Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[CH3:3].CS[C:17]1[NH:22][C:21](=[O:23])[C:20]([O:24][C:25]2[CH:26]=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=2)=[CH:19][N:18]=1>N1C=CC=CC=1>[CH3:3][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:17]2[NH:22][C:21](=[O:23])[C:20]([O:24][C:25]3[CH:26]=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=3)=[CH:19][N:18]=2)[N:9]=1)[CH3:1]
Reactant: CSc1ncc(Oc2ccc(C)nc2)c(=O)[nH]1
Reactant: CN(C)Cc1nc(CSCCN)cs1
Solvent: c1ccncc1
Product: Cc1ccc(Oc2cnc(NCCSCc3csc(CN(C)C)n3)[nH]c2=O)cn1

Procedure:
Following the procedure of Example 12, a mixture of 1.29 g. of 2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethylamine and 1.38 g. of 2-methylthio-5-(6-methyl-3-pyridyl)oxy-4-pyrimidone in pyridine solution were heated to refluxing temperature for about 88 hours. After this time, the solvent was removed by evaporation in vacuo and the residue dissolved in ethanol. The ethanolic solution was evaporated to dryness. The residue was subjected to high pressure liquid chromatography over silica using a gradient elution technique with an ethyl acetate/ethanol/ammonium hydroxide solvent system as the eluant. Fractions shown by tlc to contain 2-[2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl]amino-5-(6-methyl-3-pyridyl)oxy-4-pyrimidone were combined and the solvent removed by evaporation. The resulting residue was rechromatographed on a silica preparative plate using 3% ammoniated ethanol as the solvent. 2-[2-(2-Dimethylaminomethyl-4-thiazolylmethylthio)ethyl]amino-5-(6-methyl-3-pyridyl)oxy-4-pyrimidone free base thus obtained was converted to the corresponding trihydrochloride salt by standard procedures. 2-[2-(2-Dimethylaminomethyl-4-thiazolylmethylthio)ethyl]amino-5-(6-methyl-3-pyridyl)oxy-4-pyrimidone trihydrochloride melted at about 216°-220° C. after recrystallization from a mixture of ethanol, ethyl acetate and ether. Yield=0.36 g.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:15][C:16]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:17]=1[CH:18]=[CH:19][CH:20]=[C:21]2[OH:26])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[I-].[Na+].[OH2:29]>CN(C)C=O.O1CCCC1>[CH2:3]([O:15][C:16]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:17]=1[CH:18]=[CH:19][CH:20]=[C:21]2[O:26][CH2:17][CH:16]([OH:15])[CH2:25][OH:29])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCOc1cccc2c(O)cccc12
Reactant: O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCOc1cccc2c(OCC(O)CO)cccc12
Reaction time: 8 h

Procedure:
To a suspension of 2.19 g of 50% sodium hydride in 80 ml of dimethylformamide, under argon, was added with stirring a solution of 12 g of 5-(dodecyloxy)-1-naphthalenol in 60 ml of tetrahydrofuran over 1/2 hour. A 2 g portion of sodium iodide and 9.77 g of solketal mesylate were added and the mixture was stirred overnight. The mixture was diluted with water and extracted with ether. The ether extract was washed with dilute sodium hydroxide, then brine, dried, filtered through silica gel and the solvent removed. The residue was refluxed in a mixture of 100 ml of methanol, 16 ml of water and 1 ml of concentrated sulfuric acid for one hour, then cooled and the solid collected. This solid was dissolved in boiling chloroform containing magnesium sulfate and activated carbon and filtered through diatomaceous earth. The filtrate was evaporated and the residue recyrstallized from carbon tetrachloride, giving 8 g of the desired compound as an off-white solid, mp 143°-144° C.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1>[Hg].C(OCC)(=O)C>[CH:3]12[C:4](=[O:5])[O:6][C:1](=[O:7])[CH:2]1[CH:3]1[C:4](=[O:5])[O:6][C:1](=[O:7])[CH:2]12
Reactant: O=C1C=CC(=O)O1
Agent: [Hg]
Solvent: CCOC(C)=O
Product: O=C1OC(=O)C2C1C1C(=O)OC(=O)C21
Yield: 3.3 %

Procedure:
In a 1 liter-glass flask equipped with a 500 W moderate-pressure mercury lamp, 100 g (1.02 M) of maleic anhydride and 1 kg of ethyl acetate were placed and mixed to provide a homogeneous solution. Under stirring in an agron atmosphere, the solution was irradiated with light by using the mercury lamp for 8 hours at 20° C. to precipitate a crystal. After the reaction, the crystal was recovered by filtration to obtain 3.3 g of cyclobutanetetracarboxylic dianhydride (100% trans form).
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O-:6])=O.[Cl:11][C:12]1[CH:20]=[C:19]2[C:15]([C:16]([NH2:21])=[N:17][NH:18]2)=[CH:14][CH:13]=1.Cl.CN(C)CCCN=C=NCC>ClCCl>[Cl:11][C:12]1[CH:20]=[C:19]2[C:15]([C:16]([NH:21][C:4](=[O:6])/[CH:3]=[CH:2]/[C:1]([O:8][CH2:9][CH3:10])=[O:7])=[N:17][NH:18]2)=[CH:14][CH:13]=1
Reactant: CCOC(=O)/C=C/C(=O)[O-]
Reactant: Nc1n[nH]c2cc(Cl)ccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)/C=C/C(=O)Nc1n[nH]c2cc(Cl)ccc12
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
865 mg of monoethyl fumarate are added to 1 g of 6-chloro-1H-indazole-3-amine in 50 cm3 of dichloromethane. 1.4 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride are then introduced and the mixture is stirred for 30 minutes at about 20° C. The resulting mixture is washed with 50 cm3 of distilled water and then with 50 cm3 of saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulphate, filtered and then evaporated under reduced pressure (2 kPa; 40° C.). 2 g of a brick-coloured gummy mass are obtained, and are purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 4.5 cm), eluting with a cyclohexane/ethyl acetate mixture (90/10 by volume) and collecting 40 cm3 fractions. The fractions containing the expected product are combined and then evaporated under reduced pressure (2 kPa) at a temperature in the region of 40° C. After drying (90 Pa; 45° C.), 900 mg of ethyl 4-[(6-chloro-1H-indazol-3-yl)amino]-4-oxo-2-butenoate, (E form), melting at 220° C., are obtained.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:6][OH:7])[CH2:4][OH:5].CO[C:10](OC)([CH3:12])[CH3:11].O1CCCC1>C(N(CC)CC)C>[CH3:11][C:10]1([CH3:12])[O:5][CH2:4][CH:3]([CH2:6][OH:7])[CH2:2][O:1]1
Reactant: COC(C)(C)OC
Reactant: OCC(CO)CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(C)OCC(CO)CO1
Temperature: 20 °C
Reaction time: 1 h
Yield: 106.8 %

Procedure:
A mixture of 2-Hydroxymethyl-1,3-propanediol (9.0 g, 61.6 mmol), 2,2-dimethoxypropane (11.7 ml, 95.2 mmol) 4-toluenesulphonic acid monohydrate (0.49 g, 2.58 mmol) and tetrahydrofuran (450 ml) was stirred at 20° C. for 1 hour. Triethylamine (5 ml) was then added and the solvent removed under reduced pressure. Chromatography on silica gel (eluted with chloroform ethanol, 10.1) afforded the title compound (9.62 g, 78%) as a colourless oil. 1R: υmax (film) 3431, 2993, 2943, 2874, 1482, 1456, 1373 cm-1. 1H NMR: δH [(CD3)2SO] 1.30(6H, s, 2×CH3), 1.69(1H,m,CH), 3.38(2H,dd, J=5.2, 6.6 Hz, CH2OH), 3.61(2H,dd, J=11.8, 7.1 Hz, 2×H(ax)), 3.82 (2H, dd, J=11.8, 4.4 Hz, 2×H(eq)), 4.53(1H, t, J=5.2 Hz, D2O exchangable, OH). Found: C, 56.73; H, 9.80%. C7H14O3.0.01H2O requires: C, 56.80; H, 9.69%.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22](=[S:24])[NH2:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:26][C:27](=O)[CH3:28].C(O)C>ClCCl>[CH3:28][C:27]1[N:23]=[C:22]([C:16]2([C:13]3[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:11][CH:12]=3)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[S:24][CH:26]=1
Reactant: NC(=S)C1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: CC(=O)CCl
Solvent: ClCCl
Solvent: CCO
Product: Cc1csc(C2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)n1
Yield: 60.7 %

Procedure:
4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbothioamide (100 mg, 0.29 mmol), chloroacetone (46 μL, 0.57 mmol) and ethanol (5 mL) were combined and heated at reflux for 18 hours. The reaction mixture was concentrated in vacuo to give a cream coloured solid. This was dissolved in dichloromethane (100 mL) and washed with saturated NaHCO3 solution (50 mL). The organic extract was dried using Na2SO4, filtered and concentrated in vacuo. The compound was purified by column chromatography using 15 g of silica gel, eluting with dichloromethane:methanol:ammonia (97:3:0.3) to dichloromethane:methanol:ammonia (94:6:0.6) to give the title compound as a white solid (68 mg, 61%). 1H NMR (400 MHz, CDCl3) δ7.3 (d, 2H), 6.9 (d, 2H), 6.75 (s, 1H), 4.0 (t, 2H), 3.83 (m, 2H), 3.7 (m, 2H), 2.75-2.58 (m, 8H), 2.4 (s, 3H), 2.35 (m, 2H), 2.03 (m, 2H), 1.8 (m, 4H)
Reaction SMILES: [CH:1]([CH:3]1[O:7]B(O)[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]1=2)=[CH2:2].Br[C:14]1[N:19]=[C:18]([NH:20][C:21]2[CH:25]=[C:24]([CH:26]3[CH2:28][CH2:27]3)[NH:23][N:22]=2)[C:17]([Cl:29])=[CH:16][N:15]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[Cl:29][C:17]1[C:18]([NH:20][C:21]2[CH:25]=[C:24]([CH:26]3[CH2:28][CH2:27]3)[NH:23][N:22]=2)=[N:19][C:14]([C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[CH:3]([OH:7])[CH:1]=[CH2:2])=[N:15][CH:16]=1
Reactant: C=CC1OB(O)c2ccccc21
Reactant: Clc1cnc(Br)nc1Nc1cc(C2CC2)[nH]n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C=CC(O)c1ccccc1-c1ncc(Cl)c(Nc2cc(C3CC3)[nH]n2)n1
Temperature: 90 °C
Reaction time: 3 h
Yield: 46.6 %

Procedure:
The mixture of 3-vinylbenzo[c][1,2]oxaborol-1(3H)-ol (2.2 g, 13.4 mmol, 1.3 eq), 2-bromo-5-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (3.3 g, 10.5 mmol, 1.0 eq), Pd(PPh3)4 (1.3 g, 1.1 mmol, 0.11 equiv.) and saturated aq Na2CO3 (5 mL) in 1,4-dioxane (30 mL) was stirred at 90° C. for 3 h under N2, then, cooled to rt and partitioned between EtOAc and water. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give 1-(2-(5-chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)phenyl)prop-2-en-1-ol (1.8 g, 47%). LC-MS (m/z)=368.0 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[C:24]1([C:34](O)=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1>>[Cl:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:34]([C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][CH:25]=2)=[O:35])=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c(-c2cccc(Cl)c2)s1
Reactant: O=C(O)c1cccc2ccccc12
Product: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc3ccccc23)c(-c2cccc(Cl)c2)s1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-[5-(3-chloro-phenyl)-2-methyl-thiazol-4-yl]-methanone with Naphthalene-1-carboxylic acid. LC-MS (basic): tR=0.95 min; [M+H]+=502.3.
Reaction SMILES: CCN(CC)CC.[N:8]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[N+:9]=[N-:10].C(Cl)(=O)C(C)(C)C.[CH2:24]([C@H:31]1[CH2:35][O:34][C:33](=[O:36])[NH:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1>[N:8]([CH2:11][CH2:12][CH2:13][C:14]([N:32]1[C@@H:31]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:35][O:34][C:33]1=[O:36])=[O:16])=[N+:9]=[N-:10]
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: [N-]=[N+]=NCCCC(=O)O
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: [N-]=[N+]=NCCCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 74 %

Procedure:
NEt3 was added to a stirred mixture of 4-azidobutanoic acid in THF (0.3 M) cooled to −78° C. and stirring was continued at this temperature for 10 min. Pivaloyl chloride (1.3 eq) was added dropwise. The resulting mixture was warmed to 0° C. and stirred for 1 h before re-cooling to −78° C. In a separate flask, (4S)-4-benzyl-1,3-oxazolidin-2-one was dissolved in THF (0.8 M) and cooled to −78° C. before dropwise addition of N-BuLi (1.6M, 1.35 eq.) over 10 min. The mixture was stirred at −78° C. for 1 h and then transferred into the −78° C. solution of mixed anhydride using a syringe. The reaction was stirred at −78° C. for 1 h, then at RT for a further 1 h. The reaction was quenched by addition of sat. aq. NH4Cl before partitioning between H2O and EtOAc. The layers were separated and the aqueous phase re-extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by FC eluting with 10 to 30% EtOAc/PE to give the product as a colourless oil (74%). (ES+) m/z 289 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:14]=2C=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:30])C=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:14]=2[OH:30])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cc(Br)ccc2C=O)C1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(Oc2cc(Br)ccc2O)C1
Reaction time: 15 h

Procedure:
To a CH2Cl2 (280 mL) solution of the title compound of Step B (24.7 g, 69.4 mmol) was added 77% m-CPBA (23.3 g, 104 mmol). After 15 h, 10% Na2S2O5 (aq.) was added and the solution allowed to stir until the aqueous was KI paper negative then extracted with CH2Cl2 (2×). The combined organic layers were washed with saturated NaHCO3 (aq.), concentrated and treated with MeOH (220 mL) and 1N NaOH (220 mL). After 15 h, the reaction was partially concentrated to remove the MeOH, acidified with 1M KHSO4 (220 mL) and extracted with CH2Cl2 (2×). The combined organic layers were washed with brine and dried providing a brown solid that was triturated with EtOAc/hexanes giving 17.6 g (74%) of the title compound as a white solid. 1H NMR (CDCl3): 7.03 (dd, J=8.5, 2.1 Hz, 1H), 6.84 (d, J=8.5 Hz, 1H), 6.64 (d, J=2.2 Hz, 1H), 4.93-4.89 (m, 1H), 4.34 (dd, J=10.1, 6.8 Hz, 1H), 4.03 (dd, J=9.9, 3.7 Hz, 1H), 1.46 (s, 9H).
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[NH:13][C:12]1=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[C:24]([O:28][C:29]([NH:31][C@@H:32]([C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1)[CH3:33])=[O:30])([CH3:27])([CH3:26])[CH3:25]>CN(C=O)C>[C:24]([O:28][C:29]([NH:31][C@@H:32]([C:34]1[CH:40]=[CH:39][C:37]([NH:38]/[C:4](=[C:11]2\[C:12](=[O:23])[NH:13][C:14]3[C:19]\2=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)/[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[CH:36][CH:35]=1)[CH3:33])=[O:30])([CH3:25])([CH3:26])[CH3:27]
Reactant: CCOC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1ccc(N)cc1
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)OC(C)(C)C)c1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 89 from 3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and (R)-4-(1-tert.butoxycarbonylamino-ethyl)-aniline in DMF.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[N:5]([CH3:7])[CH3:6].[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[C:17]2=[O:24]>>[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[C:17]2([C:2]1[CH:3]=[C:4]([N:5]([CH3:7])[CH3:6])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[OH:24]
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: COc1ccc(N(C)C)cc1Br
Product: COc1ccc(N(C)C)cc1C1(O)C(=O)Nc2ccc(Cl)cc21
Yield: 80.2 %

Procedure:
With 500 mg of the compound obtained in Step 190-2 and 270 mg of 5-chloroisatin as starting materials, 397 mg of the title compound (brown solid) was obtained by a similar method to Step 21-1.
Reaction SMILES: CN(C)C1CC2C(=CC=CC=2)C1.[CH3:13][S:14](Cl)(=[O:16])=[O:15].[CH2:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH:19]1[OH:27].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:13][S:14]([O:27][CH:19]1[CH2:20][C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:18]1)(=[O:16])=[O:15]
Reactant: OC1Cc2ccccc2C1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)C1Cc2ccccc2C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OC1Cc2ccccc2C1
Temperature: 20 °C
Reaction time: 16 h
Yield: 98.5 %

Procedure:
N,N-Dimethyl-2-indanamine (107). Methanesulfonyl chloride (11.5 mL, 149 mmol) was added dropwise to a stirred solution of 2-indanol (106) (20 g, 149 mmol) and iPr2NEt (28.6 mL, 164 mmol) in DCM (300 mL) at 0° C., and the solution stirred at 20° C. for 16 h. The solution was washed with 1 M HCl (80 mL), aqueous saturated NaHCO3 solution (80 mL) and brine (100 mL), dried and the solvent evaporated. The residue was recrystallised from EtOH to give 2,3-dihydro-1H-inden-2-yl methanesulfonate (31.14 g, 98%) as a white solid. Aqueous HNMe2 (40%, 180 mL, 1.42 mol) was added slowly to a stirred solution of mesylate (30.25 g, 143 mmol) in DMF (200 mL) and the solution stirred at 20° C. for 16 h. The solution was partitioned between EtOAc (400 mL) and water (800 mL) and the organic fraction washed with water (3×80 mL), brine (100 mL), dried and the solvent evaporated. The residue was suspended in 1 M HCl (400 mL) and washed with DCM (3×80 mL). The pH of the aqueous fraction was adjusted to 14 with NaOH, the mixture chilled at 5° C. for 8 h and the precipitate filtered. The precipitate was washed with water (50 mL) and dried to give amine 107 (21.54 g, 93%) as a light gray solid: 1H NMR δ 7.10-7.17 (m, 4H, Harom), 3.01-3.08 (m, 3H, H-2, CH2), 2.82-2.91 (m, 2H, CH2), 2.31 [s, 6H, N(CH3)2].
Reaction SMILES: [C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[C:12]([CH:13]=O)=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].[CH2:17]([NH2:22])[CH2:18][CH2:19][CH2:20][CH3:21].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CCOC(C)=O>ClCCCl>[C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[C:12]([CH2:13][NH:22][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1
Reactant: CCCCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CCCCCNCc1cncn1Cc1ccc(C#N)cc1
Reaction time: 120 h

Procedure:
To a solution of the aldehyde 6 (132 mg) in 3 mL of 1,2-dichloroethane at 0° C. was added 4Å powdered molecular sieves (300 mg), n-pentylamine (0.217 mL), and sodium triacetoxyborohydride (260 mg). After five days, the reaction was poured into EtOAc and washed with water, sat. aq. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the amine 7 as a brown oil which was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:13]=[C:6]2[C:7]([O:9][C:10](=[O:12])[NH:11][C:5]2=[CH:4][CH:3]=1)=O.[NH:14]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:17](=O)[C:15]1=O.FC1C=C2C(=CC=1)NC(=O)C2=O>>[CH3:17][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:24]=1[N:14]=[C:15]1[C:7](=[O:9])[C:6]3[C:5]([N:11]1[C:10]2=[O:12])=[CH:4][CH:3]=[CH:2][CH:13]=3
Reactant: O=C1Nc2ccccc2C1=O
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Agent: O=C1Nc2ccc(F)cc2C1=O
Product: Cc1cccc2c(=O)n3c(nc12)C(=O)c1ccccc1-3
Yield: 31 %

Procedure:
Using the procedure in Example 12 and substituting 3-methylisatoic anhydride for 5-chloroisatoic anhydride and isatin for 5-fluoroisatin gave the title compound in 31% yield: mp 247°-248° C.; 1H NMR (300 MHz, CDCl3) δ 8.64 (d, 1H), 8.28 (d, 1H), 7.92 (d, 1H), 7.78 (dt, 1H), 7.70 (d, 1H), 7.55 (t, 1H), 7.43 (dt, 1H), 275 (s, 1H); MS (M+H)+ 263, (M+CH4CN)+ 304.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1([OH:18])[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]21[CH2:17][CH2:16][CH2:15][CH2:14]2.C(N(CC)CC)C.[Cl:26][C:27]([Cl:34])([Cl:33])[CH2:28][O:29][C:30](Cl)=[O:31]>C(Cl)Cl>[OH:18][C:4]1([CH2:3][CH2:2][NH:1][C:30](=[O:31])[O:29][CH2:28][C:27]([Cl:34])([Cl:33])[Cl:26])[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]21[CH2:14][CH2:15][CH2:16][CH2:17]2
Reactant: NCCC1(O)CCc2ccccc2C12CCCC2
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCC1(O)CCc2ccccc2C12CCCC2)OCC(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.1 %

Procedure:
A solution of the product from Example 9 (0.88 g, 3.59 mmol) and triethylamine (0.40 g, 3.78 mmol) in 10 mL of CH2Cl2 was cooled to 0° C. and treated dropwise with 2,2,2-trichloroethylchloroformate (0.80 g, 3.78 mmol) in 2 mL CH2Cl2. The resulting solution was stirred at 0° C. for 30 minutes and warmed to room temperature. The reaction mixture was washed with saturated aq. NaHCO3 solution (10 mL). The aqueous phase was extracted with CH2Cl2 (10 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated. The residue was purified by chromatography (silica gel, 10:1 heptane/ethyl acetate) to give the title compound (1.18 g, 78%) as a viscous oil.
Reaction SMILES: [Br:1][C:2]1[C:6]([CH2:7]Cl)=[CH:5][N:4]([C:9]([CH2:12][CH3:13])([CH3:11])[CH3:10])[N:3]=1.[I-:14].[Na+]>CC(C)=O>[Br:1][C:2]1[C:6]([CH2:7][I:14])=[CH:5][N:4]([C:9]([CH2:12][CH3:13])([CH3:11])[CH3:10])[N:3]=1
Reactant: [I-]
Reactant: CCC(C)(C)n1cc(CCl)c(Br)n1
Agent: [Na+]
Solvent: CC(C)=O
Product: CCC(C)(C)n1cc(CI)c(Br)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
To a solution of 3-bromo-4-(chloromethyl)-1-tert-pentyl-1H-pyrazole (725 mg, 2.73 mmol) in acetone (25 mL) was added sodium iodide (4.09 g, 27.3 mmol). The reaction was heated at reflux for 2 hours, then cooled to room temperature and stirred overnight. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium thiosulfate and brine. The organics were dried over sodium sulfate, filtered, and concentrated to yield the title compound (824 mg, 85%) as a brown oil. 1H NMR (400 MHz, CDCl3, δ): 7.47 (s, 1H), 4.26 (s, 2H), 1.83 (q, J=7.41 Hz, 2H), 1.50 (s, 6H), 0.67 (t, J=7.51 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)=[O:7])=[CH:4][C:3]=1[NH:20][S:21]([C:24]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=1[O:32][CH3:33])(=[O:23])=[O:22].CO[C:36]1C=CC(OC)=C[C:37]=1S(Cl)(=O)=O>>[CH2:36]([O:14][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:18]=[CH:19][C:2]([Cl:1])=[C:3]([NH:20][S:21]([C:24]3[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=3[O:32][CH3:33])(=[O:23])=[O:22])[CH:4]=2)=[CH:10][CH:11]=1)[CH3:37]
Reactant: COc1ccc(OC)c(S(=O)(=O)Nc2cc(C(=O)Nc3ccc(C(=O)O)cc3)ccc2Cl)c1
Reactant: COc1ccc(OC)c(S(=O)(=O)Cl)c1
Product: CCOC(=O)c1ccc(NC(=O)c2ccc(Cl)c(NS(=O)(=O)c3cc(OC)ccc3OC)c2)cc1

Procedure:
4-[4-Chloro-3-(2,5-dimethoxy-benzenesulfonylamino)-benzoylamino]-benzoic acid, MS (ISP): m/e=489.2 (M−H), was prepared in analogy to example 21, steps A to D. Step C was performed using 2,5-dimethoxy-benzenesulfonyl chloride and yielded 4-[4-chloro-3-(2,5-dimethoxy-benzenesulfonylamino)-benzoylamino]-benzoic acid ethyl ester, which was hydrolyzed in step D.