Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[N:17]=[CH:16][CH:15]=2)[CH2:10]1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O.[F:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]=C=O)=[CH:35][CH:34]=1.C(N(CC)CC)C>C(Cl)Cl>[F:32][C:33]1[CH:38]=[CH:37][C:36]([NH:39][C:6]([NH:8][CH:9]2[CH2:13][CH2:12][N:11]([C:14]3[C:23]4[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=4)[N:17]=[CH:16][CH:15]=3)[CH2:10]2)=[O:7])=[CH:35][CH:34]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccnc3cc(Cl)ccc23)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(F)cc1)NC1CCN(c2ccnc3cc(Cl)ccc23)C1

Procedure:
A solution of 4-[3-(tert-butoxycarbonylamino)pyrrolidin1-yl]-7-chloroquinoline (214 mg, 0.62 mmol) in CH2Cl2 (5 mL) is treated with trifluoroacetic acid (1 mL). After 1 h the reaction mixture is concentrated. The residue is dissolved in CH2Cl2 (10 mL), and 4-fluorophenyl isocyanate (70 μL, 0.62 mmol) and triethylamine (1 mL) are added. The reaction mixture is concentrated, and the residue is purified by column chromatography and an aqueous work-up step yielding the title product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]2[C:11](=[O:16])[NH:12][NH:13][C:14]=2[CH3:15])[CH:5]=[CH:6][C:7]=1[CH3:8].C(=O)([O-])[O-].[K+].[K+].[C:23](OC(=O)C)(=[O:25])[CH3:24].C(O)(=O)C>CN(C)C=O.O>[C:23]([N:13]1[C:14]([CH3:15])=[C:10]([CH2:9][C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([F:1])[CH:3]=2)[C:11](=[O:16])[NH:12]1)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(Cc2c(C)[nH][nH]c2=O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)n1[nH]c(=O)c(Cc2ccc(C)c(F)c2)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.2 %

Procedure:
4-[(3-Fluoro-4-methylphenyl)methyl]-1,2-dihydro-5-methyl-3H-pyrazol-3-one (1.00 g) was suspended in N,N-dimethyl-formamide (5 mL) at room temperature. Potassium carbonate (0.376 g) was added to the suspension, and the mixture was stirred for 30 minutes. Acetic anhydride (0.486 g) was added to the reaction mixture in a dropwise manner at room temperature. The mixture was stirred at room temperature overnight and at 50° C. for 2 hours. The mixture was cooled to room temperature under stirring, the mixed solution of glacial acetic acid (0.164 g) and water (5.0 g) was added to the mixture. After confirming the precipitation of the crystals, water (25 g) was added to the mixture. The obtained crystals were collected by filtration and washed with water. The obtained wet crystals were dried under reduced pressure to give a yellowish-white solid of 1-acetyl-4-[(3-fluoro-4-methylphenyl)methyl]-1,2-dihydro-5-methyl-3H-pyrazol-3-one (0.502 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:16]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:17]=[CH:18][N:19]=4)[S:8][C:7]=3[C:6]=2[N:28]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][N:31]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CC#N.O>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[N:16]1[C:15]([C:9]2[S:8][C:7]3[C:6]4[N:28]=[C:2]([C:33]5[CH:32]=[N:31][C:30]([F:29])=[CH:35][CH:34]=5)[CH:3]=[CH:4][C:5]=4[O:14][CH2:13][CH2:12][C:11]=3[CH:10]=2)=[N:19][CH:18]=[N:17]1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Reactant: CC1(C)OB(c2ccc(F)nc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC#N
Product: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(-c4ccc(F)nc4)ccc2OCC3)c(F)c1
Temperature: 80 °C
Yield: 83.8 %

Procedure:
9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (4.16 g, 10 mmol), 2-Fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (2.67 g, 12 mmol), Cs2CO3 (6.50 g, 20 mmol), Pd(dppf)Cl2 (730 mg, 1.0 mmol) and CH3CN—H2O (1:1, 40 mL) were added in a 50 mL of sealed tube, and the mixture was heated at 80° C. for 60 min under N2. The reaction mixture was filtered to gather the solution and water was added. The mixture was extracted by DCM (50 mL×3). The combined organic layers were dried over Na2SO4, concentrated in vacuo, and purified by preparative TLC to give 2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-(6-fluoro-pyridin-3-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (4.0 g, yield: 84%). 1HNMR (DMSO-d6, 400 MHz): δ8.68 (s, 1H), 8.43 (t, J=4.8 Hz, 2H), 8.12-8.01 (m, 1H), 8.00-7.92 (m, 1H), 7.84 (t, J=2.8 Hz, 1H), 7.58-7.50 (m, 2H), 7.26 (s, 2H), 4.39 (s, 2H), 3.24 (s, 2H), 2.23 (s, 3H). ESI-MS: m/z=478 [M+H+]
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[N+:10]([O-])([OH:12])=[O:11]>O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[C:4]([CH3:9])[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(Cl)c(Cl)c1
Solvent: O
Product: Cc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
To stirred 3,4-dichloro-toluene 4 (10.0 g, 62.2 mmol) at 0° C. was slowly added fuming nitric acid (20.0 mL). The mixture was stirred for 2 hrs at RT, then water added (200 mL) and the reaction mixture filtered. The filtrate was purified by silica gel chromatography using 5% ethyl acetate in hexanes to give the title compound 11.7 g (92%). 1H NMR (400 MHz, CDCl3) δ8.14 (s, 1 H, Ar), 7.47 (s , 1 H, Ar), 2.59 (s, 3 H, CH3).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH:7]([OH:8])[CH2:6][CH:5]([C:9]2[N:14]=[C:13]3[NH:15][N:16]=[C:17]([I:18])[C:12]3=[C:11](C)[N:10]=2)[O:4]1.[OH-].[NH4+:21]>>[NH2:21][C:11]1[N:10]=[C:9]([CH:5]2[O:4][CH:3]([CH2:2][OH:1])[CH:7]([OH:8])[CH2:6]2)[N:14]=[C:13]2[NH:15][N:16]=[C:17]([I:18])[C:12]=12
Reactant: Cc1nc(C2CC(O)C(CO)O2)nc2[nH]nc(I)c12
Reactant: [NH4+]
Agent: [OH-]
Product: Nc1nc(C2CC(O)C(CO)O2)nc2[nH]nc(I)c12

Procedure:
Compound 8 (6.8 g, 17.35 mmol) was stirred in 200 mL of concentrated ammonium hydroxide (sealed container) at room temperature for 36 h. The mixture was evaporated and the residue was precipitated from acetonitrile-ether. The solid was filtered and dried: 5.36 g (82%) yield. NMR and spectral data on this compound is identical to
Reaction SMILES: C([Li])CCC.[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22](Br)=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1.[CH3:32][N:33]1[C:37]([CH:38]=[O:39])=[CH:36][N:35]=[C:34]1[CH3:40].O>O1CCCC1>[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22]([CH:38]([C:37]3[N:33]([CH3:32])[C:34]([CH3:40])=[N:35][CH:36]=3)[OH:39])=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1
Reactant: Cc1ncc(C=O)n1C
Reactant: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1nc2ccc(C(O)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Temperature: 23 °C
Reaction time: 0.05 h

Procedure:
A solution of n-butyllithium in hexanes (1.6 M, 1.5 mL, 2.3 mmol) was added dropwise to a stirring solution of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxyquinoline (1 g, 2.3 mmol, Intermediate 4: step d) in tetrahydrofuran (18 mL) at −78° C. After 3 minutes, a solution of 1,2-dimethyl-1H-imidazole-5-carbaldehyde (347 mg, 2.8 mmol) in tetrahydrofuran (5 mL) was added dropwise. After 5 minutes, the flask was placed into an ice-water bath. After 30 minutes, water (10 mL) was added and the biphasic mixture was allowed to warm to 23° C. The mixture was partitioned between half-saturated sodium chloride solution (50 mL) and ethyl acetate (100 mL). The layers were separated. The organic layer was dried with sodium sulfate and the dried solution was filtered. Silica gel (3 g) was added to the filtrate and the solvent was removed by rotary evaporation to afford a free-flowing powder. The powder was loaded onto a column of silica gel for purification. Elution with ethyl acetate initially, grading to 7% methanol-ethyl acetate provided the title compound as an off-white solid. 1H NMR (500 MHz, CDCl3) δ ppm 8.24-8.22 (m, 1H), 7.86-7.84 (m, 1H), 7.82 (d. J=8.6 Hz, 1H), 7.68 (d, J=1.7 Hz, 1H), 7.62-7.59 (m, 1H), 7.58-7.54 (m, 2H), 7.38-7.35 (m, 2H), 6.54 (s, 1H), 6.44-6.41 (m, 1H), 6.00 (s, 1H), 4.33 (s, 2H), 4.09 (s, 3H), 3.47 (s, 3H), 2.33 (s, 3H); MS (ESI): mass calcd. for C26H24ClN5O2, 473.2; m/z found, 474.0 [M+H]+.
Reaction SMILES: [Li].[CH3:2][N:3]([C:5](=O)[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)[NH2:4].O.[OH-].[Na+]>C1COCC1>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][N:3]([CH3:2])[NH2:4])=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=O)N(C)N)cc1
Agent: [Li]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN(C)N)cc1
Temperature: 25 °C
Yield: 51.5 %

Procedure:
Tetrahydrofuran (40 ml) was added to lithium aluminumhydride (1.94 g), the mixture was heated and stirred gently under an argon atmosphere, and a solution (10 ml) of 4-methoxybenzoic acid N-methyl hydrazide (4.78 g) prepared in the Step 14-1-1 in THF was added thereto. The resulting mixture was further stirred for 15 hours under heat reflux. The mixture was allowed to cool to a room temperature, and then water (2 ml) and a 1-N sodium hydroxide aqueous solution (7.5 ml) were added dropwise to the mixture. The reaction solution was filtered through a celite, and the filtrate was concentrated under a reduced pressure. The concentrate was purified by silica gel column chromatography (dichloromethane:methanol=50:1) to give the title compound (2.27 g, 45%).
Reaction SMILES: Cl.[C:2]1([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:18]C(=O)C)=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([NH:8][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)(=[O:11])=[O:10])=[CH:13][CH:14]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccccc2)cc1
Agent: Cl
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)Nc2ccccc2)cc1
Reaction time: 1 h

Procedure:
An aqueous 6N solution of HCl (40 mL) was cautiously added with stirring to a solution of 3 (20 g, 68 mmol) in ethanol (80 mL). After heating under reflux for 3 h, the reaction mixture was evaporated to dryness in vacuo and the residue was dissolved in water. The pH of the solution was adjusted to 8-9 using 1N aq. NH4OH. After stirring for 1 h, the white solid that gradually precipitated was collected by filtration. The filter cake was washed with ice-cold water, dried under vacuum, and recrystallized from hot ethanol to give to give 4-amino-N-phenyl-benzenesulfonamide (4) (also called 207-33 or LED207) (10.9 g, 65%) as a white solid, mp 194-195° C. 1H NMR (CD3COCD3, 300 MHz) δ 8.64 (br s, 1H), 7.50-7.45 (m, 2H), 7.25-7.18 (m, 4H), 7.04-6.98 (m, 1H), 6.67-6.62 (m, 2H), 5.44 (br s, 2H); 13C NMR (CD3COCD3, 75 MHz) δ 152.9, 138.8, 129.3 (2C), 129.1 (2C), 126.3, 124.0, 120.5 (2C), 113.1 (2C).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=[CH:13][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CO.C(Cl)Cl>[CH3:17][O:16][C:14]([C:11]1[CH:12]=[CH:13][C:7]2[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[S:9][C:8]=2[CH:10]=1)=[O:15]
Reactant: COC(=O)c1ccc2cc(C(=O)OC)sc2c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc2cc(C(=O)O)sc2c1
Reaction time: 5 h

Procedure:
To a solution of benzo[b]thiophene-2,6-dicarboxylic acid dimethyl ester (139 mg, 0.56 mmol) in THF/MeOH (2/2 mL) was added 1 N NaOH (555 μL). After 5 h, the solution was diluted with CH2Cl2 and acidified with 5% citric acid. The combined organic fractions were dried, filtered, and concentrated to yield the desired acid, which was used without further purification. MS (EI): cal'd (MH+) 237.01, exp (MH+) 237.13.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH2:6].Cl[C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][C:10]=1[N+:20]([O-:22])=[O:21]>C(OCC)(=O)C>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH:6][C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][C:10]=1[N+:20]([O-:22])=[O:21]
Reactant: CCOC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CN(C)CCCN
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(NCCCN(C)C)c([N+](=O)[O-])c1
Temperature: 125 °C
Reaction time: 12 h
Yield: 101.2 %

Procedure:
N,N-Dimethy-1,3-propanediamine (1.41 g) was added to ethyl 4-chloro-3-nitrobenzoate (1.59 g) and stirred for 12 hours at 125° C. The reaction mixture, with ethyl acetate added thereto, was washed with 1N sodium hydroxide aqueous solution, water, and saturated brine successively, dried over sodium sulfate anhydride, and concentrated, thereby yielding the entitled compound (2.07 g) as brown oil.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:3]=1[CH2:4][N:5]1[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[NH:8][C:7]2[N:14]=[CH:15][C:16](I)=[CH:17][C:6]1=2.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([C:31]([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)=[O:32])[CH2:27][CH2:26]1>>[F:1][C:2]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:3]=1[CH2:4][N:5]1[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[NH:8][C:7]2[N:14]=[CH:15][C:16]([C:36]3[CH:35]=[CH:34][C:33]([C:31]([N:28]4[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]4)=[O:32])=[CH:38][CH:37]=3)=[CH:17][C:6]1=2
Reactant: CC1(C)Nc2ncc(I)cc2N(Cc2cc(F)ccc2F)C1=O
Reactant: CN1CCN(C(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CN1CCN(C(=O)c2ccc(-c3cnc4c(c3)N(Cc3cc(F)ccc3F)C(=O)C(C)(C)N4)cc2)CC1
Yield: 55 %

Procedure:
1-(2,5-Difluorobenzyl)-7-iodo-3,3-dimethyl-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (45 mg) was reacted with (4-methylpiperazin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]methanone as in General Procedure 4A to give the title compound as a white solid (55% yield). M.p. 204-206° C., LCMS: m/z=506.16 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.56 (s, 6H), 2.33 (s, 3H), 2.36-2.54 (m, 4H), 3.36-3.54 (m, 2H), 3.73-3.83 (m, 2H), 5.14 (s, 1H), 5.21 (s, 2H), 6.84-6.88 (m, 1H), 6.93-6.98 (m, 1H), 7.07-7.13 (m, 1H), 7.19 (d, J=1.5 Hz, 1H), 7.43 (m, 4H), 8.03 (d, J=2.0 Hz, 1H).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH:19]=[C:18](I)[CH:17]=[N:16]2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([Mg]Cl)(C)C.CO[B:28]1[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]1.[NH4+].[Cl-]>C1COCC1>[Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH:19]=[C:18]([B:28]3[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]3)[CH:17]=[N:16]2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COB1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](n2cc(I)cn2)CC1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(C)OB(c2cnn([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)CC3)c2)OC1(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A stirred solution of 1-(trans-4-{[tert-butyl(dimethyl)silyl]-oxy}cyclohexyl)-4-iodo-1H-pyrazole (1.14 g, 2.80 mmol) in THF (30.0 mL) was cooled to 0° C. and treated with isopropylmagnesium chloride (2.0 M in THF, 2.31 mL, 4.63 mmol), added dropwise under an atmosphere of nitrogen over 5 min. The reaction mixture was stirred at 0° C. for another 1 h, then treated 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.95 mL, 5.6 mmol) and stirred at RT for another hour. The mixture was treated with saturated aqueous NH4Cl (10 mL) and extracted with EtOAc (3×20 mL). The extracts were washed with water (10 mL), brine (15 mL), and dried over Na2SO4. Solvent was removed under reduced pressure to give a residue which was purified by flash chromatography (10% EtOAc:hexane) to provide 1.10 g (96%) of the title compound. MS (ESI): 405.95 [M+H]+; HPLC tR=3.21 min.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[CH:10]=[CH:9][N:8]=1)=[O:5].[H][H]>CO.C(Cl)Cl.CC(O)=O.[Pt]>[NH2:20][C:17]1[CH:16]=[CH:15][C:14]([O:13][C:11]2[CH:10]=[CH:9][N:8]=[C:7]([NH:6][C:4](=[O:5])[CH2:3][O:2][CH3:1])[CH:12]=2)=[CH:19][CH:18]=1
Reactant: [H][H]
Reactant: COCC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1
Agent: [Pt]
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: COCC(=O)Nc1cc(Oc2ccc(N)cc2)ccn1

Procedure:
A solution of 2-methoxy-N-(4-(4-nitrophenoxy)pyridin-2-yl)acetamide (730 mg, 2.41 mmol) in MeOH/DCM (1:1 v/v, 80 mL) containing AcOH (5 drops) was subjected to hydrogenation by passage through a Thales H-cube (1.0 mL min−1, RT, 70 mm 10% Pt/C Cat-Cart, full hydrogen mode) and was then evaporated in vacuo. The residue was partitioned between DCM (20 mL) and saturated aqueous NaHCO3 solution (10 mL). The organic layer was washed with brine (20 mL) and was dried (MgSO4) and evaporated in vacuo to afford the title compound, Intermediate H1, as a white solid (0.63 g, 91%); Rt 0.88 min (Method 2); m/z 274 (M+H)+ (ES+).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH2:13][N:12]([C:17]1[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][CH:18]=1)[CH2:11][CH2:10]2>C(Cl)Cl>[OH:23][C:20]1[CH:21]=[CH:22][C:17]([N:12]2[CH2:11][CH2:10][C:9]3[C:14](=[CH:15][CH:16]=[C:7]([OH:6])[CH:8]=3)[CH2:13]2)=[CH:18][CH:19]=1
Reactant: COc1ccc(N2CCc3cc(OC)ccc3C2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(N2CCc3cc(O)ccc3C2)cc1
Temperature: 25 °C
Yield: 80.6 %

Procedure:
A 1.0 M solution of boron tribromide in CH2Cl2 (0.54 mL) was added dropwise to a cooled (−15° C.) solution of 6-methoxy-2-(4-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline (0.036 g) in CH2Cl2 (1.4 mL). After 30 min the reaction was warmed to room temperature. After 2 h the reaction was diluted with CH2Cl2 (30 mL) and washed successively with saturated aqueous sodium bicarbonate (2×20 mL) and saturated aqueous sodium chloride (1×15 mL). The organic extract was dried and evaporated. The resulting residue was purified by chromatography on silica gel (eluant; a gradient of 0 to 20% methanol in dichloromethane) to give the title compound (0.026 g); MS: 242.0 (MH+); HPLC tR: 0.46 min; 1H NMR (DMSO-d6): 9.14 (s, 1H), 8.79 (s, 1H), 6.94 (d, 1H, J=6 Hz), 6.85 (d, 2H, J=6.65 (d, 2H J=9 Hz), 6.56 (d, 1H, J=6 Hz), 6.52 (s, 1H), 4.06.(s, 2H), 3.28 (t, 2H, J=6 Hz), 2.78 (t, 2H, J=6 Hz).
Reaction SMILES: C([NH:7][C:8]1[N:13]=[N:12][C:11]([CH2:14][C:15]([O-:17])=[O:16])=[CH:10][CH:9]=1)(=O)C(C)(C)C.[CH3:18][Si](C=[N+]=[N-])(C)C.C(OCC)C>Cl.O>[NH2:7][C:8]1[N:13]=[N:12][C:11]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:9]=1
Reactant: CC(C)(C)C(=O)Nc1ccc(CC(=O)[O-])nn1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: COC(=O)Cc1ccc(N)nn1
Reaction time: 1 h

Procedure:
A solution of 2-(6-pivalamidopyridazin-3-yl)acetate (740 mg, 2.52 mmol) in 6 N hydrochloric acid (24 mL) was heated to 105° C. for 12 h, then cooled and concentrated in vacuo. The resulting crude residue was redissolved in methanol (10 mL) and treated dropwise with a 2 N solution of trimethylsilyldiazomethane in diethylether (2.52 mL, 5.04 mmol). After 1 h, the mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water and brine, dried (sodium sulfate), filtered and concentrated to provide title compound. LC-MS (IE, m/z): 168 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH3:12])[C:8]([O:20][CH3:21])=[C:7]2[C:3]=1[C:4]1[CH:32]=[C:31]([CH3:33])[CH:30]=[N:29][C:5]=1[N:6]2[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].[CH2:34]([S:36]([C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[CH:43][CH:44]=1)(=[O:38])=[O:37])[CH3:35].O1CCOCC1.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:16]([O:15][C:13]([N:11]([CH3:12])[C:9]1[C:8]([O:20][CH3:21])=[C:7]2[C:3]([C:4]3[CH:32]=[C:31]([CH3:33])[CH:30]=[N:29][C:5]=3[N:6]2[C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])=[C:2]([C:41]2[CH:42]=[CH:43][CH:44]=[C:39]([S:36]([CH2:34][CH3:35])(=[O:37])=[O:38])[CH:40]=2)[CH:10]=1)=[O:14])([CH3:18])([CH3:19])[CH3:17]
Reactant: CCS(=O)(=O)c1cccc(B(O)O)c1
Reactant: COc1c(N(C)C(=O)OC(C)(C)C)cc(Br)c2c3cc(C)cnc3n(C(=O)OC(C)(C)C)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)c1cccc(-c2cc(N(C)C(=O)OC(C)(C)C)c(OC)c3c2c2cc(C)cnc2n3C(=O)OC(C)(C)C)c1
Temperature: 140 °C

Procedure:
A 5 mL microwave vial was charged with Compound 250 (520 mg, 1.0 mmol), 3-(ethylsulfonyl)phenylboronic acid (321 mg, 1.5 mmol) and Pd(PPh3)4 (116 mg, 0.10 mmol). To the mixture was added dioxane (2 mL) and a saturated aqueous solution of K2CO3 (1 mL). The reaction mixture was heated at 140° C. for 20 min. in microwave. The reaction was diluted with EtOAc and washed with water and brine. The organic extracts were dried (Na2SO4) and concentrated and the crude Compound 251 was taken forward for Boc deprotection.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[C:4]([CH3:10])[CH:3]=1.[NH:11]([C:13]([O:15]CC)=O)[NH2:12]>CN1C(=O)CCC1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[NH:9][C:13](=[O:15])[NH:11][N:12]=2)[CH:5]=[C:4]([CH3:10])[CH:3]=1
Reactant: CCOC(=O)NN
Reactant: Cc1cc(Cl)nc(C#N)c1
Solvent: CN1CCCC1=O
Product: Cc1cc(Cl)nc(-c2n[nH]c(=O)[nH]2)c1
Temperature: 160 °C
Yield: 10.3 %

Procedure:
A mixture of 6-chloro-4-methylpicolinonitrile (3 g, 19.66 mmol) and ethyl hydrazinecarboxylate (8.19 g, 79 mmol) in NMP (6 mL) was heated in a sealed tube at 160° C. overnight. The residue was purified by column chromatography eluting with a gradient of 0-80% EtOAc in heptanes. The product-containing fractions were collected and evaporated in vacuo to give the title compound as a yellow semi-solid (428 mg). ESI-MS m/z [M+H]+211.6.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][C:9]2[C:10]3[CH2:31][NH:30][CH2:29][CH2:28][C:11]=3[N:12]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:26]=[CH:25][N:24]=[C:23]4[CH3:27])=[CH:18][CH:17]=3)[N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:32](=O)[CH2:33][OH:34]>>[CH:1]1([CH2:7][CH2:8][C:9]2[C:10]3[CH2:31][N:30]([CH2:32][CH2:33][OH:34])[CH2:29][CH2:28][C:11]=3[N:12]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:26]=[CH:25][N:24]=[C:23]4[CH3:27])=[CH:18][CH:17]=3)[N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=CCO
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(CCC4CCCCC4)n2)CNCC3)cc1
Product: Cc1nccn1-c1ccc(Nc2nc(CCC3CCCCC3)c3c(n2)CCN(CCO)C3)cc1

Procedure:
2-(4-(2-Cyclohexylethyl)-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanol was synthesised from 4-(2-cyclohexylethyl)-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (example 47a) and glycol aldehyde according to the general procedure for reductive amination.