Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH3:8])=[C:5]([Br:7])[N:6]=1.[C:9]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][C@@H:17]1[CH2:22][CH:23]([CH3:25])[CH3:24])([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[Br:7][C:5]1[N:6]=[C:2]([N:19]2[CH2:20][CH2:21][N:16]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[C@@H:17]([CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:18]2)[S:3][C:4]=1[CH3:8]
Reactant: Cc1sc(Br)nc1Br
Reactant: CC(C)C[C@H]1CNCCN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1sc(N2CCN(C(=O)OC(C)(C)C)[C@@H](CC(C)C)C2)nc1Br
Temperature: 25 °C

Procedure:
2,4-dibromo-5-methyl-thiazole (1.189 g, 3.563 mmol), (S)—N-Boc-2-isobutylpiperazine (863.5 mg, 3.563 mmol) and potassium carbonate (1.477 g, 10.69 mmol) in DMF (15 mL) were heated at 95° C. for 18 h. Cooled to rt, diluted with EtOAc, washed with water, brine, dried (MgSO4), filtered and concentrated in vacuo. Crude product purified by flash chromatography (40 g SiO2, 0 to 5% EtOAc/petrol) to leave impure product as a very pale orange sticky oil (930 mg, 49% based on 78.9% purity); 1H NMR DMSO-d6 δ 0.90 (t, 6H), 1.36-1.31 (br m, 2H), 1.42 (s, 9H), 1.46-1.42 (masked signal, 1H), 2.18 (s, 3H), 3.02-2.91 (m, 2H), 3.14 (dd, 1H), 3.60 (d, 1H), 3.78-3.68 (m, 1H), 3.86 (d, 1H), 4.19 (br s, 1H); ES+ 420.11.
Reaction SMILES: Cl[C:2]1[C:7]2=[CH:8][N:9]([C:11]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:12]=3[C:13]#[N:14])[N:10]=[C:6]2[C:5]([F:20])=[CH:4][N:3]=1.[Br:21][Si](C)(C)C>C(#N)CC>[Br:21][C:2]1[C:7]2=[CH:8][N:9]([C:11]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:12]=3[C:13]#[N:14])[N:10]=[C:6]2[C:5]([F:20])=[CH:4][N:3]=1
Reactant: C[Si](C)(C)Br
Reactant: N#Cc1cccc(F)c1-n1cc2c(Cl)ncc(F)c2n1
Solvent: CCC#N
Product: N#Cc1cccc(F)c1-n1cc2c(Br)ncc(F)c2n1
Temperature: 80 °C
Yield: 100 %

Procedure:
2-(4-Chloro-7-fluoropyrazolo[4,3-c]pyridin-2-yl)-3-fluorobenzonitrile (520 mg, 1.79 mmol) was suspended in propionitrile (35 mL), under an atmosphere of nitrogen and bromotrimethylsilane (0.646 mL, 6.76 mmol) was added. The reaction mixture was heated at 80° C. for 4.5 hours. The resultant mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The layers were separated and the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a solid (600 mg, 100% yield). This was used in the next step without purification. LCMS (Method F): RT=3.30 min, m/z: 335 [M+H+].
Reaction SMILES: [CH2:1]([S:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][OH:43])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CCCCC(CCC(OS([O-])(=O)=O)CC(C)C)CC.[Na+].[C:64](Cl)([Cl:66])=[O:65]>C(N(CC)CC)C>[CH2:1]([S:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][C:64]([Cl:66])=[O:65])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=C(Cl)Cl
Reactant: CCCCCCCCCCCCSCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO
Agent: CCCCC(CC)CCC(CC(C)C)OS(=O)(=O)[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCSCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOC(=O)Cl

Procedure:
For example, C12H25S(CH2CH2O)10H, such as Tergitol 12-M10, can be reacted with phosgene in the presence of triethyl amine to yield the corresponding acid chloride, C12H25S(CH2CH2O)10COCl, which in turn, is reacted with a fluoroaliphatic alcohol such as (CF3)2CFO--CF2CF2 --CH2CH2CONH(CH2)3OH, disclosed in U.S. Pat. No. 3,697,564, in the presence of triethylamine in diethyl ether to yield a product of the formula (CF3)2CFO--CF2CF2CH2CH2CONH(CH2)3OCO(OCH2CH2)10S--C12H25.
Reaction SMILES: P(Br)(Br)[Br:2].[Br:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([F:13])=[CH:8][C:7]=1[CH2:14]O>ClCCl.C(OCC)C>[Br:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([F:13])=[CH:8][C:7]=1[CH2:14][Br:2]
Reactant: OCc1cc(F)c(Cl)cc1Br
Reactant: BrP(Br)Br
Solvent: CCOCC
Solvent: ClCCl
Product: Fc1cc(CBr)c(Br)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.55 mmol of phosphorous tribromid is added dropwise to a solution of 1 mmol of (2-Bromo-4-chloro-5-fluoro-phenyl)-methanol in 40 ml of dichloromethane. The trouble reaction solution is stirred at room temperature for 2 hours, diluted with 100 ml of diethylether and decanted. The supernatant is washed with 10 ml of 2N sodium bicarbonate solution, 20 ml of water and 20 ml of brine, dried over sodium sulfate, filtered and concentrated under reduced pressure at 28° C. to afford the title compound which is identified based on the Rf value.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1.[Br:13][CH2:14][C@H:15]1[C:24]2[C:19](=[C:20]([O:26][CH3:27])[C:21]([CH3:25])=[CH:22][CH:23]=2)[CH2:18][C@@H:17]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[O:16]1>CN1C(=O)CCC1>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:31]2[CH2:32][CH2:33][CH:28]([C@@H:17]3[CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[C:21]([CH3:25])[C:20]=4[O:26][CH3:27])[C@H:15]([CH2:14][Br:13])[O:16]3)[CH2:29][CH2:30]2)=[CH:5][CH:4]=1
Reactant: COc1c(C)ccc2c1C[C@@H](C1CCNCC1)O[C@H]2CBr
Reactant: FC(F)(F)c1ccc(CBr)cc1
Solvent: CN1CCCC1=O
Product: COc1c(C)ccc2c1C[C@@H](C1CCN(Cc3ccc(C(F)(F)F)cc3)CC1)O[C@H]2CBr
Reaction time: 4 h

Procedure:
Add 4-trifluoromethylbenzyl bromide (7.2 g) and NMP (20 mL) to REM bound (1R,3S)-4-(1-bromomethyl-5-methoxy-6-methyl-isochroman-3-yl)-piperidine (2.0 g 0.78 mmol/g of loading) in a 50 mL shaking vessel. Shake the reaction mixture at room temperature overnight, filter and wash three times each with NMP, dichloromethane, methanol, and dichloromethane. To this resin add of dichloromethane (18.6 mL) and of DIEA (1.4 mL). Shake the resulting mixture at room temperature overnight, filter and wash the resin twice each with dichloromethane, methanol, and dichloromethane. Combine the filtrates concentrate and add Amberlite IRA-67 (2.0 g) with of dichloromethane (20 mL). Shake the resulting mixture at room temperature for 4 hours, filter and wash twice each with dichloromethane, methanol, and dichloromethane. Combine the filtrates and concentrate to yield the title compound. CIMS 512.1 (MH+), tR (min)=3.52.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1)=[O:5].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:32]1[N:36]2[C:37]3[C:42]([NH:43][CH2:44][C:35]2=[CH:34][CH:33]=1)=[CH:41][CH:40]=[CH:39][CH:38]=3>O1CCCC1>[CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([N:43]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]3[CH:32]=[CH:33][CH:34]=[C:35]3[CH2:44]2)=[O:12])=[CH:9][CH:8]=1)=[O:5]
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: c1ccc2c(c1)NCc1cccn1-2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3-c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 0.51 g of, 4-[(2-methylbenzoyl)-amino]benzoyl chloride and 0.36 g of 1,1'-carbonyldiimidazole in 6 ml of tetrahydrofuran is stirred at room temperature for 1 hour. To the reaction mixture is added 0.17 g of 4,5-dihydropyrrolo-[1,2-a]-quinoxaline followed by heating at reflux for 60 hours. The volatiles are concentrated in vacuo to a residue which is dissolved in ethyl acetate. The organic layer is washed with 1N HCl, 1M NaHCO3, brine, dried with Na2SO4 and filtered through hydrous magnesium silicate. The volatiles are concentrated in vacuo to a residue which is chromatographed by elution with 1:2 ethyl acetate-hexanes to give 0.14 g of the desired product as a white solid, m.p. 206°-2070° C.;
Reaction SMILES: [C:1]1(=[N:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:9]1[C:16](Cl)=[N:15][C:13](Cl)=[N:12][C:10]=1Cl>N1C=CC=CC=1>[C:1]1(=[N:7][O:8][C:10]2[N:12]=[C:13]([O:8][N:7]=[C:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[N:15]=[C:16]([O:8][N:7]=[C:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: ON=C1CCCCC1
Solvent: c1ccncc1
Product: C1CCC(=NOc2nc(ON=C3CCCCC3)nc(ON=C3CCCCC3)n2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 86.1 %

Procedure:
To a cold (0° C.) solution of cyclohexanone oxime (4.53 g, 0.04 mol) in dry pyridine (20 ml) is added cyanuric chloride (1.84 g, 0.01 mol). An exothermic reaction occurs and the temperature rises to 22° C. The solution is then stirred 15 h at room temperature and then poured into 200 ml of ice-cold water. The precipitated solid is filtered off, dried and recrystallized from dichloromethane-hexane to afford 3.57 g of the title compound as a white solid. The compound decomposes without melting above 120° C. (DSC data).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[C:6]([CH3:16])([CH3:15])[CH2:5]1)(=[O:3])[CH3:2].[N+:17]([O-])([O-:19])=[O:18].[K+].O>FC(F)(F)C(O)=O>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=2)[C:6]([CH3:16])([CH3:15])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])[O-]
Reactant: COc1ccc2c(c1)C(C)(C)CN2C(C)=O
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1cc2c(cc1[N+](=O)[O-])N(C(C)=O)CC2(C)C
Temperature: 0 °C
Yield: 86.5 %

Procedure:
A solution of 1-acetyl-3,3-dimethyl-5-(methyloxy)-2,3-dihydro-1H-indole (2.44 g, 11.13 mmol, see PCT Int. Appl. (2001), WO 2001023374 A1 20010405) in trifluoroacetic acid (50 mL) was stirred at 0° C. and potassium nitrate (1.181 g, 11.68 mmol) was added in one portion. The reaction was maintained at 0° C. for 3 hours and poured into water. The solids were collected via filtration to afford 1-acetyl-3,3-dimethyl-5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole (2.545 g, 87% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.41 (s, 1 H), 7.34 (s, 1 H), 3.91 (s, 3 H), 2.15 (s, 2 H), 1.36 (s, 6 H). Note: proton resonance corresponding to acetyl was extremely broad and/or not evident for a variety of lots.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:35])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([Br:26])[CH:21]=4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:27])[C:12]=2[C:28](=[O:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.C1(C)C=CC=CC=1.CCOC(C)=O.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:4][C:5]1([CH3:35])[CH2:6][CH2:7][N:8]([C:11]2[N:16]3[N:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([Br:26])[CH:21]=4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:27])[C:12]=2[C@H:28]([OH:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:9][CH2:10]1)[CH:2]=[CH2:3]
Reactant: C=CCOC1(C)CCN(c2c(C(=O)C(=O)OCC)c(C)nc3cc(-c4cccc(Br)c4)nn23)CC1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=CCOC1(C)CCN(c2c([C@H](O)C(=O)OCC)c(C)nc3cc(-c4cccc(Br)c4)nn23)CC1
Temperature: -35 °C
Reaction time: 0.5 h
Yield: 77.1 %

Procedure:
To a stirred yellow solution of ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-oxoacetate (22 g, 40.6 mmol) in anhydrous toluene (800 mL) was added 1M (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole/toluene (16.25 mL, 16.25 mmol). The mixture was cooled to −35° C. and catechoborane (7.11 mL, 56.9 mmol) was added over 5 min. After 30 min, the reaction mixture was slowly warmed to −15° C. and stirred for additional 2 h. A this point LCMS indicated approx 60% conversion, so mixture was cooled to −35° C. and 3.5 mL of catechoborane was added and stirred at −15° C. for 2 h. At his point LCMS indicates completion of reaction. Mixture was then dluted with EtOAc (1 L) and sat. Na2CO3 (300 mL). The mixture was stirred vigorously for 30 min, and the organic phase washed with sat Na2CO3 (2×200 mL) each time vigorously stirring for 30 min, dried (Na2SO4), filtered, concentrated and the residue was purified by silica gel chromatography (5-70% EtOAc/hexane) to afford desired (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (17 g, 31.3 mmol, 77% yield) as off-white solid. 1H NMR (500 MHz, CDCl3) δ 8.19-8.10 (m, 1H), 7.95 (d, J=7.9 Hz, 1H), 7.58-7.52 (m, 1H), 7.33 (t, J=7.8 Hz, 1H), 6.86-6.82 (m, 1H), 6.10 (dd, J=10.8, 5.1 Hz, 1H), 5.57 (d, J=5.2 Hz, 1H), 5.48 (d, J=16.9 Hz, 1H), 5.27 (d, J=10.2 Hz, 1H), 4.35 (dq, J=10.8, 7.2 Hz, 1H), 4.23 (dq, J=10.7, 7.1 Hz, 1H), 4.03 (dt, J=5.2, 1.5 Hz, 2H), 2.65 (s, 3H), 2.00 (d, J=14.5 Hz, 2H), 1.84 (br. s., 2H), 1.36 (s, 3H), 1.29-1.24 (m, 3H). LCMS (M+H)=543.4.
Reaction SMILES: [C:1]1([C:7]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]3[CH2:12][NH:13][CH2:14][CH2:15][N:10]3[C:9](=[O:16])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[C:32](Cl)(=[O:41])[O:33][C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1>O1CCCC1>[F:40][C:37]1[CH:38]=[CH:39][C:34]([O:33][C:32]([N:13]2[CH2:14][CH2:15][N:10]3[C:9](=[O:16])[O:8][C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:11]3[CH2:12]2)=[O:41])=[CH:35][CH:36]=1
Reactant: O=C(Cl)Oc1ccc(F)cc1
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)C2CNCCN12
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Oc1ccc(F)cc1)N1CCN2C(=O)OC(c3ccccc3)(c3ccccc3)C2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.9 %

Procedure:
To a solution of hexahydro-1,1-diphenyl-3H-oxazolo[3,4-a]pyrazin-3-one (50 mg, 0.17 mmol) in tetrahydrofuran (2 mL) were sequentially added diisopropylethylamine (0.30 mL, 1.7 mmol) and 4-fluorophenyl chlorocarbonate (45 mg, 0.26 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, and the residue was purified with silica gel column chromatography (hexane:ethyl acetate=3:1) and crystallized from diisopropyl ether to obtain the title compound (58 mg, yield 79%).
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1([CH3:12])[CH2:9][C:8](=[O:10])[CH2:7][C:6](=[O:11])[CH2:5]1>CC(O)=O>[Br:1][CH:7]1[C:8](=[O:10])[CH2:9][C:4]([CH3:12])([CH3:3])[CH2:5][C:6]1=[O:11]
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: BrBr
Solvent: CC(=O)O
Product: CC1(C)CC(=O)C(Br)C(=O)C1
Reaction time: 2 h

Procedure:
Bromine (0.51 mL, 10 mmol) was added dropwise to a solution of 5,5-dimethylcyclohexane-1,3-dione (1.4 g, 10 mmol) in AcOH (20 mL) at r.t. The reaction mixture was stirred for 2 h and then the product was isolated by filtration. The precipitate was washed with Et2O (2×100 mL) and then dried in vacuo give the title compound in quantitative yield as a light brown solid, which was used without further purification. LCMS (ES+) 218.9 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([S:6]([O-:9])(=O)=[O:7])=[CH:2]1.[Na+].P(Cl)(Cl)(Cl)(Cl)[Cl:12]>C(OCC)C>[NH:1]1[CH:5]=[CH:4][C:3]([S:6]([Cl:12])(=[O:9])=[O:7])=[CH:2]1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=S(=O)([O-])c1cc[nH]c1
Agent: [Na+]
Solvent: CCOCC
Product: O=S(=O)(Cl)c1cc[nH]c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.6 %

Procedure:
A suspension of 16.9 g (100 mmol) of Compound 1 and 22.9 g (110 mmol) of phosphorus pentachloride in 750 ml of diethyl ether was stirred at room temperature for 2 hours, and was then refluxed for 4 hours. After the reaction mixture was allowed to cooled down, it was filtered. The filtrate was washed successively with ice water (twice), a chilled, saturated aqueous solution of sodium hydrogencarbonate, ice water and a chilled, saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, whereby 11.2 g of 3-pyrrolesulfonyl chloride were obtained as crude crystals.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3]([OH:5])=[O:4].[Cl:8][C:9]([Cl:13])([Cl:12])[CH2:10]O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[C:1]([O:7][CH2:10][C:9]([Cl:13])([Cl:12])[Cl:8])(=[O:6])[CH2:2][C:3]([OH:5])=[O:4]
Reactant: O=C(O)CC(=O)O
Reactant: OCC(Cl)(Cl)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: O=C(O)CC(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Yield: 18.4 %

Procedure:
A mixture of finely powdered malonic acid (10.4 g, 0.1 mol), 2,2,2-trichloroethanol (9.6 mL, 0.1 mol) and p-toluenesulfonic acid monohydrate (570 mg, 3% in benzene (30 mL) was stirred under azeotropic reflux for 26 hours, then cooled at room temperature. The unreacted malonic acid (4.6 g) was filtered and washed with benzene (2×10 mL). Water (50 mL) was added to the filtrate followed by portionwise addition of sodium bicarbonate until a basic pH was reached. The aqueous phase was decanted, washed with ether (3×50 mL), then acidified with concentrated aqueous HCl and extracted with methylene chloride (4×50 mL). The combined extracts were washed with brine (25 mL), dried over MgSO4, filtered and evaporated in vacuo to give 2,2,2-trichloroethyl hydrogen malonate (4.34 g, 18.4 mmol, 18%) that slowly crystallized; m.p. 42°-43°; NMR (CDCl3): δ11.0 (S, CO2H), 4.83 (S, --OCH2CCl3 ), 3.61 (S, --O2C--CH2CO2 --).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[S:3]1(=[O:14])=[O:13].[C:15](=O)([O-:17])[O-:16].C[Mg+2].Cl.C(OCC)C>CN(C)C=O>[CH3:1][N:2]1[CH:7]([C:15]([OH:17])=[O:16])[C:6](=[O:8])[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[S:3]1(=[O:13])=[O:14]
Reactant: O=C([O-])[O-]
Reactant: CN1CC(=O)c2ccccc2S1(=O)=O
Agent: C[Mg+2]
Agent: Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CN1C(C(=O)O)C(=O)c2ccccc2S1(=O)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
To 6.34 g (0.03 mole) 3,4-dihydro-2-methyl-4-oxo-1,2-benzothiazine 1,1-dioxide, 19.5 g (0.15 mole) methylmagnesiumcarbonate in 150 ml N,N-dimethyl formamide were added. The mixture was stirred at 140°-150° C. for 2 hours. The resulting solution was poured quickly into a mixture of 200 ml conc-hydrochloric acid, 200 g ice chips and 500 ml diethyl ether. After stirring the mixture for 10 minutes, the diethylether layer was separated and the separated diethyl ether solution was evaporated in vacuo. The precipitated pale yellow crystals were filtered and recrystallized in dilute methanol solution to obtain 7.21 g of the title compound as white crystals. Yield: 94%
Reaction SMILES: NC1N(C(OC(C)(C)C)=O)N=C([C:14]2[CH:67]=[CH:66][C:17]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23](C4SC(N5CCC6C(=C(C(=O)N(C7SC8C=CC=CC=8N=7)COCC[Si](C)(C)C)C=CC=6)C5)=NC=4C(OCC)=O)=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)C=1C#N.NC1N(C(OC(C)(C)C)=O)N=C(C2C=CC(O)=CC=2)C=1C#N.[N:92]1([CH2:97][CH2:98][OH:99])[CH2:96][CH2:95][CH2:94][CH2:93]1.C(OC1C=CC(O)=CC=1)C1C=CC=CC=1>>[CH2:19]([O:18][C:17]1[CH:16]=[CH:15][C:14]([O:99][CH2:98][CH2:97][N:92]2[CH2:96][CH2:95][CH2:94][CH2:93]2)=[CH:67][CH:66]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: OCCN1CCCC1
Reactant: CCOC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1-c1ccc(COc2ccc(-c3nn(C(=O)OC(C)(C)C)c(N)c3C#N)cc2)cc1
Agent: CC(C)(C)OC(=O)n1nc(-c2ccc(O)cc2)c(C#N)c1N
Agent: Oc1ccc(OCc2ccccc2)cc1
Product: c1ccc(COc2ccc(OCCN3CCCC3)cc2)cc1

Procedure:
Compound 106A was prepared in a similar manner to the synthesis of compound 35A by substituting compound 34D and compound 31F with 2-(pyrrolidin-1-yl)ethanol and 4-(benzyloxy)phenol, respectively: DCI (+)MS: 298 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][O:30][C:24]=3[CH:23]=2)[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][O:30][C:24]=4[CH:23]=3)[C:10]3[CH:15]=[C:14]([C:16]([F:17])([F:19])[F:18])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: FC(F)(F)c1cc2c(NCc3ccc4c(c3)OCO4)nc(Cl)nc2s1
Reactant: c1c[nH]cn1
Product: FC(F)(F)c1cc2c(NCc3ccc4c(c3)OCO4)nc(-n3ccnc3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-6-trifluoromethyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-trifluoromethyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[N:5][C:6]([C@@H:9]([NH2:11])[CH3:10])=[N:7][CH:8]=1.[Br:12][C:13]1[C:14]([NH:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)=[N:15][C:16](Cl)=[N:17][CH:18]=1.CCN(C(C)C)C(C)C>CCCCO>[Br:12][C:13]1[C:14]([NH:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)=[N:15][C:16]([NH:11][C@H:9]([C:6]2[N:7]=[CH:8][C:3]([F:2])=[CH:4][N:5]=2)[CH3:10])=[N:17][CH:18]=1
Reactant: C[C@H](N)c1ncc(F)cn1
Reactant: Cc1cc(Nc2nc(Cl)ncc2Br)n[nH]1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2nc(N[C@@H](C)c3ncc(F)cn3)ncc2Br)n[nH]1
Temperature: 165 °C
Yield: 47 %

Procedure:
To a microwave vial was added (S)-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Method 7, 369 mg, 2.08 mmol), 5-bromo-2-chloro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Method 38, 500 mg, 1.73 mmol), and DIEA (468 mg, 3.8 mmol). Anhydrous n-BuOH (5 mL) was added, and the vial was heated in microwave oven at 165° C. for 5 hours. The reaction mixture was concentrated. The resulting residue was separated by silica gel column to afford desired product (320 mg, 47%). LC-MS, 393 (M+1). 1H NMR δ 12.02 (s, 1H), 8.82 (s, 2H), 7.94 (s, 1H), 7.48 (s, 0.55H), 5.90 (s, 0.41H), 5.09 (s, 1H), 2.19 (m, 3H), 1.49 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:3]=1[O:4][CH:5]([CH3:9])[C:6](=[O:8])[CH3:7].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>CO>[Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:3]=1[O:4][CH:5]([CH3:9])[C:6](=[O:8])[CH:7]=[CH:17][N:18]([CH3:20])[CH3:19]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)C(C)Oc1ccc(Cl)cc1Cl
Solvent: CO
Product: CC(Oc1ccc(Cl)cc1Cl)C(=O)C=CN(C)C
Temperature: 120 °C

Procedure:
A mixture of 3-(2,4-dichlorophenoxy)-2-butanone (4.66 g) and N,N-dimethylformamide dimethylacetal (2.38 g) was heated under argon in an oil bath at 120° C. for 11 hours. The methanol produced in the reaction was removed under reduced pressure and the residue was triturated with n-hexane. The solid was collected by filtration and washed with cold diethyl ether to give 4-(2,4-dichlorophenoxy)-1-(dimethylamino)-1-penten-3-one. Yield 4.07 g.
Reaction SMILES: C(S[CH:6]1[N:9]([CH:10]([C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[C:8](=[O:30])[CH2:7]1)(C)(C)C.[Cl:31]Cl>C(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[Cl:31][CH:6]1[N:9]([CH:10]([C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[C:8](=[O:30])[CH2:7]1
Reactant: CC(C)(C)SC1CC(=O)N1C(C(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)C(C)(C)C
Reactant: ClCl
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)C(=O)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)CC1Cl
Temperature: -50 °C
Yield: 90.9 %

Procedure:
A solution of 439 mg (1.0 mmol) of p-nitrobenzyl 2-(4-tert-butylthio-2-oxo-1-azetidinyl)-4,4-dimethyl-3-oxopentanoate in 20 ml of dry methylene chloride is cooled to -50° C. and a solution of 166 mg of chlorine in 1.6 ml of carbon tetrachloride is added. After stirring the mixture for thirty minutes at -50° C., the solvent is evaporated in vacuo and the residue is recrystallized from methylene chloride/hexane, the product (348 mg) being obtained as a crystalline solid as a 6:4 mixture of the diastereomeric title compounds.