Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>CN(C=O)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([N:1]=[CH:12][N:13]([CH3:15])[CH3:14])=[N:3][CH:4]=1)#[N:7]
Reactant: COC(OC)N(C)C
Reactant: N#Cc1ccc(N)nc1
Solvent: CN(C)C=O
Product: CN(C)C=Nc1ccc(C#N)cn1
Temperature: 130 °C

Procedure:
To a stirred solution of 6-aminonicotinonitrile (L-1) (8.7 g, 73 mmol) in DMF (35 mL) was added N,N-dimethylformamide dimethyl acetal (35 mL, 294 mmol). The reaction mixture was heated to 130° C. overnight. After cooled to room temperature, the volatiles were removed under reduced pressure to afford the desired intermediate N′-(5-cyanopyridin-2-yl)-N,N-dimethylformamidine.
Reaction SMILES: C1(CCOC2C=CC(C(NC(CC3C=CC(CCC)=CC=3)C(NCCO)=O)=O)=CC=2)CC1.[OH:33][CH2:34][CH2:35][NH:36][C:37](/[C:39](/[NH:51][C:52](=[O:70])[C:53]1[CH:58]=[CH:57][C:56]([O:59][C:60]2[CH:65]=[CH:64][C:63]([C:66]([F:69])([F:68])[F:67])=[CH:62][CH:61]=2)=[CH:55][CH:54]=1)=[CH:40]/[C:41]1[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][CH:42]=1)=[O:38]>>[OH:33][CH2:34][CH2:35][NH:36][C:37](=[O:38])[CH:39]([NH:51][C:52](=[O:70])[C:53]1[CH:58]=[CH:57][C:56]([O:59][C:60]2[CH:61]=[CH:62][C:63]([C:66]([F:67])([F:68])[F:69])=[CH:64][CH:65]=2)=[CH:55][CH:54]=1)[CH2:40][C:41]1[CH:42]=[CH:43][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:45][CH:46]=1
Reactant: O=C(NCCO)/C(=C/c1ccc(C(F)(F)F)cc1)NC(=O)c1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Agent: CCCc1ccc(CC(NC(=O)c2ccc(OCCC3CC3)cc2)C(=O)NCCO)cc1
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(=O)NCCO)c1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Yield: 89.2 %

Procedure:
A reaction similar to that described in Example (1 (1e) was conducted using N-{(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethyl)phenyl]vinyl}-4-[4-(trifluoromethyl)phenoxy]benzamide (172 mg) to give 154 mg of the title compound (white powder).
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])N1C=CN=C1.[Br:10][C:11]1[CH:12]=[C:13]([C:17]([OH:22])([CH2:20][CH3:21])[CH2:18][CH3:19])[CH:14]=[CH:15][CH:16]=1>O1CCCC1>[Br:10][C:11]1[CH:12]=[C:13]([C:17]([CH2:18][CH3:19])([O:22][Si:2]([CH3:1])([CH3:8])[CH3:9])[CH2:20][CH3:21])[CH:14]=[CH:15][CH:16]=1
Reactant: C[Si](C)(C)n1ccnc1
Reactant: CCC(O)(CC)c1cccc(Br)c1
Solvent: C1CCOC1
Product: CCC(CC)(O[Si](C)(C)C)c1cccc(Br)c1
Reaction time: 8 h
Yield: 59 %

Procedure:
N-trimethylsilylimidazole (8.2 mL, 55.81 mol) was added to a solution of the crude 3-(3-bromo-phenyl)-pentan-3-ol in tetrahydrofuran (100 mL) in a nitrogen atmosphere at room temperature, and the mixture was stirred overnight. The reaction mixture was poured into distilled water, followed by extraction with dichloromethane. The extract was washed with brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography (n-hexane:ethyl acetate=40:1) to give the title compound as a colorless oil (8.7 g, 59% in two steps).
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[N+:19]([O-])=O)(=[O:3])[CH3:2].N[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][N:24]=1>C(O)C>[C:1]([C:4]1[C:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[NH:19][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][N:24]=1)(=[O:3])[CH3:2]
Reactant: Nc1ccc([N+](=O)[O-])cn1
Reactant: CCn1nc(-c2ccccc2)c(C(C)=O)c([N+](=O)[O-])c1=O
Solvent: CCO
Product: CCn1nc(-c2ccccc2)c(C(C)=O)c(Nc2ccc([N+](=O)[O-])cn2)c1=O
Yield: 34.1 %

Procedure:
To a solution of 80 mg (0.278 mmol) of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) in 4 ml of ethanol, 77 mg (0.556 mmol) of 2-amino-5-nitropyridine was added. The resulting mixture was irradiated in microwave oven for seven hours at 120° C. The final product was collected by filtration and washed with diethylether to yield the title compound (36 mg, 34.3% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:11]([NH:13][CH2:14][C:15]([CH2:21][NH:22][C:23]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][N:27]2[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([OH:20])[C:16]([F:19])([F:18])[F:17])[CH3:12]>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:13]([CH2:11][CH3:12])[CH2:14][C:15]([OH:20])([CH2:21][NH:22][C:23]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][N:27]2[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:16]([F:18])([F:17])[F:19])=[O:6]
Reactant: CCNCC(O)(CNc1cc(C)cc2c1cnn2-c1ccccc1)C(F)(F)F
Reactant: O=C(O)c1ccccc1Cl
Product: CCN(CC(O)(CNc1cc(C)cc2c1cnn2-c1ccccc1)C(F)(F)F)C(=O)c1ccccc1Cl

Procedure:
Prepared similarly to Example 11 from 2-chlorobenzoic acid and 3-(ethylamino)-1,1,1-trifluoro-2-{[(6-methyl-1-phenyl-1H-indazol-4-yl)amino]methyl}-2-propanol.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([OH:30])[CH2:16][N:17]2[C:29]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:23]3[C:18]2=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:19]1[C:18]2[N:17]([CH2:16][CH:15]([OH:30])[CH2:14][N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]=2[CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CC(O)Cn2c3ccccc3c3ccccc32)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OC(CN1CCNCC1)Cn1c2ccccc2c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 121.5 %

Procedure:
At rt to a solution of Example 2 (3.4 g, 8.30 mmol) in DCM (120 mL) is added TFA (30 mL). The resulting mixture is stirred at rt for 30 min. Concentration in vacuo gives an oily residue. Flash chromatography on a 7×18 cm2 column of SiO2 using DCM:MeOH:TEA (40:5:3) as eluting solvent and removal of the solvent gives the title compound (3.12 g, 92%) as a white foam. Slow addition of HCl (30 mL, 4 eq, 1M in Et2O) into a solution of the above compound in EtOH (40 mL) gives the hydrochloride salt of the title compound as beige crystals in a quantitative yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:15]([OH:17])=O)[C:5](=[O:14])[N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][C:29]=1[O:30][CH3:31])[N:26]=[CH:25][CH:24]=[C:23]2[O:32][C:33]1[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][C:34]=1[F:40].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([C:15]([NH:39][C:36]2[CH:37]=[CH:38][C:33]([O:32][C:23]3[C:22]4[C:27](=[CH:28][C:29]([O:30][CH3:31])=[C:20]([O:19][CH3:18])[CH:21]=4)[N:26]=[CH:25][CH:24]=3)=[C:34]([F:40])[CH:35]=2)=[O:17])[C:5](=[O:14])[N:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=1
Reactant: O=C(O)c1cc(Br)cn(-c2ccccc2)c1=O
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)c4cc(Br)cn(-c5ccccc5)c4=O)cc3F)c2cc1OC
Reaction time: 8 h
Yield: 87.5 %

Procedure:
5-Bromo-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylic acid (0.458 g, 1.6 mmol), 4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorobenzenamine (0.49 g, 1.6 mmol), EDC (0.45 g, 2.3 mmol), and HOAt (0.21 g, 1.6 mmol) were added to a reaction flask then suspended in N,N-dimethylformamide (7.0 mL). N,N-diisopropylethylamine (0.95 ml, 5.5 mmol) was added to the reaction mixture and stirring was continued at room temperature overnight. The reaction mixture was diluted with ethyl acetate and water and then extracted with ethyl acetate. A precipitate formed between the layers. The aqueous layer was filtered and the precipitate collected. The filtered aqueous layer was extracted with ethyl acetate (1×). The combined ethyl acetate layers were washed with brine and then dried over sodium sulfate. The precipitate was dissolved in dichloromethane and also dried over sodium sulfate. All of the organic layers were combined and concentrated under vacuum. The remaining residue was purified by silica gel chromatography (1% methanol/dichloromethane to 2% methanol/dichloromethane) to give 5-bromo-N-(4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl)-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide as a yellow solid (0.846 g, 1.4 mmol, 92% yield). MS (ESI pos. ion) m/z: 590 (MH+). Calc'd exact mass for C29H21BrFN3O5: 589.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][C:22]#[CH:23])[CH:18]=3)[N:13]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([N+:31]([O-])=O)[CH:26]=3)[C:12](=[O:34])[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(OCC)(=O)C.O>C(O)(=O)C.[Fe]>[NH2:31][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[CH2:24][N:13]1[C:14]2[C:19](=[CH:18][C:17]([O:20][CH2:21][C:22]#[CH:23])=[CH:16][CH:15]=2)[C:10]([C:7]2[CH:8]=[CH:9][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:5][CH:6]=2)=[N:11][C:12]1=[O:34]
Reactant: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2Cc1cccc([N+](=O)[O-])c1
Agent: [Fe]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2Cc1cccc(N)c1
Temperature: 40 °C
Reaction time: 8 h
Yield: 110.5 %

Procedure:
A mixture of 5.7 g (12.57 mmol) of the aromatic nitro-compound prepared in step B and 5.7 g (0.10 mol; 8 eq.) iron powder in 85 ml acetic acid is heated to 40° C. and stirred overnight. After 16 h another 3.5 g iron powder is added and stirring continued for 4 h. The brown suspension is distributed between ethyl acetate and water. The organic layer is washed with sodium bicarbonate solution and brine. Concentration in vacuo leaves 5.88 g of yellow foam. Flash chromatography (petroleum ether/ethyl acetate) yields 2.80 g (53%) of a yellow solid. m.p. 186° C.
Reaction SMILES: CO[C:3]1[CH2:8][CH2:7][CH2:6][C:5](=[O:9])[CH:4]=1.[CH2:10]([Mg]Br)[CH3:11].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOCC.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[CH2:10]1[C:3]2([CH2:8][CH2:7][CH2:6][C:5](=[O:9])[CH2:4]2)[CH2:11]1
Reactant: CC[Mg]Br
Reactant: COC1=CC(=O)CCC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: O
Product: O=C1CCCC2(CC2)C1
Temperature: 25 °C
Yield: 32.6 %

Procedure:
3-Methoxy-cyclohex-2-enone (7.8 g, 61.83 mmol) was dissolved in Et2O (100 mL) and titanium tetraisopropoxide (20.1 mL, 68.01 mmol) was added. To the resulting brown solution ethylmagnesium bromide solution (3M, 60 mL, 180 mmol) was added dropwise over 70 minutes. A precipitate formed over the course of the addition. After 2 hours at RT the now dark brown/black reaction mixture was carefully quenched with saturated aqueous NH4Cl. A dark gray precipitate formed and was filtered off over Celite. The aqueous layer was extracted twice with Et2O. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and evaporated. The residue was taken up in Et2O (100 mL) and p-toluenesulfonic acid monohydrate (0.588 g, 3.091 mmol) was added. The resulting brown solution was stirred at RT over the weekend before being evaporated. The remaining brown oil was purified by SiO2 chromatography (330 g SiO2, hexanes/EtOAc 0 to 7% EtOAc) to give 2.5 g of spiro[2.5]octan-5-one as a light yellow liquid (32% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:20]=[C:19](Br)[C:18]([C:22]#[N:23])=[C:17]([CH:24]2[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]2)[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:44]([NH2:51])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:20]=[C:19]([NH:51][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:18]([C:22]#[N:23])=[C:17]([CH:24]2[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]2)[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3ccccc3OCc3ccccc3)nc(Br)c2C#N)C1
Reactant: NCc1ccccc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3ccccc3OCc3ccccc3)nc(NCc3ccccc3)c2C#N)C1
Temperature: 70 °C
Reaction time: 12 h
Yield: 92 %

Procedure:
To a stirred solution of tert-butyl 3-{6-[2-(benzyloxy)phenyl]-2-bromo-3-cyano-4-pyridinyl}-1-piperidinecarboxylate (0.300 g, 0.547 mmol) in DMSO were added triethylamine (0.229 mL, 1.341 mmol) and benzylamine (0.147 g, 1.367 mmol). The mixture was stirred at 70° C. for 12 hrs. After cooled to room temperature, the reaction mixture was quenched with water and extracted with ethyl acetate. The separated organic phase was washed with brine, dried over Na2SO4, filtrated, and concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1-2/1) to give tert-butyl 3-{6-[2-(benzyloxy)phenyl]-2-benzylamino-3-cyano-4-pyridinyl}-1-piperidinecarboxylate as a yellow amorphous. (0.290 g, yield; 92%)
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1)(=[O:4])=[O:3].Cl.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:25])=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]([CH:26]2[CH2:31][CH2:30][N:29]([C:11]([C:10]3[CH:9]=[CH:8][C:7]([CH2:6][NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:15][CH:14]=3)=[O:13])[CH2:28][CH2:27]2)=[O:25])=[CH:22][CH:23]=1
Reactant: CS(=O)(=O)NCc1ccc(C(=O)O)cc1
Reactant: O=C(c1ccc(Cl)cc1)C1CCNCC1
Agent: Cl
Product: CS(=O)(=O)NCc1ccc(C(=O)N2CCC(C(=O)c3ccc(Cl)cc3)CC2)cc1
Yield: 54.5 %

Procedure:
Using 4-(methanesulfonylaminomethyl)benzoic acid (100 mg) and (4-chlorophenyl)(piperidin-4-yl)methanone hydrochloride (113 mg) and by the reaction and treatment in the same manner as in Example 86, the title compound (103 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9](Cl)(=[O:11])[CH3:10]>>[OH:8][C:4]1[CH:3]=[C:2]([NH:1][C:9](=[O:11])[CH3:10])[CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)Cl
Reactant: Nc1cccc(O)c1
Product: CC(=O)Nc1cccc(O)c1
Yield: 56.7 %

Procedure:
By using 3-aminophenol (1.0 g) and acetyl chloride (359 mg) as starting materials, the title compound (392 mg) was obtained in the same manner as that of Reference Example 18.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:22])[CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)[OH:10].[CH:23]([C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1)=[O:24].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:21][C:6]1[CH:5]=[N+:4]([O-:22])[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)[O:10][C:29](=[O:30])[C:28]1[CH:32]=[CH:33][C:25]([CH:23]=[O:24])=[CH:26][CH:27]=1
Reactant: COc1ccc([C@@H](O)Cc2c(Cl)c[n+]([O-])cc2Cl)cc1OC
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2ccc(C=O)cc2)cc1OC
Yield: 90.6 %

Procedure:
A solution of (S)-3,5-dichloro-4-(2-(3,4-dimethoxyphenyl)-2-hydroxyethyl)pyridine 1-oxide (0.688 g, 2 mmol), 4-formylbenzoic acid (0.300 g, 2 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.767 g, 4 mmol) and 4-(dimethylamino)pyridine (0.122 g, 1 mmol) in anhydrous DCM (30 mL) was stirred at RT for 21 h. The reaction mixture was partitioned between saturated aqueous NaHCO3 (20 mL) and DCM (10 mL) and filtered through a phase separator. The solvent was removed in vacuo and the crude material was purified by silica gel column chromatography eluting with 1:1 DCM:EtOAc to afford (S)-3,5-dichloro-4-(2-(3,4-dimethoxyphenyl)-2-((4-formylbenzoyl)oxy)ethyl)pyridine 1-oxide as an off-white solid (0.863 g, 91%).
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][O:15][CH3:16])[CH:10]=[CH:9][C:8]=1[C:17]1[C:18](=[O:34])[O:19][C:20]2[C:25]([C:26]=1[CH2:27][CH:28]=[O:29])=[CH:24][CH:23]=[C:22]([O:30][CH2:31][O:32][CH3:33])[CH:21]=2>C(O)C>[CH3:3][O:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][O:15][CH3:16])[CH:10]=[CH:9][C:8]=1[C:17]1[C:18](=[O:34])[O:19][C:20]2[C:25]([C:26]=1[CH2:27][CH2:28][OH:29])=[CH:24][CH:23]=[C:22]([O:30][CH2:31][O:32][CH3:33])[CH:21]=2
Reactant: COCOc1ccc(-c2c(CC=O)c3ccc(OCOC)cc3oc2=O)c(OCOC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COCOc1ccc(-c2c(CCO)c3ccc(OCOC)cc3oc2=O)c(OCOC)c1
Reaction time: 0.5 h

Procedure:
Sodium borohydride (17 mg, 0.45 mmol, 0.5 eq.) was dissolved in ethanol (5 mL), then added into the solution of [3-(2,4-Bis-methoxymethoxy-phenyl)-7-methoxymethoxy-2-oxo-2H-chromen-4-yl]-acetaldehyde (400 mg, 0.90 mmol, 1 eq.) ethanol (10 mL) at −10° C. and the reaction mixture was stirred for 30 minutes. The solvent was evaporated and the resulting residue was dissolved in ethyl acetate (100 mL) and washed twice with brine. The organic layer was dried over anhydrous sodium sulfate then concentrated to yield the crude product which was purified by flash chromatography eluted with 50% ethyl acetate to yield the title compound 3-(2,4-Bis-methoxymethoxy-phenyl)-4-(2-hydroxy-ethyl)-7-methoxymethoxy-chromen-2-one as a solid.
Reaction SMILES: [OH-].[Na+].Br[CH:4]([CH:7]([C:9]1[CH:13]=[CH:12][S:11][CH:10]=1)[OH:8])[CH2:5][OH:6]>O.C(O)C>[O:8]1[CH:7]([C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)[CH:4]1[CH2:5][OH:6]
Reactant: OCC(Br)C(O)c1ccsc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: OCC1OC1c1ccsc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
0.8 g of sodium hydroxide in 15 ml of water is added to a solution of 2.4 g of (2RS,3SR)-2-bromo-3-(thiophen-3-yl)-propane-1,3-diol in 25 ml of ethanol. The reaction mixture is stirred for 40 minutes at room temperature, the ethanol is evaporated off in vacuo and the residue is diluted with 400 ml of water. Extraction is carried out with dichloromethane (3×100 ml), the extracts are dried over sodium sulfate and the solvent is evaporated off. The residue is chromatographed on silica gel with dichloromethane/acetone (9:1). The title compound is obtained in the form of light-yellow crystals, m.p.=63°-65° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)(=O)=O.C(OC([N:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]=[C:33]1Cl)=O)(C)(C)C>>[N:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[NH:34][C:33]=1[C:7]1[N:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1
Reactant: CN1CCC(c2c[nH]c3ccc(OS(=O)(=O)C(F)(F)F)nc23)CC1
Reactant: CC(C)(C)OC(=O)n1c(Cl)nc2ccccc21
Product: CN1CCC(c2c[nH]c3ccc(-c4nc5ccccc5[nH]4)nc23)CC1

Procedure:
O-Trifluoromethanesulfonyl-3-(1-methylpiperidin-4-yl)-5-hydroxy-4-aza-1H-indole (150 mg, 0.413 mmol) and 1-t-butyloxycarbonyl-2-chlorobenzimidazole (104 mg, 0.413 mmol) were converted to the title compound by the procedure of Example 7 except that after chromatography there was a mixture of protected and de-protected products. Therefore, 80 mg of the mixture was dissolved in 20 mL of dichloromethane and 1 mL of trifluoroacetic acid was added. The mixture was stirred for 2 hours and then taken up in water. The reaction was partitioned between 3 mL of 1N aqueous sodium hydroxide and 3 mL of 3:1 chloroform:isopropanol to give 51.2 mg. (37%). MS(FD) m/e 331.8 (M+).
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][OH:6])[CH3:2].[H-].[Na+].[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[C:29](Cl)[N:28]=[N:27][C:26]=2[CH2:32][CH2:33][CH2:34][CH3:35])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>C1COCC1>[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[C:29]([O:6][CH2:5][CH2:4][N:3]([CH2:7][CH3:8])[CH2:1][CH3:2])[N:28]=[N:27][C:26]=2[CH2:32][CH2:33][CH2:34][CH3:35])=[CH:21][CH:20]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCN(CC)CCO
Reactant: CCCCc1nnc(Cl)cc1-c1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCc1nnc(OCCN(CC)CC)cc1-c1ccc(OCc2ccccc2)cc1
Reaction time: 0.17 h

Procedure:
To a stirred solution of 2-diethylamino-ethanol (0.42 mmol, 50 mg) in THF at room temperature was added NaH (0.85 mmol, 20 mg). Stirring continued for 10 min then 4-(4-benzyloxy-phenyl)-3-butyl-6-chloro-pyridazine (Example 1, 0.14 mmol, 50 mg) was added. The resulting mixture was stirred at 50-55° C. overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The product was purified by column chromatography using 10% methanolic solution of ammonia (2.0 M ammonia in methanol) in ethyl acetate to provide {2-[5-(4-benzyloxy-phenyl)-6-butyl-pyridazin-3-yloxy]-ethyl}-diethyl-amine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:37])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:15]([CH2:31][C@@H:32]([OH:36])[C:33]([OH:35])=[O:34])[NH:16][C:17]([C:19]3[NH:23][C:22](=[O:24])[N:21]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:20]=3)=[O:18])=[CH:10][CH:9]=2)[CH:7]=1.[C:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40]Cl.[Na+].[I-].CC1C=CC=C(C)N=1>CN(C=O)C.O>[CH2:43]([O:42][C:38]([O:39][CH2:40][O:34][C:33](=[O:35])[C@H:32]([OH:36])[CH2:31][N:15]([CH2:14][C:11]1[CH:10]=[CH:9][C:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[F:37])=[CH:13][CH:12]=1)[NH:16][C:17]([C:19]1[NH:23][C:22](=[O:24])[N:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:20]=1)=[O:18])=[O:45])[CH3:44]
Reactant: CCOC(=O)OCCl
Reactant: O=C(NN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)C[C@@H](O)C(=O)O)c1nn(-c2ccccc2)c(=O)[nH]1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1cccc(C)n1
Product: CCOC(=O)OCOC(=O)[C@H](O)CN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1nn(-c2ccccc2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 4.5 %

Procedure:
To a solution of (R)-3-[N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)-N′-(5-oxo-1-phenyl-4,5-dihydro-1H-[1,2,4]triazole-3-carbonyl)hydrazino]-2-hydroxypropionic acid (200 mg, 335 μmol) in dry DMF (10 mL) was added chloromethyl ethyl carbonate (69 mg, 503 μmol), NaI (101 mg, 670 μmol) and 2,6-dimethylpyridine (143 mg, 1.3 mmol) in portions at room temperature. The resulting mixture was stirred at room temperature for 8 hours. Water (15 mL) was added and the mixture was extracted with EtOAc (3×20 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (PE:EtOAc=3:1˜1:100) to yield the title compound as a white solid (9.5 mg). LC-MS: 627.9 [M+H]+. 1H NMR: (CDCl3, 400 MHz) δ 1.25 (t, J=7.1 Hz, 3H), 3.44 (br, 2H), 4.17-4.35 (m, 4H), 4.50 (s, 1H), 5.75-5.78 (m, 2H), 7.10 (t, J=9.3 Hz, 1H), 7.28-7.40 (m, 1H), 7.42-7.52 (m, 7H), 7.87 (s, 2H), 8.37 (s, 1H).