Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]1[C:19]([O:20]C)=[N:18][C:17]2[C:12]1=[N:13][C:14]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[N:15][C:16]=2[NH2:22])(C)(C)C.Cl>C(OCC)C.CCCC(C)C.O1CCOCC1>[NH2:22][C:16]1[N:15]=[C:14]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])[N:13]=[C:12]2[C:17]=1[NH:18][C:19](=[O:20])[N:11]2[CH2:10][CH2:9][CH2:8][NH2:7]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCNC(=O)OC(C)(C)C)c2n1
Agent: Cl
Solvent: CCCC(C)C
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN)c2n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The product from step (i) (1.1 g) was dissolved in methanol/DCM (1/1, 40 ml). 4N—HCl in dioxane (10 ml) was added and the mixture stirred at rt for 20 h. The resultant was concentrated under reduced pressure, which afforded the subtitle compound. Yield 0.9 g.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11](CC2C=CC=CC=2)[CH2:10][CH:9]1[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)OC(Cl)C>ClCCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH:9]1[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: CCOC(=O)C1CNCCN1Cc1ccccc1
Reaction time: 0.25 h
Yield: 61.6 %

Procedure:
To a solution of ethyl 1,4-dibenzylpiperazine-2-carboxylate (6.76 g, 20 mmol) in 1,2-dichloroethane (20 mL) was added 1-chloroethyl carbonochloridate (3.15 g, 22 mmol) dropwise over a period of 30 minutes at 0° C., and the mixture was stirred at the temperature for another 15 minutes. Then the mixture was stirred at 90° C. for 1 hour. The mixture was concentrated in vacuo, and to the residue was added methanol (15 mL). The mixture was stirred at 70° C. for 1 hour and concentrated in vacuo. The residue was diluted with water and washed with DCM. The aqueous layer was adjusted to pH 9 with NaHCO3 aqueous solution and extracted with DCM. The organic layer was dried over Na2SO4, and concentrated in vacuo to give the title compound as yellow oil (3.06 g, 60%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH:6]=[CH:7][S:8][CH3:9])[C:3](O)=[O:4].C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1.O>C(OCC)(=O)C>[Cl:23][C:24]1[CH:30]=[CH:29][C:27]([NH:28][C:3](=[O:4])[C:2]([CH3:10])([CH3:1])[CH:6]=[CH:7][S:8][CH3:9])=[CH:26][CH:25]=1
Reactant: CSC=CC(C)(C)C(=O)O
Reactant: Nc1ccc(Cl)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CCOC(C)=O
Product: CSC=CC(C)(C)C(=O)Nc1ccc(Cl)cc1
Reaction time: 16 h
Yield: 32.1 %

Procedure:
A solution of 0.5 g of 2,2-dimethyl-4-methylthio-3-butenoic acid in 20 mL of ethyl acetate was treated with 0.6 g of carbonyldiimidazole, and the solution was heated for 10 minutes at reflux. After the solution had cooled, 0.65 g of p-chloroaniline was added and heating continued for 16 hours. The solution was then cooled, poured into water and extracted into ethyl acetate. The organic layer was washed with 50 mL of 1N HCl, dried over MgSO4, and concentrated. The residual solid was recrystallized from CHCl3 /hexane to give 0.27 g of N-(4-chlorophenyl)-2,2-dimethyl-4-(methylthio)-3-butenamide, m.p. 105°-106° C.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:5]=1[O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=[O:10].S([O-])(O)(=O)=O.[Na+].C(OCC)(=O)C>C(O)(C)C.C(Cl)Cl>[Cl:3][C:4]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:5]=1[O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9][OH:10]
Reactant: O=Cc1ccccc1Oc1ccc(Cl)cc1Cl
Agent: O=S(=O)([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Solvent: ClCCl
Product: OCc1ccccc1Oc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.7 %

Procedure:
Sodium borohydride (119 mg, 3.15 mmol) was added to a solution of 2-(2,4-dichlorophenoxy)benzaldehyde (600 mg, 2.25 mmol) in isopropanol (10 ml) and DCM (20 ml). The reaction mixture was stirred for 2 hours at room temperature. A 10% aqueous solution of sodium hydrogensulphate (200 ml) was added dropwise. Ethyl acetate (300 ml) was added successively. The phases were separated. The aqueous phase was extracted with ethyl acetate (100 ml). The combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate (200 ml) and dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (100 g), using ethyl acetate/heptane 1:3 as eluent, to give 440 mg of 1-[2-(2,4-dichlorophenoxy)phenyl]methanol.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Cl:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([Cl:18])[C:16]=1Cl.C(N(CC)CC)C>CN1C(=O)CCC1>[Cl:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([Cl:18])[C:16]=1[N:7]1[CH2:8][CH2:9][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]1
Reactant: Clc1cncc(Cl)c1Cl
Reactant: CC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CC(=O)N1CCN(c2c(Cl)cncc2Cl)CC1
Yield: 24.3 %

Procedure:
General procedure C was followed using acetylpiperazine (35 mg, 0.27 mmol), 3,4,5-trichloropyridine (50 mg, 0.27 mmol), triethylamine (0.76 μL, 0.54 mmol) and NMP (1.5 mL). The crude product was purified by flash column chromatography on silica gel (hexane/EtOAc, 1:1) to furnish the title compound as a white solid (18 mg, 24%), m.p. 144-146° C.; umax (CHCl3)/cm−1 3008, 2909, 2856, 1638, 1558, 1470, 1441, 1282, 1240, 1152, 1098; m/z (ESI) C11H14Cl2N3O requires 274.0508, found [M+H]+ 274.0513.
Reaction SMILES: [CH3:1][Si:2]([CH3:13])([CH3:12])[O:3][C:4]1([C:10]#N)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[H-].C([Al+]C(C)C)(C)C.CCCCCC.[OH2:28]>ClCCl>[CH3:1][Si:2]([CH3:13])([CH3:12])[O:3][C:4]1([CH:10]=[O:28])[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1
Reactant: C[Si](C)(C)OC1(C#N)CCOCC1
Reactant: O
Agent: CC(C)[Al+]C(C)C
Agent: [H-]
Solvent: CCCCCC
Solvent: ClCCl
Product: C[Si](C)(C)OC1(C=O)CCOCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 29 %

Procedure:
4-(Trimethylsilyloxy)tetrahydro-2H-pyran-4-carbonitrile (1.00 g, 5.02 mmol) was dissolved in dichloromethane (20 mL). To this, a 1 mol/L solution of diisopropylaluminum hydride in hexane (7.76 mL, 7.76 mmol) was added at −78° C. and the mixture was stirred at room temperature for 20 minutes. The reaction was stopped by addition of water (7.76 mL) at 0° C. The mixture was stirred at room temperature for 1 hour and then filtered through Celite. The solvent was evaporated off under reduced pressure and the residue was dissolved in tetrahydrofuran (10 mL). To this, a saturated aqueous ammonium chloride solution was added and the mixture was stirred at room temperature for 30 minutes. Then, extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1) to give 4-(trimethylsilyloxy)tetrahydro-2H-pyran-4-carbaldehyde (297 mg, yield: 29%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH:14]3[CH2:17][N:16]([C:18](=[O:21])[CH2:19][CH3:20])[CH2:15]3)=[N:11][N:10](C(=O)CC)[C:9]2=[O:26])=[C:4]([F:27])[CH:3]=1.[N:28]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35](B(O)O)[CH:36]=2)[CH:31]=[CH:30][CH:29]=1.C(O)C>O1CCOCC1.C(=O)([O-])[O-].[K+].[K+].ClCCl>[F:27][C:4]1[CH:3]=[C:2]([C:35]2[CH:36]=[C:37]3[C:32]([CH:31]=[CH:30][CH:29]=[N:28]3)=[CH:33][CH:34]=2)[CH:7]=[CH:6][C:5]=1[N:8]1[C:12]([CH2:13][CH:14]2[CH2:15][N:16]([C:18](=[O:21])[CH2:19][CH3:20])[CH2:17]2)=[N:11][NH:10][C:9]1=[O:26]
Reactant: OB(O)c1ccc2cccnc2c1
Reactant: CCC(=O)N1CC(Cc2nn(C(=O)CC)c(=O)n2-c2ccc(Br)cc2F)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCO
Product: CCC(=O)N1CC(Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4cccnc4c3)cc2F)C1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
In a microwave vial purged with nitrogen, a mixture of 4-(4-bromo-2-fluorophenyl)-2-propanoyl-5-[(1-propanoyl-3-azetidinyl)methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (0.37 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.02 mmol) and 7-quinoline boronic acid (0.39 mmol) in 1,4-dioxane (2 mL) and 2M aq potassium carbonate (2 mL) was stirred at 100° C. in an oil bath for 1 h. The reaction was cooled to room temperature and the layers were separated. The aqueous layer was acidified to pH˜5.5 using 1N HCl solution and extracted with ethyl acetate (50 mL). The organic layers were combined, dried over magnesium sulphate, and concentrated in vacuo to give a tan solid. Trituration in dichloromethane followed by treatment with hot ethanol (5 mL), which was allowed to cool to room temperature, and then filtration afforded the desired product as a white solid, 93% pure. Subsequent purification of the filtrate and white solid by reverse phase HPLC (20-60% acetonitrile/water with 0.1% NH4OH) provided the title compound as a white solid (119 mg, 74%). MS(ES)+ m/e 432.1 [M+H]+.
Reaction SMILES: [H-].[Na+].[Br-].[CH3:4][S+](C)(C)=O.[C:9]([O:13][C:14]([NH:16][CH2:17][C:18]1[C:19]([CH2:42][CH2:43][CH3:44])=[N:20][C:21]2[C:26]([C:27]=1[C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=1)=[CH:25][C:24](/[CH:35]=[CH:36]/[C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:23][CH:22]=2)=[O:15])([CH3:12])([CH3:11])[CH3:10].[Cl-].[NH4+]>CS(C)=O>[C:9]([O:13][C:14]([NH:16][CH2:17][C:18]1[C:19]([CH2:42][CH2:43][CH3:44])=[N:20][C:21]2[C:26]([C:27]=1[C:28]1[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=1)=[CH:25][C:24]([CH:35]1[CH2:4][CH:36]1[C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:23][CH:22]=2)=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: CCCc1nc2ccc(/C=C/C(=O)OCC)cc2c(-c2ccc(C)cc2)c1CNC(=O)OC(C)(C)C
Reactant: C[S+](C)(C)=O
Agent: [Br-]
Agent: [Cl-]
Agent: [H-]
Solvent: CS(C)=O
Product: CCCc1nc2ccc(C3CC3C(=O)OCC)cc2c(-c2ccc(C)cc2)c1CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.9 %

Procedure:
To a suspension of sodium hydride (60% in oil, 120 mg, 3 mmol) in dimethyl sulfoxide (10 ml) was added trimethylsulfoxonium bromide (605 mg, 3.5 mmol), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added ethyl (2E)-3-[3-{[(tert-butoxycarbonyl)amino]methyl}-4-(4-methylphenyl)-2-propylquinolin-6-yl]acrylate (0.73 g, 1.5 mmol) and the mixture was stirred at room temperature for 1 hr. Saturated aqueous ammonium chloride solution was poured into the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from diisopropyl ether to give ethyl 2-[3-{[(tert-butoxycarbonyl)amino]methyl}-4-(4-methylphenyl)-2-propylquinolin-6-yl]cyclopropane-1-carboxylate (0.61 g, yield 81%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH2:12][CH:13]2[O:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[O:10])=[CH:4][CH:3]=1.Br[CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH2:12][CH:13]2[O:18][CH2:17][CH2:16][N:15]([CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH2:14]2)=[O:10])=[CH:4][CH:3]=1
Reactant: Fc1ccc(OCCBr)cc1
Reactant: O=C(NCC1CNCCO1)Nc1ccc(Cl)cc1
Product: O=C(NCC1CN(CCOc2ccc(F)cc2)CCO1)Nc1ccc(Cl)cc1
Yield: 46.3 %

Procedure:
Example 40 was prepared in an analogous manner to Example 19 using a mixture of Intermediate 9 (0.01 g) and 1-(2-bromoethoxy)-4-fluorobenzene (0.0089 g) to give the title compound (0.007 g). LC-MS (System A): Rt 2.69 mins, Mass Spectrum m/z 408 [MH+].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].[CH3:13][N:14](C)C=O>[C-]#N.[C-]#N.[Zn+2].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>[C:13]([C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6])#[N:14]
Reactant: CN(C)C=O
Reactant: COC(=O)c1ccc(C)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COC(=O)c1ccc(C)c(C#N)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
A mixture of methyl 3-bromo-4-methylbenzoate (compound 1.6, 18 g, 78.58 mmol, 1.00 equiv), Zn(CN)2 (11.1 g, 94.87 mmol, 1.20 equiv), and Pd(PPh3)4 (7.3 g, 6.32 mmol, 0.08 equiv) in N,N-dimethylformamide (250 mL) was stirred under a nitrogen atmosphere at 100° C. overnight. After cooling to room temperature, the reaction was then quenched by careful addition of 200 mL of FeSO4 (aq., sat.) and diluted with ethyl acetate. The resulting mixture was stirred vigorously then filtered through celite and washed with 1 M FeSO4, water, and ethyl acetate. The layers were separated and the aqueous phase was extracted with 2×500 mL of ethyl acetate. The combined organic layers were washed with 3×200 mL of brine, dried over (Na2SO4), and concentrated under reduced pressure. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:50) as eluent to yield 11 g (76%) of the title compound as an off-white solid.
Reaction SMILES: [CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=2[O:2]1.[Cl:12][C:13]1[N:14]=[C:15](Cl)[C:16]2[CH:21]=[C:20]([Cl:22])[S:19][C:17]=2[N:18]=1>>[Cl:12][C:13]1[N:14]=[C:15]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:10]3[O:11][CH2:1][O:2][C:3]=3[CH:4]=2)[C:16]2[CH:21]=[C:20]([Cl:22])[S:19][C:17]=2[N:18]=1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: Clc1nc(Cl)c2cc(Cl)sc2n1
Product: Clc1nc(NCc2ccc3c(c2)OCO3)c2cc(Cl)sc2n1

Procedure:
Following the procedure of Example 1, the reaction of 3,4-methylenedioxybenzylamine with 2,4,6-trichloro-thieno-[2,3-d]-pyrimidine gives 2,6-dichloro-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine
Reaction SMILES: O=C1CCC(=O)N1[O:8][C:9](=O)[CH2:10][CH2:11][CH:12]([NH:20][C:21](=[O:47])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[NH2:49][CH2:50][CH2:51][O:52][CH2:53][CH2:54][O:55][CH2:56][C:57]([NH:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH2:66][C:67]([OH:69])=[O:68])=[O:58].NCCOCCOCC(O)=O.CCN(C(C)C)C(C)C>C(O)C>[C:43]([O:42][C:40](=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C:21](=[O:47])[NH:20][C@H:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:10][C:9](=[O:8])[NH:49][CH2:50][CH2:51][O:52][CH2:53][CH2:54][O:55][CH2:56][C:57](=[O:58])[NH:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH2:66][C:67]([OH:69])=[O:68])([CH3:46])([CH3:44])[CH3:45]
Reactant: NCCOCCOCC(=O)NCCOCCOCC(=O)O
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(=O)NC(CCC(=O)ON1C(=O)CCC1=O)C(=O)OC(C)(C)C
Agent: NCCOCCOCC(=O)O
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(=O)N[C@@H](CCC(=O)NCCOCCOCC(=O)NCCOCCOCC(=O)O)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 96 %

Procedure:
To a solution of 2-(19-tert-Butoxycarbonylnonadecanoylamino)pentanedioic acid 1-tert-butyl ester 5-(2,5-dioxopyrrolidin-1-yl)ester (2.50 g, (prepared similarly as described in WO 2005/012347) and [2-(2-{2-[2-(2-Aminoethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetic acid (1.47 g, alternative name: 8-amino-3,6-dioxaoctanoic acid dimer, IRIS Biotech GmbH, Cat. No. PEG1221) in ethanol (40 ml) was added DIPEA (1.26 ml). The mixture was stirred at room temperature over night and then concentrated in vacuo. To the residue was added aqueous 0.1 N HCl (150 ml) and ethyl acetate (200 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (100 ml). The combined organic layeres were washed with water and brine, dried (magnesium sulphate) and concentrated in vacuo to give an oil, which crystalised on standing. Yield 96% (3.1 g). LC-MS (electrospray): m/z=874.49.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[N:9]=2)[N:5]=[C:4]([NH2:25])[C:3]=1[NH2:26].C([O-])=O.[NH4+]>CO.[Pd]>[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][N:10]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:16]2[C:8]([C:6]2[N:5]=[C:4]([NH2:25])[C:3]([NH2:26])=[CH:2][N:7]=2)=[N:9]1
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc(Cl)c1N
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Nc1cnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Temperature: 25 °C

Procedure:
6-Chloro-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4,5-pyrimidinediamine (74 mg, 0.20 mmol) from example V was dissolved in MeOH (4 ml), and Pd/C (10%, 20 mg) and ammonium formate (126 mg, 2.00 mmol, 10 equivalents) were added. The mixture was heated under reflux for 2 days and then allowed to cool to room temperature before the catalyst was filtered off. Purification took place by preparative HPLC (column: Cromsil 120 ODS, C-18, 10 μm, 250×30 mm, flow rate 50 ml/min, room temperature, gradient: water acetonitrile at 0 min: 90:10, at 28 min 5:95) afforded the desired product.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=1.C(N)(=[S:15])C.Cl.O>CN(C=O)C>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:4]=[CH:5][C:6]([C:9]([NH2:10])=[S:15])=[CH:7][CH:8]=1
Reactant: CC(N)=S
Reactant: N#Cc1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: NC(=S)c1ccc(C(F)(F)F)cc1
Temperature: 95 °C
Reaction time: 6 h
Yield: 73.4 %

Procedure:
A solution of α,α,α-trifluoro-p-tolunitrile (603.5 g, 3.53 mol) in dry DMF (2 L) under N2 was heated at 70° C. and the Thioacetamide (505 g, 1.9 eq.) was added. The reaction mixture was treated with HCl gas before 15 minutes and was stirred at 95° C. for 6 hours. This treatment was operated 3 times and the mixture was stirred at rt for 24 hours. After cooling at 0° C., water was added and the residue was extracted with diethyl ether (4*1 L). The organic layer was washed with water (3*1 L), dried over Na2SO4 and then evaporated off. The brownish powder was washed with pentane (3 L) to give the title compound (530.3 g, 2.59 mol) as brown solid in a 73% yield.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([C:15]#[N:16])=[CH:5][C:6]2[O:13][CH2:12][CH:11]=[CH:10][CH2:9][O:8][C:7]=2[CH:14]=1>CO>[O:8]1[C:7]2=[CH:14][C:3]3[CH2:2][NH:1][C:15](=[NH:16])[C:4]=3[CH:5]=[C:6]2[O:13][CH2:12][CH:11]=[CH:10][CH2:9]1
Reactant: N#Cc1cc2c(cc1CN)OCC=CCO2
Agent: N#Cc1cc2c(cc1CN)OC/C=C\CO2
Agent: N=C1NCc2cc3c(cc21)OC/C=C\CO3
Solvent: CO
Product: N=C1NCc2cc3c(cc21)OCC=CCO3
Temperature: 40 °C

Procedure:
The residue prepared in STEP B above (0.174 g, 0.80 mmol) was dissolved in dry methanol (30 ml) and heated to 40° C. for 2 h. The resulting mixture was concentrated in vacuo to yield (Z)-9,10-dihydro-2H-[1,4]dioxocino[2,3-f]isoindol-8(5H)-imine as a residue. 1H NMR (CD3OD): δ 7.39 (s, 1H), 7.07 (s, 1H), 5.93-5.90 (m, 2H), 5.01 (d, 2H), 4.42 (s, 2H), 3.34 m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([OH:25])=O)=[C:16]3[N:15]=2)[C:5]([CH3:8])=[N:6][CH:7]=1.C1C=C[C:29]2N(O)N=[N:32][C:30]=2[CH:31]=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C.C1(N)CC1>C(Cl)Cl>[CH:30]1([NH:32][C:23]([C:22]2[CH:21]=[N:20][N:17]3[CH:18]=[CH:19][C:14]([N:10]4[CH2:11][CH2:12][CH2:13][CH:9]4[C:4]4[C:5]([CH3:8])=[N:6][CH:7]=[C:2]([F:1])[CH:3]=4)=[N:15][C:16]=23)=[O:25])[CH2:31][CH2:29]1
Reactant: On1nnc2ccccc21
Reactant: Cc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1
Agent: CCN=C=NCCCN(C)C
Agent: NC1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ncc(F)cc1C1CCCN1c1ccn2ncc(C(=O)NC3CC3)c2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77.1 %

Procedure:
To a solution of (R)-5-(2-(5-fluoro-2-methylpyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation O, 50 mg, 0.15 mmol) in DCM (2 mL) was added HOBt (40 mg, 0.29 mmol) followed by EDCI (84 mg, 0.44 mmol). The solution was stirred at ambient temperature for 15 minutes, then treated with triethylamine (61 μL, 0.44 mmol) followed by cyclopropylamine (31 μL, 0.44 mmol). After stirring for 16 hours the mixture was partitioned between saturated NH4Cl solution (20 mL) and DCM (20 mL) and the aqueous layer was extracted with DCM (2×10 mL). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography, eluting with 2-4% MeOH/DCM, to afford the title product as white solid (44 mg, 79%). MS (apci) m/z=381.1 (M+H).
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH2:14]Cl)[N+:8]([O-:16])=[C:7]2[C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1>CO>[Cl:3][C:4]1[CH:13]=[CH:12][C:11]2[N:10]=[C:9]([NH:2][CH3:1])[CH2:14][N+:8]([O-:16])=[C:7]([C:17]3[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=3)[C:6]=2[CH:5]=1
Reactant: [O-][n+]1c(CCl)nc2ccc(Cl)cc2c1-c1ccc(O)cc1
Reactant: CN
Solvent: CO
Product: CNC1=Nc2ccc(Cl)cc2C(c2ccc(O)cc2)=[N+]([O-])C1
Reaction time: 7 h

Procedure:
To a saturated solution of methylamine in 600 ml of methanol in an ice bath was added 19.2 g (0.60 mole) of 6-chloro-2-chloromethyl-4-(4-hydroxyphenyl) quinazoline 3-oxide. The solution was stirred for 7 hr in an ice bath, and 10 hr at room temperature and then evaporated under reduced pressure. The residue was acidified with dilute acetic acid, stirred with ether and filtered to give 19 g of product. Recrystallization for analysis from ethyl acetate gave colorless plates, mp 278°-279° dec.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C([Mg]Cl)(C)C.[C:17]1([CH:23]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26](=[O:33])[C:25]2=[O:34])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Cl-].[NH4+]>ClCCl.O1CCCC1>[C:35]1([CH:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]([OH:33])([C:8]3[CH:9]=[C:10]4[C:5]([CH2:4][CH2:3][CH2:2][O:1]4)=[CH:6][C:7]=3[OH:11])[C:25]2=[O:34])[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Reactant: Oc1ccc2c(c1)CCCO2
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1cc2c(cc1O)CCCO2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A 500 mL round-bottom flask was charged with chroman-6-ol (9.2 g, 61 mmol) and tetrahydrofuran (120 mL). A 2 M solution of isopropylmagnesium chloride in tetrahydrofuran (32.5 mL, 65.0 mmol) was added at 5° C. and the reaction mixture was stirred for 15 min and concentrated in vacuo. To the residue was added dichloromethane (180 mL), followed by a solution of 1-(diphenylmethyl)-1H-indole-2,3-dione (18.8 g, 60.0 mmol) in dichloromethane (180 mL) at 5° C. The reaction mixture was allowed to warm to ambient temperature and stirred for 24 h. Saturated aqueous ammonium chloride (7 mL) was added and the reaction mixture was concentrated in vacuo. Trituration of the residue in methanol/water (1/100, 200 mL) afforded 1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-3,4-dihydro-2H-chromen-7-yl)-1,3-dihydro-2H-indol-2-one. A mixture of the 1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-3,4-dihydro-2H-chromen-7-yl)-1,3-dihydro-2H-indol-2-one, triethylsilane (23.2 g, 200 mmol), trifluoroacetic acid (50.0 g, 438 mmol) and dichloromethane (200 mL) was stirred at ambient temperature for 20 h and concentrated in vacuo. Trituration of the residue in diethyl ether (150 mL) afforded 1-(diphenylmethyl)-3-(6-hydroxy-3,4-dihydro-2H-chromen-7-yl)-1,3-dihydro-2H-indol-2-one (24.3 g, 90%) as an off-white solid: MS (ES+) m/z 448.0 (M+1).