Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.Cl.[NH2:14][CH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:16]1=[O:29].[CH2:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33][CH2:32][CH:31]1[C:40](O)=[O:41].ON1C2C=CC=CC=2N=N1>C(N(CC)CC)C.C(Cl)Cl>[O:29]=[C:16]1[CH:15]([NH:14][C:40]([CH:31]2[CH2:32][CH2:33][C:34]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:30]2)=[O:41])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]1[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCN1C(=O)C(N)c2ccccc21
Reactant: O=C(O)C1CCc2ccccc2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCN1C(=O)C(NC(=O)C2CCc3ccccc3C2)c2ccccc21
Reaction time: 1 h
Yield: 75.4 %

Procedure:
Under ice cooling, 1.10 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride was added to a stirred mixture of 1.22 g of 3-amino-2,3-dihydro-1-pentyl-1H-indol-2-one hydrochloride, 0.93 g of 1,2,3,4-tetrahydronaphthalene-2-carboxylic acid, 0.72 g of 1-hydroxybenzotriazole and 40 ml of methylene chloride. After the reaction mixture was stirred under ice cooling for 1 hour, 1.0 ml of triethylamine was added to the mixture. The resulting mixture was stirred under ice cooling for 2 hours and then stirred at room temperature for 2 hours. The solvent was removed by evaporation under reduced pressure. The residue was extracted with ethyl acetate, and the extract was washed and dried. After removal of solvent, the residual solid was recrystallized from ethyl acetate-hexane to afford 1.36 g of N-(2,3-dihydro-2-oxo-1-pentyl-1H-indol-3-yl)-1,2,3,4-tetrahydronaphthalene-2-carboxamide as colorless crystals. Melting point: 127° to 132° C., IR (Nujol) (cm-1): 3280, 1725, 1640, 1610, MS (m/z): 376 (M+), 218 (base), 147, 31.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:13]2[C:12]3[CH:11]=[C:10]([CH3:16])[CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH2:4][CH2:3]1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:40]#[C:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[C:44]([F:50])[CH:43]=1>C1(C)C=CC=CC=1>[F:50][C:44]1[CH:43]=[C:42]([C:41]#[C:40][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:16])=[CH:11][C:12]=3[C:13]3[CH2:14][CH2:15][N:2]([CH3:1])[CH2:3][CH2:4][C:5]2=3)[CH:47]=[CH:46][C:45]=1[O:48][CH3:49]
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)CC3
Reactant: COc1ccc(C#CBr)cc1F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: Cc1ccccc1
Product: COc1ccc(C#Cn2c3c(c4cc(C)ccc42)CCN(C)CC3)cc1F
Temperature: 80 °C

Procedure:
3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg, 0.46 mmol), CuSO4.5H2O (23 mg, 0.093 mmol), 1,10-Phenanthroline (33 mg, 0.18 mmol) and K3PO4 (197 mg, 0.93 mmol) and 4-(bromoethynyl)-2-fluoro-1-methoxybenzene (116 mg, 0.51 mmol) in toluene (5 mL) were added and flushed with nitrogen. The reaction mixture was heated at 80° C. for 16 h. The reaction was monitored by LCMS. The reaction mixture was filtered through Celite, washed with DCM. The organic layer was concentrated and purified by column chromatography (100-200 mesh size silica gel, 60-80% ethyl acetate in hexane) to get 6-((3-fluoro-4-methoxyphenyl)ethynyl)-3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole which was repurified by prep TLC to get 8 mg product as brown solid. 1HNMR (CDCl3, freebase) δ (ppm): 7.40 (d, 1H), 7.22 (m, 3H), 7.10 (d, 1H), 6.95 (t, 1H), 3.90 (s, 3H), 3.15 (m, 2H), 2.90 (m, 6H), 2.50 (s, 3H), 2.42 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][N:4]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@@H:16]3C[C@H](NC(=O)CO)[C@@H:18]([OH:26])[C@H:17]3[OH:27])=[C:9]([NH:28][CH2:29][CH:30]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:8]=2)[N:3]=1.ClC1N=C2C(N=CN2[C@@H]2C[C@H:56]([NH:58][C:59]([CH2:61][O:62]C(=O)C)=[O:60])[C@@H:55](O)[C@H]2O)=C(NCC(C2C=CC=CC=2)C2C=CC=CC=2)N=1>>[CH2:56]([NH:58][C:59]([C@@H:61]1[C@@H:18]([OH:26])[C@@H:17]([OH:27])[C@H:16]([N:13]2[CH:12]=[N:11][C:10]3[C:14]2=[N:15][C:7]([N:4]2[CH:5]=[N:6][C:2]([NH2:1])=[N:3]2)=[N:8][C:9]=3[NH:28][CH2:29][CH:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:62]1)=[O:60])[CH3:55]
Reactant: CC(=O)OCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: Nc1ncn(-c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)CO)[C@@H](O)[C@H]4O)c3n2)n1
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(-n4cnc(N)n4)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound is prepared analogously to N-{(1S,2R,3S,4R)-4-[2-(3-Amino-[1,2,4]triazol-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-hydroxy-acetamide (intermediate ZW), by substituting (2S,3S,4R,5R)-5-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-3,4-dihydroxy-tetrahydro-furan-2-carboxylic acid ethylamide (Intermediate ZY) for acetic acid {(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentylcarbamoyl}-methyl ester (Intermediate Q1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)[C:7]([O:9]C)=[O:8])([O-:3])=[O:2].[ClH:22]>C1(C)C=CC=CC=1.CCO>[ClH:22].[N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)[C:7]([OH:9])=[O:8])([O-:3])=[O:2]
Reactant: COC(=O)c1ccc(OCCN2CCCC2)c([N+](=O)[O-])c1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C(O)c1ccc(OCCN2CCCC2)c([N+](=O)[O-])c1
Yield: 90 %

Procedure:
Methyl 3-nitro-4-[2-(1-pyrrolidinyl)ethoxy]benzoate (5.9 g, 20 mmol) was mixed with 60 mL of 5 N aqueous HCl and refluxed 16 h. It was mixed with toluene/EtOH and concentrated under reduced pressure to dryness. The resulting solid was tritrated with hot EtOAc to afford 5.7 g (18 mmol, 90%) of the benzoic acid hydrochloride.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:21][CH2:22][CH3:23])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[C:14]2[S:18][C:17](=[O:19])[NH:16][C:15]2=[O:20])=[CH:9][CH:8]=1)[CH3:2].[H][H]>O1CCOCC1.[Pd]>[CH2:22]([O:21][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH:14]2[S:18][C:17](=[O:19])[NH:16][C:15]2=[O:20])=[CH:11][CH:12]=1)[CH3:23]
Reactant: CCOC(COc1ccc(C=C2SC(=O)NC2=O)cc1)OCC
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Product: CCOC(COc1ccc(CC2SC(=O)NC2=O)cc1)OCC
Yield: 100 %

Procedure:
A solution of 5-[4-[(2,2-diethoxy)ethoxy]phenyl methylene]thiazolidin-2,4-dione (8.0 g, 23.7 mmol) obtained in example 1, in 1,4-dioxane (100 mL) was reduced with hydrogen in the presence of 10% palladium on charcoal (16.0 g) at 60 psi for 60 h. The mixture was filtered through a bed of celite. The filtrate was evaporated to dryness under reduced pressure; purified by column chromatography using EtOAc:pet. ether (1:1) as an eluent to afford the title compound (8.04 g, 67%) as a colourless liquid.
Reaction SMILES: [Na+].[OH:2]C1C=CC(S([O-])(=O)=O)=CC=1[N+]([O-])=O.[CH:16]1([N:22]=[C:23]=[N:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C1(=O)N(NCCCCCC(O)=O)C(=O)C=C1>CN(C)C=O>[CH:25]1([NH:24][C:23]([NH:22][CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[O:2])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)[O-])ccc1O
Agent: O=C(O)CCCCCNN1C(=O)C=CC1=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
One molar equivalent (2.24 g) of 4-hydroxy-3-nitro-benzene sulfonic acid sodium salt (HNSA) is mixed together with one molar equivalent (2.06 g) of dicyclohexylcarbodiimide and one molar equivalent (2.10 g) of N-maleimido-6-aminocaproic acid in 25 ml of dimethylformamide (DMF) at room temperature overnight. A white precipitate of dicyclohexyl urea is formed. The precipitate is filtered and 300 ml diethyl ether is added to the mother liquor. After about 10 minutes to 4 hours a gummy solid precipitate from the mother liquor is formed. This solid will contain 58% of active HNSA ester and 42% of free HNSA.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9](O)(O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].Cl.[F:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:26])[NH:24][NH2:25])=[CH:18][CH:17]=1>>[F:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:23](=[O:26])[NH:24][N:25]=[C:9]2[C:10](=[O:11])[C:4]3[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=3)[C:7]2=[O:8])=[CH:20][CH:21]=1
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Reactant: NNC(=O)Nc1ccc(F)cc1
Agent: Cl
Product: O=C(NN=c1c(=O)c2ccccc2c1=O)Nc1ccc(F)cc1

Procedure:
ninhydrin, 4-(4-fluorophenyl)-semicarbazide hydrochloride
Reaction SMILES: [N:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH2:8][NH2:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:16][C:17]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:18]=1[C:19](O)=[O:20].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:16][C:17]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:18]=1[C:19]([NH:9][CH2:8][CH:7]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:20]
Reactant: Cc1ccc(Cl)c(C(=O)O)c1
Reactant: NCC(c1ccccn1)N1CCOCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(Cl)c(C(=O)NCC(c2ccccn2)N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
A mixture of (2-morpholin-4-yl-2-pyridin-2-ylethyl)amine (62.2 mg, 0.3 mmol), 2-chloro-5-methylbenzoic acid (54 mg, 0.315 mmol), PyBOP (187 mg, 0.36 mmol) and DIPEA (78 mg, 0.60 mmol) in DCM (1.5 mL) was stirred at room temperature overnight. The mixture was purified by preparative HPLC to yield the title compound (100 mg, yield: 90%). LCMS (MH+): m/z=360.0, tR (minutes, Method A)=0.89
Reaction SMILES: C[O:2][C:3](=[O:33])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:32])[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH3:31])=[CH:25][CH:24]=2)=[CH:16][CH:15]=1)(=[O:13])=[O:12].[OH-].[Li+].Cl>C1COCC1>[CH2:30]([O:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][C:21]([NH:20][C:17]2[CH:18]=[CH:19][C:14]([S:11]([NH:10][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[C:3]([OH:33])=[O:2])(=[O:13])=[O:12])=[CH:15][CH:16]=2)=[O:32])=[CH:28][CH:27]=1)[CH3:31]
Reactant: CCOc1ccc(CC(=O)Nc2ccc(S(=O)(=O)Nc3ccccc3C(=O)OC)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOc1ccc(CC(=O)Nc2ccc(S(=O)(=O)Nc3ccccc3C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
The title D compound, 2-{4-[2-(4-ethoxy-phenyl)-acetylamino]-benzenesulfonyl-amino}-benzoic acid methyl ester (189.1 mg, 0.356 mmol) is dissolved in 4 mL of THF and 1.07 mL of 1 N aqueous lithium hydroxide is added. The mixture is stirred at RT for 3 days and is then concentrated under a stream of nitrogen. The residue is taken up in warm water (20 mL) to give a clear solution. The solution is added slowly to 30 mL of 1 N aqueous HCl. The resulting precipitate is collected by filtration, washed with water, and dried under vacuum to give 2-{4-[2-(4-ethoxy-phenyl)-acetylamino]benzenesulfonylamino}benzoic acid: m.p. 241-242° C.: ESI-MS 455 [M+1]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[I:11](Cl)Cl)([O-:3])=[O:2].[OH-:14].[Na+]>>[N+:1]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[I:11]=[O:14])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1I(Cl)Cl
Reactant: [OH-]
Agent: [Na+]
Product: O=Ic1ccc(Cl)cc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
2-Nitro-4-chloro(dichloroiodo)benzene (2.0 g) was added to 100 mL of cold (about 5° C.) 20 percent aqueous solution of sodium hydroxide. The mixture was stirred for 0.5 hr, and the desired orange product was subsequently isolated by filtration and air dried; yield, 1.13 g; m.p. 118° C. (decomposed (dec.)).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)[N:6]=[C:5]2[CH2:16][CH2:17][CH2:18][C:4]=12.[NH2:19][C:20]1[CH:28]=[CH:27][C:23]([CH2:24][CH2:25][OH:26])=[CH:22][CH:21]=1>>[ClH:2].[C:11]1([CH3:15])[CH:12]=[CH:13][CH:14]=[C:9]([C:7]2[N:6]=[C:5]3[CH2:16][CH2:17][CH2:18][C:4]3=[C:3]([NH:19][C:20]3[CH:28]=[CH:27][C:23]([CH2:24][CH2:25][OH:26])=[CH:22][CH:21]=3)[CH:8]=2)[CH:10]=1
Reactant: Cc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Reactant: Nc1ccc(CCO)cc1
Agent: Cl
Product: Cc1cccc(-c2cc(Nc3ccc(CCO)cc3)c3c(n2)CCC3)c1
Yield: 75.8 %

Procedure:
Following General Procedure A2, 4-chloro-2-(m-tolyl)-6,7-dihydro-5H-cyclopenta[b]pyridine hydrochloride (0.075 g, 0.27 mmol) was reacted with 4-aminophenethyl alcohol (0.044 g, 0.32 mmol), followed by the formation of the hydrochloride salt to afford the title compound (0.078 g, 100%) as a brown solid. MW=380.91. 1H NMR (DMSO-d6, 500 MHz) δ 13.88 (s, 1H), 9.75 (s, 1H), 7.56 (s, 1H), 7.52-7.44 (m, 2H), 7.41 (d, J=7.5 Hz, 1H), 7.38-7.26 (m, 4H), 6.93 (s, 1H), 3.64 (t, J=6.9, 2H), 3.59 (t, J=6.9 Hz, 1H), 3.15 (t, J=7.6 Hz, 2H), 2.91 (t, J=7.6 Hz, 2H), 2.76 (t, J=6.9 Hz, 2H), 2.39 (m, 3H), 2.24 (quin, J=7.6, 2H); APCI MS m/z 345 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=[O:27])[CH2:13][CH:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:11][C:4]=2[CH:3]=1.O.[NH2:29][NH2:30]>O1CCOCC1>[C:15]1([CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13][C:12]([N:10]2[CH2:9][CH2:8][C:5]3[N:6]=[N:7][C:2]([NH:29][NH2:30])=[CH:3][C:4]=3[CH2:11]2)=[O:27])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NN
Reactant: O=C(CC(c1ccccc1)c1ccccc1)N1CCc2nnc(Cl)cc2C1
Solvent: C1COCCO1
Solvent: O
Product: NNc1cc2c(nn1)CCN(C(=O)CC(c1ccccc1)c1ccccc1)C2

Procedure:
7.6 g of 3-chloro-6-(3,3-diphenylpropionyl)-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine in 40 cc of hydrazine hydrate and 40 cc of dioxane are stirred at a bath temperature of 100° during 12 hours. The mixture is cooled with ice, whereupon the title compound precipitates and is recrystallized from ethanol/water (ratio 6:1). The title compound has a M.P. of 208°-211° (decomp.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:21])[S:9]([C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[N:29]=[C:30]([NH2:33])[S:31][CH:32]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH3:21])[S:9]([C:12]2[CH:13]=[CH:14][C:15]([C:16]([NH:33][C:30]3[S:31][CH:32]=[C:28]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=4)[N:29]=3)=[O:18])=[CH:19][CH:20]=2)(=[O:10])=[O:11])=[CH:6][CH:7]=1
Reactant: Nc1nc(-c2ccccn2)cs1
Reactant: CN(c1ccc(F)cc1)S(=O)(=O)c1ccc(C(=O)O)cc1
Product: CN(c1ccc(F)cc1)S(=O)(=O)c1ccc(C(=O)Nc2nc(-c3ccccn3)cs2)cc1

Procedure:
4-(N-(4-fluorophenyl)-N-methylsulfamoyl)benzoic acid (4) (100 mg, 0.32 mmol) was treated with 4-(pyridin-2-yl)thiazol-2-amine (48 mg, 0.27 mmol) using method C. The residue was purified using flash chromatography eluting with EtOAc. The resulting solid was triturated with diethyl ether to give 4-(N-(4-fluorophenyl)-N-methylsulfamoyl)-N-(4-(pyridin-2-yl)thiazol-2-yl)benzamide as a yellow solid. Yield: 34 mg (27%). 1H-NMR: 8.61 (d, J=4.5 Hz, 1H), 8.29 (d, J=8.5 Hz, 2H), 8.02 (d, J=8.5 Hz, 1H), 7.93-7.83 (m, 2H), 7.65 (d, J=8.5 Hz, 2H), 7.36-7.31 (m, 1H), 7.24-7.12 (m, 4H), 3.17 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.I[CH3:12].[H-].[Na+]>CN(C=O)C>[CH3:12][O:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1
Reactant: CI
Reactant: N#Cc1ccc(CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1ccc(C#N)cc1
Reaction time: 2 h

Procedure:
To a solution of 4-(hydroxymethyl)benzonitrile (5 g, 37.6 mmol) in DMF (100 mL) was added iodomethane (7.03 mL, 113 mmol) and NaH (1.502 g, 37.6 mmol). The reaction aged at rt for 2 h and was then partitioned between EtOAc and H2O. The organic layer was separated and washed with H2O (2×), brine, dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography on silica gel gradient eluted with 0-20% EtOAc/hexane to afford the title compound. HPLC/MS: 148.1 (M+1); Rt=2.28 min.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5](=[O:24])[C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:22])/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)=[CH:8][C:7]=1[Cl:23].CC(C)=O>CO>[CH3:3][O:4][C:5](=[O:24])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]([OH:22])/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)=[CH:8][C:7]=1[Cl:23]
Reactant: COC(=O)c1ccc(C(=O)/C=C/c2cccc(O)c2)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)=O
Product: COC(=O)c1ccc(C(O)/C=C/c2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.3 %

Procedure:
Sodium borohydride (25 mg, 0.66 mmol) was added to a solution of (E)-2-chloro-4-[3-(3-hydroxyphenyl)-1-oxoprop-2-en-1-yl]benzoic acid methyl ester (Example 91; 316 mg, 1 mmol) in methanol (3 mL). The solution was stirred at room temperature for 3 h, then acetone (1 mL) was added and the solution was stirred for a further 10 min. The solvent was evaporated, ethyl acetate (15 mL) was added and the solution was washed with 0.5N hydrochloric acid solution (10 mL) and brine. Each of the aqueous layers was extracted in turn with ethyl acetate (10 mL). The combined organic layers were dried (MgSO4), filtered, evaporated and the resulting solid was triturated with diethyl ether to furnish rac.-(E)-2-chloro-4-[1-hydroxy-3-(3-hydroxyphenyl)prop-2-en-1-yl]benzoic acid methyl ester (310 mg, 97% yield) as a colorless solid.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH2:16][CH2:17][OH:18])[C:10]=1[CH:19]([C:21]1[CH:26]=[CH:25][C:24]([O:27]CC2C=CC=CC=2)=[C:23]([O:35][CH3:36])[CH:22]=1)[OH:20])C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH2:16][CH2:17][OH:18])[C:10]=1[CH:19]([OH:20])[C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([O:35][CH3:36])[CH:22]=1
Reactant: COc1cc(C(O)c2c(OCc3ccccc3)c(=O)ccn2CCO)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COc1cc(C(O)c2c(O)c(=O)ccn2CCO)ccc1O

Procedure:
Under normal pressure and at room temperature, 1.1 g of 3-benzyloxy-2-[(4-benzyloxy-3-methoxy-phenyl)-hydroxy-methyl]-1-(2-hydroxy-ethyl)-1H-pyridin-4-one are hydrogenated in 50 ml of methanol over 0.2 g of palladium on carbon (5%) until 2 mol of H2 per mol of starting material have been taken up. Removal of the catalyst and recrystallisation from ethanol yield 3-hydroxy-1-(2-hydroxy-ethyl)-2-[hydroxy-(4-hydroxy-3-methoxy-phenyl)-methyl]-1H-pyridin-4-one. M.p.: 179°-190° C.
Reaction SMILES: Cl.[OH:2][C@H:3]1[CH2:7][CH2:6][NH:5][C@@H:4]1[C:8]([O:10][CH3:11])=[O:9].CCN(CC)CC.[Cl:19][CH2:20][C:21](Cl)=[O:22]>C1C=CC=CC=1>[Cl:19][CH2:20][C:21]([N:5]1[CH2:6][CH2:7][C@H:3]([OH:2])[C@H:4]1[C:8]([O:10][CH3:11])=[O:9])=[O:22]
Reactant: COC(=O)[C@H]1NCC[C@@H]1O
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1[C@@H](O)CCN1C(=O)CCl
Reaction time: 24 h
Yield: 67 %

Procedure:
To a solution of the methyl (3S)-3-hydroxy-L-prolinate hydrochloride (D68, 1.8 g, 9.9 mmol) and Et3N (3 ml, 21.8 mmol) in 10 ml of dry benzene at the temperature of 7-8° C. was added dropwise a solution of chloroacetyl chloride (0.87 ml, 10.9 mmol) in 5 ml of dry benzene. After 24 h at rt, the precipitated was filtered off and washed with AcOEt. The filtrate was evaporated, and the crude oil was purified by flash chromatography column (Cy/AcOEt 1/4 as eluent). The title compound was isolated as a colourless oil (1.48 g). Yield 67%.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([CH3:7])([SH:6])[CH3:5].C(N(CC)CC)C.[C:15]1(=[O:21])[O:20][C:18](=[O:19])[CH2:17][CH2:16]1>C(Cl)Cl>[CH3:5][C:4]([SH:6])([CH3:7])[CH2:3][NH:2][C:15]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[O:21]
Reactant: CC(C)(S)CN
Reactant: O=C1CCC(=O)O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(S)CNC(=O)CCC(=O)O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 94.5 %

Procedure:
To an ice-cooled suspension of 1-amino-2-methylpropan2-thiol hydrochloride (5.06 g, 35.72 mmol) in methylene chloride (100 mL) was added triethylamine (5.0 mL, 35.87 mmol) followed by succinic anhydride (3.50 g, 34.96 mmol). The resulting clear solution was stirred at 0° C. or 10 minutes, then at room temperature for 2 hours. Evaporation of the volatiles under reduced pressure gave a residue which was partitioned between 2 N hydrochloric acid (100 mL) and ethyl acetate (100 mL). The aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (5 mL), dried over sodium sulfate and evaporated to dryness. The residue was triturated with ether-hexane to afford the title compound as a white solid (6.78 g, 94.4%). Mp. 86-87° C.; 1H NMR (300 MHz, CDCl3): δ1.34 (s, 6H), 1.55(s, 1H), 2.59 (t, J=6.6 Hz, H), 2.70 (t, J=6.6 Hz, 2H), 3.32 (d, J=8.0 Hz, 2), 6.58 (br t, J=5.9 Hz, 1H), 10.73 (br s, 1H); 13C NMR (75 MHz, CDCl3): δ29.57, 29.79, 30.79, 172.50, 176.81; LCMS (m/e): 223 (M+H2O), 206 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[NH:8][CH:9]=[N:10][C:6]=2[C:5]([C:11](O)=O)=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].O=P(Cl)(Cl)Cl.S(N)([NH2:25])(=O)=O>S1(CCCC1)(=O)=O>[CH3:1][C:2]1[C:7]2[NH:8][CH:9]=[N:10][C:6]=2[C:5]([C:11]#[N:25])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15]
Reactant: NS(N)(=O)=O
Reactant: Cc1c([N+](=O)[O-])cc(C(=O)O)c2nc[nH]c12
Solvent: O=P(Cl)(Cl)Cl
Solvent: O=S1(=O)CCCC1
Product: Cc1c([N+](=O)[O-])cc(C#N)c2nc[nH]c12
Temperature: 120 °C

Procedure:
A mixture of 7-Methyl-6-nitro-1H-benzimidazole-4-carboxylic Acid (23) (16.99 g, 76.90 mmol), POCl3 (15.76 mL, 169 mmol), and sulfamide (14.767 g, 154 mmol) in sulfolane (77 mL) is heated to about 120° C. for about 3 hours. The reaction mixture is cooled to ambient temperature and added to ice water (1 L). The resultant mixture is cooled to about 0° C. filtered to provide 7-Methyl-6-nitro-1H-benzimidazole-4-carbonitrile (24), as an off white solid (12.54 g, 80% Yield).
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]([C:10]([OH:12])=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][NH2:9].[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>C1COCC1.C([O-])([O-])=O.[K+].[K+]>[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:3][C@H:4]([C:10]([OH:12])=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][S:20]([C:17]2[CH:18]=[CH:19][C:14]([CH3:13])=[CH:15][CH:16]=2)(=[O:22])=[O:21])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCCCC[C@H](N)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)NCCCC[C@H](NS(=O)(=O)c2ccc(C)cc2)C(=O)O)cc1
Reaction time: 2 h
Yield: 75 %

Procedure:
To a stirred solution of L-lysine dihydrochloride (1 mmol) in a mixture of THF and 1M K2CO3 (3 mL/3 mL) was added 4-methylbenzenesulfonyl chloride (381 mg, 2.00 mmol). The reaction mixture was stirred for 2 h and then quenched with 1N HCl and extracted twice with EtOAc. The combined organic extracts were dried over MgSO4 and concentrated. The crude was purified by flash chromatography using hexane/EtOAc/AcOH (30:69.4/0.6) to give 75% of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C@H:10]([CH2:11][C:12](O)=[O:13])[O:9][CH2:8][CH2:7][C:6]=2[CH:15]=1.B.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C@H:10]([CH2:11][CH2:12][OH:13])[O:9][CH2:8][CH2:7][C:6]=2[CH:15]=1
Reactant: O=C(O)C[C@@H]1OCCc2cc(Br)ccc21
Agent: B
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCC[C@@H]1OCCc2cc(Br)ccc21
Reaction time: 1 h

Procedure:
To a solution of 2-((1S)-6-bromo-3,4-dihydro-1H-2-benzopyran-1-yl)acetic acid (21.3 g, 78.6 mmol) in anhydrous THF (65 mL) under an atmosphere of nitrogen and cooled to 0° C., was added dropwise borane.THF complex in THF (1M) (94 mL, 94 mmol). After stirring for 1 h between 0 and 10° C., the reaction mixture was treated with aqueous sodium carbonate then extracted into toluene. The organic layer was washed with dilute aqueous hydrochloric acid, then concentrated in vacuo to give the title compound as a white solid.