Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]([C:13]2[N:21]=[C:20]([CH3:22])[N:19]=[C:18]3[C:14]=2[N:15]=[CH:16][N:17]3[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[C:9](F)=[N:10][CH:11]=1.[NH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[N:34][CH:35]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.O>O1CCCC1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]([C:13]2[N:21]=[C:20]([CH3:22])[N:19]=[C:18]3[C:14]=2[N:15]=[CH:16][N:17]3[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[C:9]([NH:29][C:30]2[CH:35]=[N:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)=[N:10][CH:11]=1
Reactant: Cc1nc(-c2cc(C3OCCO3)cnc2F)c2ncn(C3CCCCO3)c2n1
Reactant: COc1ccc(N)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Nc2ncc(C3OCCO3)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 77.8 %

Procedure:
6-(5-(1,3-Dioxolan-2-yl)-2-fluoropyridin-3-yl)-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (4.557 g, 11.82 mmol) and 5-amino-2-methoxypyridine (1.507 g, 12.14 mmol) were dissolved in tetrahydrofuran (80 mL) and cooled in an ice water bath. Then, LiHMDS (Aldrich 1.0 M in THF, 36.0 mL, 36.0 mmol) was added via syringe over about 10 minutes. The reaction was stirred under nitrogen at 0° C. for 40 minutes, and then the reaction was treated with water (100 mL) and warmed to room temperature. The layers were separated, and the aqueous phase was extracted with DCM. The aqueous phase was diluted with brine and extraction with DCM was continued. The combined organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel filter (600 mL fritted filter, about 3 inches of silica gel, 80:1 DCM/2 N ammonia in MeOH to 50:1 DCM/2 N ammonia in MeOH) to give 5-(1,3-dioxolan-2-yl)-N-(6-methoxypyridin-3-yl)-3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-amine (4.500 grams, 71% purity, 52% yield over two steps). MS MS (ESI pos. ion) m/z 446. Calculated exact mass for C23H23N7O3: 445 (M+—C2H4O). 1H NMR (CDCl3, 400 MHz) δ 12.69 (s, 1H), 9.91 (s, 1H), 8.44 (d, J=2.74 Hz, 1H), 8.41 (d, J=2.15 Hz, 1H), 8.29 (s, 1H), 8.23 (dd, J=8.80 Hz, 2.74 Hz, 1H), 6.79 (d, J=8.80 Hz, 1H), 5.94 (s, 1H), 5.87 (dd, J=10.56 Hz, 2.15 Hz, 1H), 4.24-4.17 (m, 3H), 4.12-4.05 (m, 2H), 3.96 (s, 3H), 3.88-3.79 (m, 1H), 2.91 (s, 3H), 2.19-2.00 (m, 3H), 1.93-1.77 (m, 3H).
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[Cl:5][C:6]1[CH:11]=[C:10]([CH2:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[O:14])[CH:9]=[CH:8][N:7]=1>O.C(O)(=O)C>[Cl:5][C:6]1[CH:11]=[C:10]([C:12](=[N:1][OH:3])[C:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[O:14])[CH:9]=[CH:8][N:7]=1
Reactant: O=C(Cc1ccnc(Cl)c1)c1ccc(F)cc1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(C(=NO)c1ccnc(Cl)c1)c1ccc(F)cc1
Temperature: 10 °C
Reaction time: 3 h

Procedure:
With stirring and cooling in a water bath (about 10° C.), a solution of NaNO2 (0.85 g; 12.3 mmol) in H2O (10 ml) was added dropwise over a period of 2.5 min to a solution of 21a (3.0 g; 12 mmol) in glacial acetic acid. After the addition had ended, the reaction mixture was stirred at room temperature for 0.5 h, H2O (60 ml) was added and stirring at room temperature was continued for 3 h. The light-beige precipitate was filtered off, washed with water and dried under reduced pressure over CaCl2.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].[Si:7](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.N1C=CN=C1.O>CN(C)C=O>[O:5]([CH2:4][CH2:3][CH2:2][CH2:1][OH:6])[Si:7]([C:20]([CH3:23])([CH3:22])[CH3:21])([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCCCCO
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCCCCO)(c1ccccc1)c1ccccc1
Yield: 64.9 %

Procedure:
To a solution of 1.00 g (10.2 mmol) of 1,4-butanediol in 20 ml of dry dimethylformamide were added 2.80 g (10.2 mmol) of tert-butyldiphenylsilyl chloride and 3.47 g (51.0 mmol) of imidazole in an atmosphere of argon. The mixture was allowed to react at 0° C. for 24 hours. To the solution was added water followed by extraction with dichloromethane. The organic layer was washed with water and concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography for separation and purification. Elution with dichloromethane-methanol (100:1) yielded 2.17 g (6.62 mmol) of 4-(tert-butyldiphenylsiloxy)-1-butanol.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=3)[C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:12])=[O:11])=[C:7]([CH3:25])[C:6]=2[CH:26]=1.[Li+].C[Si]([N-:32][Si](C)(C)C)(C)C>>[NH2:32][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=3)[C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:12])=[O:11])=[C:7]([CH3:25])[C:6]=2[CH:26]=1
Reactant: CCOC(=O)c1cccc(NS(=O)(=O)c2sc3ccc(Br)cc3c2C)c1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: CCOC(=O)c1cccc(NS(=O)(=O)c2sc3ccc(N)cc3c2C)c1
Yield: 18.7 %

Procedure:
The intermediate ethyl 3-{[(5-amino-3-methyl-1-benzothien-2-yl)sulfonyl]amino}benzoate was prepared from ethyl 3-{[(5-bromo-3-methyl-1-benzothien-2-yl)sulfonyl]amino}benzoate (Intermediate 18) (45 mg, 0.1 mmol) and LiHMDS (1M in THF, 120 μL, 0.12 mmol) according to General Procedure 4, described in Example 45, using a modified reaction time and reaction temperature (100° C., 1500 s, microwave reactor) yielding 7.3 mg of ethyl 3-{[(5-amino-3-methyl-1-benzothien-2-yl)sulfonyl]-amino}benzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH2:39][CH3:40])[C:6]=1[C:7]1[CH:8]=[C:9]([C:12]([NH:14][C@@H:15]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]([F:38])([F:37])[F:36])[CH2:16][N:17]2C(=O)C3C(=CC=CC=3)C2=O)=[O:13])[S:10][CH:11]=1.NN>CO>[NH2:17][CH2:16][C@@H:15]([NH:14][C:12]([C:9]1[S:10][CH:11]=[C:7]([C:6]2[N:5]([CH2:39][CH3:40])[N:4]=[CH:3][C:2]=2[Cl:1])[CH:8]=1)=[O:13])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]([F:38])([F:37])[F:36]
Reactant: CCn1ncc(Cl)c1-c1csc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)c1
Agent: NN
Solvent: CO
Product: CCn1ncc(Cl)c1-c1csc(C(=O)N[C@H](CN)Cc2ccccc2C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide (350 mg, 0.60 mmol) was dissolved in MeOH (5 mL) and treated with NH2NH2 (0.5 mL, 15.93 mmol). The mixture was stirred at RT overnight, and concentrated. The residue was purified by column chromatography (silica, 2-5% MeOH in CHCl3 (0.5% NH4OH) affording the free base of the title compound, which was treated with HCl(aq) in MeOH to give title compound (0.16 g, 51%) as a off white solid: LC-MS (ES) m/z=457 (M+H)+. 1H NMR (d4-MeOD, 400 MHz) δ ppm 7.97-7.94 (m, 2H), 7.71 (d, J=7.8 Hz, 1H), 7.61 (s, 1H), 7.56-7.51 (m, 2H), 7.43 (dd, J=7.6, 7.6 Hz, 1H), 4.67 (m, 1H), 4.22 (q, J=7.1 Hz, 2H), 3.36-3.12 (m, 4H), and 1.38 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:19][C:18]3[C:20]([C:25]4[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=4[Cl:32])=[CH:21][C:22]([F:24])=[CH:23][C:17]=3[CH2:16][CH:15]=[CH:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.C(O)C.[Pt](=O)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:19][C:18]3[C:20]([C:25]4[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=4[Cl:32])=[CH:21][C:22]([F:24])=[CH:23][C:17]=3[CH2:16][CH2:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C=CCc3cc(F)cc(-c4c(Cl)cccc4Cl)c3O2)cc1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCCc3cc(F)cc(-c4c(Cl)cccc4Cl)c3O2)cc1
Yield: 86.5 %

Procedure:
A solution (R)-(9-(2,6-dichlorophenyl)-7-fluoro-2,5-dihydrobenzo[b]oxepin-2-yl)methyl 4-methylbenzene-sulfonate (0.7 g, 1.4 mmol) in ethyl acetate/ethanol (10/10 mL) was added platinum (IV) oxide (0.2 g) and the mixture hydrogenated at 45 psi of hydrogen for 14 hours. The reaction mixture was then filtered through celite and the filtrate concentrated under reduced pressure. Chromatography with 10–30% ethyl acetate in hexanes afforded 0.60 g (85%) of (R)-(9-(2,6-dichlorophenyl)-7-fluoro-2,3,4,5-tetrahydrobenzo[b]oxepin-2-yl)methyl 4-methylbenzene-sulfonate as a colorless oil. [α]D25=+24.81° (c=6.6 mg/0.7 mL MeOH); MS (ES) m/z 512.1 ([M+NH4]+).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[CH3:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([CH3:32])[C:23]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH:19]=O.S([O-])(O)=O.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C.O>[CH2:25]([O:24][C:23]1[C:16]([CH3:15])=[CH:17][C:18]([C:19]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=3[O:13][CH3:14])[N:1]=2)=[CH:21][C:22]=1[CH3:32])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Cc1cc(C=O)cc(C)c1OCc1ccccc1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCc4ccccc4)c(C)c3)nc2c1
Temperature: 150 °C
Reaction time: 16 h
Yield: 77.7 %

Procedure:
A mixture of 2-amino-4,6-dimethoxy-benzamide (0.71 g, 3.71 mmol), 3,5-dimethyl-4-benzyloxy benzaldehyde (0.94 g, 3.90 mmol), sodium hydrogensulfite (0.68 g, 3.90 mmol) and p-toluenesulfonic acid (70 mg, 0.37 mmol) in N,N-dimethylacetamide (25 mL) was stirred at 150° C. for 16 h. The reaction mixture was cooled to room temperature and diluted with water (200 mL). The resulting solid was collected by filtration and washed with hexanes to afford 2-(4-benzyloxy-3,5-dimethyl-phenyl)-5,7-dimethoxy-3H-quinazolin-4-one as a white solid (1.2 g, 79%).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([O:13][CH3:14])=[C:5]([CH3:12])[C:6]([CH3:11])=[C:7]([O:9][CH3:10])[CH:8]=1.[C:15]([O-:18])(=[O:17])[CH3:16].[Na+]>C(O)(=O)C.O>[C:15]([O:18][CH2:2][C:3]1[C:4]([O:13][CH3:14])=[C:5]([CH3:12])[C:6]([CH3:11])=[C:7]([O:9][CH3:10])[CH:8]=1)(=[O:17])[CH3:16]
Reactant: COc1cc(CCl)c(OC)c(C)c1C
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(COC(C)=O)c(OC)c(C)c1C
Temperature: 25 °C
Yield: 93.1 %

Procedure:
A mixture of intermediate C (5 g, 0.023 mole) and anhydrous sodium acetate (7.1 g, 0.086 mole) in glacial acetic acid (35 ml) was refluxed for 20 hours. The reaction mixture was cooled to room temperature, diluted with 50 ml of water and extracted with dichloromethane. The organic extracts were washed with saturated sodium bicarbonate solution, dried, and concentrated to yield a dark syrup, which eventually crystallized to give 5.1 g of crude 5-acetoxymethyl-1,4-dimethoxy-2,3-dimethylbenzene (intermediate D).
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([NH2:11])=[CH:6][C:5]=1[O:12][CH2:13][CH2:14][O:15][CH3:16].[OH-].[Na+].O>C(O)C>[NH2:11][C:7]1[C:8]([Cl:10])=[CH:9][C:4]([C:3]([OH:17])=[O:2])=[C:5]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:6]=1
Reactant: COCCOc1cc(N)c(Cl)cc1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COCCOc1cc(N)c(Cl)cc1C(=O)O
Yield: 78 %

Procedure:
A solution of 4-amino-5-chloro-2-(2-methoxyethoxy)benzoic acid methyl ester (2.75 g, 10.6 mmol) in 95% ethanol (20 mL) was treated with 50% sodium hydroxide (10 mL) and water (10 mL), and refluxed for one hour. The ethanol was removed in vacuo and replaced with water. The aqueous solution was extracted with ether (20 mL) and acidified to pH 4 with concentrated hydrochloric acid (16 mL). A solid soon precipitated, and this was filtered, washed with water, air dried, and recrystallized from ethyl acetate (2 crops) to afford 2.03 g (75%) of fine pale tan needles; mp 119°-120° C.
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH2:5][CH2:4][NH:3]1.C(N(CC)CC)C.[Cl:21][C:22]1[N:27]=[C:26](Cl)[C:25]([CH3:29])=[C:24]([CH2:30][O:31][CH3:32])[N:23]=1>CN(C)C=O>[CH3:32][O:31][CH2:30][C:24]1[N:23]=[C:22]([Cl:21])[N:27]=[C:26]([N:3]2[CH2:4][CH2:5][C:6]3[C:11](=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=3)[CH:2]2[CH3:1])[C:25]=1[CH3:29]
Reactant: COCc1nc(Cl)nc(Cl)c1C
Reactant: COc1ccc2c(c1)CCNC2C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCc1nc(Cl)nc(N2CCc3cc(OC)ccc3C2C)c1C
Yield: 91.3 %

Procedure:
After 1-methyl-6-methoxy-1,2,3,4-tetrahydroisoquinoline(1.2 g, 6.8 mmol) and triethylamine(0.96 ml, 6.9 mmol) were added to a suspension of 2,4-dichloro-6-methoxymethyl-5-methylpyrimidine(1.3 g, 6.3 mmol) in dimethylformamide, 2.0 g of the titled compound was obtained in accordance with the same procedure as in Step 1 of Example 35. (Yield: 73.6%)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][CH:5]1[CH2:7][CH:6]1[C:8]1[CH:13]=[CH:12][C:11]([O:14]C)=[C:10]([F:16])[CH:9]=1.B(Br)(Br)Br.CO>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:17])[CH2:4][CH:5]1[CH2:7][CH:6]1[C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([F:16])[CH:9]=1
Reactant: COC(=O)CC1CC1c1ccc(OC)c(F)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: COC(=O)CC1CC1c1ccc(O)c(F)c1
Temperature: -78 °C
Reaction time: 3 h
Yield: 84.4 %

Procedure:
After [2-(3-fluoro-4-methoxy-phenyl)-cyclopropyl]-acetic acid methyl ester (0.067 g, 0.28 mmol) obtained in Step E was dissolved in anhydrous DCM (2 mL), BBr3 1M DCM solution (0.42 mL, 0.42 mmol) was added thereto at −78° C., and the mixture was stirred at room temperature for 3 hours. After the termination of the reaction, the reactant was added with MeOH, concentrated under reduced pressure, and then purified by column chromatography (eluent, EtOAc/Hex=1/2) to obtain the title compound (0.053 g, 84%).
Reaction SMILES: Cl.Cl[C:3]1[C:4]2[NH:15][C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:5]=2[N:6]=[CH:7][N:8]=1.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[NH:16]([C:3]1[C:4]2[NH:15][C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:5]=2[N:6]=[CH:7][N:8]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Clc1ncnc2c1[nH]c1ccccc12
Reactant: Nc1ccccc1
Agent: Cl
Solvent: CCO
Product: c1ccc(Nc2ncnc3c2[nH]c2ccccc23)cc1
Yield: 105.3 %

Procedure:
A solution of 4-chloroindolo[3,2-d]pyrimidinehydrochloride (240 mg, 1.0 mmol) [Monge, A.; Palop, J. A.; Goni, T.; Martinez-Crespo, F.; Recalde, I. J. Het. Chem., 1986, 23, 647-9.], and aniline (0.273 mL, 3 mmol) in ethanol (1 mL) is heated at reflux for 3 h, during which time the reaction becomes a thick suspension. After cooling to 25 C. and diluting with ethanol (4 ml) the mixture is filtered, and the crude product washed with water (15 mL), and ethanol (15 mL), giving 274 mg tan solid, which is recrystallized from DMF/water affording pure 4-anilinoindolo[3,2-d]pyrimidine hydrochloride (82 mg, 27%). 1H NMR (DMSO): δ12.79 (1H, brs), 11.04 (1H, brs), 8:94 (1H, s), 8.27 (1H, d, J=8.2 Hz), 7.96 (2H, d, J=7.5 Hz), 7.85 (1H, d, J=8.4 Hz), 7.71 (1H, t, J=7.7 Hz), 7.49 (2H, t, J=8.0 Hz), 7.41 (1H, t, J=7.6 Hz), 7.24 (1H, t, J=7.4 Hz).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[CH:7]=[N:8][N:9]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:10]=2[CH:11]=[C:12]([C:14]#[N:15])[CH:13]=1)=[O:4].[OH-].[Na+].Cl>O.CO>[C:14]([C:12]1[CH:13]=[C:5]([C:3]([OH:4])=[O:2])[C:6]2[CH:7]=[N:8][N:9]([C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[C:10]=2[CH:11]=1)#[N:15]
Reactant: COC(=O)c1cc(C#N)cc2c1cnn2-c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: N#Cc1cc(C(=O)O)c2cnn(-c3ccc(F)cc3)c2c1
Temperature: 25 °C

Procedure:
To a stirred solution of 6-cyano-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid methyl ester (0.30 g, 1.1 mmol) in water (10 mL) and methanol (10 mL) was added a 2 N aqueous sodium hydroxide (10 mL, 20 mmol). The mixture was warmed at reflux for 1 hour, cooled to room temperature, and acidified with 1 N aqueous HCl (pH=3-4). The white solid was collected by filtration, washed with MeOH (10 mL) and dried to afford 6-cyano-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].F[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1[O:20][CH3:21].C(=O)([O-])[O-].[K+].[K+]>O>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([O:9][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=2[O:20][CH3:21])=[CH:3][C:2]=1[Cl:1]
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: COc1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1cc([N+](=O)[O-])ccc1Oc1ccc(Cl)c(Cl)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 81.9 %

Procedure:
A mixture of 3,4-dichlorophenol (38 g, 233.13 mmol, 1.00 equiv), 1-fluoro-2-methoxy-4-nitrobenzene (40 g, 233.75 mmol, 1.00 equiv) and potassium carbonate (64 g, 463.77 mmol, 1.99 equiv) N,N-dimethylformamide (250 mL) was stirred overnight at 60° C. The resulting solution was diluted with 1000 mL of water, extracted with 3×200 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×500 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum to yield 60 g (82%) of 1,2-dichloro-4-(2-methoxy-4-nitrophenoxy)benzene as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:18])([C:13]#[C:14][CH:15]([CH3:17])[CH3:16])[C:9]([F:12])([F:11])[F:10])=[CH:6][C:5]([Cl:19])=[CH:4][CH:3]=1.N1C=CC=CC=1.Br[CH2:27][C:28](Br)=[O:29].[H-].[Na+]>CCOCC>[Cl:19][C:5]1[CH:4]=[CH:3][C:2]2[NH:1][C:28](=[O:29])[CH2:27][O:18][C:8]([C:13]#[C:14][CH:15]([CH3:16])[CH3:17])([C:9]([F:10])([F:11])[F:12])[C:7]=2[CH:6]=1
Reactant: CC(C)C#CC(O)(c1cc(Cl)ccc1N)C(F)(F)F
Reactant: O=C(Br)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(C)C#CC1(C(F)(F)F)OCC(=O)Nc2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62.8 %

Procedure:
To a stirred ice-cooled solution of 4.37 g (15 mmol) of 6-amino-3-chloro-α-(isopropylethynyl)-α-(trifluoromethyl)benzyl alcohol in 200 mL of dry ether was added 2.4 mL of dry pyridine and, quickly dropwise, 1.40 mL (16 mmol) of bromoacetyl bromide. After 30 min, the reaction mixture was diluted with ether, washed with water and aqueous sodium bicarbonate, dried and evaporated. The residue was dissolved in 150 mL of dry DMF and was treated at 0° with 400 mg of 100% sodium hydride (16.7 mmol) for 20 min. The cooling bath was removed, and the reaction was allowed to proceed at ambient temperature for 1.5 h. The reaction mixture was poured onto a mixture of 1.2 L of water and 300 mL of saturated aqueous sodium chloride and this was extracted 3 times with ether. The combined extracts were washed with brine, dried, and evaporated to a solid which was crystallized by dissolving in hot ethyl acetate and adding hexanes. This material was recrystallized from ethyl acetate/hexane to afford 3.125 g of pure title compound as a crystalline solid: mp 183-183.5°; HRMS Calcd. for C15H14NO2ClF3 (M+H)+: 332.066516. Found: 332.065892.
Reaction SMILES: [NH2:1][C@@H:2]([CH:5]([CH2:8][CH3:9])[CH2:6][CH3:7])[CH2:3][OH:4].C(N(CC)CC)C.[Cl:17][C:18]1[S:22][C:21]([S:23](Cl)(=[O:25])=[O:24])=[CH:20][CH:19]=1>C(Cl)Cl>[Cl:17][C:18]1[S:22][C:21]([S:23]([NH:1][C@H:2]([CH2:3][OH:4])[CH:5]([CH2:8][CH3:9])[CH2:6][CH3:7])(=[O:25])=[O:24])=[CH:20][CH:19]=1
Reactant: CCC(CC)[C@H](N)CO
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(CC)[C@@H](CO)NS(=O)(=O)c1ccc(Cl)s1
Temperature: 0 °C
Yield: 45.2 %

Procedure:
To a reaction vessel was added a mixture of 3-pentanone (6.4 g), triethyl phosphonoacetate (34 g), NaH (3.6 g), and enough dry THF (250 mL), at 0° C. and maintained for 8 h to obtain α,β-unsaturated ester (ethyl 3-ethylpent-2-enoate) (2) (93%). This was followed by passing hydrogen gas (1 atm) over 10% Pd/C (250 mg), in MeOH (100 mL), for about 12 h at 25° C. To the reaction mixture was further added LiAlH4 (1.8 g), and dry THF (100 mL), at 0° C. for 12 h to obtain alcohol (3-ethylpentan-1-ol) (3) (83% for two steps). Alcohol (3) (6 g), was reacted with (o-iodoxy benzoic acid) (21.6 g), in dry DMSO (65 mL), at 25° C. for 2 h to yield aldehyde (3-ethylpentanal) (4). This is followed by addition of PhNO (nitrosobenzene)(5 g), L-proline (20 mol %)(1.3 g), in acetonitrile (250 mL), at −20° C. for 24 h and then added NaBH4 (7 g), in MeOH (100 mL). To the mixture is passed H2 gas (1 atm) over 10% Pd/C (250 mg), in MeOH (100 mL), for 12 h at 25° C., (77% over two steps) to obtain diol (3-ethylpentane-1,2-diol) (5). Then tert-butyl silylchloride (TBSCl) (7.5 g), in imidazole (4.5 g), and methylene chloride (200 mL), is added to the diol (5) at 0-25° C. (addition at 0° C. stirring at 25° C.) for 2 h to obtain (3-ethyl-2-hydroxy-pent-1-yloxy(tert-butyl)dimethylsilane) (6) (81%) followed by treatment with mesyl chloride (7.7 g), in triethyl amine (20 mL), for 45 min to yield (7). To the protected diol (3-ethyl-2-methansolphonyl-pent-1-yloxy(tert-butyl)dimethylsilane) (7) was added NaN3 (4 g), in dry DMF (100 mL), at 60° C. for 30 h, (78% for two steps) to obtain compound (2-azido-3-ethylpentyloxy tet-butyl dimethylsilane) (8). To the compound (8) was added LiAlH4 (2 g), in dry THF (100 mL), at 50° C. for 12 h to afford (S)-2-amino 3ethyl pentan-1-ol (9)(75%). A mixture of (S)-2-amino 3ethyl pentan-1-ol (9) (200 mg) and methylene chloride (20 mL) was placed under argon, and cooled to 0° C. Triethyl amine (484 mg) was added followed by the drop wise addition of 5-chlorothiophene-2-sulfonyl chloride (347.2) in methylene chloride (5 mL) for 30 min to obtain (S)—N-(5-chlorothiophene-2-sulfonyl)-β,β-diethylalaninol (1A) (45.2% overall yield and 98% ee).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:24]=[CH:23][C:12]([O:13][C:14]3[NH:18][C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[N:15]=3)=[CH:11][CH:10]=2)O1.Br[C:27]1[C:28]2[N:39]=[CH:38][CH:37]=[CH:36][C:29]=2[N:30]2[C:35]=1[CH2:34][CH2:33][CH2:32][CH2:31]2.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.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>[NH:18]1[C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[N:15]=[C:14]1[O:13][C:12]1[CH:11]=[CH:10][C:9]([C:27]2[C:28]3[N:39]=[CH:38][CH:37]=[CH:36][C:29]=3[N:30]3[C:35]=2[CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:24][CH:23]=1
Reactant: Brc1c2n(c3cccnc13)CCCC2
Reactant: CC1(C)OB(c2ccc(Oc3nc4ccccc4[nH]3)cc2)OC1(C)C
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: COCCOC
Solvent: O
Product: c1ccc2[nH]c(Oc3ccc(-c4c5n(c6cccnc46)CCCC5)cc3)nc2c1
Temperature: 150 °C
Yield: 13.2 %

Procedure:
To a suspension of 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-1H-benzo[d]imidazole (320 mg), 10-bromo-6,7,8,9-tetrahydropyrido[2,3-b]indolizine (217 mg) and K2CO3 (119 mg) in DME (4 mL) and water (1 mL) was added Pd(PPh3)4 (100 mg). The mixture was heated at 150° C. for 40 min under microwave irradiation. The mixture was poured into water and extracted with AcOEt. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (43.4 mg).