Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][NH:9][C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:6][CH:5]=1)([O-])=O.[BH4-].[Na+]>C1COCC1.CO.[Ni](Br)Br>[N:11]1[CH:12]=[CH:13][CH:14]=[N:15][C:10]=1[NH:9][CH2:8][C:7]1[CH:16]=[CH:17][C:4]([NH2:1])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(CNc2ncccn2)cc1
Agent: Br[Ni]Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(CNc2ncccn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26 %

Procedure:
In THF (20 ml) and methanol (20 ml) was dissolved N-(4-nitrobenzyl)-N-(2-pyrimidinyl)amine (921 mg, 4.00 mmol), and to the mixture were added at 0° C. nickel bromide (137 mg) and sodium boro hydride(955 mg). The mixture was stirred at room temperature for 30 minutes and concentrated under reduced pressure. To the residue were added ethyl acetate, THF and water, and the insoluble materials were filtered off. The aqueous layer was extracted with ethyl acetate-THF, and the organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified with column chromatography (silica gel 30 g, ethyl acetate/hexane=1/1), and the desired fraction was concentrated under reduced pressure. To the residue was added diethylether, and the insoluble materials were filtered, which were washed with diethylether and dried under reduced pressure to give 4-[N-(2-pyrimidinyl)aminomethyl]aniline (208 mg, 1.04 mmol, 26%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([NH:17][C@H:18]2[CH2:22][CH2:21][N:20]([S:23]([C:26]3[C:27]4[C:28]([Cl:36])=[CH:29][N:30]=[CH:31][C:32]=4[CH:33]=[CH:34][CH:35]=3)(=[O:25])=[O:24])[CH2:19]2)=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C(OC(N1CCN(CC(O)=O)CC1)=O)(C)(C)C.COCC(O)=O>>[N:11]1([CH2:14][C:15]([NH:17][C@@H:18]2[CH2:22][CH2:21][N:20]([S:23]([C:26]3[C:27]4[C:28]([Cl:36])=[CH:29][N:30]=[CH:31][C:32]=4[CH:33]=[CH:34][CH:35]=3)(=[O:25])=[O:24])[CH2:19]2)=[O:16])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(CC(=O)N[C@H]2CCN(S(=O)(=O)c3cccc4cncc(Cl)c34)C2)CC1
Agent: CC(C)(C)OC(=O)N1CCN(CC(=O)O)CC1
Agent: COCC(=O)O
Agent: Cl
Product: O=C(CN1CCNCC1)N[C@@H]1CCN(S(=O)(=O)c2cccc3cncc(Cl)c23)C1

Procedure:
(S)-3-[2-[4-(tert-butoxycarbonyl)piperazin-1-yl]acetyl]amino-1-(4-chloro-5-isoquinolinesulfonyl)pyrrolidine can be prepared from hydrochloride of the compound prepared in Example 19-2 by using 2-[4-(tert-butoxycarbonyl)piperazin-1-yl]acetic acid in the method of Example 56-1 instead of 2-methoxyacetic acid, and the protective group of the obtained compound can be removed according to the method described in Example 1-1, Step B to obtain the title compound.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[NH2:11][C:12]1[C:17]([Cl:18])=[CH:16][C:15]([NH:19][C:20](=[O:25])[C:21]([Cl:24])([Cl:23])[Cl:22])=[CH:14][C:13]=1[Cl:26]>>[Cl:26][C:13]1[CH:14]=[C:15]([NH:19][C:20](=[O:25])[C:21]([Cl:24])([Cl:22])[Cl:23])[CH:16]=[C:17]([Cl:18])[C:12]=1[NH:11][CH:1]=[O:3]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1c(Cl)cc(NC(=O)C(Cl)(Cl)Cl)cc1Cl
Solvent: O=CO
Product: O=CNc1c(Cl)cc(NC(=O)C(Cl)(Cl)Cl)cc1Cl
Temperature: 5 °C
Reaction time: 20 h
Yield: 69.1 %

Procedure:
Acetic anhydride (600 mL, 6.4 mol) and 90% formic acid (275 mL, 5.4 mol) are heated to reflux for 45 minutes and then cooled to 5° C. The N-(4-amino-3,5-dichlorophenyl)-trichloroacetamide (464 g., 1.44 mol) is added to the mixed anhydride solution and mechanically stirred for 20 hours at room temperature. Then the reaction mixture is poured onto ice (2 liters). When the stirred slurry reaches room temperature, it is collected by suction filtration and washed with water (1.5 liters) and dried to constant weight yielding 348.7 grams of N-(3,5-dichloro-4-formamidophenyl)-trichloroacetamide with a mass spectral analysis of m/e+· 348 for C9H5Cl5N2O2.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3([NH:19]S(C(C)(C)C)=O)[CH2:18][O:17][CH2:16]3)=[CH:11][CH:10]=2)[C:5]([N+:26]([O-:28])=[O:27])=[CH:4][CH:3]=1.Cl.CCCCCC>C(Cl)Cl.O1CCOCC1>[ClH:1].[NH2:19][C:15]1([C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:6]3[C:5]([N+:26]([O-:28])=[O:27])=[CH:4][CH:3]=[C:2]([Cl:1])[N:7]=3)=[CH:14][CH:13]=2)[CH2:16][O:17][CH2:18]1
Reactant: CC(C)(C)S(=O)NC1(c2ccc(Nc3nc(Cl)ccc3[N+](=O)[O-])cc2)COC1
Agent: Cl
Solvent: CCCCCC
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC1(c2ccc(Nc3nc(Cl)ccc3[N+](=O)[O-])cc2)COC1
Reaction time: 0.17 h

Procedure:
Deprotection/protection step: To a solution of N-(3-{4-[(6-chloro-3-nitropyridin-2-yl)amino]phenyl}oxetan-3-yl)-2-methylpropane-2-sulfinamide (95 mg) in DCM (5 ml) was added dropwise a solution of hydrogen chloride in dioxane (4 M, 111 ul) at room temperature. The reaction mixture was stirred for 10 min. Hexane was added to the suspension and the solid was filtered to give N-[4-(3-aminooxetan-3-yl)phenyl]-6-chloro-3-nitropyridin-2-amine hydrochloride. To a suspension of N-[4-(3-aminooxetan-3-yl)phenyl]-6-chloro-3-nitropyridin-2-amine hydrochloride in THF (3 mL) chilled to 0° C. was added saturated sodium bicarbonate solution (6 mL) and followed by a solution of di-tert-butyl dicarbonate (145 mg) in THF (3 mL) dropwise. After being stirred at room temperature over night, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and brine. The organics were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (10-100% ethyl acetate in hexanes) gave the product (59 mg, 2 steps 63%). 400 M Hz 1H-NMR (DMSO-d6) δ: 10.14 (s, 1H), 8.55 (d, J=8.7 Hz, 1H), 8.10 (brs, 1H), 7.62 (d, J=8.7 Hz, 2H), 7.49 (d, J=8.7 Hz, 2H), 7.01 (d, J=8.7 Hz, 1H), 4.82 (d, J=6.4 Hz, 2H), 4.68 (d, 2H, J=6.4 Hz), 1.50-1.10 (m, 9H); LCMS: 421 [M+H].
Reaction SMILES: [Cl:1][C:2]1[O:3][CH:4]=[C:5]([CH2:7][OH:8])[N:6]=1.[CH3:9][S:10](Cl)(=[O:12])=[O:11].C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl>[CH3:9][S:10]([O:8][CH2:7][C:5]1[N:6]=[C:2]([Cl:1])[O:3][CH:4]=1)(=[O:12])=[O:11]
Reactant: OCc1coc(Cl)n1
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1coc(Cl)n1
Reaction time: 1 h

Procedure:
A solution of (2-chloro-1,3-oxazol-4-yl)methanol (5 g, 37.44 mmol, 1 eq, prepared according to the method described in Tetrahedron Lett. (2004), 45, 3797-3802) in dichloromethane (250 ml) is reacted with methanesulfonyl chloride (3.19 ml, 41.19 mmol, 1.1 eq) in the presence of triethylamine (5.79 ml, 41.19 mmol, 1.1 eq) at 0° C. After 1 h 30, the mixture is poured into a saturated solution of ammonium chloride and extracted twice with dichloromethane. The organic layer is dried over magnesium sulfate, filtered and concentrated under vacuum to afford 7.9 g of (2-chloro-1,3-oxazol-4-yl)methyl methanesulfonate i59. This product is used in the next step without further purification or analysis.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH:8][C:9](=O)[C:10]([F:13])([F:12])[F:11])[CH:5]=[CH:4][C:3]=1[O:15][CH3:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N-:36]=[N+:37]=[N-:38].[Na+]>>[Br:1][C:2]1[CH:7]=[C:6]([N:8]2[C:9]([C:10]([F:13])([F:12])[F:11])=[N:38][N:37]=[N:36]2)[CH:5]=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: COc1ccc(NC(=O)C(F)(F)F)cc1Br
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1ccc(-n2nnnc2C(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.3 %

Procedure:
A mixture of 705 mg (2.4 mmol) of 2-bromo-4-(trifluoroacetamido)anisole and 625 mg (2.4 mmol) of triphenylphosphine in 25 mL of CC14 was heated at reflux. After 4 h, a second 625 mg portion of triphenylphosphine was added and heating was continued for 16 h. The reaction mixture was cooled and concentrated in vacuo. The residue was dissolved in 15 mL of DMF, treated with 650 mg (10.0 mmol) of NaN3 and stirred at rt. After 1.5 h, the reaction mixture was concentrated in vacuo and the residue was partitioned between 200 mL of ether and 100 mL of H2O. The layers were separated; the organic layer was washed with 2×100 mL of H2O, dried over MgSO4 and concentrated in vacuo. Flash chromatography on 40 g of silica gel using 4:1 v/v hexanes/ether as the eluant afforded 700 mg (91%) of the title compound as an oil. 1H NMR (500 MHz, CDCl3): δ 4.01 (s, 3H), 7.07 (d, J=8.5, 1H), 7.43 (dd, J=8.5, 2.5), 7.71 (d, J=2.5, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:12][C:11](=[CH2:13])[CH2:10][CH:9]1[C:14]1[NH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[C:30]([C:35]5[NH:36][C:37]([CH:40]6[CH2:44][CH2:43][CH2:42][N:41]6[C:45](=[O:58])[CH:46]([NH:53][C:54]([O:56][CH3:57])=[O:55])[CH:47]6[CH2:52][CH2:51][O:50][CH2:49][CH2:48]6)=[N:38][CH:39]=5)[CH:31]=4)[CH:26]=3)=[CH:21][CH:20]=2)=[CH:17][N:18]=1)=O)(C)(C)C.Cl.[CH3:60][O:61][C:62]([NH:64][CH:65]([C:69]1[CH:70]=[N:71][CH:72]=[CH:73][CH:74]=1)[C:66]([OH:68])=O)=[O:63].[Na+].[Cl-].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:60][O:61][C:62](=[O:63])[NH:64][CH:65]([C:69]1[CH:70]=[N:71][CH:72]=[CH:73][CH:74]=1)[C:66]([N:8]1[CH2:12][C:11](=[CH2:13])[CH2:10][CH:9]1[C:14]1[NH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[C:30]([C:35]5[NH:36][C:37]([CH:40]6[CH2:44][CH2:43][CH2:42][N:41]6[C:45](=[O:58])[CH:46]([NH:53][C:54]([O:56][CH3:57])=[O:55])[CH:47]6[CH2:52][CH2:51][O:50][CH2:49][CH2:48]6)=[N:38][CH:39]=5)[CH:31]=4)[CH:26]=3)=[CH:21][CH:20]=2)=[CH:17][N:18]=1)=[O:68]
Reactant: COC(=O)NC(C(=O)O)c1cccnc1
Reactant: C=C1CC(c2ncc(-c3ccc(-c4ccc5cc(-c6cnc(C7CCCN7C(=O)C(NC(=O)OC)C7CCOCC7)[nH]6)ccc5c4)cc3)[nH]2)N(C(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=C1CC(c2ncc(-c3ccc(-c4ccc5cc(-c6cnc(C7CCCN7C(=O)C(NC(=O)OC)C7CCOCC7)[nH]6)ccc5c4)cc3)[nH]2)N(C(=O)C(NC(=O)OC)c2cccnc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 12.4 %

Procedure:
2-(5-{4-[6-(2-{1-[2-Methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-phenyl}-1H-imidazol-2-yl)-4-methylene-pyrrolidine-1-carboxylic acid tert-butyl ester (64 mg, 0.0816 mmol) was dissolved in DCM (1 mL) and HCl (4N dioxane, 1 mL) was added. After 20 minutes all volatiles were removed in vacuo. The crude material was dissolved in DMF (1 mL) and Methoxycarbonylamino-pyridin-3-yl-acetic acid/NaCl (1:1, 22 mg, 0.0816 mmol), HATU (31 mg, 0.0816 mmol), and DIEA (31.5 mg, 0.245 mmol) were added and stirring at room temperature was continued. After 30 minutes, aqueous HCl (1N, 0.1 mL) was added and the reaction mixture was purified via RP-HPLC (eluent: water/MeCN w/ 0.1% TFA). The product containing fractions were lyophilized to yield the product (8.9 mg).
Reaction SMILES: [CH:1]1[N:6]=[C:5]2[N:7]([C@@H:10]3[O:14][C@H:13]([CH2:15][O:16][P:17]([O:20][P:21]([O:24][P:25]([OH:28])([OH:27])=[O:26])([OH:23])=[O:22])([OH:19])=[O:18])[C@@H:12]([OH:29])[CH2:11]3)[CH:8]=[N:9][C:4]2=[C:3]([NH2:30])[N:2]=1.[OH:31]P(=O)(OC[C@H]1O[C@@H](N2C=C(C)C(=O)NC2=O)C[C@@H]1O)OP(=O)(OP(=O)(O)O)O.P(OC[C@H]1O[C@@H](N2C3N=C(N)NC(=O)C=3N=C2)C[C@@H]1O)(OP(OP(O)(O)=O)(O)=O)(=O)O.P(OC[C@H]1O[C@@H](N2C=CC(N)=NC2=O)C[C@@H]1O)(OP(OP(O)(O)=O)(O)=O)(=O)O>>[P:17]([O:16][CH2:15][C@H:13]1[O:14][C@@H:10]([N:7]2[C:5]3[N:6]=[CH:1][N:2]=[C:3]([NH2:30])[C:4]=3[N:9]=[CH:8]2)[C@H:11]([OH:31])[C@@H:12]1[OH:29])([O:20][P:21]([O:24][P:25]([OH:28])([OH:27])=[O:26])([OH:23])=[O:22])(=[O:19])[OH:18]
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)[nH]c1=O
Reactant: Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O1
Agent: Nc1ccn([C@H]2C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)n1
Agent: Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)[nH]1
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O

Procedure:
1 μL 6.25 mM dNTP mixture of equimolar amounts of dATP, dTTP, dGTP, dCTP
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:11]1[N:15](CCC#N)[N:14]=[N:13][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.Cl>ClCCl>[CH2:1]([O:8][CH2:9][C@H:10]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[C:11]1[N:12]=[N:13][NH:14][N:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)c1nnnn1CCC#N
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)c1nn[nH]n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 400 mg of tert-butyl {(1R)-2-(benzyloxy)-1-[1-(2-cyanoethyl)-1H-tetrazol-5-yl]ethyl}carbamate in 10 ml of dichloromethane was added 0.9 ml of 1,8-diazabicyclo[5.4.0]undeca-7-ene, followed by stirring at room temperature for 2 hours. The reaction mixture was added to a mixture of ice and 1 M hydrochloric acid, followed by extraction with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was then evaporated under reduced pressure to obtain 343 mg of tert-butyl [(1R)-2-(benzyloxy)-1-(2H-tetrazol-5-yl)ethyl]carbamate.
Reaction SMILES: [CH2:1]([CH:11]([CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68]CCCCCC)[CH2:12][N:13]=[C:14]([C:16]1[C:25]2[C:24]([C:26]([OH:28])=[O:27])=[C:23]([Br:29])[C:22]([Br:30])=[C:21]([C:31]([OH:33])=[O:32])[C:20]=2[C:19]([C:34](=[N:36][CH2:37][CH:38]([CH2:51][CH2:52][CH2:53][CH2:54]CCCCCC)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]CCCCCC)[OH:35])=[C:18]([Br:61])[C:17]=1[Br:62])[OH:15])[CH2:2][CH2:3][CH2:4]CCCCCC.C(C(CCCCCC)CN)CCC>>[CH2:51]([CH:38]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:37][N:36]=[C:34]([C:19]1[C:20]2[C:21]([C:31]([OH:33])=[O:32])=[C:22]([Br:30])[C:23]([Br:29])=[C:24]([C:26]([OH:28])=[O:27])[C:25]=2[C:16]([C:14](=[N:13][CH2:12][CH:11]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH3:68])[OH:15])=[C:17]([Br:62])[C:18]=1[Br:61])[OH:35])[CH2:52][CH2:53][CH3:54]
Reactant: CCCCCCCCCCCCC(CCCCCCCCCC)CN=C(O)c1c(Br)c(Br)c(C(O)=NCC(CCCCCCCCCC)CCCCCCCCCCCC)c2c(C(=O)O)c(Br)c(Br)c(C(=O)O)c12
Agent: CCCCCCC(CN)CCCC
Product: CCCCCCC(CCCC)CN=C(O)c1c(Br)c(Br)c(C(O)=NCC(CCCC)CCCCCC)c2c(C(=O)O)c(Br)c(Br)c(C(=O)O)c12
Yield: 25 %

Procedure:
The same synthetic method for compound 22 was used except using 2-butyloctyl amine instead of 2-decyltetradecyl amine, and the yield was 25% (calculated based on TBNDA as a starting material).
Reaction SMILES: [CH2:1]([C:4]1[C:12]2[O:11][N:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[C:8]=2[CH:7]=[CH:6][C:5]=1[CH2:17][CH2:18][CH2:19][CH2:20][OH:21])[CH2:2][CH3:3].CCN(CC)CC.[CH3:29][S:30](Cl)(=[O:32])=[O:31].Cl>C(Cl)Cl>[CH3:29][S:30]([O:21][CH2:20][CH2:19][CH2:18][CH2:17][C:5]1[CH:6]=[CH:7][C:8]2[C:9]([C:13]([F:15])([F:14])[F:16])=[N:10][O:11][C:12]=2[C:4]=1[CH2:1][CH2:2][CH3:3])(=[O:32])=[O:31]
Reactant: CCCc1c(CCCCO)ccc2c(C(F)(F)F)noc12
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1c(CCCCOS(C)(=O)=O)ccc2c(C(F)(F)F)noc12
Reaction time: 2 h

Procedure:
To a solution of 4-[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]butan-1-ol, from this Example step 4, in CH2Cl2 (25 mL) was added Et3N (0.42 mL, 2.99 mmol) and methanesulfonyl chloride (0.17 mL, 2.2 mmol) at 0° C. The mixture was stirred from 0° C. to room temperature for 2 hours. 0.5N HCl was added and the mixture extracted 3 times with CH2Cl2. Combined organic extracts were washed with water and brine then dried over Na2SO4. The solvent was evaporated in vacuo to give the title compound.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[N:19]([CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[N:19]([CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)CCn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)c2ccc(F)cc21
Temperature: 80 °C
Yield: 58.6 %

Procedure:
N-tert-Butyl-2-(1-(2-(dimethylamino)ethyl)-6-fluoro-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (0.085 g, 153 μmol) was placed in a sealed tube and dissolved in dichloromethane (2 mL). Trifluoroacetic acid (1.75 g, 1.18 mL, 15.3 mmol) was added and the tube sealed and the mixture heated at to 80° C. After 15 h the mixture was cooled and then concentrated in vacuo. The residue was crystallized from dichloromethane/methanol and cyclohexane to give N-tert-butyl-2-(1-(2-(dimethylamino)ethyl)-6-fluoro-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (38 mg, 89.7 μmol, 58.5%) as a white powder. MS (M+H)+=424; 1H NMR (CDCl3) δ: 9.07 (s, 1H), 8.42-8.50 (m, 1H), 8.24 (s, 1H), 7.33-7.41 (m, 1H), 7.02 (s, 1H), 4.88 (s, 2H), 3.68-3.79 (m, 2H), 2.85 (s, 7H), 1.55 (s, 6H).
Reaction SMILES: C([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([O:13][CH3:14])[CH:7]=1)C>CO.O>[OH:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][C:4]([OH:15])=[O:3])=[CH:7][C:8]=1[O:13][CH3:14]
Reactant: CCOC(=O)Cc1ccc(O)c(OC)c1
Solvent: O
Solvent: CO
Product: COc1cc(CC(=O)O)ccc1O
Temperature: 25 °C
Reaction time: 14 h
Yield: 96.4 %

Procedure:
A mixture of (4-hydroxy-3-methoxy-phenyl)-acetic acid ethyl ester (2 g, 9.51 mmol) and LiOH monohydrate (1.2 g, 28.5 mmol) in MeOH (20 ml) and water (10 ml) was stirred at RT for 14 h. The reaction mixture was concentrated under vacuum, diluted into water and neutralized by the addition of HCl 2 M in water (14.3 ml). The resulting slurry was extracted with DCM (3×) and AcOEt (2×) and the combined organic fractions were dried over Na2SO4, filtered and evaporated to dryness to yield the crude title compound (1.67 g, 9.17 mmol, 96%) as a brownish solid, which was used in the next step without further purification. HPLC: AtRet=0.77 min; LC-MS: m/z 183.4 [M+H]+; 1H NMR (400 MHz, DMSO-d6): 3.43 (s, 2H), 3.74 (s, 3H), 6.61-6.66 (m, J=8.1, 2.0, 1H), 6.67-6.72 (m, 1H), 6.81 (d, J=2.0, 1H), 8.81 (s, 1H), 12.17 (s, 1H).
Reaction SMILES: [CH2:1]([C@H:8]([NH:28][C:29]([C@@H:31]([NH:36][C:37](=[O:40])[O:38][CH3:39])[C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@@H:9]([OH:27])[CH2:10][C@@H:11]([NH:19]C(OC(C)(C)C)=O)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH-].[Na+]>C1COCC1>[NH2:19][C@@H:11]([CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:10][C@H:9]([OH:27])[C@@H:8]([NH:28][C:29]([C@@H:31]([NH:36][C:37](=[O:40])[O:38][CH3:39])[C:32]([CH3:34])([CH3:35])[CH3:33])=[O:30])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](N)Cc1ccccc1)C(C)(C)C
Temperature: 60 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
A solution containing the product from Example 8A (16.97 g, 30.6 mmol) in THF (150 mL) was treated with HCl solution (50 mL, 4 N in dioxane), stirred at 60° C. for 2 hours, cooled and adjusted to pH 8 with 10% NaOH solution. The reaction mixture was partitioned between ethyl acetate and water, and the organic phase was washed with brine and concentrated to give the title compound (13.74 g).
Reaction SMILES: [CH:1]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:2]=1[CH:3]=[C:4]1[N:10]2[CH2:9][C:8]2[CH:15]=[CH:16][CH:17]=[CH:18][C:7]=2[NH:6][C:5]1=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].C1COCC1.[OH-].[Na+]>O>[CH:1]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:2]=1[CH:3]=[C:4]1[N:10]2[CH2:9][C:8]2[CH:15]=[CH:16][CH:17]=[CH:18][C:7]=2[NH:6][CH2:5]1
Reactant: O=C1Nc2ccccc2Cn2c1cc1ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc2c(c1)Cn1c(cc3ccccc31)CN2
Temperature: 25 °C
Yield: 97.6 %

Procedure:
A mixture of 7.1 g (0.0286 mole) of 6H-indolo[2,1-c][1,4]benzodiazepin-12(11H)-one, the product of Example 1, 2.17 g (0.057 mole) of LAH and 100 ml of THF was refluxed for 5 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature followed by the addition of 2.1 ml of water, 2.1 ml of 15% NaOH solution and 6.3 ml of water. The white solid obtained after 0.5 hour was filtered to give a light yellow filtrate which was concentrated in vacuo to give 6.54 g of off-white solid. Recrystallization from i-PrOH/EtOAc gave the title compound as a white solid, mp 176°-177° C.
Reaction SMILES: [C:1]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CC(C)([O-])C.[K+].Cl[CH2:23][C:24]1[S:28][CH:27]=[C:26]([C:29]([O:31][CH3:32])=[O:30])[CH:25]=1.O>CN(C=O)C.C(OCC)(=O)C>[C:12]([O:11][C:9]([N:8]([CH2:23][C:24]1[S:28][CH:27]=[C:26]([C:29]([O:31][CH3:32])=[O:30])[CH:25]=1)[C:1]([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2])=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Reactant: COC(=O)c1csc(CCl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1csc(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
To a solution of 3.69 g of di-tert-butyl imidodicarbonate in 54 ml of DMF was added 1.91 g of potassium tert-butoxide at 0° C. under argon, followed by stirring at room temperature for 1 hour. A solution of 2.7 g of methyl 5-(chloromethyl)thiophene-3-carboxylate in 8.1 ml of DMF was slowly added thereto, followed by stirring at room temperature overnight. Water and ethyl acetate were added to the reaction solution, followed by carrying out an extraction operation, and the organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain 4.394 g of methyl 5-{[bis(tert-butoxycarbonyl)amino]methyl}thiophene-3-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[CH:12][NH:11][C:8]=3[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C.CC#N>[CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[CH:12][N:11]([CH:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH3:21])[C:8]=3[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: Cc1nnc2ccc3[nH]ccc3n12
Reactant: BrCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: Cc1nnc2ccc3c(ccn3C(C)c3ccccc3)n12
Temperature: 45 °C

Procedure:
To a mixture of 1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (10 mg, 0.058 mmol, isolated from Example 2, Step 5 during a preparation wherein the methylation of Step 2 of that Example was incomplete) and K2CO3 (0.024 g, 0.17 mmol) in DMF (0.22 mL) was added 1-(bromoethyl)benzene (12 μL, 0.087 mmol, Acros). The mixture was heated to 45° C. for 3 hours. The mixture was diluted with MeCN and filtered, then the product was isolated by preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) (3.3 mg, 20%).