Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][CH2:25][CH:26]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH3:27])[C:21]([Cl:33])=[CH:20][N:19]=1>>[Cl:33][C:21]1[C:22]([NH:24][CH2:25][CH:26]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH3:27])=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: CC(CNc1nc(Cl)ncc1Cl)NS(C)(=O)=O
Reactant: COCCN1CCc2ccc(N)cc2CC1
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(NCC(C)NS(C)(=O)=O)n3)cc2CC1

Procedure:
N-(2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-1-methyl-ethyl)-methanesulfonamide was prepared from 3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and N-[2-(2,5-dichloro-pyrimidin-4-ylamino)-1-methyl-ethyl]-methanesulfonamide in an analogous manner to Example 300. Product isolated as a white solid (96 mg, 58%). LCMS (m/e) 483 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 7.95 (s, 1H), 7.35-7.23 (m, 2H), 7.05 (d, 1H, J=8.0 Hz), 6.93 (s, 1H), 5.70-5.62 (m, 1H), 5.40-5.31 (m, 1H), 3.55 (t, 2H, J=5.7 Hz), 3.53-3.43 (m, 1H), 3.39 (s, 3H), 2.97-2.87 (m, 4H) 2.90 (s, 3H), 2.80-2.69 (m, 6H), 1.31 (d, 3H, J=6.6 Hz).
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.[S-:13][C:14]#[N:15].[K+].O>C(O)(=O)C>[CH3:2][N:3]1[CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:15][C:14]1=[S:13]
Reactant: CNCC(=O)c1ccccc1
Reactant: N#C[S-]
Agent: Cl
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: Cn1cc(-c2ccccc2)[nH]c1=S
Temperature: 140 °C
Yield: 47.3 %

Procedure:
An adaptation of the method reported by Kjellin and Sandström, Acta Chem. Scand. 1969, 23, 2879-2887 was used. A mixture of 2-methylamino-1-phenyl-ethanone hydrochloride (0.754 g, 4.06 mmol) (see e.g. Hyde et al. J. Am. Chem. Soc. 1928, 50, 2287-2292; Shang et al. Chem. Eur. J. 2007, 13, 7780-7784) and potassium thiocyanate (0.434 g, 4.46 mmol) in acetic acid (12 mL) was heated at 140° C. for 10 minutes using a microwave synthesizer. Dilution with water (50 mL) and cooling in an ice bath caused the product to precipitate. It was collected by filtration, washed with water, and vacuum dried to yield the title compound (0.365 g, 47%) pure as an off-white solid. 1H NMR (500 MHz, DMSO-d6): δ12.66 (br s, 1H), 7.65 (d, J=7.6 Hz, 2H), 7.60 (s, 1H), 7.39 (I, J=7.8 Hz, 2H), 7.27 (t, J=7.4 Hz, 1H), 3.49 (s, 3H).
Reaction SMILES: C1C=CC=CC=1.[CH3:7][NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11].[H-].[Na+].[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>C(#N)C>[CH3:7][N:8]([Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[C:9](=[O:14])[C:10]([F:13])([F:12])[F:11]
Reactant: CNC(=O)C(F)(F)F
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: c1ccccc1
Product: CN(C(=O)C(F)(F)F)[Si](C)(C)C(C)(C)C

Procedure:
To 800 ml of dry benzene:acetonitrile (v/v, 1:1) was added 127 g (1.0 mole) of N-methyl-trifluoroacetamide. To this solution, while stirring and maintaining the temperature at 0 degress C., was slowly added 23.5 g (0.98 mole) of sodium hydride. The solution was then stirred for 4 hours at 4 degrees C. At this time, 173.34 g (1.15 mole) of t-butyldimethylsilyl chloride was added in four equal aliquots over a period of 80 minutes. After the last addition the solution was stirred for 2 hours at 4 degrees C. The precipitate of sodium chloride was then removed from the reaction mixture by filtration under dry nitrogen and the resulting filter cake washed twice with 100 ml each of dry benzene. Washings and filtrate were combined and concentrated. The remaining yellow solution was fractionally distilled with the distillate at 158-172 degrees C. being collected. Redistillation of this fraction gave the desired product.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[Cl:9][C:10]1[CH:11]=[C:12]([CH:29]=O)[C:13]2[O:18][CH:17]([C:19]([F:22])([F:21])[F:20])[C:16]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:15][C:14]=2[CH:28]=1>C(O)C.O>[Cl:9][C:10]1[CH:11]=[C:12]([CH:29]=[N:2][OH:3])[C:13]2[O:18][CH:17]([C:19]([F:22])([F:21])[F:20])[C:16]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:15][C:14]=2[CH:28]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)cc(C=O)c2OC1C(F)(F)F
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1=Cc2cc(Cl)cc(C=NO)c2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.4 h

Procedure:
Hydroxylamine hydrochloride (1.30 g, 18.7 mmol), sodium acetate (1.50 g, 19.4 mmol), and a mixture of ethanol-water (80:20, 15 mL) were stirred at room temperature for 0.4 hours. The aldehyde (Example 76, Step 3)(3.07 g, 9.0 mmol) was dissolved in a solution of ethanol-water (4:1, 25 mL) and added to this mixture and stirred at 100° C. for 1 hour. The reaction was filtered hot and the filtrate allowed to cool to room temperature. An orange solid crystallized in the filtrate which was collected by vacuum filtration. The solid was dissolved in ethyl acetate and the solution washed with water, brine, dried over MgSO4, concentrated in vacuo. The resulting solid was recrystallized from ethyl acetate-hexane yielding the oxime as a tan powder (1.50 g, 47%): mp 186.6–187.6° C. 1H NMR (acetone-d6/300 MHz) 10.87 (s, 1H), 8.34 (s, 1H), 7.90 (s, 1H), 7.77 (d, 1H, J=2.6 Hz), 7.60 (d, 1H, J=2.6 Hz), 6.02 (q, 1H, J=7.1 Hz), 4.35 (m, 2H), 1.34 (t, 3H, J=7.0 Hz).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=[O:14])[C:11](Cl)=[O:12])=[CH:2]1.[CH2:15]([NH2:23])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC#N>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=[O:14])[C:11]([NH:23][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:12])=[CH:2]1
Reactant: NCCc1ccccc1
Reactant: O=C(Cl)C(=O)c1c[nH]c2ccccc12
Solvent: CC#N
Product: O=C(NCCc1ccccc1)C(=O)c1c[nH]c2ccccc12

Procedure:
2-(1H-Indol-3-yl)-2-oxo-N-phenethyl-acetamide was synthesized following scheme I above starting from (1H-indol-3-yl)-oxo-acetyl chloride and phenethylamine. Yield (61%). HPLC ret. time 3.17 min, 10-99% CH3CN, 5 min run; 1H NMR (400 MHz, DMSO-d6) δ 12.23 (s, 1H), 8.79 (t, J=5.9 Hz, 1H), 8.67 (s, 1H), 8.23 (m, 1H), 7.53 (m, 1H), 7.33-7.19 (m, 7H), 3.47 (m, 2H), 2.85 (t, J=7.4 Hz, 2H); ESI-MS 293.3 m/z (MH+).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[C:8]([Cl:15])[C:9]([Cl:14])=[C:10]([Cl:13])[C:11]([Cl:12])=[C:4]2[C:3]1=[O:16].[CH3:17][S:18](Cl)(=[O:20])=[O:19].C(N(CC)CC)C>C(Cl)Cl>[CH3:17][S:18]([O:1][N:2]1[C:3](=[O:16])[C:4]2=[C:11]([Cl:12])[C:10]([Cl:13])=[C:9]([Cl:14])[C:8]([Cl:15])=[C:5]2[C:6]1=[O:7])(=[O:20])=[O:19]
Reactant: O=C1c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)N1O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)ON1C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C1=O
Yield: 87 %

Procedure:
N-Methanesulfonyloxytetrachlorophthalimide was prepared by the following procedure. To a flask equipped with a stirrer and addition funnel were added N-hydroxytetrachlorophthalimide (9.00 g, 0.030 mol), methanesulfonyl chloride (3.60 g, 0.032 mol), and 200 mL of methylene chloride. The mixture was cooled in ice and a solution of triethylamine (5.0 mL, 0.036 mol) in 25 mL of methylene chloride was added slowly. Upon completion of this addition the reaction mixture was diluted with 200 mL of methylene chloride and washed successively with water (250 mL), 5% aqueous sodium bicarbonate (250 mL), and water (250 mL). The organic layer which contained a substantial amount of precipitated product was evaporated, and the resulting solid was dried by addition of toluene and evaporation to give 9.89 g (87.0%) of pale yellow crystalline N-methanesulfonyloxytetrachlorophthalimide: mp 240°-241°; uv (CH3CN) 240 (51,400), 329 (2736), 340 nm (2937); ir (KBr) 3040 (w), 3020 (w), 2940 (w), 1800 (m), 1700 (vs), 1375 (s), 1330 (m), 1310 (m), 1180 (s), 1120 (m), 1030 (s), 965 (m), 790 (m), 725 (s); nmr (CDCl3) 3.53 (s); mass spectrum 376.8472 (calcd for C9H3NO5Cl4S: 376.8783). Anal. Calcd for C9H3NO5Cl4S: C, 28.52; H, 0.80; N, 3.70; O, 21.11; Cl, 37.42; S, 8.46. Found: C, 28.52, 28.94, 28.92; H, 0.80, 1.07, 1.05; N, 3.70, 3.84, 3.82; Cl, 37.42, 37.08.
Reaction SMILES: [C:1]1([C:7]2[N:16]=[C:15]([C:17]([O:19]CC)=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:22]1[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]1.C([Li])CCC>CCCCCC.O1CCCC1>[C:1]1([C:7]2[N:16]=[C:15]([C:17]([N:22]3[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]3)=[O:19])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1nc(-c2ccccc2)nc2ccccc12
Reactant: OC1CCNCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(c1nc(-c2ccccc2)nc2ccccc12)N1CCC(O)CC1

Procedure:
The procedure of Example 24 is followed using ethyl 2-phenylquinazoline-4-carboxylate (2 g), piperidin-4-ol (1.4 g), a 1.6M solution of butyllithium in hexane (18 ml) and tetrahydrofuran (30 ml) as the starting materials. After recrystallisation from a mixture of methanol and methylene chloride, 1-[(2-phenylquinazolin-4-yl)-carbonyl]-piperidin-4-ol (2.1 g), melting at 209° C., is obtained.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[N:7]=[C:6]([CH3:19])[C:5]=2[C:20]([N:22]2[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]2)=[O:21])[CH2:3][CH2:2]1.Cl.[OH:30][CH2:31][C@@H:32]1[C@H:36]([NH:37][C:38](=[O:40])[CH3:39])[CH2:35][CH2:34][NH:33]1>>[CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[N:7]=[C:6]([CH3:19])[C:5]=2[C:20]([N:22]2[CH2:27][CH2:26][CH:25]([N:33]3[CH2:34][CH2:35][C@@H:36]([NH:37][C:38](=[O:40])[CH3:39])[C@H:32]3[CH2:31][OH:30])[CH2:24][CH2:23]2)=[O:21])[CH2:3][CH2:2]1
Reactant: CC(=O)N[C@@H]1CCN[C@@H]1CO
Reactant: Cc1nn(-c2cccc(C(F)(F)F)c2)c(C2CC2)c1C(=O)N1CCC(=O)CC1
Agent: Cl
Product: CC(=O)N[C@@H]1CCN(C2CCN(C(=O)c3c(C)nn(-c4cccc(C(F)(F)F)c4)c3C3CC3)CC2)[C@@H]1CO

Procedure:
The title compound was prepared from 1-[5-Cyclopropyl-3-methyl-1-(3-trifluoromethyl-phenyl)-1H-pyrazole-4-carbonyl]-piperidin-4-one (Example 181B) and N-((2S,3R)-2-hydroxymethyl-pyrrolidin-3-yl)-acetamide hydrochloride in direct analogy to the general procedure used in example 129. MS: 534.2 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6](Br)[CH:5]=1.[CH:12]1(/[CH:18]=[C:19](\B2OC(C)(C)C(C)(C)O2)/[CH2:20][OH:21])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[F-].[Cs+]>O1CCOCC1.C1(P([Pd-4](P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6](/[C:19](/[CH2:20][OH:21])=[CH:18]\[CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:5]=1
Reactant: COC(=O)c1cccc(Br)c1
Reactant: CC1(C)OB(/C(=C\C2CCCCC2)CO)OC1(C)C
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: COC(=O)c1cccc(/C(=C\C2CCCCC2)CO)c1
Yield: 74.7 %

Procedure:
Following the method of example 46a, Suzuki coupling of 3-bromo-benzoic acid methyl ester (1.05 g, 4.88 mmol) with (E)-3-cyclohexyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-prop-2-en-1-ol (1.48 g, 5.56 mmol) in the presence of tetrakis(triphenylphosphino)palladium(0) (0.32 g, 0.28 mmol) and cesium fluoride (2.2 g, 14 mmol) in dioxane (15 mL) gives the title compound (1.0 g). MS (m/e): 257 (M+H−H2O).
Reaction SMILES: [N:1]1([CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:11]([OH:14])[CH2:12][OH:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[N+:21]([C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1)([O-:23])=[O:22]>N1C=CC=CC=1>[OH:14][CH:11]([CH:10]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:12][O:13][C:28](=[O:29])[C:27]1[CH:26]=[CH:25][C:24]([N+:21]([O-:23])=[O:22])=[CH:32][CH:31]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: OCC(O)C(c1ccccc1)n1ccc2ccccc21
Solvent: c1ccncc1
Product: O=C(OCC(O)C(c1ccccc1)n1ccc2ccccc21)c1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h

Procedure:
To a solution of (2RS,3RS)-3-indol-1-yl-3-phenyl-propane-1,2-diol (EXAMPLE 1, step 1, 1.83 g, 6.9 mmol) in anhydrous pyridine (25 mL), p-nitrobenzoyl chloride (1.3 g, 6.9 mmol) in 1 mL of pyridine was added at −10° C. dropwise. After stirring for 30 minutes, the reaction mixture was cooled with an ice bath and quenched with water and a 2N aqueous solution of hydrochloric acid until the solution was pH=3 and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated to give (2RS,3RS)-4-nitro-benzoic acid 2-hydroxy-3-indol-1-yl-3-phenyl-propyl ester quantitatively as a yellow solid. MS (ESI) m/z 417 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1[C:6]([N+:7]([O-])=O)=[C:5]([NH:10][C:11]([C:13]2[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=2[C:15]([O:17][CH3:18])=[O:16])=[O:12])[S:4][N:3]=1.[H][H]>CO.[Pd]>[NH2:7][C:6]1[C:2]([CH3:1])=[N:3][S:4][C:5]=1[NH:10][C:11]([C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16])=[O:12]
Reactant: COC(=O)c1ccccc1C(=O)Nc1snc(C)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccccc1C(=O)Nc1snc(C)c1N

Procedure:
Methyl 2-((3-methyl-4-nitroisothiazol-5-yl)carbamoyl)benzoate was suspended in MeOH (30 mL), Pd/C 10% (477.1 mg, 4.483 mmol) was added and the mixture was hydrogenated at RT under 1 atm of hydrogen (balloon pressure) for 2 h. The catalyst was filtered off and the mixture was concentrated in vacuo, yielding methyl 2-((4-amino-3-methylisothiazol-5-yl)carbamoyl)benzoate. (150 mg, 100%). MS (ES+) 292.1.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[NH:7][CH3:8].[CH3:13][O:14][C:15]1[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][N:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:13][O:14][C:15]1[CH:20]=[C:19]([O:21][C:2]2[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=2)[NH:7][CH3:8])[CH:18]=[CH:17][N:16]=1
Reactant: COc1cc(O)ccn1
Reactant: CNc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CNc1cc(Oc2ccnc(OC)c2)ccc1[N+](=O)[O-]
Yield: 66 %

Procedure:
A solution of 5-fluoro-N-methyl-2-nitroaniline (US2003-675927, 3.30 g, 19.4 mmol), 2-methoxypyridin-4-ol (2.70 g, 21.6 mmol) produced in Example (16b) and cesium carbonate (10.6 g, 32.4 mmol) in DMF (20 mL) was stirred at 80° C. for two hours. After leaving to cool, water (100 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (100 mL). The organic layer was washed with water (100 mL) twice and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography (hexane/ethyl acetate, 2:1) to obtain the title compound (3.90 g, 66%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:19])/[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[C:9]([CH2:20][CH3:21])[C:8]([CH3:22])=[C:7]2[C:3]=1[C:4](=[O:23])[O:5][CH2:6]2.CO.O.[C:27]1(C)C=CC(S(O)(=O)=O)=CC=1>>[NH2:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:19])/[CH2:14][CH2:15][C:16]([O:18][CH3:27])=[O:17])=[C:9]([CH2:20][CH3:21])[C:8]([CH3:22])=[C:7]2[C:3]=1[C:4](=[O:23])[O:5][CH2:6]2
Reactant: CCc1c(C)c2c(c(N)c1C/C=C(\C)CCC(=O)O)C(=O)OC2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CCc1c(C)c2c(c(N)c1C/C=C(\C)CCC(=O)OC)C(=O)OC2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 2.5 g of (E)-6-(4-amino-1,3-dihydro-6-ethyl-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoic acid in 50 ml (1.234 mol) of methanol is added 0.125 g of p-toluenesulfonic acid monohydrate. The solution is stirred at room temperature for 2 days and then concentrated to a small volume, and the residue partitioned between water and ethyl acetate. The organic layer is dried over magnesium sulfate and concentrated to give methyl (E)-6-(4-amino-1,3-dihydro-6-ethyl-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate.
Reaction SMILES: Cl[CH:2]([C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:9][C:8]=1[CH3:18])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][C:21]=1[F:30].C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CN(C)C(=O)C.O>[F:30][C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][C:20]=1[NH:19][CH:2]([C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:9][C:8]=1[CH3:18])[CH2:3][CH:4]([CH3:6])[CH3:5])[C:24]([OH:26])=[O:25]
Reactant: COC(=O)c1ccc(N)c(F)c1
Reactant: Cc1oc(-c2ccccc2)cc1C(Cl)CC(C)C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1oc(-c2ccccc2)cc1C(CC(C)C)Nc1ccc(C(=O)O)cc1F
Temperature: 80 °C
Reaction time: 8 h
Yield: 37.1 %

Procedure:
A mixture of 3-(1-chloro-3-methylbutyl)-2-methyl-5-phenylfuran (1.3 g), methyl 4-amino-3-fluorobenzoate (1.7 g), sodium carbonate (1.1 g) and sodium iodide (3.0 g) in N,N-dimethylacetamide (20 mL) was stirred overnight at 80° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL). 2N Lithium hydroxide (6 mL) was added, and the mixture was stirred at 70° C. for 6 hr. The reaction mixture was poured into water, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (10% ethyl acetate/hexane to 50% ethyl acetate/hexane) to give the title compound (0.7 g, 40%) as an amorphous compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([S:9](Cl)(=[O:11])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.Cl.[CH3:23][CH:24]1[CH:29]=[C:28]([CH3:30])[CH:27]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[O:26][NH:25]1>ClCCl>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([S:9]([N:25]2[CH:24]([CH3:23])[CH:29]=[C:28]([CH3:30])[CH:27]([C:31]3[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=3)[O:26]2)(=[O:11])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc(C2ONC(C)C=C2C)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C2ON(S(=O)(=O)c3ccc(NC(C)=O)cc3)C(C)C=C2C)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred suspension of 4-N-acetylsulphanilyl chloride (2.7 g, 11.55 mmol) and triethylamine (1.95 g, 19.25 mmol) in dichloromethane (50 ml) was added portionwise solid 3,6-dihydro-3,5-dimethyl-6-(4-methoxyphenyl)-2H-1,2-oxazine hydrochloride (1.97 g, 7.70 mmol). The resulting solution was stirred at room temperature for 5 h then washed with water three times, aqueous sodium hydroxide (2M), water and brine. The organic phase was dried over magnesium sulphate, filtered and evaporated, the resulting foam was purified on flash silica eluting with ethylacetate-hexane (3:2) to give 2-(4-acetamidobenzenesulphonyl)-3,6-dihydro-3,5-dimethyl-6-(4-methoxyphenyl)-2H-1,2-oxazine as a white foam. 1H NMR (CDCl3) δ 1.39(3H,s), 1.41(3H, d), 2.20(3H, s), 3.79(3H, s), 4.45(1H, m), 5.19(1H, s), 5.68(1H, d), 6.80(2H, d), 7.13(2H, d), 7.57(1H, bs), 7.59(2H, d), 7.80(2H, d).
Reaction SMILES: [K].[CH3:2][S:3]([NH:6][C:7](=O)[CH3:8])(=[O:5])=[O:4].[N+:10]([C:13]1[CH:20]=[CH:19]C(CBr)=[CH:15][CH:14]=1)([O-:12])=[O:11].[OH-].[Na+]>CN(C=O)C.O>[N+:10]([C:13]1[CH:20]=[CH:19][C:8]([CH2:7][NH:6][S:3]([CH3:2])(=[O:5])=[O:4])=[CH:15][CH:14]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CC(=O)NS(C)(=O)=O
Agent: [K]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)NCc1ccc([N+](=O)[O-])cc1
Reaction time: 2 h
Yield: 86 %

Procedure:
A mixture of N-(methylsulphonyl)acetamide potassium salt (23 g) and 4-nitrobenzyl bromide (24 g) in dry DMF (160 ml) was stirred in an oil bath at 130° for 2 h. After standing overnight at room temperature, a solution of sodium hydroxide (8 g) in water (50 ml) was added and the mixture stirred under nitrogen for 0.75 h. The mixture was diluted with water (900 ml) and the product extracted into ethyl acetate (2×400 ml). The combined extract was washed with brine (3×200 ml), dried (Na2SO4) and evaporated in vacuo to leave an orange solid (22 g).
Reaction SMILES: [Cl:1][C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[CH:7]=[O:8].[CH3:9][Mg]Br.C(O)(C)C>O1CCCC1>[Cl:1][C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[CH:7]([OH:8])[CH3:9]
Reactant: O=CC1=C(Cl)CCC1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CC(O)C1=C(Cl)CCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.6 %

Procedure:
Under an argon atmosphere, 2-chloro-1-cyclopentenecarbaldehyde (630 mg, 4.82 mmol) was dissolved in anhydrous tetrahydrofuran (19 ml), methylmagnesium bromide (1.4M toluene solution, 4.1 ml) was added dropwise at 0° C., and the mixture was stirred at room temperature for 30 minutes. Isopropanol (2 ml) was added at 0° C., and the solvent was evaporated under reduced pressure. 1N Hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane:ethyl acetate=10:1-6:1) to give the title compound (294 mg, 2.01 mmol, 41.6%).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([NH2:13])[CH3:12]>CO>[CH2:11]([NH:13][C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[CH:4][CH:3]=1)[CH3:12]
Reactant: NC(=O)c1ccc(Cl)nn1
Reactant: CCN
Solvent: CO
Product: CCNc1ccc(C(N)=O)nn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 6-chloropyridazine-3-carboxamide (28.5 g, 0.18 mol) in methanol (200 ml) was treated with aqueous ethylamine (70% solution, 77 ml). The reaction was heated at reflux for 3½ hours. The reaction was allowed to cool to ambient temperature and stand overnight. The precipitate was filtered and washed with a small volume of water and dried to give 6-(ethylamino)pyridazine-3-carboxamide as pink solid (8.9 g). [The filtrates were evaporated to a small volume diluted with cold water (100 ml) and more of the desired solid was filtered-off, washed with water and dried (12.8 g). Total yield (21.7 g, 72%)].
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:16]([CH:19]1[NH:23][C:22](=[O:24])[CH2:21][NH:20]1)([CH3:18])[CH3:17].C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([N:20]1[CH2:21][C:22](=[O:24])[NH:23][CH:19]1[CH:16]([CH3:18])[CH3:17])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C1NCC(=O)N1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CC(C)C1NC(=O)CN1C(=O)CNC(=O)OCc1ccccc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 84.4 %

Procedure:
Into an ice-cold solution of N-(benzyloxycarbonyl) glycine (26 g) and 2-isopropyl-4-imidazolidinone (16 g) in THF (260 ml), a solution of DCC (25.4 g) in THF (100 ml) was added dropwise. After stirring for 2 hours at 20° C., the precipitate was filtered off and the filtrate was evaporated to dryness. Crystallization of the residue from 2-propanol yielded 33.5 g of the title compound, m.p. 137°-139° C.