Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH2:20][C:21]1([CH3:29])[CH2:26][O:25][C:24]([CH3:28])([CH3:27])[O:23][CH2:22]1)(=O)=O>CN(C)C=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:20][C:21]2([CH3:29])[CH2:26][O:25][C:24]([CH3:28])([CH3:27])[O:23][CH2:22]2)=[CH:4][N:3]=1
Reactant: Oc1cnc(Cl)nc1
Reactant: CC1(COS(C)(=O)=O)COC(C)(C)OC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC1(COc2cnc(Cl)nc2)COC(C)(C)OC1
Temperature: 90 °C
Reaction time: 24 h
Yield: 30.2 %

Procedure:
To a solution of 9.50 g (72.8 mmol) of 2-chloro-5-hydroxypyrimidine in 100 ml of N,N-dimethylformamide, 26.1 g (80.1 mmol) of cesium carbonate and 24.3 g (102 mmol) of 5-(methanesulfonyloxymethyl)-2,2,5-trimethyl-1,3-dioxane, which was synthesized by the method described in V. W. Gash, Journal of Organic Chemistry, 1972, Vol. 37, p. 2197-2201, were added, and the mixture was stirred at 90° C. for 24 hours. After completion of the reaction, the insoluble material was filtered off and washed with ethyl acetate, and then 0.5 N sodium hydroxide aqueous solution was added to the filtrate and separation was performed. The obtained aqueous layer was further extracted with ethyl acetate. The obtained organic layers were combined, washed with water and saturated sodium chloride aqueous solution in order and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Toluene was added to the obtained residue, and the precipitate was obtained by filtration and washed with toluene and n-heptane to provide 6.00 g of the title compound as a white solid (yield: 30%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH:15]([CH3:17])[CH3:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[Cl:27][CH2:28][C:29](Cl)=[O:30]>ClCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH:15]([CH3:17])[CH3:16])[C:29](=[O:30])[CH2:28][Cl:27])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)NC1CCN(Cc2ccccc2)CC1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(C(=O)CCl)C1CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 50.3 %

Procedure:
To a mixture of 1-benzyl-4-(isopropylamino)piperidine (8 g, 34.45 mmol) and DIPEA (7.2 mL, 41.3 mmol) in 200 mL of dichloromethane was added dropwise a solution of 2-chloroacetyl chloride (3.01 mL, 37.9 mmol) in dichloromethane (400 mL) at 0° C. The reaction mixture was stirred at 0° C. for 15 min and then at room temperature for 2 h. The reaction mixture was then washed with saturated sodium bicarbonate, brine, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by flash column chromatography (ethyl acetate/hexane/triethylamine: 42.5/56.5/1) to give 5.35 g of the title intermediate as a viscous oil (50% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1[NH:10][C:11](=[O:19])OC1C=CC=CC=1.[F:20][C:21]1[CH:22]=[C:23]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:24]=[C:25]([F:27])[CH:26]=1>>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1[NH:10][C:11]([N:31]1[CH2:30][CH2:29][N:28]([C:23]2[CH:22]=[C:21]([F:20])[CH:26]=[C:25]([F:27])[CH:24]=2)[CH2:33][CH2:32]1)=[O:19]
Reactant: Fc1cc(F)cc(N2CCNCC2)c1
Reactant: Cc1cc(O)c(NC(=O)Oc2ccccc2)cc1C
Product: Cc1cc(O)c(NC(=O)N2CCN(c3cc(F)cc(F)c3)CC2)cc1C
Yield: 80 %

Procedure:
Phenyl N-[2-hydroxy-4,5-dimethylphenyl)carbamate and 1-(3,5-difluorophenyl)piperazine were reacted by the same way with the example 228 to obtain the titled compound.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[O:12]=[C:13]1[C:25]2[CH:24]=[C:23]([C:26](O)=[O:27])[CH:22]=[CH:21][C:20]=2[C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[N:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:26]([C:23]3[CH:22]=[CH:21][C:20]4[C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[C:13](=[O:12])[C:25]=4[CH:24]=3)=[O:27])[CH:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1ccc2cccnc2c1
Reactant: O=C(O)c1ccc2c(c1)C(=O)c1ccccc1-2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(Nc1ccc2cccnc2c1)c1ccc2c(c1)C(=O)c1ccccc1-2
Temperature: 25 °C

Procedure:
To a solution of 7-aminoquinoline (D55) (35 mg, 0.24 mmol) in DCM (3 ml) was added 9-oxo-9H-fluorene-2-carboxylic acid (60 mg, 0.27 mmol), (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (68 mg, 0.36 mmol) and 4-dimethylaminopyridine (5 mg, 0.04 mmol) and the reaction stirred at room temperature then at reflux until complete by tlc. After cooling to room temperature the resultant precipitate was filtered off to give the title compound as an off-white solid. MS(ES): MH+ 351, M-H+ 349
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[C:13]([C@@H:17]1[CH2:22][CH2:21][C@H:20](O)[CH2:19][CH2:18]1)([CH3:16])([CH3:15])[CH3:14]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][C@H:20]1[CH2:21][CH2:22][C@H:17]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:18][CH2:19]1)[CH:6]=[CH:5]2
Reactant: CC(C)(C)[C@H]1CC[C@@H](O)CC1
Reactant: Oc1ccc2cc(Br)ccc2n1
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(Br)ccc3n2)CC1

Procedure:
6-bromo-2-hydroxyquinoline was treated with cis-4-tert-butylcyclohexanol under Mitsunobu conditions, affording 6-bromo-2-((trans)-4-tert-butylcyclohexyloxy)quinoline. 6-bromo-2-((trans)-4-tert-butylcyclohexyloxy)quinoline was then exposed to n-butyllithium and DMF, providing 6-formyl-2-((trans)-4-tert-butylcyclohexyloxy)quinoline. This aldehyde was then treated with 3-aminopropionic acid and sodium cyanoborohydride to afford the title compound, 3-((2-((trans)-4-tert-butylcyclohexyloxy)quinolin-6-yl)methylamino)propanoic acid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][C:4]2([NH:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15](/[CH:18]=[CH:19]/[C:20](O)=[O:21])[CH:16]=[CH:17][C:9]=3[O:8]2)[CH2:3]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:37][O:38][CH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][O:40]1>C(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][C:4]2([NH:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15](/[CH:18]=[CH:19]/[C:20]([NH:37][O:38][CH:39]4[CH2:44][CH2:43][CH2:42][CH2:41][O:40]4)=[O:21])[CH:16]=[CH:17][C:9]=3[O:8]2)[CH2:3]1
Reactant: NOC1CCCCO1
Reactant: CN1CCCC2(C1)NC(=O)c1cc(/C=C/C(=O)O)ccc1O2
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CN1CCCC2(C1)NC(=O)c1cc(/C=C/C(=O)NOC3CCCCO3)ccc1O2
Yield: 88.6 %

Procedure:
A suspension of (±)-(E)-3-{1′-methyl-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-acrylic acid (208 mg, 0.61 mmol) in DCM (7 ml) was treated with TEA (0.14 ml, 1.0 mmol) and then with EDC (196 mg, 1.03 mmol), HOBt (140 mg, 1.03 mmol) and NH2OTHP (97 mg, 0.82 mmol) following the procedure described in Example 30, Step B, giving (±)-(E)-3-{1′-methyl-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide (217 mg) as a light yellow solid.
Reaction SMILES: C([O:8][C@@H:9]1[C@@:13]([CH2:23][O:24][S:25]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)(=[O:27])=[O:26])([CH2:14][O:15]CC2C=CC=CC=2)[O:12][C@@H:11]([N:35]2[CH:42]=[CH:41][C:39](=[O:40])[NH:38][C:36]2=[O:37])[C@@H:10]1[O:43][S:44]([C:47]1[CH:52]=[CH:51][C:50]([CH3:53])=[CH:49][CH:48]=1)(=[O:46])=[O:45])C1C=CC=CC=1>C(O)C.[OH-].[Pd+2].[OH-]>[C:50]1([CH3:53])[CH:51]=[CH:52][C:47]([S:44]([O:43][C@@H:10]2[C@H:9]([OH:8])[C@@:13]([CH2:23][O:24][S:25]([C:28]3[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=3)(=[O:26])=[O:27])([CH2:14][OH:15])[O:12][C@H:11]2[N:35]2[CH:42]=[CH:41][C:39](=[O:40])[NH:38][C:36]2=[O:37])(=[O:46])=[O:45])=[CH:48][CH:49]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@]2(COCc3ccccc3)O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](OS(=O)(=O)c3ccc(C)cc3)[C@@H]2OCc2ccccc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)OC[C@]2(CO)O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](OS(=O)(=O)c3ccc(C)cc3)[C@@H]2O)cc1
Reaction time: 48 h
Yield: 51.5 %

Procedure:
To a solution of compound 75 (0.80 g, 1.0 mmol) in absolute ethanol (2 cm3) was added 20% palladium hydroxide over carbon (0.80 g) and the mixture was degassed several times with hydrogen and stirring was continued under hydrogen for 48 h. The catalyst was filtered off and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane/methanol (99:1, v/v) as eluent to give nucleoside 76A (0.30 g, 49%) as a white solid material. δH (CD3OD) 7.67 (4H, m), 7.45 (1H, d, J 8.2 Hz), 7.34 (4H, m), 5.86 (1H, d, J 8.0 Hz), 5.40 (1H, d, J 8.1 Hz), 4.95 (1H, m), 4.35 (1H, d, J 5.0 Hz), 4.17 (2H, m), 3.61 (2H, s), 2.40 (6H, s). δC (CD3OD) 165.4, 151.6, 147.5, 146.6, 141.3, 134.0, 133.8, 131.4, 130.9, 129.2, 128.9, 103.7, 88.0, 85.4, 80.7, 72.4, 71.0. 64.3, 21.7, 21.6. FAB-MS m/z 583 [M+H]+.
Reaction SMILES: [O:1]=[C:2]([CH3:35])[CH2:3][S:4]([C:7]1[CH:8]=[C:9]([C@H:18]2[CH2:22][CH2:21][C@H:20]([C:23]3[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=3)[O:19]2)[CH:10]=[C:11]([OH:17])[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:6])=[O:5].Br[CH2:37][CH2:38][CH2:39][OH:40].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)C>[O:1]=[C:2]([CH3:35])[CH2:3][S:4]([C:7]1[CH:8]=[C:9]([C@H:18]2[CH2:22][CH2:21][C@H:20]([C:23]3[CH:24]=[C:25]([O:33][CH3:34])[C:26]([O:31][CH3:32])=[C:27]([O:29][CH3:30])[CH:28]=3)[O:19]2)[CH:10]=[C:11]([O:17][CH2:37][CH2:38][CH2:39][OH:40])[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:5])=[O:6]
Reactant: OCCCBr
Reactant: CCCOc1c(O)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCOc1c(OCCCO)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)=O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of trans-2-[3-(2-oxopropylsulfonyl)-4-propoxy-5-hydroxyphenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (30 mg, 0.059 mmol), 3-bromo-1-propanol (12 uL, 0.13 mmol) and potassium carbonate (17 mg, 0.12 mmol) in DMF (0.5 mL) was heated at 80° C. with stirring under nitrogen for 1 h. The reaction mixture was cooled and diluted with ethyl ether. It was washed with water (2x), brine, dried, filtered, and evaporated to a residue, which was purified by preparative TLC (hexane-ethyl acetate; 7:3, v/v) to give the title compound: Rf 0.3; NMR (CDCl3) δ 2.38 (s, SO2CH2COCH3), 4.15 & 4.24 (2 t, OCH2CH2), 4.48 (s, SO2CH2), 5.22 (m, H-2 & H-5).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([I:13])=[CH:7][C:6]=1[O:14][CH3:15].N1C=CN=C1.[C:21]([Si:25](Cl)([CH3:27])[CH3:26])([CH3:24])([CH3:23])[CH3:22].O>CN(C)C=O>[O:1]([CH2:2][CH2:3][O:4][C:5]1[C:6]([O:14][CH3:15])=[CH:7][C:8]([I:13])=[CH:9][C:10]=1[O:11][CH3:12])[Si:25]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:27])[CH3:26]
Reactant: COc1cc(I)cc(OC)c1OCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(I)cc(OC)c1OCCO[Si](C)(C)C(C)(C)C
Temperature: 50 °C
Reaction time: 3 h
Yield: 95.3 %

Procedure:
To a solution of 4-(2-hydroxyethoxy)-1-iodo-3,5-dimethoxybenzene (2.76 g, 8.52 mmol) synthesized by the process shown in Reference Example 5 in dimethylformamide (25 mL) were added imidazole (1.16 g, 17.0 mmol) and t-butylchlorodimethylsilane (1.61 g, 10.7 mmol), and the mixture was stirred at 50° C. for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate-hexane (1:1). The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to yield 4-[2-(t-butyldimethylsiloxy)-ethoxy]-1-iodo-3,5-dimethoxybenzene as a colorless oil (3.56 g, yield: 95%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([C:28]5[CH:29]=[N:30][C:31](F)=[CH:32][CH:33]=5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1.[CH3:35][NH:36][CH3:37]>CN1C(=O)CCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([C:28]5[CH:33]=[CH:32][C:31]([N:36]([CH3:37])[CH3:35])=[N:30][CH:29]=5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(-c4ccc(F)nc4)ccc2OCC3)c(F)c1
Reactant: CNC
Solvent: CN1CCCC1=O
Product: CN(C)c1ccc(-c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)cn1
Temperature: 150 °C
Yield: 12.2 %

Procedure:
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 (470 mg, 1.0 mmol), from the procedure for 249, Dimethyl-amine (98 mg, 1.2 mmol) DIPEA (340 mg, 3 mmol) and NMP (4 mL) were added in a 10 mL of sealed tube, and the mixture was heated by microwave at 150° C. for 120 min under N2. The reaction mixture was filtered to gather the solution and water was added. The mixture was extracted by DCM (20 mL×3). The combined organic layers were dried over Na2SO4, concentrated in vacuo, and purified by preparative HPLC to give 339 (61.4 mg, yield: 12%). 1HNMR (DMSO-d6, 400 MHz): δ8.74 (s, 1H), 8.31 (s, 1H), 8.06 (d, J=9.2 Hz, 1H), 7.91-7.87 (m, 1H), 7.73-7.71 (m, 2H), 7.42-7.40 (m, 2H), 7.19 (d, J=4.4 Hz, 1H), 7.19 (d, J=8.8 Hz, 1H), 6.77 (d, J=8.8 Hz, 1H), 4.31 (s, 2H), 3.16-3.11 (m, 8H). ESI-MS: m/z=503 [M+H+]
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:11]=2)=[CH:6][CH:5]=1)([O-])=O>O1CCCC1>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:11]=2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(-c2nc(-c3cccnc3)no2)cc1
Solvent: C1CCOC1
Product: Nc1ccc(-c2nc(-c3cccnc3)no2)cc1
Yield: 45 %

Procedure:
A solution of 5-(4-nitrophenyl)-3-(3-pyridyl)-1,2,4-oxadiazole in tetrahydrofuran is reduced according to the procedure of Example 13 to give the title compound in 45% yield.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C1C=C(Cl)C=C(C(OO)=[O:18])C=1>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[N+:4]([O-:18])[C:3]=1[C:8]#[N:9]
Reactant: Cc1cccnc1C#N
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1ccc[n+]([O-])c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Methylpyridine-2-carbonitrile (10 g, 85 mmol) was taken up in DCM (180 mL) and mCPBA (20.9 g, 93 mmol) was added. The resulting mixture was stirred at room temperature overnight. Additional mcpba (9.49 g, 42 mmol) was added and stirring continued at room temperature for 24 hours. Saturated aqueous NaHCO3 and the resulting mixture was extracted with EtOAc (3×), followed by 20% MeOH—CHCl3 (2×). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. Purification of the residue by silica gel chromatography (0-20% MeOH/EtOAc) gave the title compound as a white solid.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:15]([O-])([OH:17])=[O:16]>CC(O)=O>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(Cc2ccccc2)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(Cc2ccccc2)ccc1O
Reaction time: 3 h

Procedure:
To a solution of 4-benzylphenol (10.0 g, 54.3 mmol) in 300 mL AcOH at ambient temperature was added slowly dropwise a solution of nitric acid, red fuming (2.28 mL, 54.3 mmol) in 100 mL AcOH over 1-2 h. The reaction was allowed to stir for 3 h, poured onto ice, and the resulting solid was collected by filtration, rinsing with water to give 4-benzyl-2-nitrophenol as a yellow solid. MS (ESI) m/z: Calculated: 229.1; Observed: 227.8 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](SC)=[N:7][CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1.[CH3:23][NH:24][CH3:25]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:24]([CH3:25])[CH3:23])=[N:7][CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1
Reactant: CSC1=NCC(c2ccc([N+](=O)[O-])cc2)c2cc(Cl)ccc21
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)C1=NCC(c2ccc([N+](=O)[O-])cc2)c2cc(Cl)ccc21

Procedure:
400 mg of 6-chloro-1-methylthio-4-(4-nitrophenyl)-3,4-dihydroisoquinoline (compound 1) were heated with 20 ml of dimethylamine in THF at 120° C. in a shaking autoclave under inert gas for 20 hours. Removal of the solvent by distillation was followed by MPLC chromatography on an MPRC cartridge with a mixture of 10 parts by volume of ethyl acetate, 5 parts by volume of n-heptane, 5 parts by volume of dichloromethane, 5 parts by volume of methanol and 1 part by volume of concentrated aqueous ammonia solution. Semisolid, partly amorphous product.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.Br[CH2:14][C:15]1[CH:16]=[C:17]([CH:30]=[CH:31][CH:32]=1)[CH2:18][N:19]1C(=O)C2C(=CC=CC=2)C1=O.CN>CN(C=O)C.C(OCC)(=O)C>[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:14][C:15]1[CH:16]=[C:17]([CH:30]=[CH:31][CH:32]=1)[CH2:18][NH2:19])[CH:8]=[CH:7]2
Reactant: Fc1ccc2[nH]ccc2c1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cccc(CBr)c1
Agent: CN
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NCc1cccc(Cn2ccc3cc(F)ccc32)c1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 110.5 %

Procedure:
Sodium hydride (55% dispersion in oil, 63 mg, 1.44 mmol) was added to a solution of 5-fluoro-indol (150 mg, 1.11 mmol) in dry DMF (3 mL). The mixture was stirred under nitrogen for 15 min. 2-(3-Bromomethyl-benzyl)-isoindole-1,3-dione (403 mg, 1.22 mmol) was added and the mixture was stirred at room temperature over night. After cooling, aqueous methylamine (40%, 5 mL) was added and this mixture was heated at 80° C. over night. Ethyl acetate was added and the organic phase was washed three times with water, brine, dried and concentrated to give 312 mg of the sub-title compound sufficiently pure for the next step.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:36])=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16](CCOC)=[C:17]([O:20][CH:21]4[CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].ClC1C(F)=C(NC2C3C(=C[C:52]([OH:68])=[C:53]([O:56][CH:57]4CN(C(OC(C)(C)C)=O)C4)C=3)N=CN=2)C=CC=1F>>[NH:23]1[CH2:24][CH:21]([O:20][C:17]2[CH:18]=[C:19]3[C:14](=[CH:15][C:16]=2[O:68][CH2:52][CH2:53][O:56][CH3:57])[N:13]=[CH:12][N:11]=[C:10]3[NH:9][C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[C:3]=2[F:36])[CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cc3c(Nc4ccc(F)c(Cl)c4F)ncnc3cc2O)C1
Reactant: COCCc1cc2ncnc(Nc3ccc(F)c(Cl)c3F)c2cc1OC1CN(C(=O)OC(C)(C)C)C1
Product: COCCOc1cc2ncnc(Nc3ccc(F)c(Cl)c3F)c2cc1OC1CNC1
Yield: 100 %

Procedure:
The procedure of step 2) of Example 115 was repeated except for using the compound obtained in step 1) instead of tert-butyl 3-(4-(3-chloro-2,4-difluorophenylamino)-7-hydroxyquinazolin-6-yloxy)azetidin-1-carboxylate to obtain the title compound (37 mg, 100%).
Reaction SMILES: [C:1]1([C:7]2[NH:12][C:11]3[CH:13]=[N:14][CH:15]=[CH:16][C:10]=3[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17](Cl)(=[O:21])[CH2:18][CH2:19][CH3:20]>>[C:1]1([C:7]2[NH:12][C:11]3[CH:13]=[N:14][CH:15]=[CH:16][C:10]=3[N:9]([C:17](=[O:21])[CH2:18][CH2:19][CH3:20])[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCC(=O)Cl
Reactant: c1ccc(C2=NNc3ccncc3N2)cc1
Product: CCCC(=O)N1N=C(c2ccccc2)Nc2cnccc21
Yield: 78 %

Procedure:
3-Phenyl-1,4-dihydropyrido[3,4-e]-as-triazine is reacted with butyryl chloride as described in Example 2 to obtain 3-phenyl-1-butyryl-1,4-dihydropyrido[3,4-e]-as-triazine with a yield of 78%; m.p.: 225°-226° C.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14](Cl)=[CH:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[CH2:21][CH2:22][CH2:23][CH3:24])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[CH2:21][CH2:22][CH2:23][CH3:24])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCCCc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Reactant: C1CCNC1
Agent: Cl
Product: CCCCc1cc2c(N3CCCC3)ccnc2cc1OCc1ccccc1
Reaction time: 24 h
Yield: 101.2 %

Procedure:
A solution of 1 g (3.07 mmol) of 7-benzyloxy-6-butyl-4-chloro-quinoline hydrochloride in 2.5 ml (30.7 mmol) of pyrrolidine was heated at 60° C. with stirring under an argon atmosphere for 24 h after which time the reaction was completed according to HPLC analysis. The excess pyrrolidine was evaporated off, and the residue was partitioned between EtOAc and water. The layers were separated and the aqueous layer once extracted with AcOEt. The combined organic layers were washed with water then saturated NaCl solution, dried over magnesium sulphate and concentrated in vacuo to give 1.12 g (97.4%) of the 7-benzyloxy-6-butyl-4-pyrrolidin-1-yl-quinoline as a brown oil. ISP mass spectrum, m/e: 361.3 (M+1 calculated for C24H28N2O: 361).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].O[N:9]=[C:10]1[CH2:18][CH2:17][CH2:16][C:15]2[N:14]([CH2:19][C:20]([OH:22])=[O:21])[C:13]([CH3:23])=[CH:12][C:11]1=2.[I-].[Na+]>C(O)(=O)C.C1(C)C(C)=CC=CC=1>[C:1]([NH:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[C:13]([CH3:23])[N:14]2[CH2:19][C:20]([OH:22])=[O:21])(=[O:3])[CH3:2]
Reactant: Cc1cc2c(n1CC(=O)O)CCCC2=NO
Reactant: CC(=O)OC(C)=O
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1C
Product: CC(=O)Nc1cccc2c1cc(C)n2CC(=O)O
Temperature: 95 °C
Reaction time: 1.25 h

Procedure:
Acetic anhydride (1.0 mL, 10.6 mmol) was added to a stirred slurry of 2-[4-(hydroxyimino)-2-methyl-4,5,6,7-tetrahydro-1H-indol-1-yl]acetic acid (2.0 g, 9.0 mmol) in a mixture of acetic acid (10 mL) and xylene (10 mL) at r.t. in reaction flask 1 (mildly exothermic addition) then the mixture was held with stirring for 75 mins. Meanwhile, reaction flask 2 was charged with acetic acid (5 mL), xylene (5 mL), acetic anhydride (2.6 mL, 27.5 mmol), and sodium iodide (270 mg, 1.80 mmol) and the mixture was heated to 90-100° C. with stirring. The contents of reaction flask 1 were transferred to reaction flask 2 in aliquots over a period of 1.5 h, whilst maintaining the reaction temperature at 90-100° C. Reaction flask 1 was rinsed with a mixture of xylene (2 mL) and acetic acid (2 mL) which was transferred into reaction flask 2. Subsequently, the reaction mixture was maintained at 100° C. for a further 2.5 h and was then allowed to cool to r.t. The liquid phase was decanted off from a thick residue in the reaction flask and the residue was washed with acetic acid (5 mL) followed by xylene (5 mL). The decanted liquid and washes were combined and evaporated to dryness in vacuo to leave a dark brown residue. Analysis by HPLC and LC-MS showed 29.2 area % of a peak giving m/z 247 (MH+).
Reaction SMILES: [C:1]([C:4]1[C:5]([C:19](=O)[CH3:20])=[C:6]([CH3:18])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([CH3:17])[CH:11]=2)[C:8]=1[CH3:9])(=O)[CH3:2].[NH2:22][NH2:23]>C(O)C>[CH3:17][C:12]1[CH:11]=[C:10]([N:7]2[C:8]([CH3:9])=[C:4]3[C:5]([C:19]([CH3:20])=[N:22][N:23]=[C:1]3[CH3:2])=[C:6]2[CH3:18])[CH:15]=[CH:14][C:13]=1[OH:16]
Reactant: NN
Reactant: CC(=O)c1c(C(C)=O)c(C)n(-c2ccc(O)c(C)c2)c1C
Solvent: CCO
Product: Cc1cc(-n2c(C)c3c(C)nnc(C)c3c2C)ccc1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-[4-acetyl-1-(4-hydroxy-3-methyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone (100 mg, 0.32 mmol) in ethanol (5 mL) was added hydrazine (20 μL). After stirring at rt for 1 h, the reaction mixture was poured into ice water (25 mL). The resulting precipitate was filtered, washed with diethyl ether (20 mL), and then dried under vacuum to afford 2-methyl-4-(1,4,5,7-tetramethyl-pyrrolo[3,4-d]pyridazin-6-yl)-phenol as a pale yellow solid: 1H NMR (CD3OD, 500 MHz) δ 7.09 (d, 1H), 7.03 (s, 1H), 6.97 (d, 1H), 3.00 (s, 6H), 2.59 (s, 6H), 2.34 (s, 3H); MS (ESI) 282 (M+H)+.