33])[CH3:34].[NH2:38][CH:39]1[CH2:44][CH2:43][N:42]([C:20]2[S:21][C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:26]=[CH:27][C:2]([Cl:1])=[CH:3][C:4]=3[C:28]([F:29])([F:31])[F:30])[N:8]=[CH:9]4)[C:18](=[O:25])[N:19]=2)[CH2:41][CH2:40]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CC(C)(C)OC(=O)NC1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CC1
Product: NC1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CC1

Procedure:
(1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidin-4-yl)-carbamic acid tert-butyl ester was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and piperidin-4-yl-carbamic acid tert-butyl ester following General Procedure C. The compound was used directly following General Procedure H to provide 2-(4-Amino-piperidin-1-yl)-5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one.
Reaction SMILES: [OH:1][C:2]1[C:11]([OH:12])=[C:10]2[C:5]([C:6](=[O:16])[C:7]([C:13](O)=[O:14])=[CH:8][O:9]2)=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O>>[OH:1][C:2]1[C:11]([OH:12])=[C:10]2[C:5]([C:6](=[O:16])[C:7]([C:13]([Cl:19])=[O:14])=[CH:8][O:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1coc2c(O)c(O)ccc2c1=O
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1coc2c(O)c(O)ccc2c1=O

Procedure:
7,8-Dihydroxychromone-3-carboxylic acid (6.6 g) together with thionyl chloride (25 ml) were refluxed for one hour. Certain unreacted thionyl chloride remained in the reaction mixture was distilled off, and after addition of benzene to the residue, the mixture was again subjected to distillation. To the residue was added n-hexane to cause solidification of the residue. The solid matter thus formed was recovered by filtration. There was thus obtained the desired product (7.2 g).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].Cl[C:5]1[C:10]([C:11]([NH:13][C:14]2[C:15]([Cl:21])=[N:16][CH:17]=[CH:18][C:19]=2[CH3:20])=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1.CCCCCC>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[Cl:21][C:15]1[C:14]([NH:13][C:11]([C:10]2[C:5]([NH:3][CH2:1][CH3:2])=[N:6][CH:7]=[CH:8][CH:9]=2)=[O:12])=[C:19]([CH3:20])[CH:18]=[CH:17][N:16]=1
Reactant: Cc1ccnc(Cl)c1NC(=O)c1cccnc1Cl
Reactant: CCN
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Solvent: CCCCCC
Product: CCNc1ncccc1C(=O)Nc1c(C)ccnc1Cl
Temperature: 165 °C
Reaction time: 8 h
Yield: 76.2 %

Procedure:
Ethylamine (12.7 g) was added to a suspension of 21.0 g of the 2-chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3-pyridinecarboxamide in 150 ml of xylene in a steel bomb. The mixture was then heated in an oil bath to 165° C. for 6 hrs. and then stirred overnight at room temperature. The solvent was removed in vacuo and water added to the residue. The product was extracted with ether, dried (sodium sulfate) and concentrated to give an oil. This was dissolved in ethyl acetate followed by hexane at which time a precipitate formed. The solid was filtered and dried to give 16.5 g of the title compound, m.p. 122°-124° C.