Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[O:16][CH:15]=[CH:14][C:13]=3[C:12]([CH3:18])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C1C(=O)N(Br)C(=[O:22])C1.OP([O-])([O-])=O.[K+].[K+]>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]([CH:18]=[O:22])=[C:13]3[C:17]=2[O:16][CH:15]=[CH:14]3)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2ccc(C)c3ccoc23)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(-c2ccc(C=O)c3ccoc23)cc1
Temperature: 25 °C
Yield: 74.2 %

Procedure:
To a solution of 7-(4-methoxyphenyl)-4-methylbenzofuran (1.27 g, 5.34 mmol) in carbon tetrachloride (150 ml) was added NBS (1.05 g, 5.87 mmol) and AIBN (50 mg). The solution was brought to reflux for 2 h, cooled to room temperature, and the solids were filtered off. The solution was then concentrated and anhydrous CH3CN (50 ml) was added. Then potassium benzeneselenite (Syper, Ludwik; Mlochowski, Jacek Synthesis 1984, 9, 747–752) (1.33 g, 5.87 mmol), and K2HPO4 (0.93 g, 5.34 mmol) were added and the reaction was heated to reflux for 1 h after which it was allowed to cool to room temperature. The solution was then passed through a silica plug and the plug was washed with 30% EtOAc/hexanes after which the CH3CN was stripped off under hi vacuum. Chromatography (100% CH2Cl2) removed the Ph2Se2 by-product to afford 1.0 g (75%) of product as a white solid: mp 143–144° C.; 1H NMR (300 MHz, DMSO-d6): δ 3.85 (3H, s), 7.15 (2H, d, J=8.7 Hz), 7.57 (1H, d, J=2.1 Hz), 7.75 (1H, d, J=7.8 Hz), 7.96 (3H, appt), 8.33 (1H, d, J=2.1 Hz), 8.04 (1H, d, J=2.2 Hz); MS (ESI) m/z 253 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].[N+:13]([O-])([O-:15])=[O:14].[K+].O>S(=O)(=O)(O)O>[F:1][C:2]1[CH:11]=[CH:10][C:9]([N+:13]([O-:15])=[O:14])=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12]
Reactant: O=C1CCCc2c(F)cccc21
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: O=C1CCCc2c(F)ccc([N+](=O)[O-])c21
Reaction time: 0.5 h

Procedure:
14 gm of the compound prepared in (7) above was dissolved into 100 ml of concentrated sulfuric acid. After cooling the solution, a solution of 9.05 gm of potassium nitrate in 80 ml of concentrated sulfuric acid was added dropwise while maintaining the internal temperature below 5° C. The stirring was continued for a further 30 minutes. The resultant reaction mixture was poured into ice-cooled water and extracted with chloroform. The extract was washed with saturated aqueous solution of sodium bicarbonate, water, and saturated brine in this order, and dried over anhydrous sodium'sulfate. The solvent was evaporated and residue was recrystallized in methanol to obtain 9.15 gm of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:16][C:8]3([CH2:13][CH2:12][CH:11]([O:14][CH3:15])[CH2:10][CH2:9]3)[C:7](=[NH:17])[C:6]=2[CH:18]=1.O=[C:20]([CH3:24])[C:21](=[S:23])[NH2:22]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:16][C:8]3([CH2:9][CH2:10][CH:11]([O:14][CH3:15])[CH2:12][CH2:13]3)[C:7]3([NH:22][C:21](=[S:23])[C:20]([CH3:24])=[N:17]3)[C:6]=2[CH:18]=1
Reactant: CC(=O)C(N)=S
Reactant: COC1CCC2(CC1)Oc1ccc(Br)cc1C2=N
Solvent: CO
Product: COC1CCC2(CC1)Oc1ccc(Br)cc1C21N=C(C)C(=S)N1
Temperature: 60 °C
Reaction time: 24 h
Yield: 21.4 %

Procedure:
5-Bromo-4′-methoxy-3H-spiro[benzofuran-2,1′-cyclohexan]-3-imine (Example 29 Step 2, 1.37 g, 4.41 mmol) and 2-oxopropanethioamide (Intermediate 2, 0.909 g, 8.81 mmol) were dissolved in dry MeOH (25 mL) and the resulting orange solution was heated at 60° C. under a nitrogen atmosphere overnight. More 2-oxopropanethioamide (400 mg) was added and stirring continued. After 24 h the mixture was allowed to cool to r.t. and the solvent was evaporated. Purification by flash chromatography using a gradient of 0-100% EtOAc in heptane afforded 373 mg of the title compound (21% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.35 (m, 1 H), 1.47 (m, 3 H), 1.87 (m, 2 H), 1.97 (m, 2 H), 2.29 (s, 3 H), 3.13 (s, 3 H), 4.11 (m, 1 H), 6.99 (d, 1 H), 7.16 (d, 1 H), 7.48 (dd, 1 H); MS (ES+) m/z 396 [M+H]+.
Reaction SMILES: F[C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[NH:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O>[O:11]1[CH2:12][CH2:13][CH:8]([C:7]2[C:2]([O:30][C:27]3[CH:26]=[CH:25][C:24]([NH:23][C:15]4[S:14][C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=5[N:16]=4)=[CH:29][CH:28]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)[CH2:9][CH2:10]1
Reactant: Oc1ccc(Nc2nc3ccccc3s2)cc1
Reactant: Fc1ncccc1C1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: c1cnc(Oc2ccc(Nc3nc4ccccc4s3)cc2)c(C2CCOCC2)c1
Temperature: 180 °C

Procedure:
A glass microwave reaction vessel was charged with 2-fluoro-3-(tetrahydro-2H-pyran-4-yl)pyridine (0.3904 g, 2.154 mmol), 4-(benzo[d]thiazol-2-ylamino)phenol (0.783 g, 3.23 mmol), and cesium carbonate (2.106 g, 6.46 mmol) in N-Methyl-2-pyrrolidinone (7.18 mL). The reaction mixture was stirred and heated in a Biotage Initiator microwave reactor at 180° C. for 30 min. Reaction was worked up via seperatory funnel. The crude product was purified by reverse-phase preparative HPLC using a Phenomenex Synergi column, 4 micron, MAX-RP, 80 Å, 150×30 mM, 0.1% TFA in ACN/H2O, gradient 15% to 100% over 15 min. Further purification was pursued by absorbing crude product onto a plug of silica gel and chromatographed through a Biotage pre-packed silica gel column (25M), eluting with a gradient of 5% to 60% EtOAc in hexane, to provide N-(4-(3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yloxy)phenyl)benzo[d]thiazol-2-amine. MS (ESI, pos. ion) m/z: 404.0 (M+1). IC50 (uM) +++++.
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][CH:21]4[CH2:27][CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH:22]4[F:35])[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[ClH:36]>C(Cl)(Cl)Cl>[ClH:36].[ClH:36].[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][CH:21]4[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH:22]4[F:35])[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CC(C)(C)OC(=O)N1CCCC(Oc2cccc3ccc(-c4nnc5ccccn45)nc23)C(F)C1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: FC1CNCCCC1Oc1cccc2ccc(-c3nnc4ccccn34)nc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of the product from Step D (0.10 g, 0.21 mmol) in CHCl3 (2.1 mL) was added HCl (2.1 mL, 8.4 mmol, 4.0M in 1,4-Dioxane) and the reaction was stirred at ambient temperature for 5.0 hours. The resulting off-white suspension was directly filtered and the solid was washed with Et2O and dried in vacuo. This provided 0.089 g (88%) of the desired product as an off-white solid. MS ESI (+) m/z 378.1 (M+1) detected.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5](Cl)=O.[NH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[NH:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:16][CH:15]=[CH:14][CH:13]=2.Cl.N1C=CC=CC=1>N1C=CC=CC=1>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:19]([CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:8]=1
Reactant: COCCC(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCCCNc1c(N)cnc2ccccc12
Agent: Cl
Solvent: c1ccncc1
Product: COCCc1nc2cnc3ccccc3c2n1CCCCNC(=O)OC(C)(C)C
Reaction time: 4 h

Procedure:
3-Methoxypropionyl chloride (15.4 g, 126 mmol) was added dropwise over a period of 20 minutes to a chilled (ice bath) solution of tert-butyl N-{4-[(3-aminoquinolin-4-yl)amino]butyl}carbamate (38 g, 115 mmol, U.S. Pat. No. 6,541,485, Example 2, Part B) in pyridine. The reaction mixture was stirred for 4 hours and then allowed to stand at ambient temperature over the weekend. Pyridine hydrochloride (3.9 g, 34 mmol) was added and the reaction mixture was heated at reflux overnight. The reaction mixture was concentrated under reduced pressure and the residue was diluted with dichloromethane (250 mL) and aqueous sodium bicarbonate (250 mL). The layers were separated. The separatory funnel was rinsed with a small amount of methanol to remove a residue coating the walls. The combined organics were concentrated under reduced pressure. The residue was purified by prep HPLC (COMBIFLASH system eluting first with a gradient of 0 to 5% methanol in dichloromethane containing 1% ammonium hydroxide and then with a gradient of 5 to 10% methanol in dichloromethane containing 1% ammonium hydroxide) to provide 18 g of tert-butyl N-{4-[2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}carbamate.
Reaction SMILES: C([NH:11][C@H:12]([C:16]([OH:18])=[O:17])[CH:13]([CH3:15])[CH3:14])(OCC1C=CC=CC=1)=O.[Br:19][C:20]1[CH:27]=[C:26]([Br:28])[CH:25]=[C:22]([CH:23]=O)[C:21]=1[OH:29]>>[Br:19][C:20]1[CH:27]=[C:26]([Br:28])[CH:25]=[C:22]([CH:23]=[N:11][C@H:12]([C:16]([OH:18])=[O:17])[CH:13]([CH3:15])[CH3:14])[C:21]=1[OH:29]
Reactant: O=Cc1cc(Br)cc(Br)c1O
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Product: CC(C)[C@H](N=Cc1cc(Br)cc(Br)c1O)C(=O)O
Yield: 68 %

Procedure:
The desired product was prepared in the same manner as the latter half procedure of Reference Example 1. That is, carbobenzoxy-(S)-valine piperizide (0.32 g, 1 mmol) was hydrogenated and then condensed with 3,5-dibromosalicylaldehyde (0.42 g, 1.5 mmol) to obtain 0.30 g (68%) of the desired N-(3,5-dibromosalicylidene)-(S)-valine piperizide, which was further recrystallized from methanol. m.p. 143.2°-145.4° C. [α]26D +50.1° (c 0.97, CHCl3)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH3:27])=[C:24]([CH:26]=1)[NH2:25]>>[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH3:27])=[C:24]([CH:26]=1)[NH:25][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccncc2)n1
Reactant: COc1ccc(C)c(N)c1
Product: COc1ccc(C)c(Nc2cc(C(F)(F)F)nc(-c3ccncc3)n2)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 5-methoxy-2-methylaniline (27 mg, 0.193 mmol) similar to Example 13 and isolated as a pink solid (23 mg, 33%). 1H NMR (CDCl3): 8.77 (d, J=5.7 Hz, 2H), 8.27 (d, J=5.7 Hz, 2H), 7.32 (s, 1H), 7.26 (d, J=9.0 Hz, 1H), 6.99 (s, 1H), 6.70 (s, 1H), 6.85 (dd, J=2.7, 8.4 Hz, 1H), 3.82 (s, 3H), 2.24 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:14]([CH2:15][CH2:16][CH:17]=O)=[CH:13][N:12]=[CH:11]2)=[CH:5][CH:4]=1)#[N:2].CC(C)([O-])C.[K+]>C(O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]3[CH:11]=[N:12][CH:13]=[C:14]3[CH2:15][CH2:16][CH:17]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(Cn2cncc2CCC=O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Product: N#Cc1ccc(C2=CCCc3cncn32)cc1

Procedure:
A solution of 0.24 g of 1-(p-cyanophenylmethyl)-5-(2-formylethyl)-1H-imidazole in 10 ml of anhydrous ethanol is refluxed under nitrogen for 2 h with 20 mg of potassium tert-butoxide, cooled and evaporated to yield the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH:17]([CH2:18][OH:19])[CH2:16][N:15]3[N:20]=[C:21]([I:26])[C:22]([C:23](O)=[O:24])=[C:14]3[CH2:13]2)=[O:11])=[CH:5][CH:4]=1)#[N:2].C[N:28](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl-].[NH4+]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([N:12]2[CH:17]([CH2:18][OH:19])[CH2:16][N:15]3[N:20]=[C:21]([I:26])[C:22]([C:23]([NH2:28])=[O:24])=[C:14]3[CH2:13]2)=[O:11])=[CH:7][CH:8]=1)#[N:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: N#Cc1ccc(NC(=O)N2Cc3c(C(=O)O)c(I)nn3CC2CO)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(NC(=O)N2Cc3c(C(N)=O)c(I)nn3CC2CO)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.8 %

Procedure:
To a solution of Intermediate 351F (0.12 g, 0.257 mmol) in dry DMF (3 mL) was added HATU (0.195 g, 0.512 mmol), diisopropylethylamine (224 μL, 1.128 mmol) and ammonium chloride (0.0687 g, 1.128 mmol) and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated completely to dryness and the crude was partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and the filtrate concentrated. The crude product was purified by silica gel chromatography (12 g REDISEP® column, eluting with 3-5% methanol in chloroform). Fractions containing the product were combined to afford Intermediate 351G (0.08 g, 67%) as an off-white solid. MS(ES): m/z=467 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 9.29 (s, 1H), 7.69-7.74 (m, 2H), 7.63-7.69 (m, 2H), 7.37-7.48 (m, 1H), 6.93 (br. s., 1H), 5.22 (d, J=18.07 Hz, 1H), 5.13 (t, J=5.27 Hz, 1H), 4.72 (d, J=4.52 Hz, 1H), 4.51 (d, J=18.57 Hz, 1H), 4.31-4.38 (m, 1H), 4.20-4.28 (m, 1H), 3.43 (t, J=6.02 Hz, 2H).
Reaction SMILES: [NH:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=O)[O:3]C1=O.[Br:13][C:14]1[C:15]([CH3:21])=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17]>CN(C=O)C.O>[NH2:1][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:4]([NH:17][C:16]1[CH:18]=[CH:19][CH:20]=[C:14]([Br:13])[C:15]=1[CH3:21])=[O:3]
Reactant: Cc1c(N)cccc1Br
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(Br)cccc1NC(=O)c1ccccc1N
Yield: 5.9 %

Procedure:
A suspension of 1H-benzo[d][1,3]oxazine-2,4-dione (10.00 g, 61.3 mmol) in DMF (150 mL) was treated with 3-bromo-2-methylaniline (13.69 g, 73.6 mmol) and heated to reflux overnight. The cooled mixture was diluted with water and extracted with EtOAc. The whole mixture was filtered to remove grey solids and the layers of the filtrate were separated. The organic phase was washed with water, dried and concentrated. The residue was purified by column chromatography on silica gel (330 g), eluting with EtOAc-hexanes (gradient from 0-50%), to give 2-amino-N-(3-bromo-2-methylphenyl)benzamide as tan solid (1.1 g, 6% yield). A second eluent from the column gave 3-(3-bromo-2-methylphenyl)quinazoline-2,4(1H,3H)-dione [Intermediate 4B] as a tan solid (3.4 g, 17% yield).
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[C:24]3[N:23]=[CH:22][N:21]=[C:19]([NH2:20])[C:18]=3[N:17]=[CH:16]2)[CH:12]=[CH:11]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C@@H:13]1([N:15]2[C:24]3[N:23]=[CH:22][N:21]=[C:19]([NH2:20])[C:18]=3[N:17]=[CH:16]2)[O:14][C@H:10]([CH2:9][OH:8])[CH:11]=[CH:12]1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C=C[C@H](n2cnc3c(N)ncnc32)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Nc1ncnc2c1ncn2[C@H]1C=C[C@@H](CO)O1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 86.8 %

Procedure:
To a solution of 16 (3.79 g, 10.92 mmol) in dry THF (40 mL), cooled in an ice-bath, was added 22 ml of a 1M solution of tetra-n-butylammonium flouride in THF (22 mL, 22.0 mmol). The mixture was stirred for 40 minutes at room temperature and concentrated. The resulting yellow syrupy residue was purified by chromatography on a silica gel column using a gradient of 3-5% methanol in CHCl3. Evaporation of the appropriate fractions yielded 2.21 g (86%) of 7: mp 184°-186° C. (methanol); 1H NMR (DMSO-d6) δ 3.59 (2H, dd, J=4.1 Hz, 5.27 Hz, 5'-H), 4.80-5.10 (2H, m, 4'-H and OH), 6.14 (1H, ddd, J=1.46 Hz, 1.76 Hz, 5.86 Hz, 2'-H), 6.47 (1H, ddd, J=1.46 Hz, 1.76 Hz, 5.87 Hz, 3'-H), 6.94 (1H, m, 1'-H), 7.25 (2H, br s, NH2), 8.157 (1H, s, 8-H), 8.167 (1H, s, 2-H).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([NH2:11])=[NH:10])[CH2:4][CH2:3]1.[O:16]=[C:17]1NC(C2C=CC=CC=2OCC=C)=N[CH:19]=[C:18]1[C:33]([O:35][CH2:36][CH3:37])=[O:34]>>[O:16]=[C:17]1[NH:11][C:9]([C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[O:6][CH2:5][CH:2]2[CH2:4][CH2:3]2)=[N:10][CH:19]=[C:18]1[C:33]([O:35][CH2:36][CH3:37])=[O:34]
Reactant: C=CCOc1ccccc1-c1ncc(C(=O)OCC)c(=O)[nH]1
Reactant: N=C(N)c1ccccc1OCC1CC1
Agent: Cl
Product: CCOC(=O)c1cnc(-c2ccccc2OCC2CC2)[nH]c1=O

Procedure:
The title compound was prepared from 2-cyclopropylmethoxybenzamidine hydrochloride in a manner similar to that described for the preparation of ethyl 1,6-dihydro-6-oxo-2-(2-allyloxyphenyl)pyrimidine-5-carboxylate in Example 8. The product had m.p. 104°-105°.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:15]1[S:16][CH:17]=[CH:18][N:19]=1)CCC>CC#N.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd](Cl)Cl>[S:16]1[CH:17]=[CH:18][N:19]=[C:15]1[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: O=Cc1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: O=Cc1ccc(-c2nccs2)cc1
Temperature: 60 °C
Yield: 79.2 %

Procedure:
To a solution of 0.500 g (2.70 mmol) of 4-bromobenzaldehyde and 1.00 g (2.67 mmol) of 2-tributylstannylthiazole in MeCN (25 mL), degassed by bubbling N2 through for 10 min, was added 0.100 g (0.140 mmol) of palladium dichloride bis(triphenylphosphine). The mixture was heated to 60° C. for 15 h. The mixture was cooled to room temperature and filtered through diatomaceous earth. The mixture was diluted with H2O and washed with EtOAc. The combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography to provide 0.400 g (79.1%) of 4-thiazol-2-yl-benzaldehyde as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@H:11]([CH2:13][N:14]3[CH:18]=[C:17]([CH3:19])[N:16]=[N:15]3)[O:10][C:9]2=[O:20])[CH:5]=[CH:6][CH:7]=1.[I:21]I>ClCCl.FC(F)(F)C([O-])=O.[Ag+]>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@H:11]([CH2:13][N:14]3[CH:18]=[C:17]([CH3:19])[N:16]=[N:15]3)[O:10][C:9]2=[O:20])[CH:5]=[CH:6][C:7]=1[I:21]
Reactant: II
Reactant: Cc1cn(C[C@H]2CN(c3cccc(F)c3)C(=O)O2)nn1
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Product: Cc1cn(C[C@H]2CN(c3ccc(I)c(F)c3)C(=O)O2)nn1
Reaction time: 8 h
Yield: 42.6 %

Procedure:
Silver trifluoroacetate (0.52 g, 2.35 mM) was added to a solution of (5R)-3-(3-fluorophenyl)-5-[(4-methyl-1H-1,2,3-triazol-1-yl)methyl]-1,3-oxazolidin-2-one (0.50 g, 1.81 mM) in dichloromethane (15 mL). Iodine (0.55 g, 2.17 mM) was added over 1.5 h, and reaction mixture was stirred overnight. After 16 h, the solids were removed by filtration and additional silver trifluoroacetate (0.38 g, 1.72 mM) and iodine (0.27 g, 1.06 mM) were added. After an additional 24 h, the reaction mixture was filtered. The filter cake was washed with methanol. The methanol filtrate was concentrated under vacuum to give 0.31 g of the title product.
Reaction SMILES: [C:1]([OH:11])(=[O:10])[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].N1C=CC=CC=1.[C:18](Cl)(=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>CC(C)=O>[C:18]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH:2]([OH:3])[C:1]([OH:11])=[O:10])(=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: O=C(O)C(O)c1ccccc1
Reactant: CCCCCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: CCCCCCCC(=O)c1ccccc1C(O)C(=O)O
Yield: 84.2 %

Procedure:
15.2 gm (0.10 mole) dl-mandelic acid was dissolved in 50 ml acetone and placed in one of two 125 ml additional funnels attached to a 250 ml three-necked round bottom flask charged with 8.0 gm (0.10 mole) pyridine in 50 ml acetone cooled in an ice water bath. The other addition funnel was charged with 16.3 gm (0.10 mole) octanoyl chloride. The contents of the two addition funnels were simultaneously added dropwise over 20 minutes to the stirred/cooled pyridine solution. The reaction was removed by rotary evaporation. The residue was dissolved in 200 ml diethyl ether and this solution was extracted with 5×150 ml 5% HCl, and then washed with 1×200 ml deionized water. The organic layer was dried over Na2SO4, filtered and the solvent removed by rotary evaporation. After drying in vacuo there remained 28.2 gm of oil. GC and 13C NMR determined this material to be 83.1% of the desired product, for an overall 84.2% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH2:10].C(N(CC)CC)C.[N+:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27](Cl)(=[O:29])=[O:28])([O-:20])=[O:19]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH:10][S:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[N+:18]([O-:20])=[O:19])(=[O:28])=[O:29]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: NCCc1ccccc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)NCCc1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
1 mL of 2-(2-chlorophenyl)ethylamine and 1.2 mL of triethylamine were dissolved in 50 mL of dichloromethane. To the solution, 1.6 g of 2-nitrobenzenesulfonyl chloride was added at 0° C., and the mixture was stirred at room temperature for 2 hours. The reaction solution was washed with saturated saline, and the organic layer was separated and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain 2.3 g of the title compound as a pale yellow crystalline solid (92%).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:18][CH2:19][CH3:20])[C:6]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:7]=2[CH:8]=O)[CH2:3][CH2:2]1.Cl.[NH2:22][OH:23].C([O-])(=O)C.[Na+]>C(O)C>[CH:1]1([CH2:4][N:5]([CH2:18][CH2:19][CH3:20])[C:6]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:7]=2[CH:8]=[N:22][OH:23])[CH2:3][CH2:2]1
Reactant: NO
Reactant: CCCN(CC1CC1)c1ccc(C(F)(F)F)cc1C=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCCN(CC1CC1)c1ccc(C(F)(F)F)cc1C=NO
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.8 %

Procedure:
To ethanol (30 ml) are added 2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzaldehyde (6.8 g), hydroxylamine hydrochloride (1.66 g) and sodium acetate (1.95 g) and the mixture is stirred at room temperature overnight. Ethanol is removed by evaporating under reduced pressure and thereto is added chloroform and water, and the mixture is separated. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=10:1→2:1) to give 2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzaldehyde oxime (5.78 g). MS (m/z): 301 [M+H]+
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:19]=[C:18]([O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([N:29]3[CH2:32][CH2:31][CH2:30]3)=[O:28])=[C:23]([F:33])[CH:22]=2)[C:11]2[CH2:12][C:13]([CH2:16][OH:17])([CH3:15])[O:14][C:10]=2[CH:9]=1)=O)(C)(C)C.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][N:36]=1>>[CH3:41][C:38]1[CH:39]=[CH:40][C:35]([NH:34][C:6]([C:8]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([N:29]4[CH2:32][CH2:31][CH2:30]4)=[O:28])=[C:23]([F:33])[CH:22]=3)[C:11]3[CH2:12][C:13]([CH2:16][OH:17])([CH3:15])[O:14][C:10]=3[CH:9]=2)=[O:5])=[N:36][CH:37]=1
Reactant: Cc1ccc(N)nc1
Reactant: CC(C)(C)OC(=O)c1cc(Oc2ccc(C(=O)N3CCC3)c(F)c2)c2c(c1)OC(C)(CO)C2
Product: Cc1ccc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)c(F)c3)c3c(c2)OC(C)(CO)C3)nc1

Procedure:
The title compound was prepared in a similar manner as described for Example 200, from 4-[4-(azetidine-1-carbonyl)-3-fluoro-phenoxy]-2-hydroxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (240a) and 2-amino-5-methyl-pyridine. 1H NMR (400 MHz, CDCl3) δ 9.01 (br. s., 1 H) 8.23 (d, J=8.59 Hz, 1 H) 8.09 (s, 1 H) 7.62 (dd, J=8.59, 1.77 Hz, 1 H) 7.53 (t, J=8.08 Hz, 1 H) 7.15 (s, 1 H) 7.11 (s, 1 H) 6.80 (dd, J=8.59, 2.27 Hz, 1 H) 6.63-6.73 (m, 1 H) 4.22 (t, J=7.71 Hz, 2 H) 4.15 (t, J=7.71 Hz, 2 H) 3.74 (d, 1 H) 3.61 (d, J=11.87 Hz, 1 H) 3.18 (d, J=16.67 Hz, 1 H) 2.79 (d, J=16.67 Hz, 1 H) 2.28-2.38 (m, 5 H) 1.46 (s, 3 H); LCMS for C27H26FN3O5 m/z 492.00 (M+H)+.