Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@H:9]([O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([O:23][CH3:24])[NH:20]2)=[C:16]([NH2:25])[N:15]=1)[CH2:10][CH2:11][CH3:12].C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][Cl:38].C(N(CC)CC)C>CN(C=O)C.O.[Cl-].[Na+].O>[Cl:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][N:20]1[C:19]([O:23][CH3:24])=[N:18][C:17]2[C:21]1=[N:22][C:14]([O:13][C@@H:9]([CH3:8])[CH2:10][CH2:11][CH3:12])=[N:15][C:16]=2[NH2:25]
Reactant: ClCCCCCBr
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCCl)c2n1
Temperature: 20 °C
Reaction time: 16 h
Yield: 73.6 %

Procedure:
2-{[(1S)-1-Methylbutyl]oxy}-8-(methyloxy)-9H-purin-6-amine trifluoroacetate (600 mg, 1.642 mmol) and potassium carbonate (567 mg, 4.11 mmol) were stirred at 60° C. in DMF (10 ml) for 1 hour under nitrogen. The reaction was cooled to room temperature when 1-bromo-5-chloropentane (0.216 ml, 1.642 mmol) and triethylamine (0.343 ml, 2.464 mmol) were added and the mixture stirred at 20° C. under nitrogen for 16 hours. The mixture was then diluted with water (10 ml) and brine (10 ml) and extracted with DCM (2×10 ml). The combined organic extracts were evaporated and the residue dissolved in DCM and purified by column chromatography using the Flashmaster II (70 g aminopropyl cartridge) with a 0-100% ethyl acetate in cyclohexane gradient over 40 minutes. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a yellow gum (430 mg).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=O.[NH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:30])([CH3:29])[CH3:28])=[CH:23][CH:22]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=N)C>CN(C)C=O.O>[OH:30][C:27]([C:24]1[CH:25]=[CH:26][C:21]([CH2:20][NH:19][C:9](=[O:11])[C:8]2[CH:12]=[CH:13][CH:14]=[N:15][C:7]=2[O:6][C:5]2[CH:16]=[CH:17][CH:18]=[C:3]([S:2][CH3:1])[CH:4]=2)=[CH:22][CH:23]=1)([CH3:29])[CH3:28]
Reactant: CC(C)(O)c1ccc(CN)cc1
Reactant: CSc1cccc(Oc2ncccc2C(=O)O)c1
Agent: CCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CSc1cccc(Oc2ncccc2C(=O)NCc2ccc(C(C)(C)O)cc2)c1
Yield: 14.1 %

Procedure:
To a stirred solution 2-(3-Methylsulfanyl-phenoxy)-nicotinic acid (2.5 grams, 9.58 mmole), 2-(4-Aminomethyl-phenyl)-propan-2-ol (1.896 grams, 11.50 mmole) and 1-hydroxybenzotriazole hydrate (1.55 grams, 11.50 mmole) in dry dimethylformamide (60 ml) was added 1-(3-dimethylamino)-propyl)-3-ethylcarbodiimide hydrochloride (2.39 grams, 12.45 mmole) and stirred over night. The mixture was diluted with 300 ml water and extracted with ethyl acetate. The combined organics were washed with water and brine, dried over MgSO4, filtered and concentrated to give a yellow oil that was purified by chromatography on silica eluting with 3.5% methanol/methylene chloride to give a white solid. Recrystalization from ethyl acetate/hexane gave a solid (0.550 g). M.P. 107-109° C.; Anal. calcd. for C23H24N2O3S: C, 67.62; H, 5.92; N, 6.86. Found: C, 67.53, H, 5.76; N, 6.91.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@H:3]1[NH:11][C:12](=[O:24])[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([F:23])[CH:17]=1)=[O:14].Cl.[N:26]1([C:31](N)=[NH:32])C=CC=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C.CC#N.O>[CH2:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@H:3]([NH:11][C:12]([C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([F:23])[CH:17]=2)=[O:14])=[O:24])[C@@H:2]1[N:1]=[C:31]([NH2:32])[NH2:26]
Reactant: N=C(N)n1cccn1
Reactant: N[C@@H]1Cc2ccccc2[C@H]1NC(=O)C(=O)Nc1ccc(Cl)c(F)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: NC(N)=N[C@@H]1Cc2ccccc2[C@H]1NC(=O)C(=O)Nc1ccc(Cl)c(F)c1
Temperature: 100 °C
Yield: 49.1 %

Procedure:
To a solution containing AWS-I-45 (16 mg, 0.047 mmol) in 1 mL DMF was added 1H-pyrazole-1-carboxamidine hydrochloride (13.9 mg, 0.095 mmol), N,N-diisopropylethylamine, (41 μL, 0.237 mmol) and a stir bar. The solution was heated to 100° C. for 16 hours and then allowed to cool. The light-red reaction mixture was diluted with 1.5 mL of MeCN/H2O (1:1) and purified by HPLC to give 9 mg (48%) of AWS-I-169 as a clear amorphous solid; [α]D25=−3.2° (c=0.72, MeOH) 1H NMR (500 MHz, CD3OD): δ 8.3 (br s, 1Hformate), 7.84 (dd J=2.5, 11.5 Hz, 1H), 7.50 (d, J=8.75 Hz, 1H), 7.43 (t, J=8.5 Hz, 1H)), 7.34-7.29 (m, 4H), 5.27 (d, J=4.5 Hz, 1H), 4.30 (m, 1H), 3.52 (dd, J=7.5 Hz, 1H), 2.93 (dd, J=5, 16.5 Hz, 1H); 13C NMR (125 MHz, CD3OD) δ 162.8, 159.4, 159.3, (d, JCF=244.4 Hz), 159.0, 141.9, 139.7, 139.1 (d, JCF=9.8 Hz), 131.9, 130.6, 129.0, 126.4, 126.3, 118.3 (d, JCF=3.3 Hz), 117.4 (d, JCF=17.8 Hz), 110.0 (d, JCF=26.3 Hz), 62.3, 59.7, 37.8. HRMS (ES+) m/z 390.1132 [(M+H)+; calcd for C18H18ClFN5O2: 390.1133].
Reaction SMILES: F[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:4]=1.C(OCC)(=[O:26])C>O=[Mn]=O>[CH:2]([C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:4]=1)=[O:26]
Reactant: NS(=O)(=O)c1ccc(-n2nc(CF)cc2-c2ccccc2)cc1
Reactant: CCOC(C)=O
Agent: O=[Mn]=O
Product: NS(=O)(=O)c1ccc(-n2nc(C=O)cc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the alcohol prepared in Example 131, Step 3 (1.1 g, 3.3 mmol) in ethyl acetate (20 mL) was added MnO2 (5 g, 60 mmol) and the mixture stirred at room temperature overnight. The mixture was Filtered through Celite and the solution was concentrated to provide the crude aldehyde.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH:29]([CH3:31])[CH3:30])=[N:8][C:9]2[C:14]([C:15]=1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][C:24]([F:27])([F:26])[F:25])=[CH:13][C:12]([Cl:28])=[CH:11][CH:10]=2)=[O:5])C.[I-].[Li+]>>[Cl:28][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH:29]([CH3:30])[CH3:31])[C:6]([C:4]([OH:5])=[O:3])=[C:15]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][C:24]([F:26])([F:25])[F:27]
Reactant: CCOC(=O)c1c(C(C)C)nc2ccc(Cl)cc2c1Cc1ccccc1OC(F)(F)F
Agent: [I-]
Agent: [Li+]
Product: CC(C)c1nc2ccc(Cl)cc2c(Cc2ccccc2OC(F)(F)F)c1C(=O)O

Procedure:
The title compound was prepared in analogy to example 20 step D from 6-chloro-2-isopropyl-4-(2-trifluoromethoxy-benzyl)-quinoline-3-carboxylic acid ethyl ester (70 mg, 0.16 mmol) and lithium iodide. Off white solid (18 mg, 27%). LC-MS (ESI): 422 (M−H)−.
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:12]=O.C([CH2:22][C:23]([NH:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=1)=[O:24])(O)=O.Cl>C1(C)C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:10]=[C:11](/[CH:12]=[CH:22]/[C:23]([NH:25][C:26]2[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=2)=[O:24])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: COc1ccc(C=O)cc1OC
Reactant: O=C(O)CC(=O)Nc1ccc(C(=O)O)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: COc1ccc(/C=C/C(=O)Nc2ccc(C(=O)O)cc2)cc1OC
Yield: 53.7 %

Procedure:
Piperidine (0.39 mL, 4.0 mmol) was added to a suspension of 3,4-dimethoxybenzaldehyde (0.66 g, 4.0 mmol) and 4-[(carboxyacetyl)amino]benzoic acid (0.74 g, 3.3 mmol) in toluene (5.0 mL) and treated according to Procedure 2, acidifying with 1 M HCl. The crude product was recrystallised from EtOH providing (E)-4-[[3-(3,4-dimethoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (0.58 g, 53%) as a yellow crystalline solid; mp 258-259° C., lit. [24] 267-269° C.; δH (400 MHz, DMSO-d6) 3.80 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 6.72 (d, J=15.6 Hz, 1H, CH═CHCO), 7.01 (d, J5′,6′=8.2 Hz, 1H, H5′), 7.20 (d, J5′,6′=8.2 Hz, 1H, H6′), 7.22 (s, 1H, H2′), 7.56 (d, J=15.6 Hz, 1H, CH═CHCO), 7.80 (d, J2,3=J5,6=8.4 Hz, 2H, H3, H5), 7.90 (d, J2,3=J5,6=8.4 Hz, 1H, H2, H6), 10.43 (s, 1H, NH), 12.68 (br s, 1H, CO2H).
Reaction SMILES: [CH3:1][NH2:2].Cl[C:4]1[C:5]([C:14]([NH:16][C:17]2[NH:21][N:20]=[N:19][N:18]=2)=[O:15])=[N:6][C:7]2[C:12]([N:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2>C(O)C>[CH3:1][NH:2][C:4]1[C:5]([C:14]([NH:16][C:17]2[NH:21][N:20]=[N:19][N:18]=2)=[O:15])=[N:6][C:7]2[C:12]([N:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: CN
Reactant: O=C(Nc1nnn[nH]1)c1nc2ccccc2nc1Cl
Solvent: CCO
Product: CNc1nc2ccccc2nc1C(=O)Nc1nnn[nH]1

Procedure:
Methylamine in ethanol (20 ml., 33%) and 3-chloro-N(1H-tetrazol-5-yl)-2-quinoxalinecarboxamide (Example 5) (2 g) were stirred together at room temperature for 8 hours. The yellow solid was collected and crystallised from ethanol and heated at 120° in a vacuum. It had m.p. 292° (d) (50%).
Reaction SMILES: [OH:1][B:2]([OH:11])[C:3]1[S:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1.[CH3:12][C:13]([CH3:18])([CH2:16]O)[CH2:14]O>C1COCC1>[CH3:12][C:13]1([CH3:18])[CH2:16][O:1][B:2]([C:3]2[S:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=2)[O:11][CH2:14]1
Reactant: O=C(O)c1ccc(B(O)O)s1
Reactant: CC(C)(CO)CO
Solvent: C1CCOC1
Product: CC1(C)COB(c2ccc(C(=O)O)s2)OC1
Yield: 100.5 %

Procedure:
5-(Dihydroxyboryl)-2-thiophenecarboxylic acid (527 mg, 3.1 mmol) and 2,2-dimethyl-propane-1,3-diol (361 mg, 3.4 mmol) are stirred in THF (10 mL) for 19 hours and concentrated in vacuo to afford 5-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-thiophene-2-carboxylic acid (748 mg) as a solid. LCMS: RT=1.15 minutes; 1H NMR [300 MHz, (CD3)2SO]: □13.15 (1H, s); 7.7 (1H, m); 7.45 (1H, m); 3.75 (4H, s); 0.95 (6H, s).
Reaction SMILES: F[C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][C:11]#[C:12][CH2:13][CH3:14])[N:5]=[CH:4][N:3]=1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>C1(C)C=CC=CC=1>[F:8][C:7]1[C:6]([O:9][CH2:10][C:11]#[C:12][CH2:13][CH3:14])=[N:5][CH:4]=[N:3][C:2]=1[N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C1CCNC1
Reactant: CCC#CCOc1ncnc(F)c1F
Solvent: Cc1ccccc1
Product: CCC#CCOc1ncnc(N2CCCC2)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.4 %

Procedure:
0.1 g of 4,5-difluoro-6-(2-pentynyloxy)pyrimidine and 0.04 g of pyrrolidine were added to 0.2 ml of toluene, then the reaction mixture was stirred at room temperature for 3 hours. Then the reaction mixture was subjected to silica gel column chromatography to obtain 0.11 g of 5-fluoro-4-(2-pentynyloxy)-6-pyrrolidinopyrimidine (referred as the present compound (5) hereinafter).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH3:9][C@H:10]1[CH2:15][NH:14][C@H:13]([CH3:16])[CH2:12][NH:11]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl:8][C:4]1[N:3]=[C:2]([N:11]2[CH2:12][C@@H:13]([CH3:16])[NH:14][CH2:15][C@@H:10]2[CH3:9])[CH:7]=[N:6][CH:5]=1
Reactant: Clc1cncc(Cl)n1
Reactant: C[C@@H]1CN[C@@H](C)CN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H]1CN(c2cncc(Cl)n2)[C@@H](C)CN1
Temperature: 90 °C
Reaction time: 6 h

Procedure:
A mixture of 2,6-dichloropyrazine (0.40 g, 2.68 mmol), trans-2,5-dimethylpiperazine (0.62 g, 5.43 mmol), K2CO3 (0.41 g, 3.0 mmol) in acetonitrile (5 mL) was stirred at 90° C. for 6 h in a sealed pyrex tube. After cooling, the reaction mixture was filtered and concentrated in vacuo. The oily residue was purified by column chromatography on silica gel using CHCl3/MeOH (9:1) as eluent. This furnished 0.15 g (25%) of the title compound as an oil. HRMS m/z calcd for C10H15ClN4 (M)+ 226.0985, found 226.0983.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:23][CH3:24])=[C:4]([C:9]([CH2:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18](Cl)[CH:17]=2)(=[O:15])=[O:14])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].BrC1C(OC)=C(C(CSC2C=CC([F:44])=CC=2)=CC=1)C(OC)=O>>[Br:1][C:2]1[C:3]([O:23][CH3:24])=[C:4]([C:9]([CH2:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([F:44])=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1c(CSc2ccc(F)cc2)ccc(Br)c1OC
Reactant: COC(=O)c1c(CS(=O)(=O)c2cccc(Cl)c2)ccc(Br)c1OC
Product: COC(=O)c1c(CS(=O)(=O)c2ccc(F)cc2)ccc(Br)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 68, starting from methyl 3-bromo-6-(4-fluorophenylthiomethyl)-2-methoxybenzoate (Intermediate 75) and used without further characterisation.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:13][C@@H:14]([OH:17])[CH2:15]Cl)([CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:5])[CH3:2].[C:18]([C:20]1[CH:21]=[C:22]([CH:26]([NH2:28])[CH3:27])[CH:23]=[CH:24][CH:25]=1)#[N:19].CCN(C(C)C)C(C)C>C(O)C>[CH2:1]([O:3][P:4]([CH2:13][C@@H:14]([OH:17])[CH2:15][NH:28][CH:26]([C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:18]#[N:19])[CH:21]=1)[CH3:27])([CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:5])[CH3:2]
Reactant: CC(N)c1cccc(C#N)c1
Reactant: CCOP(=O)(CC1CCCCC1)C[C@@H](O)CCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOP(=O)(CC1CCCCC1)C[C@@H](O)CNC(C)c1cccc(C#N)c1
Temperature: 25 °C

Procedure:
A mixture of 5.65 g of 3-chloro-2(R)-hydroxy-propyl(cyclohexylmethyl)phosphinic acid ethyl ester, 2.92 g of N-[1-(3-cyanophenyl)ethyl]amine, 2.60 g of Hunig base and 10 ml of ethanol is heated under reflux for 5 days, then cooled to room temperature and concentrated by evaporation. Chromatography of the residue on silica gel gives 3-{N-[1 -(3cyanophenyl)ethyl]amino}-2(S)-hydroxy-propyl(cyclohexylmethyl)phosphinic acid ethyl ester in the form of an oil; [α}20D =+8.6 0.8 (c=1.225 in trichloromethane).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7]([CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)=[O:8].[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>C(=S)=S>[CH3:5][O:6][C:7]([CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:16]=2)[CH2:11][CH2:10]1)=[O:8]
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)C1CCc2ccccc21
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: COC(=O)C1CCc2ccc(C(=O)c3ccccc3)cc21
Temperature: 25 °C

Procedure:
18 g of finely powdered aluminum chloride are added in portions of a solution of 8 g of indane-1-carboxylic acid methyl ester and 8.2 g of benzoyl chloride in 100 ml of carbon disulphide, whilst stirring in an anhydrous atmosphere. After completion of the addition, the reaction mixture is heated for 2 hours to the reflux temperature. It is then allowed to cool to room temperature, poured onto a mixture of 100 g of ice and 50 ml of concentrated hydrochloric acid and extracted with twice 100 ml of ether. The organic phases are combined, washed with twice 100 ml of water, dried over sodium sulphate and evaporated in vacuo. Distillation of the evaporation residue in a high vacuum gives 6-benzoyl-indane-1-carboxylic acid methyl ester in the fraction boiling at 165°-170° C (0.5 mm).
Reaction SMILES: C1(NC2C=C([C@@H](N3CCNCC3)C3C=CC(C(N(CC)CC)=O)=CC=3)C=CC=2)CCCCC1.[CH:34]1([NH:40][C:41]2[CH:42]=[C:43]([C@@H:47]([N:61]3[CH2:66][CH2:65][N:64]([CH2:67][CH:68]4CC4)[CH2:63][CH2:62]3)[C:48]3[CH:60]=[CH:59][C:51]([C:52]([N:54]([CH2:57][CH3:58])[CH2:55][CH3:56])=[O:53])=[CH:50][CH:49]=3)[CH:44]=[CH:45][CH:46]=2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>CO>[CH:34]1([NH:40][C:41]2[CH:42]=[C:43]([C@@H:47]([N:61]3[CH2:66][CH2:65][N:64]([CH2:67][CH3:68])[CH2:63][CH2:62]3)[C:48]3[CH:60]=[CH:59][C:51]([C:52]([N:54]([CH2:57][CH3:58])[CH2:55][CH3:56])=[O:53])=[CH:50][CH:49]=3)[CH:44]=[CH:45][CH:46]=2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: CCN(CC)C(=O)c1ccc([C@@H](c2cccc(NC3CCCCC3)c2)N2CCN(CC3CC3)CC2)cc1
Agent: CCN(CC)C(=O)c1ccc([C@@H](c2cccc(NC3CCCCC3)c2)N2CCNCC2)cc1
Solvent: CO
Product: CCN1CCN([C@@H](c2ccc(C(=O)N(CC)CC)cc2)c2cccc(NC3CCCCC3)c2)CC1
Yield: 61 %

Procedure:
Synthesized using COMPOUND 27 (250 mg; 0.56 mmol) and the method described for COMPOUND 72. Obtained 163 g; 61% yield. Purity (HPLC-215 nm): >99%; Optical purity (Chiral HPLC-215 nm): >99%. 1H NMR (400 MHz, CD3OD) δ 0.80 (m, 1H), 1.19 (br s, 11H), 1.59 (m, 2H), 1.88 (br s, 5H), 3.14 (br s, 11H), 3.50 (br s, 4H), 4.11 (m, 1H), 7.31 (br s, 3H), 7.67 (br s, 5H). Found: C, 53.63; H, 7.55; N, 8.05. C30H44N4O×5.0HCl×0.7H2O has C, 53.65; H, 7.56; N, 8.34%. [α]D16=+12.7 deg [c 0.50, MeOH].
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[N:17]=[C:18]([CH2:21][O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[NH:19][CH:20]=3)=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:29]([N:31]=[C:32]=[S:33])[CH3:30]>C(O)C>[CH2:29]([NH:31][C:32]([NH:4][C:3]1[CH:5]=[CH:6][C:7]([O:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[N:17]=[C:18]([CH2:21][O:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[NH:19][CH:20]=3)=[CH:14][CH:15]=2)=[CH:8][C:2]=1[F:1])=[S:33])[CH3:30]
Reactant: Nc1ccc(Oc2ccc(-c3c[nH]c(COc4ccccc4)n3)cc2)cc1F
Reactant: CCN=C=S
Solvent: CCO
Product: CCNC(=S)Nc1ccc(Oc2ccc(-c3c[nH]c(COc4ccccc4)n3)cc2)cc1F
Yield: 11 %

Procedure:
A mixture containing 2-fluoro-4-{4-[2-(phenoxymethyl)-1H-imidazol-4-yl]phenoxy}aniline (1 g, 2.66 mmol) and ethylisothiocyanate (0.31 g, 2.32 mmol) in 20 ml of ethanol is heated for five hours under reflux. The reaction mixture is concentrated in a rotavapor. After passing the residue obtained through a silica column (eluent: dichloromethane/ethanol/liquid ammonia 96/2/2), a yellow-coloured powder is obtained with a yield of 11%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:15]2[O:19][N:18]=[C:17]([C:20]3[S:24][C:23]([CH2:25][N:26]4[CH2:29][CH:28]([C:30]([O:32]C)=[O:31])[CH2:27]4)=[CH:22][C:21]=3[CH3:34])[N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O.[OH-].[Li+].C(O)(=O)C>>[F:1][C:2]1[CH:3]=[C:4]([C:15]2[O:19][N:18]=[C:17]([C:20]3[S:24][C:23]([CH2:25][N:26]4[CH2:27][CH:28]([C:30]([OH:32])=[O:31])[CH2:29]4)=[CH:22][C:21]=3[CH3:34])[N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COC(=O)C1CN(Cc2cc(C)c(-c3noc(-c4ccc(Oc5ccccc5)c(F)c4)n3)s2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(CN2CC(C(=O)O)C2)sc1-c1noc(-c2ccc(Oc3ccccc3)c(F)c2)n1
Yield: 76.1 %

Procedure:
The title compound (0.17 g) was synthesized in a yield of 74% as a white crystalline solid by conducting the reaction similar to that mentioned in Example 2 (2e) using methyl 1-({5-[5-(3-fluoro-4-phenoxyphenyl)-1,2,4-oxadiazol-3-yl]-4-methyl-2-thienyl}methyl)azetidine-3-carboxylate (0.23 g, 0.48 mmol) that was obtained in Example 11 (11g), lithium hydroxide monohydrate (46 mg, 1.1 mmol), and acetic acid (60 μL, 1.1 mmol).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][C:10]=1[C:18]#[N:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:20][C:21]1[C:22]([F:31])=[C:23]([C:27]([O:29][CH3:30])=[O:28])[S:24][C:25]=1Br.C(=O)([O-])[O-].[Na+].[Na+]>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>[Br:20][C:21]1[C:22]([F:31])=[C:23]([C:27]([O:29][CH3:30])=[O:28])[S:24][C:25]=1[C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([C:18]#[N:19])[CH:11]=1
Reactant: N#Cc1cc(B(O)O)ccc1OCc1ccccc1
Reactant: COC(=O)c1sc(Br)c(Br)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)c1sc(-c2ccc(OCc3ccccc3)c(C#N)c2)c(Br)c1F

Procedure:
(4-Benzyloxy-3-cyanophenyl)boronic acid and methyl 4,5-dibromo-3-fluorothiophene-2-carboxylate were dissolved in a mixed solution of toluene and a 1M aqueous sodium carbonate solution and the whole was heated at 110° C. for 2.5 days in the presence of tetrakis(triphenylphosphine)palladium to obtain methyl 4-bromo-5-(4-benzyloxy-3-cyanophenyl)-3-fluorothiophene-2-carboxylate. Methyl 4-bromo-5-(4-benzyloxy-3-cyanophenyl)-3-fluorothiophene-2-carboxylate and triethylamine were stirred at room temperature in 1,4-dioxane under a hydrogen atmosphere at normal pressure in the presence of palladium-carbon to obtain methyl 5-(3-cyano-4-hydroxyphenyl)-3-fluorothiophene-2-carboxylate. FN: 276.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[CH2:22][C:11]3([O:16][C:15]4[CH:17]=[CH:18][CH:19]=[N:20][C:14]=4[NH:13][C:12]3=O)[CH2:10][C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]2[CH2:22][C:11]3([O:16][C:15]4[CH:17]=[CH:18][CH:19]=[N:20][C:14]=4[NH:13][C:12]3=[S:32])[CH2:10][C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C1Nc2ncccc2OC12Cc1cc([N+](=O)[O-])cnc1C2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cnc2c(c1)CC1(C2)Oc2cccnc2NC1=S

Procedure:
A solution of 3-nitro-5,7-dihydrospiro[cyclopenta[b]pyridine-6,2′-pyrido[3,2-b][1,4]oxazin]-3′(4′H)-one from Step D (450 mg, 1.5 mmol) in toluene (3 mL) is treated with Lawesson's reagent (650 mg, 1.6 mmol) and the mixture heated at reflux for several hours. The solvent is removed in vacuo and the residue is purified by silica gel chromatography (gradient elution with 0-10% MeOH in CH2Cl2) to afford the title compound.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][S:8]([O:11][CH2:12][C:13]([CH3:32])([CH3:31])[C@@H:14]([O:23]CC1C=CC=CC=1)[C:15]([O:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[O:16])(=[O:10])=[O:9])(=[O:3])[CH3:2]>[Pd].C(O)C>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][S:8]([O:11][CH2:12][C:13]([CH3:31])([CH3:32])[C@@H:14]([OH:23])[C:15]([O:17][CH2:18][CH2:19][CH:20]([CH3:21])[CH3:22])=[O:16])(=[O:9])=[O:10])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCCS(=O)(=O)OCC(C)(C)[C@@H](OCc1ccccc1)C(=O)OCCC(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(=O)NCCCS(=O)(=O)OCC(C)(C)[C@@H](O)C(=O)OCCC(C)C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
Following the general procedure for the hydrogenolysis of benzyl ethers of Description 18, a mixture of 3-methylbutyl (2R)-4-{[3-(acetylamino)propyl]sulfonyloxy}-3,3-dimethyl-2-(phenylmethoxy)butanoate acid (29c) (0.20 g, 0.42 mmol) and 200 mg of 10 wt-% of palladium on activated carbon in 10 mL of ethanol (EtOH) was stirred overnight under a hydrogen atmosphere. After purification by mass-guided preparative HPLC, 160 mg (quant. yield) of the title compound (29) was obtained as a colorless, viscous oil. 1H NMR (400 MHz, CDCl3): δ=0.943 (d, J=6.8 Hz, 3H), 0.946 (d, J=6.8 Hz, 3H), 0.947 (s, 3H), 1.13 (s, 3H), 1.55-1.62 (m, 2H), 1.63-1.76 (m, 1H), 1.99 (s, 3H), 2.02-2.13 (m, 2H), 3.12-3.26 (m, 3H), 3.31-3.46 (m, 2H), 3.95 (d, J=9.6 Hz, 1H), 4.03 (s, 1H), 4.17 (d, J=9.2 Hz, 1H), 4.24 (t, J=6.8 Hz, 2H), 6.06-6.12 (br. m, 1H) ppm. MS (ESI) m/z: 382.00 (M+H)+, 380.04 (M−H)−. The analytical data was consistent with the proposed structure.