Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CON.[F:4][C:5]1[CH:6]=[C:7]([CH:23]=[CH:24][CH:25]=1)[CH2:8][NH:9][C:10](=[O:22])[NH:11][C:12]1[S:13][CH:14]=[C:15]([CH2:17][N:18](OC)[CH3:19])[N:16]=1.O>CC(O)=O.[Zn]>[F:4][C:5]1[CH:6]=[C:7]([CH:23]=[CH:24][CH:25]=1)[CH2:8][NH:9][C:10]([NH:11][C:12]1[S:13][CH:14]=[C:15]([CH2:17][NH:18][CH3:19])[N:16]=1)=[O:22]
Reactant: CON(C)Cc1csc(NC(=O)NCc2cccc(F)c2)n1
Agent: CON
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: CNCc1csc(NC(=O)NCc2cccc(F)c2)n1
Reaction time: 9 h
Yield: 89.6 %

Procedure:
Zinc Reduction of methoxyamine to amine (J. Natural Products 53(4), 995-999 (1990)). A solution of 2-(3-(3-fluorobenzyl)ureido)-4-(N-methoxy-N-methyl-aminomethyl)-thiazole (10.1 g, 31.1 mmol) in glacial HOAc (140 mL) was treated with micronized zinc dust (50 g) and the mixture was heated to 60-65 C with vigorous agitation. The reduction was complete in 2-16 hours and water (140 mL) was added. The mixture was filtered on Celite, the filter cake was reslurried in 1:1 HOAC:water (150 mL) and refiltered. The combine filtrate was made alkaline to pH 10 with NH4OH and cooled in ice. The solids were collected by filtration, washed with water, and dried in vacuo to afford Intermediate 5 as an off-white solid (8.2 g, 89% yield). This product could be used directly or further purified by crystallization as the hydrochloride salt (1:1 MeOH:EtOH).
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:23])[CH3:22])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:24]([C:26]1[CH:36]=[CH:35][C:29]([CH:30]=[CH:31][C:32]([OH:34])=[O:33])=[CH:28][CH:27]=1)=O.[OH-].[K+]>O1CCOCC1.CCO.O>[C:1]([N:9]1[CH2:10][CH2:11][N:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21](=[O:23])/[CH:22]=[CH:24]/[C:26]3[CH:27]=[CH:28][C:29](/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33])=[CH:35][CH:36]=3)=[CH:19][CH:20]=2)[CH2:13][CH2:14]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1ccc(N2CCN(C(=O)c3ccccc3)CC2)cc1
Reactant: O=Cc1ccc(C=CC(=O)O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCO
Product: O=C(O)/C=C/c1ccc(/C=C/C(=O)c2ccc(N3CCN(C(=O)c4ccccc4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.8 %

Procedure:
1-[4-(4-Benzoyl-piperazin-1-yl)-phenyl]-ethanone (500 mg, 1.62 mmol) was dissolved in 1,4-dioxane (3 ml) and added to a stirred solution of 4-formylcinnamic acid (286 mg, 1.62 mmol) and 1.7 M KOH (1.9 ml) in EtOH (5 ml) and water (5 ml). The resulting mixture was stirred overnight at room temperature and then heated to 40° C. for 4 h. The reaction was then quenched with 10% HCl, the resulting precipitate was filtered and washed with EtOH. The resulting green solid was dried in vacuo to give 240 mg of (E)-3-(4-{(E)-3-[4-(4-benzoyl-piperazin-1-yl)-phenyl]-3-oxo-propenyl}-phenyl)-acrylic acid as its hydrochloride salt.
Reaction SMILES: C1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10]([C:12]([C:14]3[CH:19]=[CH:18][C:17]4[O:20]C[O:22][C:16]=4[CH:15]=3)=[O:13])=[O:11])=[CH:4][C:3]=2[O:2]1.B(Br)(Br)Br.CO>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([C:10]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([OH:22])[CH:15]=2)=[O:13])=[O:11])[CH:6]=[CH:7][C:8]=1[OH:9]
Reactant: O=C(C(=O)c1ccc2c(c1)OCO2)c1ccc2c(c1)OCO2
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: O=C(C(=O)c1ccc(O)c(O)c1)c1ccc(O)c(O)c1
Reaction time: 3.5 h
Yield: 47.2 %

Procedure:
To a stirred solution of bis(3,4-methylenedioxy)benzil (500 mg) in dry CH2Cl2 (50 ml) under nitrogen, was slowly added boron tribromide (1.6 ml) then stirring continued for a further 3.5 hours. Methanol (100 ml) was added carefully, then the solvent evaporated in vacuo to a volume of 1 ml, this addition and evaporation was repeated twice more. The product was purified by column chromatography over silica gel when elution with diethylether in dichloromethane gave 3,4,3′,4′-tetrahydroxybenzil (217 mg, 47%) as a yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:12]=[C:11]([O:13][CH2:14][CH3:15])[CH:10]=[C:6]([C:7]([OH:9])=O)[CH:5]=1.O=S(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+].Cl.[CH2:28]([NH:31][CH2:32][CH3:33])[CH:29]=[CH2:30]>CN(C=O)C.C(Cl)Cl.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:12]=[C:11]([O:13][CH2:14][CH3:15])[CH:10]=[C:6]([C:7]([N:31]([CH2:28][CH:29]=[CH2:30])[CH2:32][CH3:33])=[O:9])[CH:5]=1
Reactant: C=CCNCC
Reactant: CCOc1cc(C(=O)O)cc(C(=O)OC)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: C=CCN(CC)C(=O)c1cc(OCC)cc(C(=O)OC)c1
Temperature: 80 °C

Procedure:
A solution of 1.0 g (4.45 mmol) 5-ethoxy-isophthalic acid mono methyl ester, 10 ml toluene and 0.5 ml SOCl2 is treated with one drop DMF and heated to 80° C. till the evolution of gas ceases. After cooling down the mixture is evaporated, dissolved in 5 ml DCM and added to an at 0° C. stirred mixture of 10 ml 10% aqueous Na2CO3, 0.81 g (6.7 mmol) allyl ethyl amine hydrochloride (see IVb) and 5 ml DCM. After 1 h the layers are separated and the organic layer is washed with 1N HCl, brine, dried with sodium sulfate and evaporated to yield the N-allyl-5-ethoxy-N-ethyl-isophthalamic acid methyl ester. This ester is dissolved in 20 ml MeOH, treated with 15 ml 1N NaOH and stirred for 18 h. The methanol is evaporated, the residue acidified with 1N HCl and extracted with TBME. The organic layer is dried with sodium sulfate and evaporated to yield the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=O)[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:18][O:19][NH2:20].C(N(CC)CC)C>C(Cl)(Cl)Cl.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[N:20][O:19][CH3:18])[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CON
Reactant: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 97.7 %

Procedure:
A solution was made containing (2S)-1-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidinecarboxylic acid (5.0 g, 21 mmol) and O-methylhydroxylamine hydrochloride (2.7 g, 32.8 mmol) in chloroform (100 ml) containing triethyl-amine (5.5 g, 55 mmol). The reaction mixture was then stirred at ambient temperature over-night, prior to removal of solvent. The resultant crude reaction mixture was dissolved in ethyl acetate (150 ml) and washed rapidly with 1N HCl (40 ml). The acidic layer was then extracted with ethyl acetate (3×20 ml) and the combined organic layers washed with brine before drying over magnesiom sulfate, filtering and removal of solvent in vacuo. The desired product (5.3 g, 94%) was isolated as a pale yellow oil.
Reaction SMILES: C([O:5][CH2:6][C@@H:7]([P:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:8][P:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(C)(C)C>FC(F)(F)C(O)=O>[C:10]1([P:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][C@H:7]([P:22]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:6][OH:5])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC[C@H](CP(c1ccccc1)c1ccccc1)P(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: OC[C@H](CP(c1ccccc1)c1ccccc1)P(c1ccccc1)c1ccccc1
Yield: 90.5 %

Procedure:
A solution of 0.2 g of (R)-1-t-butoxy-2,3-bis-(diphenylphosphino)propane (see Example 6) in 25 ml of anhydrous trifluoroacetic acid under argon atmosphere is stirred at room temperature for 14 hours. The trifluoroacetic acid is removed under reduced pressure. The residue is dissolved in 20 ml of dichloromethane, and washed with 5% sodium bicarbonate solution and then with water. The solvent is removed under reduced pressure and the residue is dried to yield 0.16 g of (R)-1,2-bis-(diphenylphosphino)propane-3-ol (see Formula (L) of Scheme 2) in the form of a sticky solid.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH3:12])([CH3:11])[C:9](=[O:13])[N:8]([CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[C:6]=2[N:7]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][N:29]([C:32](=[O:34])[CH3:33])[CH2:28][CH2:27]2)=[CH:22][CH:21]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1.CN(C=O)C.CCOC(C)=O>[C:32]([N:29]1[CH2:28][CH2:27][N:26]([C:23]2[CH:24]=[CH:25][C:20]([NH:19][C:2]3[N:3]=[CH:4][C:5]4[C:10]([CH3:12])([CH3:11])[C:9](=[O:13])[N:8]([CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[C:6]=4[N:7]=3)=[CH:21][CH:22]=2)[CH2:31][CH2:30]1)(=[O:34])[CH3:33]
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Reactant: CCC(CC)N1C(=O)C(C)(C)c2cnc(Cl)nc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC(CC)N1C(=O)C(C)(C)c2cnc(Nc3ccc(N4CCN(C(C)=O)CC4)cc3)nc21
Temperature: 140 °C
Yield: 88.8 %

Procedure:
To a solution of 2-chloro-7-(1-ethyl-propyl)-5,5-dimethyl-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (20 mg, 0.075 mmol) in 1,4-dioxane (1 mL) and DMF (0.2 mL) are added 1-[4-(4-amino-phenyl)-piperazin-1-yl]-ethanone (24.5 mg, 0.11 mmol) and p-toluenesulfonic acid (17 mg, 0.089 mmol). The reaction mixture is sealed in a microwave reactor and heated at 140° C. for 30 min. The mixture is diluted with EtOAc and washed with 1N NaOH solution. The organics is dried over Na2SO4, filtered, and concentrated. The residue is purified by prep-HPLC to give 30 mg of 2-[4-(4-acetyl-piperazin-1-yl)-phenylamino]-7-(1-ethyl-propyl)-5,5-dimethyl-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one as a pale yellow solid.
Reaction SMILES: [CH:1]1([OH:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[SH:9][CH:10]([CH3:14])[C:11](O)=[O:12].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH:1]1([O:8][C:11](=[O:12])[CH:10]([SH:9])[CH3:14])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(S)C(=O)O
Reactant: OC1CCCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(S)C(=O)OC1CCCCCC1

Procedure:
Reaction: ##STR127## Into a 50 ml reaction flask equipped with stirrer, thermometer, reflux condenser and heating mantle are placed 11.4 grams cycloheptanol; 22 grams of 2-mercaptopropionic acid and 0.5 grams of paratoluene sulfonic acid. The reaction mass is heated to reflux and refluxed for a period of 10 hours. At the end of the 10 hour period, the reaction mass is distilled on a micro distillation apparatus to yield the compound having the structure: ##STR128##
Reaction SMILES: I[C:2]1[C:6]2[CH:7]=[N:8][C:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:10][C:5]=2[N:4](C(OCC)=O)[CH:3]=1.[N+:23]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)([O-:25])=[O:24].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.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>[N+:23]([C:26]1[CH:31]=[CH:30][C:29]([C:2]2[C:6]3[CH:7]=[N:8][C:9]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])=[CH:10][C:5]=3[NH:4][CH:3]=2)=[CH:28][CH:27]=1)([O-:25])=[O:24]
Reactant: CCOC(=O)n1cc(I)c2cnc(C(=O)OC(C)(C)C)cc21
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1cc2[nH]cc(-c3ccc([N+](=O)[O-])cc3)c2cn1
Temperature: 77.5 °C
Yield: 18.1 %

Procedure:
To a mixture of 6-tert-butyl 1-ethyl 3-iodo-1H-pyrrolo[3,2-c]pyridine-1,6-dicarboxylate (55 mg, 0.13 mmol) and 4-nitrophenylboronic acid (67 mg, 0.4 mmol) in toluene (3 mL) and ethanol (1.5 mL), was added Pd(PPh3)4, followed by K3PO4 (2 M, 0.4 mL). The resulting mixture was purged with argon, and heated at 75-80° C. for 5 h. The desired product was purified by prep-HPLC to gave a yellow solid (8 mg, 18 % yield). 1H NMR (CDCl3) δ 8.68 (s, 1H), 8.30 (d, 2H, J=8.8 Hz), 8.00 (d, 1H, J=8.8 Hz), 7.36 (s, 1H), 7.25 (s, 1H), 1.51 (s,9H) ; LC-MS: m/z 284 (M-Bu)+.
Reaction SMILES: [C:1]([C:9]1[C:17]([N+:18]([O-])=O)=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[O:21][CH2:22][C:23]1C=CC=C[CH:24]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1C(C(=O)C2C=CC=CC=2)=C(OCCC)C=C(C=1)C(O)=O>>[NH2:18][C:17]1[C:9]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:10]([O:21][CH2:22][CH2:23][CH3:24])[CH:11]=[C:12]([CH:16]=1)[C:13]([OH:15])=[O:14]
Reactant: O=C(O)c1cc(OCc2ccccc2)c(C(=O)c2ccccc2)c([N+](=O)[O-])c1
Agent: CCCOc1cc(C(=O)O)cc(N)c1C(=O)c1ccccc1
Product: CCCOc1cc(C(=O)O)cc(N)c1Cc1ccccc1

Procedure:
By replacing in Example 24, step A, 4-benzoyl-3-benzyloxy-5-nitrobenzoic acid with 5-amino-4-benzoyl-3-n-propoxybenzoic acid and following the procedure described, 5-amino-4-benzyl-3-n-propoxybenzoic acid is obtained with a melting point of 161°- 162° C.
Reaction SMILES: C[Si](C)(C)[O-].[K+].[C:7]1([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][N:34]3[CH2:38][C@@H:37]([C:39]4[CH:50]=[CH:49][C:42]5[O:43][C:44]([CH3:48])([CH3:47])[O:45][CH2:46][C:41]=5[CH:40]=4)[O:36]C3=O)[CH:18]=2)=[O:15])=[CH:9][CH:8]=1.P([O-])([O-])([O-])=O>C1COCC1>[C:7]1([C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][NH:34][CH2:38][C@@H:37]([C:39]3[CH:50]=[CH:49][C:42]4[O:43][C:44]([CH3:47])([CH3:48])[O:45][CH2:46][C:41]=4[CH:40]=3)[OH:36])[CH:18]=2)=[O:15])=[CH:9][CH:8]=1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(NC(=O)Nc5ccc(-c6ccccc6)cc5)c4)C(=O)O3)ccc2O1
Agent: C[Si](C)(C)[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC1(C)OCc2cc([C@@H](O)CNCCCCCCOCCOCc3cccc(NC(=O)Nc4ccc(-c5ccccc5)cc4)c3)ccc2O1
Temperature: 65 °C
Yield: 80.3 %

Procedure:
Potassium trimethylsilanolate (0.090 g) was added to a solution of N-(1,1′-biphenyl-4-yl)-N′-(3-{[2-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)ethoxy]methyl}phenyl)urea (0.119 g) in deoxygenated anhydrous THF (4 ml) whilst stirring under nitrogen. The reaction mixture was heated to 65° C. for 3 h, at which point the reaction mixture was cooled to room temperature. Phosphate buffer (25 ml, pH6.5) was added and the mixture extracted with EtOAc (3×25 ml). The combined organic layers were separated and dried over Na2SO4 before filtering. Solvent evaporation in vacuo gave a residue which was purified by Biotage. Elution with 150:8:1 dichloromethane:EtOH:ammonia followed by solvent evaporation in vacuo gave the title compound (0.092 g). LCMS RT=3.16 min, ES+ve 668 (MH)+.
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:3]1.C1C=CC2N(O)N=NC=2C=1.O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:56][C:57]1[CH:58]=[C:59]([C:63](O)=[O:64])[CH:60]=[N:61][CH:62]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C@H:2]1[CH2:3][N:4]([S:8]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:16]=2)(=[O:9])=[O:10])[CH2:5][CH2:6][N:7]1[C:63]([C:59]1[CH:60]=[N:61][CH:62]=[C:57]([CH3:56])[CH:58]=1)=[O:64]
Reactant: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1
Reactant: Cc1cncc(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cncc(C(=O)N2CCN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)C[C@@H]2C)c1

Procedure:
To a solution of (3S)-3-methyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (Description 2) (100 mg, 0.324 mmol) in DMF (5 ml) was added HOBT.H2O (49.7 mg, 0.324 mmol), HBTU (123 mg, 0.324 mmol), 5-methyl-3-pyridinecarboxylic acid (44.5 mg, 0.324 mmol) and DIPEA (0.170 ml, 0.973 mmol) and the reaction mixture was stirred for 1 h at room temperature. The reaction mixture was evaporated in vacuo. The residue was dissolved in DCM (50 ml), transferred to a separating funnel and the solution was washed with aqueous NaHCO3 (5 ml), twice. The organic layer was dried with magnesium sulphate which was removed by filtration and the filtrate evaporated to dryness in vacuo. The residual oil was dissolved in 1:1 MeCN/DMSO (1.8 ml) and purified by MDAP in two batches. The fractions containing the desired product were combined and evaporated to dryness in vacuo to the title compound (95 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:32])[C:13]3[CH:14]=[CH:15][C:16]([O:18][CH2:19][O:20][CH3:21])=[CH:17][C:12]=3[O:11][CH2:10][CH:9]2[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][O:30][CH3:31])=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.Cl[CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.Cl.C([O-])([O-])=O.[K+].[K+]>CC(C)=O.O>[OH:32][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:34][CH2:35][N:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)=[CH:3][CH:4]=2)[C:13]2[CH:14]=[CH:15][C:16]([O:18][CH2:19][O:20][CH3:21])=[CH:17][C:12]=2[O:11][CH2:10][CH:9]1[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][O:30][CH3:31])=[CH:24][CH:23]=1
Reactant: COCOc1ccc(C2COc3cc(OCOC)ccc3C2(O)c2ccc(O)cc2)cc1
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COCOc1ccc(C2COc3cc(OCOC)ccc3C2(O)c2ccc(OCCN3CCCCC3)cc2)cc1
Temperature: 25 °C
Yield: 7 %

Procedure:
4-(4-Hydroxyphenyl)-4-hydroxy-7-methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-2,3-dihydro-4H-benzopyran (310 mg, 0.59 mmol) prepared in Example 15, [1-(2-chloroethyl)]piperidine.HCl (176 mg, 0.9 mmol) and K2CO3 (264 mg, 1.8 mmol) were dissolved in acetone (8 ml) and then refluxed for 62 hours. The reaction solution was cooled to room temperature and, after adding water, extracted with ethyl acetate. The organic layer thus separated was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure to remove the organic solvent. The residue was separated by column chromatography (n-hexane:ethyl acetate=1:2) to obtain 83 mg (yield: 7%) of the title compound as a white foam.
Reaction SMILES: [C:1]1(=[O:36])[N:5]([C:6]2[CH:7]=[C:8]([CH:32]=[CH:33][CH:34]=2)[C:9]([O:11][CH2:12][CH2:13][N:14](C(OC(C)(C)C)=O)[CH2:15][CH2:16][NH:17]C(OC(C)(C)C)=O)=[O:10])[C:4](=[O:35])[CH:3]=[CH:2]1.[ClH:37]>C(OCC)C>[ClH:37].[ClH:37].[C:4]1(=[O:35])[N:5]([C:6]2[CH:7]=[C:8]([CH:32]=[CH:33][CH:34]=2)[C:9]([O:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][NH2:17])=[O:10])[C:1](=[O:36])[CH:2]=[CH:3]1
Reactant: CC(C)(C)OC(=O)NCCN(CCOC(=O)c1cccc(N2C(=O)C=CC2=O)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Product: NCCNCCOC(=O)c1cccc(N2C(=O)C=CC2=O)c1
Temperature: 25 °C

Procedure:
6 g (11.93 mmol) of N—(O—(3-maleinimidobenzoyl)-2-hydroxyethyl)-N,N′-bis-tertiarybutyloxycarbonyl-1,2-diaminoethane are diluted with 60 ml (5 eq) of a 1M solution of HCl in diethylether while stirring at room temperature. After 48 h of stirring at room temperature, the fine-crystallinic precipitate is suctioned off over a G4 glass frit, freed of the HCl residues through multiple washing with anhydrous ether and dried under a vacuum. Obtained are 3.0 g (7.98 mmol) of the product as a fine-powdery yellow solid, corresponding to 66.9% of the theoretically possible yield. Elementary analysis for C15H19N3O4Cl2 (375.9 g/mol);
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[S:10](Cl)(=[O:12])=[O:11].[C:14]1([C@@H:20]([NH2:29])[C@@H:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[NH2:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.CN(C)C=O.ClCCl>[NH2:22][C@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C@H:20]([NH:29][S:10]([C:3]1[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][C:4]=1[CH3:9])(=[O:12])=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: N[C@H](c1ccccc1)[C@H](N)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cc(C)c(S(=O)(=O)N[C@H](c2ccccc2)[C@H](N)c2ccccc2)c(C)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 68.2 %

Procedure:
A solution of 2,4,6-trimethylbenzene-1-sulfonyl chloride 31 (1.54 g, 7.06 mmol, 0.99 eq) in tetrahydrofuran (75 mL) was added drop-wise at 0° C. over 70 minutes (min) to a suspension of (1R,2R)-1,2-diphenylethane-1,2-diamine 30 (1.5 g, 7.08 mmol, 1.0 eq), triethylamine (2.04 g, 2.8 mL, 2.02 mmol, 0.28 eq) and powdered potassium carbonate (1.60 g, 11.59 mmol, 1.64 eq) in a mixture of tetrahydrofuran (60 mL) and N,N-dimethylformamide (15 mL). When addition was complete the suspension was stirred at 0° C. for 3 hours (h). The reaction mixture was concentrated under reduced pressure to remove most of the tetrahydrofuran. The residual oily solid was partitioned between water (100 mL) and 3:1 ethyl acetate/heptanes. The organic phase was diluted with heptanes (50 mL) and the solution washed with water (3×100 mL) followed by brine (100 mL). The organic solution was dried over sodium sulfate, filtered and the filtrate concentrated under reduced pressure to give a pale yellow oil. The crude product was dissolved in a minimum volume of dichloromethane, adsorbed onto silica gel and dry-loaded on a column of silica gel (50 g) packed in 75% ethyl acetate/heptanes. The column was eluted with 75% ethyl acetate/heptanes (300 mL) and ethyl acetate (300 mL). Product-containing fractions were concentrated under reduced pressure to give a slightly gummy solid that was triturated with hexanes containing a small amount of methyl t-butyl ether, filtered, washed with hexanes and dried to give 1.90 g of 32 as a white solid.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:7]=[N:8][C:9](Cl)=[CH:10][CH:11]=1)(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].O.B1(C=C)OB([CH:26]=[CH2:27])OB(C=C)O1.C1C=CN=CC=1>COCCOC>[C:1]([O:4][CH2:5][C:6]1[CH:7]=[N:8][C:9]([CH:26]=[CH2:27])=[CH:10][CH:11]=1)(=[O:3])[CH3:2]
Reactant: C=CB1OB(C=C)OB(C=C)O1
Reactant: CC(=O)OCc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: c1ccncc1
Solvent: COCCOC
Product: C=Cc1ccc(COC(C)=O)cn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 90.1 %

Procedure:
Tetrakis-(triphenylphosphine)palladium(0) (5 mol %, 62.3 mg) was added to a solution of (6-chloropyridin-3-yl)methyl acetate (200 mg) in DME (10 mL) and the solution left to stir at room temperature (20 min.). K2CO3 (0.16 g, 1.1 eq.), water (3 mL) and 2,4,6-trivinylcyclotriboroxane-pyridine complex (0.29 g, 1.1 eq.) were then added to the solution and the resultant mixture heated at reflux (24 hrs). The mixture was then cooled to room temperature and extracted with diethyl ether (100 mL) and the extract washed with water (30 mL). The diethyl ether extract was dried over MgSO4 and then diluted with hexane (100 mL). The solution was filtered through aluminium oxide (2 g) and the eluent concentrated in vacuo to give a yellow oil. The oil was purified by silica gel chromatography (10-80% EtOAc/Pet ether) to yield (6-vinylpyridin-3-yl)methyl acetate as a colourless oil (172 mg, 90%). 1H NMR, 400 MHz (CDCl3): 9.16 (d, 1H, H-6, J=2.3 Hz), 8.24 (dd, 1H, H-4, J=2.3 and 8 Hz), 7.39 (d, 1H, H-3, J=8 Hz), 6.85 (dd, 1H, H-A, J=11 and 17.6 Hz), 6.33 (dd, 1H, H-C, J=1.2 and 17.6 Hz), 5.61 (1H, H-B, J=1.2 and 11 Hz), 4.40 (m, 2H, —CH2), 1.40 (m, 3H, —OCH3). 13C NMR, 100 MHz (CDCl3): 165.23, 159.07, 150.79, 137.56, 136.18, 124.72, 120.91, 120.62, 61.28, 14.25. ESI-HRMS Expected for C10H11NO2=177.0790. Found M+H=178.0868.