Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:11][CH:12]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:13]([O:16][CH3:17])[O:14][CH3:15])=O)C1C=CC=CC=1.[ClH:24].O1CCOCC1>CO.[H][H].[Pd]>[ClH:24].[CH3:17][O:16][CH:13]([O:14][CH3:15])[CH:12]([NH2:11])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(OC)C(NC(=O)OCc1ccccc1)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(OC)C(N)c1ccccc1
Yield: 91 %

Procedure:
1-Benzyloxycarbonylamino-2,2-dimethyloxy-1-phenylethane (1.21 g, 3.84 mmol) was dissolved in methanol (38.4ml), and 4 N hydrogen chloride/1,4-dioxane (0.96 ml, 3.84 mmol) and palladium black (121 mg) were added to it and hydrogenolyzed overnight at room temperature in hydrogen atmosphere. After the palladium black was removed by filtration, the filtrate was concentrated under reduced pressure, and methylene chloride and diethyl ether were added to the resulting residue. The precipitated solid was collected by filtration whereby the title compound (760.3 mg, 91% yield) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])/[CH:5]=[CH:6]/[CH:7]1[CH:14]2[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:16][CH:8]1[CH2:9]3)[CH2:13]2)[CH3:2].C(OC(=O)/C=C\C1C2CC3CC(CC1C3)C2)C.[H][H]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH2:6][CH:7]1[CH:8]2[CH2:9][CH:10]3[CH2:11][CH:12]([CH2:13][CH:14]1[CH2:15]3)[CH2:16]2)[CH3:2]
Reactant: CCOC(=O)/C=C/C1C2CC3CC(C2)CC1C3
Reactant: [H][H]
Agent: [Pd]
Agent: CCOC(=O)/C=C\C1C2CC3CC(C2)CC1C3
Solvent: CCOC(C)=O
Product: CCOC(=O)CCC1C2CC3CC(C2)CC1C3

Procedure:
The mixture of (E)-3-tricyclo[3.3.1.1-3,7]dec-2-yl-2-propenoic acid ethyl ester and (Z)-3-tricyclo[3.3.1.1-3,7]dec-2-yl-2-propenoic acid ethyl ester (0.018 mol, 4.23 g), dissolved in ethyl acetate (500 mL) was hydrogenated over 10% Pd/C catalyst (450 mg), (1 atm H2) with vigorous stirring until the uptake of hydrogen ceased (1 h). The reaction mixture was filtered through a pad of celite, and the filtrate dried (Na2SO4) and concentrated in vacuo to provide tricyclo[3.3.1.1-3,7]decane-2-propanoic acid ethyl ester as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.[C:22](Cl)(=[O:25])[CH:23]=[CH2:24]>CCOCC>[CH2:1]([O:3][C:4]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]1[C:22](=[O:25])[CH:23]=[CH2:24])=[O:5])[CH3:2]
Reactant: C=CC(=O)Cl
Reactant: CCOC(=O)C1Cc2ccccc2N1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=CC(=O)N1c2ccccc2CC1C(=O)OCC
Yield: 78.3 %

Procedure:
To a chilled and stirred mixture of 2,3-dihydroindole-2-carboxylic acid ethyl ester (14.34 g.), triethylamine (7.65 g.) and anhydrous ether (600 ml.) was added dropwise acryloyl chloride (7.1 g.) dissolved in a small amount of ether. The ice bath was removed, and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was chilled in ice, then a precipitate was removed by filtration. The filter residue was washed with ether. The combined filtrate and washing were washed with water, then with saline, and dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure on a rotary evaporator gave the titled compound (14.4 g.) as an oil.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][NH:12][CH3:13].C(N(CC)CC)C>C(Cl)Cl>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:12]([CH3:13])[CH3:11])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: CNC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)c1ccc(I)cc1

Procedure:
The title compound is prepared in analogy to example 16a from 4-iodobenzoyl chloride, N,N-dimethylamine and triethylamine in CH2Cl2 as a yellowish oil, MS (ESI) 276.0 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([O:22][CH2:23][C:24](OCC)=[O:25])[CH:12]=[C:13]([O:15][CH2:16][C:17](OCC)=[O:18])[CH:14]=1.C(OCC)(=O)C.S([O-])(O)(=O)=O.[K+]>O1CCCC1>[CH3:7][O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][CH2:17][OH:18])[CH:12]=[C:11]([O:22][CH2:23][CH2:24][OH:25])[CH:10]=1
Reactant: CCOC(=O)COc1cc(OC)cc(OCC(=O)OCC)c1
Agent: O=S(=O)([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(OCCO)cc(OCCO)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 136.9 %

Procedure:
10 ml of lithium aluminium hydride (1 M in tetrahydrofuran) are introduced into a three-necked flask under argon. After having cooled the solution to 0° C., 1.0 g (3.2 mmol) of diethyl 2,2′-[(5-methoxy-1,3-phenylene)bis(oxy)]diacetate in solution in 6 ml of tetrahydrofuran is added. The formation of a white precipitate is observed. After stirring for one hour at ambient temperature, ethyl acetate is slowly added at 0° C. The mixture is poured into a saturated aqueous solution of potassium hydrogen sulphate and the mixture is extracted with ethyl acetate. The organic phase is washed with a saturated solution of sodium chloride and dried over sodium sulphate, then concentrated to dryness. 1.0 g (78%) of a white powder is obtained.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[C:14]([CH2:15][C:16]2[CH:24]=[CH:23][C:19]([N:20]([CH3:22])[CH3:21])=[CH:18][CH:17]=2)=[C:13]([Cl:25])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([I:26])[CH:11]=2)[N:6]=1>C1(C)C=CC=CC=1>[Cl:25][C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([I:26])[CH:11]=2)[N:6]=[C:5]([O:2][CH3:1])[C:14]=1[CH2:15][C:16]1[CH:24]=[CH:23][C:19]([N:20]([CH3:22])[CH3:21])=[CH:18][CH:17]=1
Reactant: CN(C)c1ccc(Cc2c(Cl)nc3ccc(I)cc3c2Cl)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1nc2ccc(I)cc2c(Cl)c1Cc1ccc(N(C)C)cc1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
Sodium methoxide (2.9 g, 54 mmol) was added to a solution of 4-((2,4-dichloro-6-iodoquinolin-3-yl)methyl)-N,N-dimethylaniline (3.5 g, 7.7 mmol, Intermediate 24: step b) in toluene (38 mL) with stirring. The mixture was heated to 110° C. After 3 hours, additional sodium methoxide (2 g, 37.2 mmol) was added. After 18 hours, the flask was allowed to cool to 50° C. The warm mixture was filtered through Celite®, rinsing with tetrahydrofuran. Silica gel (5 g) was added to the filtrate and the solvent was removed by rotary evaporation to afford a free-flowing powder. The powder was loaded onto a column of silica gel for purification. Elution with dichloromethane initially, grading to 1% methanol-dichloromethane provided the title compound as a solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([Br:16])=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:17])[C:10]=1[Br:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(OCc2ccccc2)c1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cccc(OCc2ccccc2)c1Br
Reaction time: 8 h
Yield: 99.3 %

Procedure:
To a mixture of 3-(benzyloxy)-2-bromophenol (2.55 g, 9.14 mmol) in DMF (8 mL) was added K2CO3 (1.894 g, 13.70 mmol) and MeI (0.63 mL, 10.05 mmol) at RT. The reaction mixture was stirred overnight then quenched with water and diluted with EtOAc. The organic phase was washed with water (3×), brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (EtOAc/Heptane) to afford the title compound as a colorless oil (2.66 g, 99% yield). 1H NMR (CHLOROFORM-d) δ 7.49 (d, J=7.1 Hz, 2H), 7.36-7.43 (m, 2H), 7.30-7.35 (m, 1H), 7.20 (t, J=8.3 Hz, 1H), 6.56-6.65 (m, 2H), 5.18 (s, 2H), 3.92 (s, 3H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.Cl[CH2:14][N:15]1[CH2:19][CH:18]([CH2:20][CH2:21][CH3:22])[CH2:17][C:16]1=[O:23].O>CN(C=O)C>[Cl:3][C:4]1[N:5]([CH2:14][N:15]2[CH2:19][CH:18]([CH2:20][CH2:21][CH3:22])[CH2:17][C:16]2=[O:23])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: Clc1cc2ccccc2[nH]1
Reactant: CCCC1CC(=O)N(CCl)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC1CC(=O)N(Cn2c(Cl)cc3ccccc32)C1
Temperature: -20 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
At −78° C., NaH (60% in mineral oil; 220 mg, 5.52 mmol, 1.1 eq) is added to a solution of 2-chloro-1H-indole x160 (0.76 g, 5.02 mmol, 1 eq) in dry DMF (50 ml). The temperature is raised to −20° C. during 20 minutes, then 1-(chloromethyl)-4-propylpyrrolidin-2-one x63 (0.76 g, 5.02 mmol, 1 eq) dissolved in DMF (10 ml) is added drop wise. After 2 hours at room temperature, water (50 ml) is added. The aqueous layer is extracted with CH2Cl2 (3×30 ml). The combined organic layers are dried on anhydrous MgSO4, filtered off and concentrated under reduced pressure to obtain a liquid that is purified on silicagel (AcOEt/Benzine 1/9) yielding 1-[(2-chloro-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one 274 as a colorless liquid (605 mg).
Reaction SMILES: F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[NH+]([O-])N1)C.[CH:25]1([C:28]([OH:30])=O)[CH2:27][CH2:26]1.C(N(C(C)C)CC)(C)C.FC(F)(F)C([O-])=O.[Cl:47][C:48]1[CH:65]=[CH:64][CH:63]=[C:62]([Cl:66])[C:49]=1[CH2:50][O:51][C:52]1[CH:53]=[CH:54][C:55]2[N:59]=[C:58]([NH3+:60])[NH:57][C:56]=2[CH:61]=1>CN(C)C=O>[Cl:47][C:48]1[CH:65]=[CH:64][CH:63]=[C:62]([Cl:66])[C:49]=1[CH2:50][O:51][C:52]1[CH:53]=[CH:54][C:55]2[N:59]=[C:58]([NH:60][C:28]([CH:25]3[CH2:27][CH2:26]3)=[O:30])[NH:57][C:56]=2[CH:61]=1
Reactant: [NH3+]c1nc2ccc(OCc3c(Cl)cccc3Cl)cc2[nH]1
Reactant: O=C(O)C1CC1
Agent: CN(C)C(N(C)C)=[N+]1N[NH+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nc2ccc(OCc3c(Cl)cccc3Cl)cc2[nH]1)C1CC1
Temperature: 20 °C
Yield: 28.7 %

Procedure:
a solution of 270 mg of 1-[bis(dimethylamino)methylidene]-2,3-dihydro-1H-[1,2,3]triazolo[4,5-b]pyridin-1-ium-3-oxide hexafluorophosphate, 61 mg of cyclopropanecarboxylic acid and 176 mg of diisopropylethylamine in 40 cm3 of N,N-dimethylformamide is stirred for one hour at a temperature close to 20° C. Then 250 mg of 6-[(2,6-dichlorobenzyl)oxy]-1H-benzimidazol-2-aminium trifluoroacetate is added and the orange solution obtained is stirred for about twenty hours at about 20° C. After concentration under reduced pressure (0.2 kPa), the residue is taken up in 40 cm3 of water and the mixture obtained is extracted three times with 40 cm3 of ethyl acetate. The combined organic phases are washed three times with 40 cm3 of water, then dried over magnesium sulphate, filtered and concentrated under reduced pressure. After purification of the residue by flash chromatography on silica [eluent: dichloromethane/methanol (95/5 by volume)], we obtain 64 mg of N-{6-[(2,6-dichlorobenzyl)oxy]-1H-benzimidazol-2-yl}cyclopropanecarboxamide in the form of a white powder, which has the following characteristics:
Reaction SMILES: [OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.Br[C:24]1[CH:25]=[CH:26][C:27]([CH3:34])=[C:28]([S:30]([NH2:33])(=[O:32])=[O:31])[CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(O)C>[CH3:34][C:27]1[CH:26]=[CH:25][C:24]([C:8]2[CH:9]=[CH:10][C:5]([O:4][C@@H:3]([CH3:14])[C@H:2]([OH:1])[CH2:15][CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:6][CH:7]=2)=[CH:29][C:28]=1[S:30]([NH2:33])(=[O:32])=[O:31]
Reactant: Cc1ccc(Br)cc1S(N)(=O)=O
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(-c2ccc(O[C@@H](C)[C@H](O)CCc3cccnc3)cc2)cc1S(N)(=O)=O
Temperature: 80 °C
Yield: 35.3 %

Procedure:
Prepared according to the method described in Example 12b) from (1S,2R)-4-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy)benzeneboronic acid (0.2g, Example 33), 5-bromo-2-methylbenzenesulfonic acid amide (1.7 g, Example 78a), ethanol (3 ml), 2M aqueous sodium carbonate (0.7 ml) and tetrakis(triphenylphosphine)palladium (0) (0.03 g) with heating at 80° C. for 3 hours. After work-up, the residue was purified by normal-phase HPLC eluting with a gradient of 0-25% ethanol in dichloromethane to give the title compound as a foam (0.10 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]3[CH:34]=[CH:33][C:23]([CH2:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])=[CH:22][CH:21]=3)[N:10]=2)=[C:4]([C:35](=[O:38])[NH:36][CH3:37])[CH:3]=1.C([Si](C)(C)[O:44][CH:45]1[CH2:48][CH:47]([N:49]2[CH:53]=[C:52](B3OC(C)(C)C(C)(C)O3)[CH:51]=[N:50]2)[CH2:46]1)(C)(C)C>>[OH:44][CH:45]1[CH2:48][CH:47]([N:49]2[CH:53]=[C:52]([C:2]3[CH:7]=[CH:6][C:5]([NH:8][C:9]4[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]5[CH:21]=[CH:22][C:23]([CH2:24][P:25](=[O:32])([O:26][CH2:27][CH3:28])[O:29][CH2:30][CH3:31])=[CH:33][CH:34]=5)[N:10]=4)=[C:4]([C:35](=[O:38])[NH:36][CH3:37])[CH:3]=3)[CH:51]=[N:50]2)[CH2:46]1
Reactant: CC1(C)OB(c2cnn(C3CC(O[Si](C)(C)C(C)(C)C)C3)c2)OC1(C)C
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)cc3C(=O)NC)n2)cc1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(C5CC(O)C5)c4)cc3C(=O)NC)n2)cc1)OCC
Temperature: 25 °C

Procedure:
The title compound was prepared using the procedure from Example 97 with Diethyl (4-{[4-{[4-bromo-2-(methylcarbamoyl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate (Example 106) and 1-[3-(tert-butyl-dimethyl-silanyloxy)-cyclobutyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (Compound 100A). After Suzuki reaction and SPE pre-purification, dried material was dissolved in DCM and 1.0 M HCl in ether was added. The mixture was stirred at room temperature for half an hour. The crude was sent to MDP for purification. MS (ES+): m/z 674.34 (100) [MH+]; HPLC: tR=0.94 min (UPLC, purity).
Reaction SMILES: [C:1]1(=O)[CH:8]2[N:4]3[CH2:5][CH:6]([CH2:9][CH:2]1[CH2:3]3)[CH2:7]2.Cl.[CH2:12]([O:19][NH2:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>N1C=CC=CC=1.C(O)C>[C:13]1([CH2:12][O:19][N:20]=[C:1]2[CH:8]3[N:4]4[CH2:5][CH:6]([CH2:9][CH:2]2[CH2:3]4)[CH2:7]3)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1C2CC3CC1N(C3)C2
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: c1ccc(CON=C2C3CC4CC2N(C4)C3)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Hexahydro-2,6-methano-1H-pyrrolizin-1-one (N. Speckamp, Tetrahedron, 27, 3143 (1971)), 1.45 g, 11.0 mmol, was dissolved in a 1:1 solution of pyridine/ethanol (20 mL). O-Benzyl hydroxylamine hydrochloride (1.85 g, 11.6 mmol) was added and the solution was stirred for 20 hours at room temperature. Removal of the solvents in vacuo afforded a solid which was purified by chromatography on silica gel eluting with 10% MeOH (NH3)/CHCl3 to give hexahydro-1-[(phenylmethoxy) imino]-2,6-methano-1H-pyrrolizine.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][N:7]2[C:12](=[O:25])[CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[CH3:24].[OH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:24][C:18]1[C:19]([CH3:23])=[CH:20][CH:21]=[CH:22][C:17]=1[O:16][CH2:15][CH2:14][CH2:13][C:12]([N:7]1[C:8]2[C:3](=[C:2]([C:31]3[CH:32]=[CH:33][C:28]([CH2:27][OH:26])=[CH:29][CH:30]=3)[CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:5][CH2:6]1)=[O:25]
Reactant: OCc1ccc(B(O)O)cc1
Reactant: Cc1cccc(OCCCC(=O)N2CCCc3c(Br)cccc32)c1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4ccc(CO)cc4)cccc32)c1C
Temperature: 90 °C
Reaction time: 16 h
Yield: 93.2 %

Procedure:
To a degassed solution of 1-(5-bromo-3,4-dihydroquinolin-1(2H)-yl)-4-(2,3-dimethylphenoxy)butan-1-one (0.216 g, 0.537 mmol), 4-(hydroxymethyl)phenylboronic acid (0.122 g, 0.805 mmol) and potassium carbonate (0.223 g, 1.611 mmol) in dioxane (3.00 mL)/water (1.20 mL) was added tetrakis(triphenylphosphine)palladium (0.016 g, 0.013 mmol). Upon completion of addition, the vial was purged with argon, sealed and stirred at 90° C. for 16 h. After this time, the reaction mixture was partitioned between water and EtOAc, and the organic layer was separated. The aqueous phase was extracted with EtOAc and the combined organic layer was dried over anhydrous MgSO4, filtered, and concentrated in vacuo to provide the crude material. The crude material was purified by flash chromatography (0-50% ethyl acetate:hexanes) to afford the title compound (0.215 g, 93% yield) as a clear colorless oil. LCMS, [M+H]+=430.2.
Reaction SMILES: [C:1]([C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:9]([CH3:26])[NH:8][C:7]=1[CH2:27][SH:28])([O:3][CH2:4][CH3:5])=[O:2].S(C1(O)C=CC=CC1C(O)=O)(O)(=O)=O.[CH3:43][O:44][C:45](OC)([CH3:47])[CH3:46]>>[C:1]([C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:9]([CH3:26])[NH:8][C:7]=1[CH2:27][S:28][C:45]([O:44][CH3:43])([CH3:47])[CH3:46])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: COC(C)(C)OC
Reactant: CCOC(=O)C1=C(C)NC(CS)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Agent: O=C(O)C1C=CC=CC1(O)S(=O)(=O)O
Product: CCOC(=O)C1=C(C)NC(CSC(C)(C)OC)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2 g of 3,5-dicarboethoxy-6-methyl-2-(mercaptome-thyl) -4-(m-nitrophenyl)-1,4-dihydropyridine (4,92 mmol.) and 20 mg of 2-sulphosalicylic acid bihydrate (0,049 mmol.) are dissolved in 20 ml of 2,2-dimethoxypropane. The solution is stirred for 2 hours at room temperature, then the solvent is evaporated under reduced pressure. The residue is dissolved in ethyl acetate, washed with a NaHCO3 solution (5%, 2×10 ml) and water (3×20 ml), dried on Na2SO4 and evaporated at reduced pressure. 1.8 g of 3,5-dicarboethoxy-6-methyl-2-[2-methoxyprop-2-yl-thiomethyl]-4-(m-nitrophenyl)-1,4-dihydropyridine (thick yellow oil) are obtained.
Reaction SMILES: [CH3:1][NH2:2].Br[CH2:4][C:5]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:6]=1[C:7](OCC)=[O:8]>CO>[CH3:17][O:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:5]2[C:6]=1[C:7](=[O:8])[N:2]([CH3:1])[CH2:4]2
Reactant: CN
Reactant: CCOC(=O)c1c(CBr)cccc1OC
Solvent: CO
Product: COc1cccc2c1C(=O)N(C)C2
Temperature: 0 °C
Reaction time: 5 h
Yield: 47 %

Procedure:
A solution of methylamine (2 M in methanol) at 0° C. was added dropwise to a solution of 14.82 g of ethyl 2-bromomethyl-6-methoxybenzoate in methanol and the reaction medium was stirred for 5 hours at 0° C. and left to stir at ambient temperature for 2 days. The solvent was evaporated off and 30 ml of a saturated sodium hydrogen carbonate solution were added to the residue. The product was extracted with ethyl acetate (3×50 ml). The organic phases were combined, dried over magnesium sulfate and evaporated. The residue was purified by chromatography on silica gel. 4.52 g of 7-methoxy-2-methyl-2,3-dihydroisoindol-1-one were obtained. Yield=47%.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]1([C:16]#[C:17][CH2:18][CH2:19][CH2:20][OH:21])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.O>ClCCl>[CH3:1][S:2]([O:21][CH2:20][CH2:19][CH2:18][C:17]#[C:16][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: OCCCC#Cc1cccc2ccccc12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)OCCCC#Cc1cccc2ccccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 102 %

Procedure:
A solution of 0.85 g (7.42 mmol) of methanesulphonyl chloride in 5 ml of dichloromethane is added dropwise to a solution, cooled with an ice bath, of 1.2 g (5.71 mmol) of 5-(naphth-1-yl)pent-4-yn-1-ol, obtained in stage 3.1., and of 1.6 ml (11.4 mmol) of triethylamine in 12 ml of dichloromethane. The mixture is stirred at 0° C. for 1 hour and then at ambient temperature for 2 hours. 25 ml of water and 75 ml of dichloromethane are subsequently added. The organic phase is separated by settling and is washed with 25 ml of water and then with 25 ml of a saturated aqueous sodium chloride solution. It is dried over magnesium sulphate and evaporated to dryness to produce 1.68 g of product in the form of an orange oil used directly in the following stage.
Reaction SMILES: [N+:1]([C:4]1[C:14]2[CH2:13][NH:12][CH2:11][CH2:10][NH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:15](OC(=O)C)(=[O:17])[CH3:16].O>ClCCl>[N+:1]([C:4]1[C:14]2[CH2:13][N:12]([C:15](=[O:17])[CH3:16])[CH2:11][CH2:10][NH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1cccc2c1CNCCN2
Solvent: ClCCl
Solvent: O
Product: CC(=O)N1CCNc2cccc([N+](=O)[O-])c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.9 %

Procedure:
6-Nitro-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (140 mg, 0.74 mmol) was dissolved in dichloromethane (5 mL) and the mixture was treated with acetic anhydride (0.16 mL, 1.68 mmol). The reaction was then allowed to stir overnight at room temperature. The reaction mixture was then poured over water (10 mL) and organics were extracted with dichloromethane (3×10 mL). Combined organics were dried over Na2SO4, filtered and reduced. The crude product was then isolated and purified by flash column chromatography (0% MeOH/DCM-10% MeOH/DCM) to afford 120 mg of 1-(6-Nitro-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-ethanone as a yellow oil. LC/MS (ESI)=236.30 (M+H). 1H NMR (400 MHz, CDCl3) δ 7.26 (m, 2H), 7.07 (d, 1H, J=8.08 Hz), 6.86 (d, 1H, J=8.34 Hz), 5.95 (s, 1H), 4.64 (s, 2H), 3.55 (q, 2H, J=5.56 Hz), 3.33 (t, 2H, J=5.56 Hz), 1.97 (s, 3H).
Reaction SMILES: C([NH:5][S:6]([CH2:9][N:10]1[C:18](=[O:19])[C:17]2[N:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[C:15]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]([F:39])([F:38])[F:37])[CH:30]=3)=[N:14][C:13]=2[N:12]([CH3:40])[C:11]1=[O:41])(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][N:16]2[C:17]3[C:18](=[O:19])[N:10]([CH2:9][S:6]([NH2:5])(=[O:8])=[O:7])[C:11](=[O:41])[N:12]([CH3:40])[C:13]=3[N:14]=[C:15]2[O:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]([F:37])([F:39])[F:38])[CH:30]=2)=[CH:26][CH:25]=1
Reactant: Cn1c(=O)n(CS(=O)(=O)NC(C)(C)C)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(=O)n(CS(N)(=O)=O)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Yield: 72.4 %

Procedure:
A solution of N-tert-butyl-1-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)methanesulfonamide (120 mg, 0.195 mmol, example 71) in TFA (2 ml, 26.9 mmol) was stirred at 50° C. for 16 h. The mixture was concentrated and then purified by silica gel chromatography eluting with DCM/methanol (40:1) to give (7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)methanesulfonamide (79 mg, 72.4% yield) as white solid. 1H-NMR (DMSO-d6) δ 7.65-7.61(t, 1H), 7.49(s, 1H), 7.47-7.41(m, 6H), 7.36-7.35(d, 1H), 7.05(s, 2H), 5.45(s, 2H), 5.23(s, 2H), 3.31(s, 3H). LCMS retention time 3.004 min; LCMS MH+ 560.