Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:5][C:6]([CH:8]=[C:9]1[C:17]2[CH:16]=[CH:15][S:14][C:13]=2[CH2:12][CH2:11][CH2:10]1)=[O:7])[CH2:2][CH2:3][CH3:4].C1COCC1.C([Li])CCC.[C:28](=[O:30])=[O:29]>CCCCCC.O.CCOCC>[CH2:1]([NH:5][C:6]([CH:8]=[C:9]1[C:17]2[CH:16]=[C:15]([C:28]([OH:30])=[O:29])[S:14][C:13]=2[CH2:12][CH2:11][CH2:10]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: O=C=O
Reactant: CCCCNC(=O)C=C1CCCc2sccc21
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCNC(=O)C=C1CCCc2sc(C(=O)O)cc21
Reaction time: 2.5 h

Procedure:
To a mixture of 4-(N-butylcarbamoyl)methylidene-4,5,6,7-tetrahydrobenzo[b]thiophene (0.49 g) and THF (8 ml) was dropwise added 1.64 M n-butyl lithium (n-BuLi) in n-hexane (2.88 ml) at -70~-60° C. under nitrogen atmosphere and the mixture was stirred under the same condition for 2.5 hours. The reaction mixture was poured into a mixture of dry ice and diethyl ether (Et2O). To the mixture were added Et2O and water. The separated aqueous layer was washed with Et2O, and acidified by 6 N hydrochloric acid (HCl) and was extracted with AcOEt. The organic layer was washed with water and brine, and dried over MgSO4, and evaporated in vacuo to give 4-(N-butylcarbamoyl)methylidene-4,5,6,7-tetrahydrobenzo[b]-thiophene-2-carboxylic acid (0.38 g).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[SH:9].C[O-].[Na+].[Cl:13][CH2:14][C:15]#[N:16]>CO>[Cl:13][CH:14]([S:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[CH:2]=1)[C:15]#[N:16]
Reactant: N#CCCl
Reactant: Sc1cccc(Cl)c1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#CC(Cl)Sc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.1 %

Procedure:
15.0 g (83.8 mmol) of 2,3-dichloro-thiophenol are introduced into 50 ml of absolute methanol, 4.5 g (83.8 mmol) of sodium methanolate are added in portions, with cooling, and the mixture is stirred for 15 minutes at room temperature. 6.3 g (83.8 mmol) of chloroacetonitrile are subsequently added dropwise, and the mixture is stirred for 2 hours at room temperature and for a further 5 hours at reflux temperature. The entire batch is then filtered while hot and concentrated in vacuo. 10.8 g (59.1% of theory) of 2,3-dichloro-phenylthioacetonitrile are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[C:18]([F:21])([F:20])[F:19])[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][NH2:14])=[CH:8][CH:7]=1.[CH3:22][C:23]1[N:28]=[CH:27][C:26]([CH2:29][C:30]2[C:31](=[O:38])[N:32]=[C:33](SC)[NH:34][CH:35]=2)=[CH:25][N:24]=1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[C:18]([F:19])([F:20])[F:21])[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][NH:14][C:33]2[NH:34][CH:35]=[C:30]([CH2:29][C:26]3[CH:27]=[N:28][C:23]([CH3:22])=[N:24][CH:25]=3)[C:31](=[O:38])[N:32]=2)=[CH:8][CH:7]=1
Reactant: CSc1nc(=O)c(Cc2cnc(C)nc2)c[nH]1
Reactant: NCCc1ccc(Oc2ccc(C(F)(F)F)c(Cl)c2)cc1
Solvent: CCO
Product: Cc1ncc(Cc2c[nH]c(NCCc3ccc(Oc4ccc(C(F)(F)F)c(Cl)c4)cc3)nc2=O)cn1
Temperature: 125 °C
Reaction time: 50 h
Yield: 45.7 %

Procedure:
2-[4-(3-chloro-4-trifluoromethyl-phenoxy)-phenyl]-ethylamine (0.317 mmol, 1.01 eq) and 5-(2-methyl-pyrimidin-5-ylmethyl)-2-methylsulfanyl-1H-pyrimidin-4-one (0.322 mmol, 1 eq) were dissolved in dry ethanol (300 μL) and stirred at 125° C. for 50 hours. Solvent was evaporated and crude product was purified on Biotage SP1 Snap Si 10; 15 ml/min in the gradient of MeOH in DCM: 0-10% in 25CV. The appropriate fractions were combined and evaporated in vacuo to give the required product 2-{2-[4-(3-chloro-4-trifluoromethyl-phenoxy)-phenyl]ethylamino}-5-(2-methyl-pyrimidin-5-ylmethyl)-1H-pyrimidin-4-one (0.145 mmol, yield: 44%, HPLC-MS/UV:[M+H]+=517.97; rt: 11.53 mins; purity: 90%). 1H NMR (300 MHz; CDCl3) δ/ppm 2.65 (s, 3H), 2.92 (t, J=6.57, 2H), 3.53 (s, 2H), 3.57-3.69 (m, 2H), 5.39 (br.s., 1H), 7.01 (d, J=8.69, 1H), 7.08 (d, J=8.50 2H), 7.27-7.31 (m, 2H), 7.66 (s, 1H), 7.89 (dd, J=9.58, J=2.73, 1H), 8.36-8.42 (m, 1H), 8.51 (s, 2H), 11.21 (br.s., 1H)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH2:18][CH2:19][F:20])[CH:14]=[CH:13][C:11]=3[CH:12]=2)[CH:5]=[CH:4][N:3]=1.CO.[CH3:23][NH2:24].O>O1CCCC1>[CH3:23][NH:24][C:2]1[N:7]=[C:6]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH2:18][CH2:19][F:20])[CH:14]=[CH:13][C:11]=3[CH:12]=2)[CH:5]=[CH:4][N:3]=1
Reactant: FCCOc1ccc2cc(-c3ccnc(Cl)n3)sc2c1
Reactant: CN
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CNc1nccc(-c2cc3ccc(OCCF)cc3s2)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 63.4 %

Procedure:
2-(2-Chloropyrimidine-4-yl)-6-(2-fluoroethoxy)benzothiophene (105b, 80 mg, 0.26 mmol) obtained in Preparation Example 20 was dissolved in anhydrous tetrahydrofuran (4 mL). A 2.0 M methylamine methanol solution (NH2Me in MeOH, 0.26 mL, 0.52 mmol) was added to the reaction mixture and stirred at room temperature for 3 days. To the reaction mixture was added water and organic compounds were extracted with ethyl acetate and evaporated after a treatment with sodium sulfate. Column chromatography was performed to give the target compound 2-[2-(N-monomethylamino)pyrimidine-4-yl]-6-(2-fluoroethoxy)benzothiophene (1-35, 50 mg, 63%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][C:13]=2[C:21]2[C:22]([O:27][CH3:28])=[N:23][CH:24]=[CH:25][CH:26]=2)[CH:5]=[N:6][C:7]=1[CH:8]1[CH2:10][CH2:9]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:39][S:40](Cl)(=[O:42])=[O:41].O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([NH:18][S:40]([CH3:39])(=[O:42])=[O:41])=[O:17])=[CH:14][C:13]=2[C:21]2[C:22]([O:27][CH3:28])=[N:23][CH:24]=[CH:25][CH:26]=2)[CH:5]=[N:6][C:7]=1[CH:8]1[CH2:10][CH2:9]1
Reactant: COc1ncccc1-c1cc(C(N)=O)ccc1Oc1cnc(C2CC2)c(Cl)c1
Reactant: CS(=O)(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ncccc1-c1cc(C(=O)NS(C)(=O)=O)ccc1Oc1cnc(C2CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.1 %

Procedure:
To a solution of 4-(5-chloro-6-cyclopropylpyridin-3-yloxy)-3-(2-methoxypyridin-3-yl)benzamide (Preparation 40, 437 mg, 1.10 mmol) in anhydrous tetrahydrofuran (4 mL) under nitrogen was added 1M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (4.40 mL, 4.40 mmol). The solution was stirred 30 minutes at room temperature then methane sulfonyl chloride (340 μL, 4.40 mmol) was added and the reaction mixture was stirred 2 hours at room temperature. Water (50 mL) was added and the solution was extracted with ethyl acetate (3×20 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography eluting with Feb. 10, 1990 acetic acid/ethyl acetate/dichloromethane to afford the title compound as a white solid (230 mg, 44%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1.N1C=CC=CC=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[C:19]([NH:1][C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1sc(N)nc1C
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1sc(NC(=O)c2ccccc2)nc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 97 %

Procedure:
To a solution of ethyl 2-amino-4-methylthiazole-5-carboxylate (2.00 g, 10.00 mmol) in anhydrous dichloromethane (40 mL) was added pyridine (2.50 g, 32.00 mmol), followed by the addition of benzoyl chloride (1.90 g, 13.00 mmol) dropwise. The reaction mixture was stirred at ambient temperature for 18 h, then washed sequentially with 1 N hydrochloric acid (15 mL), saturated aqueous sodium bicarbonate (2×15 mL), and water (15 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography to afford the title compound as a white solid in 97% yield (3.0 g); 1H NMR (CDCl3, 300 MHz) δ 11.35 (s, br, 1H), 7.89 (d, J=7.4 Hz, 2H), 7.59 (t, J=7.4 Hz, 1H), 7.47 (t, J=7.6 Hz, 2H), 4.29 (q, J=7.1 Hz, 2H), 2.28 (s, 3H), 1.35 (t, J=7.1 Hz, 3H); MS (ES+) m/z 291.1 (M+1).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].S(O)(O)(=O)=O.[CH3:12][N:13]([CH3:17])[C:14]([NH2:16])=[NH:15].[C:18]([N:25]1[CH2:30][CH2:29][CH:28]([C:31](OCC)=[O:32])[C:27](=O)[CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].[Al]>CO.O>[CH3:12][N:13]([CH3:17])[C:14]1[N:16]=[C:31]([OH:32])[C:28]2[CH2:29][CH2:30][N:25]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:26][C:27]=2[N:15]=1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1=O
Reactant: CN(C)C(=N)N
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Al]
Solvent: CO
Solvent: O
Product: CN(C)c1nc(O)c2c(n1)CN(C(=O)OC(C)(C)C)CC2

Procedure:
K2CO3 (563 mg, 4.07 mmol) and 1,1-dimethylguanidine sulfate (566 mg, 2.04 mmol) were added to a suspension of ethyl N—BOC-3-oxopiperidine-4-carboxylate in MeOH (2 mL) and H2O (1 mL) in a 40 mL vial. The reaction was heated in an aluminium block at 70° C. for 90 minutes. LCMS analysis showed that the reaction was complete. The mixture was acidified to pH 3 and extracted with DCM (3×). The combined organic extracts were dried over MgSO4, filtered and concentrated to obtain tert-butyl 2-(dimethylamino)-4-hydroxy-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate as a pale yellow solid which was used without further purification. MS (ESI): mass calcd. for C14H22N4O3, 294.3. m/z found, 295.3 [M+H]+. 1H NMR (400 MHz, MeOD) δ 4.29-4.11 (m, 2H), 3.71-3.46 (m, 2H), 3.09 (s, 6H), 2.42 (t, J=5.8 Hz, 2H), 1.58-1.38 (m, 9H).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][C@H:11]([C:15]([O:17]CC2C=CC=CC=2)=[O:16])[N:10]([S:25]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][C@H:11]([C:15]([OH:17])=[O:16])[N:10]([S:25]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(S(=O)(=O)N2CN(Cc3ccccc3)C(=O)C[C@@H]2C(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(S(=O)(=O)N2CN(Cc3ccccc3)C(=O)C[C@@H]2C(=O)O)cc1

Procedure:
A mixture of benzyl 1-benzyl-3-[(4-methoxyphenyl)sulfonyl]-6-oxo-hexahydro-pyrimidine-4(R)-carboxylate (518 mg, 1.0 mmol) and 10% Pd/C (50 mg) in methanol (25 mL) hydrogen atmosphere for 45 minutes. The mixture is filtered over celite and the filtrate is collected and concentrated under reduced pressure to give 1-benzyl-3-[(4-methoxyphenyl)sulfonyl]-6-oxo-hexahydro-pyrimidine-4(R)-carboxylic acid as a glassy solid.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[C:13]2[O:12][C:11]([CH3:15])([CH3:14])[C:10](=[O:16])[C:9]=2[CH:8]=[CH:7][CH:6]=1>C(O)C.C(Cl)Cl>[CH3:3][O:4][C:5]1[C:13]2[O:12][C:11]([CH3:14])([CH3:15])[CH:10]([OH:16])[C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: COc1cccc2c1OC(C)(C)C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: COc1cccc2c1OC(C)(C)C2O

Procedure:
An aqueous solution of sodium borohydride (8.2 g, 50 ml) is added to a stirred solution of the product obtained in Step 3. (41.8 g) in ethanol (1 l) and the mixture refluxed for 3 hours and evaporated in vacuo. The residue is taken up in water and toluene, the layers are separated and the organic phase washed, dried and evaporated in vacuo affording an oil which is dissolved in methylene chloride, dried, filtered and evaporated in vacuo. The residue is dissolved in ethyl acetate and chromatographed on silica gel affording the desired product as a white solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=O.C[Si]([C:20]#[N:21])(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[ClH:28]>>[ClH:28].[NH2:21][CH2:20][C:8]1[C:9]2[C:4](=[C:3]([S:2][CH3:1])[CH:12]=[CH:11][C:10]=2[O:13][CH3:14])[CH2:5][CH2:6][CH:7]=1
Reactant: C[Si](C)(C)C#N
Reactant: COc1ccc(SC)c2c1C(=O)CCC2
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Product: COc1ccc(SC)c2c1C(CN)=CCC2

Procedure:
5-methylthio-8-methoxy-1,2,3,4-tetrahydro-1-naphthalenone is reacted with trimethylsilylcyanide followed by lithium aluminum hydride, and the resulting intermediate hydroxy amino compound is dehydrated with HCl, according to the procedure of Examples 1 and 3, to yield 1-aminomethyl-5-methylthio-8-methoxy-3,4-dihydronaphthalene HCl.
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](OCC2C=CC=CC=2)=[O:18])=[CH:13][C:12]=1[CH2:27][CH2:28][CH2:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[CH:32][CH:31]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C>[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:18])[NH:2][CH3:1])=[CH:13][C:12]=1[CH2:27][CH2:28][CH2:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[CH:32][CH:31]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN
Reactant: O=C(O)c1ccc(CCCc2cc(C(=O)OCc3ccccc3)ccc2OCc2ccccc2)cc1
Solvent: CCO
Product: CNC(=O)c1ccc(OCc2ccccc2)c(CCCc2ccc(C(=O)O)cc2)c1
Temperature: 100 °C

Procedure:
To a 33% solution (16 ml) of methylamine in ethanol was added 4-[3-(2-benzyloxy-5-benzyloxycarbonylphenyl)propyl]benzoic acid (1.25 g). The mixture was heated at 100° C. for 12 hours in an autoclave. The solvent was evaporated and the residue extracted with ethyl acetate (100 ml) and washed with 1N aqueous HCl (100 ml) , dried (MgSO4), filtered and evaporated. The residue was subjected to chromatography on silica gel, eluting with EtOAc. The title product was purified by trituration with diethyl ether (150 mg) mpt. 163°-166° C.
Reaction SMILES: [CH2:1]1[C@@H:5]2[CH2:6][NH:7][CH2:8][C@@H:4]2[CH2:3][N:2]1[C:9]1[N:14]=[N:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][NH:24][CH:25]=3)=[CH:17][C:16]=2[OH:26])=[CH:11][CH:10]=1.[Si:27]([O:34][CH2:35][CH:36]=O)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].[Na].C(O)(=O)C>C(Cl)Cl>[Si:27]([O:34][CH2:35][CH2:36][N:7]1[CH2:6][C@@H:5]2[CH2:1][N:2]([C:9]3[N:14]=[N:13][C:12]([C:15]4[CH:20]=[CH:19][C:18]([C:21]5[CH:22]=[N:23][NH:24][CH:25]=5)=[CH:17][C:16]=4[OH:26])=[CH:11][CH:10]=3)[CH2:3][C@@H:4]2[CH2:8]1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: Oc1cc(-c2cn[nH]c2)ccc1-c1ccc(N2C[C@H]3CNC[C@H]3C2)nn1
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Agent: [Na]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCN1C[C@@H]2CN(c3ccc(-c4ccc(-c5cn[nH]c5)cc4O)nn3)C[C@@H]2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.2 %

Procedure:
To a solution of 2-(6-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol (31.4 mg, 0.09 mmol), 2-((tert-butyldimethylsilyl)oxy)acetaldehyde (47.1 mg, 0.270 mmol), and sodium triacetoxyhydroborate (57.2 mg, 0.270 mmol) in CH2Cl2 (2 mL), was added acetic acid (0.013 mL, 0.225 mmol). The reaction mixture was stirred at RT overnight, then quenched with water and diluted with DCM. The organic layer was acidified with 1N HCl solution to pH˜3 and filtered to remove insoluble materials. The filtrate was loaded onto an SCX column, washed with MeOH, then eluted with 7N NH3 in MeOH. Concentration provided a brownish solid, 2-(6-((3a R,6aS)-5-(2-((tert-butyldimethylsilyl)oxy)ethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol (23 mg, 0.020 mmol, 51% yield), MS (M+1)=507.1.
Reaction SMILES: [Mg].[Cl:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH:11](Cl)[CH3:12].CON(C)[C:17]([C:19]1[CH:34]=[CH:33][C:22]2[N:23]([CH2:30][CH:31]=[CH2:32])[C:24](=[O:29])[N:25]([CH2:26][CH:27]=[CH2:28])[C:21]=2[CH:20]=1)=[O:18].O>C1COCC1>[CH2:30]([N:23]1[C:22]2[CH:33]=[CH:34][C:19]([C:17](=[O:18])[CH:11]([C:4]3[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=3[Cl:2])[CH3:12])=[CH:20][C:21]=2[N:25]([CH2:26][CH:27]=[CH2:28])[C:24]1=[O:29])[CH:31]=[CH2:32]
Reactant: C=CCn1c(=O)n(CC=C)c2cc(C(=O)N(C)OC)ccc21
Reactant: COc1ccc(C(C)Cl)c(Cl)c1
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: C=CCn1c(=O)n(CC=C)c2cc(C(=O)C(C)c3ccc(OC)cc3Cl)ccc21
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 52.8 %

Procedure:
A 1M suspension of Rieke magnesium in THF (1.3 ml) was added to THF (2 ml). The mixture was cooled to −10° C., and a solution of 2-chloro-1-(1-chloro-ethyl)-4-methoxy-benzene (136 mg) in THF (2 ml) was added. The mixture was stirred for 15 min. A solution of 1,3-diallyl-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid methoxy-methyl-amide (100 mg) in THF (2 ml) was added at −10° C. The mixture was stirred overnight at room temperature. Water was added and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and then concentrated to an oil. The residue was purified by flash chromatography (SiO2, 0 to 100% EtOAc/heptane) to give the title compound (72 mg) as a light yellow foam. MS (m/e)=411.2 [M+H+].
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.O=P(Cl)(Cl)[Cl:14]>>[Cl:14][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: Cc1cc(O)ncc1[N+](=O)[O-]
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(Cl)ncc1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
22.3 g of 2-hydroxy-4-methyl-5-nitropyridine and 170 ml of POCl3 are mixed together and heated at 100° C. for 3 hours. The cooled reaction medium is poured onto ice to yield a beige precipitate of 2-chloro-4-methyl-5-nitropyridine.
Reaction SMILES: [Cu]([C:4]#[N:5])C#N.Br[C:7]1[CH:8]=[N:9][CH:10]=[C:11]([F:16])[C:12]=1[CH:13]1[CH2:15][CH2:14]1>CN(C)C=O>[CH:13]1([C:12]2[C:7]([C:4]#[N:5])=[CH:8][N:9]=[CH:10][C:11]=2[F:16])[CH2:15][CH2:14]1
Reactant: Fc1cncc(Br)c1C1CC1
Reactant: N#C[Cu]C#N
Solvent: CN(C)C=O
Product: N#Cc1cncc(F)c1C1CC1
Temperature: 150 °C
Reaction time: 0.08 h

Procedure:
Copper cyanide (0.829 g, 0.00925 mol) was added at RT to a sealed tube containing 3-bromo-4-cyclopropyl-5-fluoro-pyridine (B; 1 g, 0.00462 mol) in dimethylformamide (20 mL). The reaction mixture was heated to 150° C. for 18 hr, then cooled to RT, quenched with 20% aqueous ammonia (20 mL) solution, and stirred for 5 min. It was extracted with diethyl ether (2×100 mL). The combined organic layers were washed with water (2×50 mL) and dried over anhydrous sodium sulphate to afford 4-cyclopropyl-5-fluoronicotinonitrile. MS (M+1): 163.1.
Reaction SMILES: [CH3:1][S:2]([CH:5]([CH2:16][CH2:17][CH2:18][CH:19]([O:25]C(=O)C)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH:11][C:12]([O:14]C)=[O:13])(=[O:4])=[O:3].CS(C(CCCC(OC(=O)C)CCCC=C)CCCCCCC([O-])=O)(=O)=O>>[CH3:1][S:2]([CH:5]([CH2:16][CH2:17][CH2:18][CH:19]([OH:25])[CH2:20][CH2:21][CH2:22][CH:23]=[CH2:24])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])(=[O:3])=[O:4]
Reactant: CCCCCC(CCCC(CCCCC=CC(=O)OC)S(C)(=O)=O)OC(C)=O
Agent: C=CCCCC(CCCC(CCCCCCC(=O)[O-])S(C)(=O)=O)OC(C)=O
Product: C=CCCCC(O)CCCC(CCCCCCC(=O)O)S(C)(=O)=O

Procedure:
The synthesis of this compound is carried out as in Example 3, Step E, except that the methyl 8-methylsulfonyl-12-acetoxyheptadecenoate is replaced by an equivalent quantity of 8-methylsulfonyl-12-acetoxy-16-heptadecenoate.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:13])[C:10](O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[C:16]=1[NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:10]1[N:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:16]2[C:15]([F:14])=[CH:20][CH:19]=[CH:18][C:17]=2[N:21]=1)[CH3:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1cccc(F)c1Nc1ccccc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2cccc(F)c2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.2 %

Procedure:
A mixture of (S)-2-tertbutoxycarbonylaminopropionic acid (480 mg, 2.53 mmol), 3-fluoro-N2-phenylbenzene-1,2-diamine (466 mg, 2.30 mmol), HOAt (345 mg, 2.53 mmol), 4-methylmorpholine (560 μL, 5.07 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (486 mg, 2.53 mmol) in DCM (15 mL) was stirred at RT for 2 h. The reaction mixture was then partitioned between additional DCM and an aqueous solution of NaHCO3. The organic layer was dried and concentrated in vacuo and the resulting residue (1.0 g) was dissolved in AcOH (20 mL) and stirred for 18 h at 70° C. After cooling to RT, volatiles were evaporated under reduced pressure and the residue was partitioned between EtOAc and a saturated solution of NaHCO3. The organic layer was washed with water, followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-30% EtOAc in DCM) affording [(S)-1-(7-Fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tertbutyl ester as a yellow/orange oil (631 mg, 77%). LCMS: RT 3.64 min [M+H]+ 356.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.[CH3:16][C:17](C)([CH3:21])[C:18](O)=O.OS(O)(=O)=O.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+].C(=O)=O.[NH4+].[OH-]>CC#N.O.[N+]([O-])([O-])=O.[Ag+]>[C:17]([C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=1)([CH3:21])([CH3:18])[CH3:16]
Reactant: COc1cc([N+](=O)[O-])c2ncccc2c1
Reactant: CC(C)(C)C(=O)O
Agent: [Ag+]
Agent: O=C=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC#N
Product: COc1cc([N+](=O)[O-])c2nc(C(C)(C)C)ccc2c1
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 62 %

Procedure:
6-Methoxy-8-nitroquinoline (1 mmol) (scheme 1) was dissolved in CH3CN (5 mL) while reaction mixture was warmed to 70° C. Silver nitrate (0.6 mmol), trimethylacetic acid (2.5 mmol), and 10% H2SO4 (10 mL) was then added to the reaction mixture. A freshly prepared solution of ammonium persulfate (3 mmol) in water (10 mL) was added drop wise to the pre-heated (70° C.) mixture during 10 minutes. The heating source was then removed and reaction proceeded with evolution of carbon dioxide. After 10 minutes, reaction mixture was poured onto ice, and resulting mixture was made alkaline with addition of 30% NH4OH. Extracted with ethyl acetate (4×50 mL), and combined extracts were washed with NaCl solution (2×10 mL). Dried over Na2SO4 and solvent removed in vacuo to afford oil, which on flash column chromatography over silica gel (230-400 mesh) gave 2-tert-Butyl-6-methoxy-8-nitroquinoline in good yield.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1([F:41])[O:30][C:29]2[CH:31]=[CH:32][C:33]([C:35]3([C:38]([OH:40])=O)[CH2:37][CH2:36]3)=[CH:34][C:28]=2[O:27]1.[NH2:42][C:43]1[CH:44]=[C:45]2[CH:51]=[C:50]([C:52]([CH3:55])([CH3:54])[CH3:53])[N:49]([CH2:56][CH2:57][OH:58])[C:46]2=[CH:47][N:48]=1.C(N(CC)CC)C>CN(C=O)C>[C:52]([C:50]1[N:49]([CH2:56][CH2:57][OH:58])[C:46]2=[CH:47][N:48]=[C:43]([NH:42][C:38]([C:35]3([C:33]4[CH:32]=[CH:31][C:29]5[O:30][C:26]([F:25])([F:41])[O:27][C:28]=5[CH:34]=4)[CH2:36][CH2:37]3)=[O:40])[CH:44]=[C:45]2[CH:51]=1)([CH3:55])([CH3:53])[CH3:54]
Reactant: CC(C)(C)c1cc2cc(N)ncc2n1CCO
Reactant: O=C(O)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ncc2n1CCO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
HATU (38 mg, 0.10 mmol) was added to a solution of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (24 mg, 0.10 mmol), 2-(5-amino-2-tert-butyl-1H-pyrrolo[2,3-c]pyridin-1-yl)ethanol (23 mg, 0.10 mmol) and triethylamine (42 μL, 0.30 mmol) in DMF (1 mL). The mixture was stirred at room temperature for 1 hour. The mixture was filtered and purified by reverse-phase HPLC (10-99% CH3CN—H2O with 0.035% TFA) to yield N-(2-tert-butyl-1-(2-hydroxyethyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 457.2, found 458.5 (M+1)+. Retention time 1.77 minutes. 1H NMR (400 MHz, DMSO-d6) δ 9.54 (br s, 1H), 8.84 (s, 1H), 7.83 (s, 1H), 7.58 (d, J=1.7 Hz, 1H), 7.45 (d, J=8.3 Hz, 1H), 7.35 (dd, J=8.3, 1.7 Hz, 1H), 6.67 (s, 1H), 4.58 (t, J=5.7 Hz, 2H), 3.76 (t, J=5.7 Hz, 2H), 1.58 (m, 2H), 1.46 (s, 9H), 1.28 (m, 2H).