Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC(C(F)(F)F)=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][CH:17]=[C:18]([CH2:20][N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:19]=2)=[CH:11][CH:10]=1.[F:27][C:28]([F:44])([F:43])[C:29]1[O:33][N:32]=[C:31]([C:34]2[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=2)[C:37](O)=[O:38])[N:30]=1>>[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][CH:17]=[C:18]([CH2:20][N:21]3[CH2:22][CH2:23][N:24]([C:37]([C:36]4[CH:40]=[CH:41][CH:42]=[C:34]([C:31]5[N:30]=[C:29]([C:28]([F:43])([F:27])[F:44])[O:33][N:32]=5)[CH:35]=4)=[O:38])[CH2:25][CH2:26]3)[N:19]=2)=[CH:11][CH:10]=1
Reactant: Fc1ccc(-c2nc(CN3CCNCC3)co2)cc1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cccc(-c2noc(C(F)(F)F)n2)c1)N1CCN(Cc2coc(-c3ccc(F)cc3)n2)CC1
Yield: 14 %

Procedure:
This compound was synthesized from 2-(4-fluorophenyl)-4-(piperazin-1-ylmethyl)oxazole TFA salt and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described for example 37 step 3 (34 mg, yield 14%). 1H NMR (400 MHz, CDCl3) δ 8.19-8.17 (m, 2H), 8.06-8.03 (dd, J=8.7 Hz, 5.1 Hz, 2H), 7.63-7.57 (m, 3H), 7.17-7.12 (t, J=8.7 Hz, 2H), 3.87 (m, 2H), 3.59 (s, 2H), 3.50 (m, 2H), 2.68 (m, 2H), 2.54 (m, 2H). MS (ESI) m/z: Calculated for C24H19F4N6O3: 501.14. found: 502.1 (M+H)+
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH2:4]O.[C:7]([O-:13])([O-])([O:9][CH2:10][CH3:11])[CH3:8]>P(=O)(O)(O)O>[CH3:1][C:2]([CH3:6])([CH:3]=[CH2:4])[CH2:8][C:7]([O:9][CH2:10][CH3:11])=[O:13]
Reactant: CC(C)=CCO
Reactant: CCOC(C)([O-])[O-]
Agent: O=P(O)(O)O
Product: C=CC(C)(C)CC(=O)OCC
Yield: 78.9 %

Procedure:
A mixture of 4.3 g of 3-methyl-2-buten-1-ol, 16.2 g of ethyl orthoacetate and 3 drops of phosphoric acid was reacted as described in Example V A to give 6.15 g (79% yield) of ethyl 3,3-dimethyl-4-pentenoate, b.p. 87°-88°/58 mm.
Reaction SMILES: [C:1]([NH:18][C@H:19]([C:26]([OH:28])=O)[CH2:20][O:21][C:22]([CH3:25])([CH3:24])[CH3:23])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:37]>ClCCl>[C:1]([NH:18][C@H:19]([C:26]([F:37])=[O:28])[CH2:20][O:21][C:22]([CH3:25])([CH3:24])[CH3:23])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2]
Reactant: Fc1nc(F)nc(F)n1
Reactant: CC(C)(C)OC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)F
Temperature: 0 °C
Reaction time: 8 h

Procedure:
N-FMOC-O-t-Butyl-L-serine (10 g, 26.07 mmol) (Bachem) was dissolved in dichloromethane (135 mL). Pyridine (2.11 mL, 26.07 mmol) (Aldrich) and cyanuric fluoride (3.52 g, 26.07 mmol) (Aldrich) were successively added at room temperature and the mixture was stirred overnight. Ice cold water (100 mL) was added and the resulting slurry was filtered. The filtrate was poured into a separatory funnel and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford N-FMOC-O-t-butyl-L-serinyl fluoride as a colorless oil which solidified upon standing. (Yield 9.79 g., 97%).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]([F:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:13]B(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[F:12][C:9]1[CH:10]=[N:11][C:2]([CH3:13])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(F)cnc1Cl
Reactant: CB(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1cc(F)cnc1C
Temperature: 110 °C
Yield: 70 %

Procedure:
A mixture of methyl 2-chloro-5-fluoronicotinate (step 1, 1.5 g, 7.91 mmol), tetrakis(triphenylphoshine)palladium (914 mg, 0.79 mmol), methyboronic acid (521 mg, 8.70 mmol) and potassium carbonate (3.28 g, 23.7 mmol) in 1,4-dioxane (20 ml) was heated at 110° C. for 20 h under nitrogen atmosphere. The reaction mixture was filtered through a pad of celite (Celite(trademark) (diatomaceous earth)) and the filtrate was concentrated. The residue was purified by flush column chromatography on silica gel eluting with hexane/ethyl acetate (20/1 to 4/1) to afford 936 mg (64%) of the title compound:
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28](Cl)[N:29]=4)[N:24]=[CH:23][C:22]=3[C:32](=[O:35])[CH2:33][CH3:34])=[CH:16][N:15]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:37][C:38]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[C:40]([Cl:53])[C:39]=1[OH:54]>>[C:1]([O:5][C:6](=[O:36])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:42]5[CH:43]=[C:38]([Cl:37])[C:39]([OH:54])=[C:40]([Cl:53])[CH:41]=5)[N:29]=4)[N:24]=[CH:23][C:22]=3[C:32](=[O:35])[CH2:33][CH3:34])=[CH:16][N:15]=2)[CH2:9]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CCC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: CCC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)nc2c1Nc1ccc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc1
Yield: 46.1 %

Procedure:
Following general procedure II, (R)-tert-butyl(1-(5-((6-chloro-3-propionyl-1,5-naphthyridin-4-yl)amino)pyridin-2-yl)piperidin-3-yl)carbamate (175 mg, 0.34 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (149 mg, 0.51 mmol) to afford the desired product (100 mg, 46%) as a solid: ESI MS m/z 637 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:20])[NH:5][C:6](=[O:19])[NH:7][C:8]=1[C:9](=[O:18])[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[Br:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([Br:30])[CH:29]=1)[CH2:25]Br>>[Br:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([Br:30])[CH:29]=1)[CH2:25][N:7]1[C:8]([C:9](=[O:18])[C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:20])[NH:5][C:6]1=[O:19]
Reactant: BrCc1cc(Br)cc(Br)c1
Reactant: CCc1c(C(=O)c2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(C(=O)c2cc(C)cc(C)c2)n(Cc2cc(Br)cc(Br)c2)c(=O)[nH]c1=O
Yield: 74.4 %

Procedure:
5-Ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 3,5-dibromobenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (387 mg, yield: 74.4%).
Reaction SMILES: [NH2:1][C:2]1[C:9]([Br:10])=[CH:8][C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:3]=1[CH:4]=[O:5].[NH2:15][C:16](N)=[O:17]>O>[Br:10][C:9]1[CH:8]=[C:7]([C:11]([F:14])([F:12])[F:13])[CH:6]=[C:3]2[C:2]=1[NH:1][C:16]([OH:17])=[N:15][CH:4]2[OH:5]
Reactant: Nc1c(Br)cc(C(F)(F)F)cc1C=O
Reactant: NC(N)=O
Solvent: O
Product: OC1=NC(O)c2cc(C(F)(F)F)cc(Br)c2N1
Yield: 187.7 %

Procedure:
2-Amino-3-bromo-5-(trifluoromethyl)benzaldehyde (1.74 g, 6.49 mmol, 1.00 eq) and urea (5.85 g, 97.4 mmol, 15.0 eq) were stirred at 190° C. for 3 h. The resulting solid was returned to ambient temperature, stirred in water (60 mL) for 20 min, and filtered. This was repeated for a total of three washes. The solid was dried in a desiccator to give 3.79 g of the desired product as an off-white solid. ES/MS m/z 311, 313 (MH+).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[CH3:22][C:23]1[CH:32]=[C:31]([CH2:33][O:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]3([N:50]4[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]4)[C:46](=[O:47])[NH:45][C:44](=[O:48])[NH:43][C:42]3=[O:49])=[CH:37][CH:36]=2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1.[C:56]1([CH2:62][CH2:63][CH:64]=O)[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[CH3:22][C:23]1[CH:32]=[C:31]([CH2:33][O:34][C:35]2[CH:36]=[CH:37][C:38]([C:41]3([N:50]4[CH2:55][CH2:54][N:53]([CH2:64][CH2:63][CH2:62][C:56]5[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=5)[CH2:52][CH2:51]4)[C:46](=[O:47])[NH:45][C:44](=[O:48])[NH:43][C:42]3=[O:49])=[CH:39][CH:40]=2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1
Reactant: O=CCCc1ccccc1
Reactant: Cc1cc(COc2ccc(C3(N4CCNCC4)C(=O)NC(=O)NC3=O)cc2)c2ccccc2n1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(COc2ccc(C3(N4CCN(CCCc5ccccc5)CC4)C(=O)NC(=O)NC3=O)cc2)c2ccccc2n1
Yield: 69.6 %

Procedure:
Using a procedure analogous to Example 15, the product from example 14 (100 mg, 0.125 mmol) was treated with 3-phenylpropionaldehyde (25.1 mg, 1.5 eq) to provide the title barbituric acid (80.0 mg, 70%). MS found: (M+H)+=578.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[OH:5][C:6]1[C:10](=[C:11]([O:18][CH3:19])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:9][C:8](=[O:20])[CH:7]=1>C(O)(=O)C>[CH3:19][O:18][C:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:10]1[NH:9][C:8](=[O:20])[C:7](=[N:1][OH:3])[C:6]1=[O:5]
Reactant: O=N[O-]
Reactant: COC(=C1NC(=O)C=C1O)c1ccccc1
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=C1NC(=O)C(=NO)C1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
An aqueous solution of 1.1 mmol (0.075 g) sodium nitrite was added dropwise to an ice-cooled solution of 2 mmol 4-hydroxy-5-(methoxyphenyl-methylene)-1,5-dihydropyrrol-2-one (prepared in accordance with H. Poschenrieder et al (Arch. Pharm. Pharm. Med. Chem. 1998, 331, 389-394) and H. -D. Stachel et al (J. Heterocycl. Chem. 1980, vol. 17, pp. 1195-1199 and Liebigs Ann. Chem. 1985, pp. 1692-1696)) in 5 ml glacial acetic acid, while stirring. The resulting solution was then stirred at room temperature for 30 minutes and concentrated in vacuo. The residue is purified by recrystallization from ethanol. The yield of 5-(methoxyphenylmethylene)-pyrrolidine-2,3,4-trione 3-oxime was 60%, with a melting point of 174° C.
Reaction SMILES: [CH3:1][S:2][CH3:3].[F:4][C:5]([F:14])([F:13])[C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1[NH2:8].ClN1C(=O)CCC1=O.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2][CH2:3][C:9]1[CH:10]=[CH:11][CH:12]=[C:6]([C:5]([F:4])([F:14])[F:13])[C:7]=1[NH2:8]
Reactant: Nc1ccccc1C(F)(F)F
Reactant: CSC
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSCc1cccc(C(F)(F)F)c1N
Temperature: 15 °C
Reaction time: 0.25 h

Procedure:
Dimethylsulfide, 16 ml, was syringed all at once into a solution of 25.0 grams (g) of 2-(trifluoromethyl)aniline in 400 milliliters (ml) of methylene chloride. The reaction solution was cooled to 15° C. and 29.0 g of N-chlorosuccinimide was added in small portions over a 20 minute period at such a rate that the reaction temperature did not exceed 20° C. The reaction mixture was stirred at 15° C. for 15 minutes, then 30.4 ml of triethylamine was added dropwise over 15 minutes at such a rate that the temperature did not exceed 15° C. After an additional five minutes of stirring, the reaction was refluxed overnight, allowed to cool to room temperature, washed with two 200 ml portions of 10% sodium hydroxide, the organic phase separated, dried with magnesium sulfate and filtered. The remainder of the solvent was distilled off to yield 35.8 g of the crude desired product which was used without any additional purification in subsequent reactions.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[Cl:24][C:25]1[C:26]([CH3:34])=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](O)=[O:29]>>[Cl:24][C:25]1[C:26]([CH3:34])=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28]([NH:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2)=[O:29]
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: Cc1c(Cl)cccc1C(=O)O
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc(Cl)c2C)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 3-Chloro-2-methyl-benzoic acid. LC-MS (basic): tR=0.95 min; [M+H]+=480.0.
Reaction SMILES: [CH3:1][C:2]([C:7]1[N:8]=[C:9]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]3[NH:18][N:19]=[CH:20][C:13]=23)[S:10][CH:11]=1)([CH2:5]C)[C:3]#[N:4].[OH-].[Na+].[Cl:23][O-].[Na+]>O.C([O-])([O-])=O.[Na+].[Na+]>[Cl:23][C:20]1[C:13]2[C:14](=[N:15][CH:16]=[CH:17][C:12]=2[C:9]2[S:10][CH:11]=[C:7]([C:2]([CH3:5])([CH3:1])[C:3]#[N:4])[N:8]=2)[NH:18][N:19]=1
Reactant: CCC(C)(C#N)c1csc(-c2ccnc3[nH]ncc23)n1
Reactant: [O-]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C#N)c1csc(-c2ccnc3[nH]nc(Cl)c23)n1
Yield: 4.4 %

Procedure:
2-methyl-2-[2-(1H-pyrazolo[3,4-b]pyridin-4-yl)thiazol-4-yl]butanenitrile (82 mg, 0.2894 mmol) was suspended in a solution of NaOH (46.32 mg, 1.158 mmol) in Water (5.000 mL). The mixture was sonicated to give smaller particle size and cooled in an ice-bath. Sodium hypochlorite (282.8 μL of 8% w/v, 0.3039 mmol) was added slowly dropwise over 2 minutes and the resultant mixture was stirred at ambient temperature for 3 hours. The reaction was diluted with saturated aqueous Na2CO3 and then extracted twice with EtOAc. The combined organics were dried (MgSO4), filtered, concentrated and purified by column chromatography (1:1, Petroleum ether/EtOAc) to give the pure compound as a white solid (3.9 mg, 4% Yield). 1H NMR (DMSO, 400 MHz) δ 0.93 (3H, t), 1.76 (3H, s), 1.99-2.21 (2H, m), 7.54 (1H, s), 8.00 (1H, s), 8.71 (1H, s), 14.29 (1H, br s); MS (ES+) 318.08
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[F:18][C:19]1[CH:24]=[C:23](B(O)O)[CH:22]=[CH:21][N:20]=1>>[Cl:17][C:4]1[CH:3]=[C:2]([C:23]2[CH:22]=[CH:21][N:20]=[C:19]([F:18])[CH:24]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Reactant: OB(O)c1ccnc(F)c1
Product: Cc1c2n(c3c(-c4ccnc(F)c4)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, off-white solid (67 mg, 81%), MS (ISP) m/z=330.5 [(M+H)+], mp 290.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available 2-fluoro-pyridin-4-ylboronic acid (45.8 mg, 0.325 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:10][C:11](=O)[C:12]2[N:13]([N:15]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:17]=2)[CH:14]=1.C(=O)(O)[O-].[Na+].P(Cl)(Cl)([Cl:31])=O>>[Cl:31][C:11]1[C:12]2[N:13]([N:15]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:17]=2)[CH:14]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cc2c(=O)[nH]c(-c3ccc(Cl)cc3Cl)cn2n1
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)c1cc2c(Cl)nc(-c3ccc(Cl)cc3Cl)cn2n1

Procedure:
6.86 g (19.5 mmol) of ethyl 6-(2,4-dichlorophenyl)-4-oxo-4,5-dihydropyrazolo[1,5-a]pyrazine-2-carboxylate (Example 11A) were dissolved in 50 ml of phosphoryl chloride and stirred at reflux for 12 h. The reaction mixture was poured into 1.25 l of saturated sodium bicarbonate solution, and solid sodium bicarbonate was added until a pH of 7 had been reached. The solid was filtered off and dissolved in dichloromethane and chromatographed on silica gel (mobile phase cyclohexane/ethyl acetate 10:1). This gave 6.34 g (85% of theory) of the product as a solid.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][C:7]([S:11]([N:14](CC3C=CC(OC)=CC=3OC)[C:15]3[S:19][N:18]=[CH:17][N:16]=3)(=[O:13])=[O:12])=[CH:8][CH:9]=2)[N:4]([CH3:31])[CH:3]=1.[CH3:32][N:33]1[C:37]([C:38]2[CH:43]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:41]=[CH:40][C:39]=2B(O)O)=[CH:36][CH:35]=[N:34]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(Cl)(=O)C>>[CH3:31][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([S:11]([NH:14][C:15]3[S:19][N:18]=[CH:17][N:16]=3)(=[O:12])=[O:13])[CH:6]=2)[C:2]([C:39]2[CH:40]=[CH:41][C:42]([C:44]([F:47])([F:45])[F:46])=[CH:43][C:38]=2[C:37]2[N:33]([CH3:32])[N:34]=[CH:35][CH:36]=2)=[CH:3]1
Reactant: Cn1nccc1-c1cc(C(F)(F)F)ccc1B(O)O
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Br)cn(C)c3c2)c(OC)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(=O)Cl
Product: Cn1nccc1-c1cc(C(F)(F)F)ccc1-c1cn(C)c2cc(S(=O)(=O)Nc3ncns3)ccc12
Temperature: 90 °C
Reaction time: 2 h
Yield: 73.9 %

Procedure:
A microwave vial was charged with 3-bromo-N-(2,4-dimethoxybenzyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide (Intermediate D) (48.17 mg, 0.092 mmol), (2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)boronic acid (Intermediate G) (32.3 mg, 0.120 mmol), potassium phosphate (58.6 mg, 0.276 mmol), and Pd(AmPhos)2Cl2 (3.26 mg, 4.60 μmol). The vial was flushed with Ar, then 1,4-dioxane (0.4 mL) and water (0.125 mL) were added in sequence. The vial was sealed and heated in a microwave reactor at 90° C. for 20 min. The mixture was diluted with water, then extracted with EtOAc (3×). The combined organic extracts were concentrated. The residue was taken up in MeOH (1 mL), and cooled in an ice bath for 5 min. Acetyl chloride (65.4 μl, 0.920 mmol) was added dropwise, and the resulting mixture was stirred for 2 h. The mixture was concentrated under vacuum to remove excess HCl, and the residue was taken up in 2N ammonia in methanol. The resulting mixture was again concentrated under vacuum. The crude product was purified by chromatography on silica gel (0 to 10% MeOH/DCM) to give 1-methyl-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide (35.38 mg, 0.068 mmol, 74.1% yield) as a light-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=8.37 (s, 1 H), 7.97-7.83 (m, 3 H), 7.77 (d, J=1.9 Hz, 1 H), 7.60-7.53 (m, 1 H), 7.47-7.36 (m, 2 H), 7.17 (s, 1 H), 6.35 (d, J=1.9 Hz, 1 H), 3.81 (s, 3 H), 3.22 (s, 3 H). m/z (ESI) 519.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([CH:19]=[N:20][OH:21])[C:3]=1[S:22]([CH3:24])=[O:23].[O-]CC.[Na+].[C:29](#[N:32])[CH:30]=[CH2:31]>C(O)C>[C:29]([CH2:30][CH2:31][O:21][N:20]=[CH:19][C:4]1[C:3]([S:22]([CH3:24])=[O:23])=[C:2]([NH2:1])[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=1)#[N:32]
Reactant: CS(=O)c1c(C=NO)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Reactant: C=CC#N
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CS(=O)c1c(C=NOCCC#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N

Procedure:
In a manner similar to that employed in Example 12 an ethanol solution of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboxaldehyde oxime was reacted with sodium ethoxide and acrylonitrile to give 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboxaldehyde O-(2-cyanoethyl)oxime. Compound 28, as the 85 percent (by weight) component of a mixture containing 8 percent of the oxime starting material. Mass spectrometric analysis of the product indicated the following: MS m/e=453 (M+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10][CH3:11])=[N:7][C:6]=2[CH:12]=1.C1C=C(Cl)C=C(C(OO)=[O:21])C=1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([CH3:11])=[O:21])=[N:7][C:6]=2[CH:12]=1
Reactant: CSc1nc2cc(F)ccc2s1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1nc2cc(F)ccc2s1
Temperature: 25 °C
Yield: 93.6 %

Procedure:
5-Fluoro-2-(methylthio)benzo[d]thiazole (example 40A, 0.178 g, 0.893 mmol) was dissolved in CH2Cl2 (5.96 mL). mCPBA (0.154 g, 0.893 mmol) was added in one portion and the reaction mixture was stirred at room temperature. The reaction was quenched with saturated aqueous sodium bicarbonate and diluted with dichloromethane. The aqueous layer was extracted with dichloromethane (2×). The combined organic were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. 5-Fluoro-2-(methylsulfinyl)benzo[d]thiazole (0.180 g, 94% yield) was isolated as a white solid and used without further purification.
Reaction SMILES: C([NH:8][C:9]1[C:10]([CH3:26])=[C:11]([CH3:25])[C:12]2[O:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:13]=2[C:23]=1[CH3:24])C1C=CC=CC=1>C(OCC)(=O)C.CCCCCC>[CH3:24][C:23]1[C:13]2[CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15][O:16][C:12]=2[C:11]([CH3:25])=[C:10]([CH3:26])[C:9]=1[NH2:8]
Reactant: Cc1c(C)c2c(c(C)c1NCc1ccccc1)C(c1ccccc1)CO2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(C)c2c(c(C)c1N)C(c1ccccc1)CO2
Yield: 72 %

Procedure:
Using N-benzyl-4,6,7-trimethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-amine obtained in Reference Example 276, the title compound was synthesized in the same manner as in Reference Example 30. Yield 72%. Melting point: 94-95° C. (ethyl acetate-hexane).
Reaction SMILES: [C:1]([O:6][C@@H:7]1[C@@H:15]([CH2:16][CH2:17][OH:18])[C:14](=[O:19])[O:13][CH2:12][C@H:11]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:10](=[O:28])[O:9][C@H:8]1[CH3:29])(=[O:5])[CH:2]([CH3:4])[CH3:3].N1C=CC=CC=1.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[C:1]([O:6][C@@H:7]1[C@@H:15]([CH2:16][CH2:17][O:18][S:37]([CH3:36])(=[O:39])=[O:38])[C:14](=[O:19])[O:13][CH2:12][C@H:11]([NH:20][C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[C:10](=[O:28])[O:9][C@H:8]1[CH3:29])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)C(=O)O[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC(=O)[C@@H]1CCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)C(=O)O[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC(=O)[C@@H]1CCOS(C)(=O)=O
Temperature: 22 °C
Reaction time: 8 h
Yield: 84.3 %

Procedure:
To a solution of (3S,6S,7R,8R)-3-(tert-butoxycarbonylamino)-8-(2-hydroxyethyl)-6-methyl-4,9-dioxo-1,5-dioxonan-7-yl isobutyrate (660 mg, 1.58 mmol) in CH2Cl2 (15 mL) at 0° C. was added pyridine (750 mg, 9.48 mmol), followed by methanesulfonyl chloride (362 mg, 3.16 mmol). The resulting reaction mixture was warmed up to room temperature (about 22° C.) and stirred overnight. The reaction mixture was partitioned between sat'd aqueous NaHCO3 solution (30 mL) and EtOAc (40 mL) and the phases were separated. The aqueous phase was extracted with additional EtOAc (2×30 mL) and the combined EtOAc extracts were dried over Na2SO4, filtered, and concentrated to dryness. The crude residue was purified via column chromatography (SiO2, hexanes/EtOAc gradient) to afford the title compound (660 mg, 84%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 5.24 (s, 2H), 5.06 (t, J=9.8 Hz, 1H), 4.95-4.77 (m, 2H), 4.32-4.19 (m, 1H), 4.13-4.05 (m, 1H), 3.62 (s, 1H), 2.98 (s, 3H), 2.78 (dd, J=14.9, 6.4 Hz, 1H), 2.62 (dt, J=13.9, 7.0 Hz, 1H), 2.25-2.08 (m, 1H), 1.83 (s, 1H), 1.47 (d, J=11.9 Hz, 9H), 1.28 (d, J=6.3 Hz, 3H), 1.21 (d, J=6.9 Hz, 6H); ESIMS m/z 496 ([M+H]+).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[S:7][CH:6]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)=[CH:16][CH:15]=2)[C:5]1=[O:27].[CH3:28][N:29]([CH3:34])[CH2:30][CH2:31][CH2:32]Cl.O>CN(C)C=O>[CH3:28][N:29]([CH3:34])[CH2:30][CH2:31][CH2:32][C:6]1([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)=[CH:18][CH:19]=2)[C:5](=[O:27])[N:4]([CH3:3])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[S:7]1
Reactant: CN(C)CCCCl
Reactant: CN1C(=O)C(c2ccc(OC3CCCCO3)cc2)Sc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCCC1(c2ccc(OC3CCCCO3)cc2)Sc2ccccc2N(C)C1=O
Reaction time: 0.5 h
Yield: 81 %

Procedure:
To a stirred suspension of 60% sodium hydride (3.1 g) in dimethylformamide (30 ml), 3,4-dihydro-4-methyl-3-oxo-2-[4-(tetrahydropyran-2-yloxy)phenyl]-2H-1,4-benzothiazine (25.0 g) dissolved in dimethylformamide (60 ml) is added under nitrogen atmosphere, and the mixture is stirred for 30 minutes. A solution of 3-dimethylaminopropyl chloride in dimethylformamide [prepared by mixing of 3-dimethylaminopropyl chloride hydrochloride (13.3 g) and triethylamine (11.8 ml) in dimethylformamide (50 ml) and followed by filtration to remove precipitate] is added to the reaction mixture, and the mixture is stirred for 1 hour at 65°-75° C. The mixture is poured into water and extracted with ethyl acetate. The organic layer is washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated in vacuo to give 25.1 g (81.0%) of the titled compound.