Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH:4](Br)[CH2:5][CH:6]([CH3:8])[CH3:7].[P:11]([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14]>>[P:11]([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14].[CH3:1][O:2][C:3](=[O:10])[CH:4]([P:11]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])=[O:18])[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)C(Br)CC(C)C
Agent: CCOP(OCC)OCC
Product: CCOP(=O)(OCC)C(CC(C)C)C(=O)OC
Temperature: 200 °C

Procedure:
2-Bromo-4-methyl-pentanoic acid methyl ester (193 g, 0.92M) and triethyl phosphite (330 ml, 1.84M) were heated to 150° C. The reaction temperature was increased to 200° C. over 6 h and a distillate b.p. 37°-60° C. (80 g) collected with an air condenser. The residue was distilled under high vacuum to afford 2 fractions (a) mainly triethyl phosphite b.p. 40°-80° C. at 0.4 mm Hg and (b) 4-methyl-2-(diethyl phosphono)pentanoic acid methyl ester (188 g) b.p. 96°-100° C. at 0.4 mm Hg (Found: C, 47.6; H,8.6.C11H23O5P+0.6H2O requires C, 47.7; H, 8.8%); δ(CDCl3) 0.9 (6H, dd,J=7 Hz, J=7 Hz, (CH3)2C); 1.04-2.10 (3H, m, CH2CH); 1.34 (6 H, t, J=7 Hz, (CH2CH3)2); 3.09 (1H, ddd, J=23 Hz, J=10 Hz, J=4 Hz, CHP); 3.73 (3H, s, CH3O); 4.14 (4H, m, (CH2CH3)2).
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([N:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)=[CH:16][C:15]3=[O:30])=[CH:11][CH:12]=2)[CH:7]=[N:6]1.[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1.[ClH:36]>O1CCCC1.ClCCl>[ClH:36].[OH:1][C@H:2]([CH2:3][N:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1)[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([N:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][CH:21]=4)=[CH:16][C:15]3=[O:30])=[CH:11][CH:12]=2)[CH:7]=[N:6]1
Reactant: C1CCNC1
Reactant: O=c1cc(-c2ccc(C(F)(F)F)cc2)ccn1-c1ccc2c(cnn2C[C@H]2CO2)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=c1cc(-c2ccc(C(F)(F)F)cc2)ccn1-c1ccc2c(cnn2C[C@H](O)CN2CCCC2)c1
Temperature: 45 °C
Yield: 83.1 %

Procedure:
To (S)-1-(1-(oxiran-2-ylmethyl)-1H-indazol-5-yl)-4-(4-(trifluoromethyl)phenyl)-pyridin-2(1H)-one (200 mg, 0.48 mmol) in tetrahydrofuran (5 mL) was added LiClO4 (775 mg, 7.28 mmol) followed by pyrrolidine (0.41 mL, 4.9 mmol). The reaction mixture was heated in a 45° C. oil bath for 4.5 h. The reaction mixture was cooled to ambient temperature, diluted with dichloromethane (50 ml), washed with water (25 mL) and brine (25 mL), dried (Na2SO4), and concentrated under reduced pressure. The material was purified by column chromatography (silica gel, 9:1 CH2Cl2/MeOH to 90:9:1 CH2Cl2/MeOH/conc. NH4OH). The dried residue (197 mg, 0.41 mmol) was dissolved in dichloromethane (10 mL) and HCl (1.25 M solution in methanol, 0.36 mL, 0.45 mmol) was added. The mixture was concentrated under reduced pressure and dried to afford the title compound (194 mg, 78%) as a yellow solid: mp 116-119° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.65 (br s, 1H), 8.21 (s, 1H), 8.02-8.00 (m, 2H), 7.89-7.82 (m, 5H), 7.47 (dd, J=9.0, 2.0 Hz, 1H), 6.89 (d, J=2.0 Hz, 1H), 6.74 (dd, J=7.0, 2.0 Hz, 1H), 5.75 (br s, 1H), 4.57-4.47 (m, 2H), 4.33 (br s, 1H), 3.56-2.90 (br m, 6H), 1.89 (br s, 4H); ESI MS m/z 483 [M+H]+; HPLC (Method B)>99% (AUC), tR=14.5 min; [α]23D +10.8° (c 0.11, Methanol).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([CH3:21])([CH3:20])[C:17]([OH:19])=O)=[CH:12][CH:11]=2)[CH:7]=[N:8][CH:9]=1.[CH2:22]([NH2:26])[CH:23]([CH3:25])[CH3:24]>>[CH2:22]([NH:26][C:17](=[O:19])[C:16]([C:13]1[CH:12]=[CH:11][C:10]([C:6]2[CH:7]=[N:8][CH:9]=[C:4]([CH2:3][O:2][CH3:1])[CH:5]=2)=[CH:15][CH:14]=1)([CH3:21])[CH3:20])[CH:23]([CH3:25])[CH3:24]
Reactant: COCc1cncc(-c2ccc(C(C)(C)C(=O)O)cc2)c1
Reactant: CC(C)CN
Product: COCc1cncc(-c2ccc(C(C)(C)C(=O)NCC(C)C)cc2)c1
Yield: 73 %

Procedure:
Prepared in a similar manner to example 3 from 2-(4-(5-(methoxymethyl)pyridine-3-yl)phenyl)-2-methylpropanoic acid (example 32a) and isobutylamine. Yield 73%. 1H NMR (400 MHz, DMSO): δ 0.72-0.74 (d, 6H), 1.46 (s, 6H), 1.68 (m, 1H), 2.83 (t, 2H), 3.32 (s, 3H), 4.5 (s, 2H), 7.36 (t, 1H), 7.39-7.42 (d, 2H), 7.66-7.68 (d, 2H), 7.95 (t, 1H), 8.48-8.49 (d,1H), 8.78-8.79 (d, 1H). MS (M+H, 341).
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[C:9]([O:12][CH3:13])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(N)(=O)C1C=CC=CC=1.Cl.[C:24](Cl)(=O)[C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1>>[CH3:13][O:12][C:9]1[C:10]([CH3:11])=[C:2]2[C:3]([C:4]([OH:5])=[N:6][C:24]([C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)=[N:1]2)=[CH:7][CH:8]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: COc1ccc(C(N)=O)c(N)c1C
Agent: Cl
Agent: NC(=O)c1ccccc1
Product: COc1ccc2c(O)nc(-c3ccncc3)nc2c1C
Yield: 60 %

Procedure:
The general procedure described in Example 10 was followed using 2-amino-4-methoxy-3-methyl benzamide as benzamide derivative and isonicotinoyl chloride hydrochloride as acid chloride, which gave the title compound (1.6 g, 60%), [M+H]=268.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([CH2:6][C:7](=[O:12])[NH:8]2)=[CH:4][CH:3]=1.[Cl:13][C:14]1[C:15]([F:22])=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O.N1CCCCC1>CO>[Cl:1][C:2]1[C:10]([F:11])=[C:9]2[C:5](/[C:6](=[CH:17]/[C:16]3[CH:19]=[CH:20][CH:21]=[C:14]([Cl:13])[C:15]=3[F:22])/[C:7](=[O:12])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(Cl)c1F
Reactant: O=C1Cc2ccc(Cl)c(F)c2N1
Solvent: CO
Solvent: C1CCNCC1
Product: O=C1Nc2c(ccc(Cl)c2F)/C1=C/c1cccc(Cl)c1F
Temperature: 50 °C
Yield: 72.8 %

Procedure:
To the mixture of 6-chloro-7-fluoroindolin-2-one (1.1 g, 5.9 mmol) (Natrochem) and 3-chloro-2-fluorobenzaldehyde (1.4 g, 8.9 mmol) (Aldrich) in methanol (50 mL) was added piperidine (1.5 g, 17.8 mmol) (Aldrich) dropwise. The mixture was then heated at 50° C. for 3 h. After cooled to room temperature, the mixture was concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, and aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over MgSO4, and concentrated to half its volume. The mixture was filtered and resulting precipitate was collected, dried to give the first batch of desired product (1.4 g). The filtrate was concentrated, and residue was purified by chromatography (20-40% EtOAc in hexanes) to give the second batch of desired product (0.44 g). The two batches were combined to give E/Z-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-7-fluoro-1,3-dihydro-indol-2-one as a yellow solid (Yield 1.84 g, 89%).
Reaction SMILES: [CH3:1]N(C)C=O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:17][CH2:16][CH:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14]2)=[CH:9][CH:8]=1.[H-].[Na+].CI>C(OCC)(=O)C>[F:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:17][CH2:16][CH:15]([N:18]([CH3:1])[C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:24])[CH3:23])[CH2:14]2)=[CH:11][CH:12]=1
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(F)cc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCOC(C)=O
Product: CN(C(=O)OC(C)(C)C)C1CCN(c2ccc(F)cc2)C1
Yield: 88 %

Procedure:
To an N,N-dimethylformamide solution (3.9 mL) of tert-butyl [1-(4-fluorophenyl)pyrrolidin-3-yl]carbamate (195 mg, 0.70 mmol) synthesized in Reference Synthesis Example 79, sodium hydride (28 mg, 0.70 mmol, purity 60%) and methyl iodide (44 μL, 0.70 mmol) were added at 0° C. and the resultant solution was stirred at room temperature for 1 day. To the reaction solution, the same amounts of sodium hydride and methyl iodide were further added and the resultant mixture was stirred for 1 day. After completion of the reaction, ethyl acetate was added to the reaction solution and the resultant mixture was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel (amino-based) column chromatography (hexane/ethyl acetate=9/1) to obtain the title compound (181 mg, yield 88%).
Reaction SMILES: [Cl:1][C:2]1([Cl:15])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:12][CH3:13])[C:9]=2[Cl:11])[NH:4][C:3]1=[O:14].[Cl:16]N(Cl)C(OCC)=O>CC(O)=O>[Cl:15][C:2]1([Cl:1])[C:10]2[C:5](=[C:6]([Cl:16])[CH:7]=[C:8]([O:12][CH3:13])[C:9]=2[Cl:11])[NH:4][C:3]1=[O:14]
Reactant: CCOC(=O)N(Cl)Cl
Reactant: COc1ccc2c(c1Cl)C(Cl)(Cl)C(=O)N2
Solvent: CC(=O)O
Product: COc1cc(Cl)c2c(c1Cl)C(Cl)(Cl)C(=O)N2
Temperature: 60 °C
Reaction time: 48 h
Yield: 93.9 %

Procedure:
11.54 g of 3,3,4-trichloro-5-methoxy-1 ,3-dihydro-indol-2-one (43.3 mmol) was suspended in glacial AcOH (200 mL). 3.343 g (21.7 mmol) of N,N-dichlorourethane was added and the mixture was stirred at 60° C. for 2 days. The reaction mixture was cooled to room temperature, the precipitate collected by filtration and dried on high vacuum. Re-crystallization from benzene (150 mL) yielded 6.135 g of product (containing 5% of the start. material as an impurity).
Reaction SMILES: [C:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[C:8]([C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=2)=[C:7]([C:24]([O:26][CH3:27])=[O:25])[CH:6]=1)(=[O:3])[CH3:2].[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC>[C:20]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:21]=[CH:22][C:17]([C:8]2[C:9]3[C:14](=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=3)[C:5]([O:4][C:1](=[O:3])[CH3:2])=[CH:6][C:7]=2[C:24]([O:26][CH3:27])=[O:25])=[CH:18][CH:19]=1
Reactant: COC(=O)c1cc(OC(C)=O)c2ccc(OC)cc2c1-c1ccc(Br)cc1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1cc(OC(C)=O)c2ccc(OC)cc2c1-c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
In an oven-dried placed flask under a nitrogen atmosphere, the product of Step 3 (150 g), phenylboronic acid (45 g) and sodium carbonate (85 g) were stirred in 1,2-dimethoxyethane (750 mL) and deionized water (225 mL). A nitrogen purge line was inserted directly into the reaction mixture for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (10 g) was added and the reaction mixture heated to reflux for 4.5 hours. After cooling to room temperature, the reaction mixture was slowly poured into a beaker containing deionized water (1.5 L) and ice while stirring. Concentrated hydrochloric acid was added until the pH reached 3. A separatory funnel was used to perform chloroform extractions (3×600 mL). The recovered organic layers were combined, washed with a saturated aqueous solution of sodium bicarbonate, dried over sodium sulfate and concentrated by rotary evaporation. The resulting residue was purified by column chromatography on silica gel (400 g) eluting with a solution of 30% ethyl acetate/70% hexanes. Fractions containing product were combined and concentrated by rotary evaporation yielding methyl 1-([1,1′-biphenyl]-4-yl)-4-acetoxy-7-methoxy-2-naphthoate (149 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]3[CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[C:15](=[O:17])[O:16][C:5]=2[CH:4]=1.C(N(CC)CC)C.Cl.Cl[CH2:27][CH2:28][N:29]1[CH2:34][CH:33]2[CH2:35][CH2:36][CH:30]1[CH2:31][CH2:32]2>O>[CH:30]12[CH2:36][CH2:35][CH:33]([CH2:32][CH2:31]1)[CH2:34][N:29]2[CH2:28][CH2:27][N:12]1[CH2:13][CH2:14][C:9]2[C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[O:16][C:15](=[O:17])[C:10]=2[CH2:11]1
Reactant: COc1ccc2c3c(c(=O)oc2c1)CNCC3
Reactant: ClCCN1CC2CCC1CC2
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc2c3c(c(=O)oc2c1)CN(CCN1CC2CCC1CC2)CC3
Yield: 48 %

Procedure:
Prepared by the method described for Example 27 from 1,2,3,4-tetrahydro-8-methoxy-5H-[1]benzopyrano[3,4-c]pyridin-5-one (3.0 g, 0.013 moles), triethylamine (3.9 ml, 0.028 moles), and 2-(2-chloroethyl)-2-azabicyclo[2.2.2]octane hydrochloride (2.9 g, 0.014 moles). Reflux time is 3 weeks. The crude product is dissolved in water, extracted with ethyl acetate, precipitated by the addition of solid potassium carbonate, filtered off, rinsed with water, and dried to yield the final product (2.3 g), mp 112°-113° C.
Reaction SMILES: [C:1]([NH:11][C@@H:12]([C:15]([OH:17])=[O:16])[CH2:13][OH:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C1COCC1.[CH3:23][C:24]1([CH3:31])[CH2:28][CH2:27][CH:26]([CH3:29])[CH:25]1O>>[CH3:23][C:24]1([CH3:31])[CH2:28][CH2:27][CH:26]([CH3:29])[CH:25]1[O:16][C:15](=[O:17])[C@@H:12]([CH2:13][OH:14])[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: O=C(N[C@H](CO)C(=O)O)OCc1ccccc1
Reactant: CC1CCC(C)(C)C1O
Solvent: C1CCOC1
Product: CC1CCC(C)(C)C1OC(=O)[C@@H](CO)NC(=O)OCc1ccccc1

Procedure:
Into a suspension of N-Cbz-D-serine (5 g) in 50 ml of dry THF containing 1 equivalent of 2,2,5-trimethylcyclopentanol is bubbled dry hydrogen chloride gas at room temperature. Upon complete solution of the mixture, the reaction is refluxed for 5 hours, then concentrated. Ethyl acetate is added, and this is washed with saturated sodium bicarbonate, water, and dried over MgSO4. Filtration followed by concentration yields N-Cbz-D-serine-2,2,5-trimethylcyclopentyl ester. 5 g of this product is dissolved in 10 ml methanol and hydrogenated in a Paar apparatus over 1 g of 5% Pd/C to yield 2,2,5-trimethylcyclopentyl-D-serinate.
Reaction SMILES: Br[CH:2]([C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[N:17])[CH:11]=1)=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:18]([NH2:26])(=[S:25])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1.C(OCC)(=O)C>O1CCCC1>[N:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:18]2[S:25][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[N:17])[CH:11]=3)[N:26]=2)[CH:20]=1
Reactant: CCOC(=O)C(Br)C(=O)c1cccc(C#N)c1
Reactant: NC(=S)c1cccnc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(-c2cccnc2)nc1-c1cccc(C#N)c1
Temperature: 65 °C
Reaction time: 16 h
Yield: 22.8 %

Procedure:
To a solution of ethyl 2-bromo-3-(3-cyanophenyl)-3-oxopropionate (1.0 g, 3.4 mmol) in 20 mL of tetrahydrofuran was added thionicotinamide (0.46 g, 3.4 mmol). The resulting mixture was stirred at 65° C. for 16 h. The reaction was allowed to cool and the solvent was evaporated in vacuo. The residue was triturated with chloroform, taken up in ethyl acetate, washed with saturated aq Na2CO3 and brine, dried (MgSO4) and concentrated in vacuo to yield a solid. Trituration with ethyl acetate left the title compound as an off-white solid (0.26 g, 23%). MS (ESI) 336.1 (M+H)+.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:8]([O:18]C(C)(C)C)=[N:9][C:10]([O:13]C(C)(C)C)=[N:11][CH:12]=1.[CH3:23][C:24]1[CH:40]=[CH:39][C:27]2[C:28](=O)[C:29]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][C:30]=3[CH2:31][CH2:32][C:26]=2[CH:25]=1>O1CCCC1>[CH3:37][C:34]1[CH:35]=[CH:36][C:29]2[CH:28]([C:7]3[C:8](=[O:18])[NH:9][C:10](=[O:13])[NH:11][CH:12]=3)[C:27]3[CH:39]=[CH:40][C:24]([CH3:23])=[CH:25][C:26]=3[CH:32]=[CH:31][C:30]=2[CH:33]=1
Reactant: Cc1ccc2c(c1)CCc1cc(C)ccc1C2=O
Reactant: CC(C)(C)Oc1ncc(Br)c(OC(C)(C)C)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1c[nH]c(=O)[nH]c1=O
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (5.6 ml of a 2.5M solution in hexanes) was added dropwise to a solution of 5-bromo-2,4-bis(1,1,-dimethylethoxy)pyrimidine (example 1 step (i)) (3.85 g) in tetrahydrofuran (30 ml) at -78° C. The solution was stirred for 30 minutes and a solution of 10,11-dihydro-2,8-dimethyl-5H-dibenzo[a,d]cyclohepten-5-one (European Patent, 1993, 0 589 322 A1) (3.0 g) in tetrahydrofuran (20 ml) was added. The mixture was stirred at -78° C. for 45 minutes and room temperature for 15 minutes and then partitioned between brine and ethyl acetate. The organic phase was dried (MgSO4) and evaporated. The residue was dissolved in glacial acetic acid (100 ml) and heated at 120° C. for 30 minutes. The solvent was evaporated and the residue azeotroped with toluene and triturated with diethyl ether to give a solid. Yield 4.03 g.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[S:13]1(=[O:29])=[O:28]>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([N:14]2[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:12]([CH2:11][CH2:10][CH2:9][CH2:8][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[S:13]2(=[O:28])=[O:29])=[CH:22][CH:23]=1
Reactant: O=S1(=O)N(CCCCBr)c2ccccc2N1c1ccc(Cl)cc1
Reactant: C1COCCN1
Product: O=S1(=O)N(CCCCN2CCOCC2)c2ccccc2N1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.3 %

Procedure:
Morpholine (2 mL, 23 mmol) was added to a round bottom flask containing (50 mg, 0.12 mmol) of 1-(4-bromobutyl)-3-(4-chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (made in general procedure IV). The reaction flask was covered with a septum and stirred overnight at room temperature. The reaction solution was concentrated in vacuo and the crude product was pre-adsorbed onto Celite and purified via Isco chromatography (Redisep, silica, gradient 1-8% methanol in dichloromethane with ammonia) to afford 29 mg (78%) of 1-(4-chlorophenyl)-3-(4-morpholin-4-ylbutyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide. HPLC purity 100.0% at 210-370 nm, 8.2 minutes Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7](I)[CH:6]=[N:5]1.[C:10]([C:12]1[CH:13]=[C:14]([C:18]2[C:19]([F:24])=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:15]=[CH:16][CH:17]=1)#[CH:11]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[F:24][C:19]1[C:18]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([C:10]#[C:11][C:7]3[CH:6]=[N:5][N:4]([CH2:3][CH2:2][F:1])[CH:8]=3)[CH:13]=2)=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: FCCn1cc(I)cn1
Reactant: C#Cc1cccc(-c2cccnc2F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CN(C)C=O
Product: FCCn1cc(C#Cc2cccc(-c3cccnc3F)c2)cn1
Temperature: 65 °C
Yield: 75.6 %

Procedure:
To a solution of 1-(2-fluoroethyl)-4-iodo-1H-pyrazole (148 mg, 0.62 mmol) in DMF (5.0 mL) is added dichlorobis(triphenylphosphine)palladium (16 mg, 0.022 mmol), copper iodide (3 mg, 0.015 mmol), TEA (0.53 mL, 3.8 mmol) and 3-(3-ethynylphenyl)-2-fluoropyridine (150 mg, 0.76 mmol). The reaction mixture is heated at 65° C. for 3 h, cooled and quenched with H2O. The aqueous layer is extracted with EtOAc. The combined organic extracts are washed with brine, dried (MgSO4) and concentrated. The crude material is purified by chromatography (silica gel, EtOAc/hexane:30/70) to afford the title compound (145 mg, 76%) as an oil. MS (+) ES: 310 (M+H)+.
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13])=[CH:8][C:7]=1C(=O)C.C1C=C(Cl)C=[C:24]([C:29]([O:31]O)=[O:30])C=1>C(Cl)(Cl)Cl>[C:29]([O:31][C:7]1[CH:8]=[C:9]([S:12]([C:15]([F:16])([F:17])[F:18])(=[O:13])=[O:14])[CH:10]=[CH:11][C:6]=1[O:5][CH2:4][C@H:2]1[CH2:3][O:1]1)(=[O:30])[CH3:24]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)c1cc(S(=O)(=O)C(F)(F)F)ccc1OC[C@H]1CO1
Solvent: ClC(Cl)Cl
Product: CC(=O)Oc1cc(S(=O)(=O)C(F)(F)F)ccc1OC[C@H]1CO1

Procedure:
Preparation according to Preparation 19 using 1-{2-[(2R)-oxiran-2-ylmethoxy]-5-[(trifluoromethyl)sulfonyl]phenyl}ethanone (1.2 g, 3.7 mmol) and m-CPBA (4.95 g, 22.5 mmol) in CHCl3 (50 ml). Crude yield 1.0 g. MS m/z (rel. intensity, 70 eV) 298 (34), 229 (77), 165 (bp), 107 (39), 79 (30).
Reaction SMILES: [OH:1][CH:2]([CH2:14][OH:15])[CH2:3][N:4]1[C:8](=[O:9])[C:7]([CH3:11])([CH3:10])[NH:6][C:5]1([CH3:13])[CH3:12].C(O[Cl:21])(C)(C)C>CO>[Cl:21][N:6]1[C:7]([CH3:10])([CH3:11])[C:8](=[O:9])[N:4]([CH2:3][CH:2]([OH:1])[CH2:14][OH:15])[C:5]1([CH3:13])[CH3:12]
Reactant: CC1(C)NC(C)(C)N(CC(O)CO)C1=O
Reactant: CC(C)(C)OCl
Solvent: CO
Product: CC1(C)C(=O)N(CC(O)CO)C(C)(C)N1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
To a 0° C. solution of 3-(2,3-dihydroxypropyl)-2,2,5,5-tetramethylimidazolidin-4-one (250 mg, 1.2 mmol) in methanol (150 ml) was added tert-butylhypochlorite (150 mg, 1.4 mmol). The mixture was stirred for 1 hour at 0° C. The reaction mixture was concentrated in vacuo, and crude material is purified by silica gel flash chromatography (0 to 10% methanol in dichloromethane) to give 256 mg (88%) of the title compound. 1H NMR (400 MHz, D2O) δ 4.06-3.98 (m, 1H), 3.62 (dd, J=12.0, 4.0 Hz, 1H), 3.56-3.44 (m, 2H), 3.36 (dd, J=14.8, 8.4 Hz, 1H), 1.54 (s, 6H), 1.38-1.37 (m, 6H). 13C NMR (100 MHz, D2O) δ 175.5, 83.9, 69.4, 66.0, 63.4, 43.6, 24.2, 23.9, 22.72, 22.4. LRMS (ESI/APCI) m/z 251 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[S:8][C:9]([SH:11])=[N:10][C:5]2=[CH:4][CH:3]=1.[CH2:12]1COCC1.C(=O)([O-])[O-].[K+].[K+].CI>C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]2[S:8][C:9]([S:11][CH3:12])=[N:10][C:5]2=[CH:4][CH:3]=1
Reactant: Sc1nc2ccc(Cl)nc2s1
Reactant: C1CCOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Product: CSc1nc2ccc(Cl)nc2s1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a round bottom flask was added 5-chloro[1,3]thiazolo[5,4-b]pyridine-2-thiol (1-1) (21.4 g, 106 mmol), anhydrous THF (400 mL), potassium carbonate (20.5 g, 148 mmol), followed by methyl iodide (16.9 g, 119 mmol). The reaction vessel was sealed and stirred at room temperature for 5 minutes. The crude reaction mixture was then suspended in ethyl acetate and washed with a saturated solution of sodium bicarbonate, followed by water, then brine, dried over sodium sulfate, filtered, and concentrated to give 5-chloro-2-(methylthio)[1,3]thiazolo[5,4-b]pyridine (1-2) as a pink solid. HRMS (M+H)+: observed=216.9658, calculated=216.9655.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].N1C=CC=CC=1.[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:21]=1[S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:21]=1[S:27]([NH:1][C:2]1[C:3]([F:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])(=[O:29])=[O:28]
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Reactant: COC(=O)c1cccc(N)c1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cccc(NS(=O)(=O)c2c(F)cccc2F)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
In a 500 mL flask was placed methyl 3-amino-2-fluorobenzoate (5.5 g, 32.5 mmol) and DCM (100 mL), and pyridine (2.9 mL, 35.8 mmol) was added. 2,6-Difluorobenzenesulfonyl chloride (7.6 g, 35.8 mmol) in DCM (50 mL) was added dropwise via addition funnel and the reaction mixture was allowed to stir at rt overnight. The reaction mixture was stripped onto silica and column chromatographed on silica with 5% to 100% EtOAc:Hexane to give 9.75 g (87%) of the title compound of Step C. 1H-NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 7.64-7.82 (m, 3H), 7.46-7.61 (m, 1H), 7.29 (t, J=8.8 Hz, 2H), and 3.81 (s, 3H). MS (ESI): 346 [M+H]+.