Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10](=[O:12])[CH3:11])=[N:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].O>CC#N>[C:24]([O:23][C:21](=[O:22])[CH2:20][N:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10](=[O:12])[CH3:11])=[N:2]1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(=O)c1n[nH]c2cnccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(=O)c1nn(CC(=O)OC(C)(C)C)c2cnccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(1H-pyrazolo[3,4-c]pyridin-3-yl)-ethanone (Sphinx Scientific laboratory LLC, catalog number: PPY-1-CS01) (2.45 g 14.44 mmol) in CH3CN (50 mL) were added potassium carbonate (3.99 g, 28.9 mmol) and tert-butyl bromoacetate (2.34 mL, 15.88 mmol). The reaction mixture was stirred at RT overnight. The crude mixture was poured into water and extracted with EtOAc (×3). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 1:0 to 0:1) to give the title compound. TLC, Rf (EtOAc)=0.7; MS: 276 [M+H]+; tR (HPLC conditions c): 2.06 min.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[CH:4][C:5]([NH2:9])=[N:6][C:7]=1[CH3:8].Cl[CH2:12][CH:13]=O.C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[C:3]([CH3:10])=[CH:4][C:5]2[N:6]([CH:12]=[CH:13][N:9]=2)[C:7]=1[CH3:8]
Reactant: Cc1cc(N)nc(C)c1Br
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1cc2nccn2c(C)c1Br
Temperature: 25 °C

Procedure:
5-Bromo-4,6-dimethyl-pyridin-2-ylamine (1.51 g, 7.5 mmol) and chloroacetaldehyde (0.95 ml, 50% in water, 7.5 mmol) were mixed with toluene (12 ml). The mixture was heated to reflux for 3 h, upon which time a dark solid residue appeared at the bottom of the reaction flask. After cooling down to rt, NaHCO3 (20 ml, sat. aq.) and CH2Cl2 (20 ml) were added. Layers were separated and the aqueous layer was further extracted with CH2Cl2 (20 ml×2). The combined CH2Cl2 was dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography on silica gel (CH2Cl2/CH3OH, 18:1) to give the 6-bromo-5,7-dimethyl-imidazo[1,2-a]pyridine as a yellow oil (985 mg, 58%, contaminated with some starting material).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][N:18]3C(=O)C4C(=CC=CC=4)C3=O)[O:13][CH2:12][C:11]=2[S:10][C:9]=1[NH2:29])=[O:7])([CH3:4])([CH3:3])[CH3:2].NN>C(O)C.ClCCl>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][NH2:18])[O:13][CH2:12][C:11]=2[S:10][C:9]=1[NH2:29])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CC(CN1C(=O)c3ccccc3C1=O)OC2
Agent: NN
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1c(N)sc2c1CC(CN)OC2
Temperature: 80 °C
Reaction time: 14 h
Yield: 87.9 %

Procedure:
In a 50-ml round-bottom flask, a suspension of 2-amino-5-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (2.00 g, 4.8 mmol) in absolute ethanol (20 ml) was flushed with nitrogen and sealed with a rubber septum. Hydrazine (0.5 ml, 15.9 mmol) was added, followed by an additional portion of absolute ethanol (20 ml) at room temperature. The reaction mixture was heated to 80° C. for 3.5 h., then allowed to stir at room temperature for 14 h. The precipitate was filtered off and washed with absolute ethanol. The filtrate was concentrated in vacuo leaving an oil, which was dissolved in dichloromethane (30 ml) and refiltered. The solvent was evaporated in vacuo affording 1.2 g (86%) of 2-amino-5-aminomethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as a solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]#[N:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O:16][C:17]([C:19]1[N:23]([CH3:24])[N:22]=[C:21]([CH3:25])[C:20]=1[CH3:26])=O)C.C(C1C=CC(C)=NC=1)C.CO.C[O-].[Na+]>O.CCCCCCC>[O:16]=[C:17]([C:19]1[N:23]([CH3:24])[N:22]=[C:21]([CH3:25])[C:20]=1[CH3:26])[CH:11]([C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=1)[C:12]#[N:13]
Reactant: CC(C)(C)c1ccc(CC#N)cc1
Reactant: CCOC(=O)c1c(C)c(C)nn1C
Agent: CCc1ccc(C)nc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCCCCCC
Solvent: CO
Solvent: O
Product: Cc1nn(C)c(C(=O)C(C#N)c2ccc(C(C)(C)C)cc2)c1C
Temperature: 92.5 °C
Yield: 84.2 %

Procedure:
In a 300 mL-reaction flask equipped with a rectification column and a separating tank, 11.3 g (65.2 mmol) of 4-tert-butylphenylacetonitrile, 10.8 g (59.5 mmol) of 1,3,4-trimethylpyrazol-5-carboxylic acid ethyl ester, 100 g of heptane, 10.0 g of 5-ethyl-2-picoline were added, the atmosphere was substituted with nitrogen, then azeotropic dehydration was carried out by heating at 90 to 95° C. for 1 hour. The temperature was maintained, 13.8 g (71.5 mmol) of 28% sodium methoxide methanol solution was added dropwise over 3 hours, and the resulting mixture was further reacted for 11 hours. After cooling to 30° C. or less, 108 g of water was added to separate out heptane phase and obtain an aqueous phase. A quantitative analysis of the obtained aqueous phase with liquid chromatography showed that the aqueous phase contained 15.5 g (yield 84.5%) of 3-oxo-2-(4-tert-butylphenyl)-3-(1,3,4-trimethylpyrazol-5-yl) propionitrile.
Reaction SMILES: COC(=O)C1C=CC=C(N[C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])C=1.[CH2:40]([O:42]C(C1SC=C(C2C=CC=C(N)C=2)N=1)=O)[CH3:41]>>[CH2:40]([O:42][C:11](=[O:38])[CH2:12][N:13]1[N:19]=[C:18]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:34])([CH3:33])[CH3:35])[C:14]1=[O:37])[CH3:41]
Reactant: CCOC(=O)c1nc(-c2cccc(N)c2)cs1
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Product: CCOC(=O)CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C(C)(C)C)C1=O

Procedure:
The title compound was obtained by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1) except that 4-(3-amino-phenyl)-thiazole-2-carboxylic acid ethyl ester (prepared in two steps from 2-bromo-3′-nitroacetophenone) was used instead of 3-amino-benzoic acid methyl ester in step e, followed by reaction of the product obtained, in place of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid ethyl ester (Example 1, step c), according to the method of Example 1, step d. 1H NMR (CDCl3) 8.49 (1H, br s), 8.09-8.07 (1H, m), 7.89 (1H, s), 7.63-7.61 (1H, m), 7.56-7.46 (3H, m), 7.40-7.28 (2H, m), 7.05 (1H, d, 7.8), 4.82 (1H, d), 4.62 (1H, d), 4.33-4.20 (2H, m), 2.81-2.77 (1H, m), 2.05-1.69 (6H, m), 1.44-1.16 (13H, m). The compound was further characterised as the N-methyl-D-glucamine salt. Found: C, 56.05; H, 6.47; N, 9.82%; C32H35N5O5S.C7H17NO5.2.0H2O requires: C, 56.24; H, 6.78; N, 10.09%.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=2[C:9]=1[C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].[Br:29][CH2:30][CH2:31]Br>C(C(C)=O)C>[CH2:1]([C:5]1[O:6][C:7]2[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=2[C:9]=1[C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:31][CH2:30][Br:29])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1oc2ccccc2c1C(=O)c1ccc(O)cc1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCc1oc2ccccc2c1C(=O)c1ccc(OCCBr)cc1
Temperature: 50 °C
Reaction time: 18 h
Yield: 56.3 %

Procedure:
A mixture of 93.5 g (0.25 mole) of 2-n-Butyl-3-(4-hydroxy-benzoyl)-benzofuran, 69 g (0.5 mole) of finely ground anhydrous potassium carbonate and 500 ml of methyl ethyl ketone was stirred and refluxed for 30 minutes. The mixture was allowed to cool to about 50° C. and 187.8 g (1 mole) of 1,2-dibromo-ethane were added in one operation. Stirring and refluxing were continued for 18 h and a further increment of 47 g of 1,2-dibromo-ethane was added. Refluxing was continued for 6 h, the course of the reaction being monitored by thin-layer chromatography (TLC). Filtration and evaporation to dryness under reduced pressure then followed. The residue was taken up in diethyl ether after which the ethereal solution was washed, first with water, then with a 10% aqueous solution of sodium hydroxide and once again with water. Drying was carried out over sodium sulphate, followed by evaporation to dryness under reduced pressure. In this way 56.5 g of 2-n-butyl-3-[ 4-(2-bromo-ethoxy)-benzoyl]-benzofuran in the form of an oil were obtained.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:12](=[O:14])[CH3:13])[CH:8]=[C:9]([OH:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:16][CH2:17][F:18].[H-].[Na+].O>CN(C=O)C>[C:1]([C:5]1[CH:6]=[C:7]([C:12](=[O:14])[CH3:13])[CH:8]=[C:9]([O:11][CH2:16][CH2:17][F:18])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: FCCBr
Reactant: CC(=O)c1cc(O)cc(C(C)(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1cc(OCCF)cc(C(C)(C)C)c1
Reaction time: 8 h

Procedure:
1-(3-tert-Butyl-5-hydroxyphenyl)ethanone (O3.106; 500 mg) was dissolved in DMF (10 ml), and 1-bromo-2-fluoroethane (195 μl) was added while stirring. Sodium hydride (80 mg) was added at RT. After stirring at RT for 3 h, the mixture was left to stand overnight and then further sodium hydride (20 mg) was added and the mixture was stirred for a further 2 h. Then water was added and the mixture was concentrated to dryness. The residue was taken up in EA and washed three times with water. The EA phase was dried over magnesium sulfate, filtered and concentrated. 600 mg of the title compound were obtained. LC-MS rt: 1.13 min [M+H]+: 239.1 (met. b)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=1)[N:8]=[CH:7]2.[NH:23]1[C:27]2=[N:28][CH:29]=[CH:30][CH:31]=[C:26]2[C:25]([CH:32]=O)=[CH:24]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:20][C:19]([C:16]1[CH:15]=[CH:14][C:13]([N:9]2[N:8]=[CH:7][C:6]3[C:11](=[C:2]([NH:1][CH2:32][C:25]4[C:26]5[C:27](=[N:28][CH:29]=[CH:30][CH:31]=5)[NH:23][CH:24]=4)[CH:3]=[CH:4][CH:5]=3)[C:10]2=[O:12])=[CH:18][CH:17]=1)([CH3:22])[CH3:21]
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CC(C)(C)c1ccc(-n2ncc3cccc(N)c3c2=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)c1ccc(-n2ncc3cccc(NCc4c[nH]c5ncccc45)c3c2=O)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 8-amino-2-(4-tert-butyl-phenyl)-2H-phthalazin-1-one (Example 1, Step E, 0.36 g, 1.1 mmol, 1 eq) and CH2Cl2 (50 mL) was added 1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (0.16 g, 1.1 mmol, 1 eq) and NaBH(OAc)3 (0.72 g, 3.4 mmol, 3.0 eq). The reaction was stirred at RT for 12 h then quenched with H2O and extracted with CH2Cl2. The organic layer was washed with H2O and brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by silica flash chromatography (10-75% EtOAc:hexane) to give the desired product as a yellow solid. MS m/e 424 (M+H)+. Calc'd for C26H25N5O-423.51.
Reaction SMILES: OC1C2C[S:17]C[C@@H](C(N)=O)NC(=O)CCCCOC(=O)C=2C(C)=C(OC)C=1.[CH3:28][Si:29]([CH3:63])([C:57]([CH3:62])([CH3:61])[CH:58]([CH3:60])[CH3:59])[O:30][C:31]1[C:48]2[CH2:47][S:46][CH2:45][C@@H:44]([C:49]([NH2:51])=O)[NH:43][C:42](=[O:52])[CH2:41][CH2:40][CH2:39][CH2:38][O:37][C:36](=[O:53])[C:35]=2[C:34]([CH3:54])=[C:33]([O:55][CH3:56])[CH:32]=1>C1(C)C=CC=CC=1>[CH3:63][Si:29]([CH3:28])([C:57]([CH3:61])([CH3:62])[CH:58]([CH3:60])[CH3:59])[O:30][C:31]1[C:48]2[CH2:47][S:46][CH2:45][C@H:44]([C:49](=[S:17])[NH2:51])[NH:43][C:42](=[O:52])[CH2:41][CH2:40][CH2:39][CH2:38][O:37][C:36](=[O:53])[C:35]=2[C:34]([CH3:54])=[C:33]([O:55][CH3:56])[CH:32]=1
Reactant: COc1cc(O[Si](C)(C)C(C)(C)C(C)C)c2c(c1C)C(=O)OCCCCC(=O)N[C@H](C(N)=O)CSC2
Reactant: COc1cc(O)c2c(c1C)C(=O)OCCCCC(=O)N[C@H](C(N)=O)CSC2
Solvent: Cc1ccccc1
Product: COc1cc(O[Si](C)(C)C(C)(C)C(C)C)c2c(c1C)C(=O)OCCCCC(=O)N[C@@H](C(N)=S)CSC2

Procedure:
The product of Example 68 was subjected in an analogous manner to the procedure described in Example 1(f) and the resulting (R)-16-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-14-methoxy -13-methyl-6,12-dioxo-1,3,4,5,6,7,8,9,10,12-decahydro -11,2,5-benzoxathiaazacyclotetradecine-4-carboxylic acid amide was reacted in toluene with an equimolar amount of 2,4-bis-(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiaphosphetane at 60° C. for 30 min. The solvent was evaporated in vacuo, and the residue was chromatographed on silica gel using ethyl acetate/hexane (1:2, v/v) as eluent, to yield (R)-16-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-14-methoxy-13-methyl-6,12-dioxo-1,3,4,5,6,7,8,9,10,12-decahydro-11,2,5-benzoxathiaazacyclotetradecine-4-thiocarboxylic acid amide as a white foam.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:50]([C:52]([C:71]1[CH:76]=[CH:75][C:74](/[CH:77]=[CH:78]/[C:79]2([OH:85])[CH2:84][CH2:83][S:82][CH2:81][CH2:80]2)=[C:73]([CH3:86])[CH:72]=1)([C:55]1[CH:60]=[CH:59][C:58](B2OC(C)(C)C(C)(C)O2)=[C:57]([CH3:70])[CH:56]=1)[CH2:53][CH3:54])[CH3:51]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:58]2[CH:59]=[CH:60][C:55]([C:52]([CH2:53][CH3:54])([C:71]3[CH:76]=[CH:75][C:74](/[CH:77]=[CH:78]/[C:79]4([OH:85])[CH2:84][CH2:83][S:82][CH2:81][CH2:80]4)=[C:73]([CH3:86])[CH:72]=3)[CH2:50][CH3:51])=[CH:56][C:57]=2[CH3:70])=[CH:7][CH:6]=1
Reactant: COC(=O)Cc1ccc(Br)cc1
Reactant: CCC(CC)(c1ccc(/C=C/C2(O)CCSCC2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(CC)(c1ccc(/C=C/C2(O)CCSCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)cc2)c(C)c1
Temperature: 110 °C
Reaction time: 2 h
Yield: 38.4 %

Procedure:
(4-Bromo-phenyl)acetic acid methyl ester (33 mg, 0.11 mmol), palladium acetate (2.2 mg, 0.0096 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (7.9 mg, 0.019 mmol), potassium phosphate (61 mg, 0.29 mmol) and water (0.2 mL) were added to a solution of 4-[(E)-2-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-vinyl]-tetrahydro-thiopyran-4-ol (Example 138-(3); 50 mg, 0.096 mmol) in toluene (2 mL). The mixture was stirred in a nitrogen atmosphere at 110° C. for two hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=1:1) to give the target compound as a colorless oil (20 mg, 38%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:16]C(=O)OC(C)(C)C)[CH2:10][CH2:11][S:12](=[O:15])(=[O:14])[NH2:13])=[CH:5][CH:4]=1>C(Cl)Cl.CO>[NH2:16][CH:9]([C:6]1[CH:7]=[CH:8][C:3]([Cl:2])=[CH:4][CH:5]=1)[CH2:10][CH2:11][S:12]([NH2:13])(=[O:14])=[O:15]
Reactant: CC(C)(C)OC(=O)NC(CCS(N)(=O)=O)c1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: NC(CCS(N)(=O)=O)c1ccc(Cl)cc1
Temperature: 22 °C
Reaction time: 24 h
Yield: 73.1 %

Procedure:
Hydrogen chloride (4M in dioxan, 1.0 mL, 4.00 mmol) was added to tert-butyl 1-(4-chlorophenyl)-3-sulfamoylpropylcarbamate (Intermediate 103) (38 mg, 0.11 mmol) in a mixture of DCM (5 mL) and methanol (2 mL) at 22° C. The resulting solution was stirred at 22° C. for 24 hours. The mixture was evaporated to dryness and the residue was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 30% (2M NH3 in MeOH) in DCM and pure fractions were evaporated to dryness to afford 3-amino-3-(4-chlorophenyl)propane-1-sulfonamide (20.00 mg, 73.8%) as a colourless gum.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:28])[N:8]([C:10]2[CH:15]=[C:14]([O:16][Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])[CH:13]=[C:12]([CH3:27])[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl[C:32]([O:34][CH2:35][C:36]([Cl:39])([Cl:38])[Cl:37])=[O:33]>C(OCC)(=O)C>[Cl:37][C:36]([Cl:39])([Cl:38])[CH2:35][O:34][C:32](=[O:33])[NH:28][C:7]1[N:8]([C:10]2[CH:15]=[C:14]([O:16][Si:17]([CH:18]([CH3:20])[CH3:19])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:22])[CH3:23])[CH:13]=[C:12]([CH3:27])[CH:11]=2)[N:9]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:6]=1
Reactant: Cc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-n2nc(C(C)(C)C)cc2N)c1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)c1
Reaction time: 0.08 h
Yield: 103 %

Procedure:
To a solution of Intermediate 54b (0.73 g, assumed 1.70 mmol) in ethyl acetate (8 mL) was added 1N sodium hydroxide solution (4.5 mL, 4.50 mmol). Stirred for 5 min then 2,2,2-trichloroethyl chloroformate (275 μL, 2.00 mmol) was added and the mixture stirred vigorously at RT for 3.5 h. Diluted with EtOAc, washed with water and brine, dried, and concentrated in vacuo. The residue was purified by FCC, using 0-15% EtOAc in cyclohexane, to give the still impure title compound (1.01 g). NMR (300 MHz, CDCl3): inter alia 1.02-1.15 (18H, m), 1.18-1.38 (12H, m), 2.34 (3H, s), 4.82 (2H, s), 6.43 (1H, s), 6.69-6.77 (2H, m), 6.84-6.96 (2H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2=O.O.NN.Cl>CS(C)=O.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2
Reactant: COc1ccc2c(c1)C(=O)C(=O)N2
Agent: Cl
Agent: NN
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc2c(c1)CC(=O)N2
Temperature: 140 °C
Reaction time: 1 h
Yield: 66.6 %

Procedure:
To a solution of 5-methoxyisatin (10.62 g, 60 mmol) in DMSO (30 mL) was added N2H4.xH2O (hydrazine hydrate, 6 mL, 120 mmol) dropwise over 5 min (exothermic). After addition, the resulting mixture was heated at 140° C. (oil temp.) for 2 h and then cooled to rt. After diluting with H2O (30 mL), 6 M HCl (12 mL, 72 mmol) was added and the resulting mixture was stirred for 1 h at rt. Ice (30 mL) was added and the reaction mixture was stirred O/N at rt. The precipitate formed was collected by suction filtration, rinsed with H2O, then dried to give the 5-methoxyoxindole (6.523 g) as a brown solid. (about 10% impurity being the oxime from starting material 5-methoxyisatin) 1H NMR (400 MHz, d6-DMSO) 6.78 (s, 1H), 6.85 (s, 1H), 6.72-6.79 (m, 2H), 3.39 (s, 3H); ESI 164.0 [M+H]+, calcd for [C9H9NO2+H]+ 164.1.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]C=O.[CH3:12][O:13][CH:14](OC)[O:15][CH3:16].Cl>O1CCOCC1.C(=O)(O)[O-].[Na+].CO>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:14]([O:15][CH3:16])[O:13][CH3:12]
Reactant: COC(OC)OC
Reactant: O=CCCCCCCCCBr
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: COC(CCCCCCCCBr)OC
Temperature: 25 °C
Yield: 97.2 %

Procedure:
To a 100 mL round-bottomed flask was added 9-bromononanal (7.2 g, 32.5 mmol), methanol (30 mL) and trimethylorthoformate (4 mL, 36.5 mmol). A solution of 4 N hydrochloric acid in dioxane (0.2 mL, 0.8 mmol) was added and the resulting mixture was refluxed for 3 h. The reaction mixture was then cooled to room temperature and solid sodium bicarbonate (100 mg, 1.2 mmol) was added. The resulting mixture was concentrated to one-fourth its original volume under reduced pressure and then ethyl acetate (50 mL) was added. The organic layer was washed with water (2×40 mL), dried (MgSO4), filtered and concentrated under reduced pressure to afford the title intermediate (8.44 g, (97% yield)) as a liquid, which as used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1.[CH2:16]1[CH2:20]OC[CH2:17]1>>[CH:16]([C:3]1[C:4]2[NH:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[S:12][C:13]=2[CH:14]=[CH:15][CH:2]=1)([CH3:20])[CH3:17]
Reactant: C1CCOC1
Reactant: Clc1ccc2c(c1)Nc1ccccc1S2
Product: CC(C)c1cccc2c1Nc1ccccc1S2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
To a solution of 2-chlorophenothiazine (4.67 g, 20 mmol) in anhydrous THF (40 mL) i-propyllithium (0.7 m solution in pentane, 100 mL, 70 mmol) was added at −75° C. (1 h). The reaction mixture had been stirred (2 h), ice-water was added slowly (30 min.) and after that the stirring was continued for 30 min. The organic layer was separated and combined with ether extracts of the aqueous phase. The combined organic phase was washed with water, dried (Na2SO4) and concentrated to give the crude product (52% yield). Compound was purified by flash chromatography (solvent system: hexane-ethyl acetate).
Reaction SMILES: [Na].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11]([NH2:13])=[O:12])=[C:5]([C:14]#[N:15])[CH:4]=1>CC(O)C>[NH2:15][C:14]1[C:5]2[C:6](=[CH:7][CH:8]=[C:3]([Br:2])[CH:4]=2)[NH:9][C:10]=1[C:11]([NH2:13])=[O:12]
Reactant: N#Cc1cc(Br)ccc1NCC(N)=O
Agent: [Na]
Solvent: CC(C)O
Product: NC(=O)c1[nH]c2ccc(Br)cc2c1N
Temperature: 25 °C
Reaction time: 14 h
Yield: 8.7 %

Procedure:
1.4 g (63.0 mmol) sodium was dissolved in 200 ml 2-propanol, thereafter 16.0 g (63.0 mmol) 2-(4-bromo-2-cyano-phenylamino)acetamide was added and the solution was stirred at room temperature for 14 h. Then, the solvent was concentrated and water was added. The resulting precipitate was sucked off and washed with water. 1.4 g (8%) 3-amino-5-bromo-1H-indole-2-carboxylic acid amide was obtained. ESI-MS [m/z]: 254, 256 [M+H]+
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[C:12]([N:13]2[CH:17]=[CH:16][CH:15]=[CH:14]2)=[CH:11][CH:10]=[CH:9][N:8]=1.[OH-].[Na+].CN(C)[CH:22]=[O:23]>>[Cl:6][C:7]1[C:12]([N:13]2[CH:17]=[CH:16][CH:15]=[C:14]2[CH:22]=[O:23])=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: CN(C)C=O
Reactant: Clc1ncccc1-n1cccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cccn1-c1cccnc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
To 14.6 g of N,N-dimethylformamide was added dropwise 8.3 g of phosphorus oxychloride under ice-cooling. The mixture was stirred at room temperature for 30 minutes. Thereto 6.5 g of 1-(2-chloro-3-pyridinyl)-1H-pyrrole was added, and the resulting mixture was stirred at 60° C. for 2 hours. The reaction mixture was allowed to cool to room temperature, and added to ice water. The mixture was adjusted to pH 4 by an addition of a 2N aqueous sodium hydroxide solution, and then extracted with ethyl acetate two times. The organic layers were combined, washed successively with water and an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel chromatography to obtain 6.05 g of 1-(2-chloro-3-pyridinyl)-1H-pyrrole-2-carbaldehyde of the formula:
Reaction SMILES: O[C:2]1C=C(C=CC=1C)C(O)=O.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:17]([OH:19])=[O:18]>>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:17]([O:19][CH3:2])=[O:18]
Reactant: Cc1ccc(C(=O)O)cc1O
Reactant: COc1cc(C(=O)O)ccc1C
Product: COC(=O)c1ccc(C)c(OC)c1

Procedure:
The process according to claim 1, wherein 3-hydroxy-4-methylbenzoic acid in the form of a mixture with 3-methoxy-4-methylbenzoic acid is reacted to give methyl 3-methoxy-4-methylbenzoate.