Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:20]1[S:24][N:23]=[CH:22][N:21]=1)[S:7]([C:10]1[CH:19]=[CH:18][C:13]2[NH:14][C:15](=[O:17])[O:16][C:12]=2[CH:11]=1)(=[O:9])=[O:8].[F:31][C:32]([F:47])([F:46])[CH2:33][N:34]1[CH2:43][CH2:42][C:41]2[C:36](=[C:37]([CH2:44]O)[CH:38]=[CH:39][CH:40]=2)[CH2:35]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[O:17]=[C:15]1[N:14]([CH2:44][C:37]2[CH:38]=[CH:39][CH:40]=[C:41]3[C:36]=2[CH2:35][N:34]([CH2:33][C:32]([F:47])([F:31])[F:46])[CH2:43][CH2:42]3)[C:13]2[CH:18]=[CH:19][C:10]([S:7]([NH:6][C:20]3[S:24][N:23]=[CH:22][N:21]=3)(=[O:8])=[O:9])=[CH:11][C:12]=2[O:16]1
Reactant: OCc1cccc2c1CN(CC(F)(F)F)CC2
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3[nH]c(=O)oc3c2)c(OC)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=c1oc2cc(S(=O)(=O)Nc3ncns3)ccc2n1Cc1cccc2c1CN(CC(F)(F)F)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-5 (16.5 mg, 0.037 mmol) and 7-5 (9.02 mg, 0.037 mmol) in THF (368 μl) at RT was treated with PS-bound triphenylphosphine (1.84 mmol/g, 40.2 mg, 0.074 mmol), and DTBAD (16.94 mg, 0.074 mmol). After 30 min, LCMS showed complete consumption of SM. Filtered through Celite and concentrated in vacuo. Dissolved in 245 uL DCM, 123 uL TFA and stirred at RT. After 30 min, diluted with 1 mL MeOH, filtered through Celite and washed with 1 mL MeOH. Concentrated in vacuo and purified by reverse-phase HPLC (C18 column, 5-70% 0.1% TFA/CH3CN:0.1% TFA/H2O) to give 7-6 as an off-white solid. 1H NMR δ (ppm) (DMSO-d6): 8.48 (1H, s), 7.78 (1H, d, J=1.69 Hz), 7.67 (1H, dd, J=8.28, 1.72 Hz), 7.25 (1H, d, J=8.33 Hz), 7.14-7.09 (2H, m), 6.92 (1H, d, J=6.83 Hz), 5.00 (2H, s), 3.99 (3H, s), 3.54 (3H, d, J=12.20 Hz), 2.90 (2H, s). HRMS C21H19F3N5O4S2 [M+H] calc 526.0825, obs. 526.0806.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH:6]1[CH3:11].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:11][CH:6]1[CH:5]([CH2:4][CH:3]=[CH2:2])[NH:9][C:8](=[O:10])[CH2:7]1
Reactant: CC1CC(=O)NC1CCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C=CCC1NC(=O)CC1C

Procedure:
The product of EXAMPLE 235 is treated with PTSA in refluxing toluene, with a Dean-Stark trap to remove water. The solvent is removed to yield the title material.
Reaction SMILES: S(O[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][C:11]1=[O:19])(C)(=O)=O.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:27][CH2:28][N:29]([CH2:6][CH2:7][CH2:8][CH2:9][CH:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]2=[O:19])[CH2:30][CH2:31]1
Reactant: CS(=O)(=O)OCCCCC1C(=O)Nc2ccccc21
Reactant: c1ccc(N2CCNCC2)nc1
Product: O=C1Nc2ccccc2C1CCCCN1CCN(c2ccccn2)CC1

Procedure:
The title compound is prepared according to process B by applying processing method 1 starting from 3-(4-mesyloxybutyl)-1,3-dihydro-2H-indol-2-one and 1-(pyridin-2-yl)-piperazine.
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3](Cl)=[O:4].[CH2:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][NH:9]1.CCN(CC)CC>C(Cl)Cl>[Cl:1][C:2]([Cl:7])([Cl:6])[C:3]([N:9]1[CH2:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8]1)=[O:4]
Reactant: c1ccc2c(c1)CNC2
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N1Cc2ccccc2C1)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
Under N2, at 0° C., trichloroacetyl chloride (0.57 mL, 5.0 mmol) was added dropwise to a stirring solution of isoindoline (1.0 g, 5.0 mmol), Et3N (0.7 mL, 0.51 g, 5.0 mmol) and CH2Cl2 (20 mL). The solution was allowed to warm to room temperature and stirred for 1 h. After evaporating the solvents in vacuo, the mixture was purified via silica gel chromatography using 8:2 hexanes/EtOAc to obtain the desired amide (1.2 g, 4.6 mmol, 91% yield). LC/MS (10-99% CH3CN), M/Z: M+1 obs=265.9; tR=3.51 min.
Reaction SMILES: [N:1]1[C:6]2[O:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH2:10][NH:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:23][C:24]1[CH:25]=[CH:26][C:27]([CH3:42])=[C:28]([CH:41]=1)[C:29]([NH:31][C:32]1[N:37]=[CH:36][C:35]([C:38](Cl)=[O:39])=[CH:34][CH:33]=1)=[O:30]>ClCCl>[N:1]1[C:6]2[O:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH2:10][N:11]([C:38]([C:35]3[CH:34]=[CH:33][C:32]([NH:31][C:29](=[O:30])[C:28]4[CH:41]=[C:24]([F:23])[CH:25]=[CH:26][C:27]=4[CH3:42])=[N:37][CH:36]=3)=[O:39])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)CNc1cccnc1O2
Reactant: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)Cl)cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)N2Cc3ccccc3Oc3ncccc32)cn1

Procedure:
As described for Example 1, 5,6-dihydropyrido[2,3-b][1,4]benzoxazepine is reacted in dichloromethane, in the presence of triethylamine, with 6-[(5-fluoro-2-methylbenzoyl)amino]pyridine-3-carbonyl chloride to give the product as white crystals, m.p. 187°-189° C.
Reaction SMILES: O=[C:2]([CH3:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5].C(OC(=O)C)(=O)C.[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N+:23]([O-])=CC=[CH:20]2.Cl>>[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[C:2]([CH2:3][C:4]([O:6][CH3:7])=[O:5])[CH:8]=[CH:20]2
Reactant: [O-][n+]1cccc2cc(Cl)ccc21
Reactant: COC(=O)CC(C)=O
Agent: Cl
Solvent: CC(=O)OC(C)=O
Product: COC(=O)Cc1ccc2cc(Cl)ccc2n1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
Methyl 3-oxobutyrate was added to an acetic anhydride solution of 6-chloroquinoline 1-oxide, followed by 30 minutes of stirring at an oil bath temperature of 40° C. Thus obtained compound was added to 10% hydrochloric acid and the mixture was reacted at room temperature to obtain methyl (6-chloroquinolin-2-yl)acetate. The compound was further treated in a similar manner to Reference Example 11, Example 22 and Example 4, successively, to obtain an objective compound.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([C:13]1[S:14][CH:15]=[C:16]([C:19]([O:21][CH3:22])=[O:20])[C:17]=1[OH:18])(=[O:12])[CH3:11]>CN(C)C1C=CN=CC=1.ClCCl>[C:10]([C:13]1[S:14][CH:15]=[C:16]([C:19]([O:21][CH3:22])=[O:20])[C:17]=1[O:18][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:12])[CH3:11]
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)c1csc(C(C)=O)c1O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1csc(C(C)=O)c1OC(=O)c1ccccc1
Reaction time: 2 h

Procedure:
3.48 mL of benzoyl chloride was added dropwise to a solution of 5.0 g of methyl 2-acetyl-3-hydroxythiophene-4-carboxylate (prepared as described in J. Chem. Soc. Perkin Trans I, 1986, 507) and 3.66 g of 4-dimethylaminopyridine in 100 mL of dichloromethane at 20-25° C. and stirred for 2 hours. The mixture was washed with 0.5N hydrochloric acid, water (2×20 mL), 2.5% aqueous sodium bicarbonate (2×40 mL) and water (2×20 mL). The organic layer was dried with sodium sulphate, evaporated to dryness in vacuo and purified by flash chromatography using chloroform/ethyl-acetate (100:1). The yield of Compound 1C was 7.089, as a yellow deliquescent solid, which was used in the next step without further purification.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Br:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[C:17]([F:20])([F:19])[F:18])[C:11]([NH2:13])=O.C(OCC)(=O)C.[OH-].[Na+]>C1COCC1.C(OCC)C>[Br:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[C:17]([F:18])([F:19])[F:20])[CH2:11][NH2:13]
Reactant: NC(=O)c1ccc(C(F)(F)F)c(Br)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: NCc1ccc(C(F)(F)F)c(Br)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
LiAlH4 (0.906 g, 23.9 mmol) was suspended in 60 mL of dry THF and cooled to 0° C. The mixture was treated with the product from Example 243B (3.2 g, 11.9 mmol) in THF (10 mL) dropwise with stirring. After 20 minutes, the mixture was warmed to room temperature 12 hours and treated in succession with ethyl acetate (2 mL), NaOH (50%, 5 mL), and diethyl ether (100 mL). The organic phase decanted, dried (Na2SO4), filtered and the filtrate was concentrated under reduced pressure to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[F:19][C:20]([F:36])([C:32]([F:35])([F:34])[F:33])[CH2:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([C:29](O)=[O:30])=[N:27][CH:28]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:29]([C:26]3[CH:25]=[CH:24][C:23]([O:22][CH2:21][C:20]([F:19])([F:36])[C:32]([F:33])([F:34])[F:35])=[CH:28][N:27]=3)=[O:30])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Reactant: O=C(O)c1ccc(OCC(F)(F)C(F)(F)F)cn1
Product: C[C@]1(c2cc(NC(=O)c3ccc(OCC(F)(F)C(F)(F)F)cn3)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 5-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid following procedure I yielded the title compound as a white solid. MS (ISP): m/z=513.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([Cl:17])=[C:12]([CH:16]=1)[C:13]([OH:15])=O)=[O:6].ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.[N:39]1([CH2:44][CH2:45][CH2:46][S:47]([C:50]2[CH:55]=[CH:54][C:53]([NH:56][C:57]3[N:62]=[CH:61][C:60]([NH2:63])=[CH:59][N:58]=3)=[CH:52][CH:51]=2)(=[O:49])=[O:48])[CH2:43][CH2:42][CH2:41][CH2:40]1>C(Cl)Cl.CN(C=O)C>[Cl:17][C:11]1[CH:10]=[CH:9][C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:18]=[CH:19][CH:20]=[C:2]([CH3:1])[CH:3]=2)=[CH:16][C:12]=1[C:13]([NH:63][C:60]1[CH:61]=[N:62][C:57]([NH:56][C:53]2[CH:54]=[CH:55][C:50]([S:47]([CH2:46][CH2:45][CH2:44][N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)(=[O:48])=[O:49])=[CH:51][CH:52]=2)=[N:58][CH:59]=1)=[O:15]
Reactant: Nc1cnc(Nc2ccc(S(=O)(=O)CCCN3CCCC3)cc2)nc1
Reactant: Cc1cccc(C(=O)Nc2ccc(Cl)c(C(=O)O)c2)c1
Agent: COc1nc(Cl)nc(OC)n1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cc1cccc(C(=O)Nc2ccc(Cl)c(C(=O)Nc3cnc(Nc4ccc(S(=O)(=O)CCCN5CCCC5)cc4)nc3)c2)c1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 44.7 %

Procedure:
To a solution of intermediate 4 (Example 7) (290 mg, 1 mmol) in anhydrous CH2Cl2 (30 mL), 2-chloro-4,6-dimethoxy-1,3,5-triazine (210 mg, 1.2 mmol) and 4-methylmorpholine (300 mg, 3 mmol) were added. After the reaction mixture was stirred at room temperature for 75 minutes, intermediate 2 (Example 3) (100 mg, 0.3 mmol) in anhydrous DMF (2.5 mL) was added into the solution. The solution was stirred under argon for overnight. The residue was dissolved in CH2Cl2 (20 mL) and washed with aqueous saturated NaHCO3 solution (20 mL). The aqueous layer was extracted with CH2Cl2 (50 mL). The combined organic phase was dried (Na2SO4) and the solvent was removed. The crude product was purified by silica gel column with CHCl3 to 10% CH3OH/CHCl3 as eluents to give the final product as a white solid (85 mg, 13%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][C:10]([CH2:12][O:13][C:4]=2[CH:3]=1)=[O:11].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH:19]=O>>[CH3:14][O:15][C:16]1[CH:17]=[C:18](/[CH:19]=[C:9]2/[C:10](=[O:11])/[C:12](=[CH:1]/[C:2]3[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:13][CH3:12])[CH:3]=3)/[O:13][C:4]3[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=3[O:8]/2)[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: COc1ccc(C=O)cc1OC
Reactant: Cc1ccc2c(c1)OCC(=O)CO2
Product: COc1ccc(/C=C2\Oc3ccc(C)cc3O/C(=C\c3ccc(OC)c(OC)c3)C2=O)cc1OC

Procedure:
Calone is reacted with 3,4-dimethoxybenzaldehyde analogously to the reaction conditions of Example 1, giving 2,4-bis[1-(3,4-dimethoxyphenyl)-meth-(Z)-ylidene]-7-methylbenzo[b]-1,4-dioxepin-3-one.
Reaction SMILES: [N:1]1[NH:2][C:3]2[CH:4]=[CH:5][C:6]([CH2:18][OH:19])=[C:7]3[CH2:13][CH2:12][C:11]4[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=4[C:9]=1[C:8]=23>[O-2].[O-2].[Mn+4]>[N:1]1[NH:2][C:17]2[CH:16]=[CH:15][CH:14]=[C:11]3[CH2:12][CH2:13][C:7]4=[C:6]([CH:18]=[O:19])[CH:5]=[CH:4][CH:3]=[C:8]4[C:9]=1[C:10]=23
Reactant: OCc1ccc2[nH]nc3c2c1CCc1ccccc1-3
Agent: [Mn+4]
Agent: [O-2]
Product: O=Cc1cccc2c1CCc1cccc3[nH]nc-2c13
Yield: 100.8 %

Procedure:
210 mg of 6,7-dihydro-2H-benzo[6,7]cyclohepta[cd]indazol-8-ylmethanol obtained in Example 1-h was treated by the procedure of Example 1-f using 500 mg of manganese dioxide, to give 210 mg of the title compound as a colorless powder.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]2[N:16]([CH:17]=1)[CH2:15][CH2:14][O:13][C:12]1[C:7]2=[CH:8][C:9]([C:19]#[C:20][C:21]([OH:27])([CH3:26])[C:22](OC)=[O:23])=[C:10]([F:18])[CH:11]=1)(=[O:3])[NH2:2].[NH3:28].CO>>[C:22]([C:21]([OH:27])([CH3:26])[C:20]#[C:19][C:9]1[C:10]([F:18])=[CH:11][C:12]2[O:13][CH2:14][CH2:15][N:16]3[C:6](=[N:5][C:4]([C:1]([NH2:2])=[O:3])=[CH:17]3)[C:7]=2[CH:8]=1)(=[O:23])[NH2:28]
Reactant: COC(=O)C(C)(O)C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2
Reactant: N
Solvent: CO
Product: CC(O)(C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2)C(N)=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of methyl 4-[4-carbamoyl-12-fluoro-9-oxa-3,6-diazatricyclo[8.4.0.0[2,6]]tetradeca-1(14),2,4,10,12-pentaen-13-yl]-2-hydroxy-2-methylbut-3-ynoate (300 mg, 0.80 mmol, 1.00 equiv) in NH3/MeOH (30 w/w %, 40 mL). The resulting solution was stirred for 12 h at 25° C. The resulting mixture was concentrated under vacuum. The resulting mixture was washed with 3×10 mL of methanol and 2×5 mL of CH3CN. The trace solvents were removed under reduced pressure. This resulted in 43 mg (15%) of 9-(3-Carbamoyl-3-hydroxy-but-1-ynyl)-8-fluoro-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid amide as a brown solid. LC-MS: (ES, m/z): 359[M+H]+; 1H-NMR: (400 MHz, DMSO-d6, ppm): δ 8.579 (d, 1H), 7.786 (s, 1H), 7.589 (br s, 1H), 7.378 (br s, 2H), 7.128 (br s, 1H), 7.029 (d, 1H), 6.423 (s, 1H), 4.600-4.410 (m, 4H), 1.612 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[CH:14]([NH:17][NH:18][C:19]([C:21]1[CH:25]=[CH:24][S:23][CH:22]=1)=[O:20])([CH3:16])[CH3:15].C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([N:17]([CH:14]([CH3:16])[CH3:15])[NH:18][C:19]([C:21]1[CH:25]=[CH:24][S:23][CH:22]=1)=[O:20])=[O:8]
Reactant: O=C(O)COc1ccc(F)cc1Br
Reactant: CC(C)NNC(=O)c1ccsc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N(NC(=O)c1ccsc1)C(=O)COc1ccc(F)cc1Br
Yield: 66.4 %

Procedure:
A solution of (2-bromo-4-fluoro-phenoxy)-acetic acid (226 mg, 0.91 mmol) and thiophene-3-carboxylic acid N′-isopropyl-hydrazide (200 mg, 1.09 mmol) in DMF (5 ml) was treated with diisopropylethyl amine (0.40 mL, 2.28 mmol) and PyBroP (636 mg, 1.37 mmol) at room temperature overnight. The reaction mixture was partitioned between 1N HCl and ethyl acetate. The organic layer was washed with brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 30-50% ethyl acetate/hexanes gradient to afford the product as a solid (251 mg, 66%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])=[CH:5][C:4]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[N:3]1.[H-].[Na+].I[CH2:22][CH3:23].O>CN(C=O)C.C(OCC)(=O)C>[CH2:22]([N:7]([C:6]1[N:2]([CH3:1])[N:3]=[C:4]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:5]=1)[C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])[CH3:23]
Reactant: CC(C)C(=O)Nc1cc(-c2cccnc2)nn1C
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCN(C(=O)C(C)C)c1cc(-c2cccnc2)nn1C
Reaction time: 0.5 h
Yield: 30.6 %

Procedure:
To a solution of N-(1-methyl-3-(pyridine-3-yl)-1H-pyrazol-5-yl)isobutyramide (0.08 g, 0.33 mmol) in DMF (0.66 ml) at 0° C. was added sodium hydride (0.016 g, 0.39 mmol, 60% dispersion in mineral oil) in one portion and the suspension was stirred for 30 minutes. The ice bath was removed and stirred for an additional 30 minutes. Iodoethane (0.06 g, 0.39 mmol) was added in one portion and stirred overnight at room temperature. Water and ethyl acetate were added and the resulting biphasic mixture was separated. The aqueous layer was extracted one time with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated to dryness. The crude product was purified by silica gel chromatography to give the title compound as a clear oil (27.5 mg, 30%): 1H NMR (300 MHz, CDCl3) δ 9.00 (bs, 1H), 8.57 (s, 1H), 8.09 (dd, J=7.9 Hz, 1H), 7.34 (dd, 1H), 6.48 (s, 1H), 4.00 (m, 1H), 3.76 (s, 3H), 3.36 (m, 1H), 2.33 (m, 1H), 1.17 (t, J=7.1 Hz, 3H), 1.08 (t, J=6.7 Hz, 6H); ESIMS m/z 273 (M+H).
Reaction SMILES: S([O:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])(C(F)(F)F)(=O)=O.[F:16][C:17]1[CH:18]=[C:19](/[CH:24]=[CH:25]/[C:26]([O:28][CH3:29])=[O:27])[CH:20]=[CH:21][C:22]=1O.C(N(C(C)C)CC)(C)C.Cl>ClCCl.O>[F:16][C:17]1[CH:18]=[C:19](/[CH:24]=[CH:25]/[C:26]([O:28][CH3:29])=[O:27])[CH:20]=[CH:21][C:22]=1[O:8][S:9]([C:12]([F:13])([F:14])[F:15])(=[O:10])=[O:11]
Reactant: COC(=O)/C=C/c1ccc(O)c(F)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)/C=C/c1ccc(OS(=O)(=O)C(F)(F)F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102 %

Procedure:
1.40 mL (8.3 mmol, 1.1 eq) of triflic anhydride are added to a solution of 1.47 g (7.5 mmol, 1 eq) of methyl (E)-3-(3-fluoro-4-hydroxyphenyl)acrylate and 1.57 mL (9.0 mmol, 1.2 eq) of diisopropylethylamine in 10 mL of dichloromethane. The reaction mixture is stirred at room temperature overnight. The reaction medium is hydrolyzed in water, acidified with 1N hydrochloric acid solution and extracted with ethyl acetate. The organic phases are combined, washed with water and dried over sodium sulfate. The solvent is evaporated off and 2.51 g of methyl (E)-3-(3-fluoro-4-trifluoromethanesulfonyloxyphenyl)acrylate are obtained in the form of a brown oil. Yield=100%
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH3:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[CH:11][CH:10]=1.C(N(CC)CC)C>CN(C)C=O>[CH3:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][N:5]2[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)=[CH:11][CH:10]=1
Reactant: Cc1ccc(CBr)cc1
Reactant: OC1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(CN2CCC(O)CC2)cc1
Reaction time: 18 h
Yield: 482.9 %

Procedure:
1.15 g (0.00114 mol) of 4-hydroxypiperidine were dissolved in 15 ml of dimethylformamide and cooled to 0°. 1.92 g (0.001037 mol) of 4-methylbenzyl bromide and 1.59 ml (0.0114 mol) of triethylamine were added under argon and the mixture was left to come to room temperature. It was stirred for 18 hrs., the solvent was distilled off and the residue was taken up in ethyl acetate. The organic phase was washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated and the residue was chromatographed on silica gel with dichloromethane/methanol (9:1) as the eluent. 1.028 g (48%) of 1-(4-methyl-benzyl)-piperidin-4-ol were obtained as beige crystals; m.p. 72°-74°.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][C:16]([O:18]CC)=[O:17])=[CH:12][C:11]([F:21])=[CH:10][CH:9]=2)=[O:5])C.Br[CH2:23][C:24]1[C:25]2[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:26]=2[S:27][CH:28]=1>>[C:16]([CH2:15][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:21])[CH:12]=2)[N:7]([CH2:23][C:24]2[C:25]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:26]=3[S:27][CH:28]=2)[C:6]=1[C:4]([OH:3])=[O:5])([OH:18])=[O:17]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)[nH]c2ccc(F)cc12
Reactant: Fc1ccc2scc(CBr)c2c1
Product: O=C(O)Cc1c(C(=O)O)n(Cc2csc3ccc(F)cc23)c2ccc(F)cc12

Procedure:
Using general procedure B, 3-ethoxycarbonylmethyl-5-fluoro-1H-indole-2-carboxylic acid ethyl ester (Lit. 10) was coupled with 3-bromomethyl-5-fluoro-benzo[b]thiophene (Lit. 18) and the product obtained was hydrolyzed to give the title compound as a white solid. MS: 400.3 ([M−H]−).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C@H:13]([OH:31])[CH2:14][C@H:15]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:16]([O:18]C(C)(C)C)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.C(N(CC)CC)C>ClCCl.FC(F)(F)C(O)=O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH2:12][C@H:13]1[CH2:14][C@H:15]([NH:23][C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[C:16](=[O:18])[O:31]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](C[C@@H](O)CNC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1C[C@H](CNC(=O)OCc2ccccc2)OC1=O
Temperature: 0 °C
Reaction time: 15 h

Procedure:
A solution of 7.60 g (17.3 mmol) of tert-butyl 5-benzyloxycarbonylamino-2(S)-tert-butoxycarbonylamino-4(R)-hydroxypentanoate (Org. Lett. (2001) 3, 20:3153-3155) in 516 ml of dichloromethane and 516 ml of trifluoroacetic acid is stirred at RT for 2 h. The solvent is evaporated. The remaining crude product is dissolved in 2.6 l of anhydrous methanol and, while stirring at 0° C., 6.3 g (28.8 mmol) of di-tert-butyl dicarbonate and 7.3 ml (52.43 mmol) of triethylamine are added. After 15 h, the reaction solution is evaporated and the residue is taken up in 1 l of ethyl acetate. After the phases have separated, the organic phase is extracted twice with a 5% citric acid solution, twice with water and once with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated. The crude product is purified by chromatography on silica gel with toluene/acetone (5/1). 4.92 g (78% of theory) of product are obtained.
Reaction SMILES: [F:1][C:2]([F:13])([C:6]1[N:11]=[CH:10][C:9]([F:12])=[CH:8][N:7]=1)[C:3]([O-:5])=O.[Na+].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:39][C:40]1[CH:48]=[CH:47][CH:46]=[CH:45][C:41]=1[C:42]([NH2:44])=[O:43].CN(C=O)C>CCOC(C)=O>[F:13][C:2]([F:1])([C:6]1[N:11]=[CH:10][C:9]([F:12])=[CH:8][N:7]=1)[C:3]([NH:39][C:40]1[CH:48]=[CH:47][CH:46]=[CH:45][C:41]=1[C:42]([NH2:44])=[O:43])=[O:5]
Reactant: NC(=O)c1ccccc1N
Reactant: O=C([O-])C(F)(F)c1ncc(F)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC(=O)c1ccccc1NC(=O)C(F)(F)c1ncc(F)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.5 %

Procedure:
To sodium 2,2-difluoro-2-(5-fluoropyrimidin-2-yl)acetate (400 mg, 1.87 mmol), HATU (850 mg, 2.24 mmol), and 2-aminobenzamide (305 mg, 2.24 mmol) was added DMF (7 mL) and the mixture was stirred at rt overnight. The mixture was diluted with EtOAc and washed with saturated aq NH4Cl, saturated aq NaHCO3, and brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-12% MeOH/DCM to afford 2-(2,2-difluoro-2-(5-fluoropyrimidin-2-yl)acetamido)benzamide (374 mg, 44%); LC-MS (ESI) m/z 333 (M+Na)+.