Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[C:12](=O)[C:10]1=[O:11].[OH-:22].[K+]>O>[CH3:21][O:20][C:16]1[CH:17]=[CH:18][C:19]2[C:14](=[C:12]([C:10]([OH:22])=[O:11])[C:5]3[C:4]([N:9]=2)=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][CH:6]=3)[CH:15]=1
Reactant: COc1ccc2c(c1)C(=O)C(=O)N2c1ccccc1OC
Reactant: [OH-]
Agent: [K+]
Solvent: O
Product: COc1ccc2nc3c(OC)cccc3c(C(=O)O)c2c1
Temperature: 25 °C

Procedure:
The crude isatin derivative from step (a) was refluxed in 60 mL of 10% potassium hydroxide in water for 4 hours. The reaction was then cooled to room temperature and filtered. The filtrate was acidified with a mixture of concentrated hydrochloric acid and ice until a dark precipitate separated out. The product was collected by filtration and dried under vacuum. Yield=0.32 g (10%).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:27]2([CH3:28])[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:16]([CH2:17][C@H:18]([CH2:20][CH2:21]2)[OH:19])=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[CH3:36][S:37]([O:19][C@H:18]1[CH2:20][CH2:21][C@@:22]2([CH3:23])[C:16](=[CH:15][CH2:14][C@@H:13]3[C@@H:24]2[CH2:25][CH2:26][C@@:27]2([CH3:28])[C@H:12]3[CH2:11][CH2:10][C@@H:9]2[C@H:7]([CH3:8])[CH2:6][CH2:5][CH2:4][CH:2]([CH3:1])[CH3:3])[CH2:17]1)(=[O:39])=[O:38]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OS(C)(=O)=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 4 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
A solution of cholesterol (19.3 g, 50.0 mmol) in anhydrous CH2Cl2 (250 mL) was cooled to 4° C. by ice-water bath. To this solution, triethylamine (13.9 mL, 100.0 mmol) was added, followed by the dropwise addition of methanesulfonyl chloride (4.3 mL, 55 mmol) in anhydrous CH2Cl2 (50 mL). The reaction was maintained at 4° C. and stirred for 3 h. When the cholesterol was consumed as analyzed by TLC (hexanes/ethyl acetate, 5:1), the solvent was removed in vacuo. The resulting residue was redissolved in CH2Cl2 (15 mL), the product was precipitated by addition of MeOH (150 mL), and the product collected by vacuum filtration. The solid was washed with MeOH (30 mL) and dried under vacuum to yield the product (23.0 g, 99.0%) as a white solid, mp 119-120° C.; 1H NMR (300 MHz, CDCl3) δ 5.41 (s, 1H), 4.56-4.45 (m, 1H), 3.00 (s, 3H), 2.57-2.43 (m, 2H), 2.04-0.81 (m, 38H), 0.67 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 138.6, 123.7, 81.9, 56.5, 56.0, 49.9, 42.2, 39.6, 39.4, 39.1, 38.7, 36.8, 36.3, 36.1, 35.7, 31.8, 31.7, 28.9, 28.1, 27.9, 24.2, 23.8, 22.8, 22.5, 20.9, 19.1, 18.6, 11.8; IR (film) ν max 3029, 2944, 2908, 2861, 1468, 1440, 1415, 1353, 1330, 1173 cm−1; ESI+m/z ((MNa)+ 487.3237, C28H48O3SNa requires 487.3222).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][C:41]=1[F:42])[CH2:5][NH:6][C:7]([C:9]1[CH:10]=[CH:11][C:12]([F:38])=[C:13]([NH:15][C:16]([C:18]2[N:22]3[CH:23]=[CH:24][C:25]([C:27]4[CH:36]=[CH:35][C:30]([C:31](OC)=[O:32])=[C:29]([F:37])[CH:28]=4)=[CH:26][C:21]3=[N:20][CH:19]=2)=[O:17])[CH:14]=1)=[O:8].[N:43]1([CH2:49][CH2:50][NH2:51])[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1.Cl>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][C:41]=1[F:42])[CH2:5][NH:6][C:7]([C:9]1[CH:10]=[CH:11][C:12]([F:38])=[C:13]([NH:15][C:16]([C:18]2[N:22]3[CH:23]=[CH:24][C:25]([C:27]4[CH:36]=[CH:35][C:30]([C:31](=[O:32])[NH:51][CH2:50][CH2:49][N:43]5[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]5)=[C:29]([F:37])[CH:28]=4)=[CH:26][C:21]3=[N:20][CH:19]=2)=[O:17])[CH:14]=1)=[O:8]
Reactant: COC(=O)c1ccc(-c2ccn3c(C(=O)Nc4cc(C(=O)NCc5ccc(F)c(F)c5)ccc4F)cnc3c2)cc1F
Reactant: NCCN1CCCCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCc1ccc(F)c(F)c1)c1ccc(F)c(NC(=O)c2cnc3cc(-c4ccc(C(=O)NCCN5CCCCC5)c(F)c4)ccn23)c1

Procedure:
Methyl 4-(3-(5-(3,4-difluorobenzylcarbamoyl)-2-fluorophenylcarbamoyl)imidazo[1,2-a]pyridin-7-yl)-2-fluorobenzoate (step 1) (50 mg, 0.087 mmol), 2-piperidin-1-yl-ethylamine (0.260 mmol), and TBD (12.07 mg, 0.087 mmol) in THF (289 μl) were heated to 70° C. for 2 days. The mixture was diluted with water (4 ml) and extracted with DCM using a phase separator. The organic portion was concentrated in vacuo and the residue was dissolved in DMSO. Purification of the crude product was carried out by preparative LC-MS. The resulting fractions were loaded onto a pre-wetted (MeOH) Isolute® SCX-2 cartridge and washed with MeOH. The product was eluted with 7M ammonia in MeOH. The resulting residue was treated with 2M HCl (in EtOH, 1 equiv) and the concentrated in vacuo to afford the title compound as a hydrochloride salt;
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([N:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([Cl:17])[C:11]2=[O:18])[C:7]([CH3:19])=[CH:6][N:5]=1)(=[O:3])[CH3:2].Cl[CH2:21][C:22]1[C:27]([F:28])=[CH:26][C:25]([F:29])=[CH:24][N:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C1OCCOCCOCCOCCOCCOC1>[C:1]([C:4]1[CH:9]=[C:8]([N:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:21][C:22]3[C:27]([F:28])=[CH:26][C:25]([F:29])=[CH:24][N:23]=3)=[C:12]([Cl:17])[C:11]2=[O:18])[C:7]([CH3:19])=[CH:6][N:5]=1)(=[O:3])[CH3:2]
Reactant: Fc1cnc(CCl)c(F)c1
Reactant: CC(=O)c1cc(-n2ccc(O)c(Cl)c2=O)c(C)cn1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1cc(-n2ccc(OCc3ncc(F)cc3F)c(Cl)c2=O)c(C)cn1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a solution of 2′-acetyl-3-chloro-4-hydroxy-5′-methyl-[1,4′]bipyridinyl-2-one of part D (500 mg, 1.7 mmol) in N,N-dimethylformamide (3 mL) was added 2-chloromethyl-3,5-difluoro-pyridine (277 mg, 1.7 mmol), potassium carbonate (590 mg, 4.28 mmol) and 18-crown-6 (10 mg) and the reaction was stirred at 60° C. for 4 h. After cooling the solution was partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over magnesium sulfate. The solution was filtered and concentrated in vacuo. The crude material was purified using normal phase chromatography (ethyl acetate/heptane) to provide alkylated product as a yellow solid (397 mg): MS (ES) m/e 420 (M+H).
Reaction SMILES: [F:1][C:2]1[C:7]2[O:8][C:9]([CH3:14])([CH3:13])[C:10](=S)[NH:11][C:6]=2[CH:5]=[C:4]([N+:15]([O-:17])=[O:16])[CH:3]=1.[Si]([N:22]=[N+:23]=[N-:24])(C)(C)C>C1COCC1.[Hg](OC(C)=O)OC(C)=O.CCOC(C)=O>[CH3:13][C:9]1([CH3:14])[O:8][C:7]2[C:2]([F:1])=[CH:3][C:4]([N+:15]([O-:17])=[O:16])=[CH:5][C:6]=2[N:11]2[N:22]=[N:23][N:24]=[C:10]12
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC1(C)Oc2c(F)cc([N+](=O)[O-])cc2NC1=S
Agent: CC(=O)O[Hg]OC(C)=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(C)Oc2c(F)cc([N+](=O)[O-])cc2-n2nnnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
To a solution of 8-fluoro-2,2-dimethyl-6-nitro-2H-benzo[b][1,4]oxazin-3(4H)-thione (1.0 g, 3.9 mmol) in THF, Hg(OAc)2 was added at 0° C. TMS-N3 was added to the reaction mixture at 0° C. and stirred for 1 hour. Reaction mixture was allowed to warm to room temperature and stirred for 3 hours. LCMS analysis of the reaction mixture indicated completion of the reaction. After 3 hours, the reaction mixture was diluted with 100 ml of EtOAc and partitioned with saturated aqueous NH4Cl (100 ml). Layers were separated and the aqueous layer was washed twice with EtOAc (50 ml). Combined EtOAc layers were dried over Na2SO4 and concentrated. The crude product was purified by column chromatography to give the product in 57% yield (0.57 g). LCMS (m/z) 266 (MH+).
Reaction SMILES: [ClH:1].[NH:2]1[CH2:5][CH2:4][CH2:3]1.[Cl:6][C:7]1[N:12]=[CH:11][C:10]([C:13]2[CH:14]=[C:15]([CH:30]=[CH:31][CH:32]=2)[CH2:16][N:17]([CH3:29])[C:18](=[O:28])[CH2:19][NH:20]C(=O)OC(C)(C)C)=[CH:9][N:8]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[ClH:6].[ClH:1].[N:2]1([C:7]2[N:8]=[CH:9][C:10]([C:13]3[CH:14]=[C:15]([CH:30]=[CH:31][CH:32]=3)[CH2:16][N:17]([CH3:29])[C:18](=[O:28])[CH2:19][NH2:20])=[CH:11][N:12]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: CN(Cc1cccc(-c2cnc(Cl)nc2)c1)C(=O)CNC(=O)OC(C)(C)C
Reactant: C1CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(Cc1cccc(-c2cnc(N3CCC3)nc2)c1)C(=O)CN
Temperature: 80 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Azetidine hydrochloride (287 mg) was suspended in DMF (5 ml), and tert-butyl (2-{[3-(2-chloropyrimidin-5-yl)benzyl](methyl)amino}-2-oxoethyl)carbamate (300 mg) and K2CO3 (849 mg) were added thereto, followed by stirring at 80° C. overnight. The reaction mixture was concentrated under reduced pressure, and then a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with CHCl3. The organic layer was dried over Na2SO4 and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc). The product was dissolved in EtOH (4 ml), and 4 M hydrogen chloride/EtOAc (2 ml) was added thereto, followed by stirring at room temperature overnight. The precipitated solid was collected by filtration to obtain N-[3-(2-azetidin-1-ylpyrimidin-5-yl)benzyl]-N-methylglycinamide dihydrochloride (295 mg).
Reaction SMILES: CC1(C)[O:6][C@@H:5]2[C@@H:7]([CH2:20][N:21]([CH3:41])[CH:22]3[CH2:25][CH:24]([CH2:26][CH2:27][C:28]4[NH:32][C:31]5[CH:33]=[CH:34][C:35]([CH:37]6[CH2:40][O:39][CH2:38]6)=[CH:36][C:30]=5[N:29]=4)[CH2:23]3)[O:8][C@@H:9]([N:10]3[CH:18]=[N:17][C:16]4[C:11]3=[N:12][CH:13]=[N:14][C:15]=4[NH2:19])[C@@H:4]2[O:3]1.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>O>[NH2:19][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[C:16]=1[N:17]=[CH:18][N:10]2[C@H:9]1[C@H:4]([OH:3])[C@H:5]([OH:6])[C@@H:7]([CH2:20][N:21]([CH3:41])[CH:22]2[CH2:25][CH:24]([CH2:26][CH2:27][C:28]3[NH:32][C:31]4[CH:33]=[CH:34][C:35]([CH:37]5[CH2:38][O:39][CH2:40]5)=[CH:36][C:30]=4[N:29]=3)[CH2:23]2)[O:8]1
Reactant: CN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(CCc2nc3cc(C4COC4)ccc3[nH]2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O)C1CC(CCc2nc3cc(C4COC4)ccc3[nH]2)C1
Temperature: 0 °C
Reaction time: 5.75 h
Yield: 54.8 %

Procedure:
To a cooled (ice bath) flask containing 9-((3aR,4R,6R,6aR)-2,2-dimethyl-6-((methyl(3-(2-(5-(oxetan-3-yl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)amino)methyl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-9H-purin-6-amine (0.28 g, 0.42 mmol) was added a precooled (ice bath) solution of trifluoroacetic acid (6.4 mL, 84 mmol) in water (0.75 mL, 42 mmol). The reaction mixture was stirred for 5.75 h at 0° C.; HPLC/LC MS indicated nearly complete consumption of starting material. At 6 h the flask was removed from the cold bath and the volatiles were removed by distillation at rt. The residue was diluted with MeOH (15 mL) and treated with potassium carbonate (0.32 g, 2.3 mmol) and water (1 mL) and the mixture was stirred for 20 min at rt; pH 2. Additional potassium carbonate (0.20 g, 1.4 mmol) was added and the mixture was stirred for 20 min; pH 8-9. The solution was filtered through a fine frit, rinsing with MeOH, and the filtrate was concentrated in vacuo to afford a tan semi-solid. Purification by column chromatography (3×8 cm silica; 10-20% 7 N methanolic NH3/CH2Cl2) afforded the title compound (123 mg, 55%) as a nearly colorless glass: MS (ESI+) for C27H34N8O4 m/z 535.3 (M+H)+; MS (ESI−) for C27H34N8O4 m/z 533.3 (M−H)−; HPLC purity >95% (ret. time 1.765 min); 1H NMR (400 MHz, d4-MeOH) mixture of cis/trans isomers δH 8.29-8.25 (m, 1H), 8.21-8.17 (m, 1H), 7.51 (s, 1H), 7.47 (d, J=8.3 Hz, 1H), 7.26 (dd, J=1.6, 8.3 Hz, 1H), 6.00-5.96 (m, 1H), 5.11 (dd, J=5.8, 8.3 Hz, 2H), 4.81-4.76 (m, 2H), 4.73-4.68 (m, 1H), 4.40-4.31 (m, 1H), 4.27-4.13 (series of m, 2H), 3.13-3.03 (m, 0.4H), 2.86-2.66 (series of m, 4.6H), 2.30-1.80 (series of m, 8.6H), 1.55-1.40 (m, 1.4H).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15]CC3C=CC=CC=3)=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1.O.[OH-].[Na+]>FC(F)(F)C(O)=O>[CH3:1][S:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([OH:15])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1
Reactant: COc1cc2c(SC)ncnc2cc1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1cc2c(SC)ncnc2cc1O
Yield: 90.8 %

Procedure:
A solution of 4-(methylthio)-6-methoxy-7-benzyloxyquinazoline (29.5 g, 0.095 mol) in trifluoroacetic acid (250 ml) was heated at reflux for 3 hours. The mixture was cooled, water was added, and the pH adjusted to pH 5 with sodium hydroxide (2.0 N). The solid was filtered, washed with water and diethyl ether and dried in vacuo. The solid was redissolved in methanol (2000 ml) and water (500 ml), the pH was adjusted to 7 with sodium hydroxyde (2.0 N) and the precipitated solid was collected by suction filtration. Drying in vacuo yielded 4-(methylthio)-6-methoxy-7-hydroxy-quinazoline (19.18 g, 91% yield):
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([C:6]([OH:8])=O)[CH2:2]1.[CH2:9]([C@H:16]1[CH2:20][NH:19][C@H:18]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)=[CH:26][CH:25]=2)=[O:22])[CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([C@H:16]1[CH2:20][N:19]([C:6]([CH:3]2[CH2:4][CH2:5][O:1][CH2:2]2)=[O:8])[C@H:18]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)=[CH:26][CH:25]=2)=[O:22])[CH2:17]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(O)C1CCOC1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1C(=O)C1CCOC1
Yield: 28.3 %

Procedure:
Proceeding as in Example 1, but substituting tetrahydrofuran-3-carboxylic acid and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 36, (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(tetrahydrofuran-3-carbonyl)pyrrolidine-2-carboxamide (8.3 mg, 28.3%). 1H-NMR (400 MHz, DMSO-D6): σ 9.95 (s, 1H), 7.56 (m, 2H), 7.27 (m, 2H), 7.19 (m, 5H), 6.92 (m, 4H), 4.46 (m, 1H), 3.86 (m, 1H), 3.66 (m, 4H), 3.31 (m, 2H), 2.63 (m, 3H), 1.94 (m, 4H). MS (EI) for C29H29FN2O4: 489.5 (MH+).
Reaction SMILES: [CH:1]([N:4]([CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20])[C:5]([NH:7][C@H:8]([C:13]([OH:15])=[O:14])[C:9]([CH3:12])([CH3:11])[CH3:10])=[O:6])([CH3:3])[CH3:2].Br[CH2:22]CCCC=C>>[CH2:16]([N:4]([CH:1]([CH3:2])[CH3:3])[C:5]([NH:7][C@H:8]([C:13]([OH:15])=[O:14])[C:9]([CH3:12])([CH3:11])[CH3:10])=[O:6])[CH2:17][CH2:18][CH2:19][CH:20]=[CH2:22]
Reactant: C=CCCCCBr
Reactant: C=CCCCN(C(=O)N[C@H](C(=O)O)C(C)(C)C)C(C)C
Product: C=CCCCCN(C(=O)N[C@H](C(=O)O)C(C)(C)C)C(C)C

Procedure:
N-{[Hex-5-en-1-yl(isopropyl)amino]carbonyl}-3-methyl-L-valine was prepared according to the procedure described for N-{[isopropyl(pent-4-en-1-yl)amino]carbonyl}-3-methyl-L-valine by using 6-bromo-1-hexene in Step 1. LRMS (ESI) m/z 299 [(M+H)+; calcd for C16H31N2O3: 299.2].
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([OH:3])=O.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:26][NH:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][CH:33]([O:36][C:37](=[O:51])[NH:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:32][CH2:31]1>C(Cl)Cl>[CH:8]([C:7]1[CH:10]=[CH:11][C:4]([C:1]([CH2:26][NH:27][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][CH:33]([O:36][C:37](=[O:51])[NH:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH2:32][CH2:31]2)=[O:3])=[CH:5][CH:6]=1)=[O:9]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CNCCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: O=Cc1ccc(C(=O)CNCCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.6 %

Procedure:
To a three-necked 1-L flask was added 4-carboxybenzaldehyde (4.77 g, 31.8 mmol), EDC (6.64 g, 34.7 mmol), HOBT (1.91 g, 31.8 mmol), and DCM (200 mL). When the mixture was homogenous, a solution of biphenyl-2-ylcarbamic acid 1-(2-methylaminoethyl)piperidin-4-yl ester (10 g, 31.8 mmol; prepared as in Preparation 4) in DCM (100 mL) was added slowly. The reaction mixture was stirred at room temperature for 16 hours and then washed with water (1×100 mL), 1N HCl (5×60 mL), 1N NaOH (1×100 mL) brine (1×50 mL), dried over sodium sulfate, filtered and concentrated to afford 12.6 g of the title compound (92% yield; 85% purity based on HPLC). MS m/z: [M+H+] calcd for C29H31N3O4, 486.2; found, 486.4. Rf=3.12 min (10-70 ACN:H2O, reverse phase HPLC).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([S:25][CH3:26])=[N:23][N:24]=2)[N:21]=1>>[CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:16]2[CH:17]=[CH:18][C:19]3[N:20]([C:22]([S:25][CH3:26])=[N:23][N:24]=3)[N:21]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCCNCC2)cc1
Reactant: CSc1nnc2ccc(Cl)nn12
Product: CSc1nnc2ccc(N3CCCN(Cc4ccccc4)CC3)nn12

Procedure:
A mixture of 1-benzyl-1,4-diazepane and 6-chloro-3-methylsulfanyl-1,2,4-triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 2 to give 6-(4-benzyl-1,4-diazepan-1-yl)-3-methylsulfanyl-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].C(#N)C.[F:9][C:10]([F:22])([F:21])[C:11]1[C:12]([S:17]([NH2:20])(=[O:19])=[O:18])=[N:13][CH:14]=[CH:15][CH:16]=1>C(N(CC)CC)C>[F:21][C:10]([F:9])([F:22])[C:11]1[C:12]([S:17]([NH:20][C:2](=[O:3])[O:4][CH3:5])(=[O:19])=[O:18])=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: COC(=O)Cl
Reactant: NS(=O)(=O)c1ncccc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)NS(=O)(=O)c1ncccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.2 %

Procedure:
Methyl chloroformate (3.31 g, 35 mmol) was added under cooling with ice to a dry acetonitrile (150 ml) solution containing 3-trifluoromethylpyridine-2-sulfonamide (7.91 g, 35 mmol) and triethylamine (16 ml), and the mixture was continuously stirred at room temperature for 3 hours. Then, the solvent was distilled off under reduced pressure, and the residue was dissolved in 300 ml of water. A small amount of insoluble substances were removed by filtration, and the filtrate was adjusted to pH of 1 to 2 with concentrated hydrochloric acid under cooling with ice. Precipitated crystals were collected by filtration and thoroughly washed with water, then washed with a solvent mixture of ethyl ether/n-hexane and dried to obtain 4.4 g of desired methyl N-(3-trifluoromethylpyridine-2-sulfonyl)carbamate. Melting point: 128°-129° C.
Reaction SMILES: NC1C=CC(C2C3C(=NC=NC=3N)N([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)N=2)=CC=1.[NH2:31][C:32]1[CH:33]=[C:34]([CH3:40])[CH:35]=[C:36]([CH3:39])[C:37]=1[OH:38].[NH2:41][C:42]1[N:47]=[CH:46][N:45]=[C:44]2[N:48]([C@H:68]3[CH2:73][CH2:72][C@@H:71]([N:74]4[CH2:79][CH2:78][N:77]([CH3:80])[CH2:76][CH2:75]4)[CH2:70][CH2:69]3)[N:49]=[C:50]([C:51]3[CH:56]=[CH:55][C:54]([NH:57][C:58]4OC5C=CC=C(C)C=5N=4)=[CH:53][CH:52]=3)[C:43]=12>>[NH2:41][C:42]1[N:47]=[CH:46][N:45]=[C:44]2[N:48]([C@H:68]3[CH2:73][CH2:72][C@@H:71]([N:74]4[CH2:75][CH2:76][N:77]([CH3:80])[CH2:78][CH2:79]4)[CH2:70][CH2:69]3)[N:49]=[C:50]([C:51]3[CH:56]=[CH:55][C:54]([NH:57][C:58]4[O:38][C:37]5[C:36]([CH3:39])=[CH:35][C:34]([CH3:40])=[CH:33][C:32]=5[N:31]=4)=[CH:53][CH:52]=3)[C:43]=12
Reactant: Cc1cc(C)c(O)c(N)c1
Reactant: Cc1cccc2oc(Nc3ccc(-c4nn([C@H]5CC[C@@H](N6CCN(C)CC6)CC5)c5ncnc(N)c45)cc3)nc12
Agent: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(N)cc4)c4c(N)ncnc43)CC2)CC1
Product: Cc1cc(C)c2oc(Nc3ccc(-c4nn([C@H]5CC[C@@H](N6CCN(C)CC6)CC5)c5ncnc(N)c45)cc3)nc2c1

Procedure:
Cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-5,7-dimethyl-1,3-benzoxazol-2-amine was prepared from cis-3-(4-aminophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.100 g, 0.246 mmol) and 6-amino-2,4-xylenol (0.034 g, 0.246 mmol) in a manner similar to that used for cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-4-methyl-1,3-benzoxazol-2-amine. The compound was formed as an off-white solid (0.031 g, 23%): 1H NMR (DMSO-d6, 400 MHz) δ 10.85 (s, 1H), 8.23 (s, 1H), 7.93 (d, 2H), 7.65 (d, 2H), 7.11 (s, 1H), 6.80 (s, 1H), 4.80 (m, 1H), 2.60-2.17 (m, 12H), 2.41 (s, 3H), 2.37 (s, 3H), 2.22 (s, 3H), 1.71-1.59 (m, 5H); RP-HPLC (25 to 100% CH3CN in 0.1 N aqueous ammonium acetate over 10 min at 1 mL/min using a Hypersil HS C18, 250×4.6 mm column) tr=8.00 min., 93%; m/z 552 (MH+).
Reaction SMILES: C[N+]1([O-])CC[O:5]CC1.Br[CH2:10][C:11]1[C:16]2[CH:17]=[CH:18][O:19][C:15]=2[C:14]([Cl:20])=[CH:13][CH:12]=1>C(#N)C>[Cl:20][C:14]1[CH:13]=[CH:12][C:11]([CH:10]=[O:5])=[C:16]2[C:15]=1[O:19][CH:18]=[CH:17]2
Reactant: C[N+]1([O-])CCOCC1
Reactant: Clc1ccc(CBr)c2ccoc12
Solvent: CC#N
Product: O=Cc1ccc(Cl)c2occc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.4 %

Procedure:
A solution of the N-methylmorpholine-N-oxide (37.64 g) in aoetonitrile (370 ml) containing 3 Å molecular sieves (36.6 g) was stirred at room temperature overnight and cooled in ice. A solution of 4-bromomethyl-7-chloro-benzofuran (39.44 g) in acetonitrile (90 ml) was added and the mixture stirred in at 0° C. for 4 h. The mixture was filtered and the filtrate evaporated to dryness. Water and ethyl acetate were added to the residue and the organic phase separated, dried (Na2SO4) and evaporated to give the title compound (21.3 g) as a pale yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][OH:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[ClH:13].[NH2:14][CH2:15][C:16](=[O:22])[CH2:17][CH2:18][C:19](O)=[O:20]>>[ClH:13].[NH2:14][CH2:15][C:16](=[O:22])[CH2:17][CH2:18][C:19]([O:10][CH2:9][C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:12][CH:11]=1)=[O:20]
Reactant: NCC(=O)CCC(=O)O
Reactant: CC(C)(C)c1ccc(CO)cc1
Agent: Cl
Product: CC(C)(C)c1ccc(COC(=O)CCC(=O)CN)cc1
Reaction time: 48 h

Procedure:
From 4-t-butylbenzyl alcohol (5.0 g; 30 mmol) and 5-amino-4-oxopentanoic acid hydrochloride (1.0 g; 6.0 mmol). The reaction was complete after 2 days. The yield was 0.84 9 (52%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[CH2:24][C:19]5(OCC[O:20]5)[CH2:18][CH2:17][C:15]=4[N:16]=3)=[CH:8][C:7]=2[F:25])[CH2:3][CH2:2]1.C1COCC1.Cl.C(=O)([O-])O.[Na+]>O.CO>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[CH2:24][CH:19]([OH:20])[CH2:18][CH2:17][C:15]=4[N:16]=3)=[CH:8][C:7]=2[F:25])[CH2:2][CH2:3]1
Reactant: Fc1cc(-c2nc3c(o2)CC2(CC3)OCCO2)ccc1OCC1CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: OC1CCc2nc(-c3ccc(OCC4CC4)c(F)c3)oc2C1
Temperature: 70 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
To 2-(4-(cyclopropylmethoxy)-3-fluorophenyl)-4,7-dihydro-5H-spiro[1,3-benzoxazole-6,2′-[1,3]dioxolane] (3.75 g) in a mixed solvent of THF (25 mL)-methanol (12.5 mL)-water (12.5 mL) was added 6 M hydrochloric acid (10.8 mL), and the mixture was stirred at 70° C. for 1 hr. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. To the organic layer was added sodium tetrahydroborate (411 mg), and the mixture was stirred at room temperature for 20 min. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.58 g).