Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C@H:4]1[C@@H:8]([Cl:9])[CH2:7][N:6]([C:10]2[N:19]=[C:18]3[C:13]([C:14](=[O:26])[C:15]([C:23]([OH:25])=[O:24])=[CH:16][N:17]3[CH:20]3[CH2:22][CH2:21]3)=[CH:12][C:11]=2[F:27])[CH2:5]1.S(=O)(=O)(O)O.[CH2:33](O)[CH3:34]>>[NH2:2][CH2:3][C@H:4]1[C@@H:8]([Cl:9])[CH2:7][N:6]([C:10]2[N:19]=[C:18]3[C:13]([C:14](=[O:26])[C:15]([C:23]([O:25][CH2:33][CH3:34])=[O:24])=[CH:16][N:17]3[CH:20]3[CH2:22][CH2:21]3)=[CH:12][C:11]=2[F:27])[CH2:5]1
Reactant: NC[C@@H]1CN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)C[C@@H]1Cl
Reactant: CCO
Agent: Cl
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cn(C2CC2)c2nc(N3C[C@@H](CN)[C@@H](Cl)C3)c(F)cc2c1=O

Procedure:
7-(cis-3-Aminomethyl-4-chloro-1-pyrrolidinyl)1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride was suspended in absolute ethanol. Sulfuric acid was added to the suspension and the mixture was refluxed for 15 hours with stirring. After evaporation of ethanol, chloroform and a 20% aqueous sodium hydroxide solution were added to the residue, and the mixture was adjusted to pH 9. The organic layer was separated and chloroform was evaporated under reduced pressure. The resulting crystals were collected by filtration to give ethyl 7-(cis-3-aminomethyl-4-chloro-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate, m.p. 163°-167° C.
Reaction SMILES: C[Mg]Cl.[O:4]1CCC[CH2:5]1.[F:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=[O:13].[C:18]1(=[O:28])[O:23][C:21](=[O:22])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12.Cl>O>[C:18]([OH:23])(=[O:28])[C:19]1[C:20](=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:21]([OH:4])=[O:22].[F:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]([OH:13])[CH3:5]
Reactant: O=Cc1ccccc1F
Reactant: C1CCOC1
Reactant: O=C1OC(=O)c2ccccc21
Agent: C[Mg]Cl
Agent: Cl
Solvent: O
Product: CC(O)c1ccccc1F
Product: O=C(O)c1ccccc1C(=O)O
Temperature: 25 °C
Yield: 88.7 %

Procedure:
Under nitrogen atmosphere, 1300 mL (2.60 mol, 1.00 eq) of 2.0M methylmagnesium chloride-tetrahydrofuran solution was cooled, and 322.7 g (2.60 mol, 1.00 eq) of 2-fluorobenzaldehyde was added while adjusting the inside temperature to −20 to +2° C., followed by stirring for 30 minutes under a cooled condition in iced water. Conversion of methylation was 99.9% by determination by gas chromatography. Subsequently, while adjusting the inside temperature to −22 to 0° C., 385.1 g (2.60 mol, 1.00 eq) of phthalic anhydride was added, followed by stirring at room temperature through the night. Conversion of acylation was 99% or greater by determination by 1H-NMR. 1300 mL (2.60 mol, 1.00 eq) of 2.0N hydrochloric acid was added to the reaction-terminated liquid, followed by extraction with 650 mL of toluene. The recovered organic layer was washed with 650 mL of brine, dried with anhydrous sodium sulfate, concentrated under reduced pressure, and vacuum dried, thereby obtaining 706.1 g of racemic 1-(2-fluorophenyl)ethyl alcohol phthalate half ester represented by the following formula,
Reaction SMILES: Cl[C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1.[C:11]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH3:10][O:9][C:7]([C:5]1[N:6]=[C:2]([N:21]2[CH2:20][CH2:19][N:18]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:23][CH2:22]2)[S:3][CH:4]=1)=[O:8]
Reactant: COC(=O)c1csc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COC(=O)c1csc(N2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 150 °C
Yield: 35.1 %

Procedure:
Methyl 2-chlorothiazole-4-carboxylate (500 mg, 2.82 mmol), N-Boc-piperazine (655 mg, 3.52 mmol) and DIPEA (736 uL, 4.22 mmol) were dissolved in DMA (10 mL) and the reaction mixture was heated in a microwave reactor at 150° C. for 45 min. The reaction mixture was partitioned between EtOAc (40 mL) and water (40 mL) and the organic fraction was washed with water (40 mL) and brine (40 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography to give the title compound as a white solid (324 mg, 35.1%). LCMS (ES+): 350.1 [MNa]+. HPLC: Rt 6.04 min, 100% purity.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@H:28]3[CH2:33][CH2:32][C@H:31]([CH2:34][OH:35])[CH2:30][CH2:29]3)=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([C:15]([CH3:27])=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[C:36]1([CH3:56])[CH:41]=[CH:40][C:39]([S:42]([O:45]S(C2C=CC(C)=CC=2)(=O)=O)(=[O:44])=[O:43])=[CH:38][CH:37]=1.[C:57](=O)(O)[O-].[Na+]>N1C=CC=CC=1>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@H:28]3[CH2:33][CH2:32][C@H:31]([CH2:34][OH:35])[CH2:30][CH2:29]3)=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([C:15]([CH3:27])=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[CH3:56][C:36]1[CH:41]=[CH:40][C:39]([S:42]([O:45][CH3:57])(=[O:44])=[O:43])=[CH:38][CH:37]=1
Reactant: O=C([O-])O
Reactant: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Agent: Cc1cc(-c2ccccc2)nc2cc(-c3nc([C@H]4CC[C@H](CO)CC4)n4ccnc(N)c34)ccc12
Agent: Cc1cc(-c2ccccc2)nc2cc(-c3nc([C@H]4CC[C@H](CO)CC4)n4ccnc(N)c34)ccc12
Agent: [Na+]
Solvent: c1ccncc1
Product: COS(=O)(=O)c1ccc(C)cc1
Reaction time: 24 h

Procedure:
trans-{4-[8-Amino-(4-methyl-2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl]cyclohexyl}methanol (200 mg, 0.43 mmol) and toluene-4-sulfonic anhydride (150 mg, 0.47 mmol) were dissolved in anhydrous pyridine (8.7 mL) under nitrogen and allowed to sit at −10° C. for 24 h. Saturated aqueous sodium bicarbonate solution (10 mL) was added to the reaction mixture, then, stirred for 10 min. The reaction mixture was concentrated in vacuo, then, partitioned between saturated aqueous sodium bicarbonate solution and dichloromethane. The organic extract was separated, washed once again with sodium bicarbonate (aq) and brine, dried over anhydrous sodium sulfate, then concentrated in vacuo. The crude mixture was purified by a silica gel column chromatography [Jones Flashmaster; 10 g column, dry-loaded with silica gel; eluted with 100% DCM to 1:1 EtOAc/DCM to 10% (7N ammonia/MeOH)/chloroform] to obtain the desired mono-tosylated product as a yellow solid; 1H NMR (d6-DMSO, 400 Hz) δ 8.29 (dd, J=8.4, 1.2 Hz, 2H), 8.22 (d, J=1.2 Hz, 1H), 8.19 (d, J=8.8 Hz, 1H), 8.06 (s, 1H), 7.90 (dd, J=8.4, 1.2 Hz, 1H), 7.82 (m, 2H), 7.69 (d, J=5.2 Hz, 1H), 7.563 (m, 2H), 7.50 (m, 3H), 7.08 (d, J=4.8 Hz, 1H), 6.19 (br s, 2H), 3.92 (d, J=5.6 Hz, 2H), 3.10 (m, 1H), 2.08 (s, 3H), 2.44 (s, 3H), 2.00 (m, 2H), 1.77 (m, 2H), 1.66 (m, 2H), 1.20 (m, 2H); MS (ES+): m/z 618.32 (40) [MH+], 426.21 (60) [M-191], 412.52 (100) [M-205]; tR(polar—5 min/MDPS) 3.03 min.
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2([CH2:12][CH2:11][CH2:10][CH:9]([CH2:13][OH:14])[CH2:8]2)OCC1.F[C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:18][C:17]=1[N+:26]([O-:28])=[O:27].O>O1CCCC1>[N+:26]([C:17]1[CH:18]=[C:19]([S:22]([NH2:25])(=[O:23])=[O:24])[CH:20]=[CH:21][C:16]=1[O:14][CH2:13][CH:9]1[CH2:10][CH2:11][CH2:12][C:7](=[O:3])[CH2:8]1)([O-:28])=[O:27]
Reactant: OCC1CCCC2(C1)OCCO2
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(OCC2CCCC(=O)C2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Into a 250 mL round-bottomed flask was added sodium hydride (0.5 g) in tetrahydrofuran (10 mL) and then 1,4-dioxaspiro[4.5]decan-7-ylmethanol (0.5 g) was added. After the mixture stirred at room temperature for 20 minutes, 4-fluoro-3-nitrobenzenesulfonamide (0.65 g) was added. The mixture was stirred at room temperature for overnight. Water (20 mL) was added slowly. The aqueous layer was extracted by dichloromethane (3×20 mL). The combined organic layers were dried over Na2SO4. After filtration, and concentration of the filtrate, the residue was purified by reverse phase chromatography, eluting with 30-60% acetonitrile in water with 0.1% trifluoroacetic acid.
Reaction SMILES: [CH2:1]([CH:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:2]=[CH2:3].[C:15](#[N:18])C=C>C1(C)C=CC=CC=1>[C:15](/[CH:3]=[CH:2]\[CH2:1][CH:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])#[N:18]
Reactant: C=CC#N
Reactant: C=CCC(C(=O)OCC)C(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C/C=C\C#N)C(=O)OCC
Reaction time: 40 h
Yield: 60.2 %

Procedure:
A solution of 100.0 mg (0.48 mmol) diethyl allylmalonate, 77.4 mg (1.45 mmol) acrylonitrile and 35.0 mg (0.05 mmol) [RuCl2(ImH2Mes)((4-chloro-2-trifluoromethyl-8-quinolinyl)methylene)] in 5 ml toluene was stirred at 110° C. To monitor the conversion and selectivity, 0.05-ml samples were taken were taken after 3 h and 40 h. Each sample was filtered over a silica gel pad, the filtrate was evaporated to dryness and analyzed by GC (column: HP-5, 5% phenyl methyl siloxan (Agilent 19091-413); injector: 250° C.; detector: 250° C.; oven: 100 to 150° C./5° C. per min, 5 min at 150° C., 150 to 200° C./5° C. per min and 200 to 300° C./20° C. per min; carrier gas: He (0.46 bar); retention times: 9.2 min diethyl allylmalonate, 17.5 min (Z)-diethyl 2-[3-cyano-2-propenyl]malonate and 18.8 min (E)-diethyl 2-[3-cyano-2-propenyl]malonate). After 3 h (66% conversion), 57% of the title compound and after 40 h (94% conversion) 83% of the title compound as an (E):(Z) mixture of 1:2 was formed. After evaporation of the solvent under reduced pressure, the crude product was purified by silica gel chromatography (cyclohexane/ethyl acetate 8:2) to yield 65.1 mg (60%) of the title compound as a (E):(Z) mixture of 1:2. MS: 226.3 (M+). 1H-NMR of diethyl 2-[3-cyano-2-propenyl]malonate (300 MHz, C6D6): (Z)-isomer: 1.29 (t, J=7.1 Hz, 6H); 2.99 (td, J=7.1, 1.5 Hz, 2H); 3.51 (t, J=7.0 Hz, 1H); 4.20-4.24 (m, 4H); 5.40-5.42 (m, 1H); 6.54 (m, 1H). (E)-isomer: 1.28 (t, J=7.1 Hz, 6H); 2.79 (td, J=7.1, 1.5 Hz, 2H); 3.46 (t, J=7.1 Hz, 1H); 4.20-4.24 (m, 4H); 5.40-5.42 (m, 1H); 6.68 (m, 1H).
Reaction SMILES: C(O[C:6](=O)[N:7]([C:9]1[N:17]=[CH:16][N:15]=[C:14]2[C:10]=1[N:11]=[CH:12][N:13]2[C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][C:28]2[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38](=[O:45])[NH:39][CH:40]([CH2:43][OH:44])[CH2:41][OH:42])[CH:29]=2)=[O:26])=[CH:20][CH:19]=1)C)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>O>[OH:42][CH2:41][CH:40]([NH:39][C:38](=[O:45])[C:30]1[CH:31]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:33]=[C:28]([NH:27][C:25]([NH:24][C:21]2[CH:22]=[CH:23][C:18]([N:13]3[CH:12]=[N:11][C:10]4[C:14]3=[N:15][CH:16]=[N:17][C:9]=4[NH:7][CH3:6])=[CH:19][CH:20]=2)=[O:26])[CH:29]=1)[CH2:43][OH:44]
Reactant: CN(C(=O)OC(C)(C)C)c1ncnc2c1ncn2-c1ccc(NC(=O)Nc2cc(C(=O)NC(CO)CO)cc(C(F)(F)F)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CNc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2cc(C(=O)NC(CO)CO)cc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
To 40.8 mg (0.063 mmol) of [9-(4-{3-[3-(2-hydroxy-1-hydroxymethyl-ethyl-carbamoyl)-5-trifluoromethylphenyl]ureido}phenyl)-9H-purin-6-yl]-methyl-carbamic acid tert-butyl ester, 1 mL of trifluoroacetic acid was added and the mixture solution was stirred at room temperature for one hour. The solvent was distilled under reduced pressure from the reaction solution and the obtained residue was dissolved in methanol (1 mL) and water (60 μL), and 43.7 mg (0.315 mmol) of potassium carbonate was added thereto, and the mixture solution was stirred at room temperature for 1.5 hours. Water was added to the reaction solution and the obtained solid was collected by filtration and dried under reduced pressure to obtain 32 mg (93%) of a target product as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[F:12][C:13]([F:26])([O:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1)[C:14]([F:17])([F:16])[F:15]>>[Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:23][C:22]1[CH:21]=[CH:20][C:19]([O:18][C:13]([F:12])([F:26])[C:14]([F:15])([F:16])[F:17])=[CH:25][CH:24]=1)=[O:9]
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Reactant: Nc1ccc(OC(F)(F)C(F)(F)F)cc1
Product: O=C(Nc1ccc(OC(F)(F)C(F)(F)F)cc1)c1cnc(Cl)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described infashion to that described in Stage 169.2 using 5-bromo-6-chloro-nicotinic acid and 4-(perfluoroethoxy)aniline to afford an off-white crystalline solid. HPLC (Condition 4) tR=6.73 min, UPLC-MS (Condition 3) tR=1.30 min, m/z=443.1 [M−H]−.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[OH:11])(=[O:3])[CH3:2].[C:12](=S)=[S:13].CC(C)([O-])C.[K+].C(O)(=O)C>C1(C)C=CC=CC=1>[Br:10][C:8]1[CH:7]=[CH:6][C:5]2[O:11][C:12]([SH:13])=[CH:2][C:1](=[O:3])[C:4]=2[CH:9]=1
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: S=C=S
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: O=c1cc(S)oc2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 2-acetyl-4-bromophenol (20 g) and carbon disulfide (7 ml) in toluene (400 ml) was added dropwise to a suspension of potassium tert.-butoxide (31.4 g) in toluene (500 ml) at 10° C. The mixture was stirred at room temperature for 72 hours. Glacial acetic acid (35 ml) was added and the mixture evaporated under reduced pressure. The residue was treated with water (200 ml) and glacial acetic acid (20 ml) to precipitate an oily solid. Light petroleum (b.p. 40-60° C.) was added and the mixture stirred for one hour, filtered and the solid was collected and washed with light petroleum to give 6-bromo-2-mercapto-4H-1-benzopyran-4-one, m.p. 230° C. (compound 1)
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[O:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][CH:9]2[CH2:13][CH2:12][NH:11][C:10]2=[O:14])=[CH:6][CH:5]=1.Br[C:20]1[S:21][C:22]([C:26]([NH:28][CH2:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)=[O:27])=[C:23]([CH3:25])[N:24]=1>>[CH3:25][C:23]1[N:24]=[C:20]([N:11]2[CH2:12][CH2:13][CH:9]([CH2:8][C:7]3[CH:15]=[CH:16][C:4]([O:3][C:2]([F:17])([F:1])[F:18])=[CH:5][CH:6]=3)[C:10]2=[O:14])[S:21][C:22]=1[C:26]([NH:28][CH2:29][C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1)=[O:27]
Reactant: O=C1NCCC1Cc1ccc(OC(F)(F)F)cc1
Reactant: Cc1nc(Br)sc1C(=O)NCc1cccnc1
Product: Cc1nc(N2CCC(Cc3ccc(OC(F)(F)F)cc3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 34 %

Procedure:
Following the procedure as described in Example 8, making variations as required to use 3-(4-(trifluoromethoxy)benzyl)pyrrolidin-2-one in place of 3-(4-fluorobenzyl)pyrrolidin-2-one to react with 2-bromo-4-methyl-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide, the title compound was obtained as a white solid in 34% yield: mp 158-160° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 8.58 (s, 1H), 8.49 (d, J=4.0 Hz, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.31-7.06 (m, 5H), 6.43 (t, J=5.7 Hz, 1H), 4.58 (d, J=5.7 Hz, 2H), 4.06 (ddd, J=11.5, 8.0, 3.1 Hz, 1H), 3.86 (td, J=11.5, 8.0 Hz, 1H), 3.23 (dd, J=13.9, 4.4 Hz, 1H), 3.08-2.94 (m, 1H), 2.83-2.74 (m, 1H), 2.60 (s, 3H), 2.34-2.19 (m, 1H), 1.94-1.87 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 174.6, 162.5, 155.4, 153.2, 149.3, 148.9, 148.0, 138.1, 136.9, 135.7, 133.9, 130.3, 123.7, 121.2, 118.3, 45.9, 44.3, 41.5, 35.7, 24.3, 17.3; MS (ES+) m/z 491.3 (M+1).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([NH:6][CH:7]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]2[CH:20]=[CH:21][CH:22]=[CH:23][C:10]=2[N:9]([CH3:24])[C:8]1=[O:25])=[O:5])[CH3:3].[Cl:26][CH2:27][C:28](Cl)=[O:29]>C(Cl)Cl>[Cl:26][CH2:27][C:28]([NH:1][C@H:2]([C:4]([NH:6][CH:7]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]2[CH:20]=[CH:21][CH:22]=[CH:23][C:10]=2[N:9]([CH3:24])[C:8]1=[O:25])=[O:5])[CH3:3])=[O:29]
Reactant: O=C(Cl)CCl
Reactant: C[C@H](N)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O
Solvent: ClCCl
Product: C[C@H](NC(=O)CCl)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O
Reaction time: 0.25 h
Yield: 97.3 %

Procedure:
A solution of 3-(L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (20.0 mg, 0.0595 mmol), α-chloroacetyl chloride (5.9 uL, 0.0744 mmol) and piperidinylmethyl polystyrene (59.5 mg, 3.6 mmol/g (Fluka)) in 1 mL of methylene chloride were shaken for 20 min. Aminomethyl polystyrene (58 mg, 3.0 mmol/g (Advanced Chemtech)) was then added and the reaction mixture was shaken for an additional 15 min. and filtered. Removal of the solvent under reduced pressure provided 23.9 mg (98%) of the crude product which was used without further purification.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][CH2:5][N:4]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])#[N:2].[N-:24]=[N+:25]=[N-:26].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[NH:24]1[C:1]([CH:3]2[CH2:8][CH:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][CH2:5][N:4]2[C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])=[N:2][N:26]=[N:25]1
Reactant: CCOC(=O)C1CCN(C(=O)OCc2ccccc2)C(C#N)C1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN(C(=O)OCc2ccccc2)C(c2nnn[nH]2)C1
Temperature: 95 °C
Yield: 98.6 %

Procedure:
1-Benzyl 4-ethyl 2-cyanopiperidine-1,4-dicarboxylate (2.5 g, 7.90 mmol) was dissolved in toluene (50 mL) and sodium azide (0.822 g, 12.64 mmol) and triethylamine hydrochloride (1.740 g, 12.64 mmol) were added and the mixture was heated at 95° C. overnight. The reaction mixture was allowed to cool to room temperature and was washed with 2 M HCl. The aqueous phase was extracted with EtOAc and the combined organic phase was dried over Na2SO4 and evaporated to yield 1-benzyl 4-ethyl 2-(1H-tetrazol-5-yl)piperidine-1,4-dicarboxylate (2.8 g, 99%). MS m/z 360 (M+H)+
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][CH2:32][NH2:33])[N:18]=[C:17]([C:34]3[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[S:40]1[CH:44]=[CH:43][CH:42]=[C:41]1[S:45](Cl)(=[O:47])=[O:46]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][CH2:32][NH:33][S:45]([C:41]3[S:40][CH:44]=[CH:43][CH:42]=3)(=[O:47])=[O:46])[N:18]=[C:17]([C:34]3[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=3)[N:16]=2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(-c2ccncc2)nc1OCCN
Reactant: O=S(=O)(Cl)c1cccs1
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(-c2ccncc2)nc1OCCNS(=O)(=O)c1cccs1

Procedure:
According to the procedure described in Example 4a) 20 mg 4-tert.-butyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-benzene-sulfonamide was reacted with thiophene-2-sulfonylchloride to give 20 mg 4-tert.-butyl-N-[6-(2-(thiophene-2-sulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-benzene-sulfonamide. LC-MS: tR=5.17 min, [M+1]+=696.57.
Reaction SMILES: [N:1]1([C:6]2[NH:11][C:10]3[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][C:9]=3[S:8](=[O:21])(=[O:20])[N:7]=2)[CH:5]=[CH:4]N=C1.[CH:22]1(CN)C[CH2:23]1>>[CH:4]1([CH2:5][NH:1][C:6]2[NH:11][C:10]3[CH:12]=[CH:13][C:14]([C:16]([F:17])([F:19])[F:18])=[CH:15][C:9]=3[S:8](=[O:20])(=[O:21])[N:7]=2)[CH2:23][CH2:22]1
Reactant: O=S1(=O)N=C(n2ccnc2)Nc2ccc(C(F)(F)F)cc21
Reactant: NCC1CC1
Product: O=S1(=O)N=C(NCC2CC2)Nc2ccc(C(F)(F)F)cc21

Procedure:
3-(Imidazol-1-yl)-7-trifluoromethyl-4H-1,2,4-benzothiadiazine 1,1-dioxide was treated with cyclopropylmethylamine according to the general procedure Method D to give the title compound; m.p. 266-268° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[CH2:5][CH:6]1[CH2:11][CH:10]([C:12]([O:14][CH3:15])=[O:13])[CH2:9][CH2:8][NH:7]1.CCN(C(C)C)C(C)C.[C:29](Cl)(=[O:32])[O:30][CH3:31]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[CH2:5][CH:6]1[CH2:11][CH:10]([C:12]([O:14][CH3:15])=[O:13])[CH2:9][CH2:8][N:7]1[C:29]([O:30][CH3:31])=[O:32]
Reactant: COC(=O)Cl
Reactant: COC(=O)C1CCNC(Cc2ccc(F)c(F)c2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(Cc2ccc(F)c(F)c2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.5 %

Procedure:
Methyl 2-(3,4-difluorobenzyl)piperidine-4-carboxylate (8.115 g, 30.14 mmol) was dissolved in DCM (200 mL) and DIPEA (6.30 mL, 36.16 mmol), then methyl carbonochloridate (3.3 mL, 41.91 mmol) was added. The solution was stirred at room temperature for 2 h. The reaction mixture was washed with 0.1 M HCl satd NaHCO3. The organic phase was passed through a phase separator and evaporated. The residue was redissolved in ether/pentane, 80/20, the solution washed with 1 M HCl 5 times, then with satd NaHCO3 and brine, dried over MgSO4, filtered and evaporated to yield dimethyl 2-(3,4-difluorobenzyl)piperidine-1,4-dicarboxylate (7.05 g, 71%). MS m/z 328 (M+H)+
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:22][NH2:23])=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:26]([O:30][C:31]([NH:33][C@H:34]([CH:38]([CH3:40])[CH3:39])[C:35](O)=[O:36])=[O:32])([CH3:29])([CH3:28])[CH3:27].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>C1COCC1>[F:25][C:2]([F:24])([F:1])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:22][NH:23][C:35](=[O:36])[C@H:34]([NH:33][C:31](=[O:32])[O:30][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:38]([CH3:40])[CH3:39])=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: NNC(=O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)NNC(=O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Temperature: -60 °C
Reaction time: 1 h
Yield: 22 %

Procedure:
In a 10 mL round-bottom flask, (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylohydrazide (0.05 g, 1.0 eq.) was dissolved in THF (5 mL) and cooled to −60° C. where (R)-2-((tert-butoxycarbonyl)amino)-3-methylbutanoic acid (0.038 g, 1.3 eq.) was introduced dropwise. T3P (50% in EtOAc) (0.16 mL, 2 eq.) was added dropwise followed by DIPEA (0.095 mL, 4 eq.) and the reaction mixture was stirred for 1 h at −60° C. The reaction mixture was concentrated under reduced pressure (25° C., 20 mm Hg) to afford the crude product that was purified by column chromatography (60/120 silica gel) using methanol/dichloromethane gradient (the column was packed in dichloromethane and the desired compound started eluting from 3% methanol/dichloromethane). Fractions containing the desired compounds were combined to afford (R,Z)-tert-butyl (1-(2-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)hydrazinyl)-3-methyl-1-oxobutan-2-yl)carbamate (0.017 g, yield: 26%). In a 10 mL round-bottom flask, (R,Z)-tert-butyl (1-(2-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)hydrazinyl)-3-methyl-1-oxobutan-2-yl)carbamate was then dissolved in dichloromethane (2 mL). TFA (0.2 mL) was added and the reaction mixture was stirred at RT for 5 h. The reaction mixture was concentrated under reduced pressure (25° C., 20 mm Hg) to afford the crude product (0.02 g), which was triturated with petroleum ether and dried under reduced pressure to yield (R,Z)-2-amino-N′-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)-3-methylbutanehydrazide 2,2,2-trifluoroacetate (0.007 g, yield: 35%).
Reaction SMILES: [CH3:1][C:2]([CH3:6])([OH:5])[C:3]#[N:4].[CH2:7]([O:9]CC)[CH3:8].[ClH:12]>C(O)C>[ClH:12].[CH3:1][C:2]([CH3:6])([OH:5])[C:3](=[NH:4])[O:9][CH2:7][CH3:8]
Reactant: CC(C)(O)C#N
Reactant: CCOCC
Agent: Cl
Solvent: CCO
Product: CCOC(=N)C(C)(C)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Four grams of 2-methyllactonitrile is added to 100 ml. of diethyl ether containing 10 ml. of ethanol followed by saturation of the resulting solution with hydrogen chloride gas. The reaction mixture is allowed to stir at room temperature for 18 hrs. and subsequently concentrated to an oil which on slurrying in ether gave 7.2 g. of the desired product.