Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(P(=O)(OCC)OCC)#N.[NH2:11][C:12]1[C:17]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:16][CH:15]=[CH:14][C:13]=1[S:25][CH2:26][C@@H:27]([C:36](O)=[O:37])[NH:28][O:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32].CN(C=O)C>CCOC(C)=O>[CH3:34][C:31]([CH3:32])([CH3:33])[C:30]([O:29][NH:28][C@@H:27]1[C:36](=[O:37])[NH:11][C:12]2[C:17]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:16][CH:15]=[CH:14][C:13]=2[S:25][CH2:26]1)=[O:35]
Reactant: CC(C)(C)C(=O)ON[C@@H](CSc1cccc(Oc2ccccc2)c1N)C(=O)O
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)ON[C@H]1CSc2cccc(Oc3ccccc3)c2NC1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 31.2 %

Procedure:
0.281 mL of diethyl cyanophosphonate (0.302 g, 1.85 mmol) is placed in a 25 mL three-necked flask containing 0.63 g of 59 (1.56 mmol) and 7.5 mL of DMF, at 0° C., followed by addition, after 10 minutes, of 0.21 mL of TEA (1.49 mmol). The reaction medium is stirred at 0° C. for 2 hours. 15 mL of EtOAc are added and the mixture is then washed with twice 15 mL of distilled water. The organic phase is dried over MgSO4, filtered and then evaporated to dryness. The crude product is chromatographed on a silica cartridge (120 g) with a heptane/EtOAc eluent (as an EtOAc gradient: 0 to 30%). 188 mg of expected product 60 are obtained (white solid).
Reaction SMILES: O.[NH2:2][C:3]1[N:8]=[C:7]([CH:9]2[CH2:11][CH2:10]2)[N:6]=[C:5]([C:12]([OH:14])=[O:13])[C:4]=1[Cl:15].[C:16](=O)(OC)OC.S(=O)(=O)(O)O.[OH-].[Na+]>O.CO>[NH2:2][C:3]1[N:8]=[C:7]([CH:9]2[CH2:11][CH2:10]2)[N:6]=[C:5]([C:12]([O:14][CH3:16])=[O:13])[C:4]=1[Cl:15]
Reactant: Nc1nc(C2CC2)nc(C(=O)O)c1Cl
Reactant: COC(=O)OC
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)c1nc(C2CC2)nc(N)c1Cl
Temperature: 70 °C
Yield: 92.3 %

Procedure:
A 500 mL multi-neck flask equipped with nitrogen bubbler, addition funnel, reflux condenser, and thermocouple was charged with 6-amino-5-chloro-2-cyclopropyl-4-pyrimidinecarboxylic acid monohydrate (47.8 g, 0.206 mol), methanol (32 g) and dimethyl carbonate (94.5 g, 1.05 mol). Concentrated sulfuric acid (50.0 g, 0.500 mol) was added over about 30 minutes with cooling to maintain the temperature below 60° C., and then the reaction mixture was heated at 70° C. for 10 h. The resulting mixture was cooled to 15° C. and diluted with 250 mL of water. The pH of the reaction mass was raised to 5-8 by adding about 42.7 g (0.534 mol) of 50 wt % aqueous NaOH over 30 minutes with cooling to maintain the temperature in the range of 10-15° C. The resulting slurry was cooled to 5° C. and filtered. The filtered wet cake was washed with water and dried to constant weight at 50° C. to give 43.3 g (93.5% yield) of the title compound with 98% purity as a solid melting at 147-148° C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:9]1.C[O:24][C:25](=[O:36])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH2:33][CH2:34]Cl>>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]2[CH2:22][CH2:21][N:20]([CH2:34][CH2:33][O:32][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[C:25]([OH:36])=[O:24])[CH2:19][CH2:18]2)=[CH:9]1
Reactant: c1ccc2c(c1)c(C1CCNCC1)cn2CCC1OCCO1
Reactant: COC(=O)c1ccccc1OCCCl
Product: O=C(O)c1ccccc1OCCN1CCC(c2cn(CCC3OCCO3)c3ccccc23)CC1

Procedure:
This compound was prepared following the procedure described in example 13 (part D) starting with 3 g (0.01 mol) of 1-(2-[1,3]dioxolan-2-yl-ethyl)-3-piperidin-4-yl-1H-indole and 2.8 g (0.013 mol) of 2-(2-chloro-ethoxy)-benzoic acid methyl ester. The crude mixture was purified by flash chromatography over silica gel affording 1.86 g (40% of yield) of 2-(2-{4-[1-(2-[1,3]dioxolan-2-yl-ethyl-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-benzoic acid.
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8]O)=[CH:6][CH:5]=[CH:4][N:3]=1.S(Cl)(Cl)=O.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([O-:23])=[O:22])=[CH:17][CH:16]=1.[Na+].C([O-])(=O)C.[K+]>C(O)CCC.C(Cl)(Cl)Cl>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([CH2:8][C:7]2[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: OCc1cccnc1F
Reactant: O=S([O-])c1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Solvent: CCCCO
Product: O=S(=O)(Cc1cccnc1F)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A chloroform (10 ml) solution of (2-fluoropyridin-3-yl)methanol (49 mg, 0.385 mmol) and thionyl chloride (0.14 ml, 1.93 mmol) was stirred at 50° C. for 3.5 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue thus obtained was dissolved in butanol (5 ml), followed by the addition of sodium 4-chlorobenzenesulfinate (92 mg, 0.462 mmol) and potassium acetate (76 mg, 0.770 mmol). The mixture was stirred at 70 to 80° C. for 12 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed successively with a saturated aqueous solution of sodium bicarbonate and brine, and then, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to flash chromatography on a silica gel column. The fraction obtained from the hexane:ethyl acetate (=2:1) eluate was concentrated under reduced pressure, whereby the title compound (59 mg, 54%) was obtained as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[CH2:11][CH2:10][N:9]2[C:15]([N:17]2[CH2:23][C:22]3[CH:24]=[C:25]([C:28]4[CH:33]=[CH:32][C:31]([C:34]5[N:35](C(OCC(C)C)=O)[CH:36]=[CH:37][N:38]=5)=[CH:30][CH:29]=4)[CH:26]=[CH:27][C:21]=3[O:20][CH2:19][CH2:18]2)=[O:16])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[CH2:11][CH2:10][N:9]2[C:15]([N:17]2[CH2:23][C:22]3[CH:24]=[C:25]([C:28]4[CH:33]=[CH:32][C:31]([C:34]5[NH:38][CH:37]=[CH:36][N:35]=5)=[CH:30][CH:29]=4)[CH:26]=[CH:27][C:21]=3[O:20][CH2:19][CH2:18]2)=[O:16])=[CH:4][CH:3]=1
Reactant: CC(C)COC(=O)n1ccnc1-c1ccc(-c2ccc3c(c2)CN(C(=O)N2CCC(=O)CC2c2ccc(F)cc2)CCO3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C1CCN(C(=O)N2CCOc3ccc(-c4ccc(-c5ncc[nH]5)cc4)cc3C2)C(c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
To a solution of 2-methylpropyl 2-[4-(4-{[2-(4-fluorophenyl)-4-oxopiperidin-1-yl]carbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)phenyl]-1H-imidazole-1-carboxylate (0.27 g, 0.44 mmol) in methanol (50 mL) was added potassium carbonate (0.37 g, 2.65 mmol) at 0° C. and the reaction mixture was stirred for 2 hours at room temperature. The solid was filtered off and the pH of the resulting solution was adjusted to 6-7 by addition of glacial acetic acid. The solvent was evaporated and the residue was dissolved in ethyl acetate (250 mL), washed with saturated aqueous sodium bicarbonate (2×50 mL), brine and dried over anhydrous sodium sulfate, filtered and concentrated. The precipitating product was collected by filtration, washed with hexane and dried to give 2-(4-fluorophenyl)-1-({7-[4-(1H-imidazol-2-yl)phenyl]-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl}carbonyl)piperidin-4-one (0.19 g, 86%). 1H NMR (400 MHz, d6-DMSO): 12.48 (s, 1H), 8.00 (d, 2H), 7.68 (d, 2H), 7.61 (d, 1H), 7.55 (dd, 1H), 7.31-7.26 (m, 3H), 710-6.92 (m, 4H), 5.20 (t, 1H), 4.59 (s, 2H), 4.23 (m, 2H), 3.73-3.63 (m, 3H), 3.31 (m, 1H), 2.85 (m, 2H), 2.61 (m, 1H), 2.30 (2t, 1H). MS (EI) for C30H27FN4O3: 511 (MH+).
Reaction SMILES: C([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][CH2:13][CH3:14])[CH:8]([CH3:15])[CH2:7]1)(OCC)=O>[OH-].[Na+]>[CH2:13]([NH:12][CH:9]1[CH2:10][CH2:11][NH:6][CH2:7][CH:8]1[CH3:15])[CH3:14]
Reactant: CCNC1CCN(C(=O)OCC)CC1C
Agent: [Na+]
Agent: [OH-]
Product: CCNC1CCNCC1C
Temperature: 110 °C
Reaction time: 120 h

Procedure:
1-Carbethoxy-4-ethylamino-3-methylpiperidine (2.3 g, 10.74 mmol) was suspended in 5 M NaOH solution (15 ml), stirred at 110° C. for 120 hr, cooled, extracted with ethyl acetate, dried (Na2SO4) and concentrated to dryness to afford 4-ethylamino-3-methylpiperidine. Yield 0.7 g (46%), C8H18N2, m/z 143, (M+1).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][C:13]2=[O:18])(=[O:11])=[O:10])=[C:5]([N+:19]([O-:21])=[O:20])[CH:4]=1.[CH2:22]([O:29][C:30]([NH:32][C:33]1[NH:34][C:35](=[O:46])[C:36]2[N:37]=[CH:38][N:39]([CH2:42][C:43](O)=[O:44])[C:40]=2[N:41]=1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([O:29][C:30]([NH:32][C:33]1[NH:34][C:35](=[O:46])[C:36]2[N:37]=[CH:38][N:39]([CH2:42][C:43]([N:15]3[CH2:16][CH2:17][N:12]([S:9]([C:6]4[CH:7]=[CH:8][C:3]([Cl:2])=[CH:4][C:5]=4[N+:19]([O-:21])=[O:20])(=[O:11])=[O:10])[C:13](=[O:18])[CH2:14]3)=[O:44])[C:40]=2[N:41]=1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C1CNCCN1S(=O)(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: O=C(O)Cn1cnc2c(=O)[nH]c(NC(=O)OCc3ccccc3)nc21
Agent: Cl
Product: O=C(Nc1nc2c(ncn2CC(=O)N2CCN(S(=O)(=O)c3ccc(Cl)cc3[N+](=O)[O-])C(=O)C2)c(=O)[nH]1)OCc1ccccc1
Yield: 58.5 %

Procedure:
The title compound (1.32 g, 60%) was synthesized by reaction of 1-(4-chloro-2-nitro-benzenesulfonyl)-piperazin-2-one HCl salt (1.25 g, 3.5 mmol) with [2-N-(benzyloxycarbonyl)-guanin-9-yl]-acetic acid (1.15 g, 3.5 mmol) as per the procedure of example 82. 1H NMR (DMSO-d6): δ 11.46 (s, 1H), 11.37 (s, 1H), 8.44˜8.31 (m, 2H), 8.09 (m, 1H), 7.82 (s, 0.6H), 7.78 (s, 0.4H), 7.46˜7.33 (m, 5H), 5.25 (s, 2H), 5.12 (s, 1.2H), 5.04 (s, 0.8H), 4.51 (s, 0.8H), 4.26 (s, 1.21H), 4.10˜4.00 (m, 2.4H), 3.92˜3.82 (m, 1.6H).
Reaction SMILES: [N+:1]([CH:4]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:14])([O-:3])=[O:2].[CH3:15][OH:16]>O>[CH3:15][O:16][C:12]1([CH2:4][N+:1]([O-:3])=[O:2])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:14])[O:13]1
Reactant: O=C1c2ccccc2C(=O)C1[N+](=O)[O-]
Reactant: CO
Solvent: O
Product: COC1(C[N+](=O)[O-])OC(=O)c2ccccc21
Reaction time: 8 h

Procedure:
A mixture of 2-nitroindane-1,3-dione (22.3g., 0.117 moles) and methanol (100 ml) was heated under reflux for 4 hours, cooled, poured into water (1 liter), allowed to stand overnight then filtered. The solid was extracted with 5% sodium bicarbonate solution (200 ml). The insoluble material was filtered off, dried, and recrystallised from ethanol to give the ψ-ester, 3-methoxy-3-nitromethylphthalide, m.p. 113°-114°. Acidification of the sodium bicarbonate filtrate, filtration and recrystallisation from ethanol gave the α-methyl ester, 2-methoxycarbonyl-ω-nitroacetophenone, m.p. 108°-9°.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:7]([OH:9])=[O:8])[NH2:3].[CH2:14]([O:16][C:17](=[O:26])[C:18]([C:24]#[N:25])=[C:19]=COCC)[CH3:15].C(N(CC)CC)C>C(O)C>[CH2:14]([O:16][C:17]([C:18]1[CH:19]=[N:3][N:2]([C:4]2[CH:5]=[C:6]([C:7]([OH:9])=[O:8])[CH:10]=[CH:11][C:12]=2[CH3:13])[C:24]=1[NH2:25])=[O:26])[CH3:15]
Reactant: Cc1ccc(C(=O)O)cc1NN
Reactant: CCOC=C=C(C#N)C(=O)OCC
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnn(-c2cc(C(=O)O)ccc2C)c1N
Temperature: 65 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
To a stirred solution of 3-hydrazino-4-methylbenzoic acid hydrochloride (Example 3A, 478 mg, 2.36 mmol, 1.0 eq) in 20 mL of ethanol were added ethyl(ethoxymethylene)cyanoacrylate (399 mg, 2.36 mmol, 1.0 eq) and triethylamine (329 μL, 2.36 mmol, 1.0 eq) and the mixture was heated at 65° C. for 5 hrs. After standing at room temperature overnight, additional 3-hydrazino-4-methylbenzoic acid hydrochloride (159 mg, 0.78 mmol, 0.3 eq) and triethylamine (110 μL, 0.78 mmol, 0.3 eq) and heated for 2.5. The mixture was cooled to room temperature and concentrated. The crude residue was purified by flash chromatography on silica gel (gradient elution from 7/3 hexanes/EtOAc to 1/1 to elute byproducts followed by EtOAc and 9/1 EtOAc/MeOH to elute product) to provide the product as a brown solid (464 mg, 68%). HPLC (4 minute 10-95 gradient) tR 1.87 min; MS m/z 290.1 [M+H]+; 1H NMR (CD3OD), δ 8.08 (d, J=7.0 Hz, 1H), 7.93 (s, 1H), 7.76 (s, 1H), 7.54 (d, J=8.0 Hz, 1H), 4.29 (q, J=7.1 Hz, 2H), 2.19 (s, 3H), 1.35 (d, J=7.1 Hz, 3H), ppm; 13C NMR (CD3OD), δ 166.5, 163.8, 150.4, 141.7, 139.9, 135.3, 130.8, 129.5, 128.6, 93.8, 58.8, 15.8, 12.9 ppm.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[CH:27]1([CH2:32][CH2:33][OH:34])[CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH:27]1([CH2:32][CH2:33][O:34][C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=2[C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Reactant: OCCC1CCCC1
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3OCCC3CCCC3)n2)c1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (75 mg; 0.197 mmol), intermediate 42.1, and 2-cyclopentylethanol (101 μl; 0.789 mmol), example 53 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: [C:1]1([C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][O:3]1)=[O:2].[H][H]>O1CCCC1>[C:5]1([CH2:4][OH:3])[C:10]([CH2:1][OH:2])=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: [H][H]
Reactant: O=C1OCc2ccccc21
Solvent: C1CCOC1
Product: OCc1ccccc1CO

Procedure:
Phthalide (5 mmol), a ruthenium complex 1 (0.025 mmol), and tetrahydrofuran (2 mL) were charged into a 100-mL autoclave equipped with a stirrer. Then, the mixture was subjected to hydrogenation at a hydrogen pressure of 5 MPa at 100° C. for 16 hours. The reaction liquid was analyzed by gas chromatography. As a result, 1,2-benzenedimethanol was obtained at a conversion rate of 66% and a selectivity of 99% or more.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7]([C:9]1[C:17]2[N:16]=[C:15]([NH:18][C:19]([C:21]3[CH:22]=[N:23][CH:24]=[C:25]([C:27]#[C:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:26]=3)=[O:20])[NH:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)=[O:8]>CO.C(O)(=O)C.[Pd]>[NH:3]1[CH:4]=[CH:5][N:1]=[C:2]1[NH:6][C:7]([C:9]1[C:17]2[N:16]=[C:15]([NH:18][C:19]([C:21]3[CH:22]=[N:23][CH:24]=[C:25]([CH2:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:26]=3)=[O:20])[NH:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: O=C(Nc1nc2c(C(=O)Nc3ncc[nH]3)cccc2[nH]1)c1cncc(C#Cc2ccccc2)c1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(Nc1nc2c(C(=O)Nc3ncc[nH]3)cccc2[nH]1)c1cncc(CCc2ccccc2)c1
Yield: 9.1 %

Procedure:
20 mg of (0.44 mmol) of 2-[(5-phenylethynyl-pyridine-3-carbonyl)-amino]-1H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide was dissolved in a mixture of 10 mL of CH3OH and 0.5 mL of acetic acid. To this stirring solution 10 mg of 10% Pd on carbon was added and the resulting mixture was hydrogenated (1 atm) at room temperature for 3.0 h. The reaction mixture was filtered, and the solid was washed with portions of methanol. The filtrate and washings were combined and evaporated to give 18 mg (88%) of 2-[(5-phenethyl-pyridine-3-carbonyl)-amino]-1H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide. LCMS: 452 (M+1)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:8][N:7]=1)[CH3:4].[Br:16][C:17]1[CH:18]=[CH:19][C:20]([O:25][CH2:26][C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)=[C:21]([CH:24]=1)[CH2:22]Br.[Cl-].[NH4+]>CN(C=O)C>[S:28]1[CH:29]=[CH:30][CH:31]=[C:27]1[CH2:26][O:25][C:20]1[CH:19]=[CH:18][C:17]([Br:16])=[CH:24][C:21]=1[CH2:22][N:5]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:8][N:7]=1)[CH2:3][CH3:4]
Reactant: BrCc1cc(Br)ccc1OCc1cccs1
Reactant: CCNc1ccc(C(=O)OC)cn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCN(Cc1cc(Br)ccc1OCc1cccs1)c1ccc(C(=O)OC)cn1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 8.1 %

Procedure:
A suspension of sodium hydride (50% dispersion 0.8 mmol, 38 mg) in DMF (2 ml) (sieve dried) was cooled to -5° C. and treated with methyl 2-(ethylamino)pyridine-5-carboxylate (0.145 g, 0.8 mmol). The reaction was stirred at -5° C. for 30 minutes and then treated with 5-bromo-2-(2-thienylmethoxy)benzyl bromide (0.29 g, 0.8 mmol) in DMF (0.5 ml). The reaction was allowed to warm to ambient temperature and stirred for 18 hours. The reaction was poured into saturated aqueous ammonium chloride. The combined organic extracts were washed once with brine, dried (MgSO4) and evaporated. The residue was purified by chromatography (eluant: diethyl ether/hexane) to give methyl 2-[N-(2-(2-thienylmethoxy)-5-bromobenzyl)N-ethylamino]pyridine-5-carboxylate as a colourless oil (0.03 g, 8%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([O:30][CH2:31][CH2:32]OS(C)(=O)=O)[C:6]=2[CH:38]=1.[C:39]1(=[O:49])[NH:43][C:42](=[O:44])[C:41]2=[CH:45][CH:46]=[CH:47][CH:48]=[C:40]12.[K]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([O:30][CH2:31][CH2:32][N:43]3[C:39](=[O:49])[C:40]4=[CH:48][CH:47]=[CH:46][CH:45]=[C:41]4[C:42]3=[O:44])[C:6]=2[CH:38]=1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(OCCOS(C)(=O)=O)c3cc(Cl)ccc32)cn1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(OCCN3C(=O)c4ccccc4C3=O)c3cc(Cl)ccc32)cn1
Temperature: 110 °C
Reaction time: 1 h
Yield: 66.6 %

Procedure:
To a solution of 7-chloro-5-(2-methanesulfonyloxyethoxy)-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.55 g) in dimethylformamide (10 ml) is added potassium phthalimide (0.2 g), and the mixture is stirred at 110° C. for one hour. The reaction solution is poured into ice-water, and the mixture is extracted with dichloromethane. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography to give 7-chloro-5-(2-phthalimidoethoxy)-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.4 g) as colorless amorphous.
Reaction SMILES: CO[C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[C:14]([CH2:15][O:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)=[CH:13][N:12]=[N:11]2)[CH:5]=1.N(C1C=C(C=CC=1)C(OC)=O)=[N+]=[N-].C([Si](C)(C)C#CCOC1CCCCO1)(C)(C)C.OS(O)(=O)=O.O1C=CCCC1.CC1C=CC(S(O)(=O)=O)=CC=1.O.[C:77]([O:80][C:81]([CH3:84])([CH3:83])[CH3:82])(=[O:79])[CH3:78].[Li]>CCCC[N+](CCCC)(CCCC)CCCC.[F-].Cl.CO.C(Cl)Cl>[C:81]([O:80][C:77](=[O:79])[CH2:78][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[C:14]([CH2:15][O:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)=[CH:13][N:12]=[N:11]2)[CH:5]=1)([CH3:84])([CH3:83])[CH3:82]
Reactant: CC(=O)OC(C)(C)C
Reactant: COC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Agent: C1=COCCC1
Agent: CC(C)(C)[Si](C)(C)C#CCOC1CCCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1

Procedure:
The title compound was prepared from (RS)-3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-benzoic acid methyl ester [prepared by the following sequence: i.) methyl 3-azidobenzoate [CAS-No. 93066-93-4] (15.55 g, 88 mmol) and (RS)-tert.-butyl-dimethyl-[3-(tetrahydro-pyran-2-yloxy)-prop-1-ynyl]-silane [CAS-No. 135294-85-8] (33.50 g, 132 mmol) were heated to 60° C. for 10 days; ii.) The obtained material (48.2 g, ca. 88 mmol) was stirred in TBAF (300 mL, 1M in THF) at 70° C. for 6 days and subsequently refluxed in 1N HCl (400 mL) for 2 h; iii.) The obtained material (16.15 g, 74 mmol) was stirred in MeOH (400 mL) and conc. H2SO4 (30 mL) at 23° C. for 11 days. iv.) Part of the obtained material (4.60 g, 19.7 mmol) was reacted with 3,4-dihydro-2H-pyran (2.67 mL, 29.5 mmol) and cat. amount p-TsOH.H2O in DCM (38 mL) at 23° C. for 20 h.] (6.20 g, 19.5 mmol) by treatment with lithium tert.-butyl acetate according to general procedure K (method b). Obtained as a yellow oil (8.47 g).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[N+:10]([O-])([OH:12])=[O:11]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: O=[N+]([O-])O
Reactant: O=Cc1ccc(Br)cc1
Agent: O=S(=O)(O)O
Product: O=Cc1ccc(Br)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.8 %

Procedure:
4-Bromobenzaldehyde (5.0 g, 27 mmol) was slowly added to concentrated sulfuric acid (25 mL) at 0 IC followed by dropwise addition of fuiming nitric acid (1.7 mL, 40.5 mmol) in concentrated sulfuric acid (8 mL). The reaction mixture was stirred at room temperature overnight, then poured onto ice water to provide 5.7 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=O.[CH3:11][C@@H:12]1[CH2:17][NH:16][CH2:15][C@H:14]([CH3:18])[NH:13]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH2:7][N:16]2[CH2:15][C@@H:14]([CH3:18])[NH:13][C@@H:12]([CH3:11])[CH2:17]2)[CH:9]=1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: O=Cc1cc(Br)ccc1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2cc(Br)ccc2O)C[C@H](C)N1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5-bromo-2-hydroxybenzaldehyde (1 g, 4.97 mmol) in DCM (50 mL) was added (2R,6S)-2,6-dimethylpiperazine (0.852 g, 7.46 mmol). The mixture was allowed to stir at RT for 40 min before sodium triacetoxyborohydride (1.582 g, 7.46 mmol) was added. The reaction was stirred at RT for 24 h. The mixture was diluted with DCM and washed with sat. NaHCO3 (aq), dried (MgSO4) and evaporated to give a white foam. This was purified by Biotage (eluent=2.5% 7M ammonia in methanol/DCM) to give the sub-title compound as a white solid. Yield: 1.32 g
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]C)=[CH:4][C:3]=1[C:10]1[C:34]([CH3:35])=[CH:33][C:13]2[N:14]=[C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:21][CH:20]=3)[N:16]=[N:17][C:12]=2[CH:11]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:10]1[C:34]([CH3:35])=[CH:33][C:13]2[N:14]=[C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:21][CH:20]=3)[N:16]=[N:17][C:12]=2[CH:11]=1
Reactant: COc1ccc(Cl)c(-c2cc3nnc(Nc4ccc(OCCN5CCCC5)cc4)nc3cc2C)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc2nc(Nc3ccc(OCCN4CCCC4)cc3)nnc2cc1-c1cc(O)ccc1Cl
Yield: 93 %

Procedure:
[7-(2-chloro-5-methoxy-phenyl)-6-methyl-benzo[1,2,4]triazin-3-yl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine (0.553 mmol, 1.0 equiv) was dissolved in 10 mL anhydrous DCM and stirred under an argon atmosphere. 6 mL of BBr3 (0.1 M) was added via syringe and the reaction was stirred at room temperature for 2 h. BBr3 was quenched with saturated NaHCO3 until pH=7. The mixture was filtered and washed with water and Et2O to give 4-chloro-3-{6-methyl-3-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-benzo[1,2,4]triazin-7-yl}-phenol, as a dark green solid (245.2 mg 93% yield). Rf=0.65 (9:1 DCM/MeOH) 1H NMR (DMSO-d6): δ 1.69 (m, 4H), 2.24 (s, 3H), 2.54 (m, 4H), 2.79 (t, J=5.9 Hz, 2H), 4.07 (t, J=5.9 Hz, 2H), 6.78 (d, J=2.9 Hz, 1H), 6.87 (dd, J=8.8 Hz, J=2.9 Hz, 1H), 6.95 (d, J=11.9 Hz, 2H), 7.38 (dd, J=8.8 Hz, J=3.6 Hz, 1H), 7.65 (s, 1H), 7.85 (s, J=9.1 Hz, 2H), 7.98 (s, 1H), 9.93 (s, 1H), 10.67 (s, 1H). MS (ES+): m/z=476. LC retention time 2.32 min.