Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: II.Br[C:4]1[CH:5]=[CH:6][C:7]([Cl:12])=[C:8]([O:10][CH3:11])[CH:9]=1.[C:13]1([P:19](Cl)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>O1CCCC1.C1(C)C=CC=CC=1>[Cl:12][C:7]1[CH:6]=[CH:5][C:4]([P:19](=[O:20])([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][C:8]=1[O:10][CH3:11]
Reactant: COc1cc(Br)ccc1Cl
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Agent: II
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(P(=O)(c2ccccc2)c2ccccc2)ccc1Cl
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
Under argon, 1 mol of Mg turnings and a spatula tip of iodine in a mixture of 100 ml of tetrahydrofuran and 100 ml of toluene were heated to 60° C. Over the course of 10 minutes, 200 g of 5-bromo-2-chloroanisole in a mixture of 200 ml of tetrahydrofuran and 200 ml of toluene were added dropwise. During the dropwise addition, the internal temperature was maintained at 60° C. by cooling. When the dropwise addition was complete, the reaction mixture was heated to reflux temperature and after-stirred for 30 minutes at this temperature. The mixture was then cooled to 0° C. and 236.8 g of diphenylphosphinic chloride were added dropwise over the course of 45 minutes. The internal temperature was maintained during this operation between 0 and 5° C. The reaction mixture was after-stirred for 5 minutes at 0° C., the cooling was switched off, and the mixture was stirred for a further 2 hours. For work-up, the reaction mixture was poured onto 1.6 liter of iced water, the organic phase was separated off, and the aqueous phase was washed again with 2×400 ml of toluene. The combined organic phases were washed with 400 ml of 2.5% strength by weight aqueous soda solution and then with 400 ml of water, and then concentrated on a rotary evaporator to a volume of 200 ml. Then, with stirring, 300 ml of n-pentane were added dropwise. The solid that precipitated out overnight was filtered off with suction, washed with n-pentane, and dried. This gave 203.5 g of a white solid. The yield was 82% and the purity was 94%.
Reaction SMILES: Cl[C:2]([C:4]1[CH:5]=[CH:6][C:7]([N+:14]([O-:16])=[O:15])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])=[O:3].C(N(CC)CC)C.[CH:24]1[N:25]=[CH:26][N:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=12>ClCCCl>[CH:24]1[N:25]=[C:26]([C:2]([C:4]2[CH:5]=[CH:6][C:7]([N+:14]([O-:16])=[O:15])=[C:8]([CH:13]=2)[C:9]([O:11][CH3:12])=[O:10])=[O:3])[N:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=12
Reactant: COC(=O)c1cc(C(=O)Cl)ccc1[N+](=O)[O-]
Reactant: c1ccn2cncc2c1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COC(=O)c1cc(C(=O)c2ncc3ccccn23)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
5.6 g (0.023 mol) of methyl 5-(chlorocarbonyl)-2-nitrobenzoate and 3.4 ml (0.024 mol) of triethylamine are added to 1.3 g (0.011 mol) of imidazo[1,5-a]pyridine [described in J. Chem. Soc., (1955), 2834-2836] dissolved in 100 ml of 1,2-dichloroethane. The mixture is stirred at ambient temperature for 4 hours. The reaction medium is concentrated under reduced pressure and then the residue is taken up in dichloromethane and a saturated aqueous sodium bicarbonate solution. The organic phase is separated by settling, washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The product is purified by column chromatography on silica gel, elution being carried out with dichloromethane. After evaporation, 3.1 g of a yellow solid are collected. Melting point: 151° C.; 1H NMR (d6-DMSO): 3.92 (3H, s), 7.39-7.42 (1H, m), 7.50-7.54 (1H, m), 8.00 (1H, s), 8.10 (1H, d), 8.25 (1H, d), 8.69 (1H, d), 8.76 (1H, s), 9.78 (1H, d)
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=[C:22]([Cl:23])[C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH3:28][CH:29]([CH3:32])[CH2:30][NH2:31]>C(#N)C>[Cl:23][C:22]1[C:16]2[O:15][CH2:14][C@H:13]([CH2:12][NH:31][CH2:30][CH:29]([CH3:32])[CH3:28])[O:18][C:17]=2[CH:19]=[C:20]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:21]=1
Reactant: CC(C)CN
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3c(Cl)cc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: CC(C)CNC[C@H]1COc2c(Cl)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 57 using [(2R)-5-chloro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.027 g, 0.062 mmol), 2-methylpropan-1-amine (0.5 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 333 (M+, 2), 292 (8), 290 (20), 86 (bp), 70 (8), 57 (9).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([OH:14])=[O:13])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.S(Cl)(Cl)=O.[CH3:19]O>C(=O)(O)[O-].[Na+]>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH2:11][C:12]([O:14][CH3:19])=[O:13])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(CC(=O)O)cc(OC)c1
Reactant: CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1cc(OC)cc(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(3,5-dimethoxyphenyl)acetic acid (5) (600 mg, 3.06 mmol) in MeOH (30 mL) was added dropwise thionyl chloride (3 mL) at 0° C., and the reaction mixture was stirred at room temperature overnight. The reaction was monitored by liquid chromatography-mass spectrometry (LCMS). The mixture was diluted with saturated sodium bicarbonate (aq., 20 mL) and extracted by EtOAc (3×20 mL). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and concentrated to give methyl 2-(3,5-dimethoxyphenyl)acetate (crude, 700 mg) as a yellow oil. MS (ES+) C11H14O4 requires: 210. found: 211 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[CH:12][C:13](=[O:16])[NH:14][N:15]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].Cl[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:19]>>[CH2:21]([O:20][C:18]([N:14]1[C:13](=[O:16])[CH:12]=[CH:11][C:10]([C:4]2[CH:5]=[C:6]([Cl:9])[C:7]([CH3:8])=[C:2]([Cl:1])[CH:3]=2)=[N:15]1)=[O:19])[CH2:22][CH2:23][CH3:24]
Reactant: Cc1c(Cl)cc(-c2ccc(=O)[nH]n2)cc1Cl
Reactant: CCCCOC(=O)Cl
Product: CCCCOC(=O)n1nc(-c2cc(Cl)c(C)c(Cl)c2)ccc1=O
Temperature: 25 °C
Yield: 92.9 %

Procedure:
A mixture of 2.55 g of 6-(3,5-dichloro-4-methylphenyl)-3-pyridazone and 6.8 g of butyl chloroformate was heated under reflux for 1 hour. The reaction mixture was then left to cool at room temperature and the precipitate produced was collected by filtration, washed with hexane and dried under reduced pressure, giving 3.3 g (93%) of the desired Compound No. 32 in the form of colourless plates melting at 153°-157° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:5](O)=[O:6].[NH4+].[Cl-].C[N:18](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.O>[Br:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[NH2:18])[CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COC(=O)c1ccc(C(=O)O)cc1Br
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(C(N)=O)cc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 52 %

Procedure:
A mixture of 3-bromo-4-(methoxycarbonyl)benzoic acid (2.5 g, 9.69 mmol), NH4Cl (1.04 g, 19.38 mmol), HATU (5.5 g, 14.5 mmol), and DIPEA (5.2 mL, 29.1 mmol) in DCM (50 mL) was stirred for 3 h at rt. Water was added and the mixture was extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE-EA (3:1) to give methyl 2-bromo-4-carbamoylbenzoate (1.3 g; yield 52%) as a white solid. MS: m/z=257.9 (M+1, ESI+).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21](Cl)=[O:22])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:11][O:10][C:8]1[CH:9]=[C:2]2[C:3]([CH:4]=[C:20]([C:17]3[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=3)[C:21](=[O:22])[O:1]2)=[CH:6][CH:7]=1
Reactant: COc1ccc(CC(=O)Cl)cc1
Reactant: COc1ccc(C=O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(-c2cc3ccc(OC)cc3oc2=O)cc1
Yield: 89.2 %

Procedure:
A suspension of 2-hydroxy-4-methoxybenzaldehyde (6.10 g), 4-methoxyphenylacetylchloride (11.1 g) and potassium carbonate (20 g) in acetone (400 ml) was heated under reflux for 2 hours. The reaction mixture was evaporated to remove the solvent, followed by addition of water. The resulting precipitates were collected by filtration and dried under reduced pressure to give 7-methoxy-3-(4-methoxyphenyl)-chromen-2-one (10.1 g, Yield 89%).
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:11][N:12]([CH2:14][C:15]([OH:17])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C@H:19]([C:32]([N:34]([C@@H:46]([CH3:54])[CH:47]([O:51][CH2:52][CH3:53])[O:48][CH2:49][CH3:50])[CH2:35][C:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][CH:37]=1)=[O:33])[CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28]>>[CH2:1]([NH:8][C:9]([NH:11][N:12]([CH2:14][C:15]([NH:18][C@H:19]([C:32]([N:34]([C@@H:46]([CH3:54])[CH:47]([O:48][CH2:49][CH3:50])[O:51][CH2:52][CH3:53])[CH2:35][C:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][CH:37]=1)=[O:33])[CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:17])[CH3:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C
Reactant: CN(CC(=O)O)NC(=O)NCc1ccccc1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)CN(C)NC(=O)NCc1ccccc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(benzylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-3) 69 mg (0.29 mmol) was coupled with tert-butyl (S)-5-amino-6-(((S)-1,1-diethoxypropan-2-yl)-(naphthalen-1-ylmethyl)amino)-6-oxohexylcarbamate (Compound IV-13) 100 mg (0.19 mmol) to obtain the title compound.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][C:6]1[NH:11][C:10]2[CH:12]=[CH:13][C:14]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:15][C:9]=2[S:8](=[O:22])(=[O:21])[CH:7]=1)C.[OH-].[Li+]>CO>[CH3:20][S:17]([NH:16][C:14]1[CH:13]=[CH:12][C:10]2[NH:11][C:6]([CH2:5][C:4]([OH:23])=[O:3])=[CH:7][S:8](=[O:21])(=[O:22])[C:9]=2[CH:15]=1)(=[O:18])=[O:19]
Reactant: CCOC(=O)CC1=CS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)C=C(CC(=O)O)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.9 %

Procedure:
A solution of (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-3-yl)-acetic acid ethyl ester (prepared as described in US patent application US 2008/0031852, 600 mg, 1.666 mmol) in methanol (30 mL) was cooled to 0° C. in an ice-water bath and treated with 2.0 M aqueous lithium hydroxide solution (4.17 mL, 8.332 mmol). The reaction mixture was allowed to warm to 25° C. and stirred for 1 h. The methanol was removed in vacuo and the reaction mixture was poured into 0.5 M aqueous hydrochloric acid solution (20 mL) on ice, extracted with ethyl acetate (3×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford an orange solid. The crude solid was triturated with diethyl ether to afford the desired product, (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-3-yl)-acetic acid (409 mg, 1.232 mmol, 73.9%), as a yellow solid. LC-MS calcd for C11H12N2O6S2 332.4. found 333.0 [M+H+].
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[Br:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH2:15]>CCOCC>[Br:11][C:12]1[CH:13]=[C:14]([NH:15][C:2](=[O:3])[O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: Nc1cccc(Br)c1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCOCC
Product: O=C(Nc1cccc(Br)c1)Oc1ccccc1

Procedure:
A solution of 1.56 g. of phenyl chloroformate in 50 ml. of ether is added dropwise to a stirred solution of 3.44 g. of 3-bromoaniline in 35 ml. of ether, the mixture is stirred for one hour at room temperature and then filtered. The filtrate is evaporated and the residue is crystallized from hexane to yield phenyl N-(3-bromophenyl)carbamate, m.p. 88°-90° C.
Reaction SMILES: C[Mg]Br.[F:4][C:5]1[C:6]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:7]([CH:10]=[C:11]([F:21])[C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:8]=[O:9].[CH3:30]COCC.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>>[F:4][C:5]1[C:6]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:7]([CH:8]([OH:9])[CH3:30])[CH:10]=[C:11]([F:21])[C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1cc(F)c(OCc2ccccc2)c(F)c1OCc1ccccc1
Reactant: CCOCC
Agent: C[Mg]Br
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Product: CC(O)c1cc(F)c(OCc2ccccc2)c(F)c1OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methylmagnesium bromide (3.0M solution in ether, 1.1 eq) is added to a 0.4M solution of Compound 23 in ether (1.0 eq) at 0° C. The reaction is stirred at 0° C. for 1 hour, then warmed to 20° C. for an additional hour, and poured into 5 volumes of 1M citric acid solution. The resulting solution is extracted with ether (2×), washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residue is purified by chromatography on silica gel (Hex/EtOAc) to yield Compound 24.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[O:23]=[C:24]1[NH:29][C:28]2[CH:30]=[C:31]([CH:34]=O)[CH:32]=[CH:33][C:27]=2[S:26][CH2:25]1.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C.CO>[CH3:21][O:20][C:17]1[CH:18]=[C:19]2[C:14]([N:13]=[CH:12][C:11](=[O:22])[N:10]2[CH2:9][CH2:8][N:5]2[CH2:4][CH2:3][CH:2]([NH:1][CH2:34][C:31]3[CH:32]=[CH:33][C:27]4[S:26][CH2:25][C:24](=[O:23])[NH:29][C:28]=4[CH:30]=3)[CH2:7][CH2:6]2)=[CH:15][CH:16]=1
Reactant: O=Cc1ccc2c(c1)NC(=O)CS2
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2c1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCc4ccc5c(c4)NC(=O)CS5)CC3)c2c1
Reaction time: 4 h
Yield: 18.9 %

Procedure:
To 3.0 mL of methanol solution containing 0.20 g of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one, 0.13 g of 3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carbaldehyde, 38 μL of acetic acid and 83 mg of sodium cyanoborohydride were added at room temperature and stirred at the same temperature for 4 hours. To the mixture, chloroform and aqueous saturated sodium hydrogen carbonate solution was added to be adjusted to pH 9.5, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed sequentially with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform:methanol=20:3], to give 60 mg of 6-(((1-(2-(7-methoxy-2-oxoquinoxaline-1-(2H)-yl)ethyl)piperidin-4-yl)amino)methyl)-2H-1,4-benzothiazine-3(4H)-one a pale yellow solid.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH3:22][S:23]([C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][CH2:30][CH2:29]2)(=[O:25])=[O:24]>>[CH3:22][S:23]([C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([C:2]1[N:7]=[CH:6][C:5]([NH:8][CH:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]3)=[CH:4][CH:3]=1)[CH2:30][CH2:29]2)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)c1ccc2c(c1)CCN2
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Br)nc2)CC1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(N3CCc4cc(S(C)(=O)=O)ccc43)nc2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Intermediate-27 using tert-butyl 4-((6-bromopyridin-3-yl)amino)piperidine-1-carboxylate and 5-(methyl-sulfonyl)indoline; MS: 473.3 (M+1).
Reaction SMILES: [N:1]1([C:10]2[N:18]=[C:17]([NH:19][CH2:20][CH:21]3[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]3)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35].C1(OC)C=CC=CC=1>C(Cl)Cl>[F:37][C:36]([F:39])([F:38])[C:34]([OH:40])=[O:35].[F:37][C:36]([F:39])([F:38])[C:34]([OH:40])=[O:35].[N:1]1([C:10]2[N:18]=[C:17]([NH:19][CH2:20][CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2nc(-n3cnc4ccccc43)c3nc[nH]c3n2)CC1
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: c1ccc2c(c1)ncn2-c1nc(NCC2CCNCC2)nc2[nH]cnc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
35 mg of the product of Example 31 are mixed with 1 ml of CH2Cl2 and 0.5 ml of TFA containing 10% of anisole. The mixture is left to stir for 2 hours at ambient temperature, followed by concentrating to dryness in the presence of toluene and of CH2Cl2. 40 mg of expected product are thus obtained.
Reaction SMILES: C(OC([N:8]1[C@@H:13]([CH3:14])[CH2:12][O:11][CH2:10][C@@H:9]1[CH3:15])=O)(C)(C)C.[Cl:16]CCl>FC(F)(F)C(O)=O>[ClH:16].[CH3:15][C@H:9]1[CH2:10][O:11][CH2:12][C@H:13]([CH3:14])[NH:8]1
Reactant: C[C@H]1COC[C@H](C)N1C(=O)OC(C)(C)C
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1COC[C@H](C)N1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (3S)-3,5-dimethylmorpholine hydrochloride (8.3 g), di-tert-butyl dicarbonate (14.34 g) and sodium hydroxide (5.48 g) in water (30 ml) were stirred at room temperature overnight. Water (50 ml) and isopropyl ether were added to the mixture and the organic layer was separated, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of ethyl acetate and n-hexane (1:9) as an eluent to give (3S,5S)-4-tert-butoxycarbonyl-3,5-dimethylmorpholine (3.55 g) and meso-4-tert-butoxycarbonyl-3,5-dimethylmorpholine (2.84 g) (the former was less polar). (3S,5S)-4-tert-butoxycarbonyl-3,5-dimethylmorpholine (3.55 g) was dissolved in a mixture of dichloromethane (20 ml) and trifluoroacetic acid (20 ml) and the mixture was stirred at room temperature for 2 hours. After removal of the solvent under reduced pressure, 1N sodium hydroxide solution (20 ml) and dichoromethane were added thereto. The organic phase was separated, dried over magnesium sulfate, and was added 4N hydrogen chloride in ethyl acetate (20 ml). The mixture was evaporated in vacuo and the residue was triturated with a mixture of dichloromethane and isopropyl ether to give (3S,5S)-3,5-dimethylmorpholine hydrochloride (1.56 g) as a white solid.
Reaction SMILES: Br[C:2]1[C:7]2=[N:8][S:9][N:10]=[C:6]2[C:5]([Br:11])=[C:4]([Cl:12])[C:3]=1[Cl:13].[CH2:14]([C:26]1[CH:27]=[C:28]([Sn](C)(C)C)[S:29][CH:30]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C1C=CC([P]([Pd]([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)=CC=1.C1(C)C=CC=CC=1>[CH2:14]([C:26]1[CH:27]=[C:28]([C:2]2[C:7]3=[N:8][S:9][N:10]=[C:6]3[C:5]([Br:11])=[C:4]([Cl:12])[C:3]=2[Cl:13])[S:29][CH:30]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: Clc1c(Cl)c(Br)c2nsnc2c1Br
Reactant: CCCCCCCCCCCCc1csc([Sn](C)(C)C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCc1csc(-c2c(Cl)c(Cl)c(Br)c3nsnc23)c1
Temperature: 105 °C
Reaction time: 48 h
Yield: 41.8 %

Procedure:
4,7-Dibromo-5,6-dichloro-benzo[1,2,5]thiadiazole (0.86 g, 2.37 mmol), (4-dodecyl-thiophen-2-yl)-trimethyl-stannane (2.26 g, 5.45 mmol), and Pd(PPh3)4 (54.8 mg) were placed in a 100 mL Schlenk flask. The system was subjected to three quick vacuum-nitrogen cycles and 40 mL anhydrous toluene was added. The mixture was heated at 105° C. for 2 days. After 2 days, 1.2 g more of (4-dodecyl-thiophen-2-yl)-trimethyl-stannane and 50 mg more of Pd(PPh3)4 were added, and the reaction mixture was stirred at 105° C. for another 2 days. After the reaction was cooled down, the solvent was removed by rotary evaporation. The product was purified by silica gel column with chloroform/hexane (v/v, 1/1) as the eluent. The final product (530 mg, yield 42%) was obtained as a yellow solid after being dried in vacuo. The compound was used directly in the next step without any further purification and characterization. 1H NMR (CDCl3, 500 MHz): δ 7.47 (d, 1H, J=1.0 Hz), 7.22 (d, 1H, J=1.0 Hz), 2.71 (t, 2H, J=8.0 Hz), 1.70 (m, 2H), 1.26 (m, 18H), 0.89 (t, 3H, 7.0 Hz).
Reaction SMILES: C([C:4]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=1)=[CH:5][S:6]([NH:9][CH:10]([CH3:12])[CH3:11])(=[O:8])=[O:7])(=O)C.[CH2:22]([O:25][CH2:26][CH2:27][O:28][C:29](=[O:34])/[CH:30]=[C:31](\[NH2:33])/[CH3:32])[CH2:23][CH3:24].[CH:35](O)(C)[CH3:36]>>[CH2:22]([O:25][CH2:26][CH2:27][O:28][C:29](=[O:34])[C:30]1[CH:4]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[C:5]([S:6](=[O:7])(=[O:8])[NH:9][CH:10]([CH3:11])[CH3:12])=[C:35]([CH3:36])[NH:33][C:31]=1[CH3:32])[CH2:23][CH3:24]
Reactant: CC(C)O
Reactant: CC(=O)C(=CS(=O)(=O)NC(C)C)c1cccc([N+](=O)[O-])c1
Reactant: CCCOCCOC(=O)/C=C(/C)N
Product: CCCOCCOC(=O)C1=C(C)NC(C)=C(S(=O)(=O)NC(C)C)C1c1cccc([N+](=O)[O-])c1
Yield: 21 %

Procedure:
A solution of 3.12 g (0.01 mol) of α-acetyl-N-isopropyl-3-nitrostyrenesulfonamide in 30 ml of isopropanol is treated with 1.87 g (0.01 mol) of 3-aminocrotonic acid 2-propoxyethyl ester and 1.16 g (0.005 mol) of DL-camphor-10-sulfonic acid in accordance with the procedure described in Example 1. After chromatography on silica gel with methylene chloride/ethyl acetate (4:1) as the elution agent the crude product is recrystallized from isopropanol. There is obtained 1.0 g (21%) of 5-(isopropylsulfamoyl)-1,4-dihydro-2.6-dimethyl-4-(3 -nitrophenyl)nicotinic acid 2-propoxyethyl ester, m.p. 155°-158°, as a colorless crystalline powder.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[CH:9][C:10]3[N:11]([CH2:12][N:13]([O:15][CH3:16])[CH:14]=3)[C:6]=2[N:5]([CH2:17][CH2:18][CH3:19])[CH2:4][C:3]=1[CH3:20].C(N(CC)CC)C.[H][H]>C(O)C.[Pd]>[CH3:16][O:15][N:13]1[CH:14]=[C:10]2[CH:9]=[N:8][C:7]3[CH:2]=[C:3]([CH3:20])[CH2:4][N:5]([CH2:17][CH2:18][CH3:19])[C:6]=3[N:11]2[CH2:12]1
Reactant: CCCN1CC(C)=C(Cl)C2=C1N1CN(OC)C=C1C=N2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCN1CC(C)=CC2=C1N1CN(OC)C=C1C=N2
Temperature: 30 °C
Reaction time: 4 h

Procedure:
2 g of intermediate A1 are suspended in 50 ml ethanol. 1 ml triethylamine and 1 g palladium catalyst are added. An autoclave is used as reaction vessel. Hydrogen is pressed in up to 20 bar pressure. Now, the mixture is stirred at 30° C. for 4 hours. After filtration the solvent is removed. The crude product is dissolved in 100 ml dichloromethane. This solution is washed with 50 ml water. The solvent is removed to isolate pure product.