Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH2:18][OH:19])[CH2:9][NH:10]C(=O)OC(C)(C)C.ClS([N:24]=[C:25]=[O:26])(=O)=O.O.C(=O)(O)[O-].[Na+]>C(#N)C>[C:25](=[O:26])([O:19][CH2:18][CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[CH2:9][NH2:10])[NH2:24]
Reactant: CC(C)(C)OC(=O)NCC(CO)c1ccccc1Cl
Reactant: O=C=NS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: NCC(COC(N)=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 344 mg (1.20 mmol) of the compound of Example 14A in 86 ml of acetonitrile was cooled to −15° C., and 314 μl (3.61 mmol) of chlorosulphonyl isocyanate were added. After 5 min, 10 ml of water were added and stirring of the reaction mixture was continued at 60° C. overnight. After cooling to RT, 10 ml of a saturated aqueous sodium bicarbonate solution were added. The mixture was extracted four times with ethyl acetate. The combined organic phases were dried over sodium sulphate and freed from the solvent on a rotary evaporator. The residue (118 mg, about 85% pure, about 37% of theory) corresponded to the title compound and was reacted further without further purification.
Reaction SMILES: [C:1]([Si:4]([CH:11]1[CH2:13][CH2:12]1)([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])(=[O:3])[CH3:2].[CH3:14][Li]>>[CH:11]1([Si:4]([C:1]([OH:3])([CH3:14])[CH3:2])([CH:8]([CH3:9])[CH3:10])[CH:5]([CH3:6])[CH3:7])[CH2:13][CH2:12]1
Reactant: CC(=O)[Si](C(C)C)(C(C)C)C1CC1
Reactant: [Li]C
Product: CC(C)[Si](C(C)C)(C1CC1)C(C)(C)O

Procedure:
According to the synthesis of 1-hydroxy-1-methylethyl(diisopropyl)methylsilane (Example 7), cyclopropyl(1-hydroxy-1-methylethyl)(diisopropyl)silane was prepared from dichloro(diisopropyl)silane (5.00 g, 27.0 mmol), ethoxyvinyl lithium (prepared from ethyl vinyl ether (2.17 g, 30.1 mmol) and tert-butyl lithium (1.9 M in pentane, 14.2 ml, 27.0 mmol) in THF (40 ml)) and cyclopropyl lithium (prepared according to Example 1 from bromocyclopropane (3.59 g, 29.7 mmol) and lithium (412 mg, 59.4 mmol) in Et2O). The crude cyclopropyl(1-ethoxyvinyl)(diisopropyl)silane was hydrolysed with acetone/1 N HCl (2:1, 72 ml), and purified by silica-gel flash chromatography (silica gel 40-63 μm, hexane/EtOAc, 9:1) to afford 2.11 g (39%) acetyl(cyclopropyl)(diisopropyl)silane. Reaction of acetyl(cyclopropyl)(diisopropyl)silane (1.00 g, 5.04 mmol) with methyl lithium (1.6 M in Et2O, 25.2 ml, 40.3 mmol) afforded after purification by silica-gel chromatography (silica gel 15-40 μm, hexane/EtOAc, 9:1) 590 mg (55%) of the odoriferous title compound.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9](=[O:11])[NH:8][C:7]=2[CH:12]=1.[CH3:15][N:16]([CH3:35])[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:22]=[N:23][C:24]([C:27]2[CH:28]=[C:29]([CH2:33]O)[CH:30]=[CH:31][CH:32]=2)=[N:25][CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[CH3:35][N:16]([CH3:15])[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[N:25][C:24]([C:27]2[CH:28]=[C:29]([CH:30]=[CH:31][CH:32]=2)[CH2:33][N:8]2[C:7]3[CH:12]=[C:3]([C:2]([F:1])([F:13])[F:14])[CH:4]=[CH:5][C:6]=3[S:10][C:9]2=[O:11])=[N:23][CH:22]=1
Reactant: CN(C)CCCOc1cnc(-c2cccc(CO)c2)nc1
Reactant: O=c1[nH]c2cc(C(F)(F)F)ccc2s1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CN(C)CCCOc1cnc(-c2cccc(Cn3c(=O)sc4ccc(C(F)(F)F)cc43)c2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 114 mg (0.52 mmol) of 5-trifluoromethyl-3H-benzothiazol-2-one, 150 mg (0.52 mmol) of {3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]phenyl}methanol and 261 mg (0.78 mmol) of polymer-bound triphenylphosphine (3mmol/g) is shaken at room temperature for 30 min. 178 mg (0.78 mmol) of di-tert-butyl azodicarboxylate are added to the suspension, and, after the mixture has been stirred at room temperature for 24 h, 50 mg (0.15 mmol) of polymer-bound triphenylphosphine (3 mmol/g) and 35 mg (0.15 mmol) of di-tert-butyl azodicarboxylate are again present and shaken at room temperature for 2 h. The reaction mixture is filtered, the filtrate is evaporated to dryness, and the residue is purified by means of preparative HPLC. The product is in the form of the trifluoroacetate; ESI: 489 (M+H); Rt.=2.81 min (method A);
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[N+:23]([O-])=O)[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[NH2:23])[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(Oc3ccc(F)cc3[N+](=O)[O-])cccc2[nH]1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2c(Oc3ccc(F)cc3N)cccc2[nH]1
Reaction time: 2 h

Procedure:
146 (1.5 g, 4.21 mmol) is dissolved in 200 ml of ethyl acetate and, after addition of Pd—C (200 mg), the mixture is hydrogenated at room temperature for 2 hours. The mixture is filtrated over celite to remove the catalyst and evaporated.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]([O:8][CH:9]1[CH2:14][CH2:13][C:12]([CH2:16][S:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([OH:15])[CH:11]([C:24]2([CH3:32])[O:31][CH:25]2[CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29])[CH:10]1[O:33][CH3:34])=[O:7])=[O:4].ClC1C=CC=C(C(OO)=[O:43])C=1>ClCCl.C(OCC)(=O)C>[Cl:1][CH2:2][C:3]([NH:5][C:6]([O:8][CH:9]1[CH2:14][CH2:13][C:12]([CH2:16][S:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:43])([OH:15])[CH:11]([C:24]2([CH3:32])[O:31][CH:25]2[CH2:26][CH:27]=[C:28]([CH3:29])[CH3:30])[CH:10]1[O:33][CH3:34])=[O:7])=[O:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC1C(OC(=O)NC(=O)CCl)CCC(O)(CSc2ccccc2)C1C1(C)OC1CC=C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC1C(OC(=O)NC(=O)CCl)CCC(O)(CS(=O)c2ccccc2)C1C1(C)OC1CC=C(C)C
Yield: 84.8 %

Procedure:
In dichloromethane (2 ml) was dissolved 4-O-(chloroacetylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-h-exenyl)-3-methoxy-1-phenylthiomethyl-1,4-cyclohexanediol (200 mg). To the solution was added, under ice-cooling, m-chloroperbenzoic acid (80.9 mg), and the mixture was stirred for 30 minutes. The reaction mixture was diluted with ethyl acetate (70 ml), which was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous saline solution, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was then purified by means of a silica gel column chromatography (carrier 10 g, developing solvent: ethyl acetate - hexane=1:2) to afford 4-O-(chloroacetylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-phenylsulfinylmethyl-1,4-cyclohexanediol (175 mg: yield 85%) as colorless powder.
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.[C:12]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)#[N:13].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[N:10]1[C:11]2[CH:2]([NH:1][CH2:18][C:17]3[CH:20]=[CH:21][C:14]([C:12]#[N:13])=[CH:15][CH:16]=3)[CH2:3][CH2:4][CH2:5][C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: NC1CCCc2cccnc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1ccc(CNC2CCCc3cccnc32)cc1
Reaction time: 42 h
Yield: 71.5 %

Procedure:
To a stirred solution of 8-amino-5,6,7,8-tetrahydroquinoline (24.3 g, 164 mmol) in dichloromethane (600 mL), at room temperature, was added 4-cyanobenzaldehyde (21.5 g, 164 mmol) and sodium triacetoxyborohydride (45 g, 210 mmol). After 42 hours, the reaction was quenched with 1N NaOH (250 mL). The phases were separated and the organic phase was washed once with brine (200 mL), dried (Na2SO4), and concentrated. Purification of the crude material by flash chromatography on silica gel (5% CH3OH/CH2Cl2) provided 30.9 g (72%) of N-(5,6,7,8-tetrahydro-8-quinolinyl)-4-cyanobenzylamine as a pale yellow solid.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]=[CH:7][C:8]1[O:9][C:10]2[C:25]([O:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:23]=[CH:22][C:11]=2[C:12]=1[CH2:13][CH2:14][O:15]C1CCCCO1)(=[O:3])[CH3:2].CCCCCC.C(OCC)(=O)C>CO.[Pd]>[C:1]([O:4][CH2:5][CH2:6][CH2:7][C:8]1[O:9][C:10]2[C:25]([O:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:23]=[CH:22][C:11]=2[C:12]=1[CH2:13][CH2:14][OH:15])(=[O:3])[CH3:2]
Reactant: COC(=O)COc1cccc2c(CCOC3CCCCO3)c(C=CCOC(C)=O)oc12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCCCCC
Product: COC(=O)COc1cccc2c(CCO)c(CCCOC(C)=O)oc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 49.6 %

Procedure:
Methyl (2-(3-acetoxy-1-propenyl)-3-(2-tetrahydropyranyloxyethyl)benzofuran-7-yloxy)acetate (199 mg) was dissolved in methanol (4 ml) and 5% Pd/C (28 mg) was added to the solution, followed by stirring the solution at room temperature for 1.5 hours under hydrogen atmosphere. After filtering the reaction solution through Celite, the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography (solvent: hexane/ethyl acetate=1/1)using silica gel to obtain the desired compound (80 mg, yield: 50%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]([F:20])([F:19])[F:18])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([O:24][C:25]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)=[O:26])[CH2:22][CH3:23].C(N1CCOCC1)C.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O>CN(C=O)C.C(OCC)(=O)C>[CH2:21]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([C:13](=[O:15])[C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:16][C:17]([F:20])([F:19])[F:18])[CH2:29][CH2:28]1)=[O:26])[CH2:22][CH3:23]
Reactant: CCCOC(=O)N1CCNCC1
Reactant: O=C(N[C@@H](CC(F)(F)F)C(=O)O)OCc1ccccc1
Agent: CCN1CCOCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCOC(=O)N1CCN(C(=O)[C@H](CC(F)(F)F)NC(=O)OCc2ccccc2)CC1
Reaction time: 12 h

Procedure:
To a solution of 118 mg (S)-2-Benzyloxycarbonylamino-4,4,4-trifluoro-butyric acid in 2 ml DMF were added 70 mg 1-propoxycarbonylpiperazine, 0.18 ml N-ethylmorpholine and 238 mg TOTU. After stirring for 12 h it was diluted with ethyl acetate and extracted with aqueous LiCl (4% w/w), aqueous NaHCO3, 0.1 M HCl and brine. The organic layer was dried over MgSO4 and concentrated to furnish the crude coupling product which was used without further purification in the next step.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[N:25]=[C:24](S(C)(=O)=O)[N:23]=1>C(#N)C>[CH3:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[N:25]=[C:24]([N:11]2[CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10]2)[N:23]=1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(OC)nc(N2CCN(Cc3ccccc3)CC2)n1
Temperature: 25 °C
Yield: 98.7 %

Procedure:
In 100 ml of acetonitrile was dissolved 10 g (0.0567 mole) of 1-benzylpiperazine, and 11.7 g (0.085 mole) of potassium carbonate and 14.8 g (0.068 mole) of 4,6-dimethoxy-2-methylsulfonylpyrimidine were added thereto. The mixture was refluxed by heating for 5 hours. The mixture was cooled to room temperature and then filtered. The filtrate was concentrated under reduced pressure, and the residue was applied to silica gel column chromatography (the eluent used was a mixture of ethyl acetate:toluene=1:9) to obtain 17.6 g of 4-(4,6-dimethoxy-2-pyrimidinyl)-1-benzylpiperazine as colorless liquid.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:9][CH:10]([O:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cccnc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cncc(OC2CNC2)c1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 64.5 %

Procedure:
To 160 mg (0.64 mmol) of 3-(1-t-butoxycarbonyl-3-azetidinyloxy)-pyridine was added 6 mL of solution containing 3 mL of TFA and 3 mL of CH2Cl2 at ice-bath temperature. The reaction solution was slowly warmed to room temperature and allowed to stir 50 min at room temperature. After 50 min, solvents were removed in vacuo and the crude product was purified by flash chromatography (9:1: 0.05, CHCl3: MeOH:conc. NH4OH) to obtain 62 mg (67%) of a white solid: 1H NMR (300 MHz, CD3OD) δ 8.23 (2H, br s), 7.38 (2H, br d), 5.24 (2H, br s), 4.58 (2H, br d), 4.20 (2H, br d, J=9.8 Hz); Mass spectrum (ESI) m/z 151.7 (M+H+).
Reaction SMILES: [N-:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Na+].[Cl:7][C:8]1[O:12][C:11]([CH:13]2[C:18]3=[C:19]4[N:31]([CH3:32])[C:30](=[O:33])[N:29]([CH3:34])[C:28](=[O:35])[C:20]4=[C:21]([C:22]4[S:23][CH:24]=[C:25]([CH3:27])[N:26]=4)[N:17]3[CH2:16][CH:15]([CH2:36]O)[S:14]2)=[CH:10][CH:9]=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>C(Cl)Cl>[N:1]1([CH2:36][C@H:15]2[S:14][C@H:13]([C:11]3[O:12][C:8]([Cl:7])=[CH:9][CH:10]=3)[C:18]3=[C:19]4[N:31]([CH3:32])[C:30](=[O:33])[N:29]([CH3:34])[C:28](=[O:35])[C:20]4=[C:21]([C:22]4[S:23][CH:24]=[C:25]([CH3:27])[N:26]=4)[N:17]3[CH2:16]2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Cc1csc(-c2c3c(=O)n(C)c(=O)n(C)c3c3n2CC(CO)SC3c2ccc(Cl)o2)n1
Reactant: c1c[n-]cn1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Product: Cc1csc(-c2c3c(=O)n(C)c(=O)n(C)c3c3n2C[C@@H](Cn2ccnc2)S[C@@H]3c2ccc(Cl)o2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium imidazolide (86 mg, 0.960 mmol) was added to a solution of racemic 10-(5-chlorofuran-2-yl)-8-(hydroxymethyl)-1,3-dimethyl-5-(4-methylthiazol-2-yl)-7,8-dihydro-1H-pyrimido[4′,5′:3,4]pyrrolo[2,1-c][1,4]thiazine-2,4(3H,10H)-dione (115 mg, 0.240 mmol) (Example 17) in DCM (24 ml) at 0° C. The mixture was stirred for 30 minutes, then trifluoromethanesulfonic anhydride (0.049 ml, 0.288 mmol) was added dropwise. The mixture was warmed to room temperature and stirred for 3 hours. The mixture was diluted with DCM (10 ml) washed with water (30 ml) and brine (30 ml). The organic layer was passed through a hydrophobic frit and evaporated under vacuum. Purification by chromatography on silica, eluting with 0-20% methanol/DCM, afford the title compound as a mixture of diastereomers.
Reaction SMILES: O[C:2]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][Br:10].C1(C)C(S(O)(=O)=O)=CC=CC=1.O>C1(C)C=CC=CC=1>[F:17][C:14]1[CH:13]=[CH:12][C:11]([C:2]([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][Br:10])=[CH:16][CH:15]=1
Reactant: OC(CCCCCCCBr)(c1ccc(F)cc1)c1ccc(F)cc1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: Fc1ccc(C(=CCCCCCCBr)c2ccc(F)cc2)cc1

Procedure:
31.9 g (80 mmol) 8-hydroxy-8,8-bis-(4-fluorophenyl)-octyl bromide dissolved in toluene are added to 0.3 g toluene sulfonic acid and the mixture is subsequently heated for an hour with water separator under reflux. After withdraw of the solvent, the residue is chromatographically purified over silica gel with petroleum ether/acetic acid ethyl ester (90/1): Yield 28.6 g (94%).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[N:3]=1.[CH3:22][O:23][C:24]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[CH:26][C:25]=1[NH:39][C:40]([C:42]1[N:43]([CH3:51])[C:44]2[C:49]([CH:50]=1)=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:41].C(=O)([O-])[O-].[Na+].[Na+]>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>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH2:12][CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[N:3]=[C:2]([C:28]3[CH:27]=[CH:26][C:25]([NH:39][C:40]([C:42]4[N:43]([CH3:51])[C:44]5[C:49]([CH:50]=4)=[CH:48][CH:47]=[CH:46][CH:45]=5)=[O:41])=[C:24]([O:23][CH3:22])[CH:29]=3)[C:10]=12
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: CN1CCN(CCCn2nc(I)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: COCCOC
Product: COc1cc(-c2nn(CCCN3CCN(C)CC3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 80 °C
Reaction time: 4.5 h
Yield: 30 %

Procedure:
A solution of 3-iodo-1-[3-(4-methylpiperazino)propyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.188 g, 0.469 mmol) in ethylene glycol dimethyl ether (16 mL) was treated with N2-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-methyl-1H-2-indolecarboxamide (0.209 g, 0.516 mmol), tetrakis(triphenylphosphine)palladium (0.033 g, 0.028 mmol), and a solution of sodium carbonate (0.119 g, 1.13 mmol) in water (8 mL). The reaction mixture was stirred for 4.5 h at 80° C. The organic solvent was removed under reduced pressure and ethyl acetate (200 mL) was added. The layers were partitioned and the aqueous layer was extracted with ethyl acetate (400 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a step-wise gradient of 20% methanol in dichloromethane to 50% methanol in dichloromethane. The column afforded 0.078 g (30%) of pure N2-(4-{4-amino-1-[3-(4-methylpiperazino)propyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-1-methyl-1H-2-indolecarboxamide. 1H NMR (DMSO-d6, 400 MHz) δ 9.442 (s, 1H), 8.258 (s, 1H), 8.122-8.1076 (d, 1H, J=8.16 Hz), 7.719-7.6991 (d, 1H, J=7.96 Hz), 7.6005-7.5793 (d, 1H, J=8.48 Hz), 7.349-7.294 (m, 4H), 7.172-7.135 (t, 1H), 4.405-4.371 (m, 2H), 4.04 (s, 3H), 3.958 (s, 3H), 3.291 (m, 2H), 2.5 (m, 3H), 2.45-2.337 (m, 5H), 2.30-2.10 (m, 3H), 2.022-2.005 (m, 2H); LCMS (Thermoquest AQA single-quad MS, Genesis C18 column, 3 μm particle size, 33×4.6 mm; 70% 50 mM ammonium acetate in water to 95% acetonitrile over 6 min, 0.8 to 0.5 mL/min) Rt 2.05 min (100%), MH+ 554.3.
Reaction SMILES: [OH:1][CH2:2][CH2:3][SH:4].[NH2:5][C:6]1[CH:11]=[N:10][C:9](Br)=[CH:8][N:7]=1>CN(C)C=O.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>[NH2:5][C:6]1[N:7]=[CH:8][C:9]([S:4][CH2:3][CH2:2][OH:1])=[N:10][CH:11]=1
Reactant: Nc1cnc(Br)cn1
Reactant: OCCS
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cnc(SCCO)cn1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
According to the method described in WO2004/052869, 2-hydroxy-1-ethanethiol (0.93 mL) and tetrakis(triphenylphosphine)palladium (3.39 g) were added to a solution of 2-amino-5-bromopyrazine (1.00 g, 5.75 mmol) in N,N-dimethylformamide (15.1 mL), and the mixture was heated and stirred at 120° C. in a sealed tube for about 3 hours. After cooling, the reaction mixture was diluted with water and extracted with a mixed solution (dichloromethane:ethanol=5:1) (100 mL×6). The organic layer was dried over anhydrous sodium sulfate and then filtrated, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=1:1, then ethyl acetate, and then ethyl acetate:methanol=10:1) and was recrystallized (using chloroform) to give the title compound as yellow needle crystals (470 mg, yield: 44%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].CCN(C(C)C)C(C)C.[NH:24](C(OC(C)(C)C)=O)[NH2:25].Cl>ClCCl.O1CCOCC1>[Cl:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:24][NH2:25])=[O:5]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: NNC(=O)c1cccc(C(F)(F)F)c1Cl
Reaction time: 8 h

Procedure:
To a solution of 2-chloro-3-(trifluoromethyl)benzoyl chloride (15 g, 61.7 mmol, commercially available from e.g. Apollo) and DIPEA (12.94 ml, 74.1 mmol) in anhydrous dichloromethane (DCM) (200 ml) cooled to 0° C. in an ice bath was slowly added 1,1-dimethylethyl hydrazinecarboxylate (8.97 g, 67.9 mmol) under an atmosphere of argon and the mixture was allowed to reach steadily room temperature overnight. It was quenched with water (100 mL), the phases were separated and the aqueous extracted with DCM (2×50 mL). The combined organics were washed with brine (50 mL) and dried over MgSO4. The orange oil isolated (circa 25 g) was the impure BOC-protected hydrazide. It was then dissolved in 1,4-Dioxane (100 ml) and treated with HCl (4M in dioxane) (154 ml, 617 mmol) overnight at room temperature. The slurry was concentrated at the buchi to obtain a yellow solid which was triturated with Et2O to afford a white coloured solid, then applied to 4×10 g SCX cartridges, washed with MeOH and finally eluted with NH3 (2M in MeOH). The basic fractions were concentrated to afford the desired product in 3.5 g as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.[NH2:22][CH2:23][C:24]([CH3:31])([CH3:30])[C:25]([O:27][CH2:28][CH3:29])=[O:26].C(=O)([O-])[O-].[K+].[K+].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:30][C:24]([CH3:31])([CH2:23][NH:22][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])[C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CCOC(=O)C(C)(C)CN
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)CNc1c([N+](=O)[O-])cnc2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of 4-chloro-3-nitroquinoline (35.0 g, 168 mmol) and triethylamine (84 mL, 0.60 mol) in dichloromethane (400 mL) was cooled to 0° C.; a solution of ethyl 3-amino-2,2-dimethylpropanoate (40.0 g, 0.220 mol) in dichloromethane (50 mL) was added dropwise. The reaction was stirred at 0° C. for 30 minutes and then at ambient temperature for four hours. The reaction was incomplete as determined by a TLC analysis, and additional ethyl 3-amino-2,2-dimethylpropionate (10.0 g, 55.0 mmol) was added. The reaction was stirred overnight; another analysis by TLC indicated the reaction was incomplete. Additional ethyl 3-amino-2,2-dimethylpropionate (5.0 g, 28 mmol) was added, and the reaction was heated at reflux for three hours. Potassium carbonate (10 g) was added, and the reaction was heated at reflux for two hours and stirred overnight at ambient temperature. Saturated aqueous sodium bicarbonate (50 mL) was added, and the reaction was stirred for three days. The organic layer was separated, washed with water (3×100 mL), dried over potassium carbonate, filtered, and concentrated under reduced pressure to provide ethyl 2,2-dimethyl-3-[(3-nitroquinolin-4-yl)amino]propanoate as an orange oil, which was mixed with material from another run and used without purification.