Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7][CH:8]([C:13]([Br:16])([Br:15])[Br:14])[CH:9]=[C:10]([CH3:12])[CH3:11])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].S([N:27]=[N+:28]=[N-])(C1C=CC(C)=CC=1)(=O)=O.C(N(CC)CC)C>C(#N)C>[N+:27](=[CH:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH:8]([C:13]([Br:14])([Br:15])[Br:16])[CH:9]=[C:10]([CH3:11])[CH3:12])=[O:6])=[N-:28]
Reactant: CC(=O)CC(=O)OC(C=C(C)C)C(Br)(Br)Br
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)=CC(OC(=O)CC(=O)C=[N+]=[N-])C(Br)(Br)Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-methyl-1-tribromomethyl-2-butenyl acetoacetate (8.32 g, 0.0198 mole) and tosyl azide (3.9 g, 0.0198 mole) in 40 ml of acetonitrile was added dropwise over a period of 35 minutes a solution of triethylamine (2.0 g, 0.020 mole) in 10 ml of acetonitrile. The resulting mixture was stirred at room temperature for 21/2 hours to give 3-methyl-1-tribromomethyl-2-butenyl diazoacetoacetate. Then 60 ml of 1N aqueous sodium hydroxide was added thereto, and the mixture was stirred at room temperature for 45 minutes. The reaction mixture was then diluted with ether, the organic phase was separated, the aqueous phase was extracted with ether, and the organic phases were combined. The ethereal solution was washed with three successive portions of 3% aqueous potassium hydroxide containing sodium chloride, then three times with saturated aqueous sodium chloride. The washed ethereal solution was dried over magnesium sulfate and treated with active charcoal. Evaporation of the ether afforded an oily residue. 3-Methyl-1-tribromomethyl-2-butenyl diazoacetate (5.78 g, 71% yield) was isolated therefrom by column chromatography.
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:13])([CH3:12])[CH2:4][CH2:5][CH2:6][CH:7]([CH3:11])[CH2:8][CH:9]=O.[CH:14]([O-:17])([CH3:16])[CH3:15].[Na+].CN(C)[CH:21]=[O:22]>>[CH3:1][O:2][C:3]([CH3:13])([CH3:12])[CH2:4][CH2:5][CH2:6][CH:7]([CH3:11])[CH2:8][CH:9]=[CH:12][C:3]([CH3:13])=[CH:4][C:21]([O:17][CH:14]([CH3:16])[CH3:15])=[O:22]
Reactant: COC(C)(C)CCCC(C)CC=O
Reactant: CN(C)C=O
Reactant: CC(C)[O-]
Agent: [Na+]
Product: COC(C)(C)CCCC(C)CC=CC(C)=CC(=O)OC(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 10 g. of 7-methoxy-3,7-dimethyloctan-1-al, 17 g. of diethyl 3-ethoxycarbonyl-2-methylprop-2-enyl phosphonate (77% trans), and 150 ml. of dimethylformamide, under nitrogen, 0°, with stirring, is added sodium isopropanolate (prepared from 1.5 g. of sodium in 150 ml. of isopropanol). After addition is complete, the reaction is stirred for 18 hours at room temperature and then worked up by extraction with hexane to yield isopropyl 11-methoxy-3,7,11-trimethyldodeca-2,4-dienoate (mostly trans-2,trans-4), which can be chromatographed and distilled for further purification.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([CH2:6][O:7][C:8]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:16][CH:15]=3)=[CH:12][N:11]=[C:10]([NH:26][C@H:27]3[CH2:32][CH2:31][C@@H:30]([CH3:33])[CH2:29][CH2:28]3)[N:9]=2)[CH2:2]1.[Cl:34][C:35]([O:37][CH3:38])=[O:36]>>[ClH:34].[CH3:33][C@@H:30]1[CH2:29][CH2:28][C@H:27]([NH:26][C:10]2[N:9]=[C:8]([O:7][CH2:6][C@@H:3]3[CH2:4][CH2:5][N:1]([C:35]([O:37][CH3:38])=[O:36])[CH2:2]3)[C:13]([C:14]3[CH:15]=[CH:16][C:17]([N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)=[CH:18][CH:19]=3)=[CH:12][N:11]=2)[CH2:32][CH2:31]1
Reactant: C[C@H]1CC[C@@H](Nc2ncc(-c3ccc(N4CCOCC4)cc3)c(OC[C@@H]3CCNC3)n2)CC1
Reactant: COC(=O)Cl
Product: COC(=O)N1CC[C@@H](COc2nc(N[C@H]3CC[C@@H](C)CC3)ncc2-c2ccc(N3CCOCC3)cc2)C1
Product: Cl

Procedure:
Using the procedure of Example 1 Step 5, 4-(((R)-pyrrolidin-3-yl)methoxy)-N-(cis-4-methylcyclohexyl)-5-(4-morpholinophenyl)pyrimidin-2-amine with methyl chloroformate to provide the title compound. 1H NMR (CDCl3, 400 MHz) δ 8.08 (s, 1H), 7.38 (d, 2H), 6.94 (d, 2H), 5.22 (sb, 1H), 4.31 (d, 2H), 4.07 (m, 1H), 3.88 (m, 4H), 3.70 (s, 3H), 3.72-3.36 (m, 4H), 2.68 (m, 1H), 2.03 (m, 2H), 1.87-1.52 (m, 6H), 1.25 (m, 3H), 0.95 (d, 3H); MS (ESI) m/z: Found: 510.3 (M+1). Calc. 509.3 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:9][C:6]([CH:7]=O)=[C:5]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=2)[CH:4]=1.[C:24]([C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:29][CH:28]=1)(=[O:26])[CH3:25].C[O-].[Li+]>CN(C)C=O.CO.O>[CH3:1][O:2][C:3]1[C:10]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:9][C:6](/[CH:7]=[CH:25]/[C:24]([C:27]2[CH:28]=[CH:29][C:30]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:31][CH:32]=2)=[O:26])=[C:5]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=2)[CH:4]=1
Reactant: COc1cc(Oc2cccc(C)n2)c(C=O)cc1-c1cccs1
Reactant: CC(=O)c1ccc(S(N)(=O)=O)cc1
Agent: C[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: COc1cc(Oc2cccc(C)n2)c(/C=C/C(=O)c2ccc(S(N)(=O)=O)cc2)cc1-c1cccs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.6 %

Procedure:
4-Methoxy-2-(6-methyl-pyridin-2-yloxy)-5-thiophen-2-yl-benzaldehyde (Ex-122A, 0.20 g, 0.62 mmol) and 4-acetylbenzenesulfonamide (Ex-26A, 0.12 g, 0.62 mmol) were dissolved in a dimethylformamide-methanol solution (4.2 mL, 7:3). After complete dissolution, lithium methoxide (0.093 g, 2.5 mmol) was added and the resulting orange slurry was stirred in the dark at room temperature for 3 h. Upon completion, as determined by HPLC, the mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×20 mL). The combined organic extracts were dried over sodium sulfate and evaporated to dryness. The crude oil was taken up in ethanol (2 mL) and warmed to 60° C. to obtain complete dissolution and allowed to cool to room temperature. The resulting precipitate was collected on filter paper and dried in vacuo to yield 0.25 g (82%) of the title compound as a yellow solid, mp 164–165° C. 1H-NMR (300 MHz, DMSO-d6) δ 8.47 (s, 1H), 8.24 (d, 2H, J=8.1 Hz), 7.98 (d, 1H, J=15.3 Hz), 7.96 (d, 2H, J=8.1 Hz), 7.78–7.85 (m, 2H), 7.77 (d, 1H, J=15.3 Hz), 7.62 (d, 1H, J=5.1 Hz), 7.57 (s, 2H), 7.19 (dd, 1H, J=5.1, 3.6 Hz), 7.04 (d, 1H, J=7.5 Hz), 6.99 (s, 1H), 6.91 (d, 1H, J=8.4 Hz), 3.90 (s, 3H), 2.33 (s, 3H). Anal. Calcd. C26H22N2O5S2: C, 61.64; H, 4.38; N, 5.53; S, 12.66. Found: C, 61.88; H, 4.47; N, 5.59; S, 12.62.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([OH:14])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[NH2:32][CH:33]1[CH:40]2[CH2:41][C:36]3([CH2:43][OH:44])[CH2:37][CH:38]([CH2:42][CH:34]1[CH2:35]3)[CH2:39]2.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([NH:32][CH:33]2[CH:34]3[CH2:42][CH:38]4[CH2:37][C:36]([CH2:43][OH:44])([CH2:41][CH:40]2[CH2:39]4)[CH2:35]3)=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cccc(OCC2CCCCC2)c1
Reactant: NC1C2CC3CC1CC(CO)(C3)C2
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1C2CC3CC1CC(CO)(C3)C2)c1cccc(OCC2CCCCC2)c1
Temperature: 20 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
3-Cyclohexylmethoxy-benzoic acid (300 mg, 1.3 mmol), HOBT (294 mg, 1.9 mmol), EDC (245 mg, 1.3 mmol), and 4-amino-1-hydroxymethyladamantane (232 mg, 1.28 mmol) were suspended in DMF (2.5 ml) before DIPEA (0.44 ml, 2.6 mmol) was added. The reaction mixture was stirred at 20° C. overnight. The reaction mixture was purified directly by Preparative HPLC to give 364 mg of the title compound as a mixture of two isomers. 1H NMR (400 MHz, CDCl3) δ: 7.29-7.34 (m, 2H), 7.21-7.26 (m, 1H), 6.98-7.04 (m, 1H), 3.79 (dd, 2H), 6.43 (dd, 1H), 4.10-4.25 (m, 1H), 3.79 (dd, 2H), 3.23 (d, 2H), 2.43 (s, 1H), 2.10-2.16 (m, 2H), 1.97-2.04 (m, 1H), 1.55-1.92 (m, 14H), 1.39-1.47 (m, 1H), 1.15-1.35 (m, 13H), 1.05 (q, 1H).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]2[C:14]2[CH:19]=[C:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:17]=[C:16]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[S:29]([OH:32])(=[O:31])=[O:30].CC(=O)OCC.O>C1COCC1>[CH:1]1([CH2:7][N:8]2[C:9]([C:14]3[CH:19]=[C:18]([C:20]([CH3:21])([CH3:23])[CH3:22])[CH:17]=[C:16]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:15]=3)=[CH:10][C:11]([S:29]([OH:32])(=[O:31])=[O:30])=[C:12]2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(O)Cl
Reactant: Cc1ccc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2)n1CC1CCCCC1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c(S(=O)(=O)O)cc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2)n1CC1CCCCC1
Temperature: -78 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
To a solution of compound 5b (1.0 g, 2.7 mmol) in THF (10 mL) was added dropwise ClSO3H (3 mL) at −78° C. This mixture was stirred at −78° C. for 3 h, then EA and cooled water was added and extracted with EA. The organic layer was washed with aq. NaHCO3, dried and concentrated to afford compound 5c (1.0 g, 83%) as yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]([CH3:22])([O:10][C:11]1[CH:12]=[C:13]([CH2:17][CH2:18][C:19](O)=[O:20])[CH:14]=[CH:15][CH:16]=1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)OCC.[BH4-].[Na+]>O1CCCC1.O1CCCC1.O.O>[OH:20][CH2:19][CH2:18][CH2:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:8]([CH3:22])([CH3:9])[C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7]
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1cccc(CCC(=O)O)c1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C)Oc1cccc(CCCO)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-[3-(1-tert-Butoxycarbonyl-1-methylethoxy)phenyl]propionic acid (10.0 g, 32.4 mmol) was dissolved in tetrahydrofuran (50 mL). Subsequently, triethylamine (3.6 g, 35.6 mmol) was added dropwise thereto. Ethyl chlorocarbonate (3.87 g, 35.6 mmol) was added under ice-cooling, and the mixture was stirred for one hour at room temperature. Sodium borohydride (2.45 g, 64.8 mmol) in tetrahydrofuran-water solution was added dropwise under ice-cooling, and the mixture was stirred for two hours at room temperature. Water was added thereto, and the reaction mixture was extracted with ethyl acetate. The organic layer was sequentially washed with diluted hydrochloric acid and saturated brine. The resultant mixture was subjected to drying over sodium sulfate, concentration under reduced pressure, and purification by silica gel chromatography (n-hexane/ethyl acetate=7/3), whereby the target compound was obtained (9.8 g (q.)).
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][Si](C=[N+]=[N-])(C)C.B(F)(F)F>CO.C1C=CC=CC=1>[NH2:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1ncccc1O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: FB(F)F
Solvent: c1ccccc1
Solvent: CO
Product: COc1cccnc1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-amino-3-hydroxypyridine (Aldrich, 200 mg) in 20% methanol/benzene (4 mL) was treated with trimethylsilyldiazomethane (1.8 mL, 2.0 M), boron trifluoride diethyletherate (0.026 mL) and stirred at room temperature for 16 hr. The solvent was evaporated in vacuo and the crude oil was purified by medium pressure liquid chromatography on a 21×300 mm silica column eluted with 50% ethyl acetate/lmethylene chloride to give the title compound (50 mg).
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([NH:8]C(=O)OC(C)(C)C)=[N:5][CH:4]=1)#[CH:2].[CH:16]1([C:19]2[CH:20]=[C:21]([NH:33][C:34](=[O:43])[C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[C:37](I)[CH:36]=3)[CH:22]=[CH:23][C:24]=2[CH2:25][N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)[CH2:18][CH2:17]1>>[NH2:8][C:6]1[S:7][C:3]([C:1]#[C:2][C:41]2[C:36]([CH3:37])=[C:35]([CH:40]=[CH:39][CH:38]=2)[C:34]([NH:33][C:21]2[CH:22]=[CH:23][C:24]([CH2:25][N:26]3[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]3)=[C:19]([CH:16]3[CH2:18][CH2:17]3)[CH:20]=2)=[O:43])=[CH:4][N:5]=1
Reactant: C#Cc1cnc(NC(=O)OC(C)(C)C)s1
Reactant: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C3CC3)c2)cc1I
Product: Cc1c(C#Cc2cnc(N)s2)cccc1C(=O)Nc1ccc(CN2CCN(C)CC2)c(C2CC2)c1

Procedure:
The title compound can be synthesized from tert-butyl (5-ethynyl-1,3-thiazol-2-yl)carbamate and N-(3-cyclopropyl-4-((4-methylpiperazin-1-yl)methyl)phenyl)-3-iodo-4-methylbenzamide in a manner similar to that described for Example 2 (nitro reduction performed in a manner similar to that described for Example 8; 0.25M in MeOH/10% AcOH). T-BOC deprotection can be performed after coupling as described in Example 5.
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH:4]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2C(C#N)(C)C(OCC)=O)=[O:8])[CH2:3][CH2:2]1.S(=O)(=O)(O)O.O.[C:30]([OH:33])(=[O:32])[CH3:31].[CH3:34]COCC>>[CH:4]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH:31]([CH3:34])[C:30]([OH:33])=[O:32])=[CH:11][CH:10]=2)=[O:8])[CH2:5][CH2:6][CH2:1][CH2:2][CH2:3]1
Reactant: CCOC(=O)C(C)(C#N)c1ccccc1C(=O)C1CCCCC1
Reactant: CC(=O)O
Reactant: CCOCC
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C(=O)O)c1ccc(C(=O)C2CCCCC2)cc1

Procedure:
2-(p-Cyclohexylcarbonyl)phenyl-2-cyanopropionic acid, ethyl ester (2.55 g, crude) was added to a mixture of concentrated sulphuric acid (5 ml), water (5 ml) and glacial acetic acid (17 ml) and the mixture was heated under reflux for 22 hours and cooled. Water (35 ml) was added and the mixture was shaken with ether (2× 50 ml). The ether solution was extracted with 2N sodium hydroxide (3× 50 ml) and the alkaline extract was acidified to pH2 with 5N hydrochloric acid. The acidic mixture was extracted with ether (2× 75 ml) and the extracts were dried over magnesium sulphate, filtered and evaporated to yield a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][N:6]=[C:5]([NH:11][C:12](=O)[CH2:13][N:14]2[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[N:15]2)[N:4]=1.Cl>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][N:6]=[C:5]([NH:11][CH2:12][CH2:13][N:14]2[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[N:15]2)[N:4]=1
Reactant: COc1cnc(NC(=O)Cn2cc([N+](=O)[O-])cn2)nc1OC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cnc(NCCn2cc([N+](=O)[O-])cn2)nc1OC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To N-(4,5-dimethoxypyrimidin-2-yl)-2-(4-nitro-1H-pyrazol-1-yl)acetamide (318 mg, 1.03 mmol) in THF (2.0 mL), BH3 THF-complex solution (1 M in THF, 4.13 mL, 4.13 mmol) was added. After stirring at rt for 1.5 h, the reaction mixture was quenched with 1 N aq. HCl-solution (4 mL, 4 mmol) followed by concentrated HCl-solution (32%, 0.5 mL). After stirring for 10 min at rt, the reaction mixture was diluted with EtOAc, washed with sat. Na2CO3-solution. The aq. layer was reextracted with EtOAc and the comb. org. layers were evaporated, dissolved in DCM and washed with brine. The org. layer was dried (MgSO4), filtered and the solvent was removed by reduced pressure. Purification was performed by FC (EtOAc/hex 1:1 to 100% EtOAc) to yield 4,5-dimethoxy-N-(2-(4-nitro-1H-pyrazol-1-yl)ethyl)pyrimidin-2-amine as a yellow solid. LC-MS conditions B: tR=0.43 min, [M+H]+=295.14.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10](B3OC(C)(C)C(C)(C)O3)=[CH:9][N:8]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1.Cl[C:31]1[N:36]=[C:35]([NH:37][C@H:38]2[CH2:43][CH2:42][CH2:41][N:40]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:39]2)[C:34]([F:51])=[CH:33][N:32]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.CCOC(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:31]3[N:36]=[C:35]([NH:37][C@H:38]4[CH2:43][CH2:42][CH2:41][N:40]([C:44]([O:46][C:47]([CH3:49])([CH3:48])[CH3:50])=[O:45])[CH2:39]4)[C:34]([F:51])=[CH:33][N:32]=3)=[CH:9][N:8]([S:20]([C:23]3[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(Cl)cnc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](Nc2nc(Cl)ncc2F)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCCN(C(=O)OC(C)(C)C)C4)n3)c3cc(Cl)cnc32)cc1
Temperature: 90 °C

Procedure:
To a solution of 5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine (1.8 g, 4.2 mmol) and tert-butyl (3S)-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]piperidine-1-carboxylate, 5a, (1.2 g, 3.7 mmol) in DME (15 mL) and H2O (5 mL) was added K2CO3 (1.7 g, 12.1 mmol). The mixture was purged with nitrogen for 15 min. To the mixture was added tetrakis triphenylphosphine palladium(0) (0.2 g, 0.2 mmol) and the reaction mixture was heated at 90° C. for 3 days. The reaction was cooled down to room temperature and then diluted with EtOAc/H2O. The layers were separated and the organic phase was washed with brine, dried (MgSO4), filtered and evaporated to dryness. The resulting residue was dissolved in CH2Cl2 and purified by silica gel chromatography (0-100% EtOAc/Hexanes) to afford the desired product, 1b.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([S:16][CH2:17][CH2:18][CH3:19])=[C:14]([C:20]([OH:22])=O)[CH:13]=[N:12]2)=[CH:7][CH:6]=1)=[O:4].[NH2:23][CH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C.C(OCC)(=O)C>[O:27]1[CH2:28][CH2:29][CH:24]([NH:23][C:20]([C:14]2[CH:13]=[N:12][N:11]([C:8]3[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][CH:9]=3)[C:15]=2[S:16][CH2:17][CH2:18][CH3:19])=[O:22])[CH2:25][CH2:26]1
Reactant: CCCSc1c(C(=O)O)cnn1-c1ccc(C(=O)OC)cc1
Reactant: NC1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCSc1c(C(=O)NC2CCOCC2)cnn1-c1ccc(C(=O)OC)cc1
Reaction time: 18 h
Yield: 56.5 %

Procedure:
1-(4-methoxycarbonylphenyl)-5-propylsulfanyl-pyrazole-4-carboxylic acid (Intermediate #7), (160 mg, 0.5 mmol), 4-aminotetrahydropyran (61 mg, 0.5 mmol), HOBT (81 mg, 0.6 mmol) and DIPEA (174 μL, 1.0 mmol) were dissolved in DMF (5 mL) and treated at ambient temperature with EDCI (115 mg, 0.6 mmol). The mixture was stirred at ambient for 18 h and then diluted with ethyl acetate (50 mL), washed with water (3×20 mL) and brine, dried (MgSO4) and volatiles removed by evaporation. The residue was purified by chromatography on silica gel (12 g silica, 0-100% EtOAc/isohexane) to give the title compound as a white solid (114 mg, 56%).
Reaction SMILES: [N:1]1([CH2:10][C:11]2[N:16]=[C:15]3[S:17][C:18]4[CH2:23][S:22][CH2:21][CH2:20][C:19]=4[C:14]3=[C:13]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:12]=2[Cl:32])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.ClC1C=CC=C(C(OO)=[O:41])C=1.O>C(Cl)Cl>[N:1]1([CH2:10][C:11]2[N:16]=[C:15]3[S:17][C:18]4[CH2:23][S:22](=[O:41])[CH2:21][CH2:20][C:19]=4[C:14]3=[C:13]([C:24]3[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=3)[C:12]=2[Cl:32])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(-c2c(Cl)c(Cn3cnc4ccccc43)nc3sc4c(c23)CCSC4)cc1
Solvent: ClCCl
Solvent: O
Product: COc1ccc(-c2c(Cl)c(Cn3cnc4ccccc43)nc3sc4c(c23)CCS(=O)C4)cc1
Reaction time: 1 h
Yield: 64.1 %

Procedure:
To a solution of the compound obtained in Example 1 (800 mg) in methylene chloride (20 ml) was added m-chloroperbenzoic acid (70%, 400 mg) under ice cooling and then the resulting mixture was stirred at the same temperature for 1 hour. The reaction mixture was poured into water and extracted with methylene chloride. The methylene chloride layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and water, dried (MgSO4), and then evaporated under reduced pressure to remove the solvent. The residue was subjected to column chromatography on silica gel to obtain 2-[(1H-benzimidazol-1-yl)methyl]-3-chloro-4-(4-methoxyphenyl)-7-oxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridine (530 mg, 64%) from the eluates with ethyl acetate-methanol (20:1). It was recrystallized from THF-hexane. Colorless prisms. Melting point 233-235° C.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[C:12]([B:13]([OH:15])[OH:14])=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1.Cl[C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:21][N:20]=1.CC(O)CC>CCCCCC>[C:29]1([C:22]2[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:19]([NH:1][C:2]3[CH:17]=[CH:16][C:5]([O:6][C:7]4[C:12]([B:13]([OH:15])[OH:14])=[CH:11][CH:10]=[CH:9][N:8]=4)=[CH:4][CH:3]=3)=[N:20][N:21]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: Clc1nnc(-c2ccccc2)c2ccccc12
Reactant: Nc1ccc(Oc2ncccc2B(O)O)cc1
Solvent: CCCCCC
Solvent: CCC(C)O
Product: OB(O)c1cccnc1Oc1ccc(Nc2nnc(-c3ccccc3)c3ccccc23)cc1
Temperature: 100 °C
Reaction time: 0.75 h

Procedure:
2-(4-Aminophenoxy)pyridin-3-ylboronic acid (478 mg, 2.08 mmol), 1-chloro-4-phenylphthalazine (500 mg, 2.08 mmol) and butan-2-ol (4.16 ml, 2.08 mmol) were placed in a sealed tube. The reaction vessel was sealed and the mixture heated to 100° C. After 1 h 45 min, the reaction was cooled to rt. Hexane was added and the precipitated tan solid was filtered off with hexanes. LCMS of the solids indicated product, 2-(4-(4-phenylphthalazin-1-ylamino)phenoxy)pyridin-3-ylboronic acid. MS Calculated for C25H19BN4O: [M]+=434. Found: [M+1]+=435.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:19](Br)[C:20]#[CH:21].[H-].[Na+]>CN(C=O)C>[Si:1]([O:8][CH2:9][CH2:10][N:11]([CH2:21][C:20]#[CH:19])[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCO[Si](C)(C)C(C)(C)C
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCN(CCO[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 800 mg of 10b and 800 μl of propargyl bromide in 8 ml of DMF was treated with 300 mg of NaH (60% dispersion in oil) at 0° C. The mixture was stirred at 0° C. for 1 hr and then for 1 hr at RT (the reaction mixture turned gradually deep brown). Then the mixture was poured onto ice water and the product was extracted with ethyl acetate. The combined organic layers were washed with water, dried and concentrated. The crude material was chromatographed over silica gel, using a gradient of heptane/ethyl acetate as eluent, to provide 650 mg of 10c. Rf (heptane/ethyl acetate 8/2) 0.50.
Reaction SMILES: [Si:1]([O:18][C@@H:19]1[CH2:24][CH2:23][C@@H:22]([C:25]([O:27][CH3:28])=[O:26])[C@H:21]([C:29]([O:31]CC2C=CC=CC=2)=[O:30])[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCO.[Pd]>[Si:1]([O:18][C@H:19]1[CH2:20][C@@H:21]([C:29]([OH:31])=[O:30])[C@H:22]([C:25]([O:27][CH3:28])=[O:26])[CH2:23][CH2:24]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H]1CC[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)[C@@H]1CC[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C[C@H]1C(=O)O
Reaction time: 16 h

Procedure:
To a solution of compound 35 (12.2 mmol) in anhydrous EtOH (50 mL) was added Pd/C 10% (20% w/w). The vessel was flushed with nitrogen and H2 was added. The reaction mixture was stirred under hydrogen atmosphere for 16 hrs. The catalyst was filtered off and washed several times with EtOH. The filtrate was concentrated in vacuo to yield compound 36 as a colourless oil in a quantitative yield.