Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:10][C:9](=[S:18])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[CH2:24][Cl:25]>CCO>[ClH:25].[CH3:32][O:31][C:27]1[CH:26]=[C:23]([CH:22]=[C:21]([O:20][CH3:19])[C:28]=1[O:29][CH3:30])[CH2:24][S:18][C:9]1[NH:8][C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C@H:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=1
Reactant: S=C1N[C@H](c2ccccc2)[C@H](c2ccccc2)N1
Reactant: COc1cc(CCl)cc(OC)c1OC
Solvent: CCO
Product: COc1cc(CSC2=N[C@@H](c3ccccc3)[C@@H](c3ccccc3)N2)cc(OC)c1OC
Product: Cl
Temperature: 25 °C
Yield: 25.1 %

Procedure:
A mixture of intermediate 25 (200 mg, 0.786 mmol) and 3,4,5-trimethoxybenzyl chloride (0.340 mg, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C. for 24 h. The reaction mixture is cooled to RT, evaporated to dryness, and the residue suspended in Et2O. The insoluble material is filtered to give 93 mg of the product 217. 1H NMR (DMSO-d6) δ 11.10 (m, 2 H), 7.25-6.90 (m, 8 H), 6.90-6.70 (m, 4 H), 5.80 (d, 2 H), 4.70 (s, 1 H), 3.78 (s, 6 H), 3.70 (s, 1 H)
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[C:6]([C:15]#[N:16])[C:5]=1[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[Cl:24])(=[O:3])[CH3:2].CO[CH:27](OC)[N:28]([CH3:30])[CH3:29]>>[Cl:24][C:18]1[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=1[C:5]1[C:6]([C:15]#[N:16])=[C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[S:8][C:4]=1[C:1](=[O:3])[CH:2]=[CH:27][N:28]([CH3:30])[CH3:29]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1sc(N2CCOCC2)c(C#N)c1-c1ccc(Cl)cc1Cl
Product: CN(C)C=CC(=O)c1sc(N2CCOCC2)c(C#N)c1-c1ccc(Cl)cc1Cl

Procedure:
A solution of 5-acetyl-4-(2,4-dichlorophenyl)-2-morpholin-4-ylthiophene-3-carbonitrile (52.3 mg, 0.000137 mol) in 1,1-dimethoxy-N,N-dimethylmethanamine (1.0 mL, 0.0075 mol) was flushed with argon and irradiated in microwave at 160° C. for 30 min. The reaction mixture was evaporated to dryness to give 4-(2, 4-dichlorophenyl)-5-(3-(dimethylamino)acryloyl)-2-morpholinothiophene-3-carbonitrile as an intermediate. The above intermediate and hydrazine hydrate (30 mg, 0.0006 mol) in AcOH (1.5 mL, 0.026 mol) was irradiated in microwave at 120° C. for 15 min. The reaction mixture was evaporated and the residue was purified by column chromatography to afford 4-(2,4-dichlorophenyl)-2-morpholino-5-(1H-pyrazol-5-yl)thiophene-3-carbonitrile (19.5 mg, 84%). LCMS: (FA) ES+ 405.06, ES− 403.23; 1H NMR (400 MHz, d4-methanol) δ: 7.65 (d, 1H), 7.45 (m, 2H), 7.33 (d, 1H), 5.48 (s, 1H), 5.45 (br, 1H), 3.85 (m, 4H), 3.54 (m, 4H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][C:12]3[N:13]=[C:14]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[S:15][C:16]=3[C:17]([O:19]CC)=[O:18])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.O1CCCC1.CO.[OH-].[Li+].Cl>O>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][C:12]3[N:13]=[C:14]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[S:15][C:16]=3[C:17]([OH:19])=[O:18])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1sc(N2CCOCC2)nc1Cc1ccc2c(c1)OCCO2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1sc(N2CCOCC2)nc1Cc1ccc2c(c1)OCCO2
Temperature: 25 °C
Yield: 83.9 %

Procedure:
Ethyl 4-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-2-(morpholin-4-yl)-1,3-thiazole-5-carboxylate (58.0 mg, 0.000148 mol) was placed in a 50 ml round bottom flask equipped with a stirbar. Tetrahydrofuran (2.25 mL, 0.0277 mol) and methanol (0.50 mL, 0.012 mol) were added and the mixture was stirred to give a clear solution. A solution of lithium hydroxide in water (2.0M, 0.750 mL, 0.00150 mol) was added in a single portion, resulting in a pale yellow solution which was stirred at room temperature under an atmosphere of nitrogen for 15 minutes. The reaction was then heated at reflux for 2.5 hours, cooled to rt, and diluted with water (˜25 ml) to give a clear slightly gray solution, which was allowed to stir at room temperature overnight under an atmosphere of nitrogen. 1 N HCl (˜1.8 ml) was slowly added to the stirring solution to lower the pH to ˜3 (pH paper) whereupon a white precipitate formed. The mixture was stirred for ˜15 minutes, at which point the solid was collected on a flitted funnel, washed with water, and dried on the funnel with house vacuum under a stream of nitrogen for several hours to yield 4-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-2-(morpholin-4-yl)-1,3-thiazole-5-carboxylic acid (110) (45 mg, 84% yield) as a slightly gray powder. LC/MS (FA) ES+ 363; 1H NMR (300 MHz, DMSO) δ 12.65 (s, 1H), 6.76-6.64 (m, 3H), 4.17 (s, 4H), 4.08 (s, 2H), 3.77-3.61 (m, 4H), 3.51-3.34 (m, 4H).
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH:20]([CH3:22])[CH3:21])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[F:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34](O)=[O:35])=[CH:26][CH:25]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34]([NH:1][CH:2]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH:20]([CH3:22])[CH3:21])[CH:14]=2)[CH:3]([C:5]2[CH:6]=[CH:7][C:8]([F:11])=[CH:9][CH:10]=2)[OH:4])=[O:35])=[CH:26][CH:25]=1
Reactant: CC(C)Oc1cccc(CC(N)C(O)c2ccc(F)cc2)c1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: CC(C)Oc1cccc(CC(NC(=O)c2ccc(F)c3ccccc23)C(O)c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[3-(isopropyloxy)phenyl]-1-propanol (0.46 g, 1.5 mmol) and 4-fluoronaphthalene-1-carboxylic acid (0.34 g, 1.8 mmol) in acetonitrile (20 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.36 g, 2.1 mmol) and 1-hydroxybenzotriazole hydrate (0.32 g, 2.1 mmol), and the mixture was stirred at room temperature for 5 hrs. To the reaction solution was added water (100 ml), and the mixture was extracted with ethyl acetate (100 ml×2). The extract was washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform:ethyl acetate=10:1) to give the objective substance (0.65 g, 91%) as crystals.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([N:14]1[CH2:18][C@H:17]([S:19][C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][C@H:15]1[C:39](O)=[O:40])(=[O:13])=[O:12].[NH2:42][C@H:43]([C:57]1[N:61]([CH2:62][CH2:63][C:64]#[N:65])[N:60]=[N:59][N:58]=1)[CH2:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[CH:47][CH:46]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[C:48]1([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH:49]=[CH:50][C:45]([CH2:44][C@H:43]([NH:42][C:39]([C@@H:15]2[CH2:16][C@@H:17]([S:19][C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:18][N:14]2[S:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)(=[O:12])=[O:13])=[O:40])[C:57]2[N:61]([CH2:62][CH2:63][C:64]#[N:65])[N:60]=[N:59][N:58]=2)=[CH:46][CH:47]=1
Reactant: O=C(O)[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1S(=O)(=O)c1ccc2ccccc2c1
Reactant: N#CCCn1nnnc1[C@@H](N)Cc1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: N#CCCn1nnnc1[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1S(=O)(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.7 %

Procedure:
A solution of 520 mg (0.9 mmol) (2S,4R)-1-(Naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidine-2-carboxylic acid and 315 mg (1 mmol) (1S)-3-[5-(1-Amino-2-biphenyl-4-yl-ethyl)-tetrazol-1-yl]-propionitrile [S. De Lombaert. Preparation of tetrazolylalkylaminomethylphosphonates as neutral endopeptidase inhibitors. U.S., 17 pp. CODEN: USXXAM. U.S. Pat. No. 5,273,990 A 931228] in 5 ml THF was cooled to 0° C. and treated with 206 mg (1.1 mmol) EDCI and 14 mg (0.09 mmol) HOBT. The reaction was stirred for 3 h at RT and partitioned between aqueous 10% KHSO4/ethyl acetate (3×). The organic phases were washed with aqueous saturated NaHCO3 solution and dried over Na2SO4. Purification by flash-chromatography on silicagel (Hexane/EtOAc 1:1) gave 639 mg (81%) (2S,4R)-1-(Naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidine-2-carboxylic acid [(S)-2-biphenyl-4-yl-1-[1-(2-cyano-ethyl)- 1H-tetrazol-5-yl]-ethyl]-amide, Mp: 122-133 slow dec, MS: 880 (MH+).
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1.C([O-])(O)=O.[Na+].[O:15](C(OC(C)(C)C)=O)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=O.Cl>O1CCOCC1.O>[C:19]([O:18][C:16]([N:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1)=[O:15])([CH3:22])([CH3:21])[CH3:20]
Reactant: O=C(O)C1CCNCC1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reaction time: 3 h
Yield: 90.7 %

Procedure:
A solution of isonipecotic acid (18) (2.6 g, 20 mmol) in 1,4-dioxane/H2O (3:2, 100 mL) was treated with NaHCO3 (8.4 g, 100 mmol, 20 mL H2O), followed by t-Boc2O (4.8 g, 22 mmol) at room temperature. After stirring for 3 h, the solution was acidified with 1 N HCl (50 mL), extracted with EtOAc (3×100 mL). The combined organic extracts were washed with saturated solution of NaHCO3 (50 mL), brine (50 mL), dried over MgSO4 and concentrated to give a white solid (19) (4.16 g, 91%). 1H NMR (500 MHz, CDCl3) δ 4.02 (br s, 2H), 2.86 (t, J=12.0 Hz, 2H), 2.50 (tt, J=11.0, 4.0 Hz, 1H), 1.91 (dd, J=13.0, 2.5 Hz, 2H), 1.65 (m, 2H), 1.46 (s, 9H), MS (ESI−) m/z 228.65 (M−H−).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[F:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][CH:8]=1.C1(C)C=CC(S(OC(C)CC[O:30][Si:31]([C:44]([CH3:47])([CH3:46])[CH3:45])([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)(=O)=O)=CC=1.Cl>C1COCC1.C(OCC)(=O)C>[Si:31]([O:30][C:13]([C:10]1[CH:9]=[CH:8][C:7]([F:6])=[CH:12][CH:11]=1)([CH:2]([CH3:1])[CH2:3][CH3:4])[C:14]([OH:16])=[O:15])([C:44]([CH3:46])([CH3:45])[CH3:47])([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Cc1ccc(S(=O)(=O)OC(C)CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: [Li]CCCC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(C)C(O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)(C(=O)O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
n-Butyl lithium (4.89 mL; 2.66 M solution in hexane) was added dropwise to a solution of 4-fluorophenylacetic acid (1 g) in THF (30 mL) at −78° C., and the reaction solution was stirred for 20 minutes. The reaction solution was heated to 0° C. and stirred for 30 minutes. Then, a solution of 3-(tert-butyldiphenylsilanyloxy)-1-methylpropyl toluene-4-sulfonate (3.2 g) in THF (10 mL) was added dropwise to the reaction solution. The reaction solution was heated to room temperature and stirred at the same temperature for 12 hours. Then, 1 N hydrochloric acid and ethyl acetate were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 986 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.[NH2:44][C:45]1([CH3:56])[CH2:48][N:47]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:46]1>CN(C=O)C.CN(C1C=CN=CC=1)C.O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:44][C:45]5([CH3:56])[CH2:48][N:47]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:46]5)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: CC1(N)CN(C(=O)OC(C)(C)C)C1
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(F)cc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC4(C)CN(C(=O)OC(C)(C)C)C4)c3n2)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.2 %

Procedure:
To a stirred solution of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (80 mg, 0.26 mmol) and DIEA (83 mg, 0.64 mmol) in 6 mL of DMF were added EDCI (98 mg, 0.51 mmol) and DMAP (88 mg, 0.72 mmol) at room temperature. 20 minutes later, tert-butyl 3-amino-3-methylazetidine-1-carboxylate (95 mg, 0.51 mmol) was added in one portion and the mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into 40 mL of water, filtered and the filter cake was washed with petroleum ether to give crude tert-butyl 3-(2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamido)-3-methylazetidine-1-carboxylate (75 mg, 76.9%) as a yellow solid. MS: (M+H)+=480.1.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:27](O)=[O:28])[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].[CH:30]1([N:33]2[CH2:38][CH2:37][CH:36]([C:39](=[N:41]O)[NH2:40])[CH2:35][CH2:34]2)[CH2:32][CH2:31]1>>[CH:30]1([N:33]2[CH2:38][CH2:37][CH:36]([C:39]3[N:41]=[C:27]([CH:13]4[CH2:14][CH:15]([C:17]5[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=5)[CH2:16][N:11]([C:9]([N:6]5[CH2:7][CH2:8][CH:3]([C:1]#[N:2])[CH2:4][CH2:5]5)=[O:10])[CH2:12]4)[O:28][N:40]=3)[CH2:35][CH2:34]2)[CH2:31][CH2:32]1
Reactant: N#CC1CCN(C(=O)N2CC(C(=O)O)CC(c3ccc(C(F)(F)F)cc3)C2)CC1
Reactant: NC(=NO)C1CCN(C2CC2)CC1
Product: N#CC1CCN(C(=O)N2CC(c3ccc(C(F)(F)F)cc3)CC(c3nc(C4CCN(C5CC5)CC4)no3)C2)CC1

Procedure:
155 mg (0.363 mmol) of the compound from Example 100A and 100 mg (0.545 mmol) of the compound from Example 75A were reacted according to the General Method 2. Yield: 76 mg (38% of theory)
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]1[S:13][C:12]([S:14]([N:17]2[CH2:22][CH2:21][CH:20]([C:23](N(OC)C)=[O:24])[CH2:19][CH2:18]2)(=[O:16])=[O:15])=[CH:11][CH:10]=1)[CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3].[CH2:29]([Li])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].Cl.CCO>C1COCC1>[CH2:1]([N:4]([CH2:8][C:9]1[S:13][C:12]([S:14]([N:17]2[CH2:18][CH2:19][CH:20]([C:23](=[O:24])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:21][CH2:22]2)(=[O:16])=[O:15])=[CH:11][CH:10]=1)[CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3]
Reactant: C=CCN(CC=C)Cc1ccc(S(=O)(=O)N2CCC(C(=O)N(C)OC)CC2)s1
Reactant: [Li]CCCCCC
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: C=CCN(CC=C)Cc1ccc(S(=O)(=O)N2CCC(C(=O)CCCCCC)CC2)s1
Temperature: -20 °C
Reaction time: 3 h
Yield: 46.7 %

Procedure:
327b (376 mg, 0.88 mmol) was dissolved in anhydrous THF and cooled to −20° C. To this solution was added dropwise at −20° C. hexyllithium (2M in hexane) (2.46 mL, 6.2 mmol). The reaction was allowed to warm to rt. during 3 h and poured on 100 mL HCl/EtOH (5%). The aqueous phase was extracted with CH2Cl2 and the combined organic layers are washed with NaOH (2N) and brine, dried over MgSO4 and evaporated to dryness. The crude material was purified by flash chromatography on silica gel using cyclohexane/EtOAc 4:1 as eluent to obtain 186 mg (47%) of (327c) as a brownish oil: H1 NMR (CDCl3) δ 7.40 (d, J=3.6 Hz, 1H), 725 (d, J=3.6 1H), 5.95 (m, 2H), 5.50 (m, 4H), 4.32 (s, 2H), 3.70-3.50 (m, 6H), 2.50 (m, 2H), 2.32 (m, 3H), 1.85 (m, 2H), 1.68 (m, 2H), 1.46 (m, 2H), 0.130-1.12 (m, 6H), 0.80 (t, J=6.6 Hz, 3H), M/Z APCI: 453.2 (M+1)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=[O:6].ClC1C=C2C([CH:16]=[CH:17][N:18]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)C2=O)=CC=1F>>[F:10][C:9]1[CH:8]=[C:7]2[C:4](=[CH:3][C:2]=1[CH3:1])[C:5](=[O:6])[N:18]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1)[CH:17]=[CH:16]2
Reactant: Cc1cc(C=O)ccc1F
Reactant: COc1ccc(Cn2ccc3cc(F)c(Cl)cc3c2=O)cc1
Product: COc1ccc(Cn2ccc3cc(F)c(C)cc3c2=O)cc1

Procedure:
Starting from 3-methyl-4-fluoro benzaldehyde, the title compound was prepared following a similar sequence as described for 7-chloro-6-fluoro-2-(4-methoxy-benzyl)-2H-isoquinolin-1-one (62). Rt=1.83 min (Method B). Detected mass: 298.1 (M+H+).
Reaction SMILES: I[C:2]1[N:3]=[C:4]([NH2:23])[C:5]2[N:6]=[C:7]([NH:20][CH2:21][CH3:22])[N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[CH:24]#[C:25][CH2:26][CH2:27][CH2:28][CH3:29]>>[C:24]([C:2]1[N:3]=[C:4]([NH2:23])[C:5]2[N:6]=[C:7]([NH:20][CH2:21][CH3:22])[N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11])#[C:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCNc1nc2c(N)nc(I)nc2n1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: C#CCCCC
Product: CCCCC#Cc1nc(N)c2nc(NCC)n([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1

Procedure:
The reaction was performed with 2-iodo-8-ethylaminoadenosine (8, 67 mg, 0.15mmol) and 1-hexyn (0.73 mmol). The mixture was purified by column chromatography (EtOAc-10% MeOH in EtOAc). Yield 49 mg (0.12 mmol, 83%), mp230–232÷C; 1H NMR (DMSO-d6) δ 6.97 (t, 1H, J=4.80 Hz, NH), 6.57 (s, 2H, NH2), 5.86 (d, 1H, J=7.55 Hz, H-1′), 5.74 (t, 1H, J=4.80 Hz, OH-2′), 5.25 d, 1H, J=6.52 Hz, OH-5′), 5.15 (d, 1H, J=4.12 Hz, OH-3′), 4.57 (q, 1H, J=6.18 Hz, H-2′), 4.08 (m, 1H, H-3′), 3.95 (m, 1H, H4′), 3.64–3.60 (m, 2H, H-5′), 3.05 (m, 2H, NHCH2), 2.36 (t, 2H, J=7.21 Hz, ≡CHCH2), 1.51–1.40 (m, 4H, CH2CH2CH3), 1.16 (t, 3H, J=7.20 Hz, NHCH2CH3), 0.89 (t, 3H, J=5.15 Hz, CH3); MS m/z 391 (M+H)+; Anal. (C18H26N6O4) C, H, N.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[C:4](F)[CH:3]=1.CN([CH:16]=[O:17])C.C[O-].[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[C:4]([O:17][CH3:16])[CH:3]=1
Reactant: Fc1cc(Br)ccc1C(F)(F)F
Reactant: CN(C)C=O
Agent: C[O-]
Agent: [Na+]
Product: COc1cc(Br)ccc1C(F)(F)F
Temperature: 0 °C
Yield: 45.5 %

Procedure:
To a 250 mL round-bottomed flask was added 4-bromo-2-fluoro-1-(trifluoromethyl)benzene (12 mL, 50 mmol) and DMF (4.0 mL, 50 mmol). The solution was stirred at 0° C. and treated with sodium methoxide (4 g, 75 mmol). The reaction mixture was stirred at room temperature for 30 minutes and 60° C. for 2 hours. The resulting milky suspension was quenched with ice at 0° C. and the separated aqueous layer was extracted with EtOAc (3×50 mL). The combined organic layers were washed with saturated sodium chloride (1×25 mL), dried over Na2SO4, and concentrated to give the crude residue which was purified with flash column chromatography ((5%→20% EtOAc in hexane) to provide 4-bromo-2-methoxy-1-(trifluoromethyl)benzene (5.80 g, 46% yield) as a light yellow oil. m/z (%): 256.1.2 (100%, M++H).
Reaction SMILES: C([O:3][C:4]([C:6]1([S:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.[CH2:32]1[CH2:36]OC[CH2:33]1.CO>[OH-].[Na+]>[CH2:31]([O:30][C:27]1[CH:26]=[CH:25][C:24]([S:21]([C:6]2([C:4]([OH:3])=[O:5])[CH2:11][CH2:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[CH2:8][CH2:7]2)(=[O:22])=[O:23])=[CH:29][CH:28]=1)[CH2:33][CH2:32][CH3:36]
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(Cc2cccc(OC)c2)CC1
Reactant: C1CCOC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3cccc(OC)c3)CC2)cc1

Procedure:
4-(4-Butoxy-benzenesulfonyl)-1-(3-methoxy-benzyl)-piperdine-4-carboxylic acid was prepared stariing from 4-(4methoxy-benzenesulfonyl)-1-(3-methoxy-benzyl)-piperidine-4-carboxylic acid ethyl ester (2.61 g, 5.34 mmol) dissolved in THF:methanol (3:1 150 ml) and 10 N NaOH (15 ml). The resulting reaction mixture was worked up asoutlined in example 83. Yield 1 g (41%); brown solid; mp 175° C.; MS: 462.0 (M+H)+
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[O:13][CH3:14].C[N:16]([C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[CH2:17][CH2:18]O.[CH:30]1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:14][O:13][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:2]=1[O:1][CH2:30][CH:17]([CH3:18])[NH:16][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CN(CCO)C(=O)OCc1ccccc1
Reactant: CCOC(=O)c1ccc(O)c(OC)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(OCC(C)NC(=O)OCc2ccccc2)c(OC)c1

Procedure:
To a stirred solution of ethyl 4-hydroxy-3-methoxybenzoate (2.01 g, 10.25 mmol), N-methyl-N-(benzyloxycarbonyl)ethanolamine (2.11 g, 10.08 mmol), PPh3 (3.26 g, 12.43 mmol) in THF was added DIAD (2.65 mL, 13.46 mmol) and the reaction mixture was heated under reflux overnight. The mixture was evaporated, and the residue was subjected to short column chromatography on silica-gel with n-hexane/EtOAc (5:1, v/v) as eluent to give ethyl 3-methoxy-4-[2-methyl-2-(benzyloxycarbonyl)aminoethoxy]benzoate as a crude product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]3)=[C:13]([O:23][CH3:24])[CH:12]=2)[N:3]=1.[OH:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1>>[CH3:24][O:23][C:13]1[CH:12]=[C:11]([NH:10][C:4]2[N:5]=[C:6]([O:8][CH3:9])[N:7]=[C:2]([O:25][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[N:3]=2)[CH:16]=[CH:15][C:14]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1
Reactant: COc1nc(Cl)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Reactant: Oc1cccnc1
Product: COc1nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)nc(Oc2cccnc2)n1

Procedure:
The title compound was prepared from (4-chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine and 3-hydroxypyridine in analogy to example 3. It was purified by column chromatography on Si—NH2 gel (Isolute) using ethyl acetate as eluent to give the title compound as a yellowish solid in 21% yield.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][C:6]=1[C:12]1[C:20]2[C:15](=[C:16]([O:21][CH3:22])[N:17]=[CH:18][CH:19]=2)[N:14]([CH3:23])[CH:13]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31].C(N(CC)CC)C.[OH-].[Na+]>ClCCl.O1CCOCC1>[F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[CH:11]=[CH:10][C:8]([NH:9][S:30]([CH3:29])(=[O:32])=[O:31])=[CH:7][C:6]=1[C:12]1[C:20]2[C:15](=[C:16]([O:21][CH3:22])[N:17]=[CH:18][CH:19]=2)[N:14]([CH3:23])[CH:13]=1
Reactant: COc1nccc2c(-c3cc(N)ccc3Oc3ccc(F)cc3F)cn(C)c12
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1nccc2c(-c3cc(NS(C)(=O)=O)ccc3Oc3ccc(F)cc3F)cn(C)c12
Temperature: 80 °C

Procedure:
A mixture of Example 2D (0.05 g, 0.131 mmol), methanesulfonyl chloride (0.031 mL, 0.393 mmol), and triethylamine (0.080 g, 0.787 mmol) in dichloromethane (3 mL) was stirred at room temperature for 2 hours. The solvent was removed, and the residue was treated with sodium hydroxide (0.656 mL, 1.31 mmol) and dioxane (3 mL). The reaction mixture was heated at 80° C. for 3 hours. After cooling, the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated to the title compound.