Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]3N=CN(C4C=CC=CC=4)[CH:16]=3)=[C:10]([C:23]([F:26])([F:25])[F:24])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[Cu]C#N.[Cl-].[Li+].C(Cl)(=[O:39])C>COCCOC.C1COCC1.C(=O)([O-])[O-].[Na+].[Na+]>[C:1]1([C:7]2[C:11]([C:12](=[O:39])[CH3:16])=[C:10]([C:23]([F:26])([F:25])[F:24])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: FC(F)(F)c1onc(-c2ccccc2)c1-c1cn(-c2ccccc2)cn1
Reactant: CC(=O)Cl
Agent: N#C[Cu]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: COCCOC
Solvent: C1CCOC1
Product: CC(=O)c1c(-c2ccccc2)noc1C(F)(F)F
Temperature: -35 °C
Reaction time: 1 h
Yield: 82.8 %

Procedure:
To a solution of 3-phenyl-4-(1-phenyl-1H-imidazol-4-yl)-5-trifluoromethyl-isoxazole (5.0 g, 23 mmol) in 1,2-dimethoxyethane (50 mL) was added BuLi (1.6 M in hexane, 22 mL, 35 mmol) at −78° C. and the resulting mixture stirred for 1 h allowing to warm up to −35° C. and then re-cooled to −78° C. To this mixture was then rapidly added a solution of copper(I) cyanide (2.1 g, 23 mmol) containing lithium chloride (1.99 g, 47 mmol) in dry THF (30 mL) and then allowed to warm up to −35° C. and then this mixture was added to a solution of acetyl chloride (9.2 g, 8.37 mL, 117 mmol) in dry THF (50 mL) at room temperature. After 4 h at room temperature the mixture was diluted with aqueous sodium carbonate and the mixture was extracted with ethyl acetate and the combined organic layers washed with brine, dried over sodium sulfate, filtered and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 4:1) afforded the title compound (4.86 g, 82%) which was obtained as a light yellow oil. MS: m/e 254.2 [M+H]+.
Reaction SMILES: C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](/[CH:24]=[CH:25]/[C:26]2[CH:39]=[CH:38][C:29]([C:30]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[O:31])=[CH:28][CH:27]=2)=[N:16]1.C(N(CC)CC)C.[CH2:47]([N:49]=[C:50]=[O:51])[CH3:48]>C1COCC1.O>[CH2:47]([NH:49][C:50]([N:35]1[CH2:36][CH2:37][N:32]([C:30](=[O:31])[C:29]2[CH:28]=[CH:27][C:26](/[CH:25]=[CH:24]/[C:17]3[C:18]4[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=4)[NH:15][N:16]=3)=[CH:39][CH:38]=2)[CH2:33][CH2:34]1)=[O:51])[CH3:48]
Reactant: CCN=C=O
Reactant: O=C(c1ccc(/C=C/c2n[nH]c3ccccc23)cc1)N1CCNCC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CCNC(=O)N1CCN(C(=O)c2ccc(/C=C/c3n[nH]c4ccccc34)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.6 %

Procedure:
A solution of dihydrochloride of Compound 18 (400 mg, 1.09 mmol) in THF (20 mL) was added with triethylamine (0.42 mL, 3.01 mmol) and ethylisocyanate (117 mg, 1.65 mmol), followed by stirring at room temperature for 3 hours. The reaction mixture was added with water, and deposited crystal was collected by filtration and was dried to obtain Compound 59 (218 mg, 55%).
Reaction SMILES: [NH2:1][C:2]1[C:9]([NH2:10])=[CH:8][CH:7]=[C:6]([N:11]2[CH2:16][CH2:15][CH2:14][CH:13]([C:17]([F:20])([F:19])[F:18])[CH2:12]2)[C:3]=1[C:4]#[N:5].[Cl:21][C:22]1[CH:38]=[CH:37][C:25]([CH2:26][NH:27][C:28]([C:30]2([C:33]([F:36])([F:35])[F:34])[CH2:32][CH2:31]2)=[O:29])=[CH:24][C:23]=1[N:39]=[C:40]=S.C(Cl)CCl>CN(C=O)C>[Cl:21][C:22]1[CH:38]=[CH:37][C:25]([CH2:26][NH:27][C:28]([C:30]2([C:33]([F:36])([F:35])[F:34])[CH2:31][CH2:32]2)=[O:29])=[CH:24][C:23]=1[NH:39][C:40]1[NH:10][C:9]2[CH:8]=[CH:7][C:6]([N:11]3[CH2:16][CH2:15][CH2:14][CH:13]([C:17]([F:20])([F:18])[F:19])[CH2:12]3)=[C:3]([C:4]#[N:5])[C:2]=2[N:1]=1
Reactant: O=C(NCc1ccc(Cl)c(N=C=S)c1)C1(C(F)(F)F)CC1
Reactant: N#Cc1c(N2CCCC(C(F)(F)F)C2)ccc(N)c1N
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: N#Cc1c(N2CCCC(C(F)(F)F)C2)ccc2[nH]c(Nc3cc(CNC(=O)C4(C(F)(F)F)CC4)ccc3Cl)nc12

Procedure:
The title compound was prepared in analogy to Example 71 using 2,3-diamino-6-(3-trifluoromethyl-piperidin-1-yl)benzonitrile (115 mg, 0.40 mmol), N-(4-chloro-3-isothiocyanatobenzyl)-1-(trifluoromethyl)cyclopropane carboxamide (135 mg; 0.40 mmol), EDC (77 mg, 0.40 mmol) and DMF (3 mL).
Reaction SMILES: [CH2:1]([N:5]([CH2:25][CH2:26][CH2:27][CH3:28])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][CH:14]=[CH:15][C:16]2[S:20][C:19]([CH:21]=O)=[CH:18][CH:17]=2)=[C:8]([O:23][CH3:24])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:29]([C:31]1[C:32](=[C:47]([C:50]#[N:51])[C:48]#[N:49])[O:33][C:34]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([C:37]([F:40])([F:39])[F:38])[C:35]=1[CH3:36])#[N:30]>C(O)C>[CH2:25]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][CH:14]=[CH:15][C:16]2[S:20][C:19]([CH:21]=[CH:36][C:35]3[C:34]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)([C:37]([F:40])([F:38])[F:39])[O:33][C:32](=[C:47]([C:50]#[N:51])[C:48]#[N:49])[C:31]=3[C:29]#[N:30])=[CH:18][CH:17]=2)=[C:8]([O:23][CH3:24])[CH:7]=1)[CH2:26][CH2:27][CH3:28]
Reactant: CCCCN(CCCC)c1ccc(C=CC=Cc2ccc(C=O)s2)c(OC)c1
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(c1ccccc1)C(F)(F)F
Solvent: CCO
Product: CCCCN(CCCC)c1ccc(C=CC=Cc2ccc(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(c3ccccc3)C(F)(F)F)s2)c(OC)c1
Temperature: 50 °C
Yield: 78.5 %

Procedure:
In 8 ml of ethanol were dissolved 220 mg (0.55 mmol) of 5-[4-(4-dibutylamino-2-methoxyphenyl)-1,3-butadienyl]thiophene-2-carboaldehyde and 192 mg (0.61 mmol) of 2-(3-cyano-4-methyl-5-phenyl-5-trifluoromethyl-2(5H)-furanylidene)propanedinitrile. After the mixture was stirred with heating at 50° C. for 2.5 hours, the product was separated by filtration and washed with ethanol. The product was purified by silica gel column chromatography to give 300 mg of a black crystal (yield: 78.1%; mp: 125-140° C.)
Reaction SMILES: [F:1][C@@H:2]1[C@@H:6]([CH2:7][OH:8])[O:5][C@@H:4]([N:9]2[C:19]3[N:18]=[C:16]([NH2:17])[NH:15][C:13](=[O:14])[C:12]=3[N:11]=[CH:10]2)[CH2:3]1.[C:20]([NH:30][C@H:31]([C:35]([O:37][CH2:38][CH:39]([CH2:44][O:45][C:46](=[O:62])[C@H:47]([CH:59]([CH3:61])[CH3:60])[NH:48][C:49]([O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:50])[CH2:40][C:41](O)=[O:42])=[O:36])[CH:32]([CH3:34])[CH3:33])([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.CN(C=O)C>[F:1][C@@H:2]1[C@@H:6]([CH2:7][O:8][C:41](=[O:42])[CH2:40][CH:39]([CH2:44][O:45][C:46](=[O:62])[C@H:47]([CH:59]([CH3:61])[CH3:60])[NH:48][C:49]([O:51][CH2:52][C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=2)=[O:50])[CH2:38][O:37][C:35](=[O:36])[C@H:31]([CH:32]([CH3:34])[CH3:33])[NH:30][C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[O:5][C@@H:4]([N:9]2[C:19]3[N:18]=[C:16]([NH2:17])[NH:15][C:13](=[O:14])[C:12]=3[N:11]=[CH:10]2)[CH2:3]1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)CC(=O)O
Reactant: Nc1nc2c(ncn2[C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)CC(=O)OC[C@H]1O[C@@H](n2cnc3c(=O)[nH]c(N)nc32)C[C@@H]1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2′,3′-dideoxy-3′-fluoroguanosine (1.35 g, 5 mmole), 3,3-bis(N-CBZ-L-valyloxymethyl)-propionic acid (3.6 g, 6 mmole), DMAP (0.061 g, 0.5 mmole) and HOBT (0.81 g, 6 mmole) was coevaporated two times with DMF and reduced to about 120 ml. DCC (1.24 g, 6 mmole) was added and the mixture was stirred overnight at room temperature. The mixture was filtered and the solution was evaporated under reduced pressure. Ethyl acetate (200 ml) was added and the organic phase washed twice with 5% acetic acid, 5% sodium hydrogen carbonate and water. The organic phase was dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography. Yield: 2.7 g
Reaction SMILES: [C:1](=[O:45])([O:33][CH2:34][CH2:35][CH2:36][O:37]CC1C=CC=CC=1)[O:2][CH2:3][O:4][C:5]1[C:6](=[O:32])[C:7]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[F:31])=[O:21])=[CH:8][N:9]2[C:14]=1[C:13](=[O:15])[N:12]1[C@@H:16]([CH3:19])[CH2:17][O:18][C@@H:11]1[CH2:10]2.[Na].FC1C=C(F)C=CC=1CNC(C1C(=O)C(O)=C2C(=O)N3[C@@H](C)CO[C@@H]3CN2C=1)=O.C(=O)(OCCCOCC1C=CC=CC=1)OCI.C(=O)([O-])[O-].[K+].[K+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[C:1](=[O:45])([O:33][CH2:34][CH2:35][CH2:36][OH:37])[O:2][CH2:3][O:4][C:5]1[C:6](=[O:32])[C:7]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[F:31])=[O:21])=[CH:8][N:9]2[C:14]=1[C:13](=[O:15])[N:12]1[C@@H:16]([CH3:19])[CH2:17][O:18][C@@H:11]1[CH2:10]2
Reactant: C[C@H]1CO[C@@H]2Cn3cc(C(=O)NCc4ccc(F)cc4F)c(=O)c(OCOC(=O)OCCCOCc4ccccc4)c3C(=O)N12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[C@H]1CO[C@@H]2Cn3cc(C(=O)NCc4ccc(F)cc4F)c(=O)c(O)c3C(=O)N12
Agent: O=C(OCI)OCCCOCc1ccccc1
Product: C[C@H]1CO[C@@H]2Cn3cc(C(=O)NCc4ccc(F)cc4F)c(=O)c(OCOC(=O)OCCCO)c3C(=O)N12
Yield: 95 %

Procedure:
{[(3S,11aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl 3-[(phenylmethyl)oxy]propyl carbonate. The title compound was prepared in 95% yield according to example 1 from 1b (1.00 g, 2.34 mmol), iodomethyl 3-[(phenylmethyl)oxy]propyl carbonate (3.24 g, 9.25 mmol), potassium carbonate (1.97 g, 14.3 mmol) and tetrabutylammonium hydrogen sulfate (1.30 g, 3.83 mmol). 1H NMR (400 MHz, CDCl3) δ ppm 10.18 (t, J=5.7 Hz, 1H), 8.37 (s, 1H), 7.35-7.20 (m, 6H), 6.83-6.72 (m, 2H), 5.92 (d, J=6.6 Hz, 1H), 5.83 (d, J=6.6 Hz, 1H), 5.25 (dd, J=9.9, 3.8 Hz, 1H), 4.65-4.50 (m, 2H), 4.46 (s, 2H), 4.37-4.22 (m, 5H), 3.86 (dd, J=12.2, 10.0 Hz, 1H), 3.62 (dd, J=8.5, 6.9 Hz, 1H), 3.55 (t, J=6.2 Hz, 2H), 2.04-1.92 (m, 2H), 1.34 (d, J=6.2 Hz, 3H); ES+ MS: 628 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:18]([CH:20]=O)=[O:19])[CH:12]=[C:13]([C:15]([OH:17])=[O:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22]([NH2:25])([CH3:24])[CH3:23]>CO>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH:12]=[C:11]([CH:18]([OH:19])[CH2:20][NH:25][CH:22]([CH3:24])[CH3:23])[CH:10]=1)[C:15]([OH:17])=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CC(=O)c1cc(OCc2ccccc2)cc(C(=O)O)c1
Reactant: CC(C)N
Solvent: CO
Product: CC(C)NCC(O)c1cc(OCc2ccccc2)cc(C(=O)O)c1
Reaction time: 1 h
Yield: 50 %

Procedure:
The 3-benzyloxy-5-carboxyphenylglyoxal (;b 120 moles) was dissolved in MeOH (1 l.) and cooled to 0°. Isopropylamine (200 ml) was added at 0° and the resulting mixture was stirred at 0° for 1 hr. before KBH4 (12.2 g, 228 moles) was added over a period of 2 hrs., portionwise. The resultant mixture was allowed to stir at room temperature overnight before it was evaporated to a residual glass. The residue was acidified with 6N HCl (1 l.) and extracted with CHCl3 (1 142 l.). The solid HCl precipitated from the CHCl3 extract upon standing; yield 21.9 g which gave 20.0 g (50%) mp. 290°- 292° dec. of the free base upon stirring in aqueous NH4OH and collecting by filtration.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:15]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:14][C:11]([C:12]#[N:13])=[C:10]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[C:27]([F:32])[CH:26]=2)[N:9]=1.C(O)(C(F)(F)F)=[O:34].[OH-].[K+].OO>O.C(O)C.O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:15]([C:16]2[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=2)=[CH:14][C:11]([C:12]([NH2:13])=[O:34])=[C:10]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[C:27]([F:32])[CH:26]=2)[N:9]=1
Reactant: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nc1OCc1ccc(F)c(F)c1
Reactant: O=C(O)C(F)(F)F
Agent: OO
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCO
Solvent: O
Product: NC(=O)c1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nc1OCc1ccc(F)c(F)c1
Temperature: 95 °C

Procedure:
To the product of Step D Example 129 (30.0 mg, 0.0516 mmol, material in the TFA salt form) was added 1,4-dioxane (4 mL), ethanol (0.5 mL), KOH (0.272 mg, 4.92 mmol), H2O (0.6 mL) and H2O2 (0.21 g). The reaction was heated to 95° C. for 22 hours. The solution was concentrated and the residue was dissolved in ethyl acetate before washing with water, drying (Na2SO4) and concentrating. The residue was purified by preparative thin layer chromatography (20 cm×20 cm, 1000 μm, silica gel) eluting with 10.5% ethyl acetate/dichloromethane affording the product. MS (electrospray) m/e 485.2 MH+ (Rt=4.2 min LC/MS).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:26][NH:27][CH2:28][CH:29]([OH:37])[C:30]1[CH:31]=[CH:32][C:33]([OH:36])=[CH:34][CH:35]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20][N:27]([CH2:28][CH:29]([OH:37])[C:30]4[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=4)[CH3:26])=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:24][CH:25]=1
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Reactant: CNCC(O)c1ccc(O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(CN(C)CC(O)c2ccc(O)cc2)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 60 °C
Reaction time: 3 h
Yield: 77.6 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (48 mg, 0.12 mmol), synephrine (Aldrich, 30 mg, 0.18 mmol) and diisopropylethylamine (31 μL, 0.18 mmol) in dry DMF (2.0 mL) was heated to 60° C., becoming a solution. The reaction was stirred for 3 hours at that temperature. After cooling to room temperature, the solution was diluted with water (5 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight at room temp. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile (10 mL, dissolved with warming and then cooled to 0° C. overnight) gave the title compound (49 mg) as a white solid.
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH:23]2[CH2:25][CH2:24]2)[C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)#[N:2].[Br:26][C:27]1[CH:28]=[C:29]([CH:34]=[CH:35][CH:36]=1)[C:30]([NH:32][OH:33])=N>>[Br:26][C:27]1[CH:28]=[C:29]([C:30]2[N:2]=[C:1]([N:3]3[CH2:4][CH2:5][CH:6]([N:9]([CH:23]4[CH2:25][CH2:24]4)[C:10](=[O:22])[C:11]4[CH:12]=[CH:13][C:14]([C:17]5[O:21][CH:20]=[N:19][CH:18]=5)=[CH:15][CH:16]=4)[CH2:7][CH2:8]3)[O:33][N:32]=2)[CH:34]=[CH:35][CH:36]=1
Reactant: N#CN1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Reactant: N=C(NO)c1cccc(Br)c1
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2nc(-c3cccc(Br)c3)no2)CC1

Procedure:
The title compound is prepared from N-(1-cyano-piperidin-4-yl)-N-cyclopropyl-4-oxazol-5-yl-benzamide and 3-bromo-N-hydroxy-benzamidine following a procedure analogous to that described in Example 1. LC (method 6): tR=2.09 min; Mass spectrum (ESI+): m/z=534/536 (Br) [M+H]+.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:18])[NH:10][CH2:11][C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C@@H:20]([CH2:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:46][CH:45]=1)[C:21]([N:23]([CH2:35][CH:36]([O:40][CH2:41][CH3:42])[O:37][CH2:38][CH3:39])[CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:34]=1[N:33]=[CH:32][CH:31]=[CH:30]2)=[O:22]>>[CH2:1]([NH:8][C:9](=[O:18])[NH:10][CH2:11][C:12]([CH3:17])([CH3:16])[C:13]([NH:19][C@@H:20]([CH2:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][C:51]([CH3:53])([CH3:52])[CH3:54])=[CH:46][CH:45]=1)[C:21]([N:23]([CH2:35][CH:36]([O:37][CH2:38][CH3:39])[O:40][CH2:41][CH3:42])[CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:34]=1[N:33]=[CH:32][CH:31]=[CH:30]2)=[O:22])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(CNC(=O)NCc1ccccc1)C(=O)O
Reactant: CCOC(CN(Cc1cccc2cccnc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1)OCC
Product: CCOC(CN(Cc1cccc2cccnc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)C(C)(C)CNC(=O)NCc1ccccc1)OCC
Yield: 86.7 %

Procedure:
According to the procedure described in the synthesis method of Compound II-1, 3-(3-benzylureido)-2,2-dimethylpropanoic acid (Compound VI-3) (152 mg, 0.61 mmol) was coupled with (S)-2-amino-3-(4-tert-butoxyphenyl)-N-(2,2-diethoxyethyl)-N-(quinolin-8-ylmethyl)propanamide (Compound IV-3) (200 mg, 0.41 mmol) and the obtained residue was purified by silica gel column chromatography (eluent: chloroform:methanol=90:10) to obtain the title compound (258.1 mg, 88%).
Reaction SMILES: [CH2:1]([S:3]([NH:6][C@@H:7]([CH:11]([CH3:13])[CH3:12])[C:8]([OH:10])=O)(=[O:5])=[O:4])[CH3:2].Cl.[F:15][C:16]1[CH:36]=[CH:35][C:19]([O:20][CH2:21][CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH2:32])=[CH:26][C:25]=2[O:33][CH3:34])=[CH:18][CH:17]=1.C(N(CC)C(C)C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O.O>[CH2:1]([S:3]([NH:6][C@@H:7]([CH:11]([CH3:13])[CH3:12])[C:8]([NH:32][CH2:31][CH2:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][CH2:22][CH2:21][O:20][C:19]2[CH:18]=[CH:17][C:16]([F:15])=[CH:36][CH:35]=2)=[C:25]([O:33][CH3:34])[CH:26]=1)=[O:10])(=[O:4])=[O:5])[CH3:2]
Reactant: COc1cc(CCN)ccc1OCCOc1ccc(F)cc1
Reactant: CCS(=O)(=O)N[C@H](C(=O)O)C(C)C
Agent: CCN(CC)C(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCS(=O)(=O)N[C@H](C(=O)NCCc1ccc(OCCOc2ccc(F)cc2)c(OC)c1)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of (S)-2-ethanesulfonylamino-3-methyl-butyric acid (0.63 g), 2-{4-[2-(4-fluoro-phenoxy)-ethoxy]-3-methoxy-phenyl}-ethylamine hydrochloride (1.0 g) and diethyl-isopropylamine (1.8 ml) in dimethylformamide (30 ml) is added benzotriazol-1-yloxy-tris-(dimethylamino)phosphonium hexafluorophosphate (1.5 g) in one portion. The reaction mixture is stirred for 2 hours at room temperature. Water (200 ml) is then added. The mixture is extracted with ethyl acetate (2×200 ml). The organic layers are washed with brine (2×200 ml), dried (MgSO4) and evaporated. The residue is purified by flash column chromatography on silica gel (ethyl acetate/hexane 2:1) and recrystallisation (ethyl acetate/hexane). (S)-2-Ethanesulfonylamino-N-(2-{4-[2-(4-fluoro-phenoxy)-ethoxy]-3-methoxy-phenyl}-ethyl)-3-methyl-butyramide is obtained, m.p. 124-125° C.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:3]=1[CH:4]([OH:20])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:6]=1.[CH2:26]([O:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH:36]=O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(O)(=O)C.[BH4-].C([Na])#N>CO>[CH2:26]([O:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:36][NH:1][C:2]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:3]=1[CH:4]([OH:20])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][NH:12][C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[CH:6]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(C(O)c2cc(Cl)ccc2N)c1
Reactant: O=Cc1ccccc1OCc1ccccc1
Agent: N#C[Na]
Agent: [BH4-]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCc1cccc(C(O)c2cc(Cl)ccc2NCc2ccccc2OCc2ccccc2)c1
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 136.3 %

Procedure:
In methanol (20 ml) were dissolved 2-amino-5-chloro-α-(3-tert-butoxycarbonylaminomethylphenyl)benzyl alcohol (0.5 g) obtained in Example 1 (2) and 2-benzyloxybenzaldehyde (0.7 g). To the solution were added acetic acid (0.15 g) and cyano sodium borohydride (0.16 g). The mixture was stirred for 40 minutes at 60° C. The reaction mixture was concentrated, to which were added water (50 ml) and ethyl acetate (60 ml), followed by subjecting the mixture to extraction. The organic layer was separated, washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by means of a silica gel column chromatography to give 2-(2-benzyloxybenzylamino)-5-chloro-α-(3-tert-butoxycarbonylaminomethylphenyl)benzyl alcohol (1.05 g) as a colorless oily product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:5]=[C:4]([CH2:15][CH3:16])[N:3]=1.[CH3:17][O:18][CH2:19][CH2:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1>C(O)(=O)C.C(=O)(O)[O-].[Na+]>[Cl:14][C:10]1[CH:9]=[C:8]([C:6]2[N:5]=[C:4]([CH2:15][CH3:16])[N:3]=[C:2]([NH:25][C:24]3[CH:23]=[CH:22][C:21]([CH2:20][CH2:19][O:18][CH3:17])=[CH:27][CH:26]=3)[N:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: CCc1nc(Cl)nc(-c2cccc(Cl)c2)n1
Reactant: COCCc1ccc(N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCc1nc(Nc2ccc(CCOC)cc2)nc(-c2cccc(Cl)c2)n1
Temperature: 75 °C
Yield: 62.2 %

Procedure:
A mixture of 2-chloro-4-(3-chlorophenyl)-6-ethyl-1,3,5-triazine (0.105 g, 0.41 mmol) and 4-(2-methoxyethyl)aniline (0.075 g, 0.49 mmol) were suspended in acetic acid (1 mL) and the mixture was heated at 75° C. for 3 h. After this time, the reaction was cooled, diluted with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, hexanes/ethyl acetate) to afford the title compound (0.094 g, 62%) as a white solid. MW=368.86. 1H NMR (DMSO-d6, 500 MHz) δ 10.21 (s, 1H), 8.41-8.30 (m, 2H), 7.72-7.68 (m, 3H), 7.61 (t, J=7.5 Hz, 1H), 7.27-7.19 (m, 2H), 3.54 (t, J=7.0 Hz, 2H), 3.25 (s, 3H), 2.80-2.75 (m, 4H), 1.32 (t, J=7.5 Hz, 3H); APCI MS m/z 369 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH3:35])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([CH3:25])=[C:16]([CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])[CH:17]=2)[CH:7]=[CH:6][C:5]=1[C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1[F:34].[OH-].[Na+].Cl>CO>[CH3:1][C:2]([CH3:36])([CH3:35])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([CH3:25])=[C:16]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:17]=2)[CH:7]=[CH:6][C:5]=1[C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1[F:34]
Reactant: CCOC(=O)CCc1cc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)ccc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(F)c(-c2ccc(COc3ccc(C)c(CCC(=O)O)c3)nc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 68.3 %

Procedure:
To a solution of ethyl 3-(5-((6-(2,2-dimethylpropyl)-5-(2-fluoro-5-methoxyphenyl)pyridin-2-yl)methoxy)-2-methylphenyl)propanoate (427 mg) in methanol (4.0 mL) was added 1N aqueous sodium hydroxide solution (8.6 mL), and the mixture was stirred at room temperature for 15 hr. 1N Hydrochloric acid was added to the reaction mixture to adjust to pH<4, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (275 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:8][NH2:9])=[N:4][CH:5]=[CH:6][N:7]=1.[CH:10](OCC)(OCC)OCC.C1(C)C(C)=CC=CC=1>C(OCC)C>[Cl:1][C:2]1[C:3]2[N:4]([CH:10]=[N:9][N:8]=2)[CH:5]=[CH:6][N:7]=1
Reactant: NNc1nccnc1Cl
Reactant: CCOC(OCC)OCC
Solvent: CCOCC
Solvent: Cc1ccccc1C
Product: Clc1nccn2cnnc12
Reaction time: 2 h
Yield: 62 %

Procedure:
A mixture of 1-(3-chloropyrazin-2-yl)hydrazine (0.90 g, 62 mmol), triethyl orthoformate (2.3 mL), 14 mmol), and dry xylene (15 mL) was refluxed with stirring for 2 h. The mixture was brought to RT, diethyl ether was added and the suspension was filtered. The solid collected was washed with diethyl ether to afford 8-chloro-[1,2,4]triazolo[4,3-a]pyrazine (0.60 g, 62% yield). MS m/z: 155.0 (M+1).