Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]2[C:3]=1[CH:4]1[CH:9]([C:10]2=[O:16])[CH2:8][CH2:7][CH2:6][CH2:5]1.C(OC(=O)C)(=O)C.[CH3:24][N:25]([CH2:27]N(C)C)[CH3:26].[Cl-].[Na+]>>[CH3:24][N:25]([CH2:27][C:13]1[C:12]([OH:15])=[C:11]2[C:3]([CH:4]3[CH:9]([C:10]2=[O:16])[CH2:8][CH2:7][CH2:6][CH2:5]3)=[C:2]([CH3:1])[CH:14]=1)[CH3:26]
Reactant: Cc1ccc(O)c2c1C1CCCCC1C2=O
Reactant: CN(C)CN(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: Cc1cc(CN(C)C)c(O)c2c1C1CCCCC1C2=O
Temperature: 90 °C

Procedure:
A mixture of 25 g of 5-methyl-8-hydroxy-1,2,3,4,4a,9a-hexahydro-9-fluorenone, 62.5 ml of acetic anhydride and 18.88 ml of bisdimethylaminomethane was stirred with heating at 90° C. for 2 hours. The reaction mixture was left to stand for cooling and then to the reaction mixture was added saturated aqueous sodium chloride solution, followed by extraction with dichloromethane. The organic layer was dried with magnesium sulfate and then the solvent was distilled off. The residue was purified by a silica gel column chromatography (eluent: ethyl acetate:n-hexane=1:10) to obtain 14.37 g of 7-dimethylaminomethyl-8-hydroxy-5-methyl-1,2,3,4,4a,9a-hexahydro-9-fluorenone.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](Cl)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:40]1[S:44][N:43]=[CH:42][CH:41]=1)CCC.O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:40]3[S:44][N:43]=[CH:42][CH:41]=3)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccns1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(-c2ccns2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O

Procedure:
A solution of tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (60 mg, 0.120 mmol), 5-(tributylstannyl)isothiazole (67.2 mg, 0.180 mmol) and tetrakis(triphenylphosphine)palladium(0) (69.2 mg, 0.060 mmol) in toluene (2.0 mL) was heated to 120° C. for 45 minutes via microwave irradiation. The reaction mixture was subsequently poured into water and was extracted with EtOAc. The extracts were dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (Flash 60 column) eluting with hexane/EtOAc (1:1) to give the title compound as a yellow solid. ESI-MS m/z [M+H]+ calc'd for C25H32FN5O6S, 550. found, 550.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[C:17]([Cl:29])[CH:16]=2)[NH:7][N:6]=1.[NH:30]1[CH2:34][CH2:33][C@H:32]([OH:35])[CH2:31]1>>[Cl:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:30]4[CH2:34][CH2:33][C@H:32]([OH:35])[CH2:31]4)[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: O[C@H]1CCNC1
Reactant: ClCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: O[C@H]1CCN(CCOc2n[nH]c3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c23)C1
Yield: 17 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine and (S)-3-pyrrolidinol to give the title compound in 17% yield; NMR Spectrum: 1.50-1.54 (m, 1H), 1.91-1.96 (m, 1H), 2.40 (dd, 1H), 2.55 (dd, 1H), 2.66 (dd, 1H), 2.80-2.89 (m, 3H), 4.16 (br s, 1H), 4.40 (t, 2H), 4.69 (br s, 1H), 5.28 (s, 2H), 7.24 (d, 1H), 7.37 (t, 1H), 7.55-7.58 (m, 2H), 7.87 (t, 1H), 7.92 (d, 1H), 8.29 (s, 1H), 8.45 (s, 1H), 8.59 (d, 1H); Mass Spectrum: 482 (MH+).
Reaction SMILES: [OH-].[Na+].CO.[CH3:5][O:6][CH:7]([O:25][CH3:26])[CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21]C(=O)C.C(Cl)(Cl)Cl.CO>CO>[CH3:26][O:25][CH:7]([O:6][CH3:5])[CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][OH:21]
Reactant: COC(COCCOCCOCCOCCOC(C)=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(COCCOCCOCCOCCO)OC
Reaction time: 0.5 h
Yield: 76 %

Procedure:
1 N NaOH/Methanol (1 ml) was added to a stirring solution of acetic acid 2-(2-{2-[2-(2,2-dimethoxy-ethoxy)-ethoxy]-ethoxy}-ethoxy)-ethyl ester (Compound 4) (110 mg, 0.34 mmol) in methanol (3 ml) at ambient temperature. The reaction was monitored by TLC (CHCl3/MeOH, 9:1) and was completed within 30 minutes. The solvent was evaporated and the residue purified by flash chromatography (CHCl3/MeOH, 9:1) to afford the product (73 mg, 76%) as a colourless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH:10]([C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16])([CH3:12])[CH3:11]>>[CH:10]([C:13]1[CH:14]=[C:15]([NH:16][C:2]2[N:7]=[C:6]([NH:16][C:15]3[CH:17]=[CH:18][CH:19]=[C:13]([CH:10]([CH3:12])[CH3:11])[CH:14]=3)[C:5]([F:9])=[CH:4][N:3]=2)[CH:17]=[CH:18][CH:19]=1)([CH3:12])[CH3:11]
Reactant: CC(C)c1cccc(N)c1
Reactant: Fc1cnc(Cl)nc1Cl
Product: CC(C)c1cccc(Nc2ncc(F)c(Nc3cccc(C(C)C)c3)n2)c1

Procedure:
In like manner to the preparation of N2,N4-bis-(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3-isopropylaniline were reacted to give N2,N4-bis-(3-isopropylphenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 29.58 min.; Purity: 98%; MS (m/e): 365 (MH+); 1H NMR (DMSO-d6): δ 10.5 (1H, s), 10.34 (1H, s), 8.41 (1H, d, J=5.1 Hz), 7.62 (1H, d, J=8.1 Hz), 7.53 (1H, s), 7.43 (1H, d, J=8.1 Hz), 7.37 (2H, m), 7.29 (1H, t, J=8.1 Hz), 7.19 (1H, d, J=7.8 Hz), 7.08 (1H, d, J=7.8 Hz), 2.88 (2H, m), 1.25 (6H, d, J=7.2 Hz), 1.201 (6H, d, J=7.2 Hz).
Reaction SMILES: C[O:2][C:3](=[O:49])[C:4]([CH3:48])([CH3:47])[CH2:5][C@@H:6]1[CH2:11][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C@@H:9]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]3[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=3[CH:36]=2)[CH2:8][N:7]1[S:37]([C:40]1[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=1)(=[O:39])=[O:38].[OH-].[Na+]>O1CCCC1.C(O)C>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([C@@H:10]2[C@@H:9]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:8][N:7]([S:37]([C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)(=[O:38])=[O:39])[C@H:6]([CH2:5][C:4]([CH3:48])([CH3:47])[C:3]([OH:49])=[O:2])[CH2:11]2)=[CH:17][CH:16]=1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](CC(C)(C)C(=O)OC)C[C@@H]3c3ccc(OC)cc3)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](CC(C)(C)C(=O)O)C[C@@H]3c3ccc(OC)cc3)cc21
Temperature: 65 °C
Reaction time: 4 h

Procedure:
To a solution of 8.62 g of 3-[(2S,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-2,2-dimethyl-propionic acid methyl ester in 20 ml tetrahydrofuran and 50 ml ethanol are added 60 ml of a 20% sodium hydroxide solution. The reaction mixture is stirred for 4 hours at 65° C. The organic solvents are evaporated under reduced pressure and the remaining solution is acidified with 6M aqueous hydrochloric acid until pH 2. This mixture is extracted with 200 ml ethyl acetate (3×). The combined organic layers are washed with brine and dried with sodiumsulfate. The organic layer is filtered and evaporated under reduced pressure. The residue is purified by flash chromatography (SiO2 60 F) to afford the title compound as a colourless foam. Rf=0.27 (EtOAc-heptane 3:1); Rt=5.10.
Reaction SMILES: [Na].[OH2:2].Cl.Cl.[CH3:5][O:6][CH2:7][C:8]1[N:9]=[C:10](N2CCNCC2)[C:11]2[S:17][CH2:16][CH2:15][CH2:14][C:12]=2[N:13]=1>CO>[OH:2][C:10]1[C:11]2[S:17][CH2:16][CH2:15][CH2:14][C:12]=2[N:13]=[C:8]([CH2:7][O:6][CH3:5])[N:9]=1
Reactant: COCc1nc2c(c(N3CCNCC3)n1)SCCC2
Reactant: O
Agent: Cl
Agent: [Na]
Solvent: CO
Product: COCc1nc(O)c2c(n1)CCCS2

Procedure:
Sodium metal (0.46 g, 0.02 gr. atm.), was dissolved in methanol (I00 ml) and the product from step A was added. The reaction mixture was refluxed for 4 hours and then most of the solvent was removed in vacuo. The addition of water afforded 1.2 g of title compound which was dried and used in step C without further purification
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]2=[C:4]([Cl:11])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:17]1[O:18][CH:19]=[CH:20][N:21]=1)CCC>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:11][C:4]1[CH:3]=[C:2]([C:17]2[O:18][CH:19]=[CH:20][N:21]=2)[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]=12
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Reactant: Clc1cc(Cl)c2c(n1)CCC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Clc1cc(-c2ncco2)nc2c1CCC2
Temperature: 110 °C
Yield: 34.1 %

Procedure:
To a solution of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine (0.152 g, 0.81 mmol) in dioxane (3 mL) was added 2-(tributylstannyl)oxazole (0.318 g, 0.89 mmol) and tetrakis(triphenylphosphine)palladium (0.046 g, 0.040 mmol). The mixture was purged with nitrogen and then heated to 110° C. under sealed conditions for 16 h. After this time, the mixture was diluted with water and extracted with ethyl acetate. The organic layer were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, hexanes/ethyl acetate) to afford the title compound (0.061 g, 34%) as a white solid. MW=220.66. 1H NMR (CDCl3, 500 MHz) δ 7.94 (s, 1H), 7.78 (s, 1H), 7.29 (s, 1H), 3.19 (t, J=7.5 Hz, 2H), 3.06 (t, J=7.5 Hz, 2H), 2.22 (quin, J=7.5 Hz, 2H); APCI MS m/z 221 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].C([Sn](CCCC)(CCCC)[C:16]([O:18]CC)=[CH2:17])CCC.Cl>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:16]([C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8])(=[O:18])[CH3:17]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: NC(=O)c1cncc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(=O)c1cncc(C(N)=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.6 %

Procedure:
A mixture of 5-bromonicotinamide (2.5 g, 12.4 mmol), tributyl(1-ethoxyvinyl)tin (5.0 g, 13.8 mmol) and dichlorobis(triphenylphosphine)palladium(II) (800 mg, 1.1 mmol) in 25 mL toluene was heated to reflux for 3 hours. The mixture was cooled to room temperature, treated with 25 mL 2N HCl (aq.), and stirred for 1 hour. The aqueous layer was washed with ethyl acetate, adjusted to pH >7 with solid K2CO3, and extracted six times into 20% isopropanol/chloroform. The combined extracts were dried (Na2SO4), filtered, and concentrated to provide the desired product (1.6 g, 78%).
Reaction SMILES: [CH3:1][C@H:2]1[O:4][C@@:3]1([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:5].[CH3:12][SH:13].[Na]>CO>[CH3:12][S:13][C@H:2]([CH3:1])[C@@:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([OH:4])[CH3:5]
Reactant: C[C@H]1O[C@]1(C)c1ccccc1
Reactant: CS
Agent: [Na]
Solvent: CO
Product: CS[C@H](C)[C@](C)(O)c1ccccc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 107.2 %

Procedure:
To a solution of trans-2,3-dimethyl-2-phenyloxirane (14 g, 76 mmol) in methanol (100 mL) was added 15% aqueous sodium methyl mercaptan solution (61 mL, 190 mmol) under nitrogen atmosphere at room temperature, and the mixture was warmed to 60° C. and stirred for 2 hours. The mixture was concentrated under reduced pressure, and the residue was extracted twice with diethyl ether (50 mL), sequentially washed with water (50 ml) and saturated aqueous sodium chloride solution (50 mL), and dried over sodium sulfate. The resultant mixture was filtrated and the solvent was evaporated to give the title compound (16 g, yield 99%) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH2:13])(=[O:12])=[O:11].[C:16](=S)=[S:17].[OH-].[K+].C(OCC)(=O)C>CN(C)C=O>[F:15][C:2]([F:1])([F:14])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]=[C:16]=[S:17])(=[O:11])=[O:12]
Reactant: S=C=S
Reactant: NS(=O)(=O)c1ccccc1OC(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=S(=O)(N=C=S)c1ccccc1OC(F)(F)F
Temperature: 35 °C

Procedure:
24.1 g (0.1 mole) of 2-trifluoromethoxy-benzene-sulphonic acid amide are dissolved in 100 ml of dimethylformamide. 7.6 g (0.1 mole) of carbon disulphide and 5.6 g (0.1 mole) of potassium hydroxide powder are added and the reaction mixture is stirred at 35° C. until a clear solution has formed. A further 5.6 g (0.1 mole) of potassium hydroxide powder are then added and stirring is continued until a clear solution is formed. 100 ml of ethyl acetate are then added dropwise at 20° C. The product thereby obtained as crystals is isolated by filtration with suction and dried under reduced pressure. The dried product is suspended in 100 ml of toluene; 20 g of liquid phosgene are added dropwise at 0° C. and the mixture is stirred at 5° C. to 10° C. for one hour and at 20° C. for two hours. After filtration, the filtrate is concentrated to give an oily residue, which essentially contains 2-trifluoromethoxy-phenylsulphonyl isothiocyanate. Because of its low stability, the product is reacted as quickly as possible--without further purification--in the process according to the invention.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][N:6]=1)=[O:4].[CH2:19]=O>C(O)=O>[CH3:19][N:11]([C:8]1[CH:9]=[CH:10][C:5]([C:3]([OH:2])=[O:4])=[N:6][CH:7]=1)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(NCc2ccccc2)cn1
Reactant: C=O
Solvent: O=CO
Product: CN(Cc1ccccc1)c1ccc(C(=O)O)nc1

Procedure:
The mixture of 4.84 g of 5-benzylaminopyridine-2-carboxylic acid methyl ester, 8 ml of 97% aqueous formic acid and 8 ml of 37% aqueous formaldehyde is heated on a steam bath for 22 hours. It is evaporated, the residue dissolved in water and the solution again evaporated. A third such cycle with acetonitrile-toluene yields a solid which is recrystallized from 90% aqueous acetonitrile, to yield the 5-(N-methyl-N-benzylamino)-pyridine-2-carboxylic acid melting at 168°-173°.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([C:11]3[O:20][C:14]4=[C:15]([NH2:19])[N:16]=[CH:17][CH:18]=[C:13]4[CH:12]=3)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.C1C(=O)N([I:28])C(=O)C1>CN(C=O)C>[I:28][C:18]1[CH:17]=[N:16][C:15]([NH2:19])=[C:14]2[O:20][C:11]([C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:5]=3[CH:4]=[CH:3][N:2]=[CH:1]4)=[CH:12][C:13]=12
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1nccc2cc(-c3cccc4cnccc34)oc12
Solvent: CN(C)C=O
Product: Nc1ncc(I)c2cc(-c3cccc4cnccc34)oc12
Reaction time: 0.08 h
Yield: 84.1 %

Procedure:
A suspension of 2-(isoquinolin-5-yl)furo[2,3-c]pyridin-7-amine (5.6 g, 21.5 mmol) in DMF (250 mL) was treated with NIS (8.73 g, 38.6 mmol) added portionwise with stirring over a period of 5 min. The mixture was stirred at RT overnight. The reaction was quenched with aqueous Na2S2O3, diluted with EtOAc (1 L) and the phases separated. The organic layer was concentrated in vacuo. Water was added to the residue resulting in the formation of a solid after stirring overnight. The material was collected by filtration and the filter cake was washed with water and hexane. The material was dried over P2O5 at 50° C. in a high vacuum oven to provide 7.0 g (84%) of the title compound as a brown solid. 1H NMR (300 MHz, CDCl3+CD3OD): δ 6.92 (s, 1H), 7.70 (t, J=8.1 Hz, 1H), 7.98 (s, 1H), 8.11 (t, J=7.5 Hz, 2H), 8.20 (d, J=6.0 Hz, 1H), 8.53 (d, J=6.0 Hz, 1H), 9.24 (s, 1H).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([NH2:11])[CH2:3][CH2:2]1.[Br:12]Br>CC(O)=O>[Br:12][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[O:1][CH2:2][CH2:3][CH:4]2[NH2:11]
Reactant: NC1CCOc2ccccc21
Reactant: BrBr
Solvent: CC(=O)O
Product: NC1CCOc2ccc(Br)cc21
Temperature: 25 °C

Procedure:
A solution of chroman-4-ylamine (2.550 g, 17.09 mmol) in AcOH (50 mL) at RT was treated with Br2 (3.01 g, 0.96 mL, 18.8 mmol) drop-wise. The reaction was stirred at RT until HPLC analysis showed complete consumption of starting material. The mixture was diluted with H2O (100 mL) and NaOH was added until the solution became basic. The aqueous layer was extracted with EtOAc until tlc analysis of the aqueous layer showed no evidence of the title compound. The combined organics were dried over MgSO4 and concentrated in vacuo to yield the crude compound, which was purified by flash column chromatography to afford the pure title compound. MS (APCI pos) 229 (M+H).
Reaction SMILES: Cl.Cl.[CH:3]1([CH2:6][N:7]([CH3:14])[CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH2:5][CH2:4]1.[F:15][C:16]([F:46])([F:45])[C:17]1[CH:18]=[C:19]([CH2:27][CH2:28][N:29]([CH3:44])[C:30](=[O:43])[CH:31](OS(C)(=O)=O)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1.C(N(CC)CC)C>CC(C)=O.C(=O)([O-])O.[Na+]>[F:15][C:16]([F:45])([F:46])[C:17]1[CH:18]=[C:19]([CH2:27][CH2:28][N:29]([CH3:44])[C:30](=[O:43])[CH:31]([N:11]2[CH2:12][CH2:13][CH:8]([N:7]([CH2:6][CH:3]3[CH2:4][CH2:5]3)[CH3:14])[CH2:9][CH2:10]2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:20]=[C:21]([C:23]([F:25])([F:26])[F:24])[CH:22]=1
Reactant: CN(CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)C(OS(C)(=O)=O)c1ccccc1
Reactant: CN(CC1CC1)C1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CN(CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)C(c1ccccc1)N1CCC(N(C)CC2CC2)CC1
Yield: 37.3 %

Procedure:
11.9 g of 4-(cyclopropylmethyl-methyl-amino)-piperidine-dihydrochloride are taken up in 400 ml of acetone and combined with 21.7 g of N-[2-(3.5-bis-trifluoromethyl-phenyl)-ethyl]-2-methanesulphonyloxy-N-methyl-2-phenyl-acetamide and 21 ml of triethylamine. The mixture is refluxed for 16 hours, then the solvent is eliminated in vacuo and the residue is taken up in 10% sodium hydrogen carbonate solution. It is extracted with ether, the combined organic phases are dried over sodium sulphate and the solvent is eliminated in vacuo. The residue is filtered with ethyl acetate/methanol/conc. ammonia solution 70:30:1 through silica gel, freed from the solvents in vacuo and crystallised in methanol with fumaric acid. The precipitate is suction filtered, washed with methanol and dried in vacuo. 9.3 g of N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-[4-(cyclopropylmethyl-methyl-amino)-piperidin-1-yl]-N-methyl-2-phenyl-acetamide are obtained as the sesquifumarate.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH:5]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([N:22]([C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:23][CH:24]([CH3:26])[CH3:25])[CH:15]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1)C.[OH-].[Na+]>CO.O1CCCC1>[Br:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([N:22]([C:27](=[O:32])[C:28]([CH3:29])([CH3:31])[CH3:30])[CH2:23][CH:24]([CH3:26])[CH3:25])[CH:15]=2)[C:4]([OH:33])=[O:3])=[CH:12][CH:11]=1
Reactant: CCOC(=O)C(Cc1ccc(Br)cc1)c1ccc(OC)c(N(CC(C)C)C(=O)C(C)(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(C(Cc2ccc(Br)cc2)C(=O)O)cc1N(CC(C)C)C(=O)C(C)(C)C

Procedure:
Thus obtained 3-(4-bromophenyl)-2-{3-[(2,2-dimethylpropionyl)isobutylamino]-4-methoxyphenyl} propionic acid ethyl ester (104 mg, 0.2 mmol) was dissolved in a mixed solvent of methanol (3 mL) and tetrahydrofuran (3 mL), and the mixture was added with a 2 mol/L aqueous sodium hydroxide solution (3 mL, 6 mmol). The solution was evaporated under reduced pressure so as to remove the solvent, the resultant residue was added with water to be dissolved, and the solution was washed with diethyl ether. The separated aqueous phase was added with a 1 mol/L hydrochloric acid so as to adjust pH of the solution as low as 4 or below. The solution was then extracted with ethyl acetate, the extract was dried over anhydrous sodium sulfate, evaporated under reduced pressure so as to remove the solvent, to thereby obtain 3-(4-bromophenyl)-2-{3-[(2,2-dimethylpropionyl)isobutyl amino]-4-methoxyphenyl}propionic acid (yield: 89 mg, yield ratio: 90%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:17]2[CH2:16][CH2:15][C:14]3[C:10](=[CH:11][N:12](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:13]=3)[C:9]=2[N:8]([CH3:37])[C:7]=1C(OC(C)(C)C)=O)=[O:5])[CH3:2]>CCO.Cl>[CH2:1]([O:3][C:4]([C:6]1[C:17]2[CH2:16][CH2:15][C:14]3[NH:13][N:12]=[CH:11][C:10]=3[C:9]=2[N:8]([CH3:37])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c2c(n(C)c1C(=O)OC(C)(C)C)-c1cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)nc1CC2
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cn(C)c2c1CCc1[nH]ncc1-2
Temperature: 80 °C

Procedure:
To a mixture of 1-methyl-7-trityl-1,4,5,7-tetrahydro-1,6,7-triaza-as -indacene-2,3-dicarboxylic acid 2-tert-butyl ester 3-ethyl ester VI (2.4 mmol) in EtOH (60 mL), 2N HCl (6 mL) was added and the reaction was heated at 80° C. for 2 h. The solvent was evaporated and the residue was washed twice with DCM/hexane. The title product was obtained as a solid (98% yield). ESI (+) MS: m/z 246 (MH+). 1H NMR: 1.27 (t, 3H), 2.78 (t, 2H), 2.97 (dt, 2H), 3.74 (s, 3H), 4.18 (q, 2H), 7.32 (s, 1H), 7.82 (s, 1H).
Reaction SMILES: [N:1]1[N:2]=[N:3][N:4]2[CH:9]=[C:8]([C@@H:10]3[CH2:12][O:11]3)[CH:7]=[CH:6][C:5]=12.[NH2:13][C:14]([CH3:26])([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[CH3:15]>C(O)C>[CH3:26][C:14]([NH:13][CH2:12][C@@H:10]([C:8]1[CH:7]=[CH:6][C:5]2[N:4]([N:3]=[N:2][N:1]=2)[CH:9]=1)[OH:11])([CH3:15])[CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1
Reactant: c1cc2nnnn2cc1[C@@H]1CO1
Reactant: COc1ccc(CCC(C)(C)N)cc1
Solvent: CCO
Product: COc1ccc(CCC(C)(C)NC[C@H](O)c2ccc3nnnn3c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.7 %

Procedure:
A solution of 509 mg (3.13 mmol) of (R)-2-(tetrazolo[1,5-a]pyrid-6-yl)oxirane and 619 mg (3.21 mmol) of 2-amino-2-methyl-4-(4-methoxyphenyl)butane in 25 ml of absolute ethanol was heated at reflux for two hours and then stirred overnight at room temperature. The reaction mixture was concentrated and the residue chromatographed on silica gel (4:1:2 ethyl acetate:n-propanol:water with 1% NH4OH) to give 497 mg of product. Recrystallization from isopropanol afforded 357 mg of crystalline tetrazole, mp. 139-40° C.