Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:12][C@H:11](/[CH:13]=[N:14]/[S:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:21][Mg]Br>C(Cl)Cl>[C:4]([Si:1]([CH3:3])([CH3:2])[O:8][C@@H:9]1[CH2:12][C@H:11]([CH:13]([NH:14][S:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])[CH3:21])[CH2:10]1)([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)S(=O)/N=C/[C@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)C1
Reactant: C[Mg]Br
Solvent: ClCCl
Product: CC(NS(=O)C(C)(C)C)[C@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 101.6 %

Procedure:
To a solution of 2-methyl-propane-2-sulfinic acid 1-[cis-3-(tert-butyldimethylsilanyloxy)-cyclobutyl]-meth-(E)-ylideneamide (640 mg, 2.02 mmol) in CH2Cl2 (10 mL) at 0° C. was slowly added methylmagnesium bromide (3.0 M in Et20, 1.14 mL, 3.43 mmol). The reaction mixture was stirred at 0° C. for 1 h then quenched with saturated aqueous NH4Cl, diluted with water and extracted with EtOAc (3×). The combined organics were dried over MgSO4 and concentrated to provide 685 mg of 2-methyl-propane-2-sulfinic acid {1-[cis-3-(tert-butyl-dimethyl-silanyloxy)-cyclobutyl]-ethyl}-amide as an off-white waxy solid which was used without further purification. 1H NMR (CDCl3, 300 MHz): δ (ppm) 4.05-4.18 (m, 1H), 3.16-3.31 (m, 1H), 2.85 (d, J=7.2 Hz, 1H), 2.21-2.44 (m, 2H), 1.59-1.76 (m, 3H), 1.20 (s, 9H), 1.18 (d, J=6.0 Hz, 3H), 0.88 (s, 9H), 0.03 (s, 6H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[C:7]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[F:18][C:19]1[CH:24]=[C:23]([CH:25]=[CH2:26])[CH:22]=[CH:21][C:20]=1[C:27]1[S:28][C:29]2[C:34]([N:35]=1)=[CH:33][CH:32]=[C:31]([C:36]1([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:38][CH2:37]1)[N:30]=2.Cl>CN(C=O)C>[F:18][C:19]1[CH:24]=[C:23]([CH:22]=[CH:21][C:20]=1[C:27]1[S:28][C:29]2[C:34]([N:35]=1)=[CH:33][CH:32]=[C:31]([C:36]1([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH2:38][CH2:37]1)[N:30]=2)[CH2:25][CH2:26][CH:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:7]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: C=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In reactor bottle under N2 were combined fine cesium carbonate (0.209 g, 0.644 mmol) and diethyl malonate (0.195 mL, 1.29 mmol) in DMF (3 mL). The resulting slurry was allowed to stir for 1 h at ambient temperature. To the mixture was added 2-(2-fluoro-4-vinylphenyl)-5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine (0.200 g, 0.537 mmol) and the reaction mixture was heated to 35° C. for 1.5 h. The reaction mixture was cooled to 0° C. and acidified using 1 N aq. HCl, extracted with EtOAc, and the organic layer was dried over MgSO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography provided diethyl 2-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenethyl)malonate. MS (ESI) m/z: calculated: 532.2; Observed: 533.1 (M++1).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([OH:14])=[O:13].[Br:15]Br>C(Cl)(Cl)Cl>[Br:15][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([OH:1])=[C:3]([C:12]([OH:14])=[O:13])[CH:4]=1
Reactant: O=C(O)c1ccc2ccccc2c1O
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: O=C(O)c1cc(Br)c2ccccc2c1O

Procedure:
To a solution of 2.50 g 1-hydroxy-2-naphthoic acid in 50 mL chloroform a solution of 0.68 mL bromine in 5 mL chloroform was added dropwise. After 16 h the reaction was concentrated to yield 3.40 g 4-bromo-1-hydroxy-naphthalene-2-carboxylic acid.
Reaction SMILES: [N+](=[CH:3][C:4]([C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)=[O:5])=[N-].[Cl:11][C:12]1[C:13](=[O:22])[C:14](=[O:21])[C:15]([Cl:20])=[C:16]([Cl:19])[C:17]=1[Cl:18]>C1C=CC=CC=1>[O:7]1[CH:8]=[CH:9][CH:10]=[C:6]1[C:4]([CH:3]1[O:22][C:13]2[C:12]([Cl:11])=[C:17]([Cl:18])[C:16]([Cl:19])=[C:15]([Cl:20])[C:14]=2[O:21]1)=[O:5]
Reactant: O=C1C(=O)C(Cl)=C(Cl)C(Cl)=C1Cl
Reactant: [N-]=[N+]=CC(=O)c1ccco1
Solvent: c1ccccc1
Product: O=C(c1ccco1)C1Oc2c(Cl)c(Cl)c(Cl)c(Cl)c2O1
Yield: 8.5 %

Procedure:
2-diazo-1-(furan-2-yl)ethanone (900 mg, 6.61 mmol) and 3,4,5,6-tetrachlorocyclohexa-3,5-diene-1,2-dione (846 mg, 10.05 mmol) were combined in dry benzene (10 ml) and refluxed vigorously for 6 hours. The solvent was evaporated to dryness, and the resulting crude material was subjected to column chromatography using 100-200 mesh range silica gel and an ethyl acetate/hexane solvent system. The crude material was a mixture of two compounds, which were separated by column chromatography. Crystallization from acetone yielded furan-2-yl(4,5,6,7-tetrachlorobenzo[d][1,3]dioxol-2-yl)methanone as a yellow solid (200 mg, 16.4%).
Reaction SMILES: [CH3:1][C:2]1[C:11]([NH:12][C:13](=[S:21])OC2C=CC=CC=2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH3:1][C:2]1[C:11]([NH:12][C:13]([N:35]2[CH2:34][CH2:33][N:32]([C:26]3[CH:25]=[C:24]([O:23][CH3:22])[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=3)[CH2:37][CH2:36]2)=[S:21])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Reactant: Cc1nc2ccccc2cc1NC(=S)Oc1ccccc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc(OC)cc(N2CCN(C(=S)Nc3cc4ccccc4nc3C)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
Phenyl N-(2-methylquinolin-3-yl)thiocarbamate(147 mg, 0.5 mmol) and 1-(3,5-dimethoxyphenyl)piperazine(112 mg, 0.5 mmol) were dissolved in anhydrous tetrahydrofuran and DBU(117 mg, 0.75 mmol) was added and then the mixture was stirred at room temperature for 2 hrs. The above solution was concentrated under the reduced pressure to remove tetrahydrofuran and purified by column chromatography(ethylacetate:hexane=1:2) to obtain the titled compound.
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17](O)=[O:18].CSC.B.O>C1COCC1>[SH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18]
Reactant: O=C(O)CCCCCCCCCCCCCCCS
Agent: B
Solvent: C1CCOC1
Solvent: O
Solvent: CSC
Product: OCCCCCCCCCCCCCCCCS
Temperature: 25 °C
Reaction time: 4 h

Procedure:
16-mercaptohexadecanoic acid (N) (0.2 g, 0.7 mmol) was dissolved in dry THF (20 mL) and borane dimethyl sulphide (1 mL, 1.1 equiv.) was slowly added under N2 atmosphere. The mixture was stirred at room temperature for 4 hr. Water was added to the solution was extracted using ethyl acetate. The organic extract was washed with 1N HCl, water and saturated sodium bicarbonate solution successively. After drying (MgSO4), the solvent was evaporated to give a white powder. Yield: 87 mg (46%)
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:26])=[C:4]([C:23](=[O:25])[CH3:24])[C:5]([OH:22])=[C:6]([O:10][CH2:11][CH2:12][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH3:14])[C:7]=1[O:8][CH3:9].[Br:27][CH2:28][CH2:29]Br>>[Br:27][CH2:28][CH2:29][O:22][C:5]1[C:6]([O:10][CH2:11][CH2:12][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH3:14])=[C:7]([O:8][CH3:9])[C:2]([Cl:1])=[C:3]([CH3:26])[C:4]=1[C:23](=[O:25])[CH3:24]
Reactant: BrCCBr
Reactant: COc1c(Cl)c(C)c(C(C)=O)c(O)c1OCCC(C)c1ccc(F)cc1
Product: COc1c(Cl)c(C)c(C(C)=O)c(OCCBr)c1OCCC(C)c1ccc(F)cc1

Procedure:
Example 7c (511 mg, 1.34 mmol) was reacted with 1,2-dibromoethane (20.0 eq.) as described under General Procedure F to afford the title compound (641 mg, quantitative yield) as a light brown oil. 1H NMR (300 MHz, CDCl3) δ 7.20-7.15 (m, 2H), 7.01-6.96 (m, 2H), 4.26 (t, J=6.2 Hz, 2H), 3.96 (t, J=6.6 Hz, 2H), 3.84 (s, 3H), 3.49 (t, J=6.2 Hz, 2H), 2.99 (m, 1H), 2.50 (s, 3H), 2.19 (s, 3H), 2.07-2.01 (m, 2H), 1.30 (d, J=6.9 Hz, 3H). MS (ES+) m/z 487.3 (M+H+).
Reaction SMILES: [C:1]1([C:7]2[C:8]3[CH2:9][CH2:10][NH:11][CH2:12][C:13]=3[C:14]3[NH:19][C:18](=[O:20])[C:17](=[O:21])[C:15]=3[CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][O:23][C:24](=[O:27])[CH2:25]Br.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:22][O:23][C:24]([CH2:25][N:11]1[CH2:10][CH2:9][C:8]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:16][C:15]3[C:17](=[O:21])[C:18](=[O:20])[NH:19][C:14]=3[C:13]=2[CH2:12]1)=[O:27]
Reactant: COC(=O)CBr
Reactant: O=C1Nc2c(cc(-c3ccccc3)c3c2CNCC3)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)CN1CCc2c(-c3ccccc3)cc3c(c2C1)NC(=O)C3=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A suspension of 5-phenyl-6,7,8,9-tetrahydro-1H-pyrrolo[3,2-h]-isoquinoline-2,3-dione (0.278 g), methylbromoacetat (107.35 μl) and potassium carbonate (0.138 g) in methanol (20 ml) was stirred at room temperature for 24 hours. The suspension was partly evaporated and water (20 ml) was added. This afforded a solid precipitate which was collected by filtration.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([CH2:13][CH2:14][C:15]([NH:17][CH:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:16])=[CH:6]2.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([CH2:13][CH2:14][C:15]([NH:17][CH:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:16])=[CH:6]2
Reactant: CCOC(=O)C(NC(=O)CCc1cnc2ccc(OC)cc2c1)C(=O)OCC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)C(NC(=O)CCc1cnc2ccc(O)cc2c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.5 %

Procedure:
To a solution of 0.39 g (1 mmol) of diethyl (6-methoxy-3-quinolyl)methylacetamidomalonate in 10 mL of dry methylene chloride was added dropwise at -70° C. a 1M solution of boron tribromide in methylene chloride. The reaction temperature was gradually raised to room temperature while stirring overnight. Then, the reaction mixture was poured into ice water and extracted with methylene chloride. The organic layer was washed with water, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel, using 1:1 ethyl acetate/methylene chloride and then ethyl acetate as eluents, to give 43 mg (11.5%) of the desired product as a solid. TLC Rf =0.46 (ethyl acetate); NMR (CDCl3) δ 8.4 (1H, bs), 7.95 (1H, d), 7.7 (1H, bs), 7.35 (1H, dd), 7.1 (1H, d), 6.8 (1H, bs), 4.25 (4H, m), 3.8 (2H, bs), 2.0 (3H, s), 1.3 (6H, m); IR (KBr) ν 3700-2800, 1740, 1660, 1645, 1620, 1500 cm-1. The product has the structural formula: ##STR88##
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[C@@H:7]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:8][CH2:9][C:10]([OH:12])=[O:11])([CH3:4])([CH3:3])[CH3:2].[CH2:22](N(CC)CC)[CH3:23].ClC(OCC)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:17]([O:16][C:14]([NH:13][C@@H:7]([CH2:8][CH2:9][C:10]([O:12][CH2:22][CH3:23])=[O:11])[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:21])=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Solvent: ClCCl
Product: CCOC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 73.2 %

Procedure:
To a solution of (S)-5-tert-butoxy-4-(tert-butoxycarbonylamino)-5-oxopentanoic acid (1.0 g, 3.3 mmol) in anhydrous CH2Cl2 (15 mL) was added triethylamine (0.69 mL, 4.95 mmol) and cooled the mixture to 0° C. with an external ice-methanol cold bath. At the same temperature, 4-dimethylaminopyridine (0.04 g, 0.33 mmol) followed by ethyl chloroformate (0.38 mL, 3.96 mmol) were added sequentially and the mixture stirred for one hour. After completion of the reaction, reaction mixture was diluted with CH2Cl2 (150 mL) and the saturated aq. NaHCO3 solution (150 mL). The layers were separated and the aqueous phase extracted with an additional CH2Cl2 (100 mL). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified on 40 g silica gel column (eluent hexanes to 30% ethyl acetate in hexanes) to afford (S)-1-tert-butyl 5-ethyl 2-(tert-butoxycarbonylamino)pentanedioate (0.80 g, 73% yield) as a thick oil. 1H NMR (CDCl3) δ ppm: 5.10 (d, J=7.8 Hz, 1H), 4.16 (m, 3H), 2.39 (m, 2H), 2.16 (m, 1H), 1.94 (m, 1H), 1.49 (s, 9H), 1.46 (s, 9H), 1.28 (t, J=7.2 Hz, 3H). MS (ESI+): 354 (M+Na)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][O:21][CH3:22]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:19][CH2:20][O:21][CH3:22])[C:6]=2[CH:11]=1
Reactant: O=c1[nH]c2cc(Br)ccc2s1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCn1c(=O)sc2ccc(Br)cc21
Reaction time: 24 h

Procedure:
5-Bromobenzo[d]thiazol-2(3H)-one (1 g) and potassium carbonate (1.502 g) were stirred in DMF (7 mL) at room temperature and 1-bromo-2-methoxyethane (0.408 mL) was added. The mixture was stirred for 24 h. The mixture was poured onto water and extracted with ethyl acetate. The extracts were washed with dilute hydrochloric acid, water and brine then dried over sodium sulfate and evaporated. Purification by flash silica chromatography eluting with 10% ethyl acetate in isohexane afforded the subtitle compound as a colourless solid (0.73 g).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[C:6]#[N:7].[H-].[Na+].[CH3:15]I>O1CCCC1>[CH3:12][O:11][C:9]1[CH:8]=[C:5]([CH:4]=[C:3]([CH2:2][O:1][CH3:15])[CH:10]=1)[C:6]#[N:7]
Reactant: COc1cc(C#N)cc(CO)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1cc(C#N)cc(OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.1 %

Procedure:
To a solution of 3-hydroxymethyl-5-methoxy-benzonitrile (261.1 mg, 1.6 mmol, example 33) in tetrahydrofuran (5 mL) cooled to 0° C. was added sodium hydride (43 mg, 1.68 mmol). The ice-bath was removed and the reaction mixture was stirred at room temperature for 15 min before methyl iodide (149 μL, 2.4 mmol) was added. The reaction mixture was stirred at room temperature for 3 h before being quenched with several drops of saturated ammonium chloride solution. The solvent was removed and the residue was taken up in diethyl ether. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solid was then filtered off, and the filtrate was concentrated in vacuo. Purification of the residue by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 12% ethyl acetate in hexanes yielded 3-methoxy-5-methoxymethyl-benzonitrile as a colorless oil (213 mg, 75%).
Reaction SMILES: C(OC(NCC(ON1C(=O)CCC1=O)=O)=O)(C)(C)C.N[C@@H](CCSC)CS([O-])(=O)=O.[Na+].C(OC([NH:39][CH2:40][C:41]([NH:43][C@@H:44]([CH2:50][CH2:51][S:52][CH3:53])[CH2:45][S:46]([OH:49])(=[O:48])=[O:47])=[O:42])=O)(C)(C)C.[ClH:54]>>[ClH:54].[NH2:39][CH2:40][C:41]([NH:43][C@@H:44]([CH2:50][CH2:51][S:52][CH3:53])[CH2:45][S:46]([OH:49])(=[O:47])=[O:48])=[O:42]
Reactant: CSCC[C@@H](CS(=O)(=O)O)NC(=O)CNC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)NCC(=O)ON1C(=O)CCC1=O
Agent: CSCC[C@H](N)CS(=O)(=O)[O-]
Agent: Cl
Product: CSCC[C@@H](CS(=O)(=O)O)NC(=O)CN

Procedure:
(S)-2-(2-aminoacetamido)-4-(methylthio)butane-1-sulfonic acid hydrochloride was synthesized by coupling a 2,5-dioxopyrrolidin-1-yl 2-(tert-butoxycarbonylamino)acetate to sodium (S)-2-amino-4-(methylthio)butane-1-sulfonate in the presence of mild base. The resulting (S)-2-(2-(tert-butoxycarbonylamino)acetamido)-4-(methylthio)butane-1-sulfonic acid was deprotected in the presence of 6M HCl(aq.) to provide the desired product. (M+H)+=256.9.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:44])=[C:4]([S:9]([N:12]([CH2:28][C:29]2[CH:30]=[C:31]([CH:41]=[CH:42][CH:43]=2)[CH2:32][NH:33]C(=O)OC(C)(C)C)[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:33][CH2:32][C:31]1[CH:30]=[C:29]([CH:43]=[CH:42][CH:41]=1)[CH2:28][N:12]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[CH:18][CH:19]=1)[S:9]([C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[OH:44])(=[O:10])=[O:11]
Reactant: CC(C)(C)OC(=O)NCc1cccc(CN(Cc2ccc(Oc3ccc(F)cc3)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1cccc(CN(Cc2ccc(Oc3ccc(F)cc3)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.2 %

Procedure:
To a solution of tert-butyl 3-((3,5-dichloro-N-(4-(4-fluorophenoxy)benzyl)-2-hydroxyphenylsulfonamido)methyl)benzylcarbamate (0.98 g, 1.48 mmol) in CH2Cl2 (15 mL) was added TFA (2.28 mL, 29.6 mmol). The reaction mixture was stirred at rt for 3 h. The mixture was concentrated and the residue was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic layer (clear solution) was washed with brine, dried over MgSO4 and concentrated to give white solid (0.65 g, 70%). 1H NMR (DMSO-d6): δ 8.50 (bs, 1H), 7.52 (s, 1H), 7.34 (d, J=2.8 Hz, 1H), 7.2.9 (d, J=2.8 Hz, 1H), 7.26-7.21 (m, 4H), 7.12-7.08 (m, 3H), 6.97-6.94 (m, 2H), 6.80 (d, J=6.8 Hz, 2H), 4.41 (s, 2H), 4.32 (s, 2H), 3.94 (s, 2H); MS (ESI): (M+H)+=561.1.
Reaction SMILES: [O:1]=[S:2]1(=[O:25])[C:7]2[CH:8]=[C:9]([O:12][C:13]3[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=3)[C:16](O)=[O:17])[CH:10]=[CH:11][C:6]=2[N:5]2[CH2:22][CH2:23][CH2:24][C:4]2=[N:3]1.C(Cl)(=O)C(Cl)=O.C[CH2:33][N:34](CC)[CH2:35]C.CNC.Cl>C(Cl)Cl.CN(C=O)C.C1COCC1>[O:1]=[S:2]1(=[O:25])[C:7]2[CH:8]=[C:9]([O:12][C:13]3[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=3)[C:16]([N:34]([CH3:35])[CH3:33])=[O:17])[CH:10]=[CH:11][C:6]=2[N:5]2[CH2:22][CH2:23][CH2:24][C:4]2=[N:3]1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1cccc(Oc2ccc3c(c2)S(=O)(=O)N=C2CCCN23)c1
Agent: CNC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cccc(Oc2ccc3c(c2)S(=O)(=O)N=C2CCCN23)c1
Reaction time: 0.5 h

Procedure:
To a suspension of the product obtained in Step C (1.40 g, 3.91 mmol) in 20 ml of CH2Cl2 there are added 2 drops of DMF and then, dropwise, 684 μl (7.81 mmol) of oxalyl chloride diluted with 2 ml of CH2Cl2. Stirring is carried out at ambient temperature for 2 hours 30 minutes; evaporation to dryness is carried out; the residue is taken up in 15 ml of CH2Cl2; 1.1 ml (7.81 mmol) of Et3N and then 2.94 ml (5.87 mmol) of a 2M solution of dimethylamine in THF are added. Stirring is carried out at ambient temperature for 1 hour. The reaction mixture is acidified with 0.5N HCl and extracted (CH2Cl2). The organic phases are combined, washed (saturated NaCl), dried (MgSO4) and evaporated. The residue is triturated in Et2O; the title product precipitates out and is recovered by filtration. Elemental micro-analysis:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7]1[C:11](Cl)=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:13]([Cl:15])=[N:14][C:6]=21.O.O1CCCC1.[Cl-].[NH4+]>C(O)C.[Zn]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7]1[CH:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:13]([Cl:15])=[N:14][C:6]=21
Reactant: Clc1nc2c3ccc(Br)cc3nn2c(Cl)c1-c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Clc1nc2c3ccc(Br)cc3nn2cc1-c1ccccc1
Temperature: 25 °C
Yield: 58 %

Procedure:
7 g (17.8 mmol) 8-Bromo-2,4-dichloro-3-phenylpyrimido[1,2-b]indazole were suspended in a mixture of 453 mL ethanol, 322 mL water and 173 mL tetrahydrofuran. After addition of 4.5 g (84.4 mmol) ammonium chloride and 7.5 g (114 mmol) zinc the mixture was stirred over night at room temperature. The mixture was filtered via a glass fibre filter, washed with THF and the organic solvents were removed. The residue was treated with a mixture of water and ethyl acetate and the organic phase was separated. The aqueous phase was extracted twice with ethyl acetate and the combined organic extracts were evaporated without prior drying because the product had already precipitated. 3.7 g (57.9%) of the title compound were isolated.
Reaction SMILES: C[O-].[Na+].CN(C=O)C.Cl.C(N(CC)CCCl)C.[Na+].[C:19]1([C:25]2[N:26]=[C:27]([CH:36]([SH:40])[C:37]([O-:39])=[O:38])[O:28][C:29]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O.Cl>[C:19]1([C:25]2[N:26]=[C:27]([CH:36]([SH:40])[C:37]([OH:39])=[O:38])[O:28][C:29]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C([O-])C(S)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: CCN(CC)CCCl
Agent: C[O-]
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)C(S)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
3 g. of sodium methylate is suspended in 100 ml. of DMF, 9.5 g. of 2-diethylaminoethyl chloride hydrochloride is added thereto, and the reaction mixture is stirred for 20 minutes at room temperature. Then, 16.7 g. of 4,5-diphenyl-2-oxazolyl-mercaptoacetic acid sodium salt is added. Under agitation, the reaction mixture is heated to 80° for 40 hours, then diluted with water, dilute hydrochloric acid is added to a pH of 2-3, and the reaction solution is washed with ethyl acetate. Then, the pH of the aqueous solution is adjusted to 9. The mixture is worked up as usual, thus obtaining the 2-diethylaminoethyl ester of 4,5-diphenyl-2-oxazolyl-mercaptoacetic acid; hydrochloride, m.p. 160°-162°.
Reaction SMILES: [NH:1]([C:8](=[O:28])[CH:9]([C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1)[C:10]([NH:12]C1C=CC=CC=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N>>[NH2:12][C:10](=[O:11])[CH:9]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:26][CH:27]=1)[C:8]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:28]
Reactant: O=C(O)c1ccc(C(C(=O)Nc2ccccc2)C(=O)Nc2ccccc2)cc1
Agent: N
Product: NC(=O)C(C(=O)Nc1ccccc1)c1ccc(C(=O)O)cc1

Procedure:
A solution of 4-[2-anilino-1-(anilinocarbonyl)-2-oxoethyl]benzoic acid (0.25 g, 0.67 mmol) in 7.0 N methanolic ammonia (1.9 mL, 13.4 mmol) in a sealed tube was heated to 160° C. for 1 hour in the microwave. The reaction was concentrated in vacuo and purified by reverse phase HPLC (15-75% MeCN/H2O with 0.05% TFA) to give the title compound as a white solid. 1H NMR (600 MHz, DMSO-d6) δ 12.90 (bs, 1H), 10.28 (s, 1H), 7.89 (d, J=8.5 Hz, 2H), 7.55 (m, 3H), 7.52 (d, J=8.5 Hz, 2H), 7.35 (bs, 1H), 7.27 (t, J=8.1 Hz, 2H), 7.03 (t, J=7.5 Hz, 1H), 4.66 (s, 1H); ESIMS calcd 299.0 (M++H), found 299.0 (M++H).