Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:11][C:12]([CH2:14][C:15]([O:17]CC)=O)=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:20][OH:21].Cl.NO.[Na]>CO>[C:1]1([NH:11][C:12]([CH2:14][C:15]([NH:20][OH:21])=[O:17])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: CCOC(=O)CC(=O)Nc1cccc2ccccc12
Agent: Cl
Agent: [Na]
Solvent: CO
Product: O=C(CC(=O)Nc1cccc2ccccc12)NO
Yield: 62 %

Procedure:
19.3 g (0.075 mol) of ethyl α-naphthylcarbamoylacetate are treated with a solution of hydroxylamine, prepared from 5.6 g (0.08 mol) of hydroxylamine hydrochloride and 3.68 g of sodium in 250 ml of methanol. After leaving the reactants in contact for 5 hours, the mixture is evaporated to dryness in vacuo, the residue is taken up in 400 ml of cold water, the solution is filtered over charcoal, and the product is precipitated cold with 3 N HCl, filtered off and washed with water. CRL 40,518 is obtained by recrystallisation from ethanol. Yield: 62%. Melting point: 184°-186° C. (with decomposition).
Reaction SMILES: Br.[NH2:2][C:3]1[C:11]([OH:12])=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:13])=[CH:5][CH:4]=1.[C:14]1([CH2:20][CH2:21][CH2:22][CH2:23][C:24](O)=[O:25])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C>CN(C)C=O.C(OCC)C>[OH:12][C:11]1[C:3]([NH:2][C:24](=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:13])[CH2:8][CH2:7]2
Reactant: Nc1ccc2c(c1O)C(=O)CC2
Reactant: O=C(O)CCCCc1ccccc1
Agent: Br
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C(CCCCc1ccccc1)Nc1ccc2c(c1O)C(=O)CC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 26.3 %

Procedure:
6-Amino-7-hydroxyindan-1-one hydrobromide (50 mg, 0.256 mmol) and 5-phenylvaleric acid (54.8 mg, 0.307 mmol) were dissolved in N,N-dimethylformamide (1.3 mL), diethyl cyanophosphate (45.7 μL, 0.307 mmol) and triethylamine (120 μL, 0.896 mmol) were added, and the mixture was stirred at room temperature for 15 min. The reaction solution was diluted with diethyl ether, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90→40/60) to give the title compound (21.8 mg, yield 26%).
Reaction SMILES: [Br:1][C:2]1[NH:11][C:5]2[N:6]=[CH:7][N:8]=[C:9](Cl)[C:4]=2[CH:3]=1.[NH2:12][C:13]1[C:22]([O:23][CH3:24])=[CH:21][C:16]2[NH:17][C:18](=[O:20])[S:19][C:15]=2[CH:14]=1>>[Br:1][C:2]1[NH:11][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:12][C:13]3[C:22]([O:23][CH3:24])=[CH:21][C:16]4[NH:17][C:18](=[O:20])[S:19][C:15]=4[CH:14]=3)[C:4]=2[CH:3]=1
Reactant: Clc1ncnc2[nH]c(Br)cc12
Reactant: COc1cc2[nH]c(=O)sc2cc1N
Product: COc1cc2[nH]c(=O)sc2cc1Nc1ncnc2[nH]c(Br)cc12

Procedure:
25 mg (108 μmol) 6-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (CAS-No: 784150-41-0) were transformed in analogy to example 1 using 6-amino-5-methoxy-1,3-benzothiazol-2(3H)-one to give after working up and purification 11.8 mg (27%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9](=[O:11])[C:8]([CH2:12][CH2:13][CH3:14])=[C:7](Cl)[C:6]=2[CH:16]=1.[CH3:17][NH:18][CH2:19][CH2:20][CH2:21][CH3:22]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9](=[O:11])[C:8]([CH2:12][CH2:13][CH3:14])=[C:7]([N:18]([CH2:19][CH2:20][CH2:21][CH3:22])[CH3:17])[C:6]=2[CH:16]=1
Reactant: CCCc1c(Cl)c2cc(Br)ccc2oc1=O
Reactant: CCCCNC
Solvent: CN(C)C=O
Product: CCCCN(C)c1c(CCC)c(=O)oc2ccc(Br)cc12

Procedure:
A solution of 6-bromo-4-chloro-3-propyl-2H-1-benzopyran-2-one (0.4 g) and N-methylbutylamine (3 ml) in dimethylformamide (2 ml) was heated under reflux for 30 minutes and then allowed to cool overnight. Evaporation followed by column chromatography yielded 6-bromo-4-(butylmethylamino)-3-propyl-2H-1-benzopyran-2-one, as an oil. (compound 18).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1I.[OH:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[C:16]([C:27]2[CH:28]=[CH:29][C:24]([OH:23])=[CH:25][CH:26]=2)=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1I
Reactant: OB(O)c1ccc(O)cc1
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: O
Solvent: COCCOC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1-c1ccc(O)cc1
Yield: 24.7 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-hydroxybiphenyl-2-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.075 g; 0.176 mmol), 4-hydroxyphenylboronic acid (0.024 g; 0.177 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 18 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.017 g (26%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-hydroxybiphenyl-2-carboxamide as a white solid.
Reaction SMILES: OS(O)(=O)=O.OO.[NH4+].[OH-].[N+]([O-])(O)=O.[CH:14]1[CH:19]=[C:18](C(O)=O)[N:17]=[C:16]([C:23]([OH:25])=[O:24])[CH:15]=1.[OH-].[Ca+2:27].[OH-].C1(S)C=CC=CC=1>[W].O>[N:17]1[CH:18]=[CH:19][CH:14]=[CH:15][C:16]=1[C:23]([O-:25])=[O:24].[N:17]1[CH:18]=[CH:19][CH:14]=[CH:15][C:16]=1[C:23]([O-:25])=[O:24].[Ca+2:27]
Reactant: O=C(O)c1cccc(C(=O)O)n1
Agent: [W]
Agent: O=S(=O)(O)O
Agent: OO
Solvent: O=[N+]([O-])O
Solvent: O
Product: O=C([O-])c1ccccn1

Procedure:
Chemicals used were of reagent grade or better. Ag (99.99%) was purchased from D. F. Goldsmith (Evanston, Ill.). Glass substrates were 18 mm diameter, No. 2 cover slips from Fisher Scientific (Pittsburgh, Pa.). Pretreatment of substrates required H2SO4, H2O2, and NH4OH, all of which were purchased from Fisher Scientific (Fairlawn, N.J.). Surfactant-free white carboxyl-functionalized polystyrene latex nanospheres with diameters of 390, 510, 600, and 720 nm were obtained from Duke Scientific Corporation (Palo Alto, Calif.) and Interfacial Dynamics Corporation (Portland, Oreg.). Tungsten vapor deposition boats were purchased from R. D. Mathis (Long Beach, Calif.). Nitric acid 70% (Fisher Scientific), dipicolinic acid (2,6-pyridinedicarboxylic acid, DPA), calcium hydroxide, and benzenethiol (Aldrich Chemical Co., Milwaukee, Wis.) were used as purchased. Water (18.2 MΩ/cm) was obtained from an ultrafilter system (Milli-Q, Millipore, Marlborough, Mass.). Calcium dipicolinate (CaDPA) was prepared from DPA and calcium hydroxide according to the method of Beiley and co-workers.
Reaction SMILES: [Li+].[OH-].[CH3:3][C:4]1[CH:5]=[C:6]([C:21]2[CH:22]=[N:23][N:24]([CH:26]([CH3:31])[C:27]([O:29]C)=[O:28])[CH:25]=2)[CH:7]=[C:8]([NH:10][C:11]2[N:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][N:12]=2)[CH:9]=1>CO.O>[CH3:3][C:4]1[CH:5]=[C:6]([C:21]2[CH:22]=[N:23][N:24]([CH:26]([CH3:31])[C:27]([OH:29])=[O:28])[CH:25]=2)[CH:7]=[C:8]([NH:10][C:11]2[N:16]=[C:15]([C:17]([F:20])([F:18])[F:19])[CH:14]=[CH:13][N:12]=2)[CH:9]=1
Reactant: COC(=O)C(C)n1cc(-c2cc(C)cc(Nc3nccc(C(F)(F)F)n3)c2)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnn(C(C)C(=O)O)c2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
LiOH (10.6 mg, 0.44 mmol) was added to a solution of methyl 2-[4-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-pyrazol-1-yl]propanoate (18 mg, 0.04 mmol) in methanol (870 μL) and water (87 μL). The reaction mixture was allowed to stir at room temperature for 3 hours then concentrated using under reduced pressure. The residue was purified by reverse phase HPLC (ACN/water with 0.1% TFA modifier) to afford 2-[4-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-pyrazol-1-yl]propanoic acid. MS ESI calcd. for C18H17F3N5O2[M+H]+ 392. found, 392. 1H NMR (500 MHz, DMOS-d6) δ 13.04 (s, 1H), 10.11 (s, 1H), 8.80 (d, J=4.9, 1H), 8.12 (s, 1H), 7.84 (s, 1H), 7.75 (s, 1H), 7.32 (s, 1H), 7.24 (d, J=4.9, 1H), 7.09 (s, 1H), 5.11 (q, J=7.3, 1H), 2.29 (s, 3H), 1.67 (d, J=7.3, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:8])([CH3:7])[CH:4]=[N:5][OH:6].ClCl.[C-:11]#[N:12].[Na+]>CCOCC.CO.O>[CH3:1][O:2][C:3]([CH3:8])([CH3:7])[C:4](=[N:5][OH:6])[C:11]#[N:12]
Reactant: [C-]#N
Reactant: COC(C)(C)C=NO
Agent: ClCl
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CO
Product: COC(C)(C)C(C#N)=NO
Reaction time: 1 h

Procedure:
53.6 g (0.46 mol) of 2-methoxy-2-methylpropionaldehyde oxime in ether (about 1M) are initially taken at from -5° to -10° C. 35.8 g (0.5 mol) of chlorine gas are passed in, after which stirring is carried out for 1 hour at this temperature and the mixture is then evaporated down at 10° C. and the residue is taken up in diethyl ether. 24.7 g (0.5 mol) of sodium cyanide in 375 ml of 20:1 methanol/H2O are initially taken at 10° C. and the above ethereal solution is rapidly added dropwise. After 4 hours at room temperature, the mixture is filtered under suction and the residue is washed with twice 100 ml of methanol. The combined solutions are evaporated down and the residue is partitioned between methyl tert-butyl ether and water. Drying the organic phase over Na2SO4, evaporating down and crystallizing from dichloromethane/n-hexane give 41.1 g (63% of theory) of a white powder of melting point 102°-104° C.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([NH:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[N:3]=1.[NH2:18][C:19]1[C:26]([CH3:27])=[CH:25][C:22]([C:23]#[N:24])=[CH:21][C:20]=1[CH3:28].C(N(C(C)C)CC)(C)C.[OH-].[Na+]>C(Cl)Cl.O1CCOCC1.CN1CCCC1=O>[C:14]([C:13]1[CH:16]=[CH:17][C:10]([NH:9][C:4]2[N:3]=[C:2]([NH:18][C:19]3[C:20]([CH3:28])=[CH:21][C:22]([C:23]#[N:24])=[CH:25][C:26]=3[CH3:27])[C:7]([CH3:8])=[CH:6][N:5]=2)=[CH:11][CH:12]=1)#[N:15]
Reactant: Cc1cc(C#N)cc(C)c1N
Reactant: Cc1cnc(Nc2ccc(C#N)cc2)nc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnc(Nc2ccc(C#N)cc2)nc1Nc1c(C)cc(C#N)cc1C
Temperature: 195 °C
Reaction time: 1 h
Yield: 202.3 %

Procedure:
4-[(4-chloro-2-pyrimidinyl)amino]benzonitrile (0.003 mol), 2,6-dibromo-4-methyl-benzenamine (0.006 mol) and 1 M HCl in diethyl ether (4.5 ml) in 1,4-dioxane (10 ml) were combined in a tube and heated under Ar until all diethyl ether had evaporated. The tube was sealed and heated at 170° C. for 2.5 days. Silica gel was added, and the solvent was evaporated. The residue was purified by flash column chromatography over silica gel (eluent gradient: CH2Cl2:CH3OH:NH4OH 100:0:0 to 99:0.9:0.1). The desired fractions were collected and the solvent was evaporated. The residue was recrystallized from acetonitrile, filtered off and dried, yielding 0.22 g (15.9%) of 4-[[4-[(2,6-dibromo-4-methylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile (compound 61). b) 4-[[4-[(4-chloro-5-methyl-2-pyrimidinyl]amino]benzonitrile (0.01541 mol), 4-amino-3,5-dimethyl-benzonitrile (0.00219 mol), 1-methyl-2-pyrrolidinone (4 ml), 1,4-dioxane (15 ml) and diisopropylethylamine (0.0154 mol) were combined in a flask under a stream of argon and heated at 160-230° C. for 16 hours. CH2Cl2 and 1N NaOH were added, and the mixture was stirred 1 hour and filtered to give a brown solid (*). The CH2Cl2 filtrate was separated and was evaporated and purified by flash column chromatography (eluent: 2% CH3OH/CH2Cl2). The desired fractions were combined, evaporated and the residue was stirred in CH2Cl2. The solid precipitate was filtered off, combined with the brown solid (*) and recrystallized from CH3CN. The precipitate was filtered off and dried, yielding 1.57 g (29%) of 4-[[2-[(4-cyanophenyl)amino]-5-methyl-4-pyrimidinyl]amino]-3,5-dimethylbenzonitrile (compound 89). c) 2-[(4-cyanophenyl)amino]-4-pyrimidinyl trifluoromethanesulfonate (0.0022 mol) and 2,6-dichloro-4-(trifluoromethyl)-benzenamine (0.0044 mol) were combined in 1,4-dioxane (2.5 ml) and heated in a sealed tube under Ar at 170° C. for 40 hours. The reaction mixture was allowed to cool to room temperature. Silica gel was added, and the solvent was evaporated. The residue was purified by flash column chromatography over silica gel (eluent gradient: CH2C2:CH3OH:NH4OH 100:0:0 to 97:2.7:0.3). The desired fractions were collected and the solvent was evaporated. The residue was recrystallized from CH3CN, filtered off and dried, yielding 0.086 g (9.2%) of 4-[[4-[[2,6-dichloro-4-(trifluoromethyl)-phenyl]amino]-2-pyrimidinyl]amino]benzonitrile (compound 66).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]([C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=4)=[CH:27][CH:26]=3)[C:16]3[C:21]([C:22]=2[CH:23]=[O:24])=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[N:11]1([C:14]2[N:15]([C:25]3[CH:26]=[CH:27][C:28]([C:31]4[CH:32]=[CH:33][N:34]=[CH:35][CH:36]=4)=[CH:29][CH:30]=3)[C:16]3[C:21]([C:22]=2[CH:23]=[O:24])=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(C=O)c3ccccc3n2-c2ccc(-c3ccncc3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=Cc1c(N2CCNCC2)n(-c2ccc(-c3ccncc3)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.3 %

Procedure:
4-[3-Formyl-1-[(4-pyridin-4-yl)phenyl]-1H-indol-2-yl]-piperazine-1-carboxylic acid tert-butyl ester (68 mg, 0.141 mmol) is dissolved in dichloromethane (1 mL), treated with trifluoroacetic acid (2 mL) and stirred for 2 hr at room temperature. The solvent is removed, the resulting oil is dissolved in water, made basic to pH around 7˜8 with 20% aq sodium hydroxide and extracted with dichloromethane. The combined organic layer is washed with brine and dried over sodium sulfate, filtered and concentrated. The residue is purified by chromatography eluting with dichloromethane-0 to 10% methanol to afford 2-piperazin-1-yl-1-[(4-pyridin-4-yl)phenyl]-1H-indole-3-carboxaldehyde (46 mg, 85%) as a light tan solid. ESI/MS 383 (M+1).
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=3[Cl:25])(=[O:16])=[O:15])[CH2:11][N:10]2[C:26]([C:28]2([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][N:33]=3)[CH2:31][NH:30][CH2:29]2)=[O:27])=[O:8])[CH2:5][CH2:4]1)#[N:2].[CH3:39]I>CO>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=3[Cl:25])(=[O:15])=[O:16])[CH2:11][N:10]2[C:26]([C:28]2([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][N:33]=3)[CH2:31][N:30]([CH3:39])[CH2:29]2)=[O:27])=[O:8])[CH2:4][CH2:5]1)#[N:2]
Reactant: COc1ccc(S(=O)(=O)[C@@H]2C[C@@H](C(=O)NC3(C#N)CC3)N(C(=O)C3(c4ccc(Cl)cn4)CNC3)C2)c(Cl)c1
Reactant: CI
Solvent: CO
Product: COc1ccc(S(=O)(=O)[C@@H]2C[C@@H](C(=O)NC3(C#N)CC3)N(C(=O)C3(c4ccc(Cl)cn4)CN(C)C3)C2)c(Cl)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of example 2 (0.05 g, 86.4 μmol, Eq: 1.00) in refluxing methanol (1 ml) was added methyl iodide (9.2 mg, 4.05 μl, 64.8 μmol, Eq: 0.75). After complete addition the mixture was stirred at 80° C. for 2 h. Additional methyl iodide (9.2 mg, 4.05 μl, 64.8 μmol, Eq: 0.75) was added and the mixture was stirred at 80° C. for 2 h, then at 20° C. over night. The mixture was purified by preparative HPLC to yield a colorless solid (3 mg; 6%). m/z=592.2 [M+H]+.
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]([C@@H:17]([NH:23][C:24]([C@@H:26]2[CH2:31][CH2:30][CH2:29][N:28]([C:32](=[O:48])[CH2:33][CH2:34][CH:35]3[CH2:40][CH2:39][N:38](C(OC(C)(C)C)=O)[CH2:37][CH2:36]3)[CH2:27]2)=[O:25])[CH2:18][C:19]([O:21]C)=[O:20])[CH:14]=[CH:15][CH:16]=1.CO.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>C(O)(C)(C)C>[F:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]([C@@H:17]([NH:23][C:24]([C@@H:26]2[CH2:31][CH2:30][CH2:29][N:28]([C:32](=[O:48])[CH2:33][CH2:34][CH:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[CH2:27]2)=[O:25])[CH2:18][C:19]([OH:21])=[O:20])[CH:14]=[CH:15][CH:16]=1
Reactant: COC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cccc(OCCOCCOCCF)c1
Agent: [Ba+2]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CC(C)(C)O
Product: O=C(O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCNCC2)C1)c1cccc(OCCOCCOCCF)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
Tert-butyl 4-{3-[(3R)-3-{[(1S)-1-(3-{2-[2-(2-fluoroethoxy)ethoxy]ethoxy}phenyl)-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (20.3 mg, 27 μmol) was solved in tert.-butanol (0.77 mL) and methanol (0.76 mL) and barium hydroxide octahydrate (42 mg, 0.13 mmol) was added. After stirring for 60 minutes room temperature the solvent was distilled off at 0° C. by high vacuum. The residue was solved in water (1 mL) and acidified by formic acid (2 mL). After 18 hours at 5° C. additional formic acid (2 mL) was added. After 3 hours at room temperature the solvent was distilled off at 0° C. by high vacuum and the residue was purified by preparative HPLC to yield 8.4 mg of (3S)-3-(3-{2-[2-(2-fluoroethoxy)ethoxy]ethoxy}phenyl)-3-[({(3R)-1-[3-(piperidin-4-yl)propanoyl]piperidin-3-yl}carbonyl)amino]propanoic acid.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:8]([CH:9]2[CH2:11][CH2:10]2)[C:7]2[C:12]([C:16]([NH:18][CH3:19])=[O:17])=[CH:13][CH:14]=[CH:15][C:6]=2[N:5]=1)[CH3:3].C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:26][C:27]1[S:28][C:29](Br)=[N:30][N:31]=1>CCO>[NH2:26][C:27]1[S:28][C:29]([NH:1][C@H:2]([C:4]2[N:8]([CH:9]3[CH2:10][CH2:11]3)[C:7]3[C:12]([C:16]([NH:18][CH3:19])=[O:17])=[CH:13][CH:14]=[CH:15][C:6]=3[N:5]=2)[CH3:3])=[N:30][N:31]=1
Reactant: CNC(=O)c1cccc2nc([C@H](C)N)n(C3CC3)c12
Reactant: Nc1nnc(Br)s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Product: CNC(=O)c1cccc2nc([C@H](C)Nc3nnc(N)s3)n(C3CC3)c12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of (S)-2-(1-aminoethyl)-1-cyclopropyl-N-methyl-1H-benzo[d]imidazole-7-carboxamide (prepared in example 20) (63.5 mg, 0.25 mmol), cesium carbonate (80 mg, 0.25 mmol) and 2-amino-5-bromo-[1,3,4]thiadiazole (44.3 mg, 0.25 mmol) in EtOH (5 mL) under N2 was stirred at rt for 18 h. The reaction mixture was concentrated in vacuo. The residue was diluted with EtOAc, washed with water, brine, dried over magnesium sulfate, and concentrated in vacuo. Purification of the residue by flash chromatography over silica gel, using 0 to 10% gradient of MeOH in DCM with 0.2% NH4OH as eluent to give 2-((1S)-1-((5-amino-1,3,4-thiadiazol-2-yl)amino)ethyl)-1-cyclopropyl-N-methyl-1H-benzimidazole-7-carboxamide: 1H NMR (400 MHz, DMSO-d6) δ 8.46-8.39 (1H, m); 7.62 (1H, d, J=8.0 Hz), 7.44 (1H, d, J=8.0 Hz), 7.24-7.16 (2H, m); 6.22 (2H, s), 5.46-5.37 (1H, m), 3.40-3.30 (1H, m), 2.82 (3H, d, J=4.0 Hz), 1.55 (3H, d, J=4.0 Hz), 1.22-1.15 (1H, m), 1.12-1.04 (1H, m), 1.01-0.92 (1H, m), 0.83-0.74 (1H, m); LC-MS (ESI) m/z 358.0 [M+H]+.
Reaction SMILES: Cl.Br[CH2:3]/[C:4](=[CH:9]\[CH3:10])/[C:5](OC)=[O:6].[CH2:11]([S:18][C:19]([CH3:30])([CH3:29])[CH:20]=[N:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[NH4+]>C1COCC1.[Zn]>[CH2:22]([N:21]1[CH:20]([C:19]([S:18][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)([CH3:30])[CH3:29])[CH2:3][C:4](=[CH:9][CH3:10])[C:5]1=[O:6])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C=NCc1ccccc1)SCc1ccccc1
Reactant: C/C=C(\CBr)C(=O)OC
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC=C1CC(C(C)(C)SCc2ccccc2)N(Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.6 %

Procedure:
To a stirred suspension of zinc dust (0.53 g) activated with hydrochloric acid in THF (20 ml), methyl 2-bromomethylcrotonate (1.50 g) dissolved in THF (10 ml) and N-(2-benzylthio-2-methylpropylidene)benzylamine (2.00 g) dissolved in THF (10 ml) were added dropwise in the order named at about 30° C. under nitrogen atmosphere and ultrasonic irradiation. The mixture was stirred overnight at room temperature. To the mixture saturated aqueous ammonium chloride solution was added. The mixture was filtered by celite. A reaction product was extracted with ethyl acetate from the filtrate. The organic layer was washed with IN hydrochloric acid, water and then saturated sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The oily residue was purified by silica gel column chromatography to give 1.03 g (40%) of the titled compound No.7-1 and 0.48 g (19%) of the titled compound No.7-2.
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[K+].[C:7]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=[CH:11][C:10](C=O)=[CH:9][CH:8]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH:1]([C:20]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[CH2:2]
Reactant: CC(C)(C)[O-]
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=Cc1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of methyltriphenylphosphonium bromide (5.10 g, 14.27 mmol) in THF (26 mL) was slowly added potassium tert-butoxide (1M solution in THF, 14.27 mL) over ˜20 min at 0° C. The reaction mixture was allowed to warm up to room temperature and stirred for 10 min. The mixture was cooled to 0° C. and a solution of 4-biphenylcarbaldehyde (2.0 g, 10.98 mmol) in THF (9 mL) was added over 20 min. The reaction mixture was allowed to warm up to room temperature and stirred for ˜19 hour. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved/suspended in DCM and filtered through a silica pad and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography [SiO2, 80 g, EtOAc/heptane] to provide vinylbiphenyl (1.845 g) as a white solid. LCMS Rt 0.79 min.
Reaction SMILES: [CH2:1]([S-:3])[CH3:2].[Na+].Cl[C:6]1[C:7]([C:12]([NH:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=2)=[O:13])=[N:8][CH:9]=[CH:10][CH:11]=1.CN(C=O)C>O>[CH2:1]([S:3][C:6]1[C:7]([C:12]([NH:14][C:15]2[CH:16]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:18]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:20]=2)=[O:13])=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:2]
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncccc1Cl
Reactant: CC[S-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1cccnc1C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 98.3 %

Procedure:
0.89 g of sodium ethanethiolate was added to a mixture of 1.56 g of 3-chloro-N-(3,5-bistrifluoromethylphenyl)picolinamide and 3 mL of DMF, and the mixture was stirred at 60° C. for 2 hours. The reaction mixture cooled to room temperature was poured to water, and the precipitated solid was taken by filtration. The resulting solid was dissolved in ethyl acetate, and the mixture was extracted with water and ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 1.64 g of 3-ethylsulfanyl-N-(3,5-bistrifluoromethylphenyl)picolinamide (hereinafter, referred to as Compound of Present Invention 10).