Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16](O)=[O:17])=[N:14][CH:15]=1.[NH2:30][CH2:31][CH2:32][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN1CCOCC1>C(Cl)Cl.C(OCC)(=O)C>[C:36]([O:35][C:34](=[O:40])[NH:33][CH2:32][CH2:31][NH:30][C:16]([C:13]1[CH:12]=[C:11]([CH3:19])[C:10]([CH:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])[S:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)(=[O:21])=[O:22])=[CH:15][N:14]=1)=[O:17])([CH3:37])([CH3:39])[CH3:38]
Reactant: Cc1cc(C(=O)O)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc(C(=O)NCCNC(=O)OC(C)(C)C)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 98.1 %

Procedure:
To a solution of 5-[(2,5-difluorophenyl)[(4-fluorophenyl)sulfonyl]methyl]-4-methylpyridine-2-carboxylic acid (374 mg, 0.888 mmol) obtained in Example 12 in methylene chloride (10 ml), tert-butyl (2-aminoethyl)carbamate (170 μl, 1.07 mmol), 1-hydroxybenzotriazole (120 mg, 0.888 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (206 mg, 1.07 mmol) and 4-methylmorpholine (116 μl, 1.07 mmol) were added, and the mixture was stirred for 19 hours at room temperature. Ethyl acetate was added to the reaction solution, and the mixture was washed sequentially with saturated aqueous sodium hydrogencarbonate and saturated brine. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting concentration residue was subjected to silica gel column chromatography, and the fraction obtained from an elution with hexane:ethylacetate (=1:1) was concentrated under reduced pressure, to obtain the title compound (491 mg, 0.871 mmol, 98%) as an amorphous substance.
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1.Cl[CH2:14][CH:15]=[CH:16][CH2:17][CH2:18][O:19][CH:20]([CH3:22])[CH3:21]>COCCOC>[CH:20]([O:19][CH2:18][CH2:17][CH:16]=[CH:15][CH2:14][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1)([CH3:22])[CH3:21]
Reactant: CC(C)OCCC=CCCl
Reactant: CC(=O)c1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: COCCOC
Product: CC(=O)c1ccc(OCC=CCCOC(C)C)cc1
Reaction time: 24 h

Procedure:
3.4 g (0.06 mol) of pulverised potassium hydroxide are added to a solution of 8.2 g (0.06 mol) of p-hydroxy-acetophenone and 14.6 g (0.09 mol) of 1-chloro-5-isopropoxy-2-pentene in 100 cc of 1,2-dimethoxyethane. The mixture is stirred at 60° during the course of 24 hours and is subsequently filtered. The filtrate is evaporated at reduced pressure, the residue is taken up in ether, and the ether solution is washed with saturated salt solution. The organic phase is dried with sodium sulphate and evaporated. The residue is chromatographed with hexane/ethyl acetate 4 : 1 on silica gel and then the 4'-(5-isopropoxy-2-pentenyloxy)-acetophenone is obtained as colourless oil. nD20 = 1.5240.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.Cl.[C:14]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].CCN(CC)CC>CN(C=O)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([N:24]2[CH2:23][CH2:22][N:21]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:26][CH2:25]2)=[CH:3][C:4]=1[N+:10]([O-:12])=[O:11])#[N:7]
Reactant: N#Cc1ccc(Br)cc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C#N)c([N+](=O)[O-])c2)CC1
Temperature: 70 °C
Yield: 96.8 %

Procedure:
To a solution of a mixture of compound 17 (3 g, 13.27 mmol) and 1-boc-piperazine hydrochloride (3.53 g, 15.92 mmol) in DMF (30 mL) was added Et3N (4.4 mL, 31.8 mmol), and the mixture was heated at 70° C. for 6 h. The mixture was cooled to room temperature, extracted with ethyl acetate (100 mL), and the organic layer was washed with brine (20 mL), dried over Na2SO4 and evaporated. Trituration with diethyl ether afforded 4.27 g (97%) of compound 18 as bright yellow solid, m.p. 138-139° C.; IR (KBr) νmax. cm−1: 3042 (Ar—H), 2252 (CN), 1690 (C═O), 1610, 1520, 1412 (C═C). 1H NMR (500 MHz, DMSO-d6) δ=1.39 (s, 9H, (CH3)3C); 3.44 (br. s, 4H, 2 CH2); 7.19 (dd, 1H, J=2.6, 9.4 Hz, H-5); 7.46 (d, 1H, J=2.7 Hz, H-2); 8.17 (d, 1H, J=2.7 Hz, H-6); 13C NMR (125.7 MHz, DMSO-d6) δ=28.11 (CH3)3C), 45.92 (CH2), 46.02 (CH2), 79.56 (CH3)3C), 109.24 (C-4), 115.61 (C-2), 116.46 (CN), 119.03 (C-6), 128.09 (C-5), 135.85 (C-3), 153.30 (C-1), 154.13 (C═O). Calculated (%) for C16H20N4O4 (332.15); C: 57.82, H: 6.07, N: 16.86. found (%); C: 57.76, H: 6.11, N: 16.80.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19](O)=[O:20])=[CH:15][CH:14]=1.[CH3:22][N:23]([CH3:38])[CH2:24][CH2:25][N:26]([CH3:37])[C:27]1[S:28][C:29]2[CH:35]=[C:34]([NH2:36])[CH:33]=[CH:32][C:30]=2[N:31]=1>>[ClH:1].[CH3:22][N:23]([CH3:38])[CH2:24][CH2:25][N:26]([CH3:37])[C:27]1[S:28][C:29]2[CH:35]=[C:34]([NH:36][C:19]([C:16]3[CH:17]=[CH:18][C:13]([C:3]4[CH:4]=[CH:5][C:6]([O:8][C:9]([F:11])([F:12])[F:10])=[CH:7][C:2]=4[Cl:1])=[CH:14][CH:15]=3)=[O:20])[CH:33]=[CH:32][C:30]=2[N:31]=1.[CH3:22][N:23]([CH3:38])[CH2:24][CH2:25][N:26]([CH3:37])[C:27]1[S:28][C:29]2[CH:35]=[C:34]([NH:36][C:19]([C:16]3[CH:17]=[CH:18][C:13]([C:3]4[CH:4]=[CH:5][C:6]([O:8][C:9]([F:11])([F:12])[F:10])=[CH:7][C:2]=4[Cl:1])=[CH:14][CH:15]=3)=[O:20])[CH:33]=[CH:32][C:30]=2[N:31]=1
Reactant: O=C(O)c1ccc(-c2ccc(OC(F)(F)F)cc2Cl)cc1
Reactant: CN(C)CCN(C)c1nc2ccc(N)cc2s1
Product: CN(C)CCN(C)c1nc2ccc(NC(=O)c3ccc(-c4ccc(OC(F)(F)F)cc4Cl)cc3)cc2s1
Product: Cl

Procedure:
The title compound is prepared by following Method A, using 2′-chloro-4′-trifluoromethoxy-biphenyl-4-carboxylic acid (0.057 g, 0.18 mmol), and N*2*-(2-Dimethylamino-ethyl)-N*2*-methyl-benzothiazole-2,6-diamine (0.38 g, 0.15 mmol) to afford 2′-chloro-4′-trifluoromethoxy-biphenyl-4-carboxylic acid {2-[(2-dimethylamino-ethyl)-methyl-amino]-benzothiazol-6-yl}-amide (0.033 g, 40%). The material is dissolved in EtOH and treated with 1.0 M HCl in EtOH (0.06 mL). Heptane is added and the resulting precipitate is collected to give 0.028 g (78%) of the hydrochloride salt. LC/MS, Retention time=5.38 nm; (m/z): calcd for C26H24ClF3N4O2S (M+H)+: 549.0; found: 549.0.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]=[C:13]([C:15](OCC)=[O:16])[C:12]([N+:20]([O-])=O)=[C:11]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH3:31])[N:10]=1.ClC1N=C([C:39](OCC)=[O:40])C([N+]([O-])=O)=C(NC2C=CC=CC=2OC)N=1.[NH2:56]C1C=CC=CC=1O.C(N(CC)C(C)C)(C)C>CN(C=O)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:10]=[C:11]2[C:12]([NH:20][C:39](=[O:40])[N:23]2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH3:31])=[C:13]([C:15]([NH2:56])=[O:16])[N:14]=1
Reactant: Nc1ccccc1O
Reactant: CCOC(=O)c1nc(Cl)nc(Nc2ccccc2OC)c1[N+](=O)[O-]
Reactant: CCOC(=O)c1nc(Nc2ccccc2O)nc(Nc2ccccc2OC)c1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(Nc3ccccc3O)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Ethyl 2-(2-hydroxyphenylamino)-6-(2-methoxyphenylamino)-5-nitropyrimidine-4-carboxylate. To a solution of ethyl 2-chloro-6-(2-methoxyphenylamino)-5-nitropyrimidine-4-carboxylate (See Example 30.A) (300 mg, 0.851 m mol) in DMF (5 mL) was added 2-aminophenol (111 mg, 1.021 mmol) and N,N-diisopropylethylamine (0.223 mL, 1.276 mmol). The reaction was stirred at room temperature overnight. Solvent was removed under reduced pressure and the resulting residue was purified by chromatography on a normal phase silica gel column (50% ethyl acetate in hexanes). Fractions containing product were combined and the solvent evaporated to provide the title compound (362 mg, 0.851 mmol, 100% yield). MS (ESI) m/z 426.2 [M+1]+.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[Cl:7][CH2:8][CH2:9][CH2:10][S:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].[Cl-].[Na+]>CO>[Cl:7][CH2:8][CH2:9][CH2:10][S:11]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:2]
Reactant: CCOC(=O)CSCCCCl
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)CS(=O)CCCCl
Temperature: 25 °C
Reaction time: 1.67 h
Yield: 95.6 %

Procedure:
To 4 ml of an aqueous solution of 0.39 g of sodium metaperiodate was added 3 ml of a methanol solution of 0.30 g of ethyl [(3-chloropropyl)thio]acetate obtained in Reference Example 1. The mixture was stirred at room temperature for 100 minutes. To the reaction mixture was added 30 ml of a saturated aqueous sodium chloride solution followed by extraction with ethyl acetate The extract was dried over anhydrous magnesium sulfate The solvent was then distilled off. The residue was applied to silica gel column chromatography. Elution with a solvent mixture of hexane-ethyl acetate (1:3) gave 0.31 g of ethyl (3-chloropropylsulfinyl)acetate.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[CH:18]1([C:21]([CH3:29])([C:23]2[N:27]=[C:26]([CH3:28])[O:25][N:24]=2)[NH2:22])[CH2:20][CH2:19]1>>[CH:18]1([C:21]([NH:22][C:15]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]3[CH2:2][CH2:3]3)=[C:9]([O:10][CH2:11][CH:12]3[CH2:13][CH2:14]3)[N:8]=2)=[O:17])([C:23]2[N:27]=[C:26]([CH3:28])[O:25][N:24]=2)[CH3:29])[CH2:20][CH2:19]1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: Cc1nc(C(C)(N)C2CC2)no1
Product: Cc1nc(C(C)(NC(=O)c2ccc(C3CC3)c(OCC3CC3)n2)C2CC2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and α-cyclopropyl-α,5-dimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1155536-64-3) as starting materials. The product was isolated by chiral chromatography on Lux 5u Amylose-2 using heptane/15% 2-propanol as eluent. The (+)-enantiomer was isolated. LC-MS (UV peak area/ESI) 100%, 383.2090 (M+H)+, αD20 (MeOH)=+49.30
Reaction SMILES: [ClH:1].Cl.[CH3:3][O:4][C:5](=[O:15])[C@H:6]([CH2:8][C:9]1[N:10]=[C:11]([NH2:14])[S:12][CH:13]=1)[NH2:7].[N:16]1([S:22]([NH:25][C@H:26]([C:34](O)=[O:35])[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:24])=[O:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.OC1C2N=NNC=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C.C(N(CC)CC)C.CN(C)C=O>[ClH:1].[CH3:3][O:4][C:5](=[O:15])[C@H:6]([CH2:8][C:9]1[N:10]=[C:11]([NH2:14])[S:12][CH:13]=1)[NH:7][C:34](=[O:35])[C@H:26]([CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[NH:25][S:22]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)(=[O:24])=[O:23]
Reactant: COC(=O)[C@@H](N)Cc1csc(N)n1
Reactant: O=C(O)[C@H](Cc1ccccc1)NS(=O)(=O)N1CCOCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1csc(N)n1)NC(=O)[C@H](Cc1ccccc1)NS(=O)(=O)N1CCOCC1
Temperature: 5 °C
Reaction time: 8 h

Procedure:
3-(2-Amino-4-thiazolyl)-L-alanine methyl ester dihydrochloride, 12 kg (43.8 mol), 13.8 kg of N-(4-morpholinylsulfonyl)-L-phenylalanine (European Published Patent Application 0399556), 6.0 kg of hydroxybenzotriazole (HOBT), and 110 L of dimethylformamide are charged into a 800 L reactor and cooled to 5° C. Triethylamine, 9.4 kg, is charged over 10 minutes and cooled to 5° C. A solution of 9.5 kg of dicyclohexylcarbodiimide in 350 L of ethyl acetate is charged into the reaction mixture over a 15 minute period at 5° C. The slurry is allowed to warm to room temperature and stirred overnight. The slurry is diluted with 424 L of ethyl acetate and filtered. The cake is washed with 50 L of ethyl acetate. The filtrate is washed with water (2×140 L) and saturated sodium bicarbonate solution (2×150 L). The solution is diluted with 193 L of isopropyl alcohol. After cooling to 5° C., anhydrous hydrogen chloride gas (3.2 kg) is added to precipitate the product. After isolation by filtration, the product is dried at 25° C. under vacuum to give 18 kg of N-(4-morpholinyl-sulfonyl)-L-phenylalanyl-3-(2-amino-4-thiazolyl)-L-alanine methyl ester monohydrochloride as a white solid, 99.6% pure by HPLC; mass spectrum (chemical ionization) 498 M+H.
Reaction SMILES: [N+](C1C=[CH:8][C:7]([O:10][C:11](=[O:28])[C@H:12]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=CC=1)([O-])=O.[NH:29]1CCOCC1>>[N:13]1([C:14]([NH2:29])=[O:16])[CH2:12][CH2:11][O:10][CH2:7][CH2:8]1.[C:17]([O:16][C:14]([NH:13][C@H:12]([C:11]([OH:28])=[O:10])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: C1COCCN1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Product: NC(=O)N1CCOCC1

Procedure:
N-tert-Butoxycarbonyl-L-phenylalanine morpholinoamide was prepared following the procedure of Example 25 Step (a) starting from N-tert-butoxycarbonyl-L-phenylalanine p-nitrophenyl ester and morpholine.
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[N:8]=[CH:9][N:10]2[C:16]3[CH:17]=[CH:18][S:19][C:15]=3[C:14](=[O:20])[N:13]3[CH2:21][CH2:22][C@H:12]3[C:11]=12)=[O:6])[C:2]#[CH:3].I[N:24]1C(=O)[CH2:27][CH2:26][C:25]1=O.C(N)CC>C(O)(=O)C>[CH2:25]([NH:24][CH2:3][C:2]1[O:6][C:5]([C:7]2[N:8]=[CH:9][N:10]3[C:16]4[CH:17]=[CH:18][S:19][C:15]=4[C:14](=[O:20])[N:13]4[CH2:21][CH2:22][C@H:12]4[C:11]=23)=[N:4][CH:1]=1)[CH2:26][CH3:27]
Reactant: O=C1CCC(=O)N1I
Reactant: C#CCNC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1sccc1-2
Solvent: CCCN
Solvent: CC(=O)O
Product: CCCNCc1cnc(-c2ncn3c2[C@@H]2CCN2C(=O)c2sccc2-3)o1
Temperature: 25 °C
Reaction time: 24 h
Yield: 7.9 %

Procedure:
A solution of 3.10 g (0.00992 mol) of (S)-8-oxo-11,11a-dihydro-8H,10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]-diazepine-1-carboxylic acid prop-2-ynylamide in 60 ml of acetic acid was treated with 3.35 g (0.0149 mol) of N-iodosuccinimide while gassing with argon. After stirring at room temperature for 24 hrs. the dark suspension obtained was completely freed from the solvents and dried azeotropically several times with toluene. The dark residue was dissolved in 60 ml of THF, treated with 7.1 ml (0.0863 mol) of propylamine and stirred at room temperature for 6 hrs. The suspension obtained was completely freed from the solvents, the residue was partitioned between ethyl acetate and 1N aqueous hydrochloric acid and extracted. The aqueous-acidic phase was made basic and extracted with ethyl acetate. The organic phase was concentrated and the dark product was chromatographed over silica gel which dichloromethane/methanol 49:1 as the eluent. There was obtained 0.29 g (8%) of (S)-1-(5-propylaminomethyl-oxazol-2-yl)-11,11 a-dihydro-8H,10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepin-8-one as yellowish crystals; m.p. 145°-147°.
Reaction SMILES: [O:1]=[S:2]1(=[O:27])[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[C:12]([C:24]([NH2:26])=[O:25])[CH:13]=[C:14]([C:17]4[CH:21]=[C:20]([CH:22]=O)[S:19][CH:18]=4)[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.CO.[NH:30]1[CH2:33][CH2:32][CH2:31]1.C([BH3-])#N.[Na+]>CS(C)=O.C(O)(=O)C>[N:30]1([CH2:22][C:20]2[S:19][CH:18]=[C:17]([C:14]3[CH:15]=[C:16]4[C:11](=[C:12]([C:24]([NH2:26])=[O:25])[CH:13]=3)[NH:10][CH:9]=[C:8]4[CH:5]3[CH2:6][CH2:7][S:2](=[O:1])(=[O:27])[CH2:3][CH2:4]3)[CH:21]=2)[CH2:33][CH2:32][CH2:31]1
Reactant: C1CNC1
Reactant: NC(=O)c1cc(-c2csc(C=O)c2)cc2c(C3CCS(=O)(=O)CC3)c[nH]c12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: NC(=O)c1cc(-c2csc(CN3CCC3)c2)cc2c(C3CCS(=O)(=O)CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 8.7 %

Procedure:
3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-5-(5-formyl-3-thienyl)-1H-indole-7-carboxamide (105 mg, 0.26 mmol) was diluted in dimethylsulfoxide (0.5 mL) and methanol (0.5 mL) in a 2 dram vial. Azetidine (75 mg, 5 eq) was added, followed by glacial acetic acid (0.3 mL). The mixture was stirred at rt for 1 h, then sodium cyanoborohydride (35 mg, 0.56 mmol, 2.1 eq) was added and the mixture was stirred at rt overnight. The mixture was filtered through a 1 g silica gel pad (commercial, in syringe tube), and the solvent was removed in vacuo. The crude product was re-diluted in a mixture of methanol and DMSO, and purified by ammonium hydroxide Gilson HPLC. The desired fractions were concentrated in an EZ2 Genevac evaporator, giving 10 mg (9%) of title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)=[CH:17][C:9]1=2.[NH2:32][CH2:33][C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:32][CH2:33][C:34]3[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=3)=[O:23])=[CH:17][C:9]1=2
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Reactant: NCc1ccncc1
Product: O=C(NCc1ccncc1)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 4-(aminomethyl)pyridine as in General Procedure 10 to give the title compound. LCMS: m/z=537.96 (M+H+); retention time=0.56 minutes.
Reaction SMILES: [S:1]([OH:5])([OH:4])(=[O:3])=[O:2].CS[C:8]1[NH:9][CH2:10][CH2:11][N:12]=1.[OH:13][CH2:14][CH2:15][NH:16][NH2:17]>C(O)C>[S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[OH:13][CH2:14][CH2:15][N:16]([C:8]1[NH:9][CH2:10][CH2:11][N:12]=1)[NH2:17]
Reactant: CSC1=NCCN1
Reactant: NNCCO
Agent: O=S(=O)(O)O
Solvent: CCO
Product: NN(CCO)C1=NCCN1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-Methylthio-2-imidazoline sulfate (2:1) (1.98 g) and 2-hydroxyethylhydrazine (2.12 g) are heated in ethanol (3 ml) at reflux for 1 hr., then stirred at 25° C. for 3 hr. The solution was diluted with ethanol (20 ml) and kept at 4° C. for 18 hr. The crystals which separated were filtered out and washed with ethanol. Weight 811 mg, mp 190°-4° C.
Reaction SMILES: [F:1][CH:2]([F:32])[O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([CH2:14][O:15][C:16]3[CH:31]=[CH:30][C:19]4[O:20][CH2:21][C:22]5[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=5[CH:24](O)[C:18]=4[CH:17]=3)=[N:11]2)=[CH:6][CH:5]=1.[SH:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37]>>[C:36]([CH2:35][CH2:34][S:33][CH:24]1[C:23]2[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=2[CH2:21][O:20][C:19]2[CH:30]=[CH:31][C:16]([O:15][CH2:14][C:10]3[CH:9]=[CH:8][C:7]4[C:12](=[CH:13][C:4]([O:3][CH:2]([F:32])[F:1])=[CH:5][CH:6]=4)[N:11]=3)=[CH:17][C:18]1=2)([OH:38])=[O:37]
Reactant: O=C(O)CCS
Reactant: OC1c2ccccc2COc2ccc(OCc3ccc4ccc(OC(F)F)cc4n3)cc21
Product: O=C(O)CCSC1c2ccccc2COc2ccc(OCc3ccc4ccc(OC(F)F)cc4n3)cc21

Procedure:
2-(7-Difluoromethoxyquinolin-2-yl)methoxy-11-hydroxy-6,11-dihydrodibenz[b,e]oxepine and 3-mercaptopropionic acid were used and reacted in the same manner as in Example 1 to obtain the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C@@H:12]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@H:13]([OH:16])[CH:14]=O.[C:24]([NH:28][C:29]([C@@H:31]1[CH2:40][C@H:39]2[C@H:34]([CH2:35][CH2:36][CH2:37][CH2:38]2)[CH2:33][NH:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C([BH3-])#N.[Na+]>C(O)(=O)C>[C:24]([NH:28][C:29]([C@@H:31]1[CH2:40][C@H:39]2[C@H:34]([CH2:35][CH2:36][CH2:37][CH2:38]2)[CH2:33][N:32]1[CH2:14][C@@H:13]([OH:16])[C@@H:12]([N:3]1[C:2](=[O:1])[C:10]2=[CH:9][CH:8]=[CH:7][CH:6]=[C:5]2[C:4]1=[O:11])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1
Reactant: O=C[C@@H](O)[C@H](Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@H](Cc1ccccc1)N1C(=O)c2ccccc2C1=O

Procedure:
309 mg of (2S,3S)-3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-2-hydroxy-4-phenylbutyraldehyde and 238 mg of N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide are dissolved in 5 ml of acetic acid and treated portionwise with 120 mg of sodium cyanoborohydride. After completion of the reaction the mixture is concentrated to dryness, treated with 10 ml of water and extracted with methylene chloride. The extracts are dried and filtered, the filtrate is concentrated and the residue is purified on silica gel with methylene chloride/methanol (95:5). N-tert.Butyl-decahydro-2-[2(R)-hydroxy-4-phenyl-3(S)-phthalimidobutyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide is obtained.
Reaction SMILES: [Li]CCCC.CCCCCC.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23](Br)=[CH:22][N:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH:27](=[O:30])[CH2:28][CH3:29].[Cl-].[NH4+]>C1COCC1>[CH2:12]([O:19][C:20]1[N:21]=[CH:22][C:23]([CH:27]([OH:30])[CH2:28][CH3:29])=[CH:24][CH:25]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCC=O
Reactant: Brc1ccc(OCc2ccccc2)nc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCC(O)c1ccc(OCc2ccccc2)nc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
In a nitrogen atmosphere at −78° C., 2.71 M n-BuLi/hexane solution (18.8 mL) was dropwise added to a THF solution of 2-(benzyloxy)-5-bromopyridine (12.2 g, 46.2 mmol) synthesized according to the method described in a reference (J. Org. Chem., 1995, Vol. 60, p. 1408), and stirred at −78° C. for 1 hour. At −78° C., propionaldehyde (4.3 mL) was dropwise added, and stirred at −78° C. for 30 minutes and then at room temperature for 3 hours. Aqueous saturated ammonium chloride solution was added to the reaction liquid, and extracted with ethyl acetate. The organic layer was washed with saturated saline, then dried with magnesium sulfate and concentrated. This was purified by silica gel column chromatography to obtain the intended compound (7.15 g, 64%) as a yellow oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:11][CH3:12])(=[O:10])[CH:8]=[CH2:9].[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[NH:20][CH:19]=[C:18]2[C:26]1[N:34]([S:35]([C:38]2[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=2)(=[O:37])=[O:36])[C:29]2=[N:30][CH:31]=[CH:32][CH:33]=[C:28]2[CH:27]=1.O>CN(C)C=O.C(OCC)(=O)C>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]([CH2:9][CH2:8][C:7]([O:11][CH3:12])=[O:10])[CH:19]=[C:18]2[C:26]1[N:34]([S:35]([C:38]2[CH:39]=[CH:40][C:41]([CH3:44])=[CH:42][CH:43]=2)(=[O:37])=[O:36])[C:29]2=[N:30][CH:31]=[CH:32][CH:33]=[C:28]2[CH:27]=1
Reactant: C=CC(=O)OC
Reactant: COc1cc2[nH]cc(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CCn1cc(-c2cc3cccnc3n2S(=O)(=O)c2ccc(C)cc2)c2cc(OC)c(OC)cc21
Reaction time: 16 h

Procedure:
0.34 g of potassium carbonate and 0.243 ml of methyl acrylate are added, dropwise, to a solution of 1 g of 2-(5,6-dimethoxy-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine in 20 ml of anhydrous dimethylformamide, under an inert argon atmosphere at a temperature in the region of 20° C. The reaction medium is agitated at the same temperature for 16 hours. 20 ml of water and 20 ml of ethyl acetate are added. After separation by settling out, the organic phase is dried over sodium sulfate, filtered, and then concentrated under reduced pressure. After purification by flash chromatography (silica, dichloromethane as eluent, argon), the fractions containing the product are concentrated under reduced pressure. 1 g of methyl 3-{5,6-dimethoxy-3-[1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]indol-1-yl}propionate is thus obtained, the characteristics of which are as follows: