Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:16])([O:14][CH3:15])[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6](Br)=[CH:5][C:4]=1[CH3:13].[CH3:17][N:18]([CH3:22])[CH2:19][C:20]#[CH:21].ClC(OC)=O>ClCCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(N(CC)CC)C.CN(C=O)C>[C:1](=[O:16])([O:14][CH3:15])[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([C:21]#[C:20][CH2:19][N:18]([CH3:22])[CH3:17])=[CH:5][C:4]=1[CH3:13]
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(Br)cc1C
Reactant: C#CCN(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: COC(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)Oc1cc([N+](=O)[O-])c(C#CCN(C)C)cc1C
Temperature: 100 °C
Yield: 19.9 %

Procedure:
To 4-bromo-2-methyl-5-nitrophenyl methyl carbonate (500 mg, 1.72 mmol), Pd(PPh3)2Cl2 (30 mg, 0.04 mmol), and CuI (3 mg, 0.02 mmol) were added DMF (5.0 mL), triethylamine (5.0 mL), and N,N-dimethylprop-2-yn-1-amine (717 mg, 919 μL, 8.62 mmol) under nitrogen atmosphere. The reaction mixture was heated under microwave irradiation at 100° C. for 15 min, resulting in product formation with partial loss of the carbonate group. The reaction was quenched with water and the aqueous layer was extracted with ethyl acetate, washed with 50% saturated NaHCO3 (2×20 mL), water, and brine. The solution was dried over Na2SO4, filtered, and dried down to a red oil. The oil was dissolved in cold (0° C.) dichloromethane (4 mL) and triethylamine (132 μL, 1.71 mmol) then treated dropwise with methyl chloroformate (132 μL, 1.71 mmol). After 5 min the reaction was quenched with water and the aqueous layer extracted with dichloromethane. The organic layer was dried over MgSO4, filtered and concentrated. Purification by silica gel chromatography (0-60% ethyl acetate/hexanes) provided 4-(3-(dimethylamino)prop-1-ynyl)-2-methyl-5-nitrophenyl methyl carbonate (100 mg, 20% yield). LC/MS m/z 293.3 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.I[C:38]1[S:39][CH:40]=[CH:41][CH:42]=1>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:38]2[S:39][CH:40]=[CH:41][CH:42]=2)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: Ic1cccs1
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1[N+](=O)[O-]

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1), bis(pinacolato)diboron and 2-iodothiophene according to the general procedure C. Obtained as a yellow solid (91 mg).
Reaction SMILES: Cl.[F:2][C:3]1[C:9]([F:10])=[C:8]([F:11])[C:7]([F:12])=[C:6]([F:13])[C:4]=1[NH2:5].[CH:14]1([NH:17][C:18]([NH:20][C:21]#[N:22])=[NH:19])[CH2:16][CH2:15]1.[OH-:23].[Na+]>O>[NH4+:5].[OH-:23].[F:2][C:3]1[C:9]([F:10])=[C:8]([F:11])[C:7]([F:12])=[C:6]([F:13])[C:4]=1[NH:5][C:21]([NH:20][C:18]([NH:17][CH:14]1[CH2:16][CH2:15]1)=[NH:19])=[NH:22]
Reactant: N#CNC(=N)NC1CC1
Reactant: Nc1c(F)c(F)c(F)c(F)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N=C(NC(=N)NC1CC1)Nc1c(F)c(F)c(F)c(F)c1F
Product: [NH4+]

Procedure:
A mixture of 7.0 g (0.035 mole) of 2,3,4,5,6-pentafluoroaniline hydrochloride and 4.4 g (0.035 mole) of 1-cyclopropyl-3-cyanoguanidine is heated at a melt for 11/2 hours. The mixture is then cooled, heated with 25 ml of water until solution and then made alkaline with 40% sodium hydroxide. The solution is extracted with ether and dried over potassium carbonate and evaporated to dryness. The residue is chromatogramed on silica gel using isopropanol:NH4OH to obtain 1-(2,3,4,5,6-pentafluorophenyl)-5-cyclopropylbiguanide.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8](Br)=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[N:6]=1)=[O:4].[F:19][C:20]([F:24])([F:23])[CH2:21][OH:22]>>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([O:22][CH2:21][C:20]([F:24])([F:23])[F:19])=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[N:6]=1)=[O:4]
Reactant: OCC(F)(F)F
Reactant: COC(=O)c1cnc(Br)c(-c2ccc(Cl)cc2)n1
Product: COC(=O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)n1

Procedure:
The title compound was synthesized in analogy to Example 48a, using 5-bromo-6-(4-chlorophenyl)-2-pyrazinecarboxylic acid methyl ester (CAN 960247-79-4) and 2,2,2-trifluoroethanol as starting materials; MS (EI) 347.1 (M+H)+.
Reaction SMILES: [OH-].[Na+].[C:3]([CH:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1)[CH:6]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[CH2:7][C:8]([O:10]C)=[O:9])#[N:4]>CO>[C:3]([CH:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1)[CH:6]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[CH2:7][C:8]([OH:10])=[O:9])#[N:4]
Reactant: COC(=O)CC(c1ccc(F)cc1)C(C#N)c1cccc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#CC(c1cccc(F)c1)C(CC(=O)O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under protective gas (Ar), 10 ml of 2 molar aqueous sodium hydroxide solution were added to 1.75 g (5.55 mmol) of methyl 4-cyano-4-(3-fluorophenyl)-3-(4-fluorophenyl)butanoate in 50.0 ml of methanol, and the mixture was stirred at 25° C. for 8 h. The methanol was removed under reduced pressure. The residue was acidified with concentrated hydrochloric acid (pH=3) and extracted three times with in each case 15 ml of dichloromethane. The combined organic phases were dried over sodium sulphate and the solvent was removed under reduced pressure. This gave 1.62 g (96.9% of theory) of the title compound in the form of colourless crystals (erythro:threo=49:51, comparison of the multiplets in the 1H-NMR in CDCl3 at 2.60 and 2.85 ppm).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([Cl:10])[C:3]=1[NH:11][C:12](=[O:27])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:14]=1>ClCCl.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:7]=[C:6]([CH:8]=[O:9])[CH:5]=[C:4]([Cl:10])[C:3]=1[NH:11][C:12](=[O:27])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26]2)[CH:14]=1
Reactant: COc1ccc(C(=O)Nc2c(Cl)cc(CO)cc2Cl)cc1OC1CCCC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2c(Cl)cc(C=O)cc2Cl)cc1OC1CCCC1

Procedure:
A solution of N-(2,6-dichloro-4-hydroxymethylphenyl)-3-cyclopentyloxy-4-methoxybenzamide (4.4 g; that is prepared as described in Example 9) in dichloromethane (30 mL) is treated with activated manganese dioxide (6.2 g), and the mixture is stirred at reflux for 24 hours. The mixture is filtered, the filtrate is evaporated, and the resulting residue is subjected to flash chromatography on silica gel, eluting with ethyl acetate, to give N-(2,6-dichloro-4-formylphenyl)-3-cyclopentyloxy-4-methoxy-benzamide (2.4 g), m.p. 96–98° C. [Elemental analysis: C, 59.0; H, 5.1; N, 3.1%; calculated: C, 58.8; H, 4.7; N, 3.4%].
Reaction SMILES: OO.[OH:3][N:4]1[C:9]([CH3:11])([CH3:10])[CH2:8][CH:7]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]2[N:22]=[C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]3[CH2:33][C:32]([CH3:35])([CH3:34])[N:31]([OH:36])[C:30]([CH3:38])([CH3:37])[CH2:29]3)[N:20]=[C:19]([Cl:39])[N:18]=2)[CH2:6][C:5]1([CH3:41])[CH3:40].S([O-])([O-])=O.[Na+].[Na+].[C:48]([OH:52])([CH3:51])([CH3:50])[CH3:49]>O.C(OCC)(=O)C>[OH:52][C:48]([CH3:51])([CH3:50])[CH2:49][O:36][N:31]1[C:32]([CH3:35])([CH3:34])[CH2:33][CH:28]([CH2:27][CH2:26][CH2:25][CH2:24][NH:23][C:21]2[N:22]=[C:17]([NH:16][CH2:15][CH2:14][CH2:13][CH2:12][CH:7]3[CH2:6][C:5]([CH3:41])([CH3:40])[N:4]([O:3][CH2:49][C:48]([CH3:51])([OH:52])[CH3:50])[C:9]([CH3:11])([CH3:10])[CH2:8]3)[N:18]=[C:19]([Cl:39])[N:20]=2)[CH2:29][C:30]1([CH3:38])[CH3:37]
Reactant: CC(C)(C)O
Reactant: CC1(C)CC(CCCCNc2nc(Cl)nc(NCCCCC3CC(C)(C)N(O)C(C)(C)C3)n2)CC(C)(C)N1O
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(O)CON1C(C)(C)CC(CCCCNc2nc(Cl)nc(NCCCCC3CC(C)(C)N(OCC(C)(C)O)C(C)(C)C3)n2)CC1(C)C
Temperature: 42.5 °C
Yield: 99.9 %

Procedure:
A total of 40 g (0.59 mol) of 50% aqueous hydrogen peroxide is added in two portions over five hours to a mixture of 43.2 g (0.076 mol) of 2,4-bis[N-(1-oxyl-2,2,6,6-tetramethylpiperidin-4-yl)butylamino]-6-chloro-s-triazine and 7.0 g (0.035 mol) of ferrous chloride tetrahydrate in 150 g of tert-butyl alcohol and 15 g of water. Another portion of 50% aqueous hydrogen peroxide (3 g, 0.044 mol) is added to the reaction mixture while the temperature is maintained at 40-45° C. for 2.25 hours. The reaction mixture is diluted with 100 g of ethyl acetate. A solution of 100 g of 20% aqueous sodium sulfite is added and the reaction mixture is heated at 60° C. for one hour to decompose residual peroxide. The aqueous layer is extracted with ethyl acetate, and the combined organic layers are concentrated. The crude product is purified by flash chromatography on silica gel with 1:1 (v/v) hexane/ethyl acetate to afford 54.1 g of the title compound.
Reaction SMILES: B1([O-])OO1.[OH2:5].O.O.O.[Na+].[CH3:10][N:11]([C:18]1[S:19][C:20]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)=[N:21][N:22]=1)[C:12](=[O:17])[CH2:13][CH2:14][S:15][CH3:16]>C(O)(=O)C.C(=O)(O)[O-].[Na+]>[CH3:10][N:11]([C:18]1[S:19][C:20]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)=[N:21][N:22]=1)[C:12](=[O:17])[CH2:13][CH2:14][S:15]([CH3:16])=[O:5]
Reactant: O
Reactant: CSCCC(=O)N(C)c1nnc(-c2cccnc2)s1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: CC(=O)O
Product: CN(C(=O)CCS(C)=O)c1nnc(-c2cccnc2)s1
Temperature: 23 °C
Reaction time: 3 h
Yield: 77.7 %

Procedure:
Sodium perborate tetrahydrate (52 mg, 0.34 mmol, 1.0 equiv) was added to a stirred solution of N-methyl-3-(methylthio)-N-(5-(pyridin-3-yl)-1,3,4-thiadiazol-2-yl)propanamide (100 mg, 0.34 mmol, 1.0 equiv) in glacial acetic acid (1.8 mL) at 23° C. The resulting suspension was stirred at 23° C. for 3 h. The reaction mixture was diluted with a saturated solution of sodium bicarbonate (50 mL) and extracted with dichloromethane (5×20 mL). The combined organic layers were dried (Na2SO4), gravity-filtered, and concentrated by rotary evaporation. The residue was rinsed with cold ethyl acetate and vacuum-filtered to afford the title compound as an off-white powder (82 mg, 78% yield): mp 138-140° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.12 (d, J=2 Hz, 1H), 8.71 (dd, J=5, 2 Hz, 1H), 8.34 (m, 1H), 7.56 (dd, J=8, 5 Hz, 1H), 3.80 (s, 3H), 2.90-3.30 (m, 3H), 2.62 (s, 3H); ESIMS m/z 311 ([M+H]+). Compounds 32, 45, 51, and 77 were prepared as described in Example 10.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH:7]([N:11]([CH2:15][CH2:16][CH3:17])[CH2:12][CH2:13][CH3:14])[CH2:8]2)=[CH:4][CH:3]=1.[Li]C(C)(C)C.CCCCC.CN([CH:31]=[O:32])C>C(OCC)C>[CH2:12]([N:11]([CH2:15][CH2:16][CH3:17])[CH:7]1[CH2:8][C:9]2[C:5](=[CH:4][CH:3]=[C:2]([CH:31]=[O:32])[CH:10]=2)[CH2:6]1)[CH2:13][CH3:14]
Reactant: CCCN(CCC)C1Cc2ccc(Br)cc2C1
Reactant: CN(C)C=O
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: CCOCC
Product: CCCN(CCC)C1Cc2ccc(C=O)cc2C1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Distilled (6-bromo-indan-2-yl)-dipropyl-amine (Example 11, 270 mg, 0.91 mmol) was dissolved in dry diethyl ether (20 mL). The solution was kept under argon and cooled to -78° C. A solution of t-BuLi in pentane 1.7M (0.7 mL, 1.20 mmol) was added and the mixture was stired at -78° C. for 1 h. Freshly distilled DMF (0.12 mL, 1.55 mmol) was added at -78° C. and the mixture was stirred at this temperature for 30 min. The reaction mixture was allowed to reach room temperature and stirred for additional 1 h. The organic layer was washed with aq. Na2CO3 (5%), the layers separated, dried (Na2CO3) and evaporated to dryness. MS m/e 245 (11, M+), 216 (100), 145 (17), 117 (22), 72 (21).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:21][CH2:22][CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:13][CH2:12][N:11]([C:14](OC(C)(C)C)=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C(O)(C(F)(F)F)=O.[Cl:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([CH3:43])[C:38]=1[S:44]([N:47]([CH2:51][CH2:52][O:53][CH2:54]C(O)=O)[CH:48]1[CH2:50][CH2:49]1)(=[O:46])=[O:45].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>ClCCl>[Cl:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([CH3:43])[C:38]=1[S:44]([N:47]([CH2:51][CH2:52][O:53][CH2:54][C:14]([N:11]1[CH2:10][CH2:9][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)([CH2:21][CH2:22][CH2:23][N:24]2[CH2:25][CH2:26][CH2:27][CH2:28]2)[CH2:13][CH2:12]1)=[O:15])[CH:48]1[CH2:50][CH2:49]1)(=[O:46])=[O:45]
Reactant: CC(C)(C)OC(=O)N1CCC(CCCN2CCCC2)(c2cccc(Cl)c2)CC1
Reactant: Cc1cccc(Cl)c1S(=O)(=O)N(CCOCC(=O)O)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cccc(Cl)c1S(=O)(=O)N(CCOCC(=O)N1CCC(CCCN2CCCC2)(c2cccc(Cl)c2)CC1)C1CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 25 %

Procedure:
A solution of tert-butyl 4-(3-chlorophenyl)-4-(3-(pyrrolidin-1-yl)propyl)piperidine-1-carboxylate (0.15 g, 0.37 mmol) in dichloromethane (3 ml) was Boc-deprotected using standard reaction conditions (see step (vi)/example 25; TFA (3-13 eq.)) and added dropwise to a solution containing 2-(2-(2-chloro-N-cyclopropyl-6-methylphenylsulfonamido)ethoxy)acetic acid [carboxylic acid 2] (1 eq.), EDCI (1.5 eq.), HOBt (1 eq.) and DIPEA (6 eq.) in dichloromethane (5 ml) at 0° C. The resulting mixture was then stirred at room temperature for 16 h. The reaction mixture was diluted with dichloromethane and washed with aq. ammonium chloride, aq. sodium hydrogen carbonate and water respectively. The organic layer was dried over sodium sulfate, concentrated in vacuo and the crude product purified by chromatography (silica). Yield: 25%
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7](Cl)[N:6]=1)[CH:2]=[CH2:3].[F:19][C:20]([F:24])([F:23])[CH2:21][NH2:22].C(N(CC)CC)C>>[CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7]([NH:22][CH2:21][C:20]([F:24])([F:23])[F:19])[N:6]=1)[CH:2]=[CH2:3]
Reactant: NCC(F)(F)F
Reactant: C=CCNc1nc(Cl)nc2ccc([N+](=O)[O-])cc12
Solvent: CCN(CC)CC
Product: C=CCNc1nc(NCC(F)(F)F)nc2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.6 %

Procedure:
A mixture of 150 mg (0.57 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline, 772 mg (5.70 mmol) of 2,2,2-trifluoroethylamine and 1.15 g (11.4 mmol) of triethylamine was stirred in a sealed tube at room temperature for 16 hours. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with chloroform (10 ml×3). After the organic layer was washed with brine and then dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by a silica gel chromatography to give 57 mg (yield: 30.8%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:3]=1.[CH3:15]CCCCCC.C(OCC)(=O)C>>[Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][CH3:15])=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:3]=1
Reactant: CCCCCCC
Reactant: Nc1nnc(Cl)cc1-c1ccccc1
Solvent: CCOC(C)=O
Product: CNc1nnc(Cl)cc1-c1ccccc1

Procedure:
The title compound was prepared in analogy to example 1, intermediate a, from 6-chloro-4-phenyl-pyridazin-3-ylamine and using a gradient of n-heptane:ethyl acetate (100:0 to 40:60) for the chromatographic purification. Light yellow solid (52%). MS (ESI+): m/z=220.064 ([M+H]+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH2:8])[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].N1CCC[C@H]1C(O)=O.[CH3:23][O:24][C:25]1[CH:66]=[CH:65][C:28]([CH2:29][N:30]2[C:34]3=[N:35][CH:36]=[CH:37][C:38]([O:39][C:40]4[CH:45]=[CH:44][C:43]([NH:46][C:47]5[N:62]=[CH:61][CH:60]=[CH:59][C:48]=5[C:49]([NH:51][C:52]5[CH:57]=[CH:56][C:55]([F:58])=[CH:54][CH:53]=5)=[O:50])=[CH:42][C:41]=4[F:63])=[C:33]3[C:32](I)=[N:31]2)=[CH:27][CH:26]=1>CS(C)=O.O.C(Cl)Cl>[CH3:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:29][N:30]2[C:34]3=[N:35][CH:36]=[CH:37][C:38]([O:39][C:40]4[CH:45]=[CH:44][C:43]([NH:46][C:47]5[N:62]=[CH:61][CH:60]=[CH:59][C:48]=5[C:49]([NH:51][C:52]5[CH:57]=[CH:56][C:55]([F:58])=[CH:54][CH:53]=5)=[O:50])=[CH:42][C:41]=4[F:63])=[C:33]3[C:32]([NH:8][CH:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[N:31]2)=[CH:65][CH:66]=1
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4ccc(Nc5ncccc5C(=O)Nc5ccc(F)cc5)cc4F)ccnc32)cc1
Reactant: CN1CCC(N)CC1
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: COc1ccc(Cn2nc(NC3CCN(C)CC3)c3c(Oc4ccc(Nc5ncccc5C(=O)Nc5ccc(F)cc5)cc4F)ccnc32)cc1
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 11.7 %

Procedure:
A 25 mL round-bottomed flask was charged with Cu(I)I (0.0108 g, 0.0568 mmol), 1-methylpiperidin-4-amine (0.0973 g, 0.852 mmol), K2CO3 (0.196 g, 1.42 mmol), L-Proline (0.0131 g, 0.114 mmol) and DMSO (2.5 mL). The reaction mixture was stirred for 5 minutes and 2-(4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenylamino)-N-(4-fluorophenyl)nicotinamide (0.200 g, 0.284 mmol) in DMSO (2.5 mL) was added. The reaction mixture was heated to 100° C. for 18 hours. The reaction mixture was cooled to ambient temperature and DCM and water (10 mL) were added. The organic layer washed with brine, dried over sodium sulfate, filtered and concentrated. The crude material was purified by silica gel chromatography, eluting with EtOAc to provide the product (23 mg, 11%). LRMS M−1 (691.2) observed.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][C:12]1[NH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[C:16]([OH:21])[CH:15]=2)C1C=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH:30]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:31]([O:33][CH2:34][CH3:35])=[O:32]>CC(C)=O.C(OCC)(=O)C>[CH2:34]([O:33][C:31](=[O:32])[CH:30]([O:21][C:16]1[CH:15]=[C:14]2[C:19]([CH:20]=[C:12]([CH2:11][NH2:10])[NH:13]2)=[CH:18][CH:17]=1)[C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH3:35]
Reactant: O=C(NCc1cc2ccc(O)cc2[nH]1)OCc1ccccc1
Reactant: CCOC(=O)C(Cl)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCOC(=O)C(Oc1ccc2cc(CN)[nH]c2c1)C(=O)OCC
Reaction time: 8 h

Procedure:
(6-Hydroxy-1H-indol-2-ylmethyl)-carbamic acid benzyl ester was dissolved in 10 ml acetone, Cs2CO3 and diethyl chloromalonate were added. The reaction is stirred overnight. HPLC and TLC indicated the reaction is done. The mixture was diluted with ethyl acetate and filtered through silica gel plug. The filtrate is concentrated and redissolved in ethanol, hydrogenated for 3 hours at 40 psi of hydrogen. The mixture is filtered, washed with ethyl acetate. The filtrate is concentrated to give 2-(2-Aminomethyl-1H-indol-6-yloxy)-malonic acid diethyl ester.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=3)[C:10]3([C:21]4=[CH:22][C:23]5[O:27][CH2:26][O:25][C:24]=5[CH:28]=[C:20]4[O:19][CH2:18]3)[C:9]2=[O:29])C=CC=CC=1>[OH-].[Pd+2].[OH-].C(O)(=O)C>[CH3:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[NH:8][C:9](=[O:29])[C:10]12[C:21]2=[CH:22][C:23]3[O:27][CH2:26][O:25][C:24]=3[CH:28]=[C:20]2[O:19][CH2:18]1
Reactant: Cc1ccc2c(c1)C1(COc3cc4c(cc31)OCO4)C(=O)N2C(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)C1(COc3cc4c(cc31)OCO4)C(=O)N2
Temperature: 60 °C
Reaction time: 96 h
Yield: 43.4 %

Procedure:
A stainless steel hydrogenating vessel was successively charged with 1′-(diphenylmethyl)-5′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.90 g, 1.95 mmol), glacial acetic acid (50.0 mL) and palladium hydroxide (0.10 g, 1.35 mmol, 20 wt % on carbon). The vessel was flushed with nitrogen, sealed then heated to 60° C. and placed under 120 Psi of H2. After 4 days of stirring, the reaction mixture was diluted with ethyl acetate and passed through a bed of celite. The filtrate was washed with water (6×100 mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography eluting with ethyl acetate/hexane (40-50%) to afford the title compound (0.25 g, 43%): mp 269-271° C.; 1H NMR (300 MHz, DMSO-d6)δ 10.45 (s, 1H), 7.00 (d, 1H), 6.87 (s, 1H), 6.76 (d, 1H), 6.63 (s, 1H), 6.21 (s, 1H), 5.87 (d, 2H); 4.64 (ABq, 2H), 2.17 (s, 3H); MS (ES+) m/z 296.28 (M+1).
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][CH2:5]C1C=CC=C2C(NC(=O)C=12)=O.O.NN.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[NH:23][CH:24]=[N:25]2.C([N:32](C(C)C)C(C)C)C>C(O)C.CCOCC>[CH3:1][O:2][N:3]=[CH:4][CH2:5][NH:32][C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[NH:23][CH:24]=[N:25]2
Reactant: CCN(C(C)C)C(C)C
Reactant: CON=CCc1cccc2c1C(=O)NC2=O
Reactant: Clc1ncnc2nc[nH]c12
Agent: NN
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: CON=CCNc1ncnc2nc[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 2 %

Procedure:
0.290 g (1.33 mmol) of N-[(2-(N-methoxyimino)ethyl]phthalimide was dissolved in 8 ml of ethanol and to the solution was added 77.7 μl (1.60 mmol) of hydrazine hydrate, followed by being refluxed for 5 hours. The reaction mixture was cooled to room temperature and then, 15 ml of ether was added thereto and the mixture was left to stand at 0° C. for 1 hour to sufficiently precipitate solids. The solids were removed by suction filtration and the filtrate was dried over sodium sulfate and concentrated to 1 ml by an avaporator. This concentrated filtrate was dissolved in 5 ml of isopropanol and to the solution were added 77.7 mg (0.503 mmol) of 6-chloropurine and 88 μl of ethyldiisopropylamine, followed by being refluxed with heating on an oil bath for 5 hours. The precipitated crystals were collected by filtration and thereafter, were purified by a thin layer chromatography (silica gel, developing agent: 10% ethanolchloroform) to give 5.2 mg (yield 2%) of the titled compound as a white powder.
Reaction SMILES: [C:1]([C:4]1[CH:28]=[CH:27][C:7]([C:8]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C@H:15]([NH:20]C(=O)C(F)(F)F)[C:16]([O:18]C)=[O:17])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[OH-].[Na+].[ClH:31].COC(=O)[C@@H](NC(=O)C(F)(F)F)CCCCN>CO>[Cl-:31].[C:1]([C:4]1[CH:28]=[CH:27][C:7]([C:8]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:16]([OH:18])=[O:17])[NH3+:20])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: Cl
Reactant: COC(=O)[C@H](CCCCNC(=O)c1ccc(C(C)=O)cc1)NC(=O)C(F)(F)F
Agent: COC(=O)[C@H](CCCCN)NC(=O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)c1ccc(C(=O)NCCCC[C@H]([NH3+])C(=O)O)cc1
Product: [Cl-]
Temperature: 60 °C

Procedure:
(S)-methyl 6-(4-acetylbenzamido)-2-(2,2,2-trifluoroacetamido)hexanoate (TU2982-136) (0.473 g) was treated 1 N aq NaOH (2.36 mL) in 10 mL MeOH at ambient temperature for 18 hours. LC-MS analysis was used to reveal the complete hydrolysis of the methyl ester, while maintaining the trifluoroamide moiety intact. The reaction was heated at 60° C. for 5 hours, at which time the amide hydrolysis was almost complete, as indicated by LC-MS analysis. The reaction mixture was cooled and concentrated under reduced pressure. The residue was treated with excess 1 N aq HCl, and concentrated to dryness under reduced pressure, affording ((S)-5-(4-acetylbenzamido)-1-carboxypentan-1-aminium chloride (TU3000-004) as a slightly yellow solid. MS (ESI+): calcd. 293.14. found 293.20 (MH+).