Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC(S([NH:10][N:11]=[CH:12][C:13](Cl)=[O:14])(=O)=O)=CC=1.[F:17][C:18]1[CH:19]=[C:20]([NH:29][C:30](=[O:35])[O:31][CH:32]([CH3:34])[CH3:33])[CH:21]=[C:22]([F:28])[C:23]=1/[CH:24]=[CH:25]/[CH2:26][OH:27].CN(C)C1C=CC=CC=1.C(N(CC)CC)C>ClCCl>[N+:11](=[CH:12][C:13]([O:27][CH2:26]/[CH:25]=[CH:24]/[C:23]1[C:18]([F:17])=[CH:19][C:20]([NH:29][C:30]([O:31][CH:32]([CH3:33])[CH3:34])=[O:35])=[CH:21][C:22]=1[F:28])=[O:14])=[N-:10]
Reactant: CC(C)OC(=O)Nc1cc(F)c(/C=C/CO)c(F)c1
Reactant: Cc1ccc(S(=O)(=O)NN=CC(=O)Cl)cc1
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)Nc1cc(F)c(/C=C/COC(=O)C=[N+]=[N-])c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Glyoxylic acid chloride p-toluenesulfonylhydrazone (4.64 g, 17.8 mmol) was added to a suspension of isopropyl 3,5-difluoro-4-[(1E)-3-hydroxyprop-1-enyl]phenylcarbamate (2.68 g, 9.89 mmol) in dichloromethane (66 mL). The mixture was cooled to 0° C. and treated with N,N-dimethylaniline (2.26 mL, 17.8 mmol). After 30 minutes, triethylamine (6.89 mL, 49.5 mmol) was added and the mixture stirred 30 minutes at 0° C. and 15 minutes at room temperature. The reaction mixture was then concentrated to ca. 15 mL and 50 mL of water added. The mixture was extracted with two portions of diethyl ether and the combined organic solutions washed with saturated NaHCO3, brine, and dried (MgSO4), filtered and concentrated. Purification by column chromatography (0-25% ethyl acetate-hexane) provided the title compound a yellow solid.
Reaction SMILES: [N+]([O-])(O[CH:4]1[O:17][C@H:16]([CH2:18][O:19][C:20](=[O:22])[CH3:21])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]([O:7][C:8](=[O:10])[CH3:9])[C@H:5]1[N:23]=[N+:24]=[N-:25])=O.[Cl:27]CCl>C(#N)C.[Cl-].C([N+](CC)(CC)CC)C>[C:8]([O:7][C@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:16]([CH2:18][O:19][C:20](=[O:22])[CH3:21])[O:17][C@H:4]([Cl:27])[C@@H:5]1[N:23]=[N+:24]=[N-:25])(=[O:10])[CH3:9]
Reactant: CC(=O)OC[C@H]1OC(O[N+](=O)[O-])[C@H](N=[N+]=[N-])[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: ClCCl
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: CC#N
Product: CC(=O)OC[C@H]1O[C@H](Cl)[C@H](N=[N+]=[N-])[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reaction time: 48 h

Procedure:
An about 1:2 mixture of the α- and β- anomers of 3,4,6-tri-O-acetyl-2-azido-2-deoxy-D-galactopyranosyl nitrate (0.377 g, 1.01 mmole) was dissolved in acetonitrile (6 ml) containing tetraethylammonium chloride (0.924 g, 5.05 mmole) and the solution was left at room temperature for 48 hours. The reaction mixture was diluted with dichloromethane (25 ml), washed with water (25 ml) and dried. Evaporation of the solvent in vacuo left a syrup (0.325 g) which showed doublets with spacings of 9.0 and 3.5 Hz at δ 5.15 and 6.20 p.p.m., respectively in the p.m.r. spectrum measured in CDCl3. These signals are assigned to the β- (XXIII) and α-anomers (XXII) for 3,4,6-tri-O-acetyl-2-azido-2-deoxy-D-galactopyranosyl chloride, respectively. Judging from the relative intensities of the signals, the product consisted of a near 10:1 mixture of the α- and β-anomers, (XXII) and (XXIII) respectively.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10]C)=[O:9])=[N:6][CH:7]=1.[F:12][C:13]([F:18])([F:17])[CH2:14][CH2:15][OH:16].C[C:20](C)([O-:22])C.[K+].[OH-].[Li+]>O>[F:12][C:13]([F:18])([F:17])[CH2:14][CH2:15][O:16][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[CH3:20][O:22][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1
Reactant: CC(C)(C)[O-]
Reactant: OCCC(F)(F)F
Reactant: COC(=O)c1cnc(Cl)cn1
Agent: [K+]
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: COc1cnc(C(=O)O)cn1
Product: O=C(O)c1cnc(OCCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
The title compound was synthesized as described for Intermediate example I-81 in 53% yield starting from methyl 5-chloropyrazine-2-carboxylate and 3,3,3-trifluoropropan-1-ol. 1 additional equivalent of 3,3,3-trifluoropropan-1-o deprotonated with potassium tert-butoxide was added at 0° C. after stirring 1 h at ambient temperature. Water must have been present because hydrolysis of the ester was performed without adding lithium hydroxide and water. The product was collected by extraction of the acidic water layer with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated in vacuo to give the title compound in a 74:26 mixture with 5-methoxypyrazine-2-carboxylic acid which was also formed in the reaction; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.81 (s, 1 H), 8.30-8.47 (m, 1 H), 4.62 (t, 2 H), 2.78-2.95 (m, 2 H); MS (ESI) m/z 237[M+H+], m/z 235[M−H];
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH2:11])=[CH:5][CH:4]=1.[C:12]([N:15]1[C:24]2[C:19](=[CH:20][C:21]([C:25](O)=[O:26])=[CH:22][CH:23]=2)[C:18]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([CH3:28])[CH2:17][C:16]1([CH3:36])[CH3:35])(=[O:14])[CH3:13].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>ClCCl>[C:12]([N:15]1[C:24]2[C:19](=[CH:20][C:21]([C:25]([NH:11][CH2:10][CH2:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[O:26])=[CH:22][CH:23]=2)[C:18]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([CH3:28])[CH2:17][C:16]1([CH3:36])[CH3:35])(=[O:14])[CH3:13]
Reactant: COc1ccc(CCN)cc1
Reactant: CC(=O)N1c2ccc(C(=O)O)cc2C(C)(c2ccccc2)CC1(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CCNC(=O)c2ccc3c(c2)C(C)(c2ccccc2)CC(C)(C)N3C(C)=O)cc1

Procedure:
Condensation of 2-(4-methoxyphenyl)ethylamine (6.1 mg) with 1-acetyl-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline-6-carboxylic acid (10 mg), under the agency of HATU (23 mg) and N,N-diisopropylethylamine (19 l)) in dichloromethane (2 ml) was performed according to the method described in example 11.
Reaction SMILES: Cl.[NH2:2][OH:3].N1C=CC=CC=1.[CH2:10]([CH:26]1[CH2:31][C:30](=[O:32])[O:29][C:27]1=[O:28])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]C>C(#N)C>[OH:3][NH:2][C:30](=[O:32])[CH2:31][CH:26]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:27]([OH:29])=[O:28]
Reactant: CCCCCCCCCCCCCCCCC1CC(=O)OC1=O
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: CCCCCCCCCCCCCCCC(CC(=O)NO)C(=O)O

Procedure:
HA-4 (2-[2-(hydroxyamino)-2-oxoethyl]heptadecanoic acid) was prepared as follows. Hydroxylamine hydrochloride (18.07 g, 0.26 moles) was dissolved in pyridine (18.49 g, 0.26 moles) by stirring the mixture for one-half hour at 26° C. n-Hexadecyl succinic anhydride (88.14 g, 0.27 moles, available from Tokyo Kasei Kogyo Co. Ltd., Tokyo, Japan) was added to the solution followed by the addition of acetonitrile (about 50 ml). The resulting mixture was refluxed for two hours, cooled, and the solvent removed under reduced pressure using a rotary evaporator. Hydrochloric acid (10%) in water (100 ml) was added to the resulting residue and the mixture filtered to recover the suspended solids. The filtrate was dispersed in water to dissolve the pyridinium hydrochloride by-product of the reaction and the dispersion filtered and the solid retained. The process of washing with water and filtering was repeated several times, yielding 2-[2-(hydroxyamino)-2-oxoethyl]heptadecanoic acid as a solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([CH:19]=O)[CH:13]=1)[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH:29]1([NH2:32])[CH2:31][CH2:30]1.[BH4-].[Na+].C([O-])(O)=O.[Na+]>CO>[C:1]([O:5][C:6](=[O:21])[N:7]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([CH2:19][NH:32][CH:29]2[CH2:31][CH2:30]2)[CH:13]=1)[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: NC1CC1
Reactant: CCN(CCc1ccc(Cl)c(C=O)c1)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: CCN(CCc1ccc(Cl)c(CNC2CC2)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.1 %

Procedure:
A mixture of [2-(4-chloro-3-formyl-phenyl)-ethyl]-ethyl-carbamic acid tert-butyl ester (80.1 mg, 0.257 mmol), Et3N (0.054 mL, 0.386 mmol) and cyclopropylamine (0.027 mL, 0.386 mmol) in MeOH (0.86 mL) was heated to reflux for 4 h. The mixture was allowed to cool to rt, and NaBH4 (24.2 mg, 0.642 mmol) was added in portions. The mixture was stirred for 1 h, and aq. sat. NaHCO3 was added. The mixture was extracted with EtOAc several times, and the combined org. extracts were washed with brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (CH2Cl2/MeOH 95:5) yielded the title compound (40 mg, 44%). LC-MS: tR=0.81 min; ES+: 353.22.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]([O:12][C:13](=[O:28])[N:14]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=1)[C:15](=[O:20])[CH2:16][CH2:17][C:18]#[CH:19])([CH3:11])([CH3:10])[CH3:9]>>[C:8]([O:12][C:13](=[O:28])[N:14]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=1)[C:15](=[O:20])[CH2:16][CH2:17][C:18]#[C:19][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: C#CCCC(=O)N(C(=O)OC(C)(C)C)c1cccc(F)c1
Reactant: Brc1ccccn1
Product: CC(C)(C)OC(=O)N(C(=O)CCC#Cc1ccccn1)c1cccc(F)c1
Yield: 60.5 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-pyridine (137 mg, 0.86 mmol) and (3-fluoro-phenyl)-pent-4-ynoyl-carbamic acid tert-butyl ester (250 mg, 0.86 mmol). Reaction time: 3 hours. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 190 mg (0.52 mmol, 60%) of (3-fluoro-phenyl)-(5-pyridin-2-yl-pent-4-ynoyl)-carbamic acid tert-butyl ester as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][C:7]2[CH:10]=[CH:11]C=[CH:13][C:6]=2O1.[ClH:14].Cl.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:21]=[CH:22][C:23]=1[O:24][CH3:25].[C:32](=[O:35])([O-])[O-].[K+].[K+].[I-].[K+]>CC(=O)CC>[ClH:14].[ClH:14].[O:35]1[C:32]2[CH:2]=[CH:3][CH:4]=[CH:9][C:8]=2[CH:7]([CH2:10][CH2:11][N:29]2[CH2:28][CH2:27][N:26]([C:20]3[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:18]([O:17][CH3:16])[CH:19]=3)[CH2:31][CH2:30]2)[CH2:6][CH2:13]1
Reactant: BrCCC1CCc2ccccc2O1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(N2CCNCC2)cc1OC
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COc1ccc(N2CCN(CCC3CCOc4ccccc43)CC2)cc1OC

Procedure:
The A isomer of 1-[2-(3,4-dihydro-1(2H)-benzopyran-4-yl)ethyl]-4-(3,4-dimethoxyphenyl)piperazine dihydrochloride is prepared by following the procedure of Example 1 but starting with the A isomer of 4-(2-bromoethyl -3,4-dihydro-(2H)-benzopyran (0.86 g), 1-(3,4-dimethoxyphenyl)piperazine dihydrochloride (1.10 g) and then dry potassium carbonate (1.38 g) and potassium iodide (0.6 g) in 2-butanone (15 cc).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:21])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:11][CH:10]=1.C1(N)CCCCC1>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:21])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:11][CH:10]=1
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccc(Cl)cc2Cl)cc1
Solvent: O
Solvent: NC1CCCCC1
Product: O=C(O)CCC(O)c1ccc(-c2ccc(Cl)cc2Cl)cc1
Yield: 70 %

Procedure:
Prepared analogous to Example 42 from 4-(2',4'-dichloro-4-biphenylyl)-4-oxo-butyric acid. Yield: 70% of theory. Melting point of the cyclohexylamine salt: 168°-169° C. (from water).
Reaction SMILES: [OH:1][C@:2]([C:32]1[CH:36]=[C:35]([CH3:37])[O:34][N:33]=1)([CH3:31])[C:3]#[C:4][C:5]1[CH:6]=[CH:7][C:8]2[O:14][CH2:13][CH2:12][N:11]3[C:15]([C:21]([NH:23][CH:24]4[CH2:29][CH2:28]O[CH2:26][CH2:25]4)=[O:22])=[C:16]([C:18]([NH2:20])=[O:19])[N:17]=[C:10]3[C:9]=2[CH:30]=1.Cl.NC1CC[C:43]([F:47])([F:46])CC1>>[F:46][C:43]1([F:47])[CH2:28][CH2:29][CH:24]([NH:23][C:21]([C:15]2[N:11]3[CH2:12][CH2:13][O:14][C:8]4[CH:7]=[CH:6][C:5]([C:4]#[C:3][C@@:2]([OH:1])([C:32]5[CH:36]=[C:35]([CH3:37])[O:34][N:33]=5)[CH3:31])=[CH:30][C:9]=4[C:10]3=[N:17][C:16]=2[C:18]([NH2:20])=[O:19])=[O:22])[CH2:25][CH2:26]1
Reactant: Cc1cc([C@](C)(O)C#Cc2ccc3c(c2)-c2nc(C(N)=O)c(C(=O)NC4CCOCC4)n2CCO3)no1
Reactant: NC1CCC(F)(F)CC1
Agent: Cl
Product: Cc1cc([C@](C)(O)C#Cc2ccc3c(c2)-c2nc(C(N)=O)c(C(=O)NC4CCC(F)(F)CC4)n2CCO3)no1

Procedure:
Prepared as described for (R)-10-(3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-yn-1-yl)-N3-(tetrahydro-2H-pyran-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2,3-dicarboxamide replacing 4-aminotetrahydropyran with 4-amino-1,1-difluorocyclohexane hydrochloride. Off-white solid 40.2 mg, 12%).
Reaction SMILES: Cl.[C:2]([N:6]1[CH:14]=[C:13]2[C:8]([C:9](=[O:20])[NH:10][C:11]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:12]2)=[N:7]1)([CH3:5])([CH3:4])[CH3:3].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([C:38](O)=[O:39])[CH:26]=[C:27]2[C:31]=1[N:30](C1CCCCO1)[N:29]=[CH:28]2.C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.Cl>CN(C)C=O.O>[C:2]([N:6]1[CH:14]=[C:13]2[C:8]([C:9](=[O:20])[NH:10][C:11]3([CH2:19][CH2:18][N:17]([C:38]([C:25]4[CH:26]=[C:27]5[C:31](=[C:23]([O:22][CH3:21])[CH:24]=4)[NH:30][N:29]=[CH:28]5)=[O:39])[CH2:16][CH2:15]3)[CH2:12]2)=[N:7]1)([CH3:5])([CH3:3])[CH3:4]
Reactant: COc1cc(C(=O)O)cc2cnn(C3CCCCO3)c12
Reactant: CC(C)(C)n1cc2c(n1)C(=O)NC1(CCNCC1)C2
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N2CCC3(CC2)Cc2cn(C(C)(C)C)nc2C(=O)N3)cc2cn[nH]c12
Reaction time: 0.08 h
Yield: 10.4 %

Procedure:
To a mixture of 2′-tert-butyl-4′,6′-dihydrospiro[piperidine-4,5′-pyrazolo[3,4-c]pyridin]-7′(2′H)-one hydrochloride salt (Intermediate 4, 25 mg, 0.075 mmol) and 7-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-carboxylic acid (Intermediate 18, 25 mg, 0.090 mmol) in N,N-dimethylformamide (0.4 mL) was added triethylamine (0.05 mL, 0.37 mmol). The mixture was stirred for 5 minutes. Then 1-propanephosphonic acid cyclic anhydride (0.09 mL, 0.1 mmol, 50% solution in ethyl acetate) was added and the reaction was stirred at room temperature overnight. The reaction was diluted with water and extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to a yellow gum. To this crude material was added hydrochloric acid (0.19 mL, 0.75 mmol, 4 M in dioxane). The mixture was stirred at room temperature overnight. The reaction was concentrated. Purification by reversed-phase HPLC gave the title compound (3.4 mg, 10%). +ESI (M+H) 437.3; HPLC retention time 2.12 minutes (Method A).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]=[O:5].[Cl:11][C:12]([Cl:17])([Cl:16])C(O)=O.Cl[C:19](Cl)(Cl)[C:20]([O-])=[O:21].[Na+].C(OC(=O)C)(=O)C>CN(C=O)C.O>[Cl:17][C:12]([Cl:11])([Cl:16])[CH:4]([O:5][C:20](=[O:21])[CH3:19])[C:3]1[CH:6]=[C:7]([F:10])[CH:8]=[CH:9][C:2]=1[F:1]
Reactant: O=Cc1cc(F)ccc1F
Reactant: O=C([O-])C(Cl)(Cl)Cl
Reactant: O=C(O)C(Cl)(Cl)Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OC(c1cc(F)ccc1F)C(Cl)(Cl)Cl
Temperature: 25 °C
Yield: 84 %

Procedure:
2,5-Difluoro-benzaldehyde (10 g, 70 mmol) was dissolved in DMF (150 mL) and trichloroacetic acid (20.2 g, 123 mmol) was added. Addition of the sodium trichloroacetate (22.5 g, 121 mmol) was initiated at 21° C. All sodium trichloroacetate was added in portions within 30 min, the temperature was kept at 23-27° C. throughout the whole reaction. One hour later the aldehyde was consumed. The reaction mixture was stirred over night at room temperature. The mixture was cooled to 2° C. and acetic anhydride (20 mL, 211 mmol) was added dropwise within 1 h. During the addition the mixture became very thick and more DMF (400 mL) was added. After addition the mixture was warmed to room temperature during 1 h. Water was added to give a solution that was extracted three times with diethyl ether. The combined organic phase washed five times with water, dried (MgSO4), filtered and evaporated to give the title compound as an yellow oil. Yield 84%, 18.2 g.
Reaction SMILES: [C:1]([O:11][C:12]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[S:15](=[O:23])(=[O:22])[N:14]([CH3:24])[C:13]=1[C:25]([OH:27])=O)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(Cl)Cl.[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1>C(OCC)C>[C:1]([O:11][C:12]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[S:15](=[O:23])(=[O:22])[N:14]([CH3:24])[C:13]=1[C:25]([NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)=[O:27])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN1C(C(=O)O)=C(OC(=O)C=Cc2ccccc2)c2ccccc2S1(=O)=O
Reactant: Nc1ccccn1
Solvent: ClCCl
Solvent: CCOCC
Product: CN1C(C(=O)Nc2ccccn2)=C(OC(=O)C=Cc2ccccc2)c2ccccc2S1(=O)=O

Procedure:
The cinnamoyl anhydride and the other mixed anhydrides of 4-cinnamoyloxy-2-methyl-2H-1,2-benzothiazine-3-carboxylic acid 1,1-dioxide prepared respectively according to Example 12 or Example 13 are directly reacted, without previous purification or recovery from their methylene chloride solution, with 2-2.5 molar equivalents of 2-aminopyridine with stirring and external cooling. After dilution with 3 volumes of diethyl ether the reaction mixture is stirred at 15° C. for 3 hours, then the procedure of Example 16 is repeated obtaining the desired 4-cinnamoyloxy-2-methyl-N-(2-pyridyl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]C(Cl)=O)=[CH:4][CH:3]=1.[CH3:12][C:13]1[O:17][C:16]([CH2:18][CH2:19][NH2:20])=[CH:15][CH:14]=1.CCN(CC)CC.C1C[O:31]CC1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:20][CH2:19][CH2:18][C:16]2[O:17][C:13]([CH3:12])=[CH:14][CH:15]=2)=[O:31])=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: Cc1ccc(CCN)o1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Solvent: CCN(CC)CC
Product: Cc1ccc(CCNC(=O)c2ccc(F)cc2)o1
Yield: 95 %

Procedure:
4-Fluorophenylacetyl chloride (0.290 mL, 2.44 mmol) was added dropwise to a solution of β-(5-methyl-2-furanyl)ethanamine (300 mg, 2.44 mmol, made according to the procedure of Yur'ev et al. J. Gen. Chem. USSR (Engl. Transl.) 33, 3444-8 (1963)) in THF (2.5 mL) at rt, followed by the dropwise addition of Et3N (0.340 mL, 2.44 mmol). Once the starting material was consumed, as was evident by HPLC, the reaction was quenched with H2O and extracted with CH2Cl2. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. Purification by flash chromatography on silica gel eluting with a gradient of 0-50% EtOAc/hexane gave 523 mg (95%) of compound 237A as a white solid. HPLC: 99% at 2.84 min (retention time) (Phenomenex-prime S5-C18 column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 248.15 [M+H]+.
Reaction SMILES: [Br-].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][C:4]=1[C@@H:11]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:12][CH2:13][N+:14]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH3:15].[C:28]([Br:33])(=[O:32])[CH:29]([CH3:31])[CH3:30]>>[Br-:33].[C:28]([O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][C:4]=1[C@@H:11]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:12][CH2:13][N+:14]([CH:19]([CH3:20])[CH3:21])([CH:16]([CH3:17])[CH3:18])[CH3:15])(=[O:32])[CH:29]([CH3:31])[CH3:30]
Reactant: CC(C)C(=O)Br
Reactant: CC(C)[N+](C)(CC[C@H](c1ccccc1)c1cc(CO)ccc1O)C(C)C
Agent: [Br-]
Product: CC(C)C(=O)Oc1ccc(CO)cc1[C@H](CC[N+](C)(C(C)C)C(C)C)c1ccccc1

Procedure:
(3R)-3-[2-hydroxy-5-(hydroxymethyl)phenyl]-N,N-diisopropyl-N-methyl-3-phenylpropan-1-aminium bromide is acylated with isobutyryl bromide to give the title compound.
Reaction SMILES: CC1C=CC(S([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][C:14]([CH3:19])([CH3:18])[CH2:13]2)(=O)=O)=CC=1.[Cl:20][C:21]1[N:26]=[CH:25][C:24](O)=[CH:23][CH:22]=1.[OH-].[K+]>CN(C=O)C>[Cl:20][C:21]1[N:26]=[CH:25][C:24]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][C:14]([CH3:18])([CH3:19])[CH2:13]2)=[CH:23][CH:22]=1
Reactant: Oc1ccc(Cl)nc1
Reactant: Cc1ccc(S(=O)(=O)OC2CCCC(C)(C)C2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC1(C)CCCC(Oc2ccc(Cl)nc2)C1
Temperature: 60 °C
Reaction time: 8 h
Yield: 78.7 %

Procedure:
Under a nitrogen atmosphere, add 3,3-dimethylcyclohexyl 4-methylbenzenesulfonate (1.2 g, 4.25 mmol), 6-chloro-pyridin-3-ol (0.5 g, 3.86 mmol) and potassium hydroxide (238 mg, 4.25 mmol) to DMF (10 mL). Heat the mixture to 60° C. and stir overnight. Add water (20 mL) and diethyl ether (20 mL) and separate the layers. Extract the aqueous layer with diethyl ether (3×20 mL). Wash the combined organic extracts with brine (20 mL), dry over Na2SO4, filter, and concentrate in vacuo. Purify by chromatography on silica gel (80 g, pre-packed cartridge) eluting with hexane/EtOAc (1:0 to 1:1 over 60 min, 80 mL/min) to obtain the desired intermediate as a white solid (728 mg, 79%). MS (APCI+) m/z: 240 (M+H)+.
Reaction SMILES: C(C1C=C(N[CH:11](C2C=CC(OC)=C(OC)C=2)[C:12]([OH:14])=[O:13])C=CC=1)(=O)N.[NH2:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][C:34]=1[F:35])[C:29]([NH2:31])=[O:30].[CH2:36]([C:38]1[CH:39]=[C:40](B(O)O)[CH:41]=[CH:42][C:43]=1[F:44])[CH3:37].O.C(O)(=O)C=O>>[C:29]([C:28]1[CH:32]=[CH:33][C:34]([F:35])=[C:26]([NH:25][CH:11]([C:40]2[CH:41]=[CH:42][C:43]([F:44])=[C:38]([CH2:36][CH3:37])[CH:39]=2)[C:12]([OH:14])=[O:13])[CH:27]=1)(=[O:30])[NH2:31]
Reactant: CCc1cc(B(O)O)ccc1F
Reactant: NC(=O)c1ccc(F)c(N)c1
Reactant: COc1ccc(C(Nc2cccc(C(N)=O)c2)C(=O)O)cc1OC
Agent: O=CC(=O)O
Solvent: O
Product: CCc1cc(C(Nc2cc(C(N)=O)ccc2F)C(=O)O)ccc1F
Yield: 48 %

Procedure:
95C was prepared in a procedure similar to that of 1A using 19B, 95B and glyoxylic acid monohydrate. Yield: 48%. 1H NMR (400 MHz, Methanol-d4) δ ppm 1.19 (t, J=7.69 Hz, 3H) 2.65 (q, J=7.47 Hz, 2H) 5.18 (s, 1H) 6.98-7.11 (m, 3 H) 7.12-7.18 (m, 1H) 7.31-7.38 (m, 1H) 7.40-7.45 (m, 1H); LCMS: 335 (M+1).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[S:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]([CH2:22][CH3:23])[CH2:19][CH2:18][C:17]2=O.Cl.[NH2:26][OH:27].C([O-])(=O)C.[Na+]>C(O)C.O>[N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[S:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]([CH2:22][CH3:23])[CH2:19][CH2:18][C:17]2=[N:26][OH:27]
Reactant: NO
Reactant: CCN1CCC(=O)c2cccc(CSc3nc4ccccc4[nH]3)c21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCN1CCC(=NO)c2cccc(CSc3nc4ccccc4[nH]3)c21
Yield: 60 %

Procedure:
8-(2-Benzimidazolyl)thiomethyl-1-ethyl-4-oxo-1,2,3,4-tetrahydroquinoline (1.5 g), hydroxylamine hydrochloride (458 mg) and sodium acetate (1.7 g) were dissolved in a mixed solvent (23 ml) of ethanol-water (20:3), and the solution was refluxed for 3 hours. After completion of the reaction, the solvent was distilled off and the resulting residue was poured into water. The precipitated crystals were collected by filtration and recrystallized from methanol to give 8-(2-benzimidazolyl)thiomethyl-1-ethyl-4-hydroxyimino-1,2,3,4-tetrahydroquinoline (0.94 g).