Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[Na+].[CH3:7][O:8][CH2:9][O:10][C@H:11]([CH3:14])[CH2:12][OH:13].[CH2:15]([N:19]1[C:23]2[CH:24]=[N:25][CH:26]=[CH:27][C:22]=2[S:21]/[C:20]/1=[N:28]\[C:29](=[O:41])[C:30]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:31]=1F)[CH2:16][CH2:17][CH3:18].OP(O)(O)=O>O1CCCC1>[CH2:15]([N:19]1[C:23]2[CH:24]=[N:25][CH:26]=[CH:27][C:22]=2[S:21]/[C:20]/1=[N:28]\[C:29](=[O:41])[C:30]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:31]=1[O:13][CH2:12][C@H:11]([O:10][CH2:9][O:8][CH3:7])[CH3:14])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)sc2ccncc21
Reactant: COCO[C@H](C)CO
Agent: CC(C)(C)[O-]
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2OC[C@@H](C)OCOC)sc2ccncc21
Temperature: 0 °C
Yield: 73.4 %

Procedure:
To a 250 mL three-necked flask were charged sodium tert-butoxide (97%, 0.69 g, 7.0 mmol), and anhydrous tetrahydrofuran (17 mL). The mixture was stirred, and cooled down to about 0° C. A solution of (R)-2-(methoxymethoxy)propan-1-ol (0.96 g, 8.0 mmol) in tetrahydrofuran (2.0 mL) was added slowly at the internal temperature <5° C. The solution was mixed at <5° C. for 30 minutes, followed by addition of the N-[(2Z)-3-butyl[1,3]thiazolo[4,5-c]pyridin-2(3H)-ylidene]-2-fluoro-5-(trifluoromethyl)benzamide (1.59 g, 4.0 mmol) from Part B of Example 1 in tetrahydrofuran (36 mL) at <0° C. The resulting mixture was stirred at about 0° C. for 4 hours or until less than 5% of starting material remains. 125 g of 1.5% H3PO4 aqueous solution was added slowly to the reaction mixture at <5° C. The resulting slurry was mixed at about 0° C. for 1 hour, and then allowed to warm up to room temperature. The slurry was stirred at room temperature for 5 hours, and the product collected by filtration. The wet cake was washed with water-acetonitrile (2:1) (20 mL), and dried under vacuum at 50° C. overnight with a slow flow of nitrogen to give a white solid (1.46 g, 73%). MS-ESI: 498 (M+1); 1H-NMR (DMSO-d6) δ 0.94 (3H, t, J=7.4 Hz), 1.24 (3H, d, J=5.9 Hz), 1.41 (2H, m), 1.81 (2H, m), 3.23 (3H, s), 4.08 (3H, m), 4.52 (2H, t, J=7.5 Hz), 4.60 (1H, d, J=6.6 Hz), 4.75 (1H, d, J=6.9 Hz), 7.28 (1H, d, J=8.8 Hz), 7.75 (1H, d, J=8.8 Hz), 7.94 (1H, d, J=5.2 Hz), 8.24 (1H, d, J=2.2 Hz), 8.44 (1H, d, J=5.2 Hz), 8.95 (1H, s). 13C-NMR (CDCl3-DMSO-d6) δ 13.51, 17.28, 19.51, 29.28, 45.17, 54.50, 70.16, 72.23, 94.42, 113.39, 117.32, 120.10 (q, J=33 Hz, C—CF3), 123.66 (q, J=268 Hz, CF3), 126.05, 127.62, 128.75, 132.90, 133.14, 134.36, 142.71, 159.70, 164.56, 172.26.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:10][CH2:9][C:8]2[C:11](=[O:20])[C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[C:14](=[O:15])[C:7]=2[CH2:6][CH2:5]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25](O)[CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:17][O:16][C:13]1[C:14](=[O:15])[C:7]2[CH2:6][CH2:5][CH:4]([CH2:3][CH2:2][O:1][C:25]3[CH:26]=[C:27]([O:31][CH3:32])[C:28]([O:29][CH3:30])=[C:23]([O:22][CH3:21])[CH:24]=3)[CH2:10][CH2:9][C:8]=2[C:11](=[O:20])[C:12]=1[O:18][CH3:19]
Reactant: COC1=C(OC)C(=O)C2=C(CCC(CCO)CC2)C1=O
Reactant: COc1cc(O)cc(OC)c1OC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC1=C(OC)C(=O)C2=C(CCC(CCOc3cc(OC)c(OC)c(OC)c3)CC2)C1=O
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 79.9 %

Procedure:
To a solution of 7-(2-hydroxyethyl)-2,3-dimethoxy-4,5,6,7,8,9-hexahydro-1H-benzo[a]cycloheptene-1,4-dione (165 mg), 3,4,5-trimethoxyphenol (335 mg), and triphenylphosphine (201 mg) in THF (3 ml) was added a solution of diethyl azodicarboxylate (148 mg) in THF (1 ml) at room temperature. The reaction mixture was stirred at room temperature for 25 min and concentrated. The residue was purified by alumina column chromatography (eluent: ethyl acetate/hexane=1/4) and with recrystallization from ethyl acetate-hexane to obtain the entitled compound (210 mg).
Reaction SMILES: [S:1]1[CH:5]=[N:4][N:3]=[C:2]1[SH:6].[H-].[Na+].[C:9]1([CH:15]([O:22][C:23]([C:25]2[N:26]3[CH:29]([CH2:30][CH2:31][C:32]=2Cl)[C@@H:28]([NH:34][C:35](=[O:65])/[C:36](/[C:58]2[N:59]=[C:60]([NH2:64])[S:61][C:62]=2[Cl:63])=[N:37]\[O:38][C:39]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:27]3=[O:66])=[O:24])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(#N)C>[C:9]1([CH:15]([O:22][C:23]([C:25]2[N:26]3[CH:29]([CH2:30][CH2:31][C:32]=2[S:6][C:2]2[S:1][CH:5]=[N:4][N:3]=2)[C@@H:28]([NH:34][C:35](=[O:65])/[C:36](/[C:58]2[N:59]=[C:60]([NH2:64])[S:61][C:62]=2[Cl:63])=[N:37]\[O:38][C:39]([C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:27]3=[O:66])=[O:24])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Sc1nncs1
Reactant: Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(Cl)CCC23)c(Cl)s1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(Sc4nncs4)CCC23)c(Cl)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 1,3,4-thiadiazole-2-thiol (0.5 g, 0.004 mol) in acetonitile (40 mL) was added sodium hydride (0.2 g, 0.0043 mol) and the mixture was stirred for 1 hour at room temperature. To the resulting suspension was added (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(triphenylmethoxyimino]-acetamido]-3-chloro-8-oxo-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate diphenylmethyl ester (2.6 g, 0.003 mol), and the mixture was stirred for 48 hours. The solvent was evaporated and the residue was partitioned between water (50 mL) and ethyl acetate (50 mL). The organic layer was dried over anhydrous MgSO4, filtered and evaporated. The resulting solid was treated with diethyl ether (50 mL), and the solid that formed was filtered and dried to give 2.1 g of crude product. The crude product was purified by chromatography on silica gel, eluting with a gradient from ethyl acetate:hexane 1:2 to neat ethyl acetate. The title product was obtained (1.1 g.)
Reaction SMILES: [CH:1]1([CH:4]=[C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]2=O)[CH2:3][CH2:2]1.B.CO.Cl>C1COCC1>[CH:1]1([CH2:4][CH:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][CH2:6]2)[CH2:2][CH2:3]1
Reactant: O=C1Nc2ccccc2C1=CC1CC1
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: c1ccc2c(c1)NCC2CC1CC1
Temperature: 25 °C

Procedure:
1.0 g (5.4 mmol) 3-cyclopropylmethylene-1,3-dihydro-indol-2-one were placed in 50 mL THF. 12 mL (12 mmol) 1M borane in THF was slowly added dropwise. The reaction mixture was refluxed for 3 h. After cooling to RT 10 mL methanol and 15 mL semi-concentrated aqueous hydrochloric acid solution were successively added dropwise and then the mixture was refluxed for 3 h. After cooling to RT it was extracted with EtOAc. The aqueous phase was made alkaline with aqueous 4M sodium hydroxide solution and extracted once again with EtOAc. The organic phase was dried, filtered and evaporated down.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([C:15]([C:20]1[N:21]=[CH:22][N:23](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:24]=1)([OH:19])[CH:16]([CH3:18])[CH3:17])[CH:9]=[CH:8]2)([CH3:3])[CH3:2]>C(O)(=O)C.O>[CH:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([C:15]([C:20]1[N:21]=[CH:22][NH:23][CH:24]=1)([OH:19])[CH:16]([CH3:18])[CH3:17])[CH:9]=[CH:8]2)([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc2c1
Solvent: CC(=O)O
Solvent: O
Product: CC(C)Oc1ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc2c1
Temperature: 50 °C
Reaction time: 18 h
Yield: 67.8 %

Procedure:
1-(6-Isopropoxynaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (0.438 g) was dissolved in a mixture of acetic acid (20 ml) and water (0.5 ml), and the solution was stirred at 50° C. for 18 h. The solvent was evaporated, and to the mixture was added ethyl acetate. The mixture was washed with saturated aqueous solution of sodium hydrogencarbonate and saturated sodium chloride solution. The organic layer was dried and concentrated. The obtained residue was purified by silica gel column chromatography (eluent, dichloromethane:methanol=40:1→20:1) to give the titled compound (0.170 g) as an amorphous product.
Reaction SMILES: S(Cl)(Cl)=O.C1(CCCC(O)=O)C=CC=CC=1.C1(CCCC(Cl)=O)C=CC=CC=1.[CH3:29][O:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][C:40]=1[O:41][CH3:42])[N:37]=[CH:36][N:35]=[C:34]2[O:43][C:44]1[CH:50]=[CH:49][C:47]([NH2:48])=[CH:46][CH:45]=1.[C:51]1([CH2:57][CH2:58][CH2:59][C:60]([N:62]=[C:63]=[S:64])=[O:61])[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>C1(C)C=CC=CC=1.C(O)C>[CH3:29][O:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][C:40]=1[O:41][CH3:42])[N:37]=[CH:36][N:35]=[C:34]2[O:43][C:44]1[CH:50]=[CH:49][C:47]([NH:48][C:63]([NH:62][C:60](=[O:61])[CH2:59][CH2:58][CH2:57][C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)=[S:64])=[CH:46][CH:45]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(CCCc1ccccc1)N=C=S
Agent: O=C(Cl)CCCc1ccccc1
Agent: O=C(O)CCCc1ccccc1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CCO
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)CCCc4ccccc4)cc3)c2cc1OC
Temperature: 100 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 4-phenylbutanoic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 4-phenylbutanoyl isothiocyanate was prepared using the resultant 4-phenylbutanoyl chloride as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-phenylbutanoyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (37 mg, yield 45%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][OH:9])[C:5]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1>C(O)C.[C].[Pd]>[O:10]([C:5]1[C:6]([CH2:8][OH:9])=[N:7][CH:2]=[CH:3][CH:4]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: OCc1nc(Cl)ccc1Oc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: OCc1ncccc1Oc1ccccc1
Reaction time: 20 h

Procedure:
To a solution of (6-chloro-3-phenoxypyridin-2-yl)methanol (88 mg) in ethanol (1.5 ml), 10 mg of 10% palladium-carbon catalyst was added, and the reaction solution was stirred for 20 hours under hydrogen atmosphere. The catalyst was filtered off through Celite, and the filtrate was distilled off under reduced pressure to afford the title compound as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].CC(C)=O>O>[CH2:15]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][CH2:10][C:11](=[O:14])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCC(c2ccc(O)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=C1CCC(c2ccc(OCc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(4-Hydroxyphenyl)cyclohexanone (4.98 g, 26.18 mmol), benzyl bromide (4.92 g, 28.79 mmol), K2CO3 (5.06 g, 36.65 mmol) and 75 mL of acetone were mixed in a reaction flask equipped with a reflux condenser. The mixture was heated to reflux and stirred overnight. The mixture was cooled to room temperature and water was added. The mixture was extracted with ethyl acetate three times. The combined organic layers were dried over Na2SO4, filtered and concentrated. The resulting solid was recrystallized in ethyl acetate to provide the titled compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.80-2.00 (m, 2 H), 2.13-2.26 (m, 2 H), 2.43-2.55 (m, 4 H), 2.91-3.05 (m, 1 H), 5.05 (s, 2 H), 6.94 (d, J=8.82 Hz, 2 H), 7.16 (d, J=8.82 Hz, 2 H), 7.28-7.48 (m, 5 H); MS (DCI) m/z 298 (M−NH4)+.
Reaction SMILES: Cl[C:2]([F:21])([F:20])[C:3](Cl)([F:18])[O:4][C:5]([Cl:17])([F:16])[C:6]([F:15])([F:14])[C:7](Cl)([F:12])[C:8](Cl)([F:10])[F:9]>[Zn].CN(C)C=O>[C:8](=[C:7]([C:6]([C:5]([O:4][C:3](=[C:2]([F:20])[F:21])[F:18])([Cl:17])[F:16])([F:15])[F:14])[F:12])([F:10])[F:9]
Reactant: FC(F)(Cl)C(F)(Cl)OC(F)(Cl)C(F)(F)C(F)(Cl)C(F)(F)Cl
Agent: [Zn]
Solvent: CN(C)C=O
Product: FC(F)=C(F)OC(F)(Cl)C(F)(F)C(F)=C(F)F
Yield: 57.6 %

Procedure:
Into a 500 ml four-necked flask equipped with a stirrer, a reflux condenser and a dropping funnel, 120 g (1.84 mol) of zinc was introduced, and 200 ml of dimethylformamide was introduced thereinto in an atmosphere of an inert gas. Then, the pressure in the system was reduced to 4 kPa, and the internal temperature was adjusted to from 50 to 55° C., and 100 g (0.23 mol) of CF2ClCFClCF2CFClOCFClCF2Cl was dropwise added thereto gradually by the dropping funnel, and the resulting product was quickly taken out by distillation during the reaction. Then, the crude product was purified to obtain 39 g (yield 60%) of pure CF2═CFCF2CFClOCF═CF2 (4-chloro-1,1,2,4,5,5,6,7,7-nonafluoro-3-oxa-1,6-heptadiene). Hereinafter this compound will be referred to as a monomer B.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][O:15][C:14]2[CH:18]=[C:19]([S:22]([O:25][C:26]3[C:31]([F:32])=[C:30]([F:33])[C:29]([F:34])=[C:28]([F:35])[C:27]=3[F:36])(=[O:24])=[O:23])[CH:20]=[CH:21][C:13]1=2.[C:37]([Zn]C#N)#[N:38]>>[C:37]([C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][O:15][C:14]2[CH:18]=[C:19]([S:22]([O:25][C:26]3[C:31]([F:32])=[C:30]([F:33])[C:29]([F:34])=[C:28]([F:35])[C:27]=3[F:36])(=[O:24])=[O:23])[CH:20]=[CH:21][C:13]1=2)#[N:38]
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(c1)OCCN2c1ccc(C(F)(F)F)cc1Br
Reactant: N#C[Zn]C#N
Product: N#Cc1cc(C(F)(F)F)ccc1N1CCOc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Temperature: 25 °C
Yield: 91.8 %

Procedure:
A round bottom flask was charged with perfluorophenyl 4-(2-bromo-4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonate (see EXAMPLE 46, STEP 1) (391 mg, 0.647 mmol), dicyanozinc (380 mg, 3.24 mmol), and palladum (0) bis(tri-tert-butylphosphine) (33.1 mg, 0.065 mmol). The flask was flushed with Ar (g), then DMAC (3235 μL) was added. A reflux condenser was attached, and the flask was lowered into a 60° C. heating bath overnight. The mixture was cooled to room temperature and diluted with water and EtOAc. A small portion of brine was added to break up an emulsion, and the layers were separated. The aq. layer was extracted with EtOAc (2×), and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The product was purified by chromatography on silica gel (40 g, 0 to 30% EtOAc/Heptane) to give perfluorophenyl 4-(2-cyano-4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonate (327 mg, 0.594 mmol) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.50 (d, J=2.2 Hz, 1 H), 8.26-8.13 (m, 1 H), 7.85 (d, J=8.5 Hz, 1 H), 7.43 (d, J=2.2 Hz, 1 H), 7.33 (dd, J=2.3, 8.8 Hz, 1 H), 6.80 (d, J=8.8 Hz, 1 H), 4.45-4.40 (m, 2 H), 3.94 (t, J=4.2 Hz, 2 H). m/z (ESI) 573.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[NH:7][C:6]2[CH:8]=[C:9]([OH:13])[CH:10]=[C:11]([CH3:12])[C:5]=2[N:4]=1.[Cl:14][C:15]1[CH:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:14][C:15]1[N:16]=[CH:17][N:18]=[C:19]([O:13][C:9]2[CH:10]=[C:11]([CH3:12])[C:5]3[N:4]=[C:3]([O:2][CH3:1])[NH:7][C:6]=3[CH:8]=2)[CH:20]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: COc1nc2c(C)cc(O)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1nc2c(C)cc(Oc3cc(Cl)ncn3)cc2[nH]1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
74 mg (0.42 mmol) 2-methoxy-4-methyl-1H-benzo[d]imidazol-6-ol and 68 mg (0.44 mmol) 4,6-dichloropyrimidine were placed in 2.0 mL DMF. 0.12 g (0.88 mmol) potassium carbonate were added and the mixture was stirred for 4 h at 50° C. The reaction mixture was combined with ice water, the substance was extracted with ethyl acetate and evaporated down i.vac.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C@H:4]([NH2:14])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(O)(=O)C.[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1.C([BH3-])#N.[Na+]>CO.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:15])[C@H:4]([NH:14][CH2:25][C:24]1[CH:27]=[CH:28][C:21]([F:20])=[CH:22][CH:23]=1)[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: COC(=O)[C@H](N)COCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)[C@@H](COCc1ccccc1)NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
A solution of (2R)-3-benzyloxy-2-aminopropanoic acid methyl ester (19 g, 78 mmol) in methanol (350 mL) under N2 was cooled to 0° C. and acetic acid (2 g, pH 2) was added, followed by the addition of 4-fluorobenzaldehyde, a compound of formula (N) (12.5 mL, 117 mmol) and sodium cyanoborohydride (7.3 g, 117 mmol) and 3 Å molecular sieves (15 g). The resulting mixture was stirred at ambient temperature for 3 hours, then filtered through Celite (MeOH). The filtrate was concentrated in vacuo to afford a clear liquid. This was taken up in ethyl acetate and washed sequentially with 10% aqueous Na2CO3 solution, water, then brine. The organic phase was then dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel afforded 14.7 g (60% yield) of (2R)-3-benzyloxy-2-(N-(4-fluorobenzyl)amino)propanoic acid methyl ester, a compound of formula (O), as a clear, colorless oil; NMR (CDCl3) 7.4-7.2 (m, 7), 7.0 (dd, 2), 4.5 (d, 2), 3.9-3.5 (m, 8) ppm, MS (LSIMS) 317.
Reaction SMILES: [C:1]1([CH:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:8]([NH2:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.COC1C=CC(C(C)CN)=CC=1>>[C:1]1([CH:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:8][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)CC(C(N)=O)c1ccccc1
Agent: COc1ccc(C(C)CN)cc1
Product: CC(C)CC(CN)c1ccccc1
Yield: 51 %

Procedure:
The titled compound was prepared from 2-phenyl-4-methylpentanoic acid amide in 51% yield in the same manner as the preparation of 2-(4-methoxyphenyl)propylamine in Example 188c. MS (ESI) 178 (MH+)
Reaction SMILES: [C:1]1([CH:7]([NH:9][C:10]([C:12]2[S:13][C:14]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([OH:32])[CH:25]=4)[N:18]=3)=[CH:15][CH:16]=2)=[O:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:33][N:34]([CH2:36][CH2:37]O)[CH3:35].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC([N+](C(OC(C)C)=O)=[N-])=O)(C)C>C1COCC1.CS(C)=O>[C:1]1([CH:7]([NH:9][C:10]([C:12]2[S:13][C:14]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH2:37][CH2:36][N:34]([CH3:35])[CH3:33])[CH:25]=4)[N:18]=3)=[CH:15][CH:16]=2)=[O:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN(C)CCO
Reactant: COc1ccc(Nc2nccc(-c3ccc(C(=O)NC(C)c4ccccc4)s3)n2)cc1O
Agent: CC(C)OC(=O)[N+](=[N-])C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: COc1ccc(Nc2nccc(-c3ccc(C(=O)NC(C)c4ccccc4)s3)n2)cc1OCCN(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 0.8 %

Procedure:
5-[2-(3-Hydroxy-4-methoxy-phenylamino)-pyrimidin-4-yl]-thiophene-2-carboxylic acid (1-phenyl-ethyl)-amide (35 mg, 78 μmol), dimethylaminoethanol (26 μL, 156 μmol), and triphenylphosphine (41 mg, 156 μmol) were dissolved in 0.14 mL THF and cooled to 0° C. Diisopropyldiazodicarboxylate (31 μL, 156 μmol) were added dropwise. The reaction mixture was slowly warmed to room temperature and stirred overnight. The crude product was diluted with DMSO and purified by mass triggered reverse phase HPLC to afford 0.3 mg of pure 5-{2-[3-(2-Dimethylamino-ethoxy)-4-methoxy-phenylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic acid (1-phenyl-ethyl)-amide (0.6 μmol, 1%). 1H NMR (500 MHz, DMSO-d6) δ 9.49 (s, 1H), 8.94 (d, J=8 Hz, 1H), 8.47 (d, J=5 Hz, 1H), 7.98 (d, J=4 Hz, 1H), 7.93 (d, J=4 Hz, 1H), 7.57 (m, 1H), 7.38 (m, 2H), 7.31 (m, 4H), 7.23 (m, 1H), 6.88 (d, J=8 Hz, 1H), 5.12 (quintet, J=7.5 Hz, 1H), 4.05 (t, J=6 Hz, 2H), 3.71 (s, 3H), 2.64 (t, J=6 Hz, 2H), 2.17 (s, 6H), 1.48 (d, J=6.5 Hz, 3H). MS: m/z 518 (M+H+).
Reaction SMILES: O1CCCC1.[CH2:6]([O:13][C:14]1[CH:15]=[C:16]([NH:20][C:21]2[C:22]([NH2:31])=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:17]=[CH:18][CH:19]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:32](Cl)(=[O:37])[CH2:33][C:34](Cl)=[O:35]>CO>[CH2:6]([O:13][C:14]1[CH:15]=[C:16]([N:20]2[C:34](=[O:35])[CH2:33][C:32](=[O:37])[NH:31][C:22]3[C:23]4[CH2:24][CH2:25][CH2:26][CH2:27][C:28]=4[CH:29]=[CH:30][C:21]2=3)[CH:17]=[CH:18][CH:19]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(Cl)CC(=O)Cl
Reactant: Nc1c(Nc2cccc(OCc3ccccc3)c2)ccc2c1CCCC2
Solvent: CO
Solvent: C1CCOC1
Product: O=C1CC(=O)N(c2cccc(OCc3ccccc3)c2)c2ccc3c(c2N1)CCCC3
Reaction time: 1 h
Yield: 32 %

Procedure:
To an anhydrous tetrahydrofuran (15 mL) solution of N2-(3-benzyloxyphenyl)-5,6,7,8-tetrahydronaphthalene-1,2-diamine (151 mg, 0.44 mmol) was added malonyl chloride (50 μL, 0.53 mmol) while stirring in ice-bath. The mixture was stirred at room temperature for 3 hours. To the mixture was added methanol (5 mL) while stirring in ice-bath. The mixture was stirred under cooling in ice-bath for 1 hour, and at room temperature for 1 hour. The solvent was removed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/1) to give the titled compound as yellow oil (58 mg, yield 32%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:30])[CH2:11][C:12]1[C:21]([CH3:22])=[C:20]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([F:29])[CH:18]=2)[CH:13]=1.C(N(CC)C(C)C)(C)C.[F:40][C:41]1[CH:49]=[CH:48][C:47]([F:50])=[CH:46][C:42]=1[C:43](Cl)=[O:44].O>C(Cl)Cl>[CH3:8][O:9][C:10](=[O:30])[CH2:11][C:12]1[C:21]([CH3:22])=[C:20]([CH:23]2[CH2:24][CH2:25][N:26]([C:43](=[O:44])[C:42]3[CH:46]=[C:47]([F:50])[CH:48]=[CH:49][C:41]=3[F:40])[CH2:27][CH2:28]2)[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([F:29])[CH:18]=2)[CH:13]=1
Reactant: O=C(Cl)c1cc(F)ccc1F
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCNCC2)c1C
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(C(=O)c3cc(F)ccc3F)CC2)c1C
Yield: 67.6 %

Procedure:
To a solution of (6-fluoro-3-methyl-4-piperidin-4-yl-naphthalen-2-yl)-acetic acid methyl ester trifluoroacetate salt (which may be prepared as described above; 102 mg, 0.237 mmol) and N,N-diisopropylethylamine (124 μL, 0.711 mmol) in methylene chloride (10.0 mL) was added 2,5-difluorobenzoyl chloride (62.7 mg, 0.355 mmol). The reaction mixture was stirred for three hours at room temperature Water (˜25 mL) was added and the mixture was extracted with methylene chloride (2×25 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered and concentrated. Silica gel chromatography (25% ethyl acetate in hexanes) afforded {4-[1-(2,5-difluoro-benzoyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (73 mg, 68%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-])=O)[CH:10]=1)[NH:7][CH:6]=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[O:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1>>[O:20]1[CH2:25][CH2:24][CH:23]([NH:11][C:9]2[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[C:5]3[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:22][CH2:21]1
Reactant: O=C1CCOCC1
Reactant: O=[N+]([O-])c1cc(Cl)cc2c(-c3ccccc3)c[nH]c12
Product: Clc1cc(NC2CCOCC2)c2[nH]cc(-c3ccccc3)c2c1

Procedure:
5-Chloro-7-nitro-3-phenyl-1H-indole prepared in Preparation 41 and tetrahydropyran-4-one were reacted according to the same procedure as Example 1 to give the title compound.