Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:3]=1[N:4]([CH3:15])[S:5]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6].ClC1C=CC=C(C(OO)=[O:29])C=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Cl:20][C:18]1[CH:17]=[CH:16][C:3]([N:4]([CH3:15])[S:5]([C:8]2[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=2)(=[O:7])=[O:6])=[C:2]([N:1]=[O:29])[CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)N(C)c2ccc(Cl)cc2N)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)N(C)c2ccc(Cl)cc2N=O)cc1
Temperature: 25 °C
Yield: 73.3 %

Procedure:
To a solution of 2′-amino-4′-chloro-N-methyl-p-toluenesulfonanilide (1.50 g (4.83 mmol)) in chloroform (20.0 ml), 70% mCPBA (m-chloro-perbenzoic acid) (2.38 g) was added with stirring at room temperature. After being stirred for 3 days at room temperature, saturated aqueous solution of sodium bicarbonate was added to the reaction mixture and the resulting mixture was extracted with chloroform. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with ethyl acetate-hexane (1:6) as eluent to give 1.15 g (73%) of the title compound as blue-green crystals.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([NH:9][C:10]([NH:12][C:13]2[N:14]=[C:15]3[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]3=[N:17][CH:18]=2)=[O:11])[CH2:4]1.[CH:30]1([S:33](Cl)(=[O:35])=[O:34])[CH2:32][CH2:31]1>>[CH:30]1([S:33]([N:3]2[CH2:8][CH2:7][CH2:6][CH:5]([NH:9][C:10]([NH:12][C:13]3[N:14]=[C:15]4[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]4=[N:17][CH:18]=3)=[O:11])[CH2:4]2)(=[O:35])=[O:34])[CH2:32][CH2:31]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NC3CCCNC3)cnc21
Agent: Cl
Product: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NC3CCCN(S(=O)(=O)C4CC4)C3)cnc21

Procedure:
1-(1-Cyclopropylsulfonyl-piperidin-3-yl)-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea was prepared in the same manner from 1-piperidin-3-yl-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea dihydrochloride and cyclopropylsulfonyl chloride.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].C([N:13]1[CH2:27][CH2:26][C:25]2[C:16](=[N:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[C:24]=2[Cl:28])[CH2:15][CH2:14]1)C>C(Cl)Cl.CCOCC>[C:5]1([O:4][C:2]([N:13]2[CH2:27][CH2:26][C:25]3[C:16](=[N:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=4[C:24]=3[Cl:28])[CH2:15][CH2:14]2)=[O:3])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCN1CCc2nc3ccccc3c(Cl)c2CC1
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(Oc1ccccc1)N1CCc2nc3ccccc3c(Cl)c2CC1
Reaction time: 8 h

Procedure:
A solution of 1.2 gm (7.7 millimols) of phenyl chloroformate in 20 ml of methylene chloride was added dropwise to a mixture of 2 gm (7.7 millimols) of 3-ethyl-11-chloro-1,2,4,5-tetrahydro-3H-azepino[4,5-b]quinoline and 15 ml of methylene chloride at 5° C. After standing overnight, the resulting mixture was diluted with ether to double its volume and was then suction-filtered. The filter cake was recrystallized from acetone.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([I:11])=[CH:6][N:5]=1.Br[CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.O>CN(C=O)C>[Cl:3][C:4]1[CH:9]=[C:8]([NH:10][CH2:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:16][CH2:15]2)[C:7]([I:11])=[CH:6][N:5]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Reactant: Nc1cc(Cl)ncc1I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CNc2cc(Cl)ncc2I)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.7 %

Procedure:
NaH (0.098 g, 3.9 mmol) was added to a solution of 2-chloro-5-iodopyridin-4-amine (0.500 g, 1.96 mmol) in DMF (12 mL) and the mixture was stirred for 30 min at r.t. The temperature was then raised to 80° C. and a solution of tert-butyl 4-(bromomethyl)-piperidine-1-carboxylate (1.093 g, 3.93 mmol) in DMF (2 mL) was added. The reaction mixture was stirred at 80° C. for 2 h, then cooled to r.t. NaH (0.050 g, 2.00 mmol) was added and the reaction mixture was heated for 1 h at 80° C. After cooling, water (40 mL) was added and the reaction mixture was partitioned between ethyl acetate and aq. NaHCO3. The organic phase was washed with brine, dried (MgSO4) and concentrated. The crude product was purified by flash silica chromatography, eluting with ethyl acetate and hexane (1/9), to give the title compound as a pink solid (0.405 g, 46%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:16](B1OC(C)(C)C(C)(C)O1)=[CH2:17].CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+]>C(O)CC>[CH:16]([C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)=[CH2:17]
Reactant: COC(=O)c1cc(Br)cc2ccccc12
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCO
Solvent: CN(C)C=O
Product: C=Cc1cc(C(=O)OC)c2ccccc2c1
Temperature: 90 °C

Procedure:
Methyl 3-bromo-1-naphthalenecarboxylate (1 eq.) and 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1 eq.) were combined in a 2:1 (v/v) mixture of DMF:n-PrOH (0.1 M). To this solution was first added Pd(PPh3)2Br2 (0.05 eq.) followed by 2 N aq. Na2CO3 (2 eq.). The biphasic suspension was evacuated and back-filled three times with nitrogen before it was heated at 90° C. for 8 h. The now black suspension was cooled to RT, diluted with water and extracted with 1:1 (v/v) hexanes:ether. The combined organic extracts were then washed further with 1 N aq. NaOH, 10% aq. HCl, water and brine. This was then dried over Na2SO4 and filtered through a pad of silica gel. Concentration of the filtrate in vacuo afforded the crude title compound as a golden yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]2[C:19]3[C:14](=[CH:15][C:16]([S:20]([O:23]C4C(F)=C(F)C(F)=C(F)C=4F)(=[O:22])=O)=[CH:17][CH:18]=3)[CH:13]=[CH:12][N:11]=2)=[C:4]([O:35][CH3:36])[CH:3]=1.[S:37]1[C:41]([NH2:42])=[N:40][CH:39]=[N:38]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(#N)C>CCOC(C)=O.Cl>[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]2[C:19]3[C:14](=[CH:15][C:16]([S:20]([NH:42][C:41]4[S:37][N:38]=[CH:39][N:40]=4)(=[O:23])=[O:22])=[CH:17][CH:18]=3)[CH:13]=[CH:12][N:11]=2)=[C:4]([O:35][CH3:36])[CH:3]=1
Reactant: Nc1ncns1
Reactant: COc1cc(Cl)c(C#N)cc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cc(Cl)c(C#N)cc1-c1nccc2cc(S(=O)(=O)Nc3ncns3)ccc12
Reaction time: 1 h
Yield: 58.6 %

Procedure:
A vial was charged with perfluorophenyl 1-(4-chloro-5-cyano-2-methoxyphenyl)isoquinoline-6-sulfonate (INTERMEDIATE VVVV, 154.38 mg, 0.285 mmol), 1,2,4-thiadiazol-5-amine (34.6 mg, 0.343 mmol), and cesium carbonate (279 mg, 0.856 mmol). Acetonitrile (1427 μl) was added, and the mixture was stirred for 1 h. The mixture was diluted with EtOAc and 0.5 N aq. HCl. The layers were separated, and the organic extract was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (12-g Redi-Sep Gold column, 0-10% MeOH/DCM, product eluted over a long period of time). The resulting white solid was taken up in MeOH and filtered. The collected solid was washed with MeOH (2×), dried under a stream of N2 (g), then dried under vacuum to give 1-(4-chloro-5-cyano-2-methoxyphenyl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide (76.6 mg, 0.167 mmol, 58.6% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=7.43 (d, J=5.7 Hz, 1H), 7.32 (d, J=1.7 Hz, 1H), 7.21 (s, 1H), 6.90 (d, J=5.6 Hz, 1H), 6.70 (s, 1H), 6.62-6.55 (m, 1H), 6.52-6.46 (m, 1H), 6.37 (s, 1H), 2.50 (s, 3H). m/z (ESI) 458.1 (M+H)+.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH:18]=[C:17]([C:19]4[C:27]5[C:22](=[CH:23][CH:24]=[C:25]([C:28]([O:30]C)=[O:29])[CH:26]=5)[NH:21][N:20]=4)[N:16]=[N:15]3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[OH-].[Li+].Cl>C1COCC1.O>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH:18]=[C:17]([C:19]4[C:27]5[C:22](=[CH:23][CH:24]=[C:25]([C:28]([OH:30])=[O:29])[CH:26]=5)[NH:21][N:20]=4)[N:16]=[N:15]3)=[CH:10][CH:9]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2[nH]nc(-c3cn(-c4ccc(CN5CCOCC5)cc4)nn3)c2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc2[nH]nc(-c3cn(-c4ccc(CN5CCOCC5)cc4)nn3)c2c1
Yield: 107.7 %

Procedure:
A solution of methyl 3-{1-[4-(morpholin-4-ylmethyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazole-5-carboxylate (351 mg; 0.84 mmol; 1.0 eq.) and lithium hydroxide (201 mg; 8.4 mmol; 10 eq.) in THF (3.5 mL) and water (3.5 mL) was stirred O/N at 40° C. A 5N solution of HCl was then added and the precipitate was filtered, rinsed with water and dried under reduced pressure at 40° C. O/N to give the title compound as a white powder (366 mg, 100%). UPLC/MS: (MS+) 405.1, (MS−) 403.1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:47][C:48]2[CH:53]=[CH:52][C:51]([O:54][CH2:55][CH3:56])=[CH:50][CH:49]=2)=[CH:4][C:5]([C@H:9]2[C@H:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@@H:13]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:12]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C@@H:11]([CH2:39][O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]O)[O:10]2)=[C:6]([OH:8])[CH:7]=1.N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:81]I>C1C=CC=CC=1.C(OCC)C>[Cl:1][C:2]1[C:3]([CH2:47][C:48]2[CH:53]=[CH:52][C:51]([O:54][CH2:55][CH3:56])=[CH:50][CH:49]=2)=[CH:4][C:5]([C@H:9]2[C@H:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@@H:13]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:12]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C@@H:11]([CH2:39][O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][I:81])[O:10]2)=[C:6]([OH:8])[CH:7]=1
Reactant: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCCCCCO)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(O)cc2Cl)cc1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCCCCCI)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(O)cc2Cl)cc1
Reaction time: 0.08 h
Yield: 93.1 %

Procedure:
To a solution of 5-chloro-4-(4-ethoxybenzyl)-2-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-((5-hydroxypentyloxy)methyl)tetrahydro-2H-pyran-2-yl)phenol (30, 459 mg, 0.58 mmol) in benzene (3 mL) under an atmosphere of nitrogen were added imidazole (448 mg, 1.76 mmol) and triphenylphosphine (467 mg, 1.76 mmol). After 5 min, iodine (448 mg, 1.76 mmol) in benzene (2 mL) was added dropwide to the reaction mixture at room temperature. The reaction solution was stirred for 1 h, diluted with diethyl ether, quenched with saturated sodium hydrogen carbonate, extracted with diethyl ether (2×). The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated in vacuo. The resulting crude residue was purified on a Biotage® purification apparatus (silica gel, 5 to 25% tetrahydrofuran in hexanes gradient) to yield the title compound (31, 485 mg, 0.54 mmol, 93%) as yellow foam.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([N+:10]([O-])=O)[NH:7][N:6]=1)=[O:4]>C(O)(=O)C.O1CCCC1.[Pd]>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([NH2:10])[NH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1cc([N+](=O)[O-])[nH]n1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)c1cc(N)[nH]n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 85.4 %

Procedure:
10.25 g (60 mmol) of 5-nitro-1H-pyrazole-3-carboxylic acid methyl ester was dissolved in 75 mL of acetic acid (AcOH) and 75 mL of tetrahydrofuran (THF). After a vacuum and argon cycle, 2.05 g (20% weight) of palladium on carbon (Pd/C 10 wt %) was added, the mixture was degassed again and filled with hydrogen from a balloon. The reaction mixture was stirred at rt under hydrogen atmosphere for 2 days. Analysis by thin layer chromatography (TLC) showed complete conversion of starting material to product. The mixture was then concentrated, the resulting purple colored oil was taken in 300 mL of ether, the finely dispersed purple impurity was filtered off, and the ether filtrate was evaporated to give 7.23 g (85% yield) of 5-amino-1H-pyrazole-3-carboxylic acid methyl ester as an off-white solid as indicated by 1H NMR; whose structure was confirmed using 1H NMR.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:7][CH2:8][CH2:9][NH2:10].[CH2:11]([N:13]=[C:14]=[S:15])[CH3:12]>>[CH2:11]([NH:13][C:14]([NH:10][CH2:9][CH2:8][NH:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1)=[S:15])[CH3:12]
Reactant: NCCNCc1nccs1
Reactant: CCN=C=S
Product: CCNC(=S)NCCNCc1nccs1

Procedure:
Reacting N-(2-thiazolylmethyl)ethylenediamine with ethyl isothiocyanate by the procedure of Example 3(b) and then chromatographing gives N-ethyl-N'-[2-(2-thiazolylmethylamino)ethyl]thiourea. Reacting this thiourea with lead cyanamide by the procedure of Example 3(b) gives N-cyano-N'-ethyl-N"-[2-(2-thiazolylmethylamino)ethyl]-guanidine.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]2[C:7]([CH3:18])([CH3:17])[N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:9][C:3]=12.C(N(CC)C(C)C)(C)C.[CH3:28][CH2:29][O:30][C:31](C)=[O:32]>C1COCC1>[NH2:1][C:2]1[N:6]([C:31]([O:30][CH2:29][CH3:28])=[O:32])[N:5]=[C:4]2[C:7]([CH3:18])([CH3:17])[N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:9][C:3]=12
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)N1Cc2c(n[nH]c2N)C1(C)C
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)n1nc2c(c1N)CN(C(=O)OC(C)(C)C)C2(C)C
Yield: 38 %

Procedure:
15 g of tert-Butyl 3-amino-6,6-dimethyl-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate (59.4 mmol) were dissolved in anhydrous THF (150 ml) and treated, at 0° C. under Ar atmosphere, first with N,N-diisopropylethylamine (50 ml) and then with ClCO2 Et (4.65 ml, 1 eq.) dropwise. 90 minutes later, the solvent was diluted with EtOAc (1 l), washed with water and then with brine, dried over sodium sulfate and evaporated. The crude product was purified by flash chromatography (hexane/EtOAc 2/8) to afford 7.3 g of 5-tert-butyl 2-ethyl 3-amino-6,6-dimethylpyrrolo[3,4-c]pyrazole-2,5(4H,6H)-dicarboxylate as the major compound in 38% yield, together with 5.7 g of 5-tert-butyl 1-ethyl 3-amino-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-1,5-dicarboxylate in 30% yield.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15])[C:3]([OH:5])=[O:4].C(OC(N1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32])=O)C>C(=O)([O-])[O-].[Na+].[Na+]>[N+:14]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH2:7][CH2:6][CH:2]([N:1]1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32])[C:3]([OH:5])=[O:4])([O-:16])=[O:15]
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: NC(CCc1ccccc1[N+](=O)[O-])C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(O)C(CCc1ccccc1[N+](=O)[O-])N1C(=O)c2ccccc2C1=O
Yield: 70.3 %

Procedure:
In an aqueous solution (150 ml) of 6.1 g of sodium carbonate is dissolved 11.7 g of 2-amino-4-(2-nitrophenyl)butyric acid, and 15 g of N-ethoxycarbonylphthalimide is added to the solution under stirring. After stirring at room temperature overnight, the insoluble material is removed by filtration, and the filtrate is made weakly acidic with concentrated hydrochloric acid. The viscous material, which separates out, is admixed with 50 ml of ethanol, followed by stirring, whereby there separate out crystals. The crystals are collected by filtration and dried to give 13 g of 4-(2-nitrophenyl)-2-phtalimidobutyric acid as colorless crystals. m.p. 177°-179° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=3)=[N:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl.[Cl:31][CH2:32][CH2:33][CH2:34][NH2:35]>O.C(Cl)(Cl)Cl>[Cl:31][CH2:32][CH2:33][CH2:34][NH:35][S:20]([C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:7]2[C:6]3[C:11](=[CH:12][C:3]([Cl:2])=[CH:4][CH:5]=3)[N:10]=[CH:9][N:8]=2)=[CH:15][CH:16]=1)(=[O:22])=[O:21]
Reactant: NCCCCl
Reactant: O=S(=O)(Cl)c1ccc(Nc2ncnc3cc(Cl)ccc23)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=S(=O)(NCCCCl)c1ccc(Nc2ncnc3cc(Cl)ccc23)cc1
Reaction time: 1 h
Yield: 60 %

Procedure:
4-(7-Chloro-4-quinazolinylamino)benzenesulphonyl chloride hydrochloride (11.7 g, 0.03 mole) was added portionwise to a well stirred mixture of sodium carbonate (45 g) in water (350 ml) and 3-chloropropylamine hydrochloride (3.9 g, 0.03 mole) in chloroform (350 ml) was added at 10° C. After about 1 hour at room temperature, the mixture was filtered and the solid was washed with water and then dried to give 7.4 g of the title compound. A sample was recrystallised from a mixture of ethanol and water to give the title compound, m.p. 168°-171° C.
Reaction SMILES: [OH:1]O.[OH-].[Na+].[Si:5]([O:12][C@@H:13]1[CH2:17][C:16](=[O:18])[CH:15]=[CH:14]1)([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6]>CO>[Si:5]([O:12][CH:13]1[CH:17]2[C@@H:16]([O:18]2)[C:15](=[O:1])[CH2:14]1)([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C=CC(=O)C1
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC1CC(=O)[C@@H]2OC12
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Hydrogen peroxide (4.5 mL, 46.3 mmol, 30% wt. % solution in water) and 1N NaOH (46 μL, 0.046 mmol) were added to a solution of enone 2 (2.5 g, 11.5 mmol) in MeOH (30 mL) at 0° C. After stirring 1.5 h at 0° C. the mixture was concentrated in vacuo, washed with saturated aqueous NH4Cl and extracted with CH2Cl2 (3×). The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to afford the above titled compound.
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]2[NH:6][C:7](=[O:16])[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[C:10](=[O:11])[C:4]=2[CH:3]=1.[CH3:19][N:20](C)C=O.Cl>O>[C:19]([C:2]1[CH:18]=[CH:17][C:5]2[NH:6][C:7](=[O:16])[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[C:10](=[O:11])[C:4]=2[CH:3]=1)#[N:20]
Reactant: O=c1[nH]c2ccc(Br)cc2c(=O)c2ccccc12
Reactant: CN(C)C=O
Agent: Cl
Solvent: O
Product: N#Cc1ccc2[nH]c(=O)c3ccccc3c(=O)c2c1

Procedure:
A mixture of 5,6-dihydro-2-bromo-6,11-dioxodibenz[b,e]azepine (151 g), cuprous cyanide (49 g) and dimethylformamide (1.1 liters) was heated under refluxing for 8.5 hours. Then, the reaction mixture was cooled, and poured into a solution containing ferric chloride (200 g), conc. hydrochloric acid (50 ml) and water (500 ml) under stirring. The precipitated crystals were collected by filtration, washed with hydrochloric acid, and further washed thoroughly in water. Then, the crystals were dried at 60°-80° C. and dissolved in dimethylformamide (700 ml) with heating. The solution was filtered on heating, concentrated to 500 ml, and allowed to stand with the addition of dioxane (300 ml). The precipitated crystals were collected by filtration, washed with dioxane, then with n-hexane, and dried to obtain 5,6-dihydro-2-cyano-6,11-dioxodibenz[b,e]azepine (75 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4](Cl)=[O:5].[F:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([F:20])[C:18]=1[NH2:19]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([N:19]([C:4](=[O:5])[C:3]1[C:2]([Cl:1])=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:11])[C:18]1[C:17]([F:20])=[CH:16][N:15]=[CH:14][C:13]=1[F:12])=[O:5]
Reactant: Nc1c(F)cncc1F
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: c1ccncc1
Product: O=C(c1c(Cl)cccc1Cl)N(C(=O)c1c(Cl)cccc1Cl)c1c(F)cncc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
2,6-Dichlorobenzoyl chloride (13.7 mL, 95.6 mmol) was added dropwise, over 10 minutes, to a solution of 3,5-difluoropyridin-4-ylamine (10.37 g, 79.7 mmol) in pyridine (160 mL) at a temperature of between 3 and 5° C., under argon. The reaction mixture was allowed to warm to room temperature over 1 hour and then stirred at room temperature for 2 hours. The volatiles were removed under reduced pressure and the resultant residue was treated with HCl (1N, 120 mL). The resultant suspension was stirred at room temperature for 45 minutes and the precipitate was collected by filtration, washing with water. A mixture of 2,6-dichloro-N-(3,5-difluoropyridin-4-yl)-benzamide and of 2,6-dichloro-N-(2,6-dichlorobenzoyl)-N-(3,5-difluoropyridin-4-yl)-benzamide (22.0 g) was obtained. A suspension of this mixture (22.0 g) in 1N NaOH (200 mL) and MeOH (200 mL) was heated at 65° C. for 7 hours then slowly cooled to room temperature. The pH of the mixture was adjusted to 4-5 by dropwise addition of 12N HCl, controlling the exotherm by the use of an ice-bath. The residue was left standing at room temperature for 18 hours and then the resultant solid was collected by filtration, washing with water, to afford the title compound as an off-white solid (14.65 g, 61% yield over two steps). LCMS (Method D): RT=2.93 min, m/z: 303 [M+H+].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17](N)[CH:16]=1)[CH2:6][P:7]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])=[O:8])[CH3:2].OS(C(F)(F)F)(=O)=O.[C:31]([O:35][C:36]([NH:38][C:39]([NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[NH:40])=[O:37])([CH3:34])([CH3:33])[CH3:32].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:22])[CH:5]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:40][C:39]([NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[N:38][C:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:37])[CH2:6][P:7]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])=[O:8])[CH3:2]
Reactant: CCOC(=O)C(CP(=O)(OCC)OCC)c1cccc(N)c1
Reactant: CC(C)(C)OC(=O)NC(=N)NC(=O)OC(C)(C)C
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(CP(=O)(OCC)OCC)c1ccccc1NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 27 h
Yield: 19.5 %

Procedure:
2-(3-aminophenyl)-3-di(ethoxy)phosphinoylpropanoic acid ethyl ester (350.0 mg, 0.96 mmol), N,N′-di(t-butoxycarbonyl)guanidine triflate (375 mg, 0.96 mmol), chloroform (10 mL) and triethylamine (133.4 mL, 0.96 mmol) were combined in a 25 ml flask and stirred at 50° C. for 27 hours. The solvents were evaporated. The resulting residue was dissolved in acetonitrile/water (8 mL) and purified by preparative chromatography. The fractions were combined and evaporated to an oil, which was dried under high vacuum for 48 hours to give 107 mg of 2-(3-N,N′-di(t-butoxycarbonyl)-guanidinophenyl)-3-di(ethoxy)phosphinoylpropanoic acid ethyl ester, which was used in the next step.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][C:7]1[O:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[CH:11]=1.[C:21](Cl)(=[O:30])[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1>>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([C:21]([C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[O:8][C:7]=2[CH2:6][C:5]2[CH:16]=[CH:17][CH:18]=[C:3]([C:2]([F:1])([F:19])[F:20])[CH:4]=2)=[O:30])=[CH:23][CH:24]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: FC(F)(F)c1cccc(Cc2cc3ccccc3o2)c1
Product: COc1ccc(C(=O)c2c(Cc3cccc(C(F)(F)F)c3)oc3ccccc23)cc1

Procedure:
Acylation of 2-(3-trifluoromethylbenzyl)benzofuran with p-anisoyl chloride is carried out as outlined in the procedure of Example 1 to give 3-(4-methoxybenzoyl)-2-(3-trifluoromethylbenzyl)benzofuran.