Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:25]1([S:31](Cl)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(OCC)(=O)C.N1C=CC=CC=1>[C:25]1([S:31]([NH:1][C:2]2[CH:3]=[C:4]([O:16][C:17](=[O:24])[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:5]=[CH:6][C:7]=2[O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Nc1cc(OC(=O)c2ccccc2)ccc1OCc1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(Oc1ccc(OCc2ccccc2)c(NS(=O)(=O)c2ccccc2)c1)c1ccccc1
Temperature: 0 °C
Yield: 54.7 %

Procedure:
To a stirred solution of benzoic acid 3-amino-4-benzyloxy-phenyl ester (5.91 g, 18.5 mmol) (which was obtained in Example 16) in ethyl acetate (100 mL) and pyridine (20 mL) at 0° C. was added dropwise phenyl sulfonyl chloride (3.26 g, 18.5 mmol) in 50 mL of ethyl acetate. After one hour at 0° C. the mixture was warmed to room temperature and stirred at room temperature over night. The reaction mixture was washed with water and the organic layer was dried (MgSO4) and concentrated. Recrystallization from CH2Cl2/hexanes gave the title compound as a white solid (4.65 g, 61%); 1H NMR (300 MHz, CDCl3) δ 4.93 (s, 2H), 6.90-7.80 (m, 15H), 8.12 (d, J=8.5 Hz, 2H), 9.81 (s, 1H); MS (ES) m/z: 458.9 (MH+, 100%); HRMS Calcd. for C26H22NO5S(MH+): 459.1141. Found: 459.1151.
Reaction SMILES: [OH:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C:5]3=O)[CH2:3]1)[CH2:9]2.Cl.[NH2:14][OH:15]>CCO.[OH-].[Na+]>[OH:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C:5]3=[N:14][OH:15])[CH2:3]1)[CH2:9]2
Reactant: O=C1C2CC3CC1CC(O)(C3)C2
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: ON=C1C2CC3CC1CC(O)(C3)C2
Temperature: 100 °C
Yield: 70.5 %

Procedure:
5-Hydroxyadmantan-2-one (TCI America, Portland, Oreg.; 3 g, 18.0 mmol) was dissolved in EtOH (20 mL) and the solution was added to a solution of hydroxylamine hydrochloride (12 g, 172.7 mmol) in 1N NaOH (16 mL). The mixture was heated at 100° C. for 1 hour. The EtOH was evaporated, and water and DCM were added. The separated aqueous layer was further extracted twice with DCM. The combined DCM layers were evaporated under vacuum. Crystallization from EtOAc gave 5-hydroxy-adamantan-2-one oxime (2.3 g, 71%).
Reaction SMILES: C[O-].[Na+].[Br:4][C:5]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:6]=1[CH:7]=O.[N:14]([CH2:17][C:18]([O:20][CH3:21])=[O:19])=[N+]=[N-]>CO>[CH3:21][O:20][C:18]([C:17]1[NH:14][C:9]2[C:6]([CH:7]=1)=[C:5]([Br:4])[CH:12]=[C:11]([F:13])[CH:10]=2)=[O:19]
Reactant: COC(=O)CN=[N+]=[N-]
Reactant: O=Cc1ccc(F)cc1Br
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc2c(Br)cc(F)cc2[nH]1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 68.2 %

Procedure:
Dry methanol (5 ml) and NaOMe (0.9 ml, 3.93 mmol, 25% wt in MeOH) were added to a three-neck flask equipped with stirrer, low-temperature thermometer, and nitrogen line. The resulting solution was cooled in a dry ice/CH3CN bath to −40° C. A solution of 2-bromo-4-fluoro-benzaldehyde (195 mg, 0.96 mmol) and methyl azidoacetate (450 mg, 3.9 mmol) in dry MeOH (5 ml) was added dropwise. The mixture was allowed to stir at −40° C. for 30 minutes before warming up to room temperature. After stirring another 3 hours, the reaction solvent was removed under reduced pressure. The residue was added to xylene (15 ml), and the organic phase was washed with H2O, brine, followed by drying over MgSO4. The resulting solution was added dropwise to a flask of xylene (30 ml) and the solution was heated at reflux overnight. After cooling to room temperature, the reaction mixture was washed with H2O, and xylene was removed under reduced pressure to give 4-bromo-6-fluoro-1H-indole-2-carboxylic acid methyl ester as a white solid (178 mg, 68%). MS: 272.1 (M−H)−.
Reaction SMILES: [Na].[CH:2]([C:5]1[CH:6]=[N:7][NH:8][C:9]=1[NH2:10])([CH3:4])[CH3:3].[C:11](OCC)(=[O:18])[CH2:12][C:13](OCC)=[O:14]>CCO>[CH:2]([C:5]1[CH:6]=[N:7][N:8]2[C:13]([OH:14])=[CH:12][C:11]([OH:18])=[N:10][C:9]=12)([CH3:4])[CH3:3]
Reactant: CC(C)c1cn[nH]c1N
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CC(C)c1cnn2c(O)cc(O)nc12
Temperature: 25 °C

Procedure:
Sodium (1.58 g, 68.7 mmol) was dissolved in EtOH (250 mL) and to this solution was added 4-isopropyl-1H-pyrazol-5-amine (7.17 g, 57 mmol) and diethyl malonate (10.2 mL, 63 mmol). The solution was heated under reflux for 16 h, cooled to rt and concentrated in vacuo. The residue was dissolved in water (60 mL) and acidified to pH=3 with 2 M HCl and the formed precipitate collected by filtration. 3-Isopropyl-5,7-dihydroxypyrazolo[1,5-α]pyrimidine was obtained as an off-white solid (8.10 g, 35% over three steps). M.p. 242-243° C. (ethanol).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13][CH2:12]1>>[NH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:11]2[CH2:12][CH2:13][CH:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:15][CH2:16]2)[CH:7]=1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Product: CC(C)(C)OC(=O)NC1CCN(c2cc(N)ccn2)CC1
Yield: 33.1 %

Procedure:
Following General procedure H, 2-chloro-4-nitropyridine (500 mg, 3.1 mmol) was reacted with tert-butyl piperidin-4-ylcarbamate (695 mg, 3.5 mmol) followed by reduction to afford the desired product (300 mg, 33%) as a purple solid: ESI MS m/z 293 [C15H24N4O2+H]+.
Reaction SMILES: Cl[C:2]1[C:3]([F:23])=[CH:4][C:5]2[C:6]([CH:22]=1)=[N:7][C:8]1[N:9]([CH2:19][CH2:20][F:21])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>N1C=CC=CC=1>[F:23][C:3]1[C:2]([N:28]2[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]2)=[CH:22][C:6]2=[N:7][C:8]3[N:9]([CH2:19][CH2:20][F:21])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=3[CH:14]=[C:5]2[CH:4]=1
Reactant: O=C(O)c1cn(CCF)c2nc3cc(Cl)c(F)cc3cc2c1=O
Reactant: CN1CCNCC1
Solvent: c1ccncc1
Product: CN1CCN(c2cc3nc4c(cc3cc2F)c(=O)c(C(=O)O)cn4CCF)CC1
Yield: 42.1 %

Procedure:
A suspension of 1.2 g of 8-chloro-7-fluoro-1-(2-fluoroethyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid in 12 cm3 of pyridine and 3.52 g of 1-methylpiperazine is heated, with stirring, at a temperature close to 110° C. for 6 hours. After treatment under the conditions described in Reference Example 3, 0.6 g of 7-fluoro-1-(2-fluoroethyl)-8-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid is obtained in the form of a yellow solid melting at 306°-308° C.
Reaction SMILES: [N+:1]([CH:4]([CH2:13]C)[CH:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[OH:6])([O-])=O>C(O)C.[Ni]>[NH2:1][CH:4]([CH3:13])[CH:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[OH:6]
Reactant: CCC(C(O)c1cccnc1)[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: CC(N)C(O)c1cccnc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-nitro-1-pyridin-3-yl-butan-1-ol (3.20 g, 17.6 mmol) in ethanol (90 mL) was purged with argon, and 200 mg of Raney-Nickel was added at room temperature. The reaction mixture was three times evacuated and refilled with hydrogen. The reaction was stirred for 16 hours under H2 at room temperature. Raney-Nickel was then filtered over Hyflo, and the Hyflo washed with EtOH. The filtrate was then concentrated in order to give 2-amino-1-pyridin-3-yl-propan-1-ol as a product (2.35 g, 88%), which was used in the next reaction step without purification. To a solution of 2-amino-1-pyridin-3-yl-propan-1-ol (700 mg, 4.60 mmol) in CH2Cl2 (20 mL) was added under argon Et3N (1.60 mL, 11.5 mmol) at 0° C., followed by triphosgene (819 mg, 2.76 mmol, dissolved in 5 mL of CH2Cl2). The reaction temperature was allowed to warm from 0° C. to room temperature within one hour. The reaction mixture was then quenched with ice cold water and a 2 M solution of Na2CO3, extracted with CH2Cl2, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography using EtOAc in hexane from 0% to 100% in order to give the product (160 mg, 20%). LC-MS: [M+H] 179.1; Rt 0.31 min; (LCMS method 1).
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([C:13]([CH3:43])([CH3:42])[C:14]([N:16]([CH3:41])[C:17]2[C:18]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH3:40])=[CH:19][C:20]([N:23]3[CH2:27][C:26](=[O:28])[CH2:25][C@H:24]3[CH2:29][O:30]C(=O)C)=[N:21][CH:22]=2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C[O-].[Na+]>CO.O.[Cl-].[Na+].O>[F:45][C:2]([F:1])([F:44])[C:3]1[CH:4]=[C:5]([C:13]([CH3:42])([CH3:43])[C:14]([N:16]([C:17]2[CH:22]=[N:21][C:20]([N:23]3[CH2:27][C:26](=[O:28])[CH2:25][C@H:24]3[CH2:29][OH:30])=[CH:19][C:18]=2[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[CH3:40])[CH3:41])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: CC(=O)OC[C@@H]1CC(=O)CN1c1cc(-c2ccccc2C)c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1ccccc1-c1cc(N2CC(=O)C[C@H]2CO)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 23.3 %

Procedure:
A solution of 60 mg (0.094 mmol) (S)-acetic acid 1-(5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4-o-tolyl-pyridin-2-yl)-4-oxo-pyrrolidin-2-ylmethyl ester and a catalytic amount of sodium methylate in 2 ml methanol was stirred at room temperature for 30 min. The reaction mixture was diluted with water and brine and extracted with three portions of dichloromethane. The combined organic extracts were dried over sodium sulfate and concentrated in vacuo. Flash column chromatography gave 13 mg (23%) of the title compound as a light brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[NH:14][C:13]4[CH2:15][CH2:16][NH:17][CH2:18][C:12]=4[C:7]=3[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:19]1([N:25]=[C:26]=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[NH:14][C:13]4[CH2:15][CH2:16][N:17]([C:26]([NH:25][C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)=[O:27])[CH2:18][C:12]=4[C:7]=3[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccccc1
Reactant: Clc1ccc2c(c1)ncc1c3c([nH]c12)CCNC3
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1)N1CCc2[nH]c3c(cnc4cc(Cl)ccc43)c2C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 68 %

Procedure:
A mixture of 0.35 g (1.4 mmol) of 3-chloro-8,9,10,11-tetrahydro-7H-pyrido[3',4':4,5]pyrrolo[3,2-c]quinoline 0.185 (1.6 mmol) of phenylisocyanate and 10 ml of tetrahydrofuran is stirred at room temperature for 3 days. The reaction mixture is filtered and the solid collected is triturated in ether to yield 0.35 g (68%) of the title compound as an off white solid: m.p.>260° C.; m/e 299.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[NH:12][C:11](=[O:13])[NH:10][C:9](=[O:14])[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:15]Br>C(O)(=O)C>[Br:15][C:8]1[C:9](=[O:14])[NH:10][C:11](=[O:13])[NH:12][C:7]=1[CH2:6][N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=c1cc(CN2CCCC2)[nH]c(=O)[nH]1
Reactant: BrBr
Solvent: CC(=O)O
Product: O=c1[nH]c(CN2CCCC2)c(Br)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 39.9 %

Procedure:
To a solution of 1.0 g of the 6-(1-pyrrolidinylmethyl)uracil, which had been obtained in Referential Example 7, in acetic acid (10 ml), 1.0 g of bromine was added dropwise, followed by stirring at room temperature for 20 hours. A crystallized matter was collected by filtration and then washed with methanol, whereby 560 mg of the title compound were obtained (yield: 40%). The melting point and NMR spectrum of the thus-obtained compound were in full conformity with those of Compound 2 synthesized by Process A in Example 2.
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[NH2:3].C(O)(=O)C.[CH:14]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=[CH:18][CH:17]=1)=O>C(O)C>[CH3:1][N:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[N:3]=[CH:14][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=[CH:18][CH:17]=1
Reactant: O=Cc1ccnc2ccccc12
Reactant: CN(N)c1ccccc1
Solvent: CCO
Solvent: CC(=O)O
Product: CN(N=Cc1ccnc2ccccc12)c1ccccc1
Temperature: 0 °C

Procedure:
One equivalent of methylphenylhydrazine (4.1 g; 0.033 mol, compound 2 was diluted in 25 ml of ethanol and 0.5 ml of glacial acetic acid in a three-necked flask on which was mounted a condenser. The reaction medium was then stirred at 0° C. 1 equivalent of 4-formylquinoline (5.28 g; 0.033 mol, compound 14) was added by spatula. After adding the aldehyde, the reaction medium was heated at 70° C. (oil bath temperature) for 4 hours.
Reaction SMILES: [C:1]([NH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24].Cl>C(Cl)Cl>[C:4]([O:3][C:1]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:11][CH2:10]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
4-(N—BOC amino) piperidine (17 kg, 84.88 mol) was dissolved in DCM (90 kg), triethylamine (10.14 kg, 100.16 mol) was added, and the resulting solution was cooled to 0-5° C. Benzyl chloroformate (16.51 kg, 96.76 mol) was added over 45 minutes while keeping the temperature at <25° C., after which the solution was aged for 30 minutes at 20° C. 2 M HCl (61 kg, 118.13 mol) was then added over 10 minutes while keeping the temperature at <25° C. The mixture was agitated for 10 minutes and then the agitation was stopped and the phases were allowed to separate. The phases were then separated from each other, and the organic phase was distilled in vacuo to a volume of 35 L. Isopropyl acetate (89 kg) was then added, and the batch was concentrated by vacuum distillation at less than 35° C. to a volume of 50 L to crystallize the title product. Heptane (47 kg) was then added over 10 minutes, and the resulting slurry cooled to and aged at 20° C. for 20 minutes, after which the aged slurry was filtered, washed with heptane (17 kg), and dried by N2 sweep on the filter to give the title product as a white solid (24.7 kg, 87%). 1H NMR (CDCl3) 7.33 (5H, m), 5.13 (2H, s), 4.47 (1H, m), 4.11 (2H, m), 3.61 (1H, m), 2.93 (2H, m), 1.94 (2H, m), 1.45 (9H, s) and 1.30 (2H, m).
Reaction SMILES: C(=O)(O)[O-].[Na+].[C:6]1([C:12]2([C:19]3[CH:28]=[C:27]([O:29][CH2:30][C:31]4[CH:40]=[CH:39][C:38]5[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=5)[N:32]=4)[CH:26]=[CH:25][C:20]=3[C:21]([NH:23][NH2:24])=[O:22])[CH2:17][CH:16]3[CH2:18][CH:13]2[CH2:14][CH2:15]3)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[N:41]#[C:42]Br>O.O1CCOCC1>[C:6]1([C:12]2([C:19]3[CH:28]=[C:27]([O:29][CH2:30][C:31]4[CH:40]=[CH:39][C:38]5[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=5)[N:32]=4)[CH:26]=[CH:25][C:20]=3[C:21]3[O:22][C:42]([NH2:41])=[N:24][N:23]=3)[CH2:17][CH:16]3[CH2:18][CH:13]2[CH2:14][CH2:15]3)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: N#CBr
Reactant: NNC(=O)c1ccc(OCc2ccc3ccccc3n2)cc1C1(c2ccccc2)CC2CCC1C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1nnc(-c2ccc(OCc3ccc4ccccc4n3)cc2C2(c3ccccc3)CC3CCC2C3)o1
Reaction time: 0.75 h

Procedure:
A solution of sodium bicarbonate (10.0 mg, 0.12 mmol) in water (267 μL) was added dropwise via syringe to a stirred solution of 4d (0.108 mmol) in dioxane (1.0 mL) at room temperature. A suspension of cyanogen bromide (13.0 mg, 0.12 mmol) in dioxane (120 μL) was added in 4 equal portions at 1 minute intervals. After approximately 45 min, the reaction mixture was poured into saturated aqueous sodium bicarbonate and extracted three times with methylene chloride. The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by preparative reversed phase HPLC on YMC Pack Pro C18 stationary phase (gradient elution; 0-75% acetonitrile/water as eluent, 0.1% TiFA as modifier). Lyophilization of the purified fractions afforded the title compound 5b, m/z (ES) 489 (MH)+.
Reaction SMILES: O[C:2]1[N:3]=[CH:4][N:5]=[C:6]2[C:13]=1[C:12]1[C@H:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10][CH2:9][C:8]=1[S:7]2.P(Cl)(Cl)([Cl:22])=O>O1CCOCC1>[Cl:22][C:2]1[N:3]=[CH:4][N:5]=[C:6]2[C:13]=1[C:12]1[C@H:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10][CH2:9][C:8]=1[S:7]2
Reactant: CCOC(=O)C[C@@H]1CCc2sc3ncnc(O)c3c21
Reactant: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: CCOC(=O)C[C@@H]1CCc2sc3ncnc(Cl)c3c21
Temperature: 110 °C
Reaction time: 4 h
Yield: 92 %

Procedure:
To a 50-mL round-bottom flask was added ethyl 2-[(3S)-12-hydroxy-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]acetate (16.2, 560 mg, 2.01 mmol, 1.00 equiv), dioxane (10 mL) and phosphoroyl trichloride (3.5 mL). The reaction was stirred for 4 h at 110° C. under nitrogen. After concentration under reduced pressure, the resulting solution was poured dropwise into saturated aqueous NaHCO3 and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine and dried over sodium sulfate. After evaporation in vacuo, the residue was purified by column chromatography on silica gel with ethyl acetate/petroleum ether (1:7) to afford ethyl 2-[(3S)-12-chloro-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]acetate (16.3, 550 mg, 92%) as a yellow oil.
Reaction SMILES: [Na].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:26]=[CH:25][CH:24]=[CH:23][C:12]=3[C:13]=2[C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[CH2:27]([N:29]([CH2:34][CH3:35])[CH2:30][CH2:31][CH2:32]Cl)[CH3:28]>C1(C)C=CC=CC=1.CO>[CH2:27]([N:29]([CH2:34][CH3:35])[CH2:30][CH2:31][CH2:32][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:10][C:11]3[CH:26]=[CH:25][CH:24]=[CH:23][C:12]=3[C:13]=2[C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:7][CH:8]=1)[CH3:28]
Reactant: Cc1ccc(C(=O)c2c(-c3ccc(O)cc3)oc3ccccc23)cc1
Reactant: CCN(CC)CCCCl
Agent: [Na]
Solvent: CO
Solvent: Cc1ccccc1
Product: CCN(CC)CCCOc1ccc(-c2oc3ccccc3c2C(=O)c2ccc(C)cc2)cc1

Procedure:
To a solution of 0.177 g. (7.7 g.-atom) of sodium dissolved in 25 ml. of dry methanol was added a solution of 2.4 g. (7.3 mmol.) of 2-p-hydroxyphenyl-3-p-methylbenzoylbenzofuran in 75 ml. of toluene and 10 ml. of methanol. The mixture was refluxed for 15 minutes, then the methanol was removed by distillation. A solution of 1.15 g. (7.7 mmol.) of 3-diethylaminopropyl chloride in 25 ml. of toluene was then added and the resulting mixture was refluxed for 6 hours. After cooling, the reaction mixture was filtered and the filtrate was concentrated to give the title compound.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([NH:10][C:11]3[C:12]4[N:13]([CH:20]=[N:21][CH:22]=4)[CH:14]=[CH:15][C:16]=3[C:17]([OH:19])=O)=[C:6]([F:23])[CH:5]=2)[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[NH2:55][O:56][CH2:57][C@@H:58]([OH:60])[CH3:59]>CN(C=O)C>[OH:60][C@@H:58]([CH3:59])[CH2:57][O:56][NH:55][C:17]([C:16]1[CH:15]=[CH:14][N:13]2[CH:20]=[N:21][CH:22]=[C:12]2[C:11]=1[NH:10][C:7]1[CH:8]=[CH:9][C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:5][C:6]=1[F:23])=[O:19]
Reactant: O=C(O)c1ccn2cncc2c1Nc1ccc(C2CC2)cc1F
Reactant: C[C@H](O)CON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](O)CONC(=O)c1ccn2cncc2c1Nc1ccc(C2CC2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 28.2 %

Procedure:
A suspension of 8-(4-cyclopropyl-2-fluoro-phenylamino)-imidazo[1,5-a]pyridine-7-carboxylic acid (0.11 g, 0.35 mmol), EDCI (0.081 g, 0.42 mmol), HOBt (0.057 g, 0.42 mmol), DIPEA (0.085 mL, 0.88 mmol) and (S)-1-aminooxy-propan-2-ol hydrochloride (0.05 g, 0.39 mmol) in DMF (1.5 mL) was stirred at room temperature for 18 hours. The reaction mixture was partitioned between DCM (5 mL) and saturated aqueous NaHCO3 (5 mL). The organic layer was washed with water (5 mL), followed by brine (5 mL), then dried (MgSO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si-PPC, gradient 0% to 60%, ethyl actetate in DCM) to give a yellow sticky solid, which was further purified by preparative HPLC (Gemini 5 micron C18 250×21.20 mm column, 0.1% formic acid, gradient acetonitrile/water, 5 to 98%, ramp time 20 minutes) to afford the title compound as a yellow solid (38 mg, 27%). LCMS (method A): RT=6.87 min, [M+H]+=385. 1H NMR (DMSO-d6) 10.54 (1H, s), 8.27 (1 H, s), 7.76 (1H, dd, J=7.37, 0.93 Hz), 7.14 (1H, t, J=8.37 Hz), 6.98 (1H, dd, J=11.87, 1.95 Hz), 6.95-6.89 (1H, m), 6.76 (1H, d, J=7.33 Hz), 6.27 (1H, s), 3.89-3.79 (1H, m), 3.72-3.62 (2H, m), 1.99-1.90 (1H, m), 1.04 (3H, d, J=6.34 Hz), 0.99-0.93 (2H, m), 0.76-0.67 (2H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]=O)=[CH:7][CH:8]=1.[CH3:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=1)=[O:13].[OH-].[Na+].Cl>O.C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]=[CH:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[O:13])=[CH:7][CH:8]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CC(=O)c1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(C=CC(=O)c2ccc(O)cc2)cc1
Temperature: 50 °C
Reaction time: 24 h
Yield: 80.4 %

Procedure:
Into an ethanol solution (5 liters) comprising 500 g (3.67 moles) of anisaldehyde and 500 g (3.67 moles) of 4-hydroxyacetophenone was dropped an aqueous solution (600 ml) of 250 g of sodium hydroxide in about 80 minutes in a stream of nitrogen. Thereafter, the mixture was heated to 50° C. and agitated for 24 hours. The reaction mixture was cooled down to room temperature, to which were added 2 liters of 12% hydrochloric acid and then 4 liters of water, whereupon crystals settled. The crystals were collected by filtration and quickly washed with ethanol, followed by drying under reduced pressure to obtain 750 g of the intended compound (2.95 moles, yield 80%). The compound was recrystallized from ethanol to obtain light yellow prismatic purified crystals. The melting point and various spectral data of the compound coincided with those of a reference compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][C:14]([CH2:18][CH2:19][OH:20])([OH:17])[CH2:13][CH2:12]1.[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>N1C=CC=CC=1>[C:21]1([S:27]([O:20][CH2:19][CH2:18][C:14]2([OH:17])[CH2:15][CH2:16][N:11]([C:3]3[CH:4]=[C:5]([O:9][CH3:10])[C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[CH2:12][CH2:13]2)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1cc(N2CCC(O)(CCO)CC2)c(Cl)cc1Cl
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: COc1cc(N2CCC(O)(CCOS(=O)(=O)c3ccccc3)CC2)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.3 %

Procedure:
A solution of 1-(2,4-dichloro-5-methoxyphenyl)-4-(2-hydroxyethyl)piperidin-4-ol (500 mg, 1.561 mmol) in pyridine (2 mL) was cooled to 0° C. and then treated with benzenesulfonyl chloride (331 mg, 1.874 mmol). The reaction was stirred at RT for 1 h before being quenched with water. The resultant mixture was extracted with EtOAc. The organic phase was concentrated in vacuo, and the resultant residue was purified by flash chromatography using 0-30% EtOAc in hexanes as the eluent to give 2-(1-(2,4-dichloro-5-methoxyphenyl)-4-hydroxypiperidin-4-yl)ethyl benzenesulfonate (340 mg, 0.739 mmol, 47% yield) was obtained as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[N:15]1([CH2:21][CH2:22]O)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:22][CH2:21][N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1O
Reactant: OCCN1CCOCC1
Product: COc1cc2c(Cl)ncnc2cc1OCCN1CCOCC1

Procedure:
The compound was synthesised according to GP 4 from 4-chloro-7-hydroxy-6-methoxy-quinazoline and 2-Morpholin-4-yl-ethanol. LC/ESI-MS: m/z=324 [M+H].