Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.Cl.[N:17]1([CH2:21][C@@H:22]([NH2:33])[C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[CH2:20][CH2:19][CH2:18]1>>[N:17]1([CH2:21][C@@H:22]([NH:33][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:25][CH:24]=2)[CH2:20][CH2:19][CH2:18]1
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Reactant: N[C@H](CN1CCC1)c1ccc(C(F)(F)F)cc1
Agent: Cl
Product: NC(=O)c1ccnc2c(N[C@H](CN3CCC3)c3ccc(C(F)(F)F)cc3)ncnc12

Procedure:
Compound 27 was prepared following general synthesis scheme 7 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with (S)-2-Azetidin-1-yl-1-(4-trifluoromethyl-phenyl)-ethylamine dihydrochloride to give the title compound as a white solid. LC/MS [417 (M+H)]; 1H NMR (400 MHz, DMSO-d6) δ 9.92 (d, J=3.4 Hz, 1H), 9.11 (d, J=7.9 Hz, 1H), 9.01 (dd, J=4.5, 1.0 Hz, 1H), 8.53 (s, 1H), 8.38 (dd, J=4.5, 1.0 Hz, 1H), 8.16 (d, J=3.4 Hz, 1H), 7.83-7.50 (m, 3H), 5.36 (q, J=7.2 Hz, 1H), 3.21-2.99 (m, 4H), 2.84 (dd, J=12.0, 5.6 Hz, 1H), 1.92 (p, J=6.9 Hz, 2H).
Reaction SMILES: [C:1]([Si:5]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[O:6][C@@H:7]1[CH2:11][C@H:10]([C:12]#[N:13])[C@@H:9]([OH:14])[CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[CH3:27]I>[Ag-]=O>[C:1]([Si:5]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[O:6][C@@H:7]1[CH2:11][C@H:10]([C:12]#[N:13])[C@@H:9]([O:14][CH3:27])[CH2:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](O[C@H]1C[C@H](O)[C@@H](C#N)C1)(c1ccccc1)c1ccccc1
Reactant: CI
Agent: O=[Ag-]
Product: CO[C@H]1C[C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C[C@@H]1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.1 %

Procedure:
A mixture of (1S,2R,4S) and (1R,2S,4R)-4-(tert-butyl-diphenyl-silanyloxy)-2-hydroxy-cyclopentanecarbonitrile (2 g, 5.47 mmol), methyliodide (15 ml; 246 mmol) and silver(I) oxide (2.54 g, 10.94 mmol) was stirred at room temperature overnight. The excess of methyliodide was removed under reduced pressure and the remaining residue was suspended in DCM and filtered through a pad of celite. The filtrate was evaporated and the remaining yellow gum was purified by silica gel column chromatography (heptane/EtOAc 90:10-80:20) to obtain 1.62 g (4 mmol, 78%) of the title compound as colorless gum. MS (EI): 380.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([S:31]([CH3:34])(=[O:33])=[O:32])=[C:6]([C:8]2[N:13]=[C:12](S(C)(=O)=O)[N:11]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][CH2:28][CH2:29][OH:30])=[O:26])=[CH:20][CH:19]=3)[CH:9]=2)[CH:7]=1.CCN(C(C)C)C(C)C.[NH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:31]([CH3:34])(=[O:32])=[O:33])=[C:6]([C:8]2[N:13]=[C:12]([N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)[N:11]=[C:10]([C:18]3[CH:19]=[CH:20][C:21]([NH:24][C:25]([NH:27][CH2:28][CH2:29][OH:30])=[O:26])=[CH:22][CH:23]=3)[CH:9]=2)[CH:7]=1
Reactant: C1COCCN1
Reactant: CS(=O)(=O)c1nc(-c2ccc(NC(=O)NCCO)cc2)cc(-c2cc(F)ccc2S(C)(=O)=O)n1
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc(F)cc1-c1cc(-c2ccc(NC(=O)NCCO)cc2)nc(N2CCOCC2)n1
Yield: 5 %

Procedure:
1-(4-(6-(5-fluoro-2-(methylsulfonyl)phenyl)-2-(methylsulfonyl)pyrimidin-4-yl)phenyl)-3-(2-hydroxyethyl)urea (275 mg, 0.23 mmol), DIPEA (804, 0.46 mmol) and morpholine (1.0 mL) were heated in a Biotage microwave at 100° C. for 30 minutes. Reaction mixture was partitioned between DCM and water, the organic phase passed through a PTFE hydrophobic frit and the solvent removed in vacuo. The residue was purified further by prep HPLC (low pH) to afford 1-(4-(6-(5-fluoro-2-(methylsulfonyl)phenyl)-2-morpholinopyrimidin-4-yl)phenyl)-3-(2-hydroxyethyl)urea (5.6 mg, 5%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:10]([I:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH:12]([Si:15](Cl)([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])([CH3:14])[CH3:13]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[C:4]2[C:10]([I:11])=[CH:9][N:8]([Si:15]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:12]([CH3:14])[CH3:13])[C:5]2=[N:6][CH:7]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Clc1cnc2[nH]cc(I)c2n1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2nc(Cl)cnc21
Temperature: 0 °C
Yield: 95 %

Procedure:
A solution of the 2-Chloro-7-iodo-5H-pyrrolo[2,3-b]pyrazine from the previous step in 30 mL of tetrahydrofuran stirring at 0° C. under argon atmosphere was treated with lithium hexamethyldisilylazide (6 mL, 1 M in hexanes, 6 mmol), followed by triisopropylsilyl chloride (1.1 mL, 5.2 mmol). After 30 m at 0° C., the solution was warmed to ambient temperature and diluted with 20% ethyl acetate in hexanes, then washed twice with water and once with brine. After drying the organic layer over magnesium sulfate, filtration was followed by solvent removal and flash chromatography of the resultant residue using 2.5% ethyl acetate in hexanes, to furnish 2-Chloro-7-iodo-5-triisopropylsilanyl-5H-pyrrolo[2,3-b]pyrazine (1.68 g, 95% over two steps).
Reaction SMILES: [CH:1]([C:3]1[C:4]([CH3:17])=[C:5]2[C:9](=[CH:10][CH:11]=1)[C@@H:8]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH2:7][CH2:6]2)=[O:2].OO.[O-:20]Cl=O.[Na+].OS([O-])=O.[Na+]>C(#N)C.O>[C:1]([C:3]1[C:4]([CH3:17])=[C:5]2[C:9](=[CH:10][CH:11]=1)[C@@H:8]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH2:7][CH2:6]2)([OH:20])=[O:2]
Reactant: [O-][Cl+][O-]
Reactant: COC(=O)C[C@H]1CCc2c1ccc(C=O)c2C
Agent: O=S([O-])O
Agent: OO
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COC(=O)C[C@H]1CCc2c1ccc(C(=O)O)c2C
Temperature: 25 °C
Yield: 91.5 %

Procedure:
To an ice-cold solution of methyl (R)-(5-formyl-4-methyl-indan-1-yl)acetate (872 mg, 3.76 mmol, from Step C), NaH2PO4 (150 mg) and 30% H2O2 (500 μL) in acetonitrile (10 mL) and H2O (2.5 mL), a solution of NaClO2 (615 mg) in H2O (4 mL) was added dropwise and the reaction mixture was allowed to warm to ambient temperature over 1 hr. After another hour, NaHSO3 (1.0 g) was added and the mixture was partitioned between EtOAc (30 mL) and 2.0 N HCl (15 mL). The layers were separated and the organic layer was washed with H2O (2×15 mL), brine (1×15 mL) dried (MgSO4) and filtered. The filtrate was concentrated in vacuo to give 854 mg of the title compound as a white solid: 1H NMR (500 MHz, CDCl3) δ 1.74-1.82 (m, 1H), 2.40-2.50 (m, 2H), 2.56 (s, 3H), 2.78 (dd, 1H, J=5.5, 15.5 Hz), 2.82-2.93 (m, 1H), 2.94-2.99 (m, 1H), 3.61-3.66 (m, 1H), 3.73 (s, 3H), 7.07 (d, 1H, J=7.8 Hz), 7.89 (d, 1H, J=8.0 Hz), 10.8-12.0 (br, s 1H); HPLC A: rt=2.74 min, m/z=249 (M+H)+.
Reaction SMILES: [N:1]1[NH:2][C:3](=[O:16])[CH2:4][CH:5]2[CH2:11][CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6]=12>C(#N)C.[Cu](Cl)Cl>[O:16]=[C:3]1[NH:2][N:1]=[C:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][CH2:10][CH2:11][C:5]2=[CH:4]1
Reactant: O=C1CC2CCCc3ccccc3C2=NN1
Agent: Cl[Cu]Cl
Solvent: CC#N
Product: O=c1cc2c(n[nH]1)-c1ccccc1CCC2
Temperature: 25 °C
Yield: 89.9 %

Procedure:
A mixture of the compound of formula (Dd), 4a,5,6,7-tetrahydro-2H-benzo[6,7]cyclohepta[c]pyridazin-3(4H)-one (4.7 g, 22 mmol) and anhydrous copper(II) chloride (6 g, 44 mmol) was refluxed in acetonitrile (45 mL) for 2 hours. After cooling to ambient temperature, the mixture was poured into ice-water (200 g) and the solid obtained was washed with 10% HCl solution twice (about 20 mL×2) and cold water twice (about 20 mL×2). After freeze-drying, the compound of formula (De), 3-oxo-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine (4.2 g, 90%) was obtained as a white solid, 1H NMR (300 MHz, CDCl3) δ: 10.80 (bs, 1H), 7.53-7.21 (m, 4H), 6.77 (s, 1H), 2.66 (t, J=6.9 Hz, 2H), 2.45 (t, J=6.9 Hz, 2H), 2.14 (quant, J=6.9 Hz, 2H); LC-MS: purity: 100%; MS (m/e): 213 (MH+).
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]([CH3:59])[NH:5][C:6](=[O:58])[C@@H:7]([CH2:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][CH2:51]C2C=CC=CC=2)=[CH:46][CH:45]=1)[NH:8][C:9](=[O:42])[C@H:10]([CH2:33][O:34][CH2:35]C1C=CC=CC=1)[NH:11][C:12](=[O:32])[C@H:13]([CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].[NH3:61].CO>>[C:18]([O:17][C:15]([NH:14][C@H:13]([C:12]([NH:11][C@H:10]([C:9]([NH:8][C@@H:7]([C:6]([NH:5][C@@H:4]([C:3]([NH2:61])=[O:2])[CH3:59])=[O:58])[CH2:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][CH2:51][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:46][CH:45]=1)=[O:42])[CH2:33][O:34][CH2:35][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:32])[CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: COC(=O)[C@@H](C)NC(=O)[C@@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C
Reactant: N
Solvent: CO
Product: C[C@@H](NC(=O)[C@@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(N)=O

Procedure:
The methyl ester of Example 10, 300 mg., is dissolved in 100 ml. of methanol saturated with ammonia and kept for 4 days at room temperature. The crude product is chromatographed on silica gel in chloroform-methanol-water (60:30:5) to yield 0.14 g.; m.p. 180°-185° C.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:18]=[C:17]([N:19]([CH2:22]C)[CH2:20]C)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH2:4][CH2:3]1.[Br:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH2:33][CH:34]=O)=[C:27]([O:36][C:37]([F:40])([F:39])[F:38])[CH:26]=1.C(O)(=O)C.[BH3-]C#N.[Na+].[ClH:49]>CO.CCOC(C)=O>[ClH:49].[ClH:49].[Br:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH2:33][CH2:34][NH:1][C@@H:2]2[CH2:7][CH2:6][C@H:5]([NH:8][C:9]3[N:18]=[C:17]([N:19]([CH3:20])[CH3:22])[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)[CH2:4][CH2:3]2)=[C:27]([O:36][C:37]([F:38])([F:39])[F:40])[CH:26]=1
Reactant: CCN(CC)c1nc(N[C@H]2CC[C@@H](N)CC2)nc2ccccc12
Reactant: O=CCCCc1ccc(Br)cc1OC(F)(F)F
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CN(C)c1nc(N[C@H]2CC[C@@H](NCCCCc3ccc(Br)cc3OC(F)(F)F)CC2)nc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of cis-N2-(4-amino-cyclohexyl)-N4,N4-dimethyl-quinazoline-2,4-diamine obtained in step C of example 9 (240 mg, 0.84 mmol) in MeOH (3 mL) were added 4-(4-bromo-2-trifluoromethoxy-phenyl)-butyraldehyde (262 mg, 0.84 mmol), acetic acid (79 mg, 1.26 mmol), and NaBH3CN (79 mg, 1.26 mmol). The reaction mixture was stirred at ambient temperature for 8 hr. The reaction was quenched with saturated aqueous NaHCO3 The aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, and purified by medium-pressure liquid chromatography (NH-silica gel, 50% EtOAc in hexane) to give a pale yellow solid. To a solution of above solid in EtOAc (2 mL) was added 4 M hydrogen chloride in EtOAc (10 mL). The mixture was stirred at ambient temperature for 1 hr and concentrated. A solution of the residue in Et2O (20 mL) was stirred at ambient tempareture for 1 hr. The solid was collected by filtration, washed with Et2O, and dried under reduced pressure to give cis-N2-{4-[4-(4-bromo-2-trifluoromethoxy-phenyl)-butylamino]-cyclohexyl}-N4,N4-dimethyl-quinazoline-2,4-diamine dihydrochloride (220 mg, 40%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[OH:12].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=S)=[C:16]([F:23])[CH:15]=1.Cl.CN(C)CCCN=C=NCC>C(O)C>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]2[O:12][C:3]3[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=3[N:1]=2)=[C:16]([F:23])[CH:15]=1
Reactant: Nc1cc(C(F)(F)F)ccc1O
Reactant: Fc1cc(Br)ccc1N=C=S
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCO
Product: Fc1cc(Br)ccc1Nc1nc2cc(C(F)(F)F)ccc2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.6 %

Procedure:
2-Amino-4-(trifluoromethyl)phenol (580 mg, 3.25 mmol) and 4-bromo-2-fluoro-1-isothiocyanatobenzene (750 mg, 3.25 mmol) were stirred in ethyl alcohol at ambient temperature for 18 h. The flask was charged with 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCI) (405 mg, 2.12 mmol), and the mixture was stirred for 2 h before being heated at reflux overnight. The reaction was allowed to cool to rt and was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with 2 N aqueous hydrochloric acid solution and water, dried (Na2SO4), and concentrated in vacuo. The crude material was suspended in ether, sonicated, and the resulting solid was collected by filtration to provide the title compound (214 mg, 18%). LC-MS m/z 375.1 (MH+), retention time 3.70 minutes.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH2:12][C:13](O)=[O:14])[CH3:11])=[C:4]([N+:16]([O-])=O)[CH:3]=1.[H][H].C1(N=C=NC2CCCCC2)CCCCC1>CO.[Pt]>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[CH2:8][CH2:9][N:10]([CH3:11])[CH2:12][C:13](=[O:14])[NH:16][C:4]=2[CH:3]=1
Reactant: CN(CCc1ccc(F)cc1[N+](=O)[O-])CC(=O)O
Reactant: [H][H]
Agent: [Pt]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CO
Product: CN1CCc2ccc(F)cc2NC(=O)C1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
{[2-(4-Fluoro-2-nitro-phenyl)-ethyl]-methyl-amino}-acetic acid (10.0 g, approximately 0.044 mole, not quite pure) in methanol (250 mL) containing platinum on sulfided carbon (5 wt. %, 1.2 g) was hydrogenated at room temperature and a hydrogen pressure of 50 psi overnight. The catalyst was removed by filtration through Celite and the filtrate was evaporated to dryness in vacuo. The residue was dissolved in pyridine (1.5 L) and the solution was cooled to 0° C., and 1,3-dicyclohexylcarbodiimide (20.0 g, 0.097 mole) was added. The reaction mixture was allowed to warm up to room temperature and stirred at room temperature for 48 hours. The solvent was removed and the residue was slurried with 10% hydrochloric acid and filtered. The filtrate was extracted with ether, the aqueous phase was made basic with sodium carbonate and then extracted with dichloromethane. The extract was dried over sodium sulfate and evaporated in vacuo. Purification by flash column chromatography (silica gel, methylene chloride) provided 2.0 g of the title compound as a white solid. 1H NMR (CDCl3): 7.85 δ (broad s, 1H); 7.15 δ (dd, 1H); 6.95 δ (d of t, 1H); 6.80 δ (dd, 1H); 3.18 δ (s, 2H); 2.78 δ (broad s, 4H); 2.40 δ (s, 3H).
Reaction SMILES: ClC1C(CCCl)=C(C2C=CC=C(OC)C=2)N=C(N2CCOCC2)N=1.NC1C=CN(C)CC=1.C[O:34][C:35]1[CH:36]=[C:37]([C:41]2[C:42]3[CH2:55][CH2:54][N:53]([C:56]4[CH:61]=[CH:60][N:59]=[C:58]([CH3:62])[CH:57]=4)[C:43]=3[N:44]=[C:45]([N:47]3[CH2:52][CH2:51][O:50][CH2:49][CH2:48]3)[N:46]=2)[CH:38]=[CH:39][CH:40]=1>>[CH3:62][C:58]1[CH:57]=[C:56]([N:53]2[C:43]3[N:44]=[C:45]([N:47]4[CH2:48][CH2:49][O:50][CH2:51][CH2:52]4)[N:46]=[C:41]([C:37]4[CH:36]=[C:35]([OH:34])[CH:40]=[CH:39][CH:38]=4)[C:42]=3[CH2:55][CH2:54]2)[CH:61]=[CH:60][N:59]=1
Reactant: COc1cccc(-c2nc(N3CCOCC3)nc3c2CCN3c2ccnc(C)c2)c1
Agent: CN1C=CC(N)=CC1
Agent: COc1cccc(-c2nc(N3CCOCC3)nc(Cl)c2CCCl)c1
Product: Cc1cc(N2CCc3c(-c4cccc(O)c4)nc(N4CCOCC4)nc32)ccn1

Procedure:
In the same manner as Example 1-A-01, from 4-[4-chloro-5-(2-chloroethyl)-6-(3-methoxyphenyl)-pyrimidin-2-yl]-morpholine and 4-amino-1-methylpyridine, 4-(3-methoxy-phenyl)-7-(2-methyl-pyridin-4-yl)-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine was obtained, and subsequently, further in the same manner as Example 1-A-09, the desired compound was obtained.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:16][N:17]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.C(N)C1C=CC=CC=1>C1C=CC=CC=1>[CH2:18]([N:17]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:16]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(-c3ccccc3)cn(Cc3ccccc3)c2CC1
Solvent: c1ccccc1
Solvent: NCc1ccccc1
Product: c1ccc(Cn2cc(-c3ccccc3)c3c2CCNCC3)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1-Benzyl-3-phenyl-4,5,7,8-tetrahydro-1H-pyrrolo[2,3-d]azepine-6-carboxylic acid tert-butyl ester. A solution of the compound (0.53 g) from Example 59, Step B, and 272 μL of benzylamine in benzene (10 mL) was heated at reflux for 24 h using a Dean-Stark apparatus. The solvent was removed, the crude material was dissolved in toluene (10 mL), and 0.38 g of (2-nitro-vinyl)-benzene was added. The mixture was stirred for 24 h at RT and concentrated in vacuo. Chromatography on SiO2 (1 to 20% EtOAc/hexanes) afforded 108.0 mg of the desired compound. MS (ESI): exact mass calculated for C26H30N2O2, 402.53. found, m/z 403.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[N:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][CH:15]([C:18]4[CH:30]=[CH:29][C:21]([O:22][CH2:23][CH2:24][CH2:25][C:26](O)=[O:27])=[CH:20][CH:19]=4)[CH2:14][CH2:13]3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1.[CH3:33][O:34][CH2:35][CH2:36][NH:37][CH3:38]>>[CH3:33][O:34][CH2:35][CH2:36][N:37]([CH3:38])[C:26](=[O:27])[CH2:25][CH2:24][CH2:23][O:22][C:21]1[CH:20]=[CH:19][C:18]([CH:15]2[CH2:16][CH2:17][N:12]([C:9]3[CH:10]=[CH:11][C:6]4[N:7]([C:3]([C:2]([F:31])([F:1])[F:32])=[N:4][N:5]=4)[N:8]=3)[CH2:13][CH2:14]2)=[CH:30][CH:29]=1
Reactant: O=C(O)CCCOc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Reactant: CNCCOC
Product: COCCN(C)C(=O)CCCOc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Yield: 50 %

Procedure:
Obtained in 50% yield by an analogous method to Example 19, starting from 4-[4-[1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenoxy]butanoic acid and N-(2-methoxyethyl)methylamine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])/[C:7](=[N:11]\[OH:12])/[C:8](=[O:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[C:14](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.O>CC(C)=O>[C:1]([O:5][C:6](=[O:13])/[C:7](=[N:11]\[O:12][CH3:14])/[C:8](=[O:10])[CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)/C(=N/O)C(=O)OC(C)(C)C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: CO/N=C(/C(C)=O)C(=O)OC(C)(C)C
Temperature: 5 °C
Reaction time: 4 h

Procedure:
626.65 g of (Z)-2-hydroxyimino-3-oxo-butyric acid tert.butyl ester are dissolved in 2.86 l of acetone. The solution is cooled to 5° C. and treated portionwise with 703.5 g of potassium carbonate. 322 ml of dimethyl sulphate are then added dropwise to the yellow suspension without cooling during 1 hour, whereby the temperature of the mixture should not rise above 25° C. The light beige suspension is stirred at 20°-25° C. for about 4 hours until starting material can no longer be detected by thin-layer chromatography. Thereafter, the mixture is poured into 7 l of water and extracted three times with 1 l of ethyl acetate each time. The combined ethyl acetate extracts are washed three times with 1 l of water each time, dried over sodium sulphate and evaporated in vacuo at 40° C. The residual yellow oil is dried for a further 6 hours in a high vacuum at 40° C. and subsequently distilled. There is obtained (Z)-2-methoxyimino-3-oxo-butyric acid tert.butyl ester as a yellow oil with a boiling point of 57° C. at 0.02 mmHg.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:9]=[N:10][N:11](C(OC(C)(C)C)=O)[CH:12]=2)=[C:6]([N:20]2[CH2:25][CH2:24][CH:23]([C:26]3[N:27]([CH2:39][CH2:40][OH:41])[CH:28]=[C:29]([C:31]4[CH:36]=[CH:35][C:34]([F:37])=[C:33]([CH3:38])[CH:32]=4)[N:30]=3)[CH2:22][CH2:21]2)[N:5]=[CH:4][N:3]=1.Cl>CO.O1CCOCC1>[NH2:1][C:2]1[N:3]=[CH:4][N:5]=[C:6]([N:20]2[CH2:25][CH2:24][CH:23]([C:26]3[N:27]([CH2:39][CH2:40][OH:41])[CH:28]=[C:29]([C:31]4[CH:36]=[CH:35][C:34]([F:37])=[C:33]([CH3:38])[CH:32]=4)[N:30]=3)[CH2:22][CH2:21]2)[C:7]=1[C:8]1[CH:12]=[N:11][NH:10][CH:9]=1
Reactant: Cc1cc(-c2cn(CCO)c(C3CCN(c4ncnc(N)c4-c4cnn(C(=O)OC(C)(C)C)c4)CC3)n2)ccc1F
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cc(-c2cn(CCO)c(C3CCN(c4ncnc(N)c4-c4cn[nH]c4)CC3)n2)ccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-butyl 4-(4-amino-6-(4-(4-(4-fluoro-3-methylphenyl)-1-(2-hydroxyethyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidin-5-yl)-1H-pyrazole-1-carboxylate (10.00 mg; 0.02 mmol) in 0.5 ml methanol was added 0.5 ml 4.0M HCl in dioxane, stirred at RT for 3 hrs, showed clean desired by LC-MS. Removed off solvent, got white solid as title compound. LC-MS: (M+1=463, obsd.=463).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35](B(O)O)[CH:36]=2)[CH:31]=[CH:30]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:35]1[CH:36]=[C:37]2[C:32]([CH:31]=[CH:30][NH:29]2)=[CH:33][CH:34]=1
Reactant: OB(O)c1ccc2cc[nH]c2c1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3ccc4cc[nH]c4c3)n(-c3ccccc3)c(=O)c12
Temperature: 100 °C
Reaction time: 18 h
Yield: 97.2 %

Procedure:
To a solution of (S)-2-(1-((6-amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (120 mg, 0.27 mmol) were added (1H-indol-6-yl)boronic acid (65 mg, 0.41 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(11)dichloride dichloromethane complex (22 mg, 0.03 mmol) and 272 μl of a 2M aqueous solution of cesium carbonate in dioxane (2 ml). The mixture was stirred under argon atmosphere at 100° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude was purified using SP1® Purification System (50% to 100%, hexane-ethyl acetate) to obtain 125 mg (94% yield) of the title compound as a white solid. Purity 98%.
Reaction SMILES: C[Si]([N-:5][Si](C)(C)C)(C)C.[Li+].Cl[CH:12]([B:15]1[O:19][C:18]([CH3:21])([CH3:20])[C:17]([CH3:23])([CH3:22])[O:16]1)[CH2:13][CH3:14].[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27]>O1CCCC1>[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27].[CH2:13]([CH:12]([B:15]1[O:19][C:18]([CH3:21])([CH3:20])[C:17]([CH3:23])([CH3:22])[O:16]1)[NH2:5])[CH3:14]
Reactant: CCC(Cl)B1OC(C)(C)C(C)(C)O1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CCC(N)B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.9 %

Procedure:
10 ml (10 mmol) of 1M lithium bis(trimethylsilyl)amide in tetrahydrofuran were added dropwise to a solution of 2.03 g (9.9 mmol) of 2-[1(RS)-chloropropyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in 20 ml tetrahydrofuran under a nitrogen atmosphere at -78° C. The solutionwas then stirred overnight at room temperature. The solvent was removed by evaporation and the residue was taken up in diethyl ether. Insoluble material was removed by filtration and the filtrate was cooled to 0° C. 2.3 ml (30 mmol) of trifluoroacetic acid were added and the solution was stirred at 0° C. for 30 minutes. The resulting precipitate was filtered off and dried to give 0.5 g of α-(RS)-ethyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-methylamine trifluoroacetate as a white solid.