Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][N:9]=1>[Pd]>[CH3:1][C@@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[N:9]=[CH:10][C:11]([NH2:14])=[CH:12][CH:13]=1
Reactant: C[C@@H]1COCCN1c1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Product: C[C@@H]1COCCN1c1ccc(N)cn1
Yield: 90.7 %

Procedure:
1.07 g (4.79 mmol) of the product obtained in step 30.1 are hydrogenated in the presence of 10% Pd/C at atmospheric pressure at 45° C. The solution obtained is evaporated under reduced pressure to give 840 mg of 6-((R)-3-methylmorpholin-4-yl)pyridin-3-ylamine.
Reaction SMILES: [CH3:1][N:2]([CH:4]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[CH:5]1[CH2:10][CH2:9][CH:8]([CH:11]=O)[CH2:7][CH2:6]1)[CH3:3].Cl.[NH2:21][OH:22]>C(O)C>[CH3:1][N:2]([CH:4]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[CH:5]1[CH2:10][CH2:9][CH:8]([CH:11]=[N:21][OH:22])[CH2:7][CH2:6]1)[CH3:3]
Reactant: NO
Reactant: CN(C)C(c1cccc(F)c1)C1CCC(C=O)CC1
Agent: Cl
Solvent: CCO
Product: CN(C)C(c1cccc(F)c1)C1CCC(C=NO)CC1
Reaction time: 3.5 h

Procedure:
The carbaldehyde 34 (6.32 g, 24 mmol) and hydroxylamine hydrochloride (2.5 g, 36 mmol) were dissolved in abs. ethanol (90 ml); basic ion exchanger Amberlyst A21 (17 g) was added and stirring was carried out for 3.5 h at RT. The ion exchanger was filtered off and washed with ethanol (2×50 ml). The solution was concentrated and the residue was adjusted to pH 11 with 5N NaOH. The aqueous phase was extracted with ethyl acetate (3×50 ml) and the organic phase was dried over sodium sulfate and concentrated in vacuo.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[N:11]=[C:10]([CH2:12]P(=O)(OC)OC)[CH:9]=[CH:8][C:6]=2[N:7]=1.C([N-]C(C)C)(C)C.[Li+].[C:33]([N:40]1[CH2:45][CH2:44][C:43](=O)[CH2:42][CH2:41]1)([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)[C:5]2[N:11]=[C:10]([CH:12]=[C:43]3[CH2:44][CH2:45][N:40]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:41][CH2:42]3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: COP(=O)(Cc1ccc2nc(Cl)nc(N3CCOCC3)c2n1)OC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of dimethyl (2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methylphosphonate from Example 117 (0.71 g) in anhydrous THF (15 mL) at 0° C. was added 2.0 M of lithium diisopropylamide in THF (1.4 eq). The resulting solution was allowed to warm to RT (room temperature) before adding a solution of 1-boc-4-piperidone (1.4 eq) in anhydrous THF (3 mL). The reaction mixture was stirred at room temperature for 1 h, then partitioned between brine and DCM. The organic layer was isolated, dried (MgSO4), concentrated and recrystallized from methanol. The light yellow solid was filtered and collected to give 0.72 g of tert-butyl 4-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methylene)piperidine-1-carboxylate as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[OH:22].Cl[C:24]1[C:29]([N+:30]([O-:32])=[O:31])=[CH:28][CH:27]=[CH:26][N:25]=1.[OH-].[K+]>C1(C)C=CC=CC=1.C1OCCOCCOCCOCCOCCOC1>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:19])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[O:22][C:24]1[C:29]([N+:30]([O-:32])=[O:31])=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ncccc3[N+](=O)[O-])c(Cl)cc2F)c1=O
Temperature: 90 °C
Reaction time: 3 h
Yield: 76.1 %

Procedure:
11.8 g of 2chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenol and 5.2 g of 2-chloro-3-nitropyridine were dissolved in 10 ml of toluene, to this were added 2.3 g of potassium hydroxide and 56 mg of 18-crown-6, and the mixture was stirred for 3 hours at 90° C. The reaction solution was cooled to room temperature, then the solvent was distilled off, and the residue was poured into ice water, and the precipitated crystals were collected by filtration to obtain 11.5 g of 2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-3-nitropyridine.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])#[N:2].Cl.[NH2:13][OH:14].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O.OC1C=CC=C2C=1N=CC=C2>[OH:14][N:13]=[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])[NH2:2]
Reactant: N#Cc1cccc(C(=O)O)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CCO
Solvent: O
Product: NC(=NO)c1cccc(C(=O)O)c1
Yield: 81.6 %

Procedure:
8-Hydroxyquinoline (5 mg, 0.03 mmol) was added to a solution of 3-cyanobenzoic acid (1 g, 6.8 mmol) in 50 mL ethanol. To this reaction mixture were added first hydroxylamine hydrochloric acid (950 mg, 13.6 mmol) in water (8 mL) followed by sodium carbonate (1.2 g, 10.9 mmol) in water (12 mL). The mixture was heated to reflux for 4 h. After removal of ethanol under reduced pressure, the residue was diluted with water, and the aqueous solution was acidified with 10% HCl to pH ˜3. The white precipitate was filtrated, washed with water and acetone and then dried under reduced pressure to afford compound 3-(N′-hydroxycarbamimidoyl)benzoic acid (1 g, yield 82%): 1H NMR (400 MHz, CDCl3) δ 13.03 (br s, 1H), 9.76 (s, 1H), 8.27-8.26 (m, 1H), 7.95-7.89 (m, 2H), 7.53 (t, J=7.8 Hz, 1H), 5.94 (br s, 2H). MS (ESI) m/z: Calculated for C8H8N2O3: 180.05. found: 180.9 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:36][CH3:37])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=2)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(O[N:46]1N=N[C:48]2[CH:49]=CC=C[C:47]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C(N)CC>CN(C=O)C>[CH2:36]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:35]=[CH:34][C:30]([C:31]([NH:46][CH2:47][CH2:48][CH3:49])=[O:32])=[CH:29][CH:28]=2)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[C:12]=2[N:13]=1)[CH3:37]
Reactant: CCN(CC)CCCNc1nc(-c2ccc(C(=O)O)cc2)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCCN
Solvent: CN(C)C=O
Product: CCCNC(=O)c1ccc(-c2nc(NCCCN(CC)CC)nc3c2ccc(=O)n3-c2c(F)cccc2F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.4 %

Procedure:
To the compound 4-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]benzoic acid (28 mg, 0.055 mmol) in DMF (0.5 mL) were added HBTU (25 mg, 0.066 mmol), triethylamine (15.5 uL, 0.11 mmol) and propylamine (6.78 uL, 0.0825 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (16.1 mg, 53%). LC-MS m/z 549 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[CH:12][C:11]([OH:14])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1.[Br:16]N1C(=O)CCC1=O.O.C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[C:12]([Br:16])[C:11]([OH:14])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(O)c(C(=O)OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(Br)c(O)c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.5 %

Procedure:
To a solution of 4-hydroxyisophthalic acid dimethyl ester (10.51 g) in THF (100 mL) was added N-bromosuccinimide (9.34 g) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. Water (200 mL) and saturated aqueous sodium bicarbonate (100 mL) were successively added to the reaction solution. The resulting precipitate was filtered, washed successively with saturated aqueous sodium bicarbonate and water, and dried to give the title compound (12.5 g).
Reaction SMILES: C([S:3]([C:6]1[C:11]([NH2:12])=[CH:10][CH:9]=[C:8]([C:13]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])=[N:15][N:16]([CH3:18])[CH:17]=2)[N:7]=1)(=O)=O)C.[C:26]([N:34]=[C:35]=S)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CCOC(C)=O>C1COCC1>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:14]1[C:13]([C:8]2[N:7]=[C:6]3[S:3][C:35]([NH:34][C:26](=[O:33])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[N:12][C:11]3=[CH:10][CH:9]=2)=[CH:17][N:16]([CH3:18])[N:15]=1
Reactant: CCS(=O)(=O)c1nc(-c2cn(C)nc2-c2ccccc2F)ccc1N
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1cc(-c2ccc3nc(NC(=O)c4ccccc4)sc3n2)c(-c2ccccc2F)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 84.6 %

Procedure:
To a solution of 2-(ethylsulfonyl)-6-(3-(2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)pyridine-3-amine (1.04 g, 2.89 mmol, 1.0 eq.) in THF under nitrogen at 0° C. was added benzoyl isothiocyanate (0.47 mL, 3.50 mmol, 1.2 eq.). The cold bath was removed, and the reaction mixture was stirred to room temperature for 20 min. It was then heated to 70° C. for 6 h. After cooling to room temperature, it was diluted with EtOAc and water. The layers were separated, and the organi layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Trituration with EtOAc afforded N-(5-(3-(2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)thiazolo[5,4-b]pyridine-2-yl)benzamide as a light tan solid (1.05 g, 85% yield).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([C:17]1[CH:18]=[N:19][C:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:21][CH:22]=1)=[O:16].[CH:29](Br)([CH3:31])[CH3:30].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(Cl)(Cl)Cl>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([C:17]1[CH:18]=[N:19][C:20]([N:23]2[CH2:24][CH2:25][N:26]([CH:29]([CH3:31])[CH3:30])[CH2:27][CH2:28]2)=[CH:21][CH:22]=1)=[O:16]
Reactant: O=C(NCCCCCCCCCCCCO)c1ccc(N2CCNCC2)nc1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CC(C)N1CCN(c2ccc(C(=O)NCCCCCCCCCCCCO)cn2)CC1

Procedure:
A solution of 0.7 g of N-(12-hydroxydodecyl)-6-(1-piperazinyl)pyridine-3-carboxamide, 0.24 g of isopropyl bromide and 0.7 g of potassium carbonate in 20 ml of dimethylformamide was stirred at 100° C. for 3 hours. The reaction solution was diluted with chloroform, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue thus obtained was chromatographed over a silica gel column to afford the title compound as a crystal.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH2:9]([O:11][C:12]1[CH:13]=[C:14]([C:21]2[C@@H:30]3[C@@H:25]([CH2:26][CH:27]=[CH:28][CH2:29]3)[C:24](=[O:31])[N:23]([CH:32]3[CH2:37][CH2:36][N:35](S(C4C=CC(C)=CC=4)(=O)=O)[CH2:34][CH2:33]3)[N:22]=2)[CH:15]=[CH:16][C:17]=1[O:18][CH2:19][CH3:20])[CH3:10]>>[CH2:9]([O:11][C:12]1[CH:13]=[C:14]([C:21]2[C@@H:30]3[C@@H:25]([CH2:26][CH:27]=[CH:28][CH2:29]3)[C:24](=[O:31])[N:23]([CH:32]3[CH2:33][CH2:34][N:35]([C:5](=[O:6])[CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8])[CH2:36][CH2:37]3)[N:22]=2)[CH:15]=[CH:16][C:17]=1[O:18][CH2:19][CH3:20])[CH3:10]
Reactant: CCOc1ccc(C2=NN(C3CCN(S(=O)(=O)c4ccc(C)cc4)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OCC
Reactant: O=C1CCCC(=O)O1
Product: CCOc1ccc(C2=NN(C3CCN(C(=O)CCCC(=O)O)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OCC

Procedure:
Prepared from glutaric anhydride and starting compound A2 as described for compound 1. After evaporating the pyridine, the residue is partitioned between ethyl acetate and 1N hydrochloric acid. The ethyl acetate solution is dried over magnesium sulfate and evaporated. Crystallisation from diethyl ether. M. p. 133-135° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10](=O)[CH3:11])=[CH:4][CH:3]=1.C(O)(=O)C.C([BH3-])#[N:24].[Na+]>N.CO>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]([NH2:24])[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(=O)C(Cc1ccc(C)cc1)c1ccccc1
Reactant: [BH3-]C#N
Agent: N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccc(CC(c2ccccc2)C(C)N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the 4-(4-methylphenyl)-3-phenylbutan-2-one (308 mg, 1.29 mmol) in 7M ammonia in MeOH (5 mL) and acetic acid (3 mL) was added sodium cyanoborohydride (130 mg, 2.06 mmol) and the reaction stirred at room temperature overnight. The reaction was quenched by pouring into 2M sodium carbonate solution and extracted into EtOAc. The aqueous layer was salted and re-extracted. The combined organic extracts were dried over MgSO4 and concentrated to give the title compound as a mixture of 4 isomers which was used without further purification. LC-MS: m/e 240 (M+H)+ (2.22 min).
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([P:18]([NH:22][CH3:23])([NH:20][CH3:21])=[O:19])[C:13]1=[O:24])=O)C1C=CC=CC=1>CO.[Pd]>[NH2:11][C@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([P:18]([NH:22][CH3:23])([NH:20][CH3:21])=[O:19])[C:13]1=[O:24]
Reactant: CNP(=O)(NC)N1CCC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: [Pd]
Solvent: CO
Product: CNP(=O)(NC)N1CCC[C@H](N)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Palladium black (52 mg) was added to a solution of (3S)-3-benzyloxycarbonylamino-1-bis(methylamino)phosphinyl-2-piperidone (524.1 mg, 1.4791 mmol) in methanol (5.2 mL), and the resulting mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere.
Reaction SMILES: N#N.C([Si](C)(C)[O:8][CH:9]([C:11]1[O:12][C:13]([CH2:16][N:17]2[N:21]=[C:20]([NH:22][C:23]([C:25]3[N:26]=[C:27]([CH3:37])[O:28][C:29]=3[C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=3)=[O:24])[CH:19]=[N:18]2)=[CH:14][N:15]=1)[CH3:10])(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CC(=O)OCC>[OH:8][CH:9]([C:11]1[O:12][C:13]([CH2:16][N:17]2[N:21]=[C:20]([NH:22][C:23]([C:25]3[N:26]=[C:27]([CH3:37])[O:28][C:29]=3[C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=3)=[O:24])[CH:19]=[N:18]2)=[CH:14][N:15]=1)[CH3:10]
Reactant: Cc1nc(C(=O)Nc2cnn(Cc3cnc(C(C)O[Si](C)(C)C(C)(C)C)o3)n2)c(-c2cccc(F)c2)o1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N#N
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nc(C(=O)Nc2cnn(Cc3cnc(C(C)O)o3)n2)c(-c2cccc(F)c2)o1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-(3-fluoro-phenyl)-2-methyl-oxazole-4-carboxylic acid (2-{2-[1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-oxazol-5-ylmethyl}-2H-[1,2,3]triazol-4-yl)-amide (110 mg, 0.21 mmol) in dry THF (2.1 mL) was treated at 0° C. with TBAF (0.42 mL of a 1M solution in THF, 0.42 mmol). The reaction mixture was stirred at 0° C. for 45 min. The mixture was then diluted with EA (10 mL), washed with NaHCO3 (10 mL) followed by brine (3×10 mL), dried over MgSO4, filtered and concentrated under reduced pressure. Purification of the residue by FC (19:1 CH2Cl2-MeOH) gave the title compound as an orange oil. TLC:rf (19:1 CH2Cl2-MeOH)=0.21. LC-MS-conditions 02: tR=0.94 min; [M+H]+=412.86.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][C:6]1[NH:7][CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[CH3:16][Si:17]([CH3:24])([CH3:23])[CH2:18][CH2:19][O:20][CH2:21]Cl.S([O-])(O)(=O)=O.[K+]>CN(C)C=O>[CH3:3][O:4][CH2:5][C:6]1[N:7]([CH2:21][O:20][CH2:19][CH2:18][Si:17]([CH3:24])([CH3:23])[CH3:16])[CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)c1cc[nH]c1COC
Reactant: C[Si](C)(C)CCOCCl
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccn(COCC[Si](C)(C)C)c1COC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
To 1250 ml of dehydrated N,N-dimethylformamide solution containing 63.1 g (1.45 mol) of sodium hydride (55% dispersed material in mineral oil) which had been washed three times with each 500 ml of dehydrated heptane was added dropwise 750 ml of dehydrated N,N-dimethylformamide solution containing 263 g (purity: 95%, 1.36 mol) of ethyl 2-methoxymethyl-1H-pyrrol-3-carboxylate obtained in Reference example 15-(c) at room temperature under argon atmosphere, and the mixture was stirred for 30 minutes. Then, 242 g (1.45 mol) of (2-trimethylsilylethoxy)methyl chloride was added dropwise to the mixture under ice-cooling, and the mixture was further stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was poured into ice-water, neutralized with 30% aqueous potassium hydrogen sulfate solution, and extracted with toluene. The organic layer after separation was washed successively with water, and then, with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 420 g (purity: 98.6%) of the title compound as a yellowish oil. (Yield: 96%)
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:13][C:12](=[O:14])[C:5]2[C:6]([C:9](O)=[O:10])=[CH:7][O:8][C:4]=2[CH2:3]1.C(Cl)(=O)C(Cl)=O.[BH4-].[Na+].C([O-])(O)=O.[Na+]>ClCCl.CN(C=O)C.C(OCC)(=O)C.C(O)(=O)C>[CH3:1][C:2]1([CH3:15])[CH2:13][C:12](=[O:14])[C:5]2[C:6]([CH2:9][OH:10])=[CH:7][O:8][C:4]=2[CH2:3]1
Reactant: CC1(C)CC(=O)c2c(C(=O)O)coc2C1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC1(C)CC(=O)c2c(CO)coc2C1
Temperature: 12.5 °C
Reaction time: 0.5 h

Procedure:
6,6-Dimethyl-4-oxo-4,5,6,7-tetrahydro-benzofuran-3-carboxylic acid (17) (1 g, 4.8 mmol) is dissolved in 80 ml dichloromethane and after addition of 187 μl DMF (2.4 mmol) the mixture is cooled to 10-15° C. Oxalylchloride (619 ul, 7.2 mmol) is added drop wise and the mixture is stirred for 30 min at room temperature. The mixture is evaporated under reduced pressure, dissolved in THF and cooled to −55° C. A solution of NaBH4 (1.3 g, 34.1 mmol) in 10 ml of DMF is added via syringe. The white suspension is allowed to stir for another 1.5 h at −55° C. 4 ml of acetic acid is added at this temperature and the mixture is poured into 150 ml of a 5% aqueous NaHCO3 solution. The mixture is diluted with ethyl acetate and washed with brine. The crude product is purified by Flash-chromatography (ethyl acetate/hexanes (4:6), silicagel).
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.B1(O)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[CH2:27][O:26]1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.C(Cl)Cl.CO>[CH3:24][N:21]1[CH2:22][CH2:23][N:18]([C:15]2[CH:14]=[CH:13][C:12]([NH:11][C:8]3[N:7]=[CH:6][C:5]4=[CH:4][CH:3]=[C:2]([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=5[CH2:27][OH:26])[N:10]4[N:9]=3)=[CH:17][CH:16]=2)[CH2:19][CH2:20]1
Reactant: CN1CCN(c2ccc(Nc3ncc4ccc(Br)n4n3)cc2)CC1
Reactant: OB1OCc2ccccc21
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Product: CN1CCN(c2ccc(Nc3ncc4ccc(-c5ccccc5CO)n4n3)cc2)CC1
Temperature: 85 °C
Yield: 74.5 %

Procedure:
(7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine (88 mg, 0.23 mmol), 3H-Benzo[c][1,2]oxaborol-1-ol (74 mg, 0.56 mmol), Cesium Carbonate (192 mg, 0.589 mmol) and Bis(tri-tert-butylphosphine)palladium (18 mg, 0.035 mmol) were placed in a vial. N,N-Dimethylformamide (4.0 mL, 52 mmol) was added to the mixture, which was “degassed” under vacuum with cooling on dry ice. The mixture was then heated in an 85° C. block under an atmosphere of Nitrogen for 2 h, then conc. in vacuo. The residue was purified on ISCO (24 g load cartridge with DCM:MeOH, then dried; 12 g column, 0-15% MeOH:DCM) to afford (2-{2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-7-yl}-phenyl)-methanol (71 mg; Yield=75%) as an orange foam. LCMS (HPLC): 0.75 min, 415 (M+H); 1H-NMR (DMSO-d6): 9.18 (s, 1H), 8.94 (s, 1H), 7.68 (d, 1H, J=7.5 Hz), 7.63 (d, 1H, J=7.5 Hz), 7.48 (m, 3H), 7.43 (m, 1H), 6.92 (d, 1H, J=4.5 Hz), 6.88 (d, 1H, J=4.5 Hz), 6.74 (d, 2H, J=9.0 Hz), 5.11 (t, 1H, J=5.3 Hz), 4.45 (d, 2H, J=5.3 Hz), 3.01 (m, 4H), 2.44 (m, 4H), 2.22 (s, 3H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[C:19]([O:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:20]=2)[NH:17][C:16]([C:28]2[S:29][CH:30]([CH2:33][C:34]([OH:36])=O)[CH2:31][N:32]=2)=[CH:15]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[NH2:60][CH2:61][CH2:62][OH:63]>CN(C)C=O.CCCCCC.C(OCC)(=O)C.O>[OH:63][CH2:62][CH2:61][NH:60][C:34](=[O:36])[CH2:33][CH:30]1[S:29][C:28]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[CH:13][C:12]([O:11][C:8]2[CH:9]=[N:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)=[CH:20][C:19]=3[O:21][CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[N:32][CH2:31]1
Reactant: NCCO
Reactant: CS(=O)(=O)c1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CS(=O)(=O)c1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C4=NCC(CC(=O)NCCO)S4)cc3c2)cn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 53 %

Procedure:
To a solution of {2-[5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetic acid (150 mg) in N,N-dimethylformamide (5 mL) were added 1-hydroxybenzotriazole monohydrate (65 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (81 mg), and 2-aminoethanol (35 mg), and the mixture was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was subjected to basic silica gel column chromatography (ethyl acetate:hexane=0:100 to 100:0, volume ratio), and crystallized from acetonitrile. The obtained crystals were recrystallized from ethyl acetate and diethyl ether to give the title compound (86 mg, yield 53%) as white crystals.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].O.[NH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[C:25]3[C:20](=[N:21][CH:22]=[N:23][C:24]=3[NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=3)[NH:19][N:18]=2)=[CH:12][CH:11]=1.C(N(CC)CC)C>C1COCC1>[Cl:33][C:29]1[CH:28]=[C:27]([NH:26][C:24]2[N:23]=[CH:22][N:21]=[C:20]3[NH:19][N:18]=[C:17]([NH:16][C:13]4[CH:14]=[CH:15][C:10]([CH2:9][NH:8][C:3]([N:2]([CH3:6])[CH3:1])=[O:4])=[CH:11][CH:12]=4)[C:25]=23)[CH:32]=[CH:31][CH:30]=1
Reactant: NCc1ccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1
Reactant: CN(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)NCc1ccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1

Procedure:
A solution of 0.0503 ml (0.548 mmol) of dimethylcarbamoyl chloride in 0.5 ml of THF is added dropwise, with stirring, to a suspension, cooled to 0° C., of 150 mg (0.391 mmol) of 3-(4-aminomethyl-phenylamino)4-(3-chloro-phenylamino)-1H-pyrazolo-[3,4-d]pyrimidine hydrate (see Step 77.5) in 2.5 ml of THF and 0.079 ml (0.567 mmol) of triethylamine. The reaction mixture is stirred at RT for 17 hours and then filtered, and the filter residue is washed in succession with THF, water, THF and diethyl ether. 4-(3-Chloro-phenylamino)-3-[4-(dimethylamino-carbonylamino-methyl)-phenylamino]-1H-pyrazolo[3,4-d]pyrimidine having a water content of 1.22% is obtained; m.p. 238-240° C.; ESI-MS: (M+H)+=437.