Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[NH2:15][C:16]1[C:21]2[C:22](=[O:30])[C:23]3[S:29][CH:28]=[CH:27][C:24]=3[CH2:25][S:26][C:20]=2[CH:19]=[CH:18][CH:17]=1>CC(N(C)C)=O>[F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4]([NH:15][C:16]1[C:21]2[C:22](=[O:30])[C:23]3[S:29][CH:28]=[CH:27][C:24]=3[CH2:25][S:26][C:20]=2[CH:19]=[CH:18][CH:17]=1)=[O:5]
Reactant: CC(O)(C(=O)O)C(F)(F)F
Reactant: Nc1cccc2c1C(=O)c1sccc1CS2
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Product: CC(O)(C(=O)Nc1cccc2c1C(=O)c1sccc1CS2)C(F)(F)F
Temperature: -10 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
In dimethylacetamide (10 ml) was dissolved 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (0.79 g, 5.0 mmol), and thionyl chloride (0.36 ml, 5.0 mmol) was added thereto at −15  C., followed by stirring at −15 to −5° C. for one hour. To the resulting mixture was added 9-amino-4,10-dihydrothieno[3,2-c][1]benzothiepin-10-one obtained in Reference Example 5 (0.62 g, 2.5 mmol), and the mixture was stirred overnight at room temperature. After the reaction mixture was concentrated under reduced pressure, the obtained oily residue was dissolved in ethyl acetate (50 ml). The organic layer was washed successively with a 5% aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the organic layer was concentrated under reduced pressure. The obtained oily residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1), followed by trituration with hexane to give 9-(3,3,3-trifluoro-2-hydroxy-2-methylpropanoylamino)-4,10-dihydrothieno[3,2-c][1]benzothiepin-10-one (0.60 g, 63%).
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([CH:30]([CH3:32])[CH3:31])=[N:13][C:14]2[C:15]([CH3:29])([CH3:28])[CH2:16][NH:17][CH2:18][C:19]=2[C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][CH:6]([C:11]1[C:12]([CH:30]([CH3:32])[CH3:31])=[N:13][C:14]2[C:15]([CH3:29])([CH3:28])[CH2:16][N:17]([CH2:38][C:37]3[CH:40]=[CH:41][C:34]([F:33])=[CH:35][CH:36]=3)[CH2:18][C:19]=2[C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C(C)C)nc2c(c1-c1ccc(F)cc1)CNCC2(C)C
Reactant: O=Cc1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)C(OC(C)(C)C)c1c(C(C)C)nc2c(c1-c1ccc(F)cc1)CN(Cc1ccc(F)cc1)CC2(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 59.3 %

Procedure:
A mixture of methyl 2-tert-butoxy-2-(4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetate (intermediate 5) (20 mg, 0.045 mmol) and 4-fluorobenzaldehyde (0.048 mL, 0.452 mmol) was stirred in CH2Cl2 (1 mL) at 0° C. for 45 min. AcOH (2.59 μl, 0.045 mmol) was added followed by NaBH(OAc)3 (9.58 mg, 0.045 mmol). After stirring at 0° C. for an additional 5 min, the reaction mixture was stirred at room temperature for 22 h. Additional NaBH(OAc)3 (9.58 mg, 0.045 mmol) and AcOH (2.59 μl, 0.045 mmol) were added and the mixture was stirred for an additional 1 h. The mixture was quenched with satd NaHCO3 and the product was extracted with CH2Cl2, dried (Na2SO4), filtered and adsorbed onto silica gel. The product was purified by flash chromatography (Biotage; 0%-50% EtOAc/hexane) to give methyl 2-tert-butoxy-2-(6-(4-fluorobenzyl)-4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetate (14.7 mg, 47% yield) as a colorless oil. 1H NMR (500 MHz, CDCl3) δ ppm 7.34 (ddd, J=2.14, 5.72, 8.32 Hz, 1H), 7.24-7.28 (m, 2H), 7.14-7.20 (m, 2H), 7.06-7.14 (m, 1H), 6.99 (t, J=8.70 Hz, 2H), 4.83 (s, 1H), 3.71 (s, 3H), 3.45-3.60 (m, 2H), 3.40 (d, J=13.43 Hz, 1H), 3.23 (d, J=15.26 Hz, 1H), 3.06 (d, J=15.26 Hz, 1H), 2.50 (d, J=10.99 Hz, 1H), 2.34 (d, J=11.29 Hz, 1H), 1.33 (d, J=2.44 Hz, 6H), 1.28 (s, 3H), 1.11 (d, J=6.71 Hz, 3H), 0.98 (s, 9H). 19F NMR (500 MHz, CDCl3) δ ppm −114.17, −116.52. LCMS (M+H) calcd for C33H41F2N2O3: 551.30. found: 551.4. By NMR.
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][NH2:11])[CH3:4].[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[S:26][C:25]([S:27](Cl)(=[O:29])=[O:28])=[N:24][N:23]=1)([O-:15])=[O:14]>>[CH2:3]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][NH:11][S:27]([C:25]1[S:26][C:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N+:13]([O-:15])=[O:14])=[N:23][N:24]=1)(=[O:28])=[O:29])[CH3:4]
Reactant: CCOC(=O)CNCCN
Reactant: O=[N+]([O-])c1ccccc1-c1nnc(S(=O)(=O)Cl)s1
Agent: Cl
Product: CCOC(=O)CNCCNS(=O)(=O)c1nnc(-c2ccccc2[N+](=O)[O-])s1

Procedure:
The title compound was synthesized by the reaction of N-(2-aminoethyl)-glycine ethyl ester 2HCl with 5-(2-nitrophenyl)-1,3,4-thiadiazole-2-sulfonyl chloride as per the procedure of example 1. 1H NMR (MHz; DMSO-d6) δ 8.16 (d, 1H), 7.81–7.78 (m, 3H), 4.02 (q, 2H), 3.34 (s, 2H), 3.21 (t, 2H), 2.70 (t, 2H), 1.15 (t, 3H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[O:5][C:4](=[O:12])[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl[CH2:20][CH2:21][CH2:22][N:23]([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH2:26][CH3:27]>>[CH2:28]([N:23]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:22][CH2:21][CH2:20][O:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[O:5][C:4](=[O:12])[C:3]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:29][CH2:30][CH3:31]
Reactant: O=c1oc2c(c(O)c1-c1ccccc1)CCCC2
Reactant: CCCCN(CCCC)CCCCl
Product: CCCCN(CCCC)CCCOc1c2c(oc(=O)c1-c1ccccc1)CCCC2
Yield: 80.5 %

Procedure:
As in Example 14, Stage B, 14.5 g. (0.06 mol) of 4-hydroxy-3-phenyl-5,6,7,8-tetrahydrocoumarin are caused to react with 16.2 g. (0.078 mol) of 1-chloro-3-dibutylaminopropane. 19.8 g. of an oil which cannot be crystallised are obtained. Yield 80.5% (theoretical yield 24.6 g.).
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[O:9]=[CH:10][C:11]1[CH:19]=[CH:18][C:16]([OH:17])=[C:13]([O:14][CH3:15])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CCO>[CH:3]1([CH2:2][O:17][C:16]2[CH:18]=[CH:19][C:11]([CH:10]=[O:9])=[CH:12][C:13]=2[O:14][CH3:15])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: BrCC1CCCCC1
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1cc(C=O)ccc1OCC1CCCCC1
Reaction time: 64 h
Yield: 93.5 %

Procedure:
Bromomethylcyclohexane (0.78 mL, 4.2 mmol) was added to a suspension of vanillin (0.43 g, 2.8 mmol) and potassium carbonate (1.17 g, 8.47 mmol) in EtOH (7.0 mL) and treated according to Procedure 3 for 64 h. 4-Cyclohexylmethoxy-3-methoxybenzaldehyde (0.65 g, 93%) was obtained as a yellow oil; δH (400 MHz, CDCl3) 1.05 (m, 2H, CH2), 1.15-1.36 (m, 4H, CH2), 1.73 (m, 2H, CH2), 1.87-1.98 (m, 2H, CH2, CH), 3.88 (d, J=6.0 Hz, 2H, OCH2), 3.92 (s, 3H, OCH3), 6.95 (d, J5,6=8.0 Hz, 1H, H5), 7.40 (d, J2,6=2.0 Hz, 1H, H2), 7.42 (dd, J5,6=8.0, J2,6=2.0 Hz, 1H, H6), 9.84 (s, 1H, CHO); δC (100 MHz, CDCl3) 25.6, 26.4, 29.8, 37.3, 56.1, 74.5, 109.3, 111.4, 126.8, 129.8, 149.9, 154.4, 190.9; vmax 1133, 1265, 1508, 1586, 1683, 2853, 2925 cm−1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Cl[C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)[N:11]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)[N:11]=1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: Oc1ccccc1Cl
Product: COc1ccc2c(Oc3ccccc3Cl)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 10 was used, starting from 2-chloro-phenol and (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(2-chloro-phenoxy)-6-methoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 382(MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=2)=[O:11])=[C:4]([F:19])[CH:3]=1.IC.[C:22](=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[N:16]([CH3:22])[CH:17]=2)=[O:11])=[C:4]([F:19])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(/C=C/c1ccc(Cl)cc1F)c1ccc(=O)[nH]c1
Agent: [K+]
Solvent: CI
Product: Cn1cc(C(=O)/C=C/c2ccc(Cl)cc2F)ccc1=O

Procedure:
In analogy to example 161, step 1, (E)-5-(3-(4-chloro-2-fluorophenyl)acryloyl)pyridin-2(1H)-one was reacted with iodomethane in the presence of potassium carbonate to give the title compound as a yellow solid, MS (ESI+): m/z=292.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:32])[C:7]([CH2:18][NH:19][C:20](=[O:31])OC3C=CC([N+]([O-])=O)=CC=3)=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[CH2:33]1[CH:38]2[CH2:39][CH:40]3[CH:42]([NH2:43])[C@@H:34]1[CH2:35][C:36]([OH:44])([CH2:41]3)[CH2:37]2>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:32])[C:7]([CH2:18][NH:19][C:20]([NH:43][CH:42]3[CH:34]4[CH2:33][CH:38]5[CH2:37][C:36]([OH:44])([CH2:41][CH:40]3[CH2:39]5)[CH2:35]4)=[O:31])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: NC1C2CC3C[C@H]1CC(O)(C3)C2
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)Oc1ccc([N+](=O)[O-])cc1
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)NC1C2CC3CC1CC(O)(C3)C2

Procedure:
1-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-3-(5-hydroxy-adamantan-2-yl)-urea was prepared starting from intermediate M and trans-4-aminoadamantan-1-ol. MS calcd. for C27H29ClN3O3 [(M+H)+] 478.2, obsd. 478.0.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]#[N:15])=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>[Ni].N>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH2:15])=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#CCc1ccc(CN2CCCC2)cc1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Product: NCCc1ccc(CN2CCCC2)cc1

Procedure:
A reaction mixture of 0.73 g (3.66 mmol) of (4-pyrrolidin-1-ylmethyl-phenyl)-acetonitrile and 0.1 g Raney nickel in 25 mL of methanolic ammonia solution is hydrogenated for 9 hours at 50° C. under 3 bar hydrogen.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][N:8]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[CH:26]=[C:25]([OH:27])[C:19]3[CH2:20][C:21]([CH3:24])([CH3:23])[O:22][C:18]=3[CH:17]=2)=[O:15])=[N:9]1.Cl[CH2:29][CH:30]1[CH2:32][CH2:31]1>C(#N)C>[CH3:7][N:8]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[CH:26]=[C:25]([O:27][CH2:29][CH:30]3[CH2:32][CH2:31]3)[C:19]3[CH2:20][C:21]([CH3:24])([CH3:23])[O:22][C:18]=3[CH:17]=2)=[O:15])=[N:9]1
Reactant: Cn1ccc(NC(=O)c2cc(O)c3c(c2)OC(C)(C)C3)n1
Reactant: ClCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cn1ccc(NC(=O)c2cc(OCC3CC3)c3c(c2)OC(C)(C)C3)n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To 60 mg of cesium carbonate (180 μmol) in a test tube (10×95 mm) was added 0.8 mL of 0.1 M solution of 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carbo-xylic acid (1-methyl-1H-pyrazol-3-yl)-amide (31a) in acetonitrile followed by 1 mL of 0.1 M solution of chloromethyl cyclopropane in acetonitrile and the reaction was stirred at 80° C. for 8 h. After the removal of solid cesium carbonate, the acetonitrile was removed, the residue was reconstituted in 1.2 mL of DMSO and subjected to HPLC purification to obtain the title compound. 1H NMR (500 MHz, DMSO-d6) δ 10.56 (s, 1 H) 7.57 (s, 1 H) 6.92 (s, 1 H) 6.54 (s, 1 H) 3.92-3.93 (d, J=5.00 Hz, 2 H) 2.94 (s, 2 H) 1.42 (s, 6 H) 0.55-0.60 (m, 2 H) 0.30-0.35 (m, 1H); LCMS for C19H23N3O3 m/z 342 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=3)[N:11]([CH3:19])[C:10]=2[CH3:20])=[CH:5][CH:4]=1.[CH2:21]([O:23][C:24](=[O:29])[C:25](Br)([CH3:27])[CH3:26])[CH3:22]>>[CH2:21]([O:23][C:24](=[O:29])[C:25]([O:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH3:19])[C:10]([CH3:20])=[C:9]2[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)([CH3:27])[CH3:26])[CH3:22]
Reactant: COc1ccc(-c2c(C)n(C)c3ccc(O)cc23)cc1
Reactant: CCOC(=O)C(C)(C)Br
Product: CCOC(=O)C(C)(C)Oc1ccc2c(c1)c(-c1ccc(OC)cc1)c(C)n2C

Procedure:
This compound was prepared from 3-(4-methoxyphenyl)-1,2-dimethyl-1H-indole-5-ol and 2-bromo-2-methylpropanoic acid ethylester analogously to Example 10.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([CH2:11][NH:12][CH:13]=O)=[N:6][C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=1[F:23].P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([F:10])[C:7]2[N:6]([CH:13]=[N:12][CH:11]=2)[C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=1[F:23])=[O:24]
Reactant: COC(=O)c1cc(F)c(CNC=O)nc1Nc1ccc(I)cc1F
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cc(F)c2cncn2c1Nc1ccc(I)cc1F
Temperature: 95 °C
Yield: 37.6 %

Procedure:
To a suspension of 5-fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-formylaminomethyl-nicotinic acid methyl ester (2.7 g, 6.2 mmol) in toluene (20 mL) was added phosphorous oxychloride (1.1 mL, 12.2 mmol). The reaction mixture was heated at 95° C. for 30 minutes. The reaction mixture was cooled to room temperature and then concentrated in vacuo. The resultant residue was dissolved in ethyl acetate and washed with water followed by a saturated aqueous solution of sodium bicarbonate, then brine. The organic phase was isolated, dried (MgSO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si-PPC, gradient 0% to 50%, ethyl acetate in hexane) to afford the title compound as a yellow solid (1.0 g, 39%). LCMS (method B): RT=3.97 min, [M+H]+=430.
Reaction SMILES: COC([CH:5]1[CH2:10][C:9]([C:18]#[N:19])([C:11]2[CH:12]=[N:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[CH2:8][CH2:7][C:6]1=[O:20])=O.[Li+].[Cl-]>CS(C)=O.O>[Cl:17][C:14]1[N:13]=[CH:12][C:11]([C:9]2([C:18]#[N:19])[CH2:8][CH2:7][C:6](=[O:20])[CH2:5][CH2:10]2)=[CH:16][CH:15]=1
Reactant: COC(=O)C1CC(C#N)(c2ccc(Cl)nc2)CCC1=O
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: N#CC1(c2ccc(Cl)nc2)CCC(=O)CC1
Temperature: 120 °C

Procedure:
A mixture of 5-cyano-5-(6-chloropyridin-3-yl)-2-oxocyclohexanecarboxylic acid methyl ester (10.6 mmol) and LiCl (21.1 mmol) in 15 mL wet DMSO was heated to 120° C. under microwave conditions for 2 h. The reaction mixture was diluted with water and extracted 3 times with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification with CC (KP-SIL™ from Biotage) using Hept/EtOAc (95/5 to 20/80) gives the desired compound as yellow solid.
Reaction SMILES: C(O)(C(F)(F)F)=O.[O:8]1[C:12]([C:13]([C:20]2[CH:25]=[CH:24][C:23]([O:26]C3CCCCO3)=[CH:22][CH:21]=2)=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][N:10]=[CH:9]1.C([O-])(O)=O.[Na+]>C(Cl)Cl.[Pd]>[OH:26][C:23]1[CH:24]=[CH:25][C:20]([CH:13]([C:12]2[O:8][CH:9]=[N:10][CH:11]=2)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:21][CH:22]=1
Reactant: CCOC(=O)C=C(c1ccc(OC2CCCCO2)cc1)c1cnco1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CC(c1ccc(O)cc1)c1cnco1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.7 %

Procedure:
TFA (10 mL) was added to a solution of 5.3 (14 mmol) in dry DCM (100 mL) and stirred at room temperature for 2 hours. To the reaction mixture was slowly added solid NaHCO3 with stirring. The reaction was then washed with saturated NaHCO3 (2×), dried over Na2SO4, and concentrated under reduced pressure. The residue was then re-dissolved in EtOH, stirred with Pd—C (1.48 g, 0.7 mmol) under hydrogen at room temperature for 14 hours. The Pd—C was removed by filtration through celite with EtOAc as eluant. After concentration, the residue was chromatographed (silica gel, 1:1 EtOAc/hexane) to afford compound 5.4 (1.3 g, 5 mmol). MS ESI (pos.) m/e 262.1 (M+H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].FC1C([O:19][C:20](=O)[CH2:21][CH2:22][CH2:23][O:24][N+:25]([O-:27])=[O:26])=C(F)C(F)=C(F)C=1F.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl.C1COCC1.C(Cl)Cl>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:20](=[O:19])[CH2:21][CH2:22][CH2:23][O:24][N+:25]([O-:27])=[O:26])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: O=C(CCCO[N+](=O)[O-])Oc1c(F)c(F)c(F)c(F)c1F
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(OC(=O)CCCO[N+](=O)[O-])cc1
Yield: 85.5 %

Procedure:
To a solution of 4-acetamidophenol (Paracetamol) (0.96 g, 6.30 mmol) TEA (0.64 g, 6.3 mmol) and DMAP (0.77 g, 6.3 mmol) in CH2Cl2/THF (9:1, 30 ml) kept at 0° C., under stirring and under nitrogen atmosphere, a solution of 4-(nitrooxy)butanoic acid pentafluorophenyl ester (2.0 g, 6.30 mmol) (Preparation 2) in CH2Cl2 (10 ml) was added. The resulting solution was kept under stirring for further 240 minutes at room temperature. The reaction mixture was poured in a pH 3 buffer solution (about 50 ml), acidified with HCl 1 N to pH 3-4 and extracted with CH2Cl2 (2×50 ml). The organic phase washed with brine (100 ml), dried on sodium sulfate and evaporated under vacuum. Purification by Flash chromatography of the residue (n-hexane/AcOEt 1:1) gave the title compound as a white solid (1.52 g, 84%). M.p., NMR and HPLC analysis were consistent with data reported in the literature.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.N1C=CC=CC=1.Cl[C:19]([CH2:21][O:22][C:23](=[O:25])[CH3:24])=[O:20]>ClCCl>[O:11]=[C:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:19]([CH2:21][O:22][C:23](=[O:25])[CH3:24])=[O:20])[CH:3]=2)[NH:7]1
Reactant: Nc1ccc2c(c1)CC(=O)N2
Reactant: CC(=O)OCC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OCC(=O)Nc1ccc2c(c1)CC(=O)N2
Temperature: 25 °C
Yield: 60.8 %

Procedure:
5-Amino-1,3-dihydro-indol-2-one 30c (500 mg, 3.38 mmol) was dissolved in 10 ml of dichloromethane under stirring at room temperature, and pyridine (470 μl, 5 mmol) was added to the solution at −40° C. in a dry ice-acetone bath. Acetic acid chlorocarbonylmethyl ester (473 mg, 3.48 mmol) was dissolved in 10 ml of dichloromethane, the resulting solution was added dropwise to the above reaction solution. Upon completion of the addition, the dry ice-acetone was removed, and the reaction mixture was allowed to warm up to room temperature and stirred overnight. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was filtered. The filter cake was washed with water (10 ml×3) and recrystallized to obtain the title compound acetic acid (2-oxo-2,3-dihydro-1H-indol-5-ylcarbamoyl)-methyl ester 44a (510 mg, yield 60.7%) as a yellow solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:20]=[CH:19][C:6]([N:7]=[CH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15](=[O:18])(=[O:17])[NH2:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C[Si]([C:25]#[N:26])(C)C>>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([NH:7][CH:8]([C:9]2[CH:14]=[CH:13][C:12]([S:15](=[O:17])(=[O:18])[NH2:16])=[CH:11][CH:10]=2)[C:25]#[N:26])=[CH:19][CH:20]=1
Reactant: CSc1ccc(N=Cc2ccc(S(N)(=O)=O)cc2)cc1
Reactant: C[Si](C)(C)C#N
Product: CSc1ccc(NC(C#N)c2ccc(S(N)(=O)=O)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(ii), but using 4-methylthio-N-(4-sulfamoylbenzylidene)aniline [prepared as described in step (i) above] and trimethylsilyl cyanide as starting materials, the title compound was obtained as a yellow powder (yield 100%).
Reaction SMILES: [CH3:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[N:12]([O-])=O.[Na+]>C(O)(=O)C.O>[N+:9]([C:8]1[CH:7]=[CH:6][CH:5]=[C:3]2[C:2]=1[CH:1]=[N:12][NH:4]2)([O-:11])=[O:10]
Reactant: Cc1c(N)cccc1[N+](=O)[O-]
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cccc2[nH]ncc12
Reaction time: 2 h
Yield: 81.4 %

Procedure:
To a solution of 2-methyl-3-nitroaniline (2.27 g, 14.91 mmol) in acetic acid (60 mL) was added a solution of sodium nitrite (1.13 g, 1.1 eq.) in water (5 mL). After 2 h, the deep red solution was poured onto ice/water and the resulting precipitate collected by filtration to yield 4-nitro-1H-indazole (67) (1.98 g, 81%).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[CH:7]1([CH3:17])[CH2:12][CH2:11][CH:10]([CH:13]([CH3:15])[CH3:14])[CH:9]([OH:16])[CH2:8]1.OS(O)(=O)=O>N1C=CC=CC=1>[CH:13]([C@@H:10]1[CH2:11][CH2:12][C@@H:7]([CH3:17])[CH2:8][C@H:9]1[O:16][C:1](=[O:5])[C:2]([O:16][C@@H:9]1[CH2:8][C@H:7]([CH3:17])[CH2:12][CH2:11][C@H:10]1[CH:13]([CH3:15])[CH3:14])=[O:3])([CH3:14])[CH3:15]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC1CCC(C(C)C)C(O)C1
Agent: O=S(=O)(O)O
Solvent: c1ccncc1
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)C(=O)O[C@@H]1C[C@H](C)CC[C@H]1C(C)C
Temperature: 25 °C

Procedure:
Oxalyl chloride (12.1 g, 96.2 mmol) was added dropwise during 20 min to a stirred solution of (−)-menthol (30.0 g, 192.0 mmol) in pyridine (240 mL) at 0° C. The reaction mixture was allowed to warm up to room temperature overnight, then added to H2SO4 (50%, containing ice, 400 mL), extracted with ether (400 mL and 200 mL), treated again with H2SO4 (50%, containing ice, 400 mL), washed with a saturated solution of NaCl (200 mL) and a saturated solution of NaHCO3 (200 mL, 2×). The organic layer was dried (Na2SO4) and concentrated. Column chromatography (SiO2, heptane/diethyl ether 9:1) gave, after drying under vacuum (0.5 mbar, 1 h), 26.2 g (74%) of an oil.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[S:14][CH:13]=[C:12]([CH3:15])[C:11]=2[CH:16]=1>C(Cl)(Cl)Cl>[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[S:14][C:13]([S:2]([Cl:1])(=[O:5])=[O:3])=[C:12]([CH3:15])[C:11]=2[CH:16]=1
Reactant: Cc1csc2ccc(Br)cc12
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: Cc1c(S(=O)(=O)Cl)sc2ccc(Br)cc12
Temperature: 0 °C
Reaction time: 3 h
Yield: 15820.2 %

Procedure:
Chlorosulfonic acid (2.20 ml, 0.033 mmol) was added dropwise at −5° C. to a solution of 5-bromo-3-methylbenzothiophene (Intermediate 9) (3.0 g, 13.2 mmol) in CHCl3 (30 mL). The reaction mixture was stirred at 0° C. for 3 h, and then poured into a mixture of ice/NaHCO3 and stirred vigorously for 5 min. The organic phase was immediately separated, dried and concentrated to give the title compound (1.70 g, 39%).
Reaction SMILES: [P:1](Cl)([S:6][CH2:7][CH2:8][CH3:9])([O:3][CH2:4][CH3:5])=[O:2].C(N(CC)CC)C.[OH:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=[O:23]>C(Cl)Cl>[P:1]([O:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:21]([CH:22]=[O:23])[CH:20]=1)([S:6][CH2:7][CH2:8][CH3:9])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCCSP(=O)(Cl)OCC
Reactant: O=Cc1cccc(O)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCSP(=O)(OCC)Oc1cccc(C=O)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of O-ethyl S-propyl chlorothiophosphate prepared by the method detailed in Example 1 was charged into a glass reaction vessel equipped with a stirrer and thermometer. The solution was cooled to a temperature of about -10° C. and triethylamine (2.23 ml) was added followed by the dropwise addition with stirring of 3-hydroxybenzaldehyde (1.95 grams; 0.016 mole) dissolved in methylene chloride (10 ml). Stirring was continued for a period of about 2 hours while maintaining the temperature of the reaction mixture at about 0° C. After this time the reaction mixture was transferred into a separatory funnel and was washed twice with water (100 ml), twice with dilute aqueous sodium hydroxide (50 ml; 0.1 N) and again twice with water (100 ml). The washed solution was then dried over anhydrous magnesium sulfate, filtered and stripped of solvent leaving an orange oil. This oil was subjected to high vacuum for a period of one hour to yield the desired product O-ethyl S-propyl O-(3-formylphenyl) thiophosphate.