Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[O:11][CH2:10][CH:9]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[O:8][C:5]2=[N:6][CH:7]=1.[Li][CH2:22]CCC.IC.[NH4+].[Cl-]>C1COCC1>[CH3:18][C:17]([Si:14]([CH3:16])([CH3:15])[O:13][CH2:12][CH:9]1[O:8][C:5]2=[N:6][CH:7]=[C:2]([CH3:22])[CH:3]=[C:4]2[O:11][CH2:10]1)([CH3:20])[CH3:19]
Reactant: [Li]CCCC
Reactant: CC(C)(C)[Si](C)(C)OCC1COc2cc(Br)cnc2O1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: Cc1cnc2c(c1)OCC(CO[Si](C)(C)C(C)(C)C)O2
Temperature: -78 °C
Reaction time: 1.25 h
Yield: 41.9 %

Procedure:
Reaction under nitrogen atmosphere. A solution of intermediate (37) (0.00194 mol) in THF was cooled to −78° C. BuLi (0.00214 mol, 2.5M) was added dropwise and the mixture was stirred for 75 minutes at −78° C. Then, iodomethane (00214 mol) was added and the reaction mixture was stirred for 45 minutes. A saturated aqueous NH4Cl solution was added and the mixture was allowed to warm to room temperature. This mixture was extracted with ethyl acetate. The separated organic layer was dried, filtered and the solvent evaporated. The residue was purified by flash column chromatography over silica gel (eluent: hexane/ethyl acetate 80/20). The desired fractions were collected and the solvent was evaporated, yielding 0.24 g of 3-[[[(1,1-dimethylethyl)dimethyl-silyl]oxy]methyl]-2,3-dihydro-7-methyl-[1,4]dioxino[2,3-b]pyridine (intermediate 38).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([NH2:11])[C:5]=2[CH2:4][CH2:3]1.CN1CCOCC1.[CH3:20][C:21]1[O:22][C:23]([CH3:29])=[CH:24][C:25]=1[C:26](Cl)=[O:27]>CCOCC>[CH3:20][C:21]1[O:22][C:23]([CH3:29])=[CH:24][C:25]=1[C:26]([NH:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH2:4][CH2:3][C:2]2([CH3:12])[CH3:1])=[O:27]
Reactant: Cc1cc(C(=O)Cl)c(C)o1
Reactant: CC1(C)CCc2c(N)cccc21
Solvent: CCOCC
Solvent: CN1CCOCC1
Product: Cc1cc(C(=O)Nc2cccc3c2CCC3(C)C)c(C)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
To 15 ml of an ether solution of 1.5 g (8.57 mmols) of 1,1-dimethylindane-4-amine,2 ml of N-methyl morpholine and 1.4 g (8.83 mmols) of 2,5-dimethyl-3-furan carboxylic acid chloride were added under cooling. The mixture was stirred at room temperature for 1 hour and then washed sequentially with water and brine. The solution was dried with magnesium sulfate. The resultant concentrate was purified with silica gel column chromatography (solvent for elution; ethyl acetate/ n-hexane =1/4), thereby obtaining 2.1 g of light yellow crystals (Compound No. 20 shown in Table 6). The yield was 85.8%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:20]([NH:22][O:23][CH2:24][CH2:25][O:26][C:27](=[O:40])[CH:28]([NH:32]C(OC(C)(C)C)=O)[CH:29]([CH3:31])[CH3:30])=[O:21])=[CH:11][C:12]3[N:16]([CH3:17])[CH:15]=[N:14][C:13]=3[C:18]=2[F:19])=[C:4]([Cl:41])[CH:3]=1.FC(F)(F)C(O)=O>>[ClH:41].[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:20]([NH:22][O:23][CH2:24][CH2:25][O:26][C:27](=[O:40])[CH:28]([NH2:32])[CH:29]([CH3:31])[CH3:30])=[O:21])=[CH:11][C:12]3[N:16]([CH3:17])[CH:15]=[N:14][C:13]=3[C:18]=2[F:19])=[C:4]([Cl:41])[CH:3]=1
Reactant: CC(C)C(NC(=O)OC(C)(C)C)C(=O)OCCONC(=O)c1cc2c(ncn2C)c(F)c1Nc1ccc(Br)cc1Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(N)C(=O)OCCONC(=O)c1cc2c(ncn2C)c(F)c1Nc1ccc(Br)cc1Cl
Product: Cl

Procedure:
A mixture of 2-tert-butoxycarbonylamino-3-methylbutyric acid 2-{[6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carbonyl]-aminooxy}-ethylester and its N-acylated isomer (0.6 g) were treated with 1.5 mL of trifluoroacetic acid for 0.5 hours. An HPLC trace of the reaction mixture showed the reaction was complete. The mixture was concentrated on a rotary evaporator and pumped on high vacuum to give yellow oil (0.9 g). The deprotected samples were submitted for HPLC purification to give purified product as a trifluoroacetic acid salt.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:7][N:6]([CH2:8][CH2:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[N:18]=3)[N:13]=[CH:12][C:11]=2[F:22])[CH2:5][C@H:4]1[OH:23].[O:24]=[C:25]1[NH:30][C:29]2[N:31]=[C:32]([CH:35]=O)[CH:33]=[CH:34][C:28]=2[S:27][CH2:26]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CCO>[F:22][C:11]1[CH:12]=[N:13][C:14]2[C:19]([C:10]=1[CH2:9][CH2:8][N:6]1[CH2:5][C@H:4]([OH:23])[C@H:3]([CH2:2][NH:1][CH2:35][C:32]3[CH:33]=[CH:34][C:28]4[S:27][CH2:26][C:25](=[O:24])[NH:30][C:29]=4[N:31]=3)[CH2:7]1)=[N:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2
Reactant: COc1ccc2ncc(F)c(CCN3C[C@H](CN)[C@H](O)C3)c2n1
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc2ncc(F)c(CCN3C[C@@H](CNCc4ccc5c(n4)NC(=O)CS5)[C@@H](O)C3)c2n1
Reaction time: 24 h
Yield: 66.9 %

Procedure:
To a stirred solution of (±)-cis-4-(aminomethyl)-1-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinol (0.23 g, 0.72 mmole) in dry CH2Cl2 (25 mL) and dry EtOH (10 mL) at RT was added 3-oxo-3,4-dihydro-2H-pyrido[1,4]thiazine-6-carboxaldehyde (0.14 g, 0.72 mmole). After 24 h, at RT was added NaBH(OAc)3 (0.23 g, 1.08 mmole). After 2 h, the reaction solution was concentrated under vacuum and purified on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) to afford the title compound (0.24 g, 66%) as light yellow solid: 1H NMR (400 MHz, CD3OD) δ 8.65 (s, 1H), 8.19 (d, J=9.0 Hz, 1H), 7.77 (d, J=7.8 Hz, 1H), 7.17 (d, J=9.0 Hz, 1H), 7.11 (d, J=8.0 Hz, 1H), 4.21 (s, 2H), 4.12 (s, 3H), 3.52 (m, 4H), 3.33 (s, 4H), 3.21 (m, 2H), 3.09 (m, 2H), 2.98 (m, 2H). LC-MS (ES) m/e 499 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=1.[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[C:11]2[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=2)=[O:24])=[CH:21][CH:20]=1
Reactant: CN1CC=C(c2c[nH]c3ccc(N)cc23)CC1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Product: CN1CC=C(c2c[nH]c3ccc(NC(=O)c4ccc(Cl)cc4)cc23)CC1
Yield: 29.7 %

Procedure:
Beginning with 1.13 gm (5.0 mMol) 5-amino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole and 0.64 mL (5.0 mMol) 4-chlorobenzoyl chloride, 0.544 gm (29.9%) of the title compound were recovered as a tan solid.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[C:15](Cl)=[O:16])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[CH2:18]([NH2:21])[C:19]#[CH:20]>O1CCCC1>[CH2:18]([NH:21][C:15]([C:13]1[C:14]2[C:5]([CH:6]=[C:7]3[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]3)=[CH:4][CH:3]=[CH:2][CH:1]=2)=[O:16])[C:19]#[CH:20]
Reactant: O=C(Cl)c1c2ccccc2cc2ccccc12
Reactant: C#CCN
Solvent: C1CCOC1
Product: C#CCNC(=O)c1c2ccccc2cc2ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.7 %

Procedure:
A solution of 13.68 g of 9-anthroyl chloride in 30 ml of tetrahydrofuran is added at 10°-15° to a solution of 10 g of propargylamine in 60 ml of tetrahydrofuran. After stirring at room temperature for 4 hours, the solvent is removed and the residue is stirred with methylene chloride and 5% aqueous sodium bicarbonate solution. The methylene chloride layer is dried and concentrated to give 14.54 g of crude N-propargyl-9-anthramide as a solid. An analytical sample (ethanol) had a melting point of 201°-202°; H nmr spectrum: τ 1.5-2.8 (m, 9); 3.7 (broad, 1); 5.7 (d of d, 2) and 7.7 (τ, 2.5 Hz, 1).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH2:7])[CH:4]=[N:3]1.[NH2:8][C:9]1[C:10]([C:16](O)=[O:17])=[N:11][C:12]([Br:15])=[CH:13][CH:14]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[NH2:8][C:9]1[C:10]([C:16]([NH:7][C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)=[O:17])=[N:11][C:12]([Br:15])=[CH:13][CH:14]=1
Reactant: Nc1ccc(Br)nc1C(=O)O
Reactant: Cn1cc(N)cn1
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: Cn1cc(NC(=O)c2nc(Br)ccc2N)cn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a 100 mL round bottom flask containing 1-methyl-1H-pyrazol-4-amine (700 mg, 7.0 mmol), 3-amino-6-bromopicolinic acid (1.86 g, 8.5 mmol) and PyBop (4.12 g, 8.0 mmol) was added methylene chloride (30 mL) and diisopropylethylamine (3.8 mL, 21.6 mmol). The reaction mixture was stirred for 24 hr at room temperature and the reaction was monitored by LCMS. Upon completion of the reaction, the solvent was distilled off and the crude material was purified via flash chromatography, heptane/ethyl acetate 0% to 100% to afford a yellow solid. A fraction of it was purified via reverse phase HPLC to afford 317. 1H NMR (400 MHz, DMSO) δ 10.25 (s, 1H), 8.03 (s, 1H), 7.70 (s, 1H), 7.43 (d, J=8.7 Hz, 1H), 7.19 (d, J=8.7 Hz, 1H), 7.02 (br, 2H), 3.81 (s, 3H). MS (ESI) m/z: 296.0/298.0 [M+H+].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH:17]=C)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I([O-])(=O)(=O)=[O:20].[Na+]>C1COCC1.O.C(OCC)(=O)C.[Os](=O)(=O)(=O)=O>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH:17]=[O:20])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=Cc1ccc2c(c1)CN(C(=O)OC(C)(C)C)C2
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1Cc2ccc(C=O)cc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
To a stirred solution of 3.79 mmol 5-vinyl-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester in 25 ml THF and 5 ml water were added 11.4 mmol sodium metaperiodate and 0.08 mmol osmium tetroxide solution (2.5% in tBuOH) and the mixture was stirred at RT for 2 h before being taken up in ethyl acetate and washed sequentially with water and brine. The organic phase was then dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (SiO2, heptane/ethyl acetate) to yield the title compound as a white solid (62% yield). MS (m/e): 192.1 ([M+H-Me2C═CH2]+, 100%).
Reaction SMILES: Cl[C:2]1([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[C:7](=[O:8])[N:6]([CH3:9])[C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[S:3]1.[CH3:21][NH2:22].C(OCC)(=O)C.O>O1CCCC1>[OH:20][C:17]1[CH:18]=[CH:19][C:14]([C:2]2([NH:22][CH3:21])[C:7](=[O:8])[N:6]([CH3:9])[C:5]3[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=3[S:3]2)=[CH:15][CH:16]=1
Reactant: CN
Reactant: CN1C(=O)C(Cl)(c2ccc(O)cc2)Sc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CNC1(c2ccc(O)cc2)Sc2ccccc2N(C)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.8 %

Procedure:
To a stirred suspension of 2-chloro-3,4-dihydro-2-(4-hydroxyphenyl)-4-methyl-3-oxo-2H-1,4-benzothiazine (11.5 g, compound No. 2) in tetrahydrofuran (40 ml), 40% aqueous methylamine solution (14.6 ml) is added. The mixture is stirred for 2 hours at room temperature, and poured into a mixture of ethyl acetate and water. The organic layer is washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo to give 10.1 g (89.8%) of the titled compound.
Reaction SMILES: [ClH:1].N[NH:3][C:4](=[NH:7])[NH:5][NH2:6].[C:8]([O-:11])(=[O:10])[CH3:9].[Na+:12].C(#[N:15])C>CC(C)=O>[C:8]([O-:11])(=[O:10])[CH3:9].[NH2:15][N+:5]([NH2:6])=[C:4]([NH2:7])[NH2:3].[Cl-:1].[Na+:12]
Reactant: N=C(NN)NN
Reactant: CC#N
Reactant: Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: NC(N)=[N+](N)N
Product: [Cl-]

Procedure:
Diaminoguanidinium acetate is synthesized by reacting diaminoguanidine hydrochloride and sodium acetate in acetone or acetonitrile. Sodium chloride is produced as a byproduct of the reaction and is removed, producing the diaminoguanidinium acetate.
Reaction SMILES: N1CCC[C@H]1C(O)=O.[N:9]1([C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=2)[CH:13]=[CH:12][CH:11]=[N:10]1.[CH3:22][C:23]1([CH3:31])[O:28][C:27](=[O:29])[CH2:26][C:25](=[O:30])[O:24]1.CC1NC(C)=C(C(OCC)=O)CC=1C(OCC)=O>C(O)C.C(O)(C)C>[N:9]1([C:14]2[CH:21]=[CH:20][C:17]([CH2:18][CH:26]3[C:27](=[O:29])[O:28][C:23]([CH3:31])([CH3:22])[O:24][C:25]3=[O:30])=[CH:16][CH:15]=2)[CH:13]=[CH:12][CH:11]=[N:10]1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Agent: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Solvent: CC(C)O
Product: CC1(C)OC(=O)C(Cc2ccc(-n3cccn3)cc2)C(=O)O1
Reaction time: 0.67 h

Procedure:
L-Proline (4.07 g, 35.0 mmol) was added to a semi-heterogeneous mixture of 4-(1H-pyrazol-1-yl)benzaldehyde (30.0 g, 174 mmol) and 2,2-dimethyl-1,3-dioxane-4,6-dione (25.6 g, 174 mmol) in ethanol (996 mL) at room temperature. After 40 minutes, diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (44.1 g, 174 mmol) was added in one portion followed by ethanol (125 mL). After overnight stirring, the mixture was concentrated under reduced pressure to afford a yellow solid. Isopropanol (300 mL) was added and the heterogeneous mixture was sonicated for 30 minutes. The mixture was filtered and the filter cake was washed with isopropanol. The solids were collected and dried under vacuum to provide the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:28])[C:9]2[CH:27]=[CH:26][C:12]3[N:13]([CH3:25])[C:14]([NH:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH2:29][C:30]1[CH:31]=[CH:32][C:33]([CH3:40])=[C:34]([S:36]([NH2:39])(=[O:38])=[O:37])[CH:35]=1>>[ClH:1].[F:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][NH:16][C:14]2[N:13]([CH3:25])[C:12]3[CH:26]=[CH:27][C:9]([N:8]([CH3:28])[C:6]4[CH:5]=[CH:4][N:3]=[C:2]([NH:29][C:30]5[CH:31]=[CH:32][C:33]([CH3:40])=[C:34]([S:36]([NH2:39])(=[O:37])=[O:38])[CH:35]=5)[N:7]=4)=[CH:10][C:11]=3[N:15]=2)=[CH:19][CH:20]=1
Reactant: Cc1ccc(N)cc1S(N)(=O)=O
Reactant: CN(c1ccc2c(c1)nc(NCc1ccc(F)cc1)n2C)c1ccnc(Cl)n1
Product: Cc1ccc(Nc2nccc(N(C)c3ccc4c(c3)nc(NCc3ccc(F)cc3)n4C)n2)cc1S(N)(=O)=O
Product: Cl

Procedure:
The title compound was prepared following the procedure of example one with N5-(2-chloro-pyrimidin-4-yl)-N2-(4-fluoro-benzyl)-1,N5-dimethyl-1H-benzoimidazole-2,5-diamine (99 mg, 0.25 mmol) and 5-amino-2-methyl-benzenesulfonamide (47 mg, 0.25 mmol) as a white solid (69 mg, 48%). 1H NMR (300 MHz, d6-DMSO+NaHCO3) δ10.28 (br s, 1H), 9.61 (br s, 1H), 8.45 (s, 1H), 7.86 (d, J=2.1 Hz, 1H), 7.63 (m, 1H), 7.52-7.59 (m, 3H), 7.37 (s, 1H), 7.31 (s, 2H), 7.13-7.26 (m, 4H), 5.74 (d, J=4.5 Hz, 1H), 4.73 (d, J=4.5 Hz, 2H), 3.71 (s, 3H), 3.48 (s, 3H), 2.50 (s, 3H). MS (ESI) m/z=547 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C:17]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:20]2[O:21][CH2:22][C:23]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([C:25]3[CH:30]=[CH:29][C:28]([N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)=[CH:27][CH:26]=3)[CH:24]=[C:19]2[C:18]=1[C:48]([O:50][CH3:51])=[O:49].N1C=CC=CC=1>C(Cl)Cl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:17]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:20]2[O:21][CH2:22][C:23]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([C:25]3[CH:30]=[CH:29][C:28]([N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)=[CH:27][CH:26]=3)[CH:24]=[C:19]2[C:18]=1[C:48]([O:50][CH3:51])=[O:49])(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)C1=C(O)c2ccccc2C2OCC(c3ccccc3)(c3ccc(N4CCCC4)cc3)C=C12
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)c2ccccc2C2OCC(c3ccccc3)(c3ccc(N4CCCC4)cc3)C=C12
Yield: 58.4 %

Procedure:
Trifluoromethanesulfonic anhydride (5.32 g, 18.9 mmol) was added dropwise to a solution of 6-hydroxy-5-methoxycarbonyl-3-phenyl-3-(4-pyrrolidinophenyl)-2H-naphtho-[1,2-b]pyran (4.8 g, 10 mmol) and pyridine (1.7 g, 21.6 mmol) in DCM (100 mL) at 0° C. under N2 with stirring. After 1 h the resulting solution was washed with HCl (100 mL, 2 M), water (100 mL), dried (MgSO4) and the solvent removed under reduced pressure. The residue was filtered through a short plug of silica using DCM as eluent. The solvent was removed under reduced pressure to give the title compound (3.57 g, 58%) as a blue powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([OH:28])[C:10]1[N:14]([CH2:15][CH2:16][CH2:17]O)[C:13]2[C:19]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[CH:20][CH:21]=[CH:22][C:12]=2[N:11]=1.CS(Cl)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:10]2=[N:11][C:12]3[C:13](=[C:19]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[CH:20]=[CH:21][CH:22]=3)[N:14]2[CH2:15][CH2:16][CH2:17][O:28]1
Reactant: CCN(CC)c1cccc2nc(C(O)c3ccc(Cl)cc3Cl)n(CCCO)c12
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCN(CC)c1cccc2nc3n(c12)CCCOC3c1ccc(Cl)cc1Cl
Temperature: 80 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
To a stirred solution of 3-{2-[(2,4-dichlorophenyl)(hydroxy)methyl]-7-(diethylamino)-1H-benzimidazol-1-yl}propan-1-ol (Reference example 207, 1.37 g, 3.24 mmol) in pyridine (16 mL) was added methanesulfonyl chloride (502 μL, 6.49 mol) at 0° C. After 1 h, the reaction mixture was diluted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in dimethylformamide (32 mL) and potassium carbonate (897 mg, 6.49 mmol) was added. After being stirred for 12 h at 80° C., the reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with a 0-20% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (341 mg, 0.844 mmol, 26%).
Reaction SMILES: [H-].[Na+].[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([OH:36])[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][N:30]=1)=[O:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:38]1[N:43]=[CH:42][N:41]=[C:40]2[N:44]([C:47]3[C:48]([CH3:55])=[C:49]([CH:52]=[CH:53][CH:54]=3)[C:50]#[N:51])[N:45]=[CH:46][C:39]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O.CCOC(C)=O>[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([O:36][C:38]1[N:43]=[CH:42][N:41]=[C:40]2[N:44]([C:47]3[CH:54]=[CH:53][CH:52]=[C:49]([C:50]#[N:51])[C:48]=3[CH3:55])[N:45]=[CH:46][C:39]=12)[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][N:30]=1)=[O:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Cc1c(C#N)cccc1-n1ncc2c(Cl)ncnc21
Reactant: Cc1ccc(NC(=O)[C@@H](O)COCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)nc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(NC(=O)[C@H](COCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)Oc2ncnc3c2cnn3-c2cccc(C#N)c2C)nc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 42.3 %

Procedure:
Sodium hydride (60% in oil) (92 mg, 2.30 mmol) was added to (S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-hydroxy-N-(5-methylpyridin-2-yl)propanamide (Intermediate AU2) (500 mg, 1.04 mmol) in anhydrous THF (25 ml) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 3-(4-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-methylbenzonitrile (Intermediate AT2) (282 mg, 1.04 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 4 hours. The reaction mixture was neutralised with 1M citric acid and diluted with water and EtOAc. The organic layer was separated and the aqueous layer re-extracted with EtOAc. The combined organics were washed with saturated brine, dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 0 to 50% EtOAc in isohexane. No separation was achieved. The column was repeated with a 0-10% MeOH/DCM gradient. Still no separation! Mixed fractions were evaporated to dryness to afford (2S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(3-cyano-2-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-methylpyridin-2-yl)propanamide (313 mg, 42.1%). m/z (ES+) (M+H)+=712.63; HPLC tR=3.85 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[CH2:9][C:10]([CH3:15])([CH3:14])[C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.[CH3:17]OC(OC)(C)C.Cl>CO.O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:16])[CH2:9][C:10]([CH3:14])([CH3:15])[C:11]([O:13][CH3:17])=[O:12])=[CH:6][CH:7]=1
Reactant: CC(C)(CC(=O)c1ccc(Br)cc1)C(=O)O
Reactant: COC(C)(C)OC
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)C(C)(C)CC(=O)c1ccc(Br)cc1
Temperature: 50 °C
Reaction time: 22 h

Procedure:
To a solution of 4-(4-bromophenyl)-2,2-dimethyl-4-oxobutanoic acid (8.33 g, 29.2 mmol) and 2,2-dimethoxypropane (3.95 g, 37.9 mmol) in methanol (100 mL) was added 1 M HCl in dioxane (2.0 mL). The reaction mixture was stirred at 50° C. for 22 h. The mixture was concentrated under reduced pressure. Toluene (2×60 mL) was added and the mixture concentrated again (2×) to afford methyl 4-(4-bromophenyl)-2,2-dimethyl-4-oxobutanoate as an off-white, semi-solid (8.60 g, 99%). This material was used in the next step without further purification. LC-MS: ret. time 3.23 min; m/z 298.8 (MH+); 1H NMR (300 MHz, CDCl3) δ 1.34 (s, 6H), 3.28 (s, 2H), 3.67 (s,3H), 7.58 (d, 2H), 7.78 (d, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]3=[N:12][C:11]=2[CH2:19][O:20][CH2:21][C:22]([OH:24])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:28])=O>ClCCl.CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]3=[N:12][C:11]=2[CH2:19][O:20][CH2:21][C:22]([Cl:28])=[O:24])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)COCc1nc2ccccn2c1C#Cc1ccc(F)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)COCc1nc2ccccn2c1C#Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.5 g (4.63 mmol) of 2-((3-((4-fluorophenyl)ethynyl)imidazo[1,2-a]pyridin-2-yl)methoxy)acetic acid were suspended in 40 ml of dichloromethane with magnetic stirring, the mixture was placed in a bath at 0° C. and then 1.215 ml (13.88 mmol) of oxalyl chloride were added dropwise, finally, a few drops of dimethylformamide were added. The cold bath was withdrawn and then the mixture was stirred at r.t. for 1 h. The reaction medium was concentrated in vacuo and immediately used in the next step.
Reaction SMILES: Cl[C:2]1[C:7]([C:8](O)=O)=[CH:6][C:5](OC[C@@H]2CCN2)=[CH:4][N:3]=1.[CH:17]1([N:23]=C=NC2CCCCC2)CCCCC1.[CH2:32](Cl)Cl>>[NH2:23][CH2:17][C:4]1[CH:5]=[CH:6][C:7]([CH2:2][NH2:3])=[CH:8][CH:32]=1
Reactant: O=C(O)c1cc(OC[C@@H]2CCN2)cnc1Cl
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: ClCCl
Product: NCc1ccc(CN)cc1

Procedure:
A solution of (S)-2-chloro-3-carboxy-5-(2-azetidinylmethoxy)pyridine 10 (R1=Cl and n=1) (2 mmol) and the linker molecule 1,4-bisaminomethylbenzene (1 mmol) in CH2Cl2 (5 mL) is prepared under argon in a flask equipped with magnetic stirrer and a drying tube. To this solution is added dicyclohexylcarbodiimide (solid, 2.2 mmol). The progress of the reaction is followed by tlc and after reaction occurs, the reaction solution is quenched in water, aqueous sodium bicarbonate is added and the aqueous mixture is extracted with methylene chloride. The organic layer is washed with aqueous Na2CO3 and with H2O, dried (Na2SO4), filtered and concentrated under reduced pressure to give the crude product. The desired compound 39 (where R1=Cl and n=1) is obtained by purification of the crude product with the use of HPLC.