Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:10]1([O:15][CH2:14][CH2:13][O:12]1)[CH3:11])[C:5]([O:7]CC)=[O:6].[OH-].[Na+].Cl>C(O)C>[CH3:1][O:2][N:3]=[C:4]([C:10]1([O:12][CH2:13][CH2:14][O:15]1)[CH3:11])[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)C(=NOC)C1(C)OCCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CON=C(C(=O)O)C1(C)OCCO1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.3 %

Procedure:
To a solution of ethyl 2-methoxyimino-3,3-ethylenedioxybutyrate (syn isomer, 180 g) in ethanol (1080 ml) was added 1 N aqueous solution of sodium hydroxide (1660 ml) and the mixture was stirred for 2 hours and 10 minutes at ambient temperature. After the reaction mixture was adjusted to pH 7.3 with 6 N hydrochloric acid, ethanol was distilled off under reduced pressure and then washed with diethyl ether (500 ml×2). To the resultant was added diethyl ether (1 l), adjusted to pH 1.5 with 6 N hydrochloric acid and then diethyl ether layer was separated. The remaining aqueous layer was further extracted with diethyl ether (350 ml), and the remaining aqueous layer was adjusted to pH 1.3 with 6 N hydrochloric acid and then further extracted with diethyl ether (350 ml×2). The diethyl ether layer and extracts were combined together, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then filtered. The filtrate was concentrated to give an oil (155.6 g) of 2-methoxyimino-3,3-ethylenedioxybutyric acid (syn isomer). (Yield: 99.3%)
Reaction SMILES: [CH2:1]([NH:8][C@@H:9]1[CH2:16][N:15]2[C:17]3[CH:18]=[C:19]([C:30]([O:32][CH3:33])=[O:31])[CH:20]=[CH:21][C:22]=3[C:23]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[C:14]2[C:13]2[CH:34]=[CH:35][C:36]([F:38])=[CH:37][C:12]=2[O:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH3-]C#N.[Na+].[C:43]([NH:50][CH2:51][CH:52]=O)([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44]>CO.CC(O)=O>[CH2:1]([N:8]([CH2:52][CH2:51][NH:50][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C@@H:9]1[CH2:16][N:15]2[C:17]3[CH:18]=[C:19]([C:30]([O:32][CH3:33])=[O:31])[CH:20]=[CH:21][C:22]=3[C:23]([CH:24]3[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]3)=[C:14]2[C:13]2[CH:34]=[CH:35][C:36]([F:38])=[CH:37][C:12]=2[O:11][CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCC=O
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](NCc1ccccc1)COc1cc(F)ccc1-3
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N(CCNC(=O)OC(C)(C)C)Cc1ccccc1)COc1cc(F)ccc1-3
Temperature: 25 °C
Yield: 71 %

Procedure:
To the solution of methyl (7R)-7-(benzylamino)-14-cyclohexyl-3-fluoro-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate in MeOH/HOAc containing NaCNBH3 from the previous step was added N-Boc-2-aminoacetaldehyde (1.5 eq) and the solution was stirred at RT. After 1 h all volatiles were evaporated. The residual material was taken up with EtOAc and the resulting solution was washed with sat. aq. NaHCO3 and brine. After drying over Na2SO4 all volatiles were evaporated in vacuo. The yellow residue was subjected to FC (PE:EtOAc, 8:2+1% NEt3). After evaporation of the solvents the product was obtained as a colourless solid (71%). (ES+) m/z 656 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][CH:3]([C:5]1[CH:10]=[C:9]([S:11](=[O:14])(=[O:13])[NH2:12])[CH:8]=[CH:7][C:6]=1[O:15][CH3:16])[OH:4].ClCCl.C1(N=C=NC2CCCCC2)CCCCC1.CN(C1C=CC=CN=1)C.[C:44](O)(=[O:46])[CH3:45]>CN(C)C=O>[C:44]([O:4][CH:3]([CH2:2][Cl:1])[C:5]1[CH:10]=[C:9]([S:11](=[O:14])(=[O:13])[NH2:12])[CH:8]=[CH:7][C:6]=1[O:15][CH3:16])(=[O:46])[CH3:45]
Reactant: CC(=O)O
Reactant: COc1ccc(S(N)(=O)=O)cc1C(O)CCl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(S(N)(=O)=O)cc1C(CCl)OC(C)=O

Procedure:
2.64 g (9.9 mmol) of α-chloromethyl-2-methoxy-5-sulphamoylbenzenemethanol and 100 ml of dichloromethane are introduced into a 250-ml round-bottomed flask. 10 ml of dimethylformamide are then added with stirring, followed by 852 μl of acetic acid, 2.56 g of dicyclohexylcarbodiimide and 121 mg of dimethylaminopyridine. The mixture is allowed to react for 1 hour at room temperature, and is then filtered and rinsed with 50 ml of 5% sodium hydrogen carbonate solution and then with 50 ml of water. The rinsing liquors are extracted with 2 times 20 ml of acetic acid, and the organic phases are then combined, dried and concentrated. On chromatographing the residue on a silica column with a 25:75 mixture of ethyl acetate and cyclohexane, 1.9 g of product are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[C:5]([C:6]([NH:8][CH3:9])=[O:7])=[CH:4][N:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[K+].[F:29][C:30]([F:44])([F:43])[C:31]1[CH:32]=[C:33]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[CH2:34]Br>O1CCCC1>[F:29][C:30]([F:44])([F:43])[C:31]1[CH:32]=[C:33]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[CH2:34][N:8]([CH3:9])[C:6](=[O:7])[C:5]1[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:11][C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: CNC(=O)c1cnc(Cl)cc1-c1ccccc1C
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccccc1-c1cc(Cl)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.4 %

Procedure:
To a solution of 10.0 g (38.4 mmol) 6-chloro-N-methyl-4-o-tolyl-nicotinamide in 190 ml tetrahydrofuran 46 ml of a 1 M solution (46 mmol) of potassium hexamethyldisilazide in tetrahydrofuran were added at 0° C. After 30 min, 8.5 ml (46 mmol) 3,5-bis(trifluoromethyl)benzyl bromide were added dropwise to the resulting suspension. After completed addition the ice-water cooling bath was removed and the reaction mixture was allowed to warm to room temperature. After 2 h the reaction was quenched with water. The mixture was adjusted to pH 3 with 1 M aqueous hydrochloric acid solution and stirred for 10 min. Basification with 1 M aqueous sodium hydroxide solution to pH 8 was followed by concentration to remove tetrahydrofuran. The aqueous residue was extracted with four portions of dichloromethane. The combined organic extracts were dried with sodium sulfate and concentrated to give 21.4 g of crude product. Column chromatography afforded 18.4 g (98.5%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1.CN(C)CCN(C)C.[Li]CCCC.CN(C)[CH:38]=[O:39]>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:38]=[O:39])[N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1
Reactant: CN(C)C=O
Reactant: Clc1nc(N2CCOCC2)c2ncn(C3CCCCO3)c2n1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1nc2c(N3CCOCC3)nc(Cl)nc2n1C1CCCCO1
Temperature: -78 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To a mixture of 4-(2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)morpholine (5 g, 20 mmol) in THF (100 mL) at −78° C. was added tetramethylethylenediamine (3.5 mL, 23 mmol) followed by 2.5 M of n-BuLi (9.3 mL, 23 mmol) dropwise. The reaction was stirred at −78° C. for 1 hour and then N,N-dimethylformamide (2.4 mL, 31 mmol) was added, continue stirred for 1 hours at −78° C. The reaction was quenched with water and extracted with EtOAc. The organic extracts were washed with water, brine, dried over MgSO4 and concentrated. The crude material was triturated with EtOAc to give pure 2-chloro-6-morpholino-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-8-carbaldehyde as a white solid (4.5 g, 80% yield). LC/MS (ESI+): m/z 353 (M+H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([O:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([OH:22])[CH2:18][CH2:17]1)[CH:7]=[N:6]2.[H-].[Na+].[CH3:25]I>C1COCC1.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([O:15][CH:16]1[CH2:21][CH2:20][CH:19]([O:22][CH3:25])[CH2:18][CH2:17]1)[CH:7]=[N:6]2
Reactant: COc1cc2ncc(O[C@H]3CC[C@H](O)CC3)nc2cc1OC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc2ncc(OC3CCC(OC)CC3)nc2cc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 44.9 %

Procedure:
A mixture of cis/trans-4-(6,7-dimethoxy-quinoxalin-2-yloxy)-cyclohexanol (170 mg, 0.56 mmole) and NaH (60%, 22.4 mg, 0.56 mmole) in anhydrous THF/DMF (10 mL/2 mL) is stirred at 0° C. for 10 min. before addition of methyl iodide (50 μL, 0.56 mmole). After being stirred at ROOM TEMPERATURE for four hours, the reaction is quenched with water (0.5 mL) and concentrated. The aqueous layer is extracted with methylene chloride (2×20 mL) and the combined organic solutions are washed with brine (5 mL). The residue after concentration is chromatographed on silica gel (30% ethyl acetate/hexane) to give 80 mg (45%) of the desired product (m.p. 85-90° C.).
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]2=[CH:13][CH:14]=1)([O-])=O.[F-:15].[K+].Cl>CS(C)=O>[F:15][C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]2=[CH:13][CH:14]=1
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: [F-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: O=C1OC(=O)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 34.8 %

Procedure:
To a reaction vessel fitted with a reflux condenser magnetic stirrer and nitrogen inlet were placed 3.35 grams (0.0174 mol) 4-nitrophthalic anhydride, 2.83 grams (0.036 mol) anhydrous potassium fluoride, and 8 ml. dry dimethyl sulfoxide. The reaction vessel was placed in an oil bath at 142°C. and kept at this temperature for about 35 minutes while stirring the reaction mixture. VPC analysis of a portion of the reaction mixture showed that the reaction was complete after about 20 minutes. The reaction mixture was cooled to room temperature and then poured into dilute aqueous hydrochloric acid and extracted with ethyl acetate to give a product which upon distillation gave 1.007 grams (about 35% yield) of 4-fluorophthalic anhydride.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[F:9].CCCCCC.C([Li])CCC.[I:21]I.[Cl-].[NH4+]>C1COCC1.CCCCCC>[F:9][C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[I:21]
Reactant: Cc1ccc(Br)c(F)c1
Reactant: II
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(I)c(F)c1
Temperature: -72 °C
Reaction time: 1 h
Yield: 104.1 %

Procedure:
Under dry nitrogen, a solution prepared by dissolving 4-bromo-3-fluorotoluene (10 g) in THF (50 mL) was cooled to −72° C. Then, a 1.6 mol/L n-butyl lithium hexane solution (35 mL) was added at −72° C. to the solution such a rate that the inside temperature was not more than −65° C., followed by further stirring at −72° C. for 1 hour. A solution prepared by dissolving iodine (14.8 g) in THF (30 mL) was added at −72° C. to the resultant mixture such a rate that the inside temperature was not more than −60° C., and the temperature was slowly increased to room temperature. Then, a saturated aqueous ammonium chloride solution and hexane were added at room temperature to separate an organic layer, and the organic layer was washed with a 10% aqueous sodium sulfite solution two times and saturated brine in that order, and then dried with sodium sulfate. The sodium sulfate was filtered off, and the organic solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to yield 13.0 g of 3-fluoro-4-iodotoluene as a yellow liquid.
Reaction SMILES: [CH:1]([S:5][C:6]1[C:11]([CH2:12]Cl)=[CH:10][CH:9]=[CH:8][N:7]=1)([CH2:3][CH3:4])[CH3:2].[CH2:14]([O:16][C:17](=[O:29])[CH2:18][CH2:19][C:20]1[CH:25]=[C:24]([F:26])[C:23]([OH:27])=[C:22]([F:28])[CH:21]=1)[CH3:15]>>[CH2:14]([O:16][C:17](=[O:29])[CH2:18][CH2:19][C:20]1[CH:25]=[C:24]([F:26])[C:23]([O:27][CH2:12][C:11]2[C:6]([S:5][CH:1]([CH2:3][CH3:4])[CH3:2])=[N:7][CH:8]=[CH:9][CH:10]=2)=[C:22]([F:28])[CH:21]=1)[CH3:15]
Reactant: CCC(C)Sc1ncccc1CCl
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Product: CCOC(=O)CCc1cc(F)c(OCc2cccnc2SC(C)CC)c(F)c1
Yield: 65 %

Procedure:
2-sec-Butylsulfanyl-3-chloromethyl-pyridine (0.06 g, 0.27 mmol) obtained in Step C of Preparation Example 33 and 3-(3,5-difluoro-4-hydroxy-phenyl)-propionic acid ethyl ester obtained in Step D of Preparation Example 2 were reacted in the same manner as in Step A of Example 1 to obtain the title compound (0.074 g, 65%).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1.[CH2:15]([C:22]1[C:27]([Cl:28])=[CH:26][C:25]([N+:29]([O-:31])=[O:30])=[CH:24][C:23]=1[Cl:32])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>ClCCl.C(Cl)(Cl)Cl>[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([C:19]2[CH:20]=[CH:21][C:16]([CH2:15][C:22]3[C:27]([Cl:28])=[CH:26][C:25]([N+:29]([O-:31])=[O:30])=[CH:24][C:23]=3[Cl:32])=[CH:17][CH:18]=2)=[O:11])=[CH:8][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cc2ccccc2)c(Cl)c1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=C(c1ccc(Cl)cc1)c1ccc(Cc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In 15 ml of dichloromethane was suspended 1.30 g of AlCl3, and a solution of 1.43 g of 4-chlorobenzoyl chloride in 3 ml of dichloromethane was added to the suspension for a period of 30 minutes. A solution of 2.00 g of 4-benzyl-3,5-dichloronitrobenzene in 2 ml of dichloromethane was added for a period of 15 minutes, and the reaction mixture was refluxed for 22 hours. The reaction mixture was poured into 25 ml of ice-water, and 30 ml of chloroform and 3 ml of conc. hydrochloric acid were added. The resulting mixture was stirred for 15 minutes at a room temperature, and the organic layer was separated, washed with water and saturated aqueous sodium bicarbonate solution, dried and concentrated to quantitatively give the above-identified compound as oil.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:16]=[CH:15][C:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14][C:8]=2[CH:7]=1)(=[O:4])=[O:3].C([N:19]([CH2:22][CH3:23])CC)C>C(O)C>[CH3:1][S:2]([NH:5][C:6]1[CH:16]=[CH:15][C:9]2[CH2:10][CH2:11][N:12]([CH2:10][CH2:9][C:8]3[CH:14]=[CH:23][C:22]([NH:19][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)[CH2:13][CH2:14][C:8]=2[CH:7]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)CCNCC2
Reactant: CCN(CC)CC
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc(CCN2CCc3ccc(NS(C)(=O)=O)cc3CC2)cc1

Procedure:
7-Methanesulphonamido-1,2,4,5-tetrahydro-3H-3-benzazepine (0.21 g), 4-[2-(methanesulphonyloxy)ethyl]methanesulphonanilide (0.26 g) (see EP-A-0245997, Preparation 7) and triethylamine (0.12 ml) were heated at reflux temperature in ethanol for 24 hours. The solvent was removed in vacuo and the residue taken up in methylene chloride, washed with aqueous sodium bicarbonate, brine and then water. The organic layer was dried (Na2SO4), evaporated in vacuo and the residue purified by column chromatography on silica eluting with methylene chloride containing methanol (0% up to 5%). The product-containing fractions were combined and evaporated to give a solid which was recrystallised to give the title compound, yield 0.05 g, m.p. 190°-193°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C@H:12]2[CH2:14][O:13]2)=[C:6]([CH:9]=1)C=O.C1C=C(Cl)C=C([C:22]([O:24]O)=[O:23])C=1>C(Cl)Cl>[CH:22]([O:24][C:6]1[CH:9]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[O:10][CH2:11][C@H:12]1[CH2:14][O:13]1)=[O:23]
Reactant: O=Cc1cc(Br)ccc1OC[C@H]1CO1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=COc1cc(Br)ccc1OC[C@H]1CO1

Procedure:
Preparation according to Preparation 2 using 5-bromo-2-[(2R)-oxiran-2-ylmethoxy]benzaldehyde (6.8 g, 26 mmol), DCM (75 ml) and m-CPBA (77%, 8.9 g, 39.5 mmol). Crude yield: 7.0 g. MS m/z (rel. intensity, 70 eV) 274 (M+, 10), 273 (M+, 9), 189 (98), 188 (bp), 57 (77).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([NH:26][C:27]([C:29]4[S:30][CH:31]=[CH:32][CH:33]=4)=[O:28])[CH:22]=[CH:23][C:24]=3[CH3:25])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:38].Cl.Cl.[NH:41]1[CH:45]=[CH:44][N:43]=[C:42]1[CH2:46][NH2:47]>>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:47][CH2:46][C:42]3[NH:41][CH:45]=[CH:44][N:43]=3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([NH:26][C:27]([C:29]4[S:30][CH:31]=[CH:32][CH:33]=4)=[O:28])[CH:22]=[CH:23][C:24]=3[CH3:25])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:38]
Reactant: NCc1ncc[nH]1
Reactant: Cc1ccc(NC(=O)c2cccs2)cc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Agent: Cl
Product: Cc1ccc(NC(=O)c2cccs2)cc1-c1nc(NCc2ncc[nH]2)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
The title compound was prepared as described in Example 1d from N-{3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylphenyl}-2-thiophenecarboxamide and (1H-imidazol-2-ylmethyl)amine dihydrochloride: LC-MS m/z 570 (M+H)+, 1.70 min (ret time).
Reaction SMILES: [NH2:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[OH-].[Na+].[CH2:18]=O.Cl>O>[CH2:18]1[C:5]2[NH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:4]=2[CH2:3][CH:2]([C:13]([OH:15])=[O:14])[NH:1]1
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C1Cc2c([nH]c3ccccc23)CN1
Reaction time: 8 h
Yield: 85.1 %

Procedure:
L-tryptophan (10.2 g, 50 mmol), NaOH (2.0 g, 50 mmol) and H2O (20 ml) were added in a 250 ml round-bottom flask, and were stirred until the mixture became clear followed by the addition of formaldehyde (37%, 50 mmol). The mixture was stirred and reacted at room temperature for 3 h. After being refluxed for another 3 h, the mixture was poured into 200 ml cold water. While being stirred, the mixture was adjusted to pH 6 with 5N HCl. White solids were precipitated and then stored at 4° C. overnight. The white solids were filtered, washed well with water and a small amount of methanol, dried, and recrystallized with methanol to obtain white solids (9.2 g, 85%), mp 308-309° C. (reference: 309-310° C.).
Reaction SMILES: Cl.[NH2:2][OH:3].[C:4]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]=[CH:21][C:22](Cl)=[O:23])=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1>O1CCCC1>[OH:3][NH:2][C:22](=[O:23])/[CH:21]=[CH:20]/[C:17]1[CH:18]=[CH:19][C:14]([NH:13][S:10]([C:7]2[CH:8]=[CH:9][C:4]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:5][CH:6]=2)(=[O:12])=[O:11])=[CH:15][CH:16]=1
Reactant: NO
Reactant: O=C(Cl)C=Cc1ccc(NS(=O)(=O)c2ccc(-c3ccccc3)cc2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(/C=C/c1ccc(NS(=O)(=O)c2ccc(-c3ccccc3)cc2)cc1)NO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of hydroxylamine hydrochloride (0.27 g, 3.88 mmol) in tetrahydrofuran (5 ml) saturated NaHCO3 solution (3 ml) was added and the resultant mixture was stirred at ambient temperature for 10 min. To the reaction mixture a solution of crude 3-[3-(3-methoxy-phenylsulfamoyl)-phenyl]-acryloyl chloride (83a) (0.27 g, 0.68 mmol) in tetrahydrofuran (3.5 ml) was added and the mixture was stirred at ambient temperature for one hour. The reaction mixture was partitioned between ethyl acetate and 2N HCl. The organic layer was washed successively with water and saturated NaCl, then the solvent was removed. The residue was crystallised from acetonitrile and washed with diethyl ether affording the title compound as a white solid (0.1 g, 37%). M.p. 190-191.5° C. 1H NMR (DMSO-d6, HMDSO) δ: 6.29 (1H, d, J=16.0 Hz); 7.16 (2H, d, J=8.0 Hz); 7.24-7.78 (8H, m); 7.86 (4H, m); 8.94 (1H, br s); 10.57 (1H, s); 10.66 (1H, br s). HPLC analysis on Zorbax SB-C18 column: impurities 4% (column size 4.6×150 mm; mobile phase acetonitrile—0.1% H3PO4F gradient from 30 to 100%; sample concentration 0.2 mg/ml; flow rate 1.0 ml/min; detector UV 254 nm). Anal. Calcd for C21H18N2O4S, %: C 63.94, H 4.60, N 7.10. Found, %: C C 63.64, H 4.45, N 7.00.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([F:29])[C:3]=1[O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[N:10][N:11]2[CH:14]([CH3:20])[C:15]([O:17]CC)=O)=[CH:7][CH:6]=1.[NH3:30]>CO>[Cl:1][C:2]1[CH:24]=[C:23]([C:25]([F:27])([F:28])[F:26])[CH:22]=[C:21]([F:29])[C:3]=1[O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[N:10][N:11]2[CH:14]([CH3:20])[C:15]([NH2:30])=[O:17])=[CH:7][CH:6]=1
Reactant: CCOC(=O)C(C)n1ncc2ccc(Oc3c(F)cc(C(F)(F)F)cc3Cl)cc21
Reactant: N
Solvent: CO
Product: CC(C(N)=O)n1ncc2ccc(Oc3c(F)cc(C(F)(F)F)cc3Cl)cc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Ethyl 2-[6-(2-chloro-4-trifluoromethyl-6-flourophenoxy)indazol-1-yl]propionate (0.41 g) (prepared as in Example 1) was dissolved in methanol (25cm3), 880 ammonia (15cm3) added and the mixture stirred at room temperature for 18 hours. The white precipitate was collected by filtration and the solvent removed from the filtrate under vacuum. The residue was purified by flash chromatography (SiO2 ; EtOAc) to give compound 19, 2-[6-(2-chloro-4-trifluoromethyl-6-fluorophenoxy)indazol-1-yl]propionamide as a white solid; total yield=250 mgs. m.pt 171°-172.5 ° C.
Reaction SMILES: [F:1][C:2]1[C:7]2[O:8][C:9]([CH3:14])([CH3:13])[C:10](=O)[NH:11][C:6]=2[CH:5]=[C:4]([N+:15]([O-:17])=[O:16])[CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19]>C1COCC1>[F:1][C:2]1[C:7]2[O:8][C:9]([CH3:14])([CH3:13])[C:10](=[S:19])[NH:11][C:6]=2[CH:5]=[C:4]([N+:15]([O-:17])=[O:16])[CH:3]=1
Reactant: CC1(C)Oc2c(F)cc([N+](=O)[O-])cc2NC1=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: C1CCOC1
Product: CC1(C)Oc2c(F)cc([N+](=O)[O-])cc2NC1=S
Yield: 69 %

Procedure:
To a solution of 8-Fluoro-2,2-dimethyl-6-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (0.75 g, 3.1 mmol) in 25 ml anhydrous THF, P2S5 (2.8 g, 6.25 mmol) was added and the reaction mixture was heated to reflux for 12 hours. Analysis of LC-MS indicated the completion of the reaction. Volatiles were removed in vacuo and the crude reaction mixture was partitioned in EtOAc (100 ml) and saturated aqueous NH4Cl (100 ml). Layers were separated and the organic layer was washed (×2) with saturated aqueous NH4Cl (50 ml). EtOAc layer was dried over Na2SO4 and concentrated to give the product in 69% yield (0.55 g). LCMS (m/z) 257 (MH+).
Reaction SMILES: [CH3:1][NH:2][C:3]([NH2:5])=[O:4].C[O-].[Na+].C(O[C:12](=[O:27])[CH:13]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=1)[C:14]([O:16]CC)=O)C.O>CN(C)C=O>[Cl:26][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[CH2:19][CH:13]1[C:12](=[O:27])[N:2]([CH3:1])[C:3](=[O:4])[NH:5][C:14]1=[O:16]
Reactant: CNC(N)=O
Reactant: CCOC(=O)C(Cc1cccc(Cl)c1)C(=O)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)NC(=O)C(Cc2cccc(Cl)c2)C1=O
Temperature: 130 °C

Procedure:
Methylurea (1.18 g, 16.0 mmol) and freshly prepared sodium methoxide (1.04 g, 19.2 mmol) were combined in dimethylformamide (15 mL) and a solution of 2-(3-chlorobenzyl)malonic acid diethyl ester (2.85 g, 10.0 mmol) in dimethylformamide (5 mL) was added. The reaction temperature was raised to 130° C. for 2 hours and then cooled to ambient temperature before water was added and the solution acidified with 2N HClaq. The resulting solid was filtered then washed with water and the dried to afford the product as a white solid, 840 mg. LC-MS: RT=2.87 mins, 267 (M+H)+ 265 (M−H)−.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:9]2[C:10](=[O:15])[O:11][C:12](=O)[NH:13][C:8]=2[CH:7]=[C:6]([C:16]([F:19])([F:18])[F:17])[CH:5]=1.C(OCC)C>CO>[NH2:13][C:8]1[CH:7]=[C:6]([C:16]([F:17])([F:18])[F:19])[CH:5]=[C:4]([Cl:3])[C:9]=1[C:10]([O:11][CH3:12])=[O:15]
Reactant: O=c1[nH]c2cc(C(F)(F)F)cc(Cl)c2c(=O)o1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Product: COC(=O)c1c(N)cc(C(F)(F)F)cc1Cl
Temperature: 60 °C
Yield: 87.3 %

Procedure:
To a stirred solution of sodium hydroxide (0.012 g, 0.31 mM) in anhydrous methanol (1.5 mL) under a nitrogen atmosphere was added 5-chloro-7-trifluoromethyl-2H-3,1-benzoxazine-2,4(1H)-dione (0.60 g, 2.3 mM). The resulting mixture was warmed to 60° C. for 0.5 hr, allowed to cool to room temperature and poured into diethyl ether. The ether was washed with water, dried (MgSO4), filtered and concentrated to leave (0.50 g, 88%) the title compound as a yellow oil; MS(CI): 254 (M+H).