Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([OH:18])=O)[CH:14]=2)[CH:9]=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[C:20]([N:24]1[CH:32]=[C:31]2[C:26]([C:27](=[O:38])[NH:28][C:29]3([CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[CH2:30]2)=[N:25]1)([CH3:23])([CH3:22])[CH3:21].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>CN(C)C=O>[C:20]([N:24]1[CH:32]=[C:31]2[C:26]([C:27](=[O:38])[NH:28][C:29]3([CH2:37][CH2:36][N:35]([C:16]([C:13]4[CH:14]=[C:15]5[C:10]([CH:9]=[CH:8][N:7]=[C:6]5[NH:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:11][CH:12]=4)=[O:18])[CH2:34][CH2:33]3)[CH2:30]2)=[N:25]1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)n1cc2c(n1)C(=O)NC1(CCNCC1)C2
Reactant: CC(C)(C)Nc1nccc2ccc(C(=O)O)cc12
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)Nc1nccc2ccc(C(=O)N3CCC4(CC3)Cc3cn(C(C)(C)C)nc3C(=O)N4)cc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 12.4 %

Procedure:
To a suspension of 1-(tert-butylamino)isoquinoline-7-carboxylic acid (24.7 mg, 0.101 mmol) and 2′-tert-butyl-4′,6′-dihydrospiro[piperidine-4,5′-pyrazolo[3,4-c]pyridine]-7′(2′H)-one hydrochloride salt (33.9 mg, 0.101 mmol) in N,N-dimethylformamide (1 mL) was added triethylamine (0.07 mL, 0.50 mmol). The reaction mixture was stirred at room temperature for 10 minutes. Then 1-propanephosphonic acid cyclic anhydride (0.07 mL, 0.12 mmol, 50% solution in ethyl acetate) was added and the reaction mixture was stirred at room temperature overnight. N,N-dimethylformamide was removed under reduced pressure and the residue was purified by reversed-phase HPLC to give 2′-(tert-butyl)-1-(1-(tert-butylamino)isoquinoline-7-carbonyl)-4′,6′-dihydrospiro[piperidine-4,5′-pyrazolo[3,4-c]pyridin]-7′(2′H)-one (6.1 mg, 24%). +ESI (m+H) 489.3; HPLC retention time 2.94 minutes (Method B).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C1([O:11][C:12](=O)[NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([C:22]3[C:30]4[C:29]([NH2:31])=[N:28][CH:27]=[N:26][C:25]=4[N:24]([CH:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)[CH:23]=3)=[O:21])[CH:15]=2)C=CC=CC=1>C1COCC1>[NH2:31][C:29]1[C:30]2[C:22]([C:20]([C:16]3[CH:15]=[C:14]([NH:13][C:12]([NH:4][CH:1]4[CH2:3][CH2:2]4)=[O:11])[CH:19]=[CH:18][CH:17]=3)=[O:21])=[CH:23][N:24]([CH:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)[C:25]=2[N:26]=[CH:27][N:28]=1
Reactant: NC1CC1
Reactant: Nc1ncnc2c1c(C(=O)c1cccc(NC(=O)Oc3ccccc3)c1)cn2C1CCCC1
Solvent: C1CCOC1
Product: Nc1ncnc2c1c(C(=O)c1cccc(NC(=O)NC3CC3)c1)cn2C1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
Cyclopropyl amine (130 mg, 2.3 mmol) was added to a solution of [3-(4-Amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-carbamic acid phenyl ester (50 mg, 0.11 mmol) in THF (3 mL). The reaction mixture was stirred at room temperature for 2 h and concentrated in vacuo. Purification by flash column chromatography (silica, 4:96→15:85 MeOH:CH2Cl2) provided the title compound as a pale yellow solid (44 mg, 95%). MS: 405.2 (MH+); HPLC Rf: 4.73 min. (HPLC method 4); HPLC purity: 100%.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][N:3]=1.[CH3:13][CH2:14][O:15][C:16]([CH:18]([C:22](OCC)=[O:23])[C:19]([CH3:21])=O)=[O:17]>C(O)(=O)C>[OH:23][C:22]1[N:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:6]=[C:2]2[N:1]=[C:19]([CH3:21])[C:18]=1[C:16]([O:15][CH2:14][CH3:13])=[O:17]
Reactant: Nc1cc(-c2ccccc2)[nH]n1
Reactant: CCOC(=O)C(C(C)=O)C(=O)OCC
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C)nc2cc(-c3ccccc3)nn2c1O
Temperature: 120 °C
Reaction time: 3 h
Yield: 93700.2 %

Procedure:
3-Amino-5-phenylpyrazole (1.56 mg) and diethyl acetomalonate (2.00 g) were dissolved in acetic acid (5.0 ml) and stirred for 3 hours at 120° C. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Ethanol was added to the residue which were then cooled to 0° C. Precipitated crystals were collected by filtration and washed with cold ethanol. The crystals were dried under reduced pressure to give ethyl 7-hydroxy-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidine-6-carboxylate (2.73 g, Y.:92%) as white crystals.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[CH:12][N:13]([C:15]([N:17]([CH3:24])[CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:16])[CH:14]=2)=[CH:6][CH:5]=1.CC(C)([O-])C.[K+].[N:31]#[C:32]Br>CN(C=O)C>[C:32]([N:21]1[CH2:22][CH2:23][CH:18]([N:17]([CH3:24])[C:15]([N:13]2[CH:14]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=3)[N:11]=[CH:12]2)=[O:16])[CH2:19][CH2:20]1)#[N:31]
Reactant: N#CBr
Reactant: COc1ccc(-c2cn(C(=O)N(C)C3CCNCC3)cn2)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2cn(C(=O)N(C)C3CCN(C#N)CC3)cn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(4-methoxyphenyl)-N-methyl-N-(piperidin-4-yl)-1H-imidazole-1-carboxamide hydrochloride (287 mg, 0.818 mmol) in DMF (5 mL) was added potassium tert-butoxide (184 mg, 1.636 mmol) and the mixture was allowed to stir at room temperature for 30 minutes, whereupon it was cooled in an ice/water bath and cyanogen bromide (0.818 mL, 2.454 mmol, 3 N dichloromethane solution) was added dropwise over 10-15 minutes. The reaction mixture was allowed to slowly warm up to room temperature over 1 h, and was then partitioned between water and dichloromethane/isopropanol (7:3). The layers were separated and the organic phase was further washed with water and brine, then dried (Na2SO4), filtered and the solvent was removed under reduced pressure. The residue was dissolved in the minimum volume of chloroform and insoluble material was removed by filtration. The filtrate was concentrated to give an off-white solid, (345 mg, 67%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][N:4]=1>CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][N:4]=1
Reactant: COc1cc(/C=C/c2ccccc2)ccn1
Solvent: CO
Product: COc1cc(CCc2ccccc2)ccn1
Reaction time: 24 h
Yield: 98.4 %

Procedure:
(E)-2-Methoxy-4-styrylpyridine (22.15 g, 104.8 mmol) was dissolved in MeOH (400 mL) and degassed with a nitrogen stream for 10 minutes. Palladium on charcoal (10%, wet, 5 g) was added and the reaction mixture was stirred under an atmosphere of hydrogen for 24 h. The reaction mixture was degassed again, and the catalyst was removed by filtration. Concentration of the filtrate provided the title compound (22 g, 98%) as a green oil: 1H NMR (500 MHz, CDCl3) δ 8.04 (d, J=5.3 Hz, 1H), 7.29-7.24 (m, 2H), 7.21-7.15 (m, 3H), 6.69-6.67 (m, 1H), 6.54 (s, 1H), 3.91 (s, 3H), 2.91-2.89 (m, 2H), 2.87-2.84 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4](=O)[C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[Cl:14])[CH2:10][C:9]([CH2:16][CH3:17])([CH3:15])[CH2:8]2.[H][H]>CO.S(=O)(=O)(O)O.[Pt](=O)=O>[CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[Cl:14])[CH2:10][C:9]([CH2:16][CH3:17])([CH3:15])[CH2:8]2
Reactant: [H][H]
Reactant: CCC1(C)Cc2cc(Cl)c(C(=O)C(=O)OC)cc2C1
Agent: O=[Pt]=O
Agent: O=S(=O)(O)O
Solvent: CO
Product: CCC1(C)Cc2cc(Cl)c(CC(=O)OC)cc2C1

Procedure:
A solution of 5.2 g of 2-ethyl-6-chloro-2-methyl-α-oxo-5-indanacetic acid methyl ester in 100 cc of methanol and 10 cc of concentrated sulphuric acid is hydrogenated at 45° and a hydrogen pressure of 5 atmospheres with the addition of 1.0 g of platinum(IV) oxide. After the take up of the theoretic amount of hydrogen the catalyst is filtered off, the solution is diluted with a 5% sodium bicarbonate solution and extracted with ether. The extract is washed with water, dried over sodium sulphate and concentrated by evaporation. The resulting title compound is purified by chromatography. Thin layer chromatogram: Rf value 0.60 (adsorbent: silica gel, eluant: chloroform).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[C:11]([O:23][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)[C:10]=1[C:33](=O)[CH2:34][C:35](=O)[C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:44][NH2:45]>C(O)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:12]=[C:11]([O:23][C:24]2[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=2)[C:10]=1[C:33]1[CH:34]=[C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[NH:45][N:44]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCOC(=O)C(=O)CC(=O)c1c(OCc2ccccc2)cc(OCc2ccccc2)cc1Oc1ccc([N+](=O)[O-])cc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(-c2c(OCc3ccccc3)cc(OCc3ccccc3)cc2Oc2ccc([N+](=O)[O-])cc2)n[nH]1
Yield: 69.7 %

Procedure:
A stirred solution of ethyl 4-[2,4-bis(benzyloxy)-6-(4-nitrophenoxy)phenyl]-2,4-dioxobutanoate (1 g, 1.75 mmol) and hydrazine hydrate (0.25 mL, 4.4 mmol) in ethanol (20 mL) was refluxed for 1 hour. The formed precipitate was filtered off and washed with ethanol and dried, to afford the title compound (0.69 g, 70% yield).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1.[F:25][C:26]1[C:36]([F:37])=[CH:35][C:29]2[C:30](=[O:34])[O:31][C:32](=[O:33])[C:28]=2[CH:27]=1>CN(C=O)C.C(OCC)(=O)C>[C:21]([O:20][C:18]([N:5]1[CH2:4][C@@H:3]([CH2:2][NH:1][C:30]([C:29]2[CH:35]=[C:36]([F:37])[C:26]([F:25])=[CH:27][C:28]=2[C:32]([OH:33])=[O:31])=[O:34])[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[O:8][CH2:7][CH2:6]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: O=C1OC(=O)c2cc(F)c(F)cc21
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CN)C1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CNC(=O)c2cc(F)c(F)cc2C(=O)O)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 68.4 %

Procedure:
To a solution of tert-butyl (6R,7R)-6-(aminomethyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (100 mg) in DMF (2 mL) was added 5,6-difluoro-2-benzofuran-1,3-dione (73.6 mg) at room temperature, and the mixture was stirred at 80° C. overnight. The reaction mixture was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (102 mg).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:20][CH2:21][N:22]1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32].CCCCCC>CN(C=O)C.O.CCOC(C)=O>[C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:20][CH2:21][N:22]3[C:23](=[O:32])[C:24]4[C:25](=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:26]3=[O:27])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCN1CCN(c2ccccc2)CC1
Temperature: 80 °C
Yield: 55.6 %

Procedure:
4-phenylpiperazine (4.50 g, 27.74 mmol) was dissolved in 30 ml DMF, then K2CO3 (11.50 g, 83.21 mmol) and N-(2-bromoethyl)phthalimide (8.46 g, 33.28 mmol) were added thereto and stirred at about 80° C. The reaction progress and completion were confirmed using TLC (hexane:EtOAc=1:1). Upon completion of the reaction, water was added to the reaction mixture and then was extracted with CH2Cl2. The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The concentrate was separated by column chromatography (hexane:EtOAc:CH2Cl2=3:1:2) to obtain the titled compound.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([OH:28])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:29]([O:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH3:40])=[CH:34][C:33]=1[CH2:41]O)[CH3:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([O:28][CH2:41][C:33]4[CH:34]=[C:35]([O:38][CH2:39][CH3:40])[CH:36]=[CH:37][C:32]=4[O:31][CH2:29][CH3:30])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1O
Reactant: CCOc1ccc(OCC)c(CO)c1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOc1ccc(OCC)c(COc2cc(-n3cnc4cnc(CO[Si](C)(C)C(C)(C)C)cc43)sc2C(=O)OC)c1

Procedure:
In a similar manner as described for example B31, 1.5 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-hydroxythiophene-2-carboxylate, 0.91 g of (2,5-diethoxyphenyl)methanol, 2.4 g of triphenylphosphine (polymer bound, ˜3 mmol/g) and 1.66 g of di-tert-butyl azodicarboxylate in 40 ml anhydrous dichloromethane yield the title compound.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH3:15].[Br:29][CH:30]=[CH:31][CH2:32]Br>>[Br:29][CH:30]=[CH:31][CH2:32][O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:5]([CH2:4][C:3]2[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:2]=2[F:1])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=2[CH3:15])=[CH:18][CH:19]=1
Reactant: Cc1c(N(Cc2ccc(O)cc2)Cc2ccc(F)cc2F)cccc1[N+](=O)[O-]
Reactant: BrC=CCBr
Product: Cc1c(N(Cc2ccc(OCC=CBr)cc2)Cc2ccc(F)cc2F)cccc1[N+](=O)[O-]

Procedure:
The product from Example 33A and 1,3-dibromo-1-propene were processed as described in Example 33B to provide the title compound.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][C:46]=1[Cl:52]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][C:46]=3[Cl:52])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Clc1ccc(CBr)c(Cl)c1
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3ccc(Cl)cc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(bromomethyl)-2,4-dichlorobenzene and isolated as colorless gum (6.5 mg, 36%). MS (m/e): 441.3 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([O:13][CH3:14])[CH:5]=[CH:4][CH:3]=1.[Br:15]Br.ClC(Cl)(Cl)Cl>O>[Br:15][C:3]1[CH:4]=[CH:5][C:6]([O:13][CH3:14])=[C:7]([C:2]=1[CH3:1])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: BrBr
Reactant: CCOC(=O)c1c(C)cccc1OC
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1c(OC)ccc(Br)c1C
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A mixture of ethyl 6-methyl-2-methoxybenzoate (8.4 g, 43.2 mmol), bromine (6.9 g, 43.2 mmol) and tetrachloromethane (170 ml) is stirred at room temperature for 60 hours. The reaction mixture is poured into water and extracted with ethyl acetate. The organic phase is separated and concentrated. The crude product is obtained as a yellow oil, 10.3 g (87% y) and is used without further purification.
Reaction SMILES: [Br:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[OH:12])=[CH:4][CH:3]=1.Br[CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:22][O:21][C:19](=[O:20])[C:18]1[CH:23]=[CH:24][C:15]([CH2:14][N:8]2[CH:7]=[CH:6][C:5]3[C:10](=[N:11][C:2]([Br:1])=[CH:3][CH:4]=3)[C:9]2=[O:12])=[CH:16][CH:17]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: Oc1nccc2ccc(Br)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cn2ccc3ccc(Br)nc3c2=O)cc1

Procedure:
The alkylation of 7-bromo-1-hydroxy-8-azaisoquinoline (1.00 g, 4.46 mmol) using methyl 4-(bromomethyl)benzoate (1.53 g, 6.69 mmol) and cesium carbonate (2.18 g, 6.69 mmol) in dimethylformamide is carried out as previously described in Example 1, Step (1). The solid is crystallized from hexanes/ethyl acetate 2:1, the white crystals collected by filtration and dried to give the desired product. Step (2): 4-[1-oxo-7-(3-phenyl-prop-1-ynyl)-1H-8-azaisoquinolin-2-ylmethyl]benzoic acid methyl ester
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[CH3:43][CH:44]1[CH2:49][CH2:48][CH2:47][CH2:46][N:45]1[C:50]1[CH:55]=[N:54][CH:53]=[C:52](B2OC(C)(C)C(C)(C)O2)[N:51]=1.I[C:66]1[C:74]2[C:69](=[CH:70][CH:71]=[C:72]([C:75]3[O:79][C:78]([NH:80][CH2:81][C:82]4[CH:87]=[CH:86][C:85]([O:88][CH3:89])=[CH:84][CH:83]=4)=[N:77][N:76]=3)[CH:73]=2)[N:68]([S:90]([C:93]2[CH:99]=[CH:98][C:96]([CH3:97])=[CH:95][CH:94]=2)(=[O:92])=[O:91])[CH:67]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:89][O:88][C:85]1[CH:86]=[CH:87][C:82]([CH2:81][NH:80][C:78]2[O:79][C:75]([C:72]3[CH:73]=[C:74]4[C:69](=[CH:70][CH:71]=3)[N:68]([S:90]([C:93]3[CH:94]=[CH:95][C:96]([CH3:97])=[CH:98][CH:99]=3)(=[O:91])=[O:92])[CH:67]=[C:66]4[C:52]3[CH:53]=[N:54][CH:55]=[C:50]([N:45]4[CH2:46][CH2:47][CH2:48][CH2:49][CH:44]4[CH3:43])[N:51]=3)=[N:76][N:77]=2)=[CH:83][CH:84]=1
Reactant: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(I)cn4S(=O)(=O)c3ccc(C)cc3)o2)cc1
Reactant: CC1CCCCN1c1cncc(B2OC(C)(C)C(C)(C)O2)n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3cncc(N5CCCCC5C)n3)cn4S(=O)(=O)c3ccc(C)cc3)o2)cc1
Temperature: 120 °C
Yield: 53 %

Procedure:
K3PO4 (327 mg, 1.539 mmol) (Reidel-de Haen), XPhos (14.67 mg, 0.031 mmol) (Strem), Pd2(dba)3 (14.09 mg, 0.015 mmol) (Strem), 2-(2-methylpiperidin-1-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazine (194 mg, 0.641 mmol) (CombiPhos Catalysts Inc.) and 5-(3-iodo-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-oxadiazol-2-amine (308 mg, 0.513 mmol) were weighed into a 5 mL glass microwave tube. The tube was purged with argon and the contents were treated with dioxane (3.0 mL) and water (0.5 mL). The tube was sealed and the suspension was heated at 120° C. for 10 min in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden). An additional 50 mg of the boronic ester were added, the tube was sealed and the mixture was heated at 120° C. for an additional 10 min. The mixture was treated with 1N NaOH and extracted with EtOAc (50 mL). The organic layer was dried over MgSO4, filtered and concentrated. Purification by flash chromatography (eluent: 20% MeOH in DCM) afforded N-(4-methoxybenzyl)-5-(3-(6-(2-methylpiperidin-1-yl)pyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (177 mg, 0.272 mmol, 53.1%) as a dark yellow solid. MS (ESI, pos. ion) m/z: 650.0 (M+1).
Reaction SMILES: CON(C)[C:4](=[O:18])[CH:5]([O:16][CH3:17])[C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[N:11]2.[Br:20][C:21]1[C:26]([O:27][CH3:28])=[CH:25][C:24]([C:29]2[O:30][CH:31]=[CH:32][CH:33]=2)=[CH:23][C:22]=1[O:34][CH3:35]>>[Br:20][C:21]1[C:22]([O:34][CH3:35])=[CH:23][C:24]([C:29]2[O:30][C:31]([C:4](=[O:18])[CH:5]([O:16][CH3:17])[C:6]3[CH:15]=[CH:14][CH:13]=[C:12]4[C:7]=3[CH:8]=[CH:9][CH:10]=[N:11]4)=[CH:32][CH:33]=2)=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: COc1cc(-c2ccco2)cc(OC)c1Br
Reactant: COC(C(=O)N(C)OC)c1cccc2ncccc12
Product: COc1cc(-c2ccc(C(=O)C(OC)c3cccc4ncccc34)o2)cc(OC)c1Br
Yield: 46 %

Procedure:
1-(5-(4-Bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(quinolin-5-yl)ethanone was synthesized from N,2-dimethoxy-N-methyl-2-(quinolin-5-yl)acetamide and 2-(4-bromo-3,5-dimethoxyphenyl)furan following the procedure used for the synthesis of Example 12. Purification by chromatography (EtOAc-hexanes) provided 1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(quinolin-5-yl)ethanone as a light yellow foam (0.102 g, 46% yield). MS: m/z 482.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C@@H:14]2[C@@H:10]([O:11]C(C)(C)O2)[C@H:9]([NH:17][C:18](=[O:20])[CH3:19])[C@@H:8]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:7]=1)=[O:5])[CH3:2].[O-]CC.[Na+]>CCO>[CH2:1]([O:3][C:4]([C:6]1[CH2:7][C@H:8]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[C@@H:9]([NH:17][C:18](=[O:20])[CH3:19])[C@H:10]([OH:11])[CH:14]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C[C@H](NC(=O)OC(C)(C)C)[C@@H](NC(C)=O)[C@@H]2OC(C)(C)O[C@H]12
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1=C[C@@H](O)[C@H](NC(C)=O)[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 94.9 %

Procedure:
Acetonide 10 (534 mg; 1.33 mmol) was dissolved in EtOH (10 mL) and 12.4 ml of ethanolic sodium ethoxide solution (0.05M) was added dropwise over period 1 min. After 5 min of stirring at room temperature reaction mixture was quenched by addition of 1 g of silica and then filtered and evaporated. Chromatography [ethyl acetate→ethyl acetate-ethanol (1:1), 5 g silica] of residue afforded 432 mg (94%) of allylalcohol 12 as white solid: m.p.=177-178° C. (ethyl acetate-hexane); Rf=0.2 (ethyl acetate); [α]20D=−9.14 (c=1, CHCl3); IR (KBr, cm−1) ν 3341, 2926, 2854, 2360, 2326, 1726, 1680, 1654, 1626, 1530, 1460, 1319, 1295, 1249, 1165, 1127, 1091, 1046, 1025, 992, 946, 908, 863, 782, 755, 735, 644, 607, 590, 571, 543, 491, 460, 437; 1H NMR (CDCl3, 600 Mhz) δ 7.35 (d, J=5.8 Hz, 1H), 6.83 (dd, J=2.4, 2.4 Hz, 1H), 5.07 (bs, 1H), 4.92 (d, J=7.9 Hz, 1H), 4.36-4.29 (m, 1H), 4.27-4.16 (m, 2H), 3.85-3.83 (m, 1H), 3.77-3.73 (m, 1H), 2.84 (dd, 1H, J=17.4, 5.1 Hz, 1H), 2.21 (dddd, J=17.4, 11.0, 2 x≈3 Hz, 1H), 2.03 (s, 3H), 1.47 (s, 9H), 1.30 (t, J=7.2 Hz, 3H); 13C NMR (CDCl3, 150 Mhz) δ 173.61, 165.86, 157.64, 139.05, 127.65, 80.87, 73.60, 61.05, 60.55, 48.05, 30.83, 28.23, 23.09, 14.17; MS (FAB+) m/z %: 343 (M++H), 287(100), 243(25), 208 (30); HRMS. Calcd for C16H27N2O6: 343.18691. Found: 343.18417; Anal. Calcd for C16H27N2O6: C, 56.13; H, 7.65; N, 8.18. Found C, 56.31; H, 7.83; N, 8.17.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:33])([CH3:32])[O:6][CH2:7][C@@H:8]([CH3:31])[C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([C:17]([CH3:30])([CH3:29])[C@@H:18]([OH:28])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)([CH3:4])[CH3:3].[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>N1C=CC=CC=1>[C:34]([O:28][C@H:18]1[CH2:19][CH2:20][C@@:21]2([CH3:22])[C:16](=[CH:15][CH2:14][C@@H:13]3[C@@H:23]2[CH2:24][CH2:25][C@@:26]2([CH3:27])[C@H:12]3[CH2:11][CH2:10][C@@H:9]2[C@H:8]([CH3:31])[CH2:7][O:6][Si:5]([C:2]([CH3:3])([CH3:1])[CH3:4])([CH3:32])[CH3:33])[C:17]1([CH3:30])[CH3:29])(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: C[C@H](CO[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H]2[C@@H]3CC=C4C(C)(C)[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: C[C@H](CO[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H]2[C@@H]3CC=C4C(C)(C)[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
v)—A solution of the alcohol 6 (132.5 g) obtained in the previous step in dry pyridine (1310 ml) was cooled to 0° C. Benzoyl chloride (65.7 ml) was added in 5 min. and the reaction mixture was stirred for 1 h at room temperature. Then it was poured into ice-water (6650 ml) and the resulting suspension was stirred over-night. The precipitate was collected by filtration and washed with water (40-50° C.). The residue was dried and purified by crystallization from acetone to give (3β,20S)-21-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4,4,20-trimethylpregn-5-en-3-ol benzoate (7) (113.6 g).