Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:4]=1[CH2:25][C:26]1[CH2:30][CH2:29][CH:28]([CH2:31][CH:32]=[O:33])[C:27]=1[CH3:34].C1(C=CC=C(O)C=1)[OH:36].Cl([O-])=O.[Na+].Cl>O1CCOCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:4]=1[CH2:25][C:26]1[CH2:30][CH2:29][CH:28]([CH2:31][C:32]([OH:36])=[O:33])[C:27]=1[CH3:34]
Reactant: Oc1cccc(O)c1
Reactant: COc1c(C)c2c(c(OS(=O)(=O)c3ccc(C)cc3)c1CC1=C(C)C(CC=O)CC1)C(=O)OC2
Agent: Cl
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1c(C)c2c(c(OS(=O)(=O)c3ccc(C)cc3)c1CC1=C(C)C(CC(=O)O)CC1)C(=O)OC2
Reaction time: 0.03 h

Procedure:
The 3-(1,3-dihydro-6-methoxy-7methyl-3-oxo-4-p-toluenesulfonyloxy-5-isobenzofuranylmethyl)-2-methylcyclopent-2-en-1-ylacetaldehyde was dissolved in dioxane (8 mL) and pH 5 buffer (3 mL) and treated with resorcinol (0.10 g). To this mixture was then added sodium chlorite (0.080 g). After 2 minutes, the reaction was diluted with ethyl acetate and made acidic with 5% hydrochloric acid. After two extractions with ethyl acetate, the combined organic layers were dried over magnesium sulfate. The residue, 3-(1,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p-toluenesulfonyloxy-5-isobenzofuranylmethyl)-2-methylcyclopent-2-en-1-ylacetic acid obtained after solvent removal was carried on without further purification.
Reaction SMILES: [O:1]=[C:2]1[CH:10](SC)[C:9]2[C:4](=[C:5]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[CH:6]=[CH:7][CH:8]=2)[NH:3]1>[Ni].O1CCOCC1>[O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[C:5]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: CSC1C(=O)Nc2c(Oc3ccccc3Cl)cccc21
Agent: [Ni]
Solvent: C1COCCO1
Product: O=C1Cc2cccc(Oc3ccccc3Cl)c2N1

Procedure:
A mixture of thus obtained 2-oxo-3-methylthio-7-(2-chlorophenoxy)indoline and Raney nickel in dioxane was treated in a similar manner to that of Preparation 15-(2) to give 2-oxo-7-(2-chlorophenoxy)indoline.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:10].[CH3:17][C:18]([C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1)([C:20]1[O:21][CH:22]=[CH:23][N:24]=1)[CH3:19]>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:31]([C:28]2[CH:27]=[CH:26][C:25]([C:18]([CH3:19])([C:20]3[O:21][CH:22]=[CH:23][N:24]=3)[CH3:17])=[CH:30][CH:29]=2)(=[O:32])=[O:33])=[C:3]([C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])[CH:4]=1
Reactant: CC(C)(c1ccc(S(=O)(=O)Cl)cc1)c1ncco1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccncc1
Product: CC(C)(c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccncc2)cc1)c1ncco1

Procedure:
The title compound was prepared from (2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 4-(1-methyl-1-oxazol-2-yl-ethyl)-benzenesulfonyl chloride following the general procedure described for the preparation of N-aryl-benzenesulfonamides. MS: m/z 482 (M++1).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[C:12]([CH3:13])=[C:11](O)[C:10]2[C:5](=[C:6]([C:15]([F:18])([F:17])[F:16])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.P(Br)(Br)([Br:23])=O>C1(C)C=CC=CC=1>[F:1][C:2]([F:20])([F:19])[C:3]1[C:12]([CH3:13])=[C:11]([Br:23])[C:10]2[C:5](=[C:6]([C:15]([F:18])([F:17])[F:16])[CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: O=P(Br)(Br)Br
Reactant: Cc1c(C(F)(F)F)nc2c(C(F)(F)F)cccc2c1O
Solvent: Cc1ccccc1
Product: Cc1c(C(F)(F)F)nc2c(C(F)(F)F)cccc2c1Br
Yield: 81 %

Procedure:
A solution of 2,8-bis(trifluoromethyl)-3-methyl-4-quinolinol (5.9 g, 20 mmol) in toluene (20 mL) was treated with POBr3 (6.0 g, 21 mmol), heated to reflux for 30 min, cooled in ice, quenched with water and extracted with EtOAc (2×50 mL). The combined extracts were dried (MgSO4), concentrated in vacuo and the resulting brown solid purified by flash chromatography [SiO2; heptane] to give the product (5.8 g, 81%) as a white crystalline solid: mp 81.9-82.3° C.; IR νmax (Nujol)/cm−1 2955, 2924, 2854, 1574, 1465, 1364, 1299, 1281, 1213, 1189, 1141; NMR δH (400 MHz, CDCl3) 2.77 (3H, s), 7.78 (1H, t, J 8.1 Hz), 8.14 (1H, d, 7.4 Hz), 8.49 (1H, d, J 8.5 Hz).
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH:6]1[C:15]2[CH:14]=[C:13]3C=CC=C[C:12]3=[CH:11][N+:10]=2[CH:9]=[CH:8][CH:7]=1.C1(C(C2C=CC=CC=2)=C)C=CC=CC=1.O>[N+](C)([O-])=O>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH:6]1[C:15]2[N+:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: c1ccc2c[n+]3ccccc3cc2c1
Agent: C=C(c1ccccc1)c1ccccc1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Solvent: C[N+](=O)[O-]
Product: c1cc[n+]2ccccc2c1

Procedure:
A mixture of 4.6 g (0.0165 mol) of benzo[b]quinolizinium perchlorate and 9 g of 1,1-diphenylethylene (0.05 mol) in 250 mL of nitromethane was heated to reflux under nitrogen for 16 h. The reaction mixture was poured into 100 mL of water, shaken, and the organic layer was separated and washed with 100 mL of water, and the nitromethane layer was concentrated in vacuo to 50 mL of its volume. To the above nitromethane layer was added 100 mL of water, the resulting mixture was concentrated in vacuo, and the residue was dissolved in 200 mL of acetonitrile and 500 mL of water. The above mixture was extracted with hexane (3×100 mL; a black oil insoluble in both hexane and acetonitrile/water was removed), and the aqueous layer was steam distilled to remove acetonitrile to yield an oil which crystallized on standing. The solid product was washed with 200 mL of ether, 200 mL of hexane, and 200 mL of ether to afford 5.1 g (67%) of 6,11-ethano-12,12-diphenyl-6,11-dihydrobenzoro]quinolizinium perchlorate, as a tan solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@@H:4]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1.[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:24]=1[C:25](Cl)=[O:26].CCN(C(C)C)C(C)C>ClCCl>[CH3:1][O:2][C:3](=[O:21])[C@@H:4]([NH:13][C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:25](=[O:26])[C:24]2[C:23]([Cl:22])=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:32])=[CH:8][CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)OC(C)(C)C
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 88.5 %

Procedure:
To a solution of (S)-3-[4-aminophenyl]-2-tert-butoxycarbonylamino-propionic acid methyl ester (37.57 g, 127.6 mmol) and 2,6-dichlorobenzoyl chloride (29.45 g, 140.6 mmol) in dichloromethane (350 mL) was added DIPEA (24.8 g, 192 mmol) at room temperature. The brown solution was stirred for 15 h at room temperature to afford a white suspension at this time TLC analysis of the mixture indicated the absence of starting material. Then, the solids were collected by filtration and the solids were washed with dichloromethane (150 mL) and air dried to obtain 52.75 g (88.4% yield) of (S)-2-tert-butoxycarbonylamino-3-[4-(2,6-dichlorobenzoylamino)phenyl]propionic acid methyl ester as a white solid: mp 192-194° C. ES(+)-HRMS m/e calcd. for C22H24Cl2N2O5 (M+H)+ 466.1062, obsd. 466.1069.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]1[CH:12]2[CH2:13][C:14](=[O:16])[CH2:15][CH:11]2[CH2:10][NH:9]1.C(=O)([O-])[O-].[K+].[K+].[N:23]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>C(#N)C>[N:23]1([C:29]([N:9]2[CH2:10][CH:11]3[CH2:15][C:14](=[O:16])[CH2:13][CH:12]3[CH2:8]2)=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: O=C1CC2CNCC2C1
Reactant: O=C(Cl)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC2CN(C(=O)N3CCOCC3)CC2C1
Yield: 100 %

Procedure:
Hexahydro-cyclopenta[c]pyrrol-5-one trifluoroacetate 1f (574 mg, 2.4 mmol) was dissolved in 20 mL of acetonitrile with stirring followed by addition of potassium carbonate (0.397 g, 2.88 mmol), and morpholine-4-carbonyl chloride (0.323 mL, 2.64 mmol) upon cooling by an ice-water bath. The reaction mixture was reacted overnight at the same temperature. The mixture was concentrated under reduced pressure and diluted with 50 mL of water. The mixture was extracted with ethyl acetate (50 mL×3). The combined organic extracts were washed with 50 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 2-(morpholine-4-carbonyl)-hexahydro-cyclopenta[c]pyrrol-5-one 7a (0.572 g, yield 77.3%) as a colorless oil.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C@@H:8]2[C@H:11]([NH:12][C:13](=[O:29])/[C:14](=[N:21]\[O:22][C:23]([CH3:28])([CH3:27])[C:24]([OH:26])=[O:25])/[C:15]3[N:16]=[C:17]([NH2:20])[S:18][CH:19]=3)[C:10](=[O:30])[N:9]2[S:31]([OH:34])(=[O:33])=[O:32])[C:3]1=[O:35].Cl.[N:37]1([C:42](=N)[NH2:43])C=CC=N1>>[NH2:20][C:17]1[S:18][CH:19]=[C:15](/[C:14](=[N:21]/[O:22][C:23]([CH3:28])([CH3:27])[C:24]([OH:26])=[O:25])/[C:13]([NH:12][C@@H:11]2[C:10](=[O:30])[N:9]([S:31]([OH:34])(=[O:32])=[O:33])[C@@H:8]2[CH2:7][N:4]2[CH2:5][CH2:6][C@@H:2]([NH:1][C:42]([NH2:43])=[NH:37])[C:3]2=[O:35])=[O:29])[N:16]=1
Reactant: N=C(N)n1cccn1
Reactant: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1CN1CC[C@@H](N)C1=O)c1csc(N)n1)C(=O)O
Agent: Cl
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1CN1CC[C@@H](NC(=N)N)C1=O)c1csc(N)n1)C(=O)O

Procedure:
Prepared in analogous manner to example 20, using 2-(((Z)-(2-(((2R,3S)-2-(((R)-3-amino-2-oxopyrrolidin-1-yl)methyl)-4-oxo-1-sulfoazetidin-3-yl)amino)-1-(2-aminothiazol-4-yl)-2-oxoethylidene)amino)oxy)-2-methylpropanoic acid and 1H-pyrazole-1-carboximidamide HCl. LCMS: m/z=574.1 (M−1); 1H NMR (400 MHz, D2O): δ 6.93 (s, 1H), 5.28 (d, J=5.6 Hz, 1H), 4.53 (m, 1H), 4.24 (t, J=9.6 & 9.2 Hz, 1H), 3.85 (dd, J=9.2 & 9.2 Hz, 1H), 3.51 (m, 1H), 3.40 (t, J=9.2 & 8.8 Hz, 1H), 3.32 (dd, 1H), 3.34 (dd, 1H), 2.43 (m, 1H), 1.87 (m, 1H), 1.36 (s, 3H), 1.32 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([N:10]2[C@@:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)([CH3:15])[C@@:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)([CH3:23])[N:12]=[C:11]2[C:31]2[CH:32]=[N:33][C:34]([C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:35][C:36]=2[O:37][CH2:38][CH3:39])=[O:9])[CH2:3][CH2:2]1.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>ClCCl>[CH3:44][S:45]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8]([N:10]2[C@@:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)([CH3:15])[C@@:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)([CH3:23])[N:12]=[C:11]2[C:31]2[CH:32]=[N:33][C:34]([C:40]([CH3:42])([CH3:41])[CH3:43])=[CH:35][C:36]=2[O:37][CH2:38][CH3:39])=[O:9])[CH2:5][CH2:6]1)(=[O:47])=[O:46]
Reactant: CS(=O)(=O)Cl
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)NC1CCNCC1
Solvent: ClCCl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)NC1CCN(S(C)(=O)=O)CC1
Reaction time: 1 h
Yield: 93.3 %

Procedure:
(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carboxylic acid piperidin-4-yl amide (56.5 mg, 0.091 mmole) in dichloromethane (6 mL) was treated with methanesulfonyl chloride (26.0 mg, 0.226 mmole, Aldrich) at 0° C. and allowed to stir for 1 h before diluted with dichloromethane (60 mL), washed with aqueous sodium carbonate (15 mL), water (15 mL) and concentrated. The residue was purified by flash column chromatography (silica gel, eluting with a gradient of 1-10% methanol in dichloromethane) to give the title compound (59.5 mg). HR-MS (ES, m/z) calculated for C35H44Cl2N5O4S [(M+H)+] 700.2486, observed 700.2482.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1.I[CH:18]([CH:20](I)[CH3:21])[CH3:19].O.O.[Sn](Cl)(Cl)(Cl)Cl>CN(C=O)C.CCO>[CH3:3][O:4][C:5]([C:6]1([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[CH2:21][CH2:20][CH2:18][CH2:19]1)=[O:16]
Reactant: CC(I)C(C)I
Reactant: COC(=O)Cc1ccc([N+](=O)[O-])cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCO
Product: COC(=O)C1(c2ccc(N)cc2)CCCC1
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 39.7 %

Procedure:
Sodium hydride (2.8 g, 60% dispersion in mineral oil) was added slowly to a solution of (4-nitro-phenyl)-acetic acid methyl ester (6.0 g, 30.7 mmol) in anhydrous DMF (30 mL) under nitrogen at a temperature in the range of 0° C. to 10° C. After stirring at a temperature in the range of 0° C. to 10° C. for 20 min, diiodobutane (7.86 mL, 61 mmol) was added drop-wise under stirring. After complete addition, the reaction mixture was warmed to a temperature in the range of 15° C. to 40° C. and stirring continued for an additional 3 hours. The reaction was quenched by adding water slowly. The mixture was extracted by ethyl acetate (3×40 mL). The combined organic extracts were washed with water, brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resultant gummy material was purified by column chromatography over silica gel to afford a pale yellow thick liquid which solidified on standing at a temperature in the range of 15° C. to 40° C. (4.1 g, 54% yield). The solid (3.4 g, 13.6 mmol) was dissolved in anhydrous EtOH and tin chloride dihydrate (13.86 g, 61 mmol) was added slowly under nitrogen. Thereafter, the mixture was heated at 90° C. for 3 hours. After evaporation of volatiles under reduced pressure, the resultant mixture was diluted with ice-water and aqueous sodium hydroxide was added to adjust pH ˜11. The mixture was extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with water, brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to afford the title compound as a granular light yellow solid (2.67 g, 88% yield).
Reaction SMILES: [CH3:1][O-:2].[Na+].[Br:4][C@H:5]1[C@@H:11]2[CH2:12][C@@H:8]([C:9](=[O:13])[O:10]2)[C@H:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Br:20])[CH2:6]1.Cl>CO>[Br:4][C@H:5]1[C@@H:11]([OH:10])[CH2:12][C@@H:8]([C:9]([O:2][CH3:1])=[O:13])[C@H:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Br:20])[CH2:6]1
Reactant: C[O-]
Reactant: O=C1O[C@H]2C[C@@H]1[C@H](c1ccccc1Br)C[C@H]2Br
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@@H]1C[C@H](O)[C@H](Br)C[C@H]1c1ccccc1Br

Procedure:
Freshly prepared sodium methoxide (0.45 M in methanol) was added to a methanol (20 mL) solution of (1R,2R,4R,5S)-4-bromo-2-(2-bromophenyl)-6-oxabicyclo [3.2.1] octan-7-one (5.43 g, 15.1 mmol) with stirrng at rt for 1.5 hours. The mixture was then treated with 0.5 M HCl (50 ml) and the methanol was removed by rotary evaporation under reduced pressure. The residue was partitioned between water and ethyl acetate and the layers separated. The aqueous phase was extracted with additional ethyl acetate and the combined organics were washed with water, 5% Na2CO3 (2×75 mL) and brine, and dried (Na2SO4). Concentration in vacuo yielded methyl (1R,2R,4R,5S)-4-bromo-2-(2-bromophenyl)-5-hydroxycyclohexanecarboxylate as a faint-yellow solid after trituration with ether/hexanes.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[Cl:21][CH2:22][C:23](Cl)=[O:24]>ClCCl>[Cl:21][CH2:22][C:23]([N:2]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)[CH3:1])=[O:24]
Reactant: O=C(Cl)CCl
Reactant: CNc1ccc(C(=O)O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C(=O)CCl)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The starting material is prepared as follows: There are added to 30 g of 4-(N-methylamino)benzoic acid in 500 ml of dichloromethane 30.7 g of Hunig base and, at 5°, 24.6 g of chloroacetyl chloride in 50 ml of dichloromethane. After stirring for 2 hours at RT, the suspension is concentrated by evaporation, and the residue is digested with water, filtered with suction and washed with 1N hydrochloric acid. The mixture is digested with ether and filtered with suction, yielding 4-(N-chloroacetyl-N-methylamino)benzoic acid having a melting point (186°) of 195°-197°. 10 g thereof are boiled under reflux for 2 hours in 150 ml methylene chloride with 5 drops of pyridine with 15 ml of thionyl chloride, concentrated by evaporation and recrystallised from hexane. The resulting 4-(N-chloroacetyl-N-methylamino)benzoic acid chloride melts at 61°-63°.
Reaction SMILES: [H-].[Na+].[SH:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH:10]([C:17]1[N:18]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:19]2[C:24]([C:25](=[O:27])[CH:26]=1)=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=[C:21](Cl)[N:20]=2)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CN(C=O)C>[NH:10]([C:17]1[N:18]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:19]2[N:20]=[C:21]([S:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:22]=[C:23]([C:28]([F:31])([F:30])[F:29])[C:24]=2[C:25](=[O:27])[CH:26]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)CS
Reactant: O=c1cc(Nc2ccccc2)n(-c2ccccc2)c2nc(Cl)cc(C(F)(F)F)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CSc1cc(C(F)(F)F)c2c(=O)cc(Nc3ccccc3)n(-c3ccccc3)c2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 27.7 %

Procedure:
NaH (60% dispersion in oil, 18.0 mg, 0.434 mmol) was added to a cooled (0° C.) and stirred solution of ethyl mercaptoacetate (0.05 mL, 0.434 mmol) in DMF. After 0.5 h, 2-anilino-7-chloro-1-phenyl-5-(trifluoromethyl)-1,8-naphthyridin-4(1H)-one (150.0 mg, 0.361 mmol) was added as a solid in a single portion. The mixture was allowed to warm to room temperature and was stirred for 24 h. The reaction was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. Purification by preparative HPLC (10% CH3CN in water with 0.1% TFA to 95% CH3CN in water, 10 mL/min, 10 min) provided ethyl {[7-anilino-5-oxo-8-phenyl-4-(trifluoromethyl)-5,8-dihydro-1,8-naphthyridin-2-yl]sulfanyl}acetate (50 mg, 53%): LCMS RT: 3.91 min, MH+: 500.2, Rf=0.24 (1:1 EtOAc:Hex).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=2[C:14]([F:17])([F:16])[F:15])[CH:4]=[CH:5][N:6]=1.C(N(CC)CC)C.[CH3:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][C:27]=1[N+:35]([O-])=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:35][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][C:26]=1[CH3:25])[C:30]([NH:13][C:10]1[CH:11]=[CH:12][C:7]([N:3]2[CH:4]=[CH:5][N:6]=[C:2]2[CH3:1])=[C:8]([C:14]([F:17])([F:15])[F:16])[CH:9]=1)=[O:31]
Reactant: Cc1nccn1-c1ccc(N)cc1C(F)(F)F
Reactant: Cc1ccc(C(=O)Cl)cc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)Nc2ccc(-n3ccnc3C)c(C(F)(F)F)c2)cc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(2-methyl-imidazol-1-yl)-3-trifluoromethyl-phenylamine (1.0 g, 4.15 mmol), triethylamine (1.74 mL, 12.5 mmol) in anhydrous CH2Cl2 (60 mL) at 0° C. is added 4-methyl-3-nitro-benzoyl chloride (660 μL, 4.57 mmol) dropwise. After stirring for 2 hours at room temperature, the reaction mixture is poured into 100 mL CH2Cl2 and 50 mL saturated NaHCO3 solution with rapid stirring. After 10 minutes, the mixture is partitioned in a separator funnel and extracted three times with 100 mL CH2Cl2. The organic extracts are washed with brine, and dried over MgSO4. Filtration and concentration under reduced pressure, afforded the desired compound, which is used in the next step without any further purification.
Reaction SMILES: [CH2:1]([C@H:8]([NH:20][C:21](=[O:31])[O:22][C@@H:23]1[C@H:30]2[C@H:26]([O:27][CH2:28][CH2:29]2)[O:25][CH2:24]1)[C@H:9]([OH:19])[CH2:10][NH:11][O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:32]1[C:36]2[CH:37]=[CH:38][C:39]([S:41](Cl)(=[O:43])=[O:42])=[CH:40][C:35]=2[O:34][CH2:33]1.C(N(C(C)C)CC)(C)C>O1CCCC1.CN(C1C=CC=CN=1)C>[O:32]1[C:36]2[CH:37]=[CH:38][C:39]([S:41]([N:11]([O:12][CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)[CH2:10][C@@H:9]([OH:19])[C@@H:8]([NH:20][C:21](=[O:31])[O:22][C@@H:23]3[C@H:30]4[C@H:26]([O:27][CH2:28][CH2:29]4)[O:25][CH2:24]3)[CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)(=[O:42])=[O:43])=[CH:40][C:35]=2[O:34][CH2:33]1
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CNOC1CCCCC1)O[C@H]1CO[C@H]2OCC[C@H]21
Reactant: O=S(=O)(Cl)c1ccc2c(c1)OCO2
Agent: CN(C)c1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CN(OC1CCCCC1)S(=O)(=O)c1ccc2c(c1)OCO2)O[C@H]1CO[C@H]2OCC[C@H]21
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.4 %

Procedure:
A mixture of (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-benzyl-3-[(cyclohexyloxy)amino]-2-hydroxypropylcarbamate (100 mg, 0.230), 1,3-benzodioxole-5-sulfonyl chloride (Eur. Pat. Appl. 583960, Feb 23, 1994, 56 mg, 0.253 mmol) and diisoproylethylamine (0.042 mL, 0.242 mmol) in anhydrous tetrahydrofuran (3 mL) was stirred at ambient temperature under an Argon atmosphere for 16 hours. A catalytic quantity of dimethylaminopyridine (˜1 mg) was added and the reaction was heated at reflux for approximately 2 hours. An additional quantity of 1,3-benzodioxole-5-sulfonyl chloride (11 mg, 0.050 mmol) was added and the reaction was heated for an additional hour. After cooling to ambient temperature, the reaction mixture was partitioned between ethyl acetate and aqueous hydrochloric acid. After separating the phases, the organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue was purified on a preparative TLC plate (20×20 cm, 500 μM) eluting with 1:1 ethyl acetate:hexane. The product band was removed, eluted with 3:1 methylene chloride : methanol, filtered, and evaporated in vacuo. The residue was triturated with water, filtered and dried under high vacuum to provide (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(cyclohexyloxy)amino]-1-benzyl-2-hydroxypropylcarbamate (123 mg, 87%) as a white solid. H1-NMR (chloroform-D3): 1.32 (m, 6H), 1.70 (m, 5H), 2.14 (m, 2H), 3.00 (m, 4H), 3.18 (b, 1H), 3.74 (m, 2H), 3.97 (m, 4H), 4.27 (m, 1H), 4.90 (m, 1H), 5.07 (m, 1H), 5.70 (d, 1H), 6.15 (s, 2H), 6.95 (d, 1H), 7.30 (m, 7H). MS(ESI): 641(M+Na).
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.[CH3:47][CH:48]([CH3:53])[CH2:49][C:50](Cl)=[O:51].O>N1C=CC=CC=1>[NH:18]1[CH:19]=[N:20][C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:41]=[C:42]([NH:46][C:50](=[O:51])[CH2:49][CH:48]([CH3:53])[CH3:47])[CH:43]=[CH:44][CH:45]=2)=[N:17]1
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: CC(C)CC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(C)CC(=O)Nc1cccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 2.1 %

Procedure:
To a solution of 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.400 g, 0.66 mmol) in pyridine (4 mL) was added 3-methylbutanoyl chloride (0.100 mL, 0.80 mmol). The reaction was stirred at room temperature for 15 h. Water (10 mL) was added and the solid collected by suction filtration. The solid was dried in a vacuum oven for 3 h. The residue was dissolved in 4 N hydrochloric acid in 1,4-dioxane (10 mL) and the mixture was stirred at room temperature for 2 h. After neutralization with aqueous sodium bicarbonate, the reaction mixture was extracted with ethyl acetate. The combined organic fractions were dried over anhydrous sodium sulfate, filtered and evaporated. Addition of dichloromethane (10 mL) to the residue gave the title compound (0.005 g, 5% yield) which was isolated by filtration: 1H NMR (DMSO-d6) δ 14.20 (br s, 1H), 13.43 (s, 1H), 10.08 (s, 1H), 8.69 (s, 1H), 8.25 (s, 1H), 8.10 (d, 1H), 7.75 (d, 1H), 7.69 (t, 3H), 7.49 (t, 1H), 2.24 (d, 2H), 2.18 (m, 1H), 0.96 (d, 6H); ES-MS (m/z) 361 [M+1]+.