Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl[C:3]1[N:8]=[CH:7][N:6]=[C:5]([N:9]2[C:13](=[O:14])[C:12]([N:15]3[CH:19]=[CH:18][N:17]=[CH:16]3)=[CH:11][NH:10]2)[CH:4]=1.Cl.[F:21][C:22]1([F:27])[CH2:26][CH2:25][NH:24][CH2:23]1.C(N(C(C)C)C(C)C)C>O1CCCC1>[F:21][C:22]1([F:27])[CH2:26][CH2:25][N:24]([C:3]2[N:8]=[CH:7][N:6]=[C:5]([N:9]3[C:13](=[O:14])[C:12]([N:15]4[CH:19]=[CH:18][N:17]=[CH:16]4)=[CH:11][NH:10]3)[CH:4]=2)[CH2:23]1
Reactant: O=c1c(-n2ccnc2)c[nH]n1-c1cc(Cl)ncn1
Reactant: FC1(F)CCNC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=c1c(-n2ccnc2)c[nH]n1-c1cc(N2CCC(F)(F)C2)ncn1

Procedure:
100 mg (0.3 mmol) of the compound from Example 13A, 58 mg (0.4 mmol) of 3,3-difluoropyrrolidine hydrochloride and 175 ml (130 mg, 1.0 mmol) of N-ethyl-N-(propan-2-yl)propane-2-amine are initially charged in 2 ml of tetrahydrofuran and reacted in a single mode microwave (Emrys Optimizer) at 120° C. for 1 h. After concentration under reduced pressure, the residue is taken up in acetonitrile/water and purified by preparative HPLC (RP 18 column; mobile phase: acetonitrile/water gradient). Yield: 111 mg (99% of theory)
Reaction SMILES: C([NH:4][C:5]1[N:9]([CH2:10][C:11](OCC)=[O:12])[N:8]=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[C:6]=1[C:23]#[C:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=O)C.[BH4-].[Na+].[OH-].[Na+]>C(O)C>[NH2:4][C:5]1[N:9]([CH2:10][CH2:11][OH:12])[N:8]=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[C:6]=1[C:23]#[C:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)Cn1nc(-c2cccc(F)c2)c(C#Cc2ccccc2)c1NC(C)=O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1c(C#Cc2ccccc2)c(-c2cccc(F)c2)nn1CCO
Temperature: 25 °C
Reaction time: 36 h
Yield: 85.4 %

Procedure:
To a solution of ethyl 2-(5-acetamido-3-(3-fluorophenyl)-4-(phenylethynyl)-1H-pyrazol-1-yl)acetate (3.25 g, 8.02 mmol) in ethanol (90 mL) was added sodium borohydride (610 mg, 16.04 mmol) and the reaction stirred at room temperature for 36 h. Additional sodium borohydride was added (305 mg, 8.02 mmol) and the reaction stirred at room temperature for 3611.25% NaOH (0.9 mL) was added and the reaction mixture was stirred at 80° C. for 3.5 h. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was washed with ethyl acetate twice and the organic phases combined, dried over MgSO4, filtered and evaporated. The crude material was suspended in diethylether (30 mL) and the product was filtered and dried in vacuo to give 2-(5-amino-3-(3-fluorophenyl)-4-(phenylethynyl)-1H-pyrazol-1-yl)ethanol as a white solid (2.2 g), which was used as such in the subsequent step.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])([O-:5])=[O:4].[CH2:13]([O:15][C:16](=[O:21])[CH2:17][CH2:18][CH2:19]Br)[CH3:14]>CN(C)C=O>[CH2:13]([O:15][C:16](=[O:21])[CH2:17][CH2:18][CH2:19][O:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[N+:3]([O-:5])=[O:4])[CH3:14]
Reactant: CCOC(=O)CCCBr
Reactant: O=[N+]([O-])c1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccccc1[N+](=O)[O-]
Reaction time: 0.33 h
Yield: 70.8 %

Procedure:
Sodium hydride (16.5 9, content: 62.4%) was suspended in N,N-dimethylformamide (500 ml). 0-nitrophenol (60 g) dissolved in N,N-dimethylformamide (100 ml) was added dropwise into the mixture with stirring in ice-bath over about 20 mins. The mixture was stirred for 1 hr. at a room temperature. 4-bromobutanoic acid ethyl ester (84.2 g) dissolved in N,N-dimethylformamide (200 ml) was added to the mixture. The solution was stirred for 15 hrs at about 70° C. N,N-dimethylformamide was evaporated in vacuo. Ethyl acetate (800 ml) was added to the residue. The mixture was washed with a water and a saturated brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel (n-hexane: ethyl acetate =5:1→3:1) to give the title compound (77.3 g) having the following physical data:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:24])([C@H:16]([S:18][CH:19]([CH2:22][OH:23])[CH2:20][OH:21])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[CH3:25][S:26]([C:29]1[CH:38]=[CH:37][C:32](/[CH:33]=[CH:34]/[CH:35]=O)=[CH:31][CH:30]=1)(=[O:28])=[O:27]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:24])([C@H:16]([S:18][C@@H:19]1[CH2:20][O:21][C@@H:35](/[CH:34]=[CH:33]/[C:32]2[CH:37]=[CH:38][C:29]([S:26]([CH3:25])(=[O:28])=[O:27])=[CH:30][CH:31]=2)[O:23][CH2:22]1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: C[C@@H](SC(CO)CO)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: CS(=O)(=O)c1ccc(/C=C/C=O)cc1
Product: C[C@@H](S[C@H]1CO[C@H](/C=C/c2ccc(S(C)(=O)=O)cc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 58 %

Procedure:
Reaction and treatment were carried out in the same manner as in Example 4 using (2R,3R)-2-[2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl)thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol and trans-4-(methylsulfonyl)cinnamaldehyde to obtain the title compound, a major product as an oil in a yield of 58%.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[CH:19][N:18]=[C:17]3[NH:24][C:25]2[S:29][N:28]=[C:27]([CH3:30])[N:26]=2)=[N:11][CH:12]=1)C.[CH2:34]([NH2:36])[CH3:35].O1CCCC1>>[CH2:34]([NH:36][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[CH:19][N:18]=[C:17]3[NH:24][C:25]2[S:29][N:28]=[C:27]([CH3:30])[N:26]=2)=[N:11][CH:12]=1)[CH3:35]
Reactant: CCN
Reactant: CCOC(COc1ccc(Oc2ccc3ncnc(Nc4nc(C)ns4)c3c2)nc1)OCC
Solvent: C1CCOC1
Product: CCNCCOc1ccc(Oc2ccc3ncnc(Nc4nc(C)ns4)c3c2)nc1

Procedure:
Using 6-{[5-(2,2-diethoxyethoxy)pyridin-2-yl]oxy}-N-(3-methyl-1,2,4-thiadiazol-5-yl)quinazoline-4-amine obtained in Example 47 and 2 M ethylamine/tetrahydrofuran solution, and in the same manner as in Example 47 or according to a method similar to it or according to a combination thereof with an ordinary method, the entitled compound (24 mg) was obtained as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:18][CH3:19])[CH:17]=1)[C:12](O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:22])=O>C1(C)C=CC=CC=1.CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:18][CH3:19])[CH:17]=1)[C:12]([Cl:22])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc(OCc2ccccc2)cc(C(=O)O)c1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc(OCc2ccccc2)cc(C(=O)Cl)c1
Reaction time: 0.5 h

Procedure:
3-(Benzyloxy)-5-methoxybenzoic acid (162) (2.57 g, 0.01 mmol) and thionyl chloride (4.80 g, 0.04 mmol) were suspended in 200 mL of dry toluene. The reaction mixture was stirred for 30 min and then dimethyl formamide (3 drops) was added. The mixture was stirred for 24 h and then evaporated to dryness. The residue was directly used for the next step without further purification.
Reaction SMILES: COC[O:4][C:5]1[C:13]([CH:14](OC)[O:15]C)=[CH:12][C:11]([I:19])=[C:10]2[C:6]=1[CH:7]([OH:30])[N:8]([C:21]([CH3:29])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:22])[C:9]2=[O:20].Cl.[CH3:32]O>CO>[OH:4][C:5]1[C:13]([CH:14]=[O:15])=[CH:12][C:11]([I:19])=[C:10]2[C:6]=1[CH:7]([O:30][CH3:32])[N:8]([C:21]([CH3:22])([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH3:29])[C:9]2=[O:20]
Reactant: CO
Reactant: COCOc1c(C(OC)OC)cc(I)c2c1C(O)N(C(C)(C)c1ccccc1)C2=O
Agent: Cl
Product: COC1c2c(O)c(C=O)cc(I)c2C(=O)N1C(C)(C)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
4-Methoxymethoxy-5-dimethoxymethyl-3-hydroxy-7-iodo-2-(1-methyl-1-phenylethyl)isoindolinone (490 mg, 0.929 mmol) was dissolved in methanol (10 mL), and the solution was treated with 10% hydrogen chloride-methanol solution (5 mL), followed by stirring at room temperature for 3 hours. The solvent was evaporated under reduced pressure and the residue was dissolved in acetonitrile (5 mL). The solution was added with 1 mol/L hydrochloric acid (5 mL) and stirred at room temperature for 1 hour. The precipitated solid was collected by filtration and washed with water, followed by drying under reduced pressure to obtain 4-hydroxy-5-formyl-3-methoxy-7-iodo-2-(1-methyl-1-phenylethyl)isoindolinone (329 mg, yield 79%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:7]([O:9][C:10]([C:12]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][C:17](Cl)=[C:18]([F:23])[CH:19]=2)[N:14]([CH2:25][CH3:26])[CH:13]=1)=[O:11])[CH3:8].N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:7]([O:9][C:10]([C:12]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][C:17]([N:1]3[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]3)=[C:18]([F:23])[CH:19]=2)[N:14]([CH2:25][CH3:26])[CH:13]=1)=[O:11])[CH3:8]
Reactant: CCOC(=O)c1cn(CC)c2cc(Cl)c(F)cc2c1=O
Reactant: C1CNCCN1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(CC)c2cc(N3CCNCC3)c(F)cc2c1=O
Reaction time: 5 h
Yield: 81 %

Procedure:
Anhydrous piperazine (10.3 g) and 1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester were added to a mixture of pyridine (9 ml) and toluene (18 ml), and the mixture was refluxed with stirring for 5 hrs. The same procedure as described in Example 1 was followed to give 8.4 g (81% yield) of 1-ethyl-6-fluoro-7-(1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester. mp: 178.5°-180° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-])=[O:10])[C:6]([NH:12][C:13]([C:15](OCC)=[O:16])=[O:14])=[CH:5][C:4]=1[C:20]([F:23])([F:22])[F:21])#[N:2].C(O)(=O)C>C(O)C.[Pd]>[C:1]([C:3]1[CH:8]=[C:7]2[C:6]([NH:12][C:13](=[O:14])[C:15](=[O:16])[N:9]2[OH:10])=[CH:5][C:4]=1[C:20]([F:23])([F:22])[F:21])#[N:2]
Reactant: CCOC(=O)C(=O)Nc1cc(C(F)(F)F)c(C#N)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: N#Cc1cc2c(cc1C(F)(F)F)[nH]c(=O)c(=O)n2O
Yield: 80.4 %

Procedure:
To a solution of 10.5 g (31.7 mmol) 2-cyano-5-ethoxalylamino-4-nitrobenzotrifluoride in 450 ml ethanol was added 45 ml glacial acetic acid. The mixture was hydrogenated at atm. pressure by using 0.2 g 5% Pd-C as a catalyst. The filtered and evaporated reaction product was recrystallized (ethylacetate-light petroleum) to give 6.91 g (81%) of 7-cyano-1-hydroxy-6-trifluoromethyl-quinoxaline-2,3(1H,4H)-dione. M.p. 180° C. decomp. 1H-NMR (DMSO-d6): 7.93 (1H, s), 7.53 (1H, s). MS (m/e): 271 (M+, 70%).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]5[N:39]=[C:38]([S:40][CH2:41][C:42]6[N:46]([CH2:47][CH2:48][CH3:49])[CH:45]=[N:44][CH:43]=6)[N:37]([CH3:50])[C:36]=5[CH:51]=4)=[O:30])=[CH:20][C:19]=3[CH:52]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:61])C=1.CSC.O>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]5[N:39]=[C:38]([S:40]([CH2:41][C:42]6[N:46]([CH2:47][CH2:48][CH3:49])[CH:45]=[N:44][CH:43]=6)=[O:61])[N:37]([CH3:50])[C:36]=5[CH:51]=4)=[O:30])=[CH:20][C:19]=3[CH:52]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc4nc(SCc5cncn5CCC)n(C)c4c2)CCN3CC(C)C)cc1
Solvent: ClCCl
Solvent: O
Solvent: CSC
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc4nc(S(=O)Cc5cncn5CCC)n(C)c4c2)CCN3CC(C)C)cc1
Temperature: -13 °C
Reaction time: 2.5 h
Yield: 3.4 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[1-methyl-2-(((1-propylimidazol-5-yl)methyl)sulfanyl)benzimidazol-6-yl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (260 mg) in dichloromethane (10 ml) was added dropwise 70% solution of 3-chloroperbenzoic acid (133 mg) in dichloromethane (10 ml) at −78° C., and the mixture was stirred for 2.5 hours at −13° C. Dimethylsulfide (0.1 ml) was added to the mixture and the mixture was allowed to be at room temperature, and stirred for 30 minutes. To the mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate, and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was separated and purified by basic silica gel column chromatography (hexane:ethyl acetate=2:5→ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[1-methyl-2-(((1-propylimidazol-5-yl) methyl)sulfinyl)benzimidazol-6-yl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (9 mg) (Compound 447) as yellow amorphous.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17](Cl)=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][CH:21]([SH:23])[CH3:22].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:1]([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17]([S:23][CH:21]([CH3:22])[CH3:20])=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)S
Reactant: Clc1cnc2c(n1)OCCN(Cc1ccccc1)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Sc1cnc2c(n1)OCCN(Cc1ccccc1)C2
Temperature: 100 °C
Yield: 32 %

Procedure:
A suspension of 8-benzyl-3-chloro-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine (300 mg), isopropylthiol (0.121 mL) and potassium carbonate (451 mg) in DMF (5 mL) was stirred with heating at 100° C. for 16 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (solvent gradient: 3→40% ethyl acetate/hexane), and further by preparative HPLC to give the title compound (111 mg, 32%) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7]2[CH:8]=[C:9](B(O)O)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:15])[O:3]1.Br[C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=1>>[F:24][C:22]1[CH:23]=[C:18]([C:9]2[CH:10]=[CH:11][C:6]3[NH:5][C:4](=[O:15])[O:3][C:2]([CH3:16])([CH3:1])[C:7]=3[CH:8]=2)[CH:19]=[C:20]([F:25])[CH:21]=1
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Reactant: Fc1cc(F)cc(Br)c1
Product: CC1(C)OC(=O)Nc2ccc(-c3cc(F)cc(F)c3)cc21

Procedure:
Prepared according to procedure B from (4,4-dimethyl-1,4-dihydro-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid and 1-bromo-3,5-difluorobenzene. A white solid: mp 218-219° C.; 1H-NMR (DMSO-d6) δ 10.4 (s, 1H), 7.67-7.65 (m, 2H), 7.49 (d, 2H, J=7.73 Hz), 7.19 (t, 1H, J=9.29 Hz), 6.96 (d, 1H, J=8.88 Hz), 1.7 (s, 6H); MS (APCI) m/z 290 ([M+H]+, 100%); Anal. Calc. For C16H13F2NO2: C, 66.43; H, 4.53; N, 4.84. Found: C, 66.01; H, 4.46; N, 4.67.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=3[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:10][CH:11]([CH3:12])[C:5]2=[N:4][N:3]=1.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[CH3:12][CH:11]1[N:10]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:8]2[CH:19]=[CH:20][CH:21]=[CH:22][C:7]=2[N:6]2[C:2]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[N:3][N:4]=[C:5]12
Reactant: CC1N=C(c2ccccn2)c2ccccc2-n2c(Br)nnc21
Reactant: C1CNCCN1
Product: CC1N=C(c2ccccn2)c2ccccc2-n2c1nnc2N1CCNCC1

Procedure:
In the manner given in Example 1, 1-bromo-4-methyl-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine is heated with piperazine to give 4-methyl-1-(piperazino)-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [OH:1][CH:2]([CH3:38])[CH2:3][S:4]([C:7]1[CH:8]=[C:9]([C@H:21]2[CH2:25][CH2:24][C@H:23]([C:26]3[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[C:28]([O:36][CH3:37])[CH:27]=3)[O:22]2)[CH:10]=[C:11]([O:17][CH2:18][CH2:19]Br)[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:6])=[O:5].[I-].[I-].[Na+].[S:42]1[CH:46]=[CH:45][N:44]=[CH:43]1>CN(C=O)C.C1(C)C=CC=CC=1>[OH:1][CH:2]([CH3:38])[CH2:3][S:4]([C:7]1[CH:8]=[C:9]([C@H:21]2[CH2:25][CH2:24][C@H:23]([C:26]3[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[C:28]([O:36][CH3:37])[CH:27]=3)[O:22]2)[CH:10]=[C:11]([O:17][CH2:18][CH2:19][C:43]2[S:42][CH:46]=[CH:45][N:44]=2)[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:6])=[O:5]
Reactant: CCCOc1c(OCCBr)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)O
Reactant: c1cscn1
Agent: [I-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCCOc1c(OCCc2nccs2)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)O

Procedure:
trans-2-[3-(2-Hydroxy-n-propylsulfonyl)-4-n-propoxy-5-(2-bromoethoxy) phenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (50 mg, 0.08 mmol)(Example 12) was converted into the corresponding iodide by treatment with sodium iodide in DMF. The iodo intermediate and thiazole (0.17 mL, 2.4 mmol) in toluene (5 mL) was heated under reflux overnight. The solution was evaporated to dryness, and the product was isolated by preparative TLC (chloroform-methanol; 9:1, v/v), Rf 0.08.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)=[O:4].Cl.O1CCOCC1.[N:25]#[C:26][NH2:27]>CCO.C(#N)C>[CH3:1][N:2]([CH3:17])[C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:26]([NH2:27])=[NH:25])=[CH:14][CH:15]=1)=[O:4]
Reactant: CN(C)C(=O)[C@@H]1CCCN1c1ccc(N)cc1
Reactant: N#CN
Agent: Cl
Solvent: CC#N
Solvent: CCO
Solvent: C1COCCO1
Product: CN(C)C(=O)[C@@H]1CCCN1c1ccc(NC(=N)N)cc1
Reaction time: 0.17 h
Yield: 63.2 %

Procedure:
To (S)-1-(4-Amino-phenyl)-pyrrolidine-2-carboxylic acid dimethylamide (Method 53; 0.67 g) was added acetonitrile (20 ml) and EtOH (2 ml). HCl in dioxane (0.86 ml, 3.48 mmol) was added and the reaction was stirred for 10 minutes, HCl salt precipitated. Cyanamide (0.2 g, 4.9 mmol) was added and the reaction was heated at reflux over the weekend. The black reaction was filtered and the black HCl salt was dissolved in water (5 ml) and basified with NaHCO3 (20 ml) solution. No solid was observed; the aqueous was further basified to pH 14 with KOH, extracted with DCM (2×100 ml), dried and solvent removed in vacuo to yield the title compound as a black gum (0.50 g, 63%). M/z 276.
Reaction SMILES: Cl.C([Si](C)(C)[O:7][CH2:8][CH2:9][NH:10][C@H:11]1[CH2:15][CH2:14][N:13]([C:16]2[CH:25]=[CH:24][C:23]3[C:22]([C:26]([NH:28][CH2:29][C:30]4([OH:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[O:27])=[C:21]([Cl:38])[CH:20]=[CH:19][C:18]=3[N:17]=2)[CH2:12]1)(C)(C)C>C1(C)C=CC=CC=1>[OH2:7].[Cl:38][C:21]1[CH:20]=[CH:19][C:18]2[N:17]=[C:16]([N:13]3[CH2:14][CH2:15][C@H:11]([NH:10][CH2:9][CH2:8][OH:7])[CH2:12]3)[CH:25]=[CH:24][C:23]=2[C:22]=1[C:26]([NH:28][CH2:29][C:30]1([OH:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:27]
Reactant: CC(C)(C)[Si](C)(C)OCCN[C@H]1CCN(c2ccc3c(C(=O)NCC4(O)CCCCCC4)c(Cl)ccc3n2)C1
Agent: Cl
Solvent: Cc1ccccc1
Product: O
Product: O=C(NCC1(O)CCCCCC1)c1c(Cl)ccc2nc(N3CC[C@H](NCCO)C3)ccc12
Reaction time: 20 h
Yield: 239.9 %

Procedure:
Premixed hydrochloric acid solution [cHCl (516.0 g), water (4813 ml)] was charged to a reaction vessel containing 2-{(3S)-3-[(2-{[tert butyl(dimethyl)silyl]oxy}ethyl)amino]pyrrolidin-1-yl}-6-chloro-N-[(1-hydroxycycloheptyl)methyl]quinoline-5-carboxamide (525.0 g) and toluene (5250 ml) at 20° C. to 30° C. The reaction mixture was stirred at 25° C. to 30° C. for 20 hours and filtered. The filter cake was washed with water (525 ml). The filtrate and wash were combined and the layers were separated. The aqueous layer was washed with toluene (2625 ml), and charged to a reaction vessel. Premixed potassium bicarbonate solution [water (1803 ml), potassium bicarbonate (601.3 g)] and n-butanol (5250 ml) were charged at 25° C. to 30° C. and the resulting mixture stirred for 67 minutes. The phases were separated and the aqueous phase extracted with n-butanol (2625 ml). The combined butanol phases were combined and washed with water (2600.0 ml) four times. At this point the butanol solution was combined with the butanol solution from a reaction of identical scale. The solution was filtered and the filter cake washed with n-butanol (1050 ml). The filtrate and wash were combined and concentrated to ca. 9.5 L at 40° C. to 50° C. n-Butanol (1050 ml) was charged and concentrated to ca. 9.5 L at 40° C. to 50° C. n-Butanol (1050 ml) was charged and concentrated to ca. 10.5 L at 40° C. to 50° C. n-Butanol (1050 ml) was charged and concentrated to ca. 10.5 L at 40° C. to 50° C. n-Butanol (1050 ml) was charged and concentrated to ca. 10.5 L at 40° C. to 50° C. The mixture was concentrated to ca 5.3 L at 40° C. to 50° C. The mixture was held at 40° C. to 50° C. for 61 hours and mixed heptanes (5250 ml) were charged at 40° C. to 50° C. The mixture was stirred at 40° C. to 50° C. for 60 minutes, at 20 to 25° C. for 92 minutes and filtered. The filter cake was washed with premixed heptanes and n-butanol [heptanes (2100 ml) n-butanol (2100 ml)]. The filter cake was dried at 40° C. for 30 hours, at 60° C. for 24 hours, at 65° C. for 19 hours and 80° C. for 9 hours to provide the title compound as an off-white solid (524.4 g).
Reaction SMILES: C(O)(=O)C.N1C=[CH:9][CH:8]=[CH:7][CH:6]=1.[ClH:11].Cl.[NH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[C:25](=[O:26])[C:24]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)=[CH:23][NH:22]2)=[N:19][CH:20]=1.COC1CCC(OC)O1>O>[ClH:11].[N:29]1[CH:30]=[CH:31][CH:32]=[C:27]([C:24]2[C:25](=[O:26])[N:21]([C:18]3[CH:17]=[CH:16][C:15]([CH2:14][N:13]4[CH:9]=[CH:8][CH:7]=[CH:6]4)=[CH:20][N:19]=3)[NH:22][CH:23]=2)[CH:28]=1
Reactant: NCc1ccc(-n2[nH]cc(-c3cccnc3)c2=O)nc1
Reactant: c1ccncc1
Agent: COC1CCC(OC)O1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: O=c1c(-c2cccnc2)c[nH]n1-c1ccc(Cn2cccc2)cn1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
565 mg (9.4 mmol) of acetic acid are initially charged in 0.3 ml of water. 744 mg (9.4 mmol) of pyridine are added slowly. 191 mg (0.6 mmol) of the compound from Example 13 and 74 mg (0.6 mmol) of 2,5-dimethoxytetrahydrofuran are then added, and the mixture is stirred at 100° C. for 16 h. The mixture is then concentrated on a rotary evaporator, 3 ml of acetonitrile and 3 ml of 1 N hydrochloric acid are added and the mixture is stirred at RT for 30 min. The solid formed is filtered off, washed once with water and dried under high vacuum.
Reaction SMILES: [CH2:1]([C:4]1[C:5]([OH:21])=[C:6]([Br:20])[CH:7]=[C:8]2[C:12]=1[C@H:11]([CH2:13][CH2:14][NH:15][C:16](=[O:19])[CH2:17][CH3:18])[CH2:10][CH2:9]2)[CH:2]=C.[O:22]=[O+][O-].[BH4-].[Na+].Cl>CO>[Br:20][C:6]1[CH:7]=[C:8]2[C:12](=[C:4]([CH2:1][CH2:2][OH:22])[C:5]=1[OH:21])[C@H:11]([CH2:13][CH2:14][NH:15][C:16](=[O:19])[CH2:17][CH3:18])[CH2:10][CH2:9]2
Reactant: O=[O+][O-]
Reactant: C=CCc1c(O)c(Br)cc2c1[C@H](CCNC(=O)CC)CC2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCC(=O)NCC[C@@H]1CCc2cc(Br)c(O)c(CCO)c21
Temperature: 25 °C
Yield: 99 %

Procedure:
A solution of (S)-N-[2-(7-allyl-5-bromo-6-hydroxyindan-1-yl)ethyl]propionamide (588 mg, 1.67 mmol.) in methanol (30 mL) was cooled to about −70° C., to which was introduced ozone for 5 minutes. After confirming the disappearance of the starting material, an excess amount of powdery sodium borohydride (510 mg, 13.4 mmol.) was added to reaction mixture at about −70° C. to decompose ozonide. The reaction mixture was warmed to room temperature, which was neutralized with dilute hydrochloric acid, followed by extracting the organic matter with a mixture of ethyl acetate:butanol=1:1. The extract solution was dried over anhydrous magnesium sulfate, from which the solvent was distilled off under reduced pressure. The residue was then washed with diethyl ether to afford the title compound (yield 0.59 g, 99%).