Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][O:25][CH2:26][CH2:27][O:28][C:29]1[CH:30]=[N:31][CH:32]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:34]=1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:33]5[CH:32]=[N:31][CH:30]=[C:29]([O:28][CH2:27][CH2:26][O:25][CH3:24])[CH:34]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: COCCOc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: COCCOc1cncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)c1

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 3-(2-methoxy-ethoxy)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 59.1.1) to give the title compound as a white solid. (HPLC: tR 2.17 min (Method A); M+H=445 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.99 (s, 1H), 8.35-8.27 (m, 2H), 8.18-8.08 (m, 2H), 8.04-7.97 (m, 1H), 7.61-7.56 (m, 1H), 7.44-7.38 (m, 1H), 4.25 (t, 2H), 3.89 (s, 3H), 3.71 (t, 2H), 3.57 (s, 3H), 3.31 (s, 3H), 1.96 (s, 3H))
Reaction SMILES: C(O[C:5]1[N:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[N:7][C:6]=1[N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)CC.COC(C1C=NC(Cl)=C(Br)N=1)=O.[F:31][C:32]([F:36])([F:35])[CH2:33][OH:34].N1CCCC1.[OH-].[K+]>>[N:14]1([C:6]2[N:7]=[CH:8][C:9]([C:11]([OH:13])=[O:12])=[N:10][C:5]=2[O:34][CH2:33][C:32]([F:36])([F:35])[F:31])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CCCOc1nc(C(=O)O)cnc1N1CCCC1
Reactant: OCC(F)(F)F
Agent: COC(=O)c1cnc(Cl)c(Br)n1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCNC1
Product: O=C(O)c1cnc(N2CCCC2)c(OCC(F)(F)F)n1
Yield: 41 %

Procedure:
In analogy to the procedure described for the synthesis of 6-propoxy-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid (example 10, step c), the title compound was synthesized from 6-bromo-5-chloro-pyrazine-2-carboxylic acid methyl ester, 2,2,2-trifluoro-ethanol (commercially available), pyrrolidine (commercially available) and subsequent saponification with KOH in 41% yield. m/z (ES+): 292.0 (M+H).
Reaction SMILES: [C:1]1([C@H:7]2[CH2:11][O:10][C:9](=[O:12])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[C:18](Cl)(=[O:27])/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[C:1]1([C@H:7]2[CH2:11][O:10][C:9](=[O:12])[N:8]2[C:18](=[O:27])/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1N[C@@H](c2ccccc2)CO1
Reactant: O=C(Cl)/C=C/c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(/C=C/c1ccccc1)N1C(=O)OC[C@@H]1c1ccccc1
Yield: 97.3 %

Procedure:
To (S)-(+)-4-phenyl-2-oxazolidinone (9.88 g, 60 mmol) in THF (150 mL) at −78° C., was added n-butyl lithium (37.7 mL, 1.6M in hexanes, 60 mmol) over a period of 30 minutes. THF (50 mL) was added to the resultant thick suspension and the reaction mixture allowed warming up to facilitate stirring. Trans-cinnamoylchloride (11.5 g, 69 mmol) in THF (30 mL) was added dropwise. The reaction was stirred at room temperature overnight. The reaction mixture was quenched with a saturated ammonium chloride solution (50 mL) and stirred for 0.5h. The solvent was removed in vacuo, the residue dissolved in ethyl acetate, washed with water (300 mL), 5% sodium bicarbonate (200 mL) and brine (100 mL) and dried over sodium sulfate. The solvent was removed in vacuo to give a pale yellow solid. The compound was crystallized from ethyl acetate and washed with hexanes to give 17.12 g (97%) of (S)-4-phenyl-3-[(E)-(3-phenyl-acryloyl)]-oxazolidin-2-one.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].[O:26]1[CH:30]=[CH:29][CH:28]=[CH:27]1>>[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5]
Reactant: c1ccoc1
Reactant: COc1ccccc1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Product: COc1ccccc1-c1cccc(-n2cnc(C(=O)c3ccco3)c2)c1

Procedure:
This compound is prepared by method C using compound 12c and furane
Reaction SMILES: CI.FC(F)(F)C(O)=O.C(O[C:15](=O)[NH:16][C:17]1[C:18]([O:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[N:19][C:20]([S:23][CH3:24])=[N:21][CH:22]=1)(C)(C)C.C(O)(C)(C)C.[F:39][C:40]([F:58])([F:57])[C:41]1[CH:42]=[C:43]([C:51]([CH3:56])([CH3:55])[C:52](Cl)=[O:53])[CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=1>>[F:39][C:40]([F:58])([F:57])[C:41]1[CH:42]=[C:43]([C:51]([CH3:56])([CH3:55])[C:52]([N:16]([C:17]2[C:18]([O:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[N:19][C:20]([S:23][CH3:24])=[N:21][CH:22]=2)[CH3:15])=[O:53])[CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=1
Reactant: CSc1ncc(NC(=O)OC(C)(C)C)c(Oc2ccc(F)cc2)n1
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CI
Solvent: CC(C)(C)O
Product: CSc1ncc(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(Oc2ccc(F)cc2)n1

Procedure:
In an analougous manner to that described in Examle 46 a) there was obtained from 4-(4-fluoro-phenoxy)-2-methylsulfanyl-pyrimidine-5-carboxylic acid, diphenylphosporylazide and t-butanol [4-(4-fluoro-phenoxy)-2-methylsulfanyl-pyrimidin-5-yl]-carbamic acid tert.-butyl ester, which was methylated with methyliodide and than deprotected with trifluoracetic acid according to Example 43b)c). The resulting [4-(4-fluoro-phenoxy)-2-methylsulfanyl-pyrimidin-5-yl]-methyl-amine was treated with 2-(3,5-bis-trifluormethyl-phenyl)-2-methyl-propionyl chloride as described in Example 43e) to give 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-phenoxy)-2-methylsulfanyl-pyrimidin-5-yl]-N-methyl-isobutyramide as a white foam, MS (EI): 547 (M+).
Reaction SMILES: [CH:1]([O:6][CH3:7])([O:4][CH3:5])OC.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.C([C:25]1[CH:30]=[CH:29][C:28]([C:31]#[C:32][C:33]2[CH:43]=[CH:42][C:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:35][CH:34]=2)=[CH:27][CH:26]=1)=O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.CO>[CH3:7][O:6][CH:1]([O:4][CH3:5])[C:25]1[CH:26]=[CH:27][C:28]([C:31]#[C:32][C:33]2[CH:34]=[CH:35][C:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:42][CH:43]=2)=[CH:29][CH:30]=1
Reactant: COC(OC)OC
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(C=O)cc2)cc1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc(C#Cc2ccc(C(OC)OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.7 %

Procedure:
Trimethyl orthoformate (51 g) and (+)-CSA (2.3 g) were added to a methanol (0.40 L)-chloroform (0.10 L) mixed solution of ethyl 4-[(4-formylphenyl)ethynyl]benzoate (27 g) as obtained in Example 10-(1), and the mixture was stirred for 3 hours at room temperature. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and then the desiccant was filtered out. Then, the solvent was distilled off under reduced pressure, and the resulting residue was purified by OH type silica gel chromatography (gradient elution with hexane/ethyl acetate=95/5→80/20) to obtain ethyl 4-{[4-(dimethoxymethyl)phenyl]ethynyl}benzoate (white solid) (21 g, 67%).
Reaction SMILES: [C:1]([O:4][C:5]1[C:14]([O:15][CH3:16])=[C:13]2[C:8]([CH:9]=[CH:10][C:11](=[O:17])[O:12]2)=[CH:7][C:6]=1[CH2:18][CH:19]=C)(=[O:3])[CH3:2].I([O-])(=O)(=O)=[O:22].[K+]>[Os](=O)(=O)(=O)=O.CCOC(C)=O.O>[C:1]([O:4][C:5]1[C:14]([O:15][CH3:16])=[C:13]2[C:8]([CH:9]=[CH:10][C:11](=[O:17])[O:12]2)=[CH:7][C:6]=1[CH2:18][CH:19]=[O:22])(=[O:3])[CH3:2]
Reactant: C=CCc1cc2ccc(=O)oc2c(OC)c1OC(C)=O
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1c(OC(C)=O)c(CC=O)cc2ccc(=O)oc12
Reaction time: 5 h

Procedure:
A solution of 0.274 g. (0.001 mole) of 7-acetoxy-6-allyl-8-methoxycoumarin in 10 ml. EtOAc/water, 1:1 was treated with 0.8 g. (0.0033 mole) of potassium periodate and 0.5 ml. of a 10% aqueous solution of osmium tetroxide (10 mg. OsO4 /ml H2O). The reactants were stirred at 25° for 5.0 hours. The organic layer was separated, and the aqueous phase was further extracted with ethyl acetate. The organic extracts were combined, dried over sodium sulfate, and evaporated to yield pure 7-acetoxy-8-methoxycoumarin-6-acetaldehyde as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]([C:9]2[CH:10]=[CH:11][C:12](=[O:18])[N:13]([CH:15]([CH3:17])[CH3:16])[N:14]=2)=[N:6][C:7]=1Br.C(N)C1C=CC=CC=1.O.C[C:35]([N:37](C)[CH3:38])=O>C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:3]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]([C:9]2[CH:10]=[CH:11][C:12](=[O:18])[N:13]([CH:15]([CH3:17])[CH3:16])[N:14]=2)=[N:6][C:7]=1[N:37]([CH3:38])[CH3:35]
Reactant: CC(=O)N(C)C
Reactant: CC(C)n1nc(-c2nc(Br)c(N)nc2-c2ccccc2)ccc1=O
Solvent: O
Solvent: NCc1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(C)n1nc(-c2nc(N(C)C)c(N)nc2-c2ccccc2)ccc1=O
Temperature: 122.5 °C

Procedure:
A mixture of 6-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone (100 mg) and benzylamine (0.085 ml) in DMA (0.2 ml) was heated at 120-125° C. for 50 hours. After addition of water (4 ml), an aqueous layer was removed by decantation to give a residue. The residue was dissolved in CHCl3, dried over MgSO4, concentrated under reduced pressure and purified by preparative TLC on silica gel (CHCl3 only). A less polar zone was gave 6-[5-amino-6-(dimethylamino)-3-phenyl-2-pyrazinyl]-2-isopropyl-3(2H)-pyridazinone as a solid (18 mg) and a more polar zone was gave 6-[5-amino-6-(benzylamino)-3-phenyl-2-pyrazinyl]-2-isopropyl-3(2H)-pyridazinone as a solid (67 mg).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([CH:9]=C)=[CH:6][C:7]=1[CH3:8].C[N+]1([O-])CC[O:15]CC1>CC#N.O.O=[Os](=O)(=O)=O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([CH:9]=[O:15])=[CH:6][C:7]=1[CH3:8]
Reactant: C=Cc1cc(C)c(Cl)nn1
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Solvent: CC#N
Product: Cc1cc(C=O)nnc1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 89.9 %

Procedure:
To a white suspension of 3-chloro-6-ethenyl-4-methylpyridazine (34.1 mg, 0.221 mmol), NaIO4 (189 mg, 0.882 mmol), 4-methylmorpholine N-oxide (28.4 mg, 0.243 mmol) in CH3CN (3 mL) and water (1.5 mL) was added OsO4 (0.013 mL, 2.206 μmol), and the mixture was stirred at room temperature for 3 days. The reaction was monitored by LCMS and starting material was observed. The reaction mixture was heated at 60° C. overnight and no more starting material was observed. Solvents were evaporated in vacuo and the residue was partitioned between EtOAc and water. The aqueous layer was extracted with additional EtOAc. The combined organic phases were washed with water, dried with over anhydrous MgSO4, filtered and concentrated under reduced pressure to give 31.1 mg of the title compound as a white solid. It will be used in the next step without prior purification.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]=1[N+:15]([O-])=O)[CH2:2][CH2:3][CH3:4].[H][H]>[Ni].CO>[NH2:15][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:6]=1[NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[C:10]([OH:12])=[O:11]
Reactant: CCCCNc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: CCCCNc1ccc(C(=O)O)cc1N
Yield: 100 %

Procedure:
A mixture of 50 parts of 4-(butylamino)-3-nitrobenzoic acid and 240 parts of methanol was hydrogenated in a Parr apparatus at 3.105Pa and at room temperature with 40 parts of Raney Nickel catalyst under nitrogen atmosphere. After the calculated amount of hydrogen was taken up, the catalyst was filtered off over diatomaceous earth and the filtrate was evaporated to dry, yielding 43.7 parts (100%) of 3-amino-4-(butylamino)benzoic acid; mp. 158° C. (int. 8).
Reaction SMILES: FC1C=C(C2C3C(=CC=C(OC)C=3)C(NCCO)=NC=2C#N)C=CC=1.Cl[C:27]1[C:36]2[C:31](=[CH:32][C:33]([O:37][CH3:38])=[CH:34][CH:35]=2)[C:30]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[F:45])=[C:29]([C:46]#[N:47])[N:28]=1.[NH2:48][CH2:49][CH:50]([OH:53])[CH2:51][OH:52]>>[OH:53][CH:50]([CH2:51][OH:52])[CH2:49][NH:48][C:27]1[C:36]2[C:31](=[CH:32][C:33]([O:37][CH3:38])=[CH:34][CH:35]=2)[C:30]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[F:45])=[C:29]([C:46]#[N:47])[N:28]=1
Reactant: COc1ccc2c(Cl)nc(C#N)c(-c3ccccc3F)c2c1
Reactant: NCC(O)CO
Agent: COc1ccc2c(NCCO)nc(C#N)c(-c3cccc(F)c3)c2c1
Product: COc1ccc2c(NCC(O)CO)nc(C#N)c(-c3ccccc3F)c2c1

Procedure:
Following the procedure for 4-(3-fluorophenyl)-1-[(2-hydroxyethyl)amino]-6-methoxyisoquinoline-3-carbonitrile, using 1-chloro-4-(2-fluorophenyl)-6-methoxyisoquinoline-3-carbonitrile in place of 1-chloro-4-(3-fluorophenyl)-6-methoxyisoquinoline-3-carbonitrile, and using racemic 1-amino-2,3-propanediol in place of 2-aminoethanol, the title compound was synthesized.
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([CH:38]=O)=[C:20]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:29])=[N:26][CH:27]=2)[CH:21]=1.[Br:40][C:41]1[CH:47]=[CH:46][C:44]([NH2:45])=[CH:43][CH:42]=1.CC(O)=O>C(Cl)Cl.ClCCCl>[Br:40][C:41]1[CH:47]=[CH:46][C:44]([NH:45][CH2:38][C:19]2[CH:18]=[CH:17][C:16]([Cl:15])=[CH:21][C:20]=2[C:22]2[CH:23]=[CH:24][C:25]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:29])=[N:26][CH:27]=2)=[CH:43][CH:42]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2C=O)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2CNc2ccc(Br)cc2)cn1
Temperature: 25 °C

Procedure:
Solid NaBH(OAc)3 (709 mg, 3.3 mmol) was added to a DCE solution (8 mL) of ethyl 3-(5-(5-chloro-2-formylphenyl)picolinamido)propanoate (603 mg, 1.7 mmol), 4-bromoaniline (287.6 mg, 1.67 mmol) and HOAc (0.10 mL, 1.7 mmol) the resulting mixture was stirred at room temperature. After 16 h the resulting mixture diluted with DCM and washed with saturated aqueous NaHCO3 and water. The organic layer was dried (Na2SO4), concentrated and purified via column chromatography to yield the title compound.
Reaction SMILES: CC(C)(OC(N[C@H]([C:16]1[N:17](CC(=O)CC)[CH:18]=[C:19](C2C=CC=CC=2)[N:20]=1)CC1C=CC=CC=1)=O)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH:17]1[C:18]2=[N:17][CH:18]=[CH:19][NH:20][CH:19]2[NH:20][CH2:16]1
Reactant: CCC(=O)Cn1cc(-c2ccccc2)nc1[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C1=CNC2NCNC2=N1
Temperature: 20 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
2-[1(S)-{(1,1-Dimethylethoxy)carbonylamino}-2-phenylethyl]-1-(2-oxo-butyl)-4-phenyl-1H-imidazole (60 mg) in a mixture of 10% TFA in DCM was stirred at about 20° C. for about 3 hours and then concentrated under reduced pressure. The resulting intermediate dihydro-imidazo-pyrazine was dissolved in methanol and borohydride supported on resin (AMBERLITE® IRA 400, Aldrich, 2.5 mmol SH4−/g; 4 eq) was added. The pH was maintained at about 5 by addition of drops of TFA. After about 2 hours of stirring at about 20° C., the mixture was filtered and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (ethyl acetate/Heptane 7:3; Rf=0.30). The tetrahydro-imidazopyrazine was obtained as a single diastereoisomer in 86% yield (38 mg). NMR (1H, 400 MHz, CDCl3) δ: 7.80-7.10 (m, 1 1H, arom. H), 4.28 (dd, 1H, 3J=10 Hz, 3J=3 Hz, H8), 3.95 (dd, 1H, 2J=11.5 Hz, 3J=3.6 Hz), 3.85 (dd, 1H, 2J=13.6 Hz, 3J=3.0 Hz), 3.60 (t, 1H, 2J=3J=11.5 Hz), 3.85 (dd, 1H, 2J=13.6 Hz, 3J=10 Hz), 2.98 (m, 2H), 1.85 (s, 1H, NH), 1.55 (m, 2H, CH2), 0.95 (t, 3H, CH3). NMR (13C, 100 MHz, CDCl3): 146.3, 140.9, 138.0, 134.4, 129.4, 128.6, 128.5, 126.6, 126.5, 124.8, 113.8, 55.9, 54.4, 50.2, 40.0, 26.6, 10.0. LC/MS: calculated MW=317.43, m/z=318.20 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.O[CH2:19][CH:20]([CH2:22]O)O>>[N:1]1[C:2]2[C:3](=[CH:4][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[CH:6][CH:7]=2)[CH:22]=[CH:20][CH:19]=1
Reactant: OCC(O)CO
Reactant: CC(C(=O)O)c1ccc(N)cc1
Agent: O=S(=O)(O)O
Product: CC(C(=O)O)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The mixture of 2-(4-Amino-phenyl)-propionic acid (1.70 g), FeSO4 7H2O (0.30 g), glycerol (4.04 g) and sulfuric acid (2 mL) was refluxed with stirring for 5 h. After cooled to room temperature, the reaction mixture was concentrated under reduced vacuum. The aqueous solution was treated with 12N—NaOH solution. The precipitated solid was filtered and the filtrate was acidified with AcOH. The resulting mixture was extracted and the combined organic layer was dried over magnesium sulfate, filtered, concentrated in vacuo. The resulting residue was chromatographed on silica gel (CH2Cl2:MeOH=15:1 to 10:1) to afford the product as a brown solid. (0.83 g, 40.0%)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[C:11]1[C:16]([Cl:17])=[CH:15][C:14]([Cl:18])=[CH:13][N:12]=1.C(Cl)(=O)C([Cl:22])=O>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:22])=[O:7])=[CH:4][C:3]=1[C:11]1[C:16]([Cl:17])=[CH:15][C:14]([Cl:18])=[CH:13][N:12]=1
Reactant: O=C(O)c1ccc(Cl)c(-c2ncc(Cl)cc2Cl)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(Cl)c(-c2ncc(Cl)cc2Cl)c1
Reaction time: 2.5 h

Procedure:
To 4-chloro-3-(3,5-dichloro-pyridin-2-yl)-benzoic acid (60 mg, 0.2 mmol) in dry DCM (0.6 mL) was added DMF (1 drop) followed by slow addition of oxalyl chloride (30 μL, 0.34 mmol). The mixture was stirred for 2.5 hrs, then concentrated to yield the corresponding 4-chloro-3-(3,5-dichloro-pyridin-2-yl)benzoyl chloride which was dissolved in DCM (1 mL). Cyclopropyl-(2-methoxy-phenyl)-amine (55 mg, 0.34 mmol), followed by diisopropylethylamine (71 μL, 0.4 mmol) were added slowly. The mixture was stirred at room temperature for 12 hrs, concentrated and purified by preparative LCMS to yield 4-chloro-N-cyclopropyl-3-(3,5-dichloro-pyridin-2-yl)-N-(2-methoxy-phenyl)-benzamide 18-1. MS (M+H)+: 446.9, tR=8.59 min (method 2)
Reaction SMILES: [C:1]([O:5][CH2:6][C@H:7]([C:16](O)=O)[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([CH3:4])([CH3:3])[CH3:2].[C:19]1(=[O:29])[NH:23][C:22](=[O:24])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=[O:52]>O1CCCC1>[C:1]([O:5][C:6](=[O:52])[C@H:7]([NH:8][C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:16][N:23]1[C:19](=[O:29])[C:20]2=[CH:28][CH:27]=[CH:26][CH:25]=[C:21]2[C:22]1=[O:24])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)OC(=O)N=NC(=O)OC(C)C
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CN1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C
Yield: 62.6 %

Procedure:
To a solution of O-tert-butyl-N-BOC-D-serine (4 g, 15.31 mmol), phthalimide (3.38 g, 22.9 mmol) and triphenyl phosphine (6.03 g, 22,9 mmol) in tetrahydrofuran (120 ml, anhydrous) was added diisopropyl azodicarboxylate (4.5 ml, 22.9 mmol). The mixture was stirred under nitrogen atmosphere over night. The tetrahydrofuran was removed on the roto-evaporator and the remainder was taken up in methylene chloride (60 ml) and loaded onto a flash silica gel column. Elution with ethyl acetate/hexanes (19%) gave tert-butyl-2(R)-[(tert-butoxycarbonyl)amino]-3-phthalimidopropionate (3.74 g) as a white powder.
Reaction SMILES: C1(P([C:14]2[CH:19]=[CH:18]C=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[OH:34][C:35]1[CH:36]=[CH:37][C:38]2[O:42][C:41]([C:43]([O:45][CH2:46][CH3:47])=[O:44])=[CH:40][C:39]=2[CH:48]=1.[C:49]([N:56]1CC[O:59][CH2:58][CH:57]1C(O)=O)([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50]>ClCCl>[C:49]([N:56]1[CH2:57][CH2:58][O:59][CH:19]([CH2:14][O:34][C:35]2[CH:36]=[CH:37][C:38]3[O:42][C:41]([C:43]([O:45][CH2:46][CH3:47])=[O:44])=[CH:40][C:39]=3[CH:48]=2)[CH2:18]1)([O:51][C:52]([CH3:53])([CH3:54])[CH3:55])=[O:50]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)c1cc2cc(O)ccc2o1
Reactant: CC(C)(C)OC(=O)N1CCOCC1C(=O)O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: ClCCl
Product: CCOC(=O)c1cc2cc(OCC3CN(C(=O)OC(C)(C)C)CCO3)ccc2o1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Triphenyl phosphine polymer bound (8.96 mmol) was suspended in anhydrous dichloromethane (20 ml) then diisopropyl azodicarboxylate (7.76 mmol) was added and the mixture was stirred for 15 minutes at room temperature. Then ethyl 5-hydroxybenzofuran carboxylate (5.97 mmol) was added over 5 minutes followed by the addition of 4-N-boc-3-morpholinecarboxylic acid (5.97 mmol) over 5 minutes too. The mixture was stirred at room temperature over night. The solvent was evaporated under vacuo and the residue purified by flash chromatography to obtain ethyl 5-(4-Boc-morpholin-2-ylmethoxy)-benzofuran-2-carboxylate: m/z=406 in MS ES+, as clear oil.
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:5]([CH3:11])[C:6](C=O)=[CH:7][N:8]=1)[CH3:2].[C:12](#[N:16])[CH2:13][C:14]#[N:15].[CH2:17](O)C>>[CH2:1]([S:3][CH:4]1[N:5]([CH:11]=[C:13]([C:12]#[N:16])[C:14]#[N:15])[CH:6]=[CH:7][N:8]1[CH3:17])[CH3:2]
Reactant: N#CCC#N
Reactant: CCO
Reactant: CCSc1ncc(C=O)n1C
Product: CCSC1N(C)C=CN1C=C(C#N)C#N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5.13 g of 2-ethylthio-1-methylimidazole-5-carbaldehyde was dissolved in 30 ml of ethanol, and 2.00 g of malononitrile was then added. The mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 2.51 g of [(2-ethylthio-1-methylimidazol-3-yl)methylidene]malononitrile.
Reaction SMILES: [SH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Br[CH2:12][CH:13]1[CH2:15][CH2:14]1>>[CH:13]1([CH2:12][S:1][C:2]2[N:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH2:15][CH2:14]1
Reactant: BrCC1CC1
Reactant: O=C(O)c1cccnc1S
Product: O=C(O)c1cccnc1SCC1CC1
Yield: 88 %

Procedure:
2-Mercapto-nicotinic acid (1 g, 6.4 mmol) and bromomethyl cyclopropane were reacted in the same manner as in Step A of Preparation Example 10 to obtain the title compound (1.19 g, 88%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([CH:26]=[CH:27][CH:28]=1)[O:18][C:19]1[S:23][C:22]([C:24]#[N:25])=[CH:21][CH:20]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>O1CCCC1>[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([CH:26]=[CH:27][CH:28]=1)[O:18][C:19]1[S:23][C:22]([CH2:24][NH2:25])=[CH:21][CH:20]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: N#Cc1ccc(Oc2cccc(OCc3ccccc3)c2)s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NCc1ccc(Oc2cccc(OCc3ccccc3)c2)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
Next, to a solution of lithium aluminum hydride (27 mg, 0.716 mmol) in tetrahydrofuran (2.0 mL) was added a solution of 5-(3-benzyloxy-phenoxy)-thiophene-2-carbonitrile obtained above (110 mg, 0.358 mmol) in tetrahydrofuran (1 mL), and the solution was stirred at room temperature for 3 hours. Water was added to the reaction solution, which was then extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was evaporated to obtain the title compound (80 mg, 72%) as a red solid. This compound was used in the next reaction without purification.