Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[CH:3]=1.[H-].[Na+].[C:21]1([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33](Cl)=[O:34])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C=O)C>[C:12]1([N:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][N:7]=3)[C:2]([O:1][C:33](=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:3][C:4]2=[O:18])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=c1cc(O)c2cccnc2n1-c1ccccc1
Reactant: O=C(Cl)CCCCCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCCCCCc1ccccc1)Oc1cc(=O)n(-c2ccccc2)c2ncccc12
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
In accordance with a process described in JP-61-246183A, 4-hydroxy-1-phenyl-1,8-naphthyridin-2(1H)-one was synthesized. To a suspension of the synthesized compound (953 mg, 4.0 mmol) in DMF (32 mL) was added sodium hydride (purity of about 60%, 176 mg, 4.4 mmol, 1.1 eq.), and the mixture was stirred at a room temperature for 40 minutes. Then, 7-phenylheptanoyl chloride (4.8 mmol, 1.2 eq.) was added thereto with cooling in an ice bath, and the mixture was stirred at a room temperature for 1.5 hours. Thereafter, the water was added to the reaction solution, and the precipitate was separated by filtration and dried to give 1-phenyl-4-(7-phenylheptanoyloxy)-1,8-naphthyridin-2(1H)-one as a form of crystal (1.52 g, yield 89%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[CH:21](=O)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C(O)(=O)C.[BH4-].[Na+]>CN(C=O)C>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: CCCCCCC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCCCCCCNc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 18 h
Yield: 41.1 %

Procedure:
A mixture of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (1.1 g, 4.0 mmol) and heptanal (3.4 mL, 24 mmol) and acetic acid (2 mL) in DMF (20 mL) was heated until all solid was dissolved. To the mixture was added sodium borohydride (605 mg, 16 mmol) and kept at room temperature for 18 h. To the mixture was added sodium borohydride (150 mg, 3.9 mmol) and kept at room temperature for 1 d. The mixture was extracted with ethyl acetate (200 mL) and water (100 mL). The organic layer was washed with water (100 mL). The solvent was removed in vacuo to give an oil. The oil was purified by column chromatography (Silca Gel, 33% EtOAc:CH2Cl2) to give 2-(2,6-Dioxo-piperidin-3-yl)-4-heptylamino-isoindole-1,3-dione as a yellow solid (610 mg, 41% yield): mp, 107-109° C.; 1H NMR (DMSO-d6) δ 0.82-0.87 (m, 3H, CH3), 1.24-1.29 (m, 8H, 4 CH2), 2.00-2.04 (m, 1H, CHH), 2.43-2.62 (m, 2H, CH2), 2.82-2.96 (m, 1H, CHH), 3.23-3.31 (m, 2H, CH2), 5.06 (dd, J=5.3, 12.4 Hz, 1H, NCH), 6.51 (t, J=5.9 Hz, 1H, NH), 7.01 (d, J=7.0 Hz, 1H, Ar), 7.07 (d, J=8.6 Hz, 1H, Ar), 7.57 (dd, J=7.4, 8.4 Hz, 1H, Ar), 11.10 (s, 1H, NH); 13C NMR (DMSO-d6) δ 13.91, 22.03, 22.17, 26.28, 28.42, 28.69, 30.98, 31.22, 34.84, 48.55, 109.03, 110.36, 117.13, 132.18, 136.24, 146.43, 167.29, 168.96, 170.05, 172.77; Anal Calcd for C20H25N3O4: C, 64.67; H, 6.78; N, 11.31. Found: C, 64.62; H, 6.76; N, 11.13.
Reaction SMILES: Br[C:2]1[C:3]([O:31][CH3:32])=[C:4]([C:16]2[CH:24]=[C:23]3[C:19]([C:20]([CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:21][CH2:22]3)=[CH:18][CH:17]=2)[CH:5]=[C:6]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[NH:10][C:9]2=[O:15])[CH:7]=1.[S:33]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34]1>>[O:15]=[C:9]1[NH:10][C:11](=[O:14])[CH:12]=[CH:13][N:8]1[C:6]1[CH:7]=[C:2]([C:35]2[CH:36]=[CH:37][S:33][CH:34]=2)[C:3]([O:31][CH3:32])=[C:4]([C:16]2[CH:24]=[C:23]3[C:19]([C:20]([CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:21][CH2:22]3)=[CH:18][CH:17]=2)[CH:5]=1
Reactant: OB(O)c1ccsc1
Reactant: COc1c(Br)cc(-n2ccc(=O)[nH]c2=O)cc1-c1ccc2c(c1)CC=C2CNS(C)(=O)=O
Product: COc1c(-c2ccsc2)cc(-n2ccc(=O)[nH]c2=O)cc1-c1ccc2c(c1)CC=C2CNS(C)(=O)=O
Yield: 33 %

Procedure:
The product from Example 63, Part A (25.9 mg, 0.050 mmol) was reacted with thiophen-3-yl boronic acid (8.1 mg, 0.063 mmol) as described in Example 63, Part B to give the title compound as an off-solid (8.6 mg, 33%). 1H NMR (300 MHz, DMSO-d6) δ 11.45 (d, J=1.84 Hz, 1H) 7.93 (d, J=2.94 Hz, 1H) 7.87 (d, J=7.72 Hz, 1H) 7.53-7.75 (m, 6H) 7.49 (t, J=6.25 Hz, 1H) 7.39 (d, J=2.57 Hz, 1H) 6.57 (s, 1H) 5.68 (dd, J=7.91, 2.02 Hz, 1H) 4.19 (d, J=5.15 Hz, 2H) 3.47 (s, 2H) 3.21 (s, 3H) 2.96 (s, 3H).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]1[C:21]([CH2:22][CH:23]([CH3:25])[CH3:24])=[C:20]2[C:11]([C:12]([NH2:26])=[N:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=32)=[N:10]1.[C:27](Cl)(=[O:29])[CH3:28]>ClCCl>[CH2:22]([C:21]1[N:9]([CH3:8])[N:10]=[C:11]2[C:20]=1[C:19]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:13]=[C:12]2[NH:26][C:27](=[O:29])[CH3:28])[CH:23]([CH3:24])[CH3:25]
Reactant: CC(=O)Cl
Reactant: CC(C)Cc1c2c(nn1C)c(N)nc1ccccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1nc2ccccc2c2c(CC(C)C)n(C)nc12
Temperature: 4 °C
Yield: 56 %

Procedure:
Triethylamine (0.49 mL, 3.53 mmol) was added to a suspension of 2-methyl-1-(2-methylpropyl)-2H-pyrazolo[3,4-c]quinolin-4-amine (prepared as described in Example 3) (0.75 g, 2.95 mmol) in dichloromethane (30 mL) and cooled to 4° C. Acetyl chloride (0.255 g, 3.24 mmol) was added in dichloromethane (5 mL) dropwise over 5 minutes to the reaction mixture and maintained at ambient temperature for 16 hours. The reaction mixture was diluted with dichloromethane (25 mL) and washed sequentially with water (25 mL), 4% sodium bicarbonate (2×25 mL), water (25 mL), and brine (25 mL). The combined organic layers were concentrated under reduced pressure and the residue was purified via column chromatography on silica gel (80 g, eluting with 0-20% CMA/chloroform), concentrated under reduced pressure, and recrystallized from diethyl ether to yield 0.49 g of N-(1-isobutyl-2-methyl-2H-pyrazolo[3,4-c]quinolin-4-yl)acetamide as white crystals, mp 130-131° C.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[C:7]([Cl:26])[CH:6]=1.[OH-].[K+].O.Cl>C(O)C>[Cl:26][C:7]1[CH:6]=[C:5]([CH2:4][C:3]([OH:27])=[O:2])[CH:10]=[CH:9][C:8]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCCCOc1ccc(CC(=O)OC)cc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCCCOc1ccc(CC(=O)O)cc1Cl
Yield: 59.5 %

Procedure:
A mixture of 69.7 g of product from Example 63, 29.55 g of potassium hydroxide, 45 of water and 800 ml ethyl alcohol is heated at reflux temperature for 89 hours. The cooled solution was made acidic (pH 2) with concentrated hydrogen chloride; followed by heating to distill off the ethyl alcohol. The solution is diluted with diethyl ether and water. The organic layer is dried and concentrated in vacuo. The residue is recrystallized from methylene chloride/hexane to give 40.0 g of the desired product as colorless needles.
Reaction SMILES: C([NH:9][C:10]([NH:12][C@H:13]([CH3:18])[C:14]([F:17])([F:16])[F:15])=[S:11])(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[CH3:18][C@@H:13]([NH:12][C:10]([NH2:9])=[S:11])[C:14]([F:17])([F:16])[F:15]
Reactant: C[C@@H](NC(=S)NC(=O)c1ccccc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C[C@@H](NC(N)=S)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
Dissolve (R)-1-benzoyl-3-(1-methyl-2,2,2-trifluoroethyl)-thiourea (6.2 g, 22.5 mmol) in methanol and add a solution of potassium carbonate (13.8 g, 100 mmol) in water (30 mL). Stir vigorously at room temperature overnight. Evaporate to dryness, dissolve residue in hot water (ca. 100 mL) and filter the resulting white crystals. Cool filtrate to 0° C., seed with crystals from hot water filtration, filter and collect resulting white crystals to obtain the desired intermediate (2.9 g, 74%). MS (ES+) m/z: 173 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:35])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[N:27][C:22]=4[CH2:21][O:20][C:19]4[CH:28]=[CH:29][C:30]([OH:32])=[CH:31][C:18]3=4)[CH2:10][C:9]2([CH3:34])[CH3:33])=[CH:4][CH:3]=1.[H-].[Na+].CN(C)[CH:40]=[O:41]>>[CH2:19]([O:20][C:40](=[O:41])[C:2]([O:32][C:30]1[CH:29]=[CH:28][C:19]2[O:20][CH2:21][C:22]3[N:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:17](=[CH:16][CH2:15][CH2:14][N:11]3[CH2:12][CH2:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)([OH:35])[C:9]([CH3:33])([CH3:34])[CH2:10]3)[C:18]=2[CH:31]=1)([CH3:7])[CH3:3])[CH3:18]
Reactant: CN(C)C=O
Reactant: CC1(C)CN(CCC=C2c3cc(O)ccc3OCc3ncccc32)CCC1(O)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(C)(C)Oc1ccc2c(c1)C(=CCCN1CCC(O)(c3ccc(Cl)cc3)C(C)(C)C1)c1cccnc1CO2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 76 %

Procedure:
To a cooled (0° C.) solution of 5-{3-[4-(4-Chloro-phenyl)-4-hydroxy-3,3-dimethyl-piperidin-1-yl]-propylidene}-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-ol (250 mg, 0.51 mmol) in dimethylformamide (7 mL) was added sodium hydride (60% dispersion in oil, 31 mg, 0.76 mmol). The resulting mixture was stirred at 0° C. for 10 min. Ethyl 2-bromo-2-methyl propionate (149 mg, 0.76 mmol) was added. Stirring at 0° C. was continued 10 min before the mixture was warmed to rt and stirred 4h. The reaction was then partitioned between ethyl acetate and water; the aqueous phase was back-extracted with additional ethyl acetate. The combined organic phases were washed thrice with water, brine and dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography (methylene chloride-95:5 methylene chloride:methanol gradient) to afford the titled compound (233 mg, 76%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1Cl)[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17](Cl)=[C:16]([NH2:21])[CH:15]=2)[CH:8]=1)=[O:6].C([O-])=O.[Na+].COCCO>[Pd].O>[NH2:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH2:21])[CH:15]=2)[CH:8]=1)=[O:6]
Reactant: Nc1cc(C(=O)c2cccc(C(=O)c3ccc(Cl)c(N)c3)c2)ccc1Cl
Agent: [Pd]
Agent: O=C[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCO
Product: Nc1cccc(C(=O)c2cccc(C(=O)c3cccc(N)c3)c2)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
In the next step, to a sealed glass reaction vessel equipped with a thermometer, stirrer and reflux condenser, 156 g (0.41 mole) of the above 1,3-bis(3-amino-4-chlorobenzoyl)benzene, 145 g (2.13 mole) of sodium formate, 787 g of 2-methoxyethanol and 43 g of water were charged and heated to 100° C. with stirring. Successively, 7.8 g of a 5% palladium/activated carbon catalyst (a product of M.E. Chemcat Co.) was gradually added and the reaction was continued at 100° C. for 3 hours with stirring. The reaction mixture was cooled to 85° C. and hot filtered to remove the catalyst. The filtrate was poured into 4 l of water. The precipitated yellow crystals were filtered, washed with water and dried. Crude crystal of the desired 1,3-bis(3-aminobenzoyl)benzene were thus obtained in an amount of 126 g (97% yield). The crystals were analyzed by high performance liquid chromatography and determined to have a purity of 85.3%. The crude 1,3-bis(3-aminobenzoyl) benzene was dissolved in 630 g of toluene by heating and hot filtered to remove insoluble matter. Successively, 89 g of a 36% aqueous hydrochloric acid solution was added to the filtrate and allowed to cool. The precipitated crystal of 1,3-bis(3-aminobenzoyl)benzene hydrochloride was recrystallized from ethanol to obtain crystals of pure 1,3-bis(3-aminobenzoyl)benzene hydrochloride. The hydrochloride was dissolved in 1 l of water and neutralized with an aqueous ammonia solution. The precipitated yellow crystals were filtered, washed with water and dried. The desired product, crystals of pure 1,3-bis(3-aminobenzoyl)benzene were thus obtained in an amount of 85g (67% yield). Melting point was 114.2°~116.9° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[NH2:10].[Br:11]N1C(=O)CCC1=O>C(#N)C>[Br:11][C:7]1[CH:6]=[C:5]([CH3:9])[C:4]([NH2:10])=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc(C)c1N
Solvent: CC#N
Product: COc1cc(Br)cc(C)c1N
Temperature: 145 °C
Yield: 21.6 %

Procedure:
To 2-methoxy-6-methyl-phenylamine (10.0 g) dissolved in acetonitrile (200 mL) was added N-bromosuccinimide (14.3 g) and the reaction mixture was heated to 145° C. for 15 minutes in a sealed microwave process vessel. The crude mixture was filtered through Celite, diluted with diethyl ether (200 mL) and washed with sodium hydroxide (2 M, 2×100 mL) and brine (1×100 mL). The organic phase was dried over magnesium sulfate, concentrated in vacuo and purified by flash chromatography to furnish 3.4 g (26%) of the title compound as a black solid. NMR (500 MHz, DMSO-d6): 2.06 (s, 3H), 3.77 (s, 3H), 4.55 (s, 2H), 6.78 (d, 1H), 6.82 (d, 1H).
Reaction SMILES: [CH:1]1([N:8]2[CH:16]=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3Cl)[S:5][C@H:4]([CH2:6][OH:7])[CH2:3][CH2:2]1.[C@@H]1(N2C3N=CN=C(N)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H]1[OH:20]>CC[N+](CC)(CC)CC.[Br-]>[C@@H:1]1([N:8]2[C:9]3[N:10]=[CH:11][N:12]=[C:13]([OH:20])[C:14]=3[N:15]=[CH:16]2)[S:5][C@H:4]([CH2:6][OH:7])[CH2:3][CH2:2]1
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: OC[C@@H]1CCC(n2cnc3c(Cl)ncnc32)S1
Agent: CC[N+](CC)(CC)CC
Agent: [Br-]
Product: OC[C@@H]1CC[C@H](n2cnc3c(O)ncnc32)S1
Reaction time: 34 h
Yield: 79 %

Procedure:
To a solution of the α/β anomers of 20 (82 mg, 0.3 mmol) in 20 mL of a 0.75 M TEAB buffer was added 3 μL adenosine deaminase. The reaction was stirred 34 h followed by lyophilization. The residue was purified by preparative TLC with 6:1 chloroform-methanol containing 1% acetic acid. The crude product was recrystallized from methanol/carbontetrachloride to give 30.5 mg (79%) of 21; mp. 195°-197 C.; [α]D25 -13.9° (c=0.1, H2O); FAB MS 253 (M+H)+ ; 1H NMR (D20) δ 8.5 (s, 1, H-2), 8.2 (s, 1, H-8), 6.2 (m, 1, 1'-H), 3.95 (m, 1, 5'-H), 3.8 (m, 2, 4'-H, 5'-H), 2.5 (m, 2, 2'-H's), 2.3 (m, 1, 3'-H), 1.9 (m, 1, 3'-H).
Reaction SMILES: [H-].[Na+].C(O[C:6](=[O:22])[CH2:7][N:8]=[C:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)C.Br.[NH2:24][C:25]1[C:30]([CH2:31]Br)=[CH:29][C:28]([Br:33])=[CH:27][N:26]=1>CN(C=O)C>[C:9](=[N:8][CH:7]1[CH2:31][C:30]2[C:25](=[N:26][CH:27]=[C:28]([Br:33])[CH:29]=2)[NH:24][C:6]1=[O:22])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: Nc1ncc(Br)cc1CBr
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1Nc2ncc(Br)cc2CC1N=C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 55.9 %

Procedure:
NaH (60% dispersion in mineral oil, 1.2 g, 30 mmole) was added portionwise over 10 min to a solution of N-(diphenylmethylene)glycine ethyl ester (8.0 g, 30 mmole) in DMF (150 mL) with stirring under Ar at 0° C. The reaction was stirred for 15 min, then 2-amino-5-bromo-3-(bromomethyl)pyridine hydrobromide (5.0 g, 14.4 mmole) was added in one portion. The reaction was allowed to warm to RT and stir for 18 h, then was concentrated under vacuum. The remaining residue was taken up in EtOAc (150 mL), hexane (150 mL), and H2O (150 mL). The resulting suspension was triturated and filtered, and the solid was dried under vacuum to give the title compound (3.27 g, 56%) as an off-white solid: 1H NMR (400 MHz, d6-DMSO) δ 10.92 (s, 1H), 8.23 (s, 1H), 7.86 (s, 1H), 7.26-7.55 (m, 10H), 4.05 (dd, 1H), 3.10 (t, 2H); MS (ES) m/e 406.0 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:4][CH2:3]1.Cl[C:19]([O:22]C(Cl)=O)(Cl)Cl>C1C=CC=CC=1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:17]=[CH:16][C:14]([N:15]=[C:19]=[O:22])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:4][CH2:3]1
Reactant: CN1CCN(S(=O)(=O)c2ccc(N)cc2)CC1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CN1CCN(S(=O)(=O)c2ccc(N=C=O)cc2)CC1
Temperature: 25 °C

Procedure:
4-(4-Methylpiperazin-1-sulfonyl)aniline (0.5 g, 1.96 mmol) dissolved in anhydrous benzene was added dropwise to a solution of trichloromethylchloroformate (0.3 mL, 2.35 mmol) in anhydrous benzene at −10° C. The mixture was warmed to room temperature for 10 minutes, then heated to 90° C. for 2 h The mixture was concentrated under reduced pressure to provide 4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl isocyanate as a solid, used as an intermediate in the production of Compound 105 IR: 1166, 1339, 2265 cm−1.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=O)=[CH:4]1)[CH3:2].C(Cl)(=O)C(Cl)=O.[Cl:21][C:22]1[CH:23]=[C:24]([CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH:25]=[CH:26][C:27]=1[NH2:28].C(N(CC)CC)C>C(Cl)Cl>[Cl:21][C:22]1[CH:23]=[C:24]([CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH:25]=[CH:26][C:27]=1[NH:28][C:12]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:3]([CH2:1][CH3:2])[CH:4]=1)=[O:14]
Reactant: CCn1cc(C(=O)O)c2ccccc21
Reactant: COC(=O)Cc1ccc(N)c(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCn1cc(C(=O)Nc2ccc(CC(=O)OC)cc2Cl)c2ccccc21
Temperature: 15 °C
Yield: 88.4 %

Procedure:
To 1-ethylindole-3-carboxylic acid (160.2 mg, 0.847 mmol) were added methylene chloride (3.5 ml) and oxalyl chloride (108.9 μl, 1.270 mmol) under stirring at 15° C. The reaction mixture was stirred for 2.5 hours at room temperature. The solvent was then distilled off under reduced pressure. To the residue was added methylene chloride (3.5 ml). Under stirring at room temperature, a solution of methyl 3-chloro-4-aminophenylacetate (177.5 mg, 0.889 mmol) in methylene chloride (3.5 ml) and triethylamine (0.37 ml, 2.667 mmol) were added and the mixture was heated under reflux for 18 hours. After the reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure. The residue was dissolved in chloroform. The resulting solution was washed with 1N HCl ad saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give methyl 3-chloro-4-((1-ethyl-3-indolylcarbonyl)amino)phenylacetate (277.7 mg, 88%) as a brown amorphous substance. The resulting compound was provided for the subsequent reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10](Br)=[CH:9][N:8]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:25][C:26]1[CH:27]=[C:28]([CH2:32][C:33]([N:35]2[C:43]3[C:38](=[CH:39][C:40](B4OC(C)(C)C(C)(C)O4)=[CH:41][CH:42]=3)[CH2:37][CH2:36]2)=[O:34])[CH:29]=[CH:30][CH:31]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.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>[NH2:1][C:2]1[C:3]2[C:10]([C:40]3[CH:39]=[C:38]4[C:43](=[CH:42][CH:41]=3)[N:35]([C:33](=[O:34])[CH2:32][C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([CH3:25])[CH:27]=3)[CH2:36][CH2:37]4)=[CH:9][N:8]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cc1cccc(CC(=O)N2CCc3cc(B4OC(C)(C)C(C)(C)O4)ccc32)c1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(Br)c3c(N)ncnc32)CC1
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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cccc(CC(=O)N2CCc3cc(-c4cn(C5CCN(C(=O)OC(C)(C)C)CC5)c5ncnc(N)c45)ccc32)c1
Temperature: 100 °C
Yield: 80.4 %

Procedure:
To 1,1-dimethylethyl 4-(4-amino-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-piperidinecarboxylate (200 mg, 0.505 mmol), and 1-[(3-methylphenyl)acetyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indole (228 mg, 0.606 mmol) dissolved in 1,4-Dioxane (4 mL) was added saturated aqueous NaHCO3 (2 mL). The mixture was then bubbled with N2 gas for 10 minutes and then Pd(Ph3P)4 (58.3 mg, 0.050 mmol) was added and then bubbled for 5 additional minutes. Then reaction was then capped and heated at 100° C. overnight. The mixture was allowed to cool then diluted with water (10 mL) then extracted with EtOAc (3×20 ml). The organics were combined, washed with brine, dried over MgSo4, filtered and concentrated to isolate a amber color oil. The oil was then purified on a 25 g Biotage SNAP column conditioned with Hexane and eluting with a gradient of 0 to 10% MeOH in DCM for 30 minutes to afford 1,1-dimethylethyl 4-(4-amino-5-{1-[(3-methylphenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-piperidinecarboxylate (230 mg, 80% yield) as a amber color oil. 1H NMR (400 MHz, DMSO-d6) δ 8.14 (s, 1H), 8.13 (s, 1H), 7.45 (s, 1H), 7.32 (s, 1H), 7.20-7.26 (m, 2H), 7.12 (s, 1H), 7.09 (t, J=7.58 Hz, 2H), 4.71-4.83 (m, 1H), 4.20 (t, J=8.46 Hz, 2H), 4.08-4.15 (m, 2H), 3.94 (s, 2H), 3.82 (s, 2H), 3.20 (t, J=8.46 Hz, 2H), 2.95 (br. s., 2H), 2.31 (s, 3H), 1.86-1.97 (m, 4H), 1.43 (s, 9H).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([S:14]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])=[N:10][NH:11]2)=[CH:7][CH:6]=1.[N-:27]=[N+:28]=[N-:29].[Na+]>CS(C)=O.O>[N:27]([CH2:2][CH2:3][O:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([S:14]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])=[N:10][NH:11]2)=[CH:7][CH:6]=1)=[N+:28]=[N-:29]
Reactant: [N-]=[N+]=[N-]
Reactant: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2cc(OCCCl)ccc12
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: [N-]=[N+]=NCCOc1ccc2c(S(=O)(=O)c3cccc4ccccc34)n[nH]c2c1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A mixture of 6-(2-chloro-ethoxy)-3-(naphthalene-1-sulfonyl)-1-H-indazole (0.19 g, 0.5 mmoles) and sodium azide (0.04 g, 0.62 mmoles) in DMSO (2 mL) was stirred together in a round bottom flask under nitrogen at 90° C. for 3 hours. Reaction mixture was cooled to room temperature, diluted with water, extracted with EtOAC, washed with water (2×), brine (1×), dried over Na2SO4, and concentrated under vacuum. Crude compound was purified by normal phase HPLC using as eluent 40% EtOAc/hexane to afford the title compound as an off white solid (0.17 g, 0.45 mmoles).
Reaction SMILES: [CH3:1][O:2][CH:3]1[C@@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@@H:6]2[C@@H:5]([CH2:13][OH:14])[O:4]1.O[N:16]1C(=O)C2C(=CC=CC=2)C1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.O.NN>C(Cl)Cl>[CH3:1][O:2][CH:3]1[C@@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@@H:6]2[C@@H:5]([CH2:13][O:14][NH2:16])[O:4]1
Reactant: COC1O[C@H](CO)[C@H]2OC(C)(C)O[C@@H]12
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: NN
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: COC1O[C@H](CON)[C@H]2OC(C)(C)O[C@@H]12
Yield: 50 %

Procedure:
The title compound was prepared using the procedure described for Example 2K by using ((3aR,4R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol (2.04 g, 10 mmol), CH2Cl2 (25 mL), 2-hydroxyisoindoline-1,3-dione (2.0 g, 12 mmol), triphenylphosphine (4.0 g, 15 mmol), diisopropylazodicarboxylate (3.0 ml, 15 mmol) and hydrazine hydrate (2.0 mL, 20 mmol) to afford 1.12 g of 04(3aR,4R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)hydroxylamine (2Y) (50%, over two steps) as a pale yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.24 (s, 3H) 1.26 (s, 3H) 3.31 (s, 3H) 3.59-3.75 (m, 2H) 4.44 (t, J=7.20 Hz, 1H) 4.56 (d, J=5.81 Hz, 1H) 4.67 (d, J=6.06 Hz, 1H) 4.92-5.00 (m, 1H). MS (ES) [M+H] calculated for C9H18NO5, 220.11; found 220.10.