Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:4]1=[O:10])[CH3:2].[H-].[Na+].[CH2:21](Br)[CH:22]=[CH2:23]>CN(C=O)C>[CH2:23]([N:5]1[CH2:6][CH2:7][CH2:8][CH2:9][C:3]([CH2:1][CH3:2])([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[C:4]1=[O:10])[CH:22]=[CH2:21]
Reactant: C=CCBr
Reactant: CCC1(c2cccc(OC)c2)CCCCNC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCN1CCCCC(CC)(c2cccc(OC)c2)C1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3-ethyl-3-(3-methoxy-phenyl)-azepan-2-one (as described in Example 8, Step A) (2.62 g, 10.6 mmol) in DMF (20 mL) at 0° C. was added NaH (0.47 g, 11.6 mmol) and the mixture was stirred for 20 min at 0° C. and 20 min at 25° C. Allyl bromide (1.1 mL, 12.7 mmol) was added. After 5 hr, additional NaH (0.12 g, 3 mmol) and allyl bromide (0.3 mL, 3.5 mmol) were added and stirring was continued for 16 hr. The reaction was quenched with H2O and the solvents removed in vacuo. The residue was partitioned between EtOAc and saturated NaHCO3 solution. The organic layer was separated, washed with brine and dried (MgSO4). Filtration and concentration gave the title compound after chromatography on silica gel with hexane and ethyl acetate 9:1.
Reaction SMILES: [CH:1]1([C:5]2[C:13]([C:14]3[NH:18][C:17]([CH2:19][CH3:20])=[N:16][N:15]=3)=[CH:12][C:8]([C:9](O)=[O:10])=[C:7]([CH2:21][CH3:22])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.[NH:45]1[CH2:50][CH2:49][CH:48]([C:51]2[CH:58]=[CH:57][C:54]([C:55]#[N:56])=[CH:53][CH:52]=2)[CH2:47][CH2:46]1>CN(C)C=O.CN(C1C=CN=CC=1)C>[CH:1]1([C:5]2[C:13]([C:14]3[NH:18][C:17]([CH2:19][CH3:20])=[N:16][N:15]=3)=[CH:12][C:8]([C:9]([N:45]3[CH2:50][CH2:49][CH:48]([C:51]4[CH:58]=[CH:57][C:54]([C:55]#[N:56])=[CH:53][CH:52]=4)[CH2:47][CH2:46]3)=[O:10])=[C:7]([CH2:21][CH3:22])[CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: CCc1nnc(-c2cc(C(=O)O)c(CC)cc2C2CCC2)[nH]1
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CCc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(CC)cc2C2CCC2)[nH]1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 40.1 %

Procedure:
To a solution of 4-cyclobutyl-2-ethyl-5-(5-ethyl-4H-1,2,4-triazol-3-yl)benzoic acid (compound 181.9, 160 mg, 0.530 mmol, 1.00 equiv) in N,N-dimethylformamide (20 mL) were added EDCI (113 mg, 0.590 mmol, 1.11 equiv), DMAP (197 mg, 1.62 mmol, 3.03 equiv), and HOBT (87.5 mg, 0.650 mmol, 1.21 equiv). After 5 min, 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 110 mg, 0.590 mmol, 1.10 equiv) was added. The resulting mixture was stirred at 25° C. for 15 h, then quenched with 100 mL of ice water. The mixture was extracted with 2×150 mL of ethyl acetate. The combined organic layers were washed with 3×150 mL of brine, dried over anhydrous sodium sulfate, and concentrated. The crude product (˜150 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (47% CH3CN up to 61% in 6 min, up to 100% in 1.5 min, down to 47% in 1.5 min); Detector, Waters 2489 254&220 nm. The fractions containing pure compound were combined and lyophilized to yield 99.5 mg (40%) of the title compound as a white solid m/z (ES+) 468 (M+H)+. 1H-NMR (300 MHz, CD3OD): δ 7.71-7.69 (m, 2H), 7.50-7.32 (m, 4H), 4.03-3.99 (m, 1H), 3.65-3.5 (m, 1H), 3.32-3.20 (m, 1H), 2.90-2.95 (m, 4H), 2.70-2.74 (m, 2H), 2.20-1.98 (m, 6H), 1.98-1.79 (m, 4H), 1.41 (t, 3H), 1.39-1.28 (m, 3H).
Reaction SMILES: Cl.Cl.NC[C@H](N1CCN(S(CC(C)C)(=O)=O)CC1)C(OC)=O.Cl.CC1C=C(COC2C=CC(S(Cl)(=O)=O)=CC=2)C2C(=CC=CC=2)N=1.[CH3:47][CH:48]([CH3:88])[CH2:49][S:50]([N:53]1[CH2:58][CH2:57][N:56]([C@@H:59]([CH2:64][NH:65][S:66]([C:69]2[CH:74]=[CH:73][C:72]([O:75][CH2:76][C:77]3[C:86]4[C:81](=[CH:82][CH:83]=[CH:84][CH:85]=4)[N:80]=[C:79]([CH3:87])[CH:78]=3)=[CH:71][CH:70]=2)(=[O:68])=[O:67])[C:60]([O:62][CH3:63])=[O:61])[CH2:55][CH2:54]1)(=[O:52])=[O:51]>>[CH3:47][C:48]([CH3:88])=[CH:49][S:50]([N:53]1[CH2:54][CH2:55][N:56]([C@@H:59]([CH2:64][NH:65][S:66]([C:69]2[CH:70]=[CH:71][C:72]([O:75][CH2:76][C:77]3[C:86]4[C:81](=[CH:82][CH:83]=[CH:84][CH:85]=4)[N:80]=[C:79]([CH3:87])[CH:78]=3)=[CH:73][CH:74]=2)(=[O:67])=[O:68])[C:60]([O:62][CH3:63])=[O:61])[CH2:57][CH2:58]1)(=[O:52])=[O:51]
Reactant: COC(=O)[C@H](CNS(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1)N1CCN(S(=O)(=O)CC(C)C)CC1
Agent: COC(=O)[C@H](CN)N1CCN(S(=O)(=O)CC(C)C)CC1
Agent: Cc1cc(COc2ccc(S(=O)(=O)Cl)cc2)c2ccccc2n1
Agent: Cl
Product: COC(=O)[C@H](CNS(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1)N1CCN(S(=O)(=O)C=C(C)C)CC1

Procedure:
In a manner analogous to example 3.6, using 621 mg (1.6 mmol) of methyl (S)-3-amino-2-[4-(2-methylpropane-1-sulfonyl)piperazin-1-yl]propanoate dihydrochloride and 876 mg (2.3 mmol) of 4-(2-methylquinolin-4-ylmethoxy)benzenesulfonyl chloride hydrochloride (prepared as described in example 17.2), 643 mg (64%) of methyl (S)-2-[4-(2-methylpropane-1-sulfonyl)piperazin-1-yl]-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propanoate are obtained in the form of an oil.
Reaction SMILES: C([O:3][C:4](=[O:34])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[NH:33][C:15]3=[N:16][C:17]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=[C:18]([C:20]4[CH:25]=[CH:24][N:23]=[CH:22][C:21]=4[F:26])[CH:19]=[C:14]3[N:13]=2)=[CH:7][CH:6]=1)C.Cl>C(O)C.[OH-].[Na+]>[F:26][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][C:20]=1[C:18]1[CH:19]=[C:14]2[N:13]=[C:12]([NH:11][C:8]3[CH:9]=[CH:10][C:5]([C:4]([OH:34])=[O:3])=[CH:6][CH:7]=3)[NH:33][C:15]2=[N:16][C:17]=1[C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1
Reactant: CCOC(=O)c1ccc(Nc2nc3cc(-c4ccncc4F)c(-c4cccnc4)nc3[nH]2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(Nc2nc3cc(-c4ccncc4F)c(-c4cccnc4)nc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.8 %

Procedure:
To a solution of 4-[6-(3-fluoro-pyridin-4-yl)-5-pyridin-3-yl-3H-imidazo[4,5-b]pyridin-2-ylamino]-benzoic acid ethyl ester (0.120 g, 0.264 mmol) in ethanol (3.5 mL), 2N sodium hydroxide aqueous solution (0.53 mL) was added. The mixture was stirred at room temperature overnight and then neutralised with 2N hydrogen chloride aqueous solution. The solvent was evaporated and the crude mixture (0.18 g) was purified by reverse phase chromatography (water/acetonitrile) to give the title compound (0.02 g, 18% of yield).
Reaction SMILES: [ClH:1].Cl.[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:35][CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[C:15]([C:26]2[CH:27]=[N:28][N:29]([CH2:31][CH2:32][O:33][CH3:34])[CH:30]=2)[CH:14]=1)[CH2:4][CH2:5][CH3:6].C=O.O.[C:45](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[ClH:1].[ClH:1].[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:35][CH:36]2[CH2:41][CH2:40][N:39]([CH3:45])[CH2:38][CH2:37]2)=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)=[C:15]([C:26]2[CH:27]=[N:28][N:29]([CH2:31][CH2:32][O:33][CH3:34])[CH:30]=2)[CH:14]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1nnc(OC2CCNCC2)cc1-c1ccc(OC2CCCCC2)c(-c2cnn(CCOC)c2)c1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)c(-c2cnn(CCOC)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 125 %

Procedure:
To a mixture of 3-butyl-4-{4-cyclohexyloxy-3-[1-(2-methoxy-ethyl)-1H-pyrazol-4-yl]-phenyl}-6-(piperidin-4-yloxy)-pyridazine dihydrochloride (0.0776 mmol, 49.9 mg) in DCM (1 mL) was added formaldehyde solution in water (37%, 0.23 mmol, 0.017 mL), and 1 drop of acetic acid. Sodium triacetoxyborohydride (0.31 mmol, 69.2 mg, 95%) was added. The reaction mixture was stirred at room temperature for 1 h and partitioned between ethyl acetate (10 mL) and saturated aq. sodium bicarbonate solution (10 mL). The ethyl acetate layer was separated and dried over sodium sulfate. The crude product was purified by column chromatography on basic alumina using 0-3% MeOH in DCM, dissolved in MeOH and treated with 4 N HCl in dioxane. The organic solvents were removed in vacuo and the residue was triturated with anhydrous diethyl ether. The yellow solid was dried overnight under high vacuum to provide the title compound (30.1 mg). LCMS: m/z 549 [M+1] 1H NMR (400 MHz, CD3OD) δ 8.24-8.27 (1H, m), 8.04-8.07 (1H, m), 7.90-7.98 (1H, m), 7.78-7.83 (1H, m), 7.37-7.43 (1H, m), 7.27-7.31 (1H, m), 5.37-5.46 (1H, m), 4.59-4.62 (1H, m), 4.38 (2H, t), 3.77 (2H, t), 3.16-3.66 (9H, m), 2.95 (3H, s), 1.25-2.59 (18H, m), 0.82 (3H, t).
Reaction SMILES: [CH:1]([Sn](CCCC)(CCCC)CCCC)=[CH2:2].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Br[C:46]1[CH:47]=[CH:48][C:49]([NH2:52])=[N:50][CH:51]=1>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:1]([C:46]1[CH:47]=[CH:48][C:49]([NH2:52])=[N:50][CH:51]=1)=[CH2:2]
Reactant: Nc1ccc(Br)cn1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=Cc1ccc(N)nc1
Yield: 74 %

Procedure:
Vinyltributyltin (13 mL, 44.6 mmol), palladium(II) acetate (0.45 g, 2.1 mmol), triethylamine (12.4 mL, 89.1 mmol) and tri-(o-tolyl)phosphine (3.69 g, 12.15 mmol) were added to a solution of 5-bromopyridin-2-amine (7.0 g, 40.5 mmol) in acetonitrile (70 mL) and the reaction mixture refluxed for 18 hours. The reaction mixture was washed with 2M sodium carbonate solution (80 mL), the organics separated, dried over magnesium sulphate, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using methanol:dichloromethane 3:97 to yield 3.6 g of product. This residue was dissolved in dichloromethane and washed with aqueous solutions of potassium fluoride and then sodium hydrogencarbonate. The organic solution was dried over magnesium sulphate, filtered and concentrated in vacuo to yield 1.9 g of final product.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.C(O[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23])C>CC#N>[N+:22]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:16]=1[NH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]1)([O-:24])=[O:23]
Reactant: CCOC(=O)N1CCC(N)CC1
Reactant: CCOc1ccncc1[N+](=O)[O-]
Solvent: CC#N
Product: CCOC(=O)N1CCC(Nc2ccncc2[N+](=O)[O-])CC1
Temperature: 25 °C

Procedure:
A mixture of ethyl 4-amino-1-piperidinecarboxylate (3.53 g, 20.5 mmol) and 4-ethoxy-3-nitropyridine (3.65 g, 21/7 mmol) in CH3CN (25 mL) was heated at reflux for 40 hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo to give an orange syrup which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][OH:33].[Cl-].[NH4+]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[O:11][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][OH:33]
Reactant: COc1ccc(OC)c(O)c1
Reactant: OCCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(OC)c(OCCCCCCCCCCCCCCO)c1
Temperature: 56 °C
Yield: 65 %

Procedure:
2,5-Dimethoxyphenol (287.1 mg) was dissolved in 30 ml of acetone, and to this solution, potassium carbonate and a solution of 14-bromotetradecan-1-ol (599.5 g) in 2 ml of acetone were added. The reaction mixture was stirred at reflux temperature (56° C.) for 24 hours, and then neutralized with saturated ammonium chloride solution. It was then extracted three times with diethyl ether. The organic layer was washed with saline solution and dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. Purification of the residue by silica gel chromatography (eluting with dichloromethane) gave 14-(2,5-dimethoxyphenoxy)tetradecan-1-ol as white crystals at a 65% yield.
Reaction SMILES: [CH:1]([C:11]([O-])=O)([C:7]([O:9]C)=[O:8])[CH2:2][CH2:3][C:4]([O-:6])=O.Br[CH:15]([CH2:20][CH2:21][CH2:22]CC)[C:16](OC)=O>>[CH2:16]([CH:11]1[C:4](=[O:6])[CH2:3][CH2:2][CH:1]1[C:7]([OH:9])=[O:8])[CH2:15][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCC(Br)C(=O)OC
Reactant: COC(=O)C(CCC(=O)[O-])C(=O)[O-]
Product: CCCCCC1C(=O)CCC1C(=O)O
Yield: 38.4 %

Procedure:
By repeating the procedure described in Example 1 (a) but starting from 195 g of methyl propane-1,1,3-tricarboxylate (F. L. M. Pattison, R. L. Buchanan and F. H. Dean, Can. J. Chem. 43(6), 1700 (1965)) and 176 g of methyl α-bromoheptanoate (H. Reinheckel, Ber. 93, 2222 (1960)), there is obtained 60 g (41%) of 2-n-pentyl-3-oxo-cyclopentanecarboxylic acid, melting at 52°C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.CO.OS(O)(=O)=O.[C:22]([O-])(O)=O.[Na+]>O>[OH:1][C:2]1[C:11]2[C:6](=[C:7]([C:12]([O:14][CH3:22])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: O=C([O-])O
Reactant: O=C(O)c1cccc2c(O)ncnc12
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cccc2c(O)ncnc12
Temperature: 50 °C

Procedure:
A 1 L round bottom flask was charged with 4-hydroxyquinazoline-8-carboxylic acid (A), MeOH (300 mL), and H2SO4 (10 mL). The reaction was heated to 50° C. for 2 days. Upon cooling to room temperature, the reaction mixture was neutralized with NaHCO3 and diluted with water. The methanol was removed in vacuo, and the precipitate was collected, washed with water and heptanes, then dried to give methyl 4-hydroxyquinazoline-8-carboxylate (18.3 g, 65%, over 2 steps combining both isomers from A and B).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].[Cl:12]OC(C)(C)C>C(Cl)Cl.C(O)(=O)C>[Cl:12][C:10]1[CH:9]=[C:5]([C:6]([OH:8])=[O:7])[C:4]([NH2:11])=[CH:3][C:2]=1[F:1]
Reactant: CC(C)(C)OCl
Reactant: Nc1cc(F)ccc1C(=O)O
Solvent: ClCCl
Solvent: CC(=O)O
Product: Nc1cc(F)c(Cl)cc1C(=O)O
Reaction time: 1.5 h
Yield: 111.2 %

Procedure:
To a solution of 4-fluoroanthranilic acid (0.882 g, 5.69 mmol) in methylene chloride (50 ML) and acetic acid (10 mL) is added tert-butyl hypochlorite (0.71 mL, 6.25 mmol) solution in dichloromethane (1 mL) dropwise over 1 minute. After 90 minutes, the reaction mixture is washed with water and brine. The organic layer is dried over MgSO4, filtered, and the filtrate concentrated to afford 5-chloro-4-fluoroanthranilic acid (1.20 g). MS CI: m/e 188 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14]S(C2C=CC=CC=2)(=O)=O)=[C:6]([CH:13]=1)/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10].Cl[CH2:25][C:26]([C:28]1[N:29](COCC[Si](C)(C)C)[CH:30]=[CH:31][N:32]=1)=[O:27]>>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:7]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:13]=2)[NH:14][C:25]=1[C:26]([C:28]1[NH:29][CH:30]=[CH:31][N:32]=1)=[O:27]
Reactant: C[Si](C)(C)CCOCn1ccnc1C(=O)CCl
Reactant: COC(=O)/C=C/c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Product: COC(=O)Cc1c(C(=O)c2ncc[nH]2)[nH]c2ccc(Cl)cc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate (Example 36, step 3) and 2-chloroacetyl-l-[2-(trimethylsilyl)ethoxymethyl]imidazole.*
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:18])=[CH:4][C:5]2[C:6]3[CH:15](O)[O:14][C:13](=O)[C:7]=3[C:8]([OH:12])=[N:9][C:10]=2[CH:11]=1.O.[NH2:20][NH2:21]>CS(C)=O>[Cl:1][C:2]1[C:3]([Cl:18])=[CH:4][C:5]2[C:6]3[CH:15]=[N:21][NH:20][C:13](=[O:14])[C:7]=3[C:8]([OH:12])=[N:9][C:10]=2[CH:11]=1
Reactant: O=C1OC(O)c2c1c(O)nc1cc(Cl)c(Cl)cc21
Reactant: NN
Solvent: O
Solvent: CS(C)=O
Product: O=c1[nH]ncc2c1c(O)nc1cc(Cl)c(Cl)cc12
Temperature: 25 °C
Reaction time: 42 h

Procedure:
1.76 g (0.0062 mol) of (RS)-7,8-dichloro-1,4-dihydroxy-1,3-dihydro-furo[3,4-c]quinolin-3-one were dissolved in 18 ml of dimethyl sulphoxide while gassing with argon. 0.31 g (0.0062 mol) of hydrazine hydrate was added thereto and the mixture was stirred at room temperature for 42 hrs. The suspension obtained was suction filtered and rinsed with ethyl acetate. Yield: 0.32 g (18%) of 8,9-dichloro-5-hydroxy-3,4-dihydro-pyridazino[4,5-c]quinolin-4-one as yellow crystals; m.p. >350° C.
Reaction SMILES: COC1C=CC(C([NH:18][C:19]2[N:27]=[C:26]([Cl:28])[N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][N:23]3[C@@H:29]2[CH2:33][C@H:32]([N:34](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[C@@H:31]([OH:49])[C@H:30]2[OH:50])C2C=CC(OC)=CC=2)=CC=1.[C:51]([OH:57])([C:53]([F:56])([F:55])[F:54])=[O:52]>ClCCl>[F:54][C:53]([F:56])([F:55])[C:51]([OH:57])=[O:52].[NH2:34][C@H:32]1[CH2:33][C@@H:29]([N:23]2[CH:22]=[N:21][C:20]3[C:24]2=[N:25][C:26]([Cl:28])=[N:27][C:19]=3[NH2:18])[C@H:30]([OH:50])[C@@H:31]1[OH:49]
Reactant: COc1ccc(C(Nc2nc(Cl)nc3c2ncn3[C@@H]2C[C@H](N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)[C@@H](O)[C@H]2O)c2ccc(OC)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nc(Cl)nc2c1ncn2[C@@H]1C[C@H](N)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(1R,2S,3R,5S)-3-(6-{[Bis-(4-methoxy-phenyl)-methyl]-amino}-2-chloro-purin-9-yl)-5-(di-Boc-amino)-cyclopentane-1,2-diol (600 mg, 0.84 mmol) is dissolved in dichloromethane (4 ml). TFA (2 ml) is added and the reaction mixture is stirred at room temperature. The reaction is shown to be complete by LCMS after 18 hours. The solvent is removed in vacuo and the title compound is obtained after purification by reverse phase column chromatography (Isolute™ C18, 0-100% acetonitrile in water—0.1% TFA). 1H nmr (MeOD, 400 MHz); 8.10(s, 1H), 4.80(m, 1H), 4.60(m, 1H), 4.30(m, 1H), 3.60(m, 1H), 2.85(m, 1H), 2.30(m, 1H). MS (ES+) m/e 285 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12][CH2:13][C:14]([F:19])([F:18])[CH:15]([F:17])[F:16])=[C:10]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+]>C1COCC1.O>[Cl:1][C:2]1[C:11]([O:12][CH2:13][C:14]([F:19])([F:18])[CH:15]([F:16])[F:17])=[C:10]([S:20]([CH2:23][CH3:24])(=[O:21])=[O:22])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCS(=O)(=O)c1ccc(C(=O)OC)c(Cl)c1OCC(F)(F)C(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1OCC(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1.600 g (4.07 mmol) of methyl 2-chloro-3-(2,2,3,3-tetrafluoropropyloxy)-4-ethylsulfonylbenzoate were dissolved in a mixture of 20 ml of THF and 20 ml of water, and with 0.218 g (5.50 mmol) of sodium hydroxide was added. The mixture was stirred at RT for 12 h and concentrated. The residue was taken up in water and admixed with 6 N HCl. The precipitate was filtered off with suction and dried. This gave 2-chloro-3-(2,2,3,3-tetrafluoropropyloxy)-4-ethylsulfonylbenzoic acid in the form of a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[C:9]1[CH:10]=[C:11]([C:15](=[O:26])[CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:12]=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B(Cl)([C@@H]1[C@@H](C)[C@H]2C(C)(C)[C@H](C2)C1)[C@@H]1[C@@H](C)[C@H]2C(C)(C)[C@H](C2)C1>C1COCC1>[C:1]([O:5][C:6]([N:8]([CH2:27][CH:28]1[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1)[C:9]1[CH:10]=[C:11]([C@H:15]([OH:26])[CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:24])[CH3:22])[CH:12]=[CH:13][CH:14]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCCC(=O)c1cccc(N(CC2CCCCC2)C(=O)OC(C)(C)C)c1
Agent: C[C@@H]1[C@@H](B(Cl)[C@H]2C[C@H]3C[C@@H]([C@@H]2C)C3(C)C)C[C@H]2C[C@@H]1C2(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(N(CC2CCCCC2)C(=O)OC(C)(C)C)c1
Temperature: 25 °C

Procedure:
A mixture of tert-butyl 3-(3-(tert-butoxycarbonyl(cyclohexylmethyl)amino)phenyl)-3-oxopropylcarbamate and (+)-Ipc2BCl in anhydrous THF is stirred at room temperature until no starting material is seen by TLC. The reaction is then quenched with aqueous NH4Cl and stirred at room temperature. Extraction with EtOAc and drying over anhydrous MgSO4 followed by flash chromatography (EtOAc—hexanes gradient) gives tert-butyl (R)-3-(3-(tert-butoxycarbonyl(cyclohexylmethyl)amino)phenyl)-3-hydroxypropylcarbamate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][C:16]1([OH:22])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O>[Pt].C(#N)C>[NH2:1][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][C:16]1([OH:22])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: O=[N+]([O-])c1cnc2ccccc2c1NCC1(O)CCOCC1
Agent: [Pt]
Solvent: CC#N
Product: Nc1cnc2ccccc2c1NCC1(O)CCOCC1
Yield: 93.6 %

Procedure:
A mixture of 4-{[(3-nitroquinolin-4-yl)amino]methyl}tetrahydro-2H-pyran-4-ol (9.00 g, 29.7 mmol) and 5% platinum on carbon (0.90 g) in acetonitrile (180 mL) was hydrogenated according to the method described in Part D of Example 9 to yield 4-{[(3-aminoquinolin-4-yl)amino]methyl}tetrahydro-2H-pyran-4-ol as a brown solid (7.60 g, 94%).
Reaction SMILES: Cl.[CH3:2][NH2:3].C(=O)([O-])[O-].[K+].[K+].C(=O)=O.[F:13][C:14]1[CH:19]=[C:18]([Cl:20])[C:17]([O:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:16][C:15]=1[N:27]1[C:31](=[O:32])[C:30]2[CH2:33][CH2:34][CH2:35][CH2:36][C:29]=2[C:28]1=[O:37]>C(#N)C>[F:13][C:14]1[CH:19]=[C:18]([Cl:20])[C:17]([O:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:16][C:15]=1[NH:27][C:28](=[O:37])[C:29]1[CH2:36][CH2:35][CH2:34][CH2:33][C:30]=1[C:31]([NH:3][CH3:2])=[O:32]
Reactant: CN
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=C=O
Solvent: CC#N
Product: CNC(=O)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1
Temperature: 25 °C
Yield: 74.9 %

Procedure:
Methylamine hydrochloride (1.70 g, 24.8 mmol) and potassium carbonate (1.70 g, 12.3 mmol), and acetonitrile (5 ml) as a solvent were placed into a round bottom flask (100 cc), followed by stirring at room temperature. After confirming the generation of carbon dioxide gas, N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (5.88 g, 16.2 mmol) was added thereto, followed by stirring at room temperature for 4 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-methyl-3,4,5,6-tetrahydrophthalamide as white crystals (4.79 g, 74.9% yield).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[CH:14]=[N:15][C:16]([C:17]([O:19]CC)=[O:18])=[C:12]3[CH2:11][N:10]([CH3:22])[C:9](=[O:23])[C:8]=2[CH:24]=1>C(O)C.O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[CH:14]=[N:15][C:16]([C:17]([OH:19])=[O:18])=[C:12]3[CH2:11][N:10]([CH3:22])[C:9](=[O:23])[C:8]=2[CH:24]=1
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1cc(Cl)ccc1-2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN1Cc2c(C(=O)O)ncn2-c2ccc(Cl)cc2C1=O
Yield: 74.6 %

Procedure:
5.4 ml of 5N sodium hydroxide solution were added dropwise to a suspension of 6.9 g (21.6 mmol) of ethyl 8-chloro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate in 5 ml of ethanol and 7 ml of water and the mixture was heated to reflux for 30 minutes. The solution was filtered while hot, concentrated to about 6 ml and acidified with 5.5 ml 5N hydrochloric acid. The product was filtered off under suction. There were obtained 4.7 g (75%) of 8-chloro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo [1,5-a][1,4]benzodiazepine-3-carboxylic acid as colourless crystals of m.p. 263°-267° (dec.).