Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:18]=2)[NH:13][CH:12]=1)O.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.O>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:18]=2)[NH:13][CH:12]=1
Reactant: OC(c1ccc(Cl)cc1Cl)c1c[nH]c2ncc(Oc3ccccc3)cc12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: Clc1ccc(Cc2c[nH]c3ncc(Oc4ccccc4)cc23)c(Cl)c1

Procedure:
To (2,4-dichloro-phenyl)-(5-phenoxy-1H-pyrrolo[9,3-b]pyridin-3-yl)-methanol (33, 30 mg, 0.078 mmol) in acetonitrile (8 mL), triethylsilane (1 mL, 7 mmol) and trifluoroacetic acid (0.5 mL, 7 mmol) were added. The reaction solution was heated to reflux for 4 hours. Then, the reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, water, and brine, dried over anhydrous magnesium sulfate, filtrated and concentrated. The crude material was suspended in acetonitrile (1˜2 mL). The precipitated material was collected with vacuum filtration to provide the compound (P-0037, 13 mg, 45%). MS (ESI) [M+H+]+=369.1 and 371.1.
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].C(C1C=CC=CC=1)(=O)C.[CH3:24][C:25]([C:27]1[CH:28]=[CH:29][C:30]([OH:34])=[CH:31][C:32]=1[OH:33])=[O:26]>>[CH3:24][C:25]([C:27]1[CH:28]=[CH:29][C:30]([O:34][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:31][C:32]=1[OH:33])=[O:26]
Reactant: ClCc1ccccc1
Reactant: CC(=O)c1ccc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)c1ccccc1
Product: CC(=O)c1ccc(OCc2ccccc2)cc1O

Procedure:
The reaction of (1) above is repeated using 1.1 molar equivalents of benzyl chloride, 1.0 molar equivalent of K2CO3, and substituting for the above acetophenone, 2,4-dihydroxyacetophenone ##STR19##
Reaction SMILES: CC1(C)CCCC(C)(C)N1.CCCCCC.C([Li])CCC.C([N:24]([CH2:33][CH3:34])[C:25]([C:27]1[CH:31]=[CH:30][O:29][C:28]=1[CH3:32])=[O:26])C.[CH2:35]([O:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44]CC#N)=[CH:40][CH:39]=1)[CH3:36].Cl>C1COCC1>[CH2:35]([O:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][CH2:34][C:33]2[NH:24][C:25](=[O:26])[C:27]3[CH:31]=[CH:30][O:29][C:28]=3[CH:32]=2)=[CH:40][CH:39]=1)[CH3:36]
Reactant: CCN(CC)C(=O)c1ccoc1C
Reactant: CCOc1ccc(CCC#N)cc1
Agent: CC1(C)CCCC(C)(C)N1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOc1ccc(CCc2cc3occc3c(=O)[nH]2)cc1
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 15.5 %

Procedure:
To a solution of 2,2,6,6-tetramethylpiperidine (11.6 mL, 68.8 mmol) in THF (100 mL) was added 1.6 M n-butyllithium hexane solution (39.0 mL, 62.4 mmol) at −78° C., and the mixture was warmed to −20° C. and stirred at the same temperature for 10 min. To this solution was added a solution of N,N-diethyl-2-methylfuran-3-carboxamide (11.3 g, 62.5 mmol) in THF (10 mL), and the mixture was further stirred for 1 hr. To the solution was added 3-(4-ethoxyphenyl)propanenitrile (11.5 g, 65.6 mmol), and the mixture was stirred at room temperature for hr. 6N Hydrochloric acid was added thereto and the mixture was extracted twice with ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained solid was washed with ethyl acetate to give the title compound (2.74 g, yield 15%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([C@H:13]([OH:15])[CH3:14])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:16][N:17]1[C:21](S(C)(=O)=O)=[N:20][N:19]=[C:18]1[C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([C@H:13]([O:15][C:21]3[N:17]([CH3:16])[C:18]([C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)=[N:19][N:20]=3)[CH3:14])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c(-c2cccnc2)nnc1S(C)(=O)=O
Reactant: C[C@@H](O)c1cc(-c2cccc(Cl)c2)on1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](Oc1nnc(-c2cccnc2)n1C)c1cc(-c2cccc(Cl)c2)on1
Temperature: 60 °C
Yield: 77.2 %

Procedure:
(1R)-1-[5-(3-chlorophenyl)isoxazol-3-yl]ethanol (5.40 g, 24.1 mmol) was dissolved in DMF (45 mL). To this 3-[4-methyl-5-(methylsulfonyl)-4H-1,2,4-triazol-3-yl]pyridine (5.75 g, 24.1 mmol) and cesium carbonate (10.1 g, 31.4 mmol) were added. After stirring over night at 60° C., water was added. The mixture was extracted with dichloromethane, followed by concentration of the organic layer in vacuo, to give a crude which was purified by column chromatography on silica using dichloromethane/methanol=98/2, to give the title compound (7.10 g, 77%). 1H NMR: 8.90 (d, 1H), 8.72 (m, 1H), 8.04 (dt, 1H), 7.76 (bs, 1H), 7.66 (m, 1H), 7.45 (m, 1H), 7.40 (m, 2H), 6.73 (s, 1H), 6.35 (q, 1H), 3.57 (s, 3H), 1.93 (d, 3H). 1H NMR (DMSO-d6): 8.90 (d, 1H), 8.71 (dd, 1H), 8.13 (dt, 1H), 7.99 (s, 1H), 7.86 (m, 1H), 7.58 (m, 3H), 7.40 (s, 1H), 6.19 (q, 1H), 3.54 (s, 3H), 1.81 (d, 3H). LC-MS (M++1)=382. [α]DRT (2.92 g/L, CDCl3)=−46.575°
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][C@@H:15]([CH3:17])[C@H:14]([CH2:18][C:19](O)=[O:20])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[CH2:22]([O:24][C:25]([C:27]1[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=1[NH2:29])=[O:26])[CH3:23]>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][C@@H:15]([CH3:17])[C@H:14]([CH2:18][C:19](=[O:20])[NH:29][C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[C:25]([O:24][CH2:22][CH3:23])=[O:26])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: C[C@@H]1Cc2cc(Br)cc3[nH]c(=O)c(=O)n(c23)[C@H]1CC(=O)O
Reactant: CCOC(=O)c1ccccc1N
Product: CCOC(=O)c1ccccc1NC(=O)C[C@H]1[C@H](C)Cc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Yield: 34.3 %

Procedure:
A procedure similar to that described in Example 52 was carried out with trans-9-bromo-5-carboxymethyl-6-methyl-6,7-dihydro- 1H, 5 H-pyrido[1,2,3-de]quinoxaline-2,3-dione (300 mg, 0,849 mmol) and o-ethoxycarbonylaniline (147 mg, 0.891 mmol) to give 153 mg of the title compound (36%): mp 238°~248° C.; 1H NMR (270 MHz, DMSO-d6) δ11.39 (s, 1H), 11.31 (s, 1H), 8.66 (d, 2H, J=8.4 Hz), 8.04 (dd, 1H, J=8.4, 1.7 Hz), 7.55 (td, 1H, J=8.4, 1.7 Hz), 7.35 (d, 1H, J=1.9 Hz), 7.19 (d, 1H, J=1.9 Hz), 7.11 (td, 1H, J=8.4, 1.7 Hz), 5.19~5.29 (m, 1H), 4.37 (q, 2H, J=7.3 Hz), 3.29 (dd, 1H, J=17.0, 5.1 Hz), 2.97 (dd, 1H, J=14.5, 4.6 Hz), 2.55~2.70 (m, 3H), 1.40 (t, 3H, J=7.3 Hz), 0.88 (d, 3H, J=6.9 Hz).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([O:9][CH3:10])[CH:3]=1.C1(P([C:34]2[CH:39]=[CH:38]C=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1([Mg]Br)CC1.Cl>O1CCCC1.Cl[Ni]Cl>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([CH:38]2[CH2:39][CH2:34]2)=[CH:3][C:4]=1[O:9][CH3:10]
Reactant: COc1cc(Br)ccc1Cl
Reactant: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Agent: Cl[Ni]Cl
Agent: Br[Mg]C1CC1
Agent: Cl
Solvent: C1CCOC1
Product: COc1cc(C2CC2)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-bromo-1-chloro-2-methoxy-benzene (1.45 g, 6.55 mmol) in dry tetrahydrofuran (10 ml), was added {1,3-bis (diphenylphosphino)-propane} dichloronickel (II) and cyclopropylmagnesium bromide (46 ml, 0.5 M in tetrahydrofuran, 23 mmols) at room temperature. The solution was stirred at room temperature for 2 hours, and then heated at 65° C. for 48 hours. Aqueous hydrochloric acid solution (1 N, 20 mL) was added, and the mixture was then cooled to room temperature and stirred for 30 minutes. The reaction mixture was partitioned between ethyl acetate and water. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (2% ethyl acetate in hexane) to yield 1-chloro-4-cyclopropyl-2-methoxy-benzene as yellow oily residue (0.81 g, 67%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([S:12][CH3:13])[N:8]([CH2:14][CH2:15][O:16][CH3:17])[C:7]2=[O:18].N(C[CH2:23][O:24][CH2:25]COC)=C=S>>[I:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([S:12][CH3:13])[N:8]([CH2:14][CH2:15][O:16][CH2:17][CH2:23][O:24][CH3:25])[C:7]2=[O:18]
Reactant: COCCOCCN=C=S
Reactant: COCCn1c(SC)nc2c(I)cccc2c1=O
Product: COCCOCCn1c(SC)nc2c(I)cccc2c1=O

Procedure:
This compound (0.81 g, 1.92 mmol) was prepared according to the procedures described for Intermediate 715a, starting from 1-isothiocyanato-2-(2-methoxyethoxyl)ethane (716a; 0.67 g, 4.21 mmol). m/z (ESI, +ve ion) 421.0 (M+H)+.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[CH:11]=[C:12]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[NH:13][C:14]=1[C:15]([F:18])([F:17])[F:16].C([O-])([O-])=O.[K+].[K+]>C(#N)C.CCOC(C)=O.O>[Br:1][C:11]1[C:10]([CH3:9])=[C:14]([C:15]([F:18])([F:16])[F:17])[NH:13][C:12]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)c1cc(C)c(C(F)(F)F)[nH]1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)c1[nH]c(C(F)(F)F)c(C)c1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-Bromosuccinimide (NBS) (17.7 g, 99.77 mmol) was portion wise added to an ice cooled solution of ethyl 4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylate (21 g, 95.02 mmol) and K2CO3 (13.7 g, 99.77 mmol) in acetonitrile. The reaction mixture was stirred for 2 h at RT. The reaction mixture was diluted with EtOAc and H2O. The aqueous layer was extracted with EtOAc (2×300 mL). Combined organic layer was dried over anhydrous Na2SO4, concentrated under reduced pressure to yield crude mass which was directly used to next step without further purification
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:24][C:25]1[C:33]2[O:32][CH:31]=[C:30]([Br:34])[C:29]=2[CH:28]=[CH:27][C:26]=1[Cl:35]>>[Br:34][C:30]1[C:29]2[CH:28]=[CH:27][C:26]([Cl:35])=[C:25]([NH:24][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]5[CH2:23][CH2:22][O:21][CH2:20][CH2:19]5)=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)[C:33]=2[O:32][CH:31]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Reactant: Nc1c(Cl)ccc2c(Br)coc12
Product: COc1cc2c(Nc3c(Cl)ccc4c(Br)coc34)ncnc2cc1OCCCN1CCOCC1
Yield: 66.4 %

Procedure:
Using an analogous procedure to that described in Example 3, 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (0.13 g) was reacted with 7-amino-3-bromo-6-chlorobenzofuran (0.186 g) to give the title compound (0.14 g); NMR Spectrum: (DMSOd6 and CF3CO2D) 2.3 (m, 2H), 3.15 (m, 2H), 3.35 (t, 2H), 3.55 (m, 2H), 3.7 (t, 2H), 4.0 (s, 3H), 4.05 (m, 2H), 4.35 (t, 2H), 7.4 (s, 1H), 7.7 (d, 2H), 8.2 (s, 1H), 8.4 (s, 1H), 8.85 (s, 1H); Mass Spectrum: M+H+ 549.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[C@H:9]1[C:14](O)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].B.CSC.CO.[H][H]>C1COCC1>[OH:13][C@H:10]1[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C@@H:9]1[CH2:14][OH:15]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)[C@H]1C(=O)O
Reactant: [H][H]
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H](O)[C@H]1CO
Temperature: 15 °C
Reaction time: 0.17 h
Yield: 99.5 %

Procedure:
The product from Example 18A (7.73 g, 33.5 mmol) in dry THF (100 mL) was treated with borane-methyl sulfide complex (10M in THF, 7.4 mL, 74 mmol) dropwise over 10 minutes. The solution was warmed to reflux for 1 hour, then cooled to 10-20° C. Methanol was added cautiously at 10-20° C. until there was no obvious evolution of hydrogen. The mixture was concentrated under reduced pressure and the white residue stirred with water (50 mL) for 10 minutes and then extracted with ethyl acetate (3×100 mL). The combined extracts were washed with brine (2×10 mL), dried (Na2SO4), and concentrated to provide the title compound as a white solid (7.24 g, 99% yield). 1H NMR (MeOH-d4, 300 MHz) δ 1.48 (s, 9H), 1.82 (m, 1H), 2.10 (m, 1H), 3.45 (m, 3H), 3.66 (m, 2H), 4.30 (m, 1H); MS (DCI/NH3) m/z 218 (M+H)+.
Reaction SMILES: [C:1]([N:8]([CH3:12])[CH2:9][CH2:10][NH2:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.Cl[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N+:16]=1[O-].C([O-])(O)=O.[Na+]>C(O)(CC)(C)C.CCO>[C:1]([N:8]([CH3:12])[CH2:9][CH2:10][NH:11][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: [O-][n+]1ccccc1Cl
Reactant: CN(CCN)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCC(C)(C)O
Solvent: CCO
Product: CN(CCNc1ccccn1)C(=O)OC(C)(C)C
Reaction time: 41.5 h

Procedure:
A mixture of N-Boc-N-(methyl)ethylenediamine (Synth. Commun. 1993, 23, 2443-2449)(849.2 mg, 4.87 mmol), 2-chloropyridine N-oxide hydrochloride (970 mg, 5.84 mmol), and NaHCO3 (2.05 g, 24.4 mmol) in tert-amyl alcohol (12 mL) was heated at reflux under argon. After 41.5 h, the reaction was cooled, diluted with EtOH, filtered, and concentrated. The residue was reconcentrated from toluene and chromatographed (silica gel, 5% CH3OH/CHCl3) to give the title compound as a viscous, yellow oil which was used without further purification (863.1 mg, 66%), MS (ES) m/e 268 [M+H]+.
Reaction SMILES: O.O.Cl.[NH2:4][C:5]([CH3:41])([CH3:40])[CH2:6][C:7]([NH:9][C@@H:10]1[CH2:16][CH2:15][C:14]2[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=2[N:12]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[NH:38][N:37]=[N:36][N:35]=3)=[CH:24][CH:23]=2)[C:11]1=[O:39])=[O:8].[NH:42]1[CH:46]=[CH:45][N:44]=[C:43]1[CH:47]=O>>[NH:42]1[CH:46]=[CH:45][N:44]=[C:43]1[CH2:47][NH:4][C:5]([CH3:41])([CH3:40])[CH2:6][C:7]([NH:9][C@@H:10]1[CH2:16][CH2:15][C:14]2[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=2[N:12]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[NH:38][N:37]=[N:36][N:35]=3)=[CH:24][CH:23]=2)[C:11]1=[O:39])=[O:8]
Reactant: O=Cc1ncc[nH]1
Reactant: CC(C)(N)CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)C1=O
Agent: Cl
Solvent: O
Product: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)C1=O)NCc1ncc[nH]1

Procedure:
The title compound was prepared from 3-amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R)-yl]butanamide hydrochloride dihydrate and 2-imidazolecarboxaldehyde by the procedure described in Example 1. Final purification carried was out by reverse phase HPLC on C18, eluting with methanol/0.1% aqueous trifluoroacetic acid using a linear gradient of 65% methanol to 80% methanol over ten minutes; retention time approximately 5.5 min. 1H NMR (200 MHz, CD3OD): δ1.41 (s, 3H), 1.45 (s, 3H), 2.0-2.7 (m, 6H), 4.37 (dd; 8, 12 Hz; 1H), 4.51 (s, 2H), 4.83 (d, 15 Hz, 1H), 5.23 (d, 15 Hz, 1H), 6.98 (d, 8 Hz, 2H), 7.1-7.4 (m, 7H), 7.4- 7.7 (m, 5H). FAB-MS: calculated for C33H35N9O2 589; found 590 (M+H, 83%).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[C:9]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:8]([CH3:17])=[CH:7][C:6]=1[NH:18][C:19]1[N:24]=[C:23]2[NH:25][N:26]=[C:27]([CH3:28])[C:22]2=[C:21]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36]([CH:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])[N:20]=1)([CH3:3])[CH3:2].Br[CH2:43][C:44]([NH2:46])=[O:45].[CH2:47](N(CC)CC)C>>[CH:1]([O:4][C:5]1[C:6]([NH:18][C:19]2[N:24]=[C:23]3[NH:25][N:26]=[C:27]([CH3:28])[C:22]3=[C:21]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[S:36]([CH:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])[N:20]=2)=[CH:7][C:8]([CH3:17])=[C:9]([CH:11]2[CH2:16][CH2:15][N:14]([CH2:43][C:44]([NH:46][CH3:47])=[O:45])[CH2:13][CH2:12]2)[CH:10]=1)([CH3:3])[CH3:2]
Reactant: NC(=O)CBr
Reactant: CCN(CC)CC
Reactant: Cc1cc(Nc2nc(Nc3ccccc3S(=O)(=O)C(C)C)c3c(C)n[nH]c3n2)c(OC(C)C)cc1C1CCNCC1
Product: CNC(=O)CN1CCC(c2cc(OC(C)C)c(Nc3nc(Nc4ccccc4S(=O)(=O)C(C)C)c4c(C)n[nH]c4n3)cc2C)CC1
Temperature: 100 °C

Procedure:
The mixture of N6-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (20 mg, 0.035 mmol), 2-bromoacetamide (0.1 N in DMF, 0.070 mmol, 0.70 mL) and triethylamine (1.0 N in DMF, 0.105 mmol, 0.105 mL) was heated at 100° C. for 10 min. The resulting reaction mixture was purified by RP-HPLC to afford 2-(4-(5-isopropoxy-4-(4-(2-(isopropylsulfonyl)phenylamino)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)-2-methylphenyl)piperidin-1-yl)-N-methylacetamide. MS (ES+): 649.3 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[C:11](=[O:23])[C:10]([O:24][CH3:25])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.CN(C=O)C.C(N(C(C)C)CC)(C)C.[CH3:40][O:41][CH2:42][C:43](Cl)=[O:44]>C(=O)([O-])[O-].[Na+].[Na+]>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:12]2[C:11](=[O:23])[C:10]([O:24][CH3:25])=[N:9][N:8]([C:4]3[CH:3]=[C:2]([NH:1][C:43](=[O:44])[CH2:42][O:41][CH3:40])[CH:7]=[CH:6][CH:5]=3)[C:13]2=[O:14])=[CH:17][CH:18]=1
Reactant: COCC(=O)Cl
Reactant: COc1nn(-c2cccc(N)c2)c(=O)n(Cc2ccc(Cl)cc2)c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCC(=O)Nc1cccc(-n2nc(OC)c(=O)n(Cc3ccc(Cl)cc3)c2=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
According to Scheme 9 Step 2: A mixture of 2-(3-aminophenyl)-4-(4-chlorobenzyl)-6-methoxy-1,2,4-triazine-3,5(2H,4H)-dione (100 mg, 0.28 mmol), DMF (4 mL), diisopropylethylamine (95 μl, 0.56 mmol) and methoxyacetyl chloride (30 μl, 0.33 mmol) was stirred under nitrogen at room temperature during 1 hour. The mixture was diluted with 50 mL of a saturated solution of sodium carbonate and the aqueous layer was extracted twice with 50 mL of DCM. The organic layers were combined to be dried over MgSO4, filtered and concentrated under reduced pressure to afford a brown solid. The crude solid was purified by flash chromatography with silica gel (Merck Flashmart prepacked column 15 g SiO2) using AcOEt/cyclohexane 4/6 as eluant to afford a beige solid. The solid was washed with diethylether to afford N-(3-(4-(4-chlorobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)-2-methoxyacetamide 4.141 (84 mg, 70%) as a white solid.
Reaction SMILES: C[N:2]([CH2:4][CH2:5][NH2:6])C.[OH:7][C:8]1[CH:13]=CC=C[N:9]=1.NC([OH:17])C>CN(C=O)C>[NH2:2][C@H:4]([C:5]([NH2:6])=[O:17])[CH2:13][C:8]([NH2:9])=[O:7]
Reactant: CC(N)O
Reactant: Oc1ccccn1
Reactant: CN(C)CCN
Solvent: CN(C)C=O
Product: NC(=O)C[C@H](N)C(N)=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
15 g (155 mmol) of polyanhydroaspartic acid (Mvisc. =19,000) are dissolved in 80 ml of DMF (anhydrous), if appropriate with gentle warming. First, 3.40 g (39 mmol) of freshly distilled dimethylaminoethylamine diluted in 20 ml of DMF are added dropwise to this solution and 1 g of anhydrous 2-hydroxypyridine is added and the mixture is stirred at room temperature for one day. 10 g (164 mmol) of aminoethanol are then added. After stirring for a further day the mixture is warmed at 50° C. for 2 h and repeatedly precipitated in anhydrous acetone.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][N:6]([CH3:24])[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])[N:13]=[CH:12][N:11]=1)=[O:8])C.[Li+].[OH-]>C1COCC1.O>[CH3:23][O:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:14]1[N:13]=[CH:12][N:11]=[C:10]([NH:9][C:7](=[O:8])[N:6]([CH2:5][C:4]([OH:25])=[O:3])[CH3:24])[CH:15]=1
Reactant: CCOC(=O)CN(C)C(=O)Nc1cc(-c2ccccc2OC)ncn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1-c1cc(NC(=O)N(C)CC(=O)O)ncn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of {3-[6-(2-methoxy-phenyl)-pyrimidin-4-yl]-1-methyl-ureido}-acetic acid ethyl ester (LVIII) (370 mg, 1.03 mmol) in a mixture of THF and water (1:1) was added a solution of LiOH (87.0 mg, 2.06 mmol) in water at ice bath temperature over 10 min and then allowed to stir for two hours at room temperature. THF was evaporated and the aqueous solution was acidified with 2N HCl. This aqueous phase was then extracted with ethyl acetate (2×100 ml), the combined organic phases were washed with water and brine, dried over anhydrous sodium sulfate and concentrated in a vacuum rotavapor to give {3-[6-(2-methoxy-phenyl)-pyrimidin-4-yl]-1-methyl-ureido}-acetic acid as a brown coloured solid. Yield: 34 mg, 10.4%.
Reaction SMILES: [C:1](=[NH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.[Br:16][C:17]1[S:21][C:20](N)=[N:19][CH:18]=1>ClCCCl>[Br:16][C:17]1[S:21][C:20]([N:14]=[C:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:19][CH:18]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: Nc1ncc(Br)s1
Agent: Br
Solvent: ClCCCl
Product: Brc1cnc(N=C(c2ccccc2)c2ccccc2)s1
Yield: 82.9 %

Procedure:
26 g of benzophenone imine are added to 34 g of 5-bromo-1,3-thiazol-2-amine hydrobromide, in suspension in 300 ml of 1,2-dichloroethane. The mixture is kept under reflux for 18 hours. The precipitate formed is filtered and the filtrate is concentrated to give 37.2 g of solid. m.p.=109° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13](/[CH:16]=[CH:17]/[C:18](O)=[O:19])[CH:14]=2)[C:9](=[O:21])[N:8]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:7]=1[CH2:27][NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:2][CH2:3][CH3:4].Cl.C([N:39]=C=NCCCN(C)C)C.[NH4+].ON1C2C=CC=CC=2N=N1.O>CN(C)C=O>[CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13](/[CH:16]=[CH:17]/[C:18]([NH2:39])=[O:19])[CH:14]=2)[C:9](=[O:21])[N:8]([CH2:22][C:23]([CH3:24])([CH3:25])[CH3:26])[C:7]=1[CH2:27][NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)(C)C)c(=O)c2ccc(/C=C/C(=O)O)cc12
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)(C)C)c(=O)c2ccc(/C=C/C(N)=O)cc12
Yield: 85.3 %

Procedure:
A solution of (E)-3-[4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-neopentyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenic acid (0.34 g, 0.7 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.27 g, 1.4 mmol) and 1-hydroxybenzotriazole ammonium salt (0.21 g, 1.4 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-diisopropyl ether to give (E)-3-[4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-neopentyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenamide (0.29 g, 87.9%) as crystals.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:4]([CH3:12])[C:3]=1[C:13]([O:15]CC)=O.[S:18]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]#[N:25])=[CH:19]1.Cl.O1CCOCC1.N>>[CH3:12][C:4]1[C:3]2[C:13](=[O:15])[NH:25][C:24]([CH2:23][C:20]3[CH:21]=[CH:22][S:18][CH:19]=3)=[N:1][C:2]=2[S:6][C:5]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: N#CCc1ccsc1
Reactant: CCOC(=O)c1sc(N)c(C(=O)OCC)c1C
Agent: Cl
Agent: N
Solvent: C1COCCO1
Product: CCOC(=O)c1sc2nc(Cc3ccsc3)[nH]c(=O)c2c1C
Reaction time: 10 h

Procedure:
515 Milligrams of diethyl 5-amino-3-methylthiophene-2,4-dicarboxylate and 296 mg of 3-thiopheneacetonitrile were added to 8 mL of 4N hydrogen chloride-dioxane solution and stirred for 10 hours. Thereafter the liquid reaction mixture was poured on ice, and its pH was adjusted to 8-9 with 25% aqueous ammonia. Whereupon precipitated crystals were recovered by filtration and washed first with water, and then with hexane. The crude crystals were recrystallized from a liquid mixture of N,N-dimethylformamide and cyclohexane, to provide 397 mg of the title compound.