Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([C:19]([OH:21])=[O:20])[CH:15]=[CH:14][C:13]=2[C:12]2[N:22](S(=O)(=O)N(C)C)[N:23]=[CH:24][C:11]=2[N:10]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.C([O-])(O)=O.[Na+]>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([C:19]([OH:21])=[O:20])[CH:15]=[CH:14][C:13]=2[C:12]2=[N:22][NH:23][CH:24]=[C:11]2[N:10]=1
Reactant: CN(C)S(=O)(=O)n1ncc2nc(-c3c(F)cccc3F)c3cc(C(=O)O)ccc3c21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc2c(c1)c(-c1c(F)cccc1F)nc1c[nH]nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.4 %

Procedure:
A 250 ml round-bottomed flask is charged with 1.46 g of 5-(2,6-difluorophenyl)-1-(dimethylsulphamoyl)-1H-pyrazolo[4,3-c]isoquinoline-7-carboxylic acid in 100 ml of DCM and then 20 ml of TFA are added. The mixture is stirred at RT for 16 h. It is concentrated under RP and the solid obtained is taken up in 30 ml of saturated aqueous NaHCO3 solution and extracted with three times 30 ml of AcOEt. The aqueous phase is acidified to a pH of 1 by addition of 37% HCl and extracted with AcOEt. The organic phase is washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated under RP to give 927 mg of 5-(2,6-difluorophenyl)-2H-pyrazolo[4,3-c]isoquinoline-7-carboxylic acid (beige solid), LC-MS-DAD-ELSD: 326(+)=(M+H)(+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]2[CH2:15][CH:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH2:13][N:12]2[C:22]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:25]=2)=O)=[O:10])=[CH:4][CH:3]=1.[H-].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9](=[O:10])[N:11]3[CH2:15][CH:14]([N:16]4[CH2:17][CH2:18][O:19][CH2:20][CH2:21]4)[CH2:13][N:12]3[C:22]=2[C:24]2[CH:29]=[CH:28][N:27]=[C:26]([O:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:25]=2)=[CH:6][CH:7]=1
Reactant: O=C(Cc1ccc(F)cc1)N1CC(N2CCOCC2)CN1C(=O)c1ccnc(Oc2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c(-c2ccc(F)cc2)c(-c2ccnc(Oc3ccccc3)n2)n2n1CC(N1CCOCC1)C2
Reaction time: 2 h
Yield: 20 %

Procedure:
To a solution of 2-(4-fluorophenyl)-1-[4-morpholin-4-yl-2-(2-phenoxy-pyrimidine-4-carbonyl)pyrazolidine-1-yl]ethanone, 19, (0.2 g, 0.4 mmol) in DMF (10 mL) at 0° C. is added NaH (0.024 g. 0.6 mmol) and the resulting solution is stirred 2 hours. The solvent is removed in vacuo the residue dissolved in methylene chloride and extracted with water, dried, and re-concentrated to afford 37 mg (20% yield) of the desired product as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([CH:27]=[CH2:28])=[CH:19][N:18]=1.[OH-].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:28][CH2:27][C:20]3[C:21]4[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:17]([CH3:16])=[N:18][CH:19]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: C=Cc1cnc(C)c2ccccc12
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ncc(CCn2c3c(c4cc(Cl)ccc42)CN(C)CC3)c2ccccc12

Procedure:
The title compound is prepared from a mixture of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole, 1-methyl-4-vinylisoquinoline and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 10 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2OCC#N)[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:34]=[CH:33][C:24]2[CH2:25][CH2:26][CH2:27][C:28](=[O:32])[N:29]([CH2:30][CH3:31])[C:23]=2[CH:22]=1>>[Cl:19][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[CH2:6][CH2:5][C:4]#[N:3])=[N:7][C:2]([NH:20][C:21]2[CH:34]=[CH:33][C:24]3[CH2:25][CH2:26][CH2:27][C:28](=[O:32])[N:29]([CH2:30][CH3:31])[C:23]=3[CH:22]=2)=[N:3][CH:4]=1
Reactant: CCN1C(=O)CCCc2ccc(N)cc21
Reactant: N#CCOc1ccccc1Nc1nc(Cl)ncc1Cl
Product: CCN1C(=O)CCCc2ccc(Nc3ncc(Cl)c(Nc4ccccc4CCC#N)n3)cc21

Procedure:
3-{2-[5-Chloro-2-(1-ethyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-8-ylamino)-pyrimidin-4-ylamino]-phenyl}-propionitrile was prepared from [2-(2,5-Dichloro-pyrimidin-4-ylamino)-phenoxy]-acetonitrile and 8-Amino-1-ethyl-1,3,4,5-tetrahydro-1-benzazepin-2-one (from Example 358a) in an analogous manner to Example 1221d. (120° C., 40 min). Obtained 83 mg (76%) as a white foam. HPLC purity: 90%, LCMS 461.22 (M+H), 1H-NMR (CDCl3, 400 MHz) δ: 8.09 (s, 1H), 7.46-7.42 (m, 1H), 7.41-7.31 (m, 4H), 7.28 (s, 1H), 7.05-6.92 (m, 3H), 4.00-3.20 (bm, 2H), 2.97 (t, J=7.2 Hz, 2 h), 2.61 (t, J=7.2 Hz, 2H), 2.28-2.22 (m, 2H), 2.22-2.2.05 (m, 2H), 1.00 (t, J=7.1 Hz, 3H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[N:12]3[N:24]=[CH:25][CH:26]=[C:11]3[N:10]=2)[CH2:4][CH2:3]1.[I:27]Cl>C(Cl)Cl>[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[N:12]3[N:24]=[CH:25][C:26]([I:27])=[C:11]3[N:10]=2)[CH2:4][CH2:3]1
Reactant: ClI
Reactant: N[C@H]1CC[C@H](Nc2cc(NCc3cccc(Cl)c3)n3nccc3n2)CC1
Solvent: ClCCl
Product: N[C@H]1CC[C@H](Nc2cc(NCc3cccc(Cl)c3)n3ncc(I)c3n2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of {5-[(trans-4-aminocyclohexyl)amino](pyrazolo[1,5-a]pyrimidin-7-yl)}[(3-chlorophenyl)methyl]amine (41.8 mg) in CH2Cl2 (565 μL) was added ICl (169 μL, 1.0 M in CH2Cl2), and the resulting mixture was stirred at room temperature for 4 h in the dark. The reaction was quenched with saturated aqueous Na2S2O3. The resulting precipitate was collected by filtration. After extraction of filtrate by CH2Cl2, the combined organic layer was washed with saturated aqueous NaCl. To this solution, the precipitate collected above was dissolved, and the solvent was removed in vacuo. The residue was purified by preparative HPLC, and the fraction contained the title compound was basified (pH 9) with saturated aqueous NaHCO3. After extraction with CH2Cl2, combined organic layer was dried over Na2SO4. The solvent was removed in vacuo, and the title compound (23.11 mg, 41% yield) was obtained as a white solid. The 1H-NMR, HPLC retention time and ESI/MS data for this compound are shown below.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][N:20]=[C:19]([CH3:22])[C:18]=3[NH:23][C:24]([O:26][CH:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])[CH3:28])=[O:25])=[CH:13][CH:12]=2)=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:4].[Li+].[OH-]>CO>[Cl:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH:27]([O:26][C:24]([NH:23][C:18]1[C:19]([CH3:22])=[N:20][O:21][C:17]=1[C:14]1[CH:15]=[CH:16][C:11]([C:6]2[C:5]([C:3]([OH:4])=[O:2])=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:12][CH:13]=1)=[O:25])[CH3:28]
Reactant: COC(=O)c1ccccc1-c1ccc(-c2onc(C)c2NC(=O)OC(C)c2ccccc2Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: Cc1noc(-c2ccc(-c3ccccc3C(=O)O)cc2)c1NC(=O)OC(C)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 4′-{4-[1-(2-chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-biphenyl-2-carboxylic acid methyl ester (0.2 μmol) in methanol was added 1N aqueous LiOH (2 mL) and stirred overnight at room temperature. The solution was stirred at 40° C. for 3 days. The mixture was purified by preparative HPLC to give the title compound.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH2:4][C:5]1([CH2:21][CH3:22])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[C:8](=[O:20])[CH2:7][O:6]1)=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:18][CH3:19].C([O-])([O-])=O.[K+].[K+]>CO.O>[CH2:21]([C:5]1([CH2:4][C:3]([OH:23])=[O:2])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[C:8](=[O:20])[CH2:7][O:6]1)=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:18][CH3:19])[CH3:22]
Reactant: CCc1cccc2c3c([nH]c12)C(CC)(CC(=O)OC)OCC3=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCc1cccc2c3c([nH]c12)C(CC)(CC(=O)O)OCC3=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
1,8-Diethyl-1,3,4,9-tetrahydro-4-oxopyrano[3,4-b]indole-1-acetic acid methyl ester 17 (1.5 g, 4.8 mmol) was suspended in 30 mL of MeOH and a solution of K2CO3 (3.5 g) in 30 mL of H2O was added. The mixture was heated to reflux, upon which the solution became homogeneous. After refluxing for 2 hours, the solution was cooled to room temperature, and the MeOH removed in vacuo. The aqueous solution was made acidic with 6N HCl, and the resulting cloudy solution was extracted with ether (2×50 mL). The ether layer was washed with 25 mL of saturated NaCl solution, then dried over MgSO4. The MgSO4 was removed and the ether was evaporated. Hexane was gradually added until a slight turbidity was observed. The solution was left at 0° C. overnight and the resultant solid was collected by filtration and dried to provide analytically pure product (1.31 g, 93%), m.p. 200°-202° C.
Reaction SMILES: Cl[C:2]1[C:3]2[C:11]([CH3:12])=[C:10]([CH3:13])[N:9]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[CH3:22])[C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.[C-:23]#[N:24].[K+]>CS(C)=O.O>[CH3:8][C:6]1[N:7]=[C:2]([C:23]#[N:24])[C:3]2[C:11]([CH3:12])=[C:10]([CH3:13])[N:9]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[CH3:22])[C:4]=2[N:5]=1
Reactant: [C-]#N
Reactant: Cc1cc(C)c(-n2c(C)c(C)c3c(Cl)nc(C)nc32)c(C)c1
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(C)c(-n2c(C)c(C)c3c(C#N)nc(C)nc32)c(C)c1
Temperature: 130 °C
Yield: 65.3 %

Procedure:
A mixture of 4-chloro-2,5,6-trimethyl-7-(2,4,6-trimethyl-phenyl)-7H-pyrrolo[2,3-d]-pyrimidine (10.000 g, 31.90 mmol) and potassium cyanide (20.75 g, 319 mmol) in 100 ml dimethylsulfoxide was heated at 130° C. oil bath over weekend. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated to give 9.61 g (99%) of brown soild. The solid was recrystallized from i-propanol to give 6.34 g (65%) of the title compound as light golden crystals, mp 188-190° C. 1H NMR (CDCl3) δ 1.8(s, 6H), 2.07(s, 3H), 2.36(s, 3H), 2.50(s, 3H), 2.65(s, 3H), 7.00(s, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:24]=[CH:23][C:12]([CH2:13][C@@H:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[NH2:15])=[CH:11][CH:10]=1)[CH3:2].F[C:27]1[N:31]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:30]=[N:29][N:28]=1>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][C@@H:14]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[NH:15][C:27]2[N:31]([CH2:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[N:30]=[N:29][N:28]=2)=[CH:23][CH:24]=1)[CH3:2]
Reactant: CCOC(=O)CCCOc1ccc(C[C@H](N)C(=O)OC(C)(C)C)cc1
Reactant: Fc1nnnn1Cc1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)CCCOc1ccc(C[C@H](Nc2nnnn2Cc2ccccc2)C(=O)OC(C)(C)C)cc1
Yield: 57.6 %

Procedure:
A solution of aminoester 4-2 (325 mg, 0.92 mmole) and 5-fluoro-1-(phenylmethyl)-1H-tetrazole (170 mg, 0.95 mmole) in 15 ml of pyridine is heated at 100° C. for 2 hours. Evaporation is then carried out under reduced pressure until a dry extract is obtained which is purified by chromatography eluting with a heptane/AcOEt mixture 50/50. 270 mg of the expected product 5-1 is obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].CC(C)([O-])C.[K+].[C:13]([O:17][C:18](=[O:29])[C:19]1[CH:24]=[CH:23][C:22](F)=[CH:21][C:20]=1[N+:26]([O-:28])=[O:27])([CH3:16])([CH3:15])[CH3:14].O>C1COCC1>[C:13]([O:17][C:18](=[O:29])[C:19]1[CH:24]=[CH:23][C:22]([O:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])=[CH:21][C:20]=1[N+:26]([O-:28])=[O:27])([CH3:16])([CH3:14])[CH3:15]
Reactant: CN(C)CCO
Reactant: CC(C)(C)OC(=O)c1ccc(F)cc1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)CCOc1ccc(C(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 35.2 %

Procedure:
To a solution of 2-dimethylaminoethanol (6.67 mL, 64.8 mmol) in anhydrous THF (100 mL), at 0° C., potassium tert-butoxide (6.66 g, 59.4 mmol) was added. The mixture was stirred at 0° C. for 1 h, then 4-fluoro-2-nitro-benzoic acid tert-butyl ester (10 g, 41.5 mmol) in anhydrous THF (50 mL) was added dropwise. After 2 hours at 0° C., the mixture was poured into water (1 L) and extracted with ethyl acetate (4×200 mL). The organic phase was washed with water, brine, dried with anhydrous sodium sulfate, filtered and evaporated to dryness. The crude was purified by flash chromatography, using dichloromethane-EtOH-33% NH4OH 9:1:0.01 as eluant, to give the title compound (4.53 g) as yellow oil.
Reaction SMILES: [CH2:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH2:4][CH2:3][CH:2]1[NH2:14].[C:15](Cl)(=[O:18])[CH2:16][CH3:17].C(N(CC)CC)C>O1CCCC1>[CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH:14][C:15](=[O:18])[CH2:16][CH3:17]
Reactant: CCC(=O)Cl
Reactant: NC1CCc2oc3ccccc3c2C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(=O)Nc1ccc2oc3c(c2c1)CCCC3
Yield: 18.9 %

Procedure:
Following the procedure of Example 1, tetrahydro-dibenzofuran-2-ylamine (0.94 g, 5.0 mmol), propionyl chloride (0.47 mL, 5.3mmol), and triethylamine (2.1 mL, 15 mmol) in tetrahydrofuran (20 mL) provided N-(6,7,8,9-tetrahydro-dibenzofuran-2-yl)-propionamide (0.23 g). Mp 164-165° C.; Anal. Calcd. for C15H17NO2: C, 74.05; H, 7.04; N, 5.76; Found: C, 74.09; H, 7.09; N, 5.78.
Reaction SMILES: [OH:1][C:2]([CH3:36])([CH3:35])[CH2:3][C@@:4]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:14]2[CH:19]=[CH:18][C:17](B3OC(C)(C)C(C)(C)O3)=[CH:16][CH:15]=2)[CH2:12][CH3:13])[CH2:6][CH2:5]1.Br[C:38]1[CH:43]=[C:42]([CH3:44])[N+:41]([O-:45])=[C:40]([CH3:46])[CH:39]=1>>[OH:1][C:2]([CH3:35])([CH3:36])[CH2:3][C@@:4]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:14]2[CH:15]=[CH:16][C:17]([C:38]3[CH:43]=[C:42]([CH3:44])[N+:41]([O-:45])=[C:40]([CH3:46])[CH:39]=3)=[CH:18][CH:19]=2)[CH2:12][CH3:13])[CH2:6][CH2:5]1
Reactant: CC[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: Cc1cc(Br)cc(C)[n+]1[O-]
Product: CC[C@@H](c1ccc(-c2cc(C)[n+]([O-])c(C)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl)-1,3-oxazinan-2-one and 4-bromo-2,6-dimethylpyridine-N-oxide following a procedure analogous to that described in Example 459 Step 4. LC-MS Method 2 tR=1.185 min, m/z=489.2; 1H NMR (CDCl3) 0.96 (t, 3H), 1.03 (s, 3H), 1.12 (s, 3H), 1.81-2.00 (m, 4H), 2.11-2.22 (m, 5H), 2.30-2.42 (m, 1H), 2.57 (s, 6H), 2.87 (m, 1H), 5.43 (m, 1H), 7.09 (d, 2H), 7.18 (m, 1H), 7.22 (m, 4H), 7.26 (m, 2H), 7.31 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@@H:9](OS(C)(=O)=O)[CH2:8][N:7]1[CH2:16][CH3:17])=[O:5])[CH3:2].[N-:18]=[N+:19]=[N-:20].[Na+]>CN(C)C=O>[N:18]([C@@H:9]1[CH2:8][N:7]([CH2:16][CH3:17])[C@H:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:10]1)=[N+:19]=[N-:20]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1CC
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1C[C@H](N=[N+]=[N-])CN1CC
Temperature: 90 °C
Reaction time: 4 h

Procedure:
A mixture of 3.5 g of (2S,4R)-2-ethoxycarbonyl-N-ethyl-4-methanesulfonyloxy pyrrolidine, 1.54 g of sodium azide and 10 ml of dimethylformamide was stirred at 90° C. for 4 hours. After cooling, the reaction mixture was poured into ice-water and extracted with ethyl acetate. The organic extract was washed with water, dried and concentrated under reduced pressure to obtain crude product. This was then subjected to a silica gel column chromatography (elution liq. toluene-ethyl acetate) to obtain pure (2S,4S)-4-azido-2-ethoxycarbonylN-ethyl pyrrolidine as an oily product. Yield 2.05 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:15]([C:16]3[N:24]=[C:23]([CH3:25])[N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][N:20]4C3CCCCO3)=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:6]=[N:7][CH:8]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:15]([C:16]3[N:24]=[C:23]([CH3:25])[N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][NH:20]4)=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:6]=[N:7][CH:8]=1
Reactant: COc1cncc(Nc2ncccc2-c2nc(C)nc3c2ncn3C2CCCCO2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cncc(Nc2ncccc2-c2nc(C)nc3[nH]cnc23)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 62.5 %

Procedure:
A suspension of N-(5-methoxypyridin-3-yl)-3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-amine (60 mg, 0.144 mmol) in DCM (3 mL) was cooled to 0° C., treated with trifluoroacetic acid (3 mL, 40.4 mmol), and the yellow solution was stirred at 0° C. for 1 h. The mixture was concentrated in vacuo, the residue was neutralized with 2 M NH3 in MeOH and then concentrated in vacuo. The crude product was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g) eluting with a gradient of 2% to 10% 2 M NH3-MeOH in DCM to give N-(5-methoxypyridin-3-yl)-3-(2-methyl-9H-purin-6-yl)pyridin-2-amine (30 mg, 0.090 mmol, 62.6% yield) as a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 13.66 (s, 1H); 13.09 (s, 1H); 9.84 (dd, J=7.82, 1.56 Hz, 1H); 8.63 (s, 1H); 8.46 (d, J=1.76 Hz, 1H); 8.41 (dd, J=4.69, 1.76 Hz, 1H); 8.20 (s, 1H); 7.95 (d, J=2.54 Hz, 1H); 7.10 (dd, J=7.82, 4.69 Hz, 1H); 3.87 (s, 3H); 2.89 (s, 3H). m/z (ESI, +ve ion) 334 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11]O)[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:37]I>ClCCl>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][I:37])[CH3:2]
Reactant: II
Reactant: CCOc1ccccc1CCO
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOc1ccccc1CCI
Temperature: 0 °C
Reaction time: 8 h
Yield: 60.7 %

Procedure:
Into a 50-mL round-bottom flask was placed dichloromethane (20 mL) and 2-(2-ethoxyphenyl)ethan-1-ol (1.33 g, 8.00 mmol, 1.00 equiv). The solution was cooled to 0° C. in a water/ice bath. Then PPh3 (2.72 g, 10.37 mmol, 1.30 equiv), imidazole (707 mg, 10.40 mmol, 1.30 equiv) and I2 (2.44 g, 9.61 mmol, 1.20 equiv) were added. The resulting solution was stirred at room temperature overnight. The reaction was then quenched by the addition of 50 mL of NaHSO3 (aq.). The organic layer was separated and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (0:100). Purification afforded 1.34 g (61%) of 1-ethoxy-2-(2-iodoethyl)benzene as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:18]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])=[O:19])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][Cl:17])=[CH:11][CH:10]=1.[C:26](Cl)(=O)[CH2:27][CH3:28]>>[C:22]([NH:21][S:18]([C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:9]3[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][Cl:17])=[CH:13][CH:14]=3)[C:26]([CH2:27][CH3:28])=[N:1][C:2]=2[CH:3]=1)(=[O:19])=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(Nc2ccc(CCCl)cc2)c(N)c1
Reactant: CCC(=O)Cl
Product: CCc1nc2cc(S(=O)(=O)NC(C)(C)C)ccc2n1-c1ccc(CCCl)cc1

Procedure:
The title compound was prepared according to the procedure described in step 5 Example 1 from 3-amino-N-(tert-butyl)-4-[4-(2-chloroethyl)anilino]benzenesulfonamide (step 4) and propionyl chloride.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]([CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][C:23](=[CH:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=3)[CH2:22][CH2:21]2)=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:10]=1)=O)C.[NH3:34]>C(O)C>[C:4]([C:6]1[S:7][C:8]([CH2:18][CH2:19][N:20]2[CH2:21][CH2:22][C:23](=[CH:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=3)[CH2:24][CH2:25]2)=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[N:10]=1)(=[O:3])[NH2:34]
Reactant: CCOC(=O)c1nc(-c2ccc(F)cc2)c(CCN2CCC(=Cc3cccc(F)c3)CC2)s1
Reactant: N
Solvent: CCO
Product: NC(=O)c1nc(-c2ccc(F)cc2)c(CCN2CCC(=Cc3cccc(F)c3)CC2)s1

Procedure:
315 mg of 2-ethoxycarbonyl-4-(4-fluorophenyl)-5-[2-[4-(3-fluorobenzylidene)piperidin-1-yl]ethyl]thiazole and 0.05 ml of 28% aqueous ammonia were stirred in 1.5 ml of ethanol for 3 days. To the mixture was added 0.50 ml of 28% aqueous ammonia to carry out additional 3 days of reaction. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by a flash column chromatography (Wako Gel C200 (manufactured by Wako Pure Chemical Industries), eluant: hexane-ethyl acetate=3:1-1:1) and recrystallized from ethanol to obtain 201 mg of 2-carbamoyl-4-(4-fluorophenyl)-5-[2-[4-(3-fluorobenzylidene)piperidin-1-yl]ethyl]thiazole.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=1.[CH3:24][CH2:25][C@H:26]([NH2:29])[CH2:27][OH:28]>>[OH:28][CH2:27][C@@H:26]([NH:29][C:21]([C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:20][N:19]=1)=[O:23])[CH2:25][CH3:24]
Reactant: CC[C@H](N)CO
Reactant: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)O)nc1
Product: CC[C@@H](CO)NC(=O)c1ccc(OCc2c(-c3ccccn3)noc2C)cn1
Yield: 72 %

Procedure:
As described for example 7, 5-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridine-2-carboxylic acid (100 mg, 0.32 mmol) was converted, using S-(+)-2-amino-1-butanol instead of isopropylamine, to the title compound (89 mg, 72%), which was obtained as a white solid. MS: m/e=383.2 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S(O[CH2:29][C@H:30]1[CH2:34][CH2:33][CH2:32][N:31]1[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])(C1C=CC(C)=CC=1)(=O)=O>CN(C=O)C>[C:38]([O:37][C:35]([N:31]1[CH2:32][CH2:33][CH2:34][CH:30]1[CH2:29][O:17][C:14]1[CH:13]=[CH:12][C:11]([O:10][CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:16][CH:15]=1)=[O:36])([CH3:41])([CH3:39])[CH3:40]
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC1COc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 55.6 %

Procedure:
To a 15 mL of anhydrous DMF was added NaH (60% dispersion in oil, 338 mg, 8.44 mmol), and the resulting reaction mixture was cooled to 0° C. p-benzyloxy phenol (1.41 g, 7.03 mmol) was added and the reaction mixture was stirred at rt for 45 min. It was then cooled to −5° C., and (R)-Boc-prolinol tosylate (2.5 g, 7.03 mmol) in anhydrous DMF (5 mL) was cooled in a separate ice-bath and added dropwise to the reaction mixture. It was then allowed to warm to rt and stirred at 92° C. for 5 h and at rt overnight. The resulting mixture was poured into 200 mL ice/water and stirred for an hour. The resulting precipitate was filtered, washed with ether, dried over MgSO4, concentrated, recrystallized with ether/hexane to give shiny yellow crystals (1.5 g, 55%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[CH2:7][CH2:8][CH2:9][CH:10]([OH:12])[CH2:11][C:5]=2[CH:4]=1.[C:15](OC(C)=C)(=[O:17])[CH3:16]>C(OC(C)C)(C)C>[C:15]([O:12][C@@H:10]1[CH2:9][CH2:8][CH2:7][C:6]2[CH:13]=[CH:14][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[CH2:11]1)(=[O:17])[CH3:16]
Reactant: COc1ccc2c(c1)CC(O)CCC2
Reactant: C=C(C)OC(C)=O
Solvent: CC(C)OC(C)C
Product: COc1ccc2c(c1)C[C@H](OC(C)=O)CCC2
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of (RS)-3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-ol (221 g), isopropenyl acetate (380 ml) and lipase PS (Amano) (221 g) in diisopropyl ether (4.8 l) was stirred at ambient temperature for 4 days. The reaction mixture was filtrated (celite) and evaporated under reduced pressure. The residue was purified by flash chromatography (silica gel, using dichloromethane and dichloromethane-methanol (20:1) successively as eluents). The first eluate gave (R)-3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl acetate (138.2 g) as a pale yellow oil and the second eluate (S)-3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-ol (104.4 g) as a colorless powder.