Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][C:8]2[NH:7][C:6]3[N:11]=[CH:12][C:13]([C:15]4[CH:20]=[CH:19][C:18]([CH2:21][N:22]5[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]5)=[CH:17][CH:16]=4)=[CH:14][C:5]=3[C:4]=2[CH:3]=1.C(N(CC)C(C)C)(C)C.[CH3:37][Si:38]([C:41]#[CH:42])([CH3:40])[CH3:39]>O1CCOCC1.C(Cl)Cl.CO.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:37][Si:38]([C:41]#[C:42][C:2]1[N:10]=[CH:9][C:8]2[NH:7][C:6]3[N:11]=[CH:12][C:13]([C:15]4[CH:20]=[CH:19][C:18]([CH2:21][N:22]5[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]5)=[CH:17][CH:16]=4)=[CH:14][C:5]=3[C:4]=2[CH:3]=1)([CH3:40])[CH3:39]
Reactant: C#C[Si](C)(C)C
Reactant: Brc1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: C[Si](C)(C)C#Cc1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Temperature: 110 °C

Procedure:
A mixture of 6-bromo-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (170 mg, 0.40 mmol), copper(I) iodide (7.7 mg, 0.04 mmol), and N,N-diisopropylethylamine (0.21 mL, 1.2 mmol) in anhydrous 1,4-dioxane (3 mL) was degassed and flushed with nitrogen. Tetrakis(triphenylphosphine)palladium(0) (47 mg, 0.04 mmol) and (trimethylsilyl)acetylene (0.34 mL, 2.4 mmol) were added and the reaction mixture heated at 110° C. for 1 h. The cooled reaction mixture was diluted with DCM (20 mL) and methanol (2 mL) and washed with water (15 mL). The organic phase was separated, dried over sodium sulfate, filtered and evaporated in vacuo to afford a residue that was purified by flash chromotagraphy (silica, 10 g column, Biotage, 0-10% methanol in (DCM containing 1% 7M ammonia in methanol) to afford a brown residue that was taken to the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:13]3[C:12](=[O:14])[CH2:11][CH2:10][C:9]=3[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:15][C:16]([CH3:18])=O.IC#N>O1CCCC1>[CH3:1][C:2]1[O:3][C:4]2[C:13]3[C:12](=[O:14])[C:11](=[C:16]([CH3:18])[CH3:15])[CH2:10][C:9]=3[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: CC(C)=O
Reactant: Cc1nc2ccc3c(c2o1)C(=O)CC3
Agent: N#CI
Solvent: C1CCOC1
Product: CC(C)=C1Cc2ccc3nc(C)oc3c2C1=O
Temperature: 50 °C
Reaction time: 9 h
Yield: 32.7 %

Procedure:
2-Methyl-6,7-dihydro-8H-indeno[5,4-d][1,3]oxazol-8-one (1.87 g, 10.0 mmol), acetone (3.68 mL, 50.0 mmol) and ICN Alumina B (manufactured by ICN, Akt.1, 20 g) were suspended in tetrahydrofuran (50 mL), and the mixture was stirred at 50° C. for 9 hr. Acetone (3.68 mL, 50.0 mmol) was added, and the mixture was further stirred for 12 hr. The reaction solution was filtered, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90→50/50) to give the title compound (742 mg, yield 33%).
Reaction SMILES: C[O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[CH:17]=3)=[C:11]([CH3:28])[N:10]=2)=[CH:7][N:6]=[C:5]([NH:29][CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[N:4]=1.[Si](I)(C)(C)C.[O-]S([O-])(=S)=O.[Na+].[Na+].C1COCC1.CCOC(C)=O>ClCCCl>[CH3:28][C:11]1[N:10]=[C:9]([C:8]2[C:3](=[O:2])[NH:4][C:5]([NH:29][CH:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)=[N:6][CH:7]=2)[CH:14]=[CH:13][C:12]=1[O:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]2[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=2)[CH:17]=1
Reactant: COc1nc(NC2CCOCC2)ncc1-c1ccc(Oc2ccnc(-c3cnn(C)c3)c2)c(C)n1
Agent: C[Si](C)(C)I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: Cc1nc(-c2cnc(NC3CCOCC3)[nH]c2=O)ccc1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 6.3 %

Procedure:
A solution of 4-methoxy-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-amine (0.125 g, 0.264 mmol) in DCE (3 mL) was treated with TMS-I (1.078 mL, 7.92 mmol), heated at 60° C. for 5 h, then cooled to RT and stirred overnight. The mixture was treated with 10% Na2S2O3 and 1:1 THF/EtOAc, stirred for 0.5 h, the layers separated, the aqueous layer extracted with EtOAc (1×) and the combined organics were washed with brine, dried over MgSO4 and concentrated to dryness. The material was treated with MeCN, heated to near-reflux and allowed to stand at RT over the weekend. The solid was removed via filtration, the filtrate concentrated to dryness and purified via silica gel chromatography (MeOH/EtOAc). The resulting material was treated with 10% MeOH/DCM, filtered to remove solids and concentrated to dryness to afford 5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4(3H)-one (7.7 mg, 6%). 1H NMR (400 MHz, DMSO-d6): δ10.96 (br s, 1H), 8.67 (s, 1H), 8.35 (d, J=5.7 Hz, 1H), 8.29-8.24 (m, 2H), 7.96 (s, 1H), 7.51 (d, J=8.6 Hz, 1H), 7.22 (d, J=2.4 Hz, 1H), 7.00 (br s, 1H), 6.60 (dd, J=5.7, 2.4 Hz, 1H), 3.98 (m, 1H), 3.87-3.80 (m, 5H), 3.39 (m, 2H), 2.34 (s, 3H), 1.85 (m, 2H), 1.47 (m, 2H); MS (ESI) m/z: 460.2 (M+H+).
Reaction SMILES: CN1CCOCC1.Cl[C:9]([O:11][CH:12]([CH3:16])[CH2:13][O:14][CH3:15])=[O:10].[C:17]([C:19]1[CH:36]=[CH:35][C:22]([O:23][CH2:24][CH:25]([NH:27][C:28](=[O:34])[C@H:29]([CH:31]([CH3:33])[CH3:32])[NH2:30])[CH3:26])=[CH:21][CH:20]=1)#[N:18].O>C(Cl)Cl>[C:17]([C:19]1[CH:20]=[CH:21][C:22]([O:23][CH2:24][CH:25]([NH:27][C:28](=[O:34])[C@H:29]([CH:31]([CH3:32])[CH3:33])[NH:30][C:9]([O:11][CH:12]([CH3:16])[CH2:13][O:14][CH3:15])=[O:10])[CH3:26])=[CH:35][CH:36]=1)#[N:18]
Reactant: COCC(C)OC(=O)Cl
Reactant: CC(COc1ccc(C#N)cc1)NC(=O)[C@@H](N)C(C)C
Solvent: ClCCl
Solvent: O
Solvent: CN1CCOCC1
Product: COCC(C)OC(=O)N[C@H](C(=O)NC(C)COc1ccc(C#N)cc1)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.6 %

Procedure:
1.0 g of N-methylmorpholine, and subsequently 0.7 g of 2-methoxy-1-methylethyl chloroformate were added to a suspension containing 1.5 g of N1 -[2-(4-cyanophenoxy)-1-methylethyl]-L-valinamide suspended in 150 ml of methylene chloride at -20° C. The mixture was allowed to sit and warm naturally to room temperature and stirred for 2 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed with water, the organic layer was dried over anhydrous magnesium sulfate and then the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 0.37 g of the desired product in the form of a white plated crystal (yield: 20%).
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:33]1[N:34]=[C:35]([NH:38][C:39]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[S:36][CH:37]=1)\[C:5]([NH:7][C@@H:8]1[C:31](=[O:32])[N:10]2[C:11]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)=[O:20])=[C:12](/[CH:15]=[CH:16]\[CH2:17]Cl)[CH2:13][S:14][C@H:9]12)=[O:6].[I-:58].[Na+]>CC(C)=O>[CH3:1][O:2]/[N:3]=[C:4](/[C:33]1[N:34]=[C:35]([NH:38][C:39]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[S:36][CH:37]=1)\[C:5]([NH:7][C@@H:8]1[C:31](=[O:32])[N:10]2[C:11]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)=[O:20])=[C:12](/[CH:15]=[CH:16]/[CH2:17][I:58])[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc(OC)cc3)=C(/C=C\CCl)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc(OC)cc3)=C(/C=C/CI)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72 %

Procedure:
To a solution of p-methoxybenzyl 7β-[(Z)-2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-[(Z)-3-chloro-1-propen-1-yl]3-cephem-4-carboxylate(1.5 g) dissolved in acetone(30 ml), sodium iodide(0.82 g) was added thereto under ice-cooling. The resulting solution was stirred for 15 minutes under ice-cooling and for additional 60 minutes at room temperature. The solvent was distilled off, and the residue was extracted with ethyl acetate. The extract was washed with a 10%-sodium thiosulfate and with a saturated brine, followed by drying with addition of anhydrous magnesium sulfate. The dried extract was concentrated under reduced pressure and the resulting precipitates were collected by filtration to obtain 1.2 g of p-methoxybenzyl 7β-[(Z)-2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-[(E)-3-iodo-1-propen-1-yl]3-cephem-4-carboxylate. The powder was dissolved in N,N-dimethylformamide(2 ml), and 5-dimethylaminomethyl-4-methylthiazole(0.31 g) was added thereto at -10° C. The resulting solution was stirred for 4 hours at -10° C. 10%-sodium thiosulfate(70 ml) was added to the reaction solution, and the resulting precipitates were collected by filtration to obtain the yellowish brown powder. The powder was stirred in 88% formic acid(1.8 ml) for an hour at 40° C., and acetone(400 ml) was added thereto. The resulting precipitates were collected by filtration and washed with acetone. The precipitates were chromatographed over silicagel [acetonitrile:distilled water 4:1(v/v)], Sephadex LH-20(or Amberlite XAD-2), and then lyophilized to obtain the target product (250 mg) as white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH:20]=[O:21])=[CH:12]1)(=[O:10])=[O:9].[BH4-].[Na+]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH2:20][OH:21])=[CH:12]1)(=[O:9])=[O:10]
Reactant: O=Cc1cn(S(=O)(=O)c2ccccc2Br)c2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1Br)n1cc(CO)c2ccccc21
Reaction time: 3.5 h

Procedure:
In a three-necked round bottom flask equipped with pressure equalizing funnel, 1-(2-Bromobenzenesulfonyl)-1H-indole-3-carboxaldehyde (D27 3.63 g, 0.01 mole) and dichloromethane (8 mL) were taken. Sodiumborohydride (0.005-0.01 mole) was added slowly at room temperature and the reaction mixture was stirred well for next 3-4 hours. After the completion of reaction (TLC, 3-5 hours), the product was isolated by distillation under reduced pressure. The residue was extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with water, followed by brine, dried over anhydrous sodium sulfate. The organic layer was evaporated under vacuum. The residue was generally an oily liquid, which was isolated and purified by flash chromatography (silica gel, EtOAc/Hexane, 2/8) to afford the title compound, which was identified by IR, NMR and mass spectral analyses.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][C:10]=1[CH3:18])=[O:4].[CH3:19][N:20]1[C:29]2[NH:28][C:27]3[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=3[NH:25][CH2:24][C:23]=2[CH:22]=[N:21]1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[CH3:1][O:2][C:3](=[O:4])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([N:25]2[CH2:24][C:23]3[CH:22]=[N:21][N:20]([CH3:19])[C:29]=3[NH:28][C:27]3[CH:30]=[CH:31][CH:32]=[CH:33][C:26]2=3)=[O:15])=[CH:11][C:10]=1[CH3:18]
Reactant: Cn1ncc2c1Nc1ccccc1NC2
Reactant: COC(=O)CCCCc1ccc(C(=O)O)cc1C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCCCc1ccc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)cc1C
Yield: 46 %

Procedure:
WSCD (822 mg, 4.3 mmol) and DMAP (273 mg, 2.2 mmol) were added to a solution of 4-(4-methoxycarbonyl-butyl)-3-methyl-benzoic acid from Example E31 (571 mg, 2.3 mmol) and 3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E11 (424 mg, 2.1 mmol) in dichloromethane (50 ml) and triethylamine (0.6 ml, 4.3 mmol). The mixture was heated at reflux for 72 h, diluted with dichloromethane, washed with 0.3M KHSO4, saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; EtOAc to 5% triethyamine: 95% EtOAc) to yield the title compound (424 mg, 46%).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][C:14](F)=[C:15]([F:20])[CH:16]=3)[NH:11][C:10]2=[O:22])=[CH:5][CH:4]=1.[CH3:23][NH2:24]>CS(C)=O>[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][C:14]([NH:24][CH3:23])=[C:15]([F:20])[CH:16]=3)[NH:11][C:10]2=[O:22])=[CH:5][CH:4]=1
Reactant: CN
Reactant: Nc1ccc(-n2c(=O)[nH]c3cc(F)c(F)cc3c2=O)cc1
Agent: Cl
Solvent: CS(C)=O
Product: CNc1cc2[nH]c(=O)n(-c3ccc(N)cc3)c(=O)c2cc1F
Temperature: 22 °C
Reaction time: 0.25 h
Yield: 76.5 %

Procedure:
The PP1-R2000 (200 L HP reactor) was charged with compound 5b (18 Kg, 1.0 eq.) and pressurized with 100±5 psig of nitrogen. Vent the nitrogen from the reactor through the atmospheric vent line then open the condenser valve and then charged dimethyl sulfoxide into the reactor (>99.7%, 105 Kg) under blanket of argon. The reactor contents were agitated at 22° C. (19-25° C.) for 15 mins. and then pulled maximum achievable vacuum on the 200 L HP reactor and close all the valves. Using the established vacuum charged to the 200 L HP reactor methylamine (33% wt % in absolute ethanol, 37.2 Kg) at a rate that maintains the internal temperature at 25±5° C. and kept a nitrogen blanket on the reagent solution during charging. After rinsing the charging line with dimethyl sulfoxide (5 Kg) closed the 200 L HP reactor condenser valve and heated the reactor contents to 110±5° C. The contents of the reactor were agitated for at least 5 hrs. at 110±5° C. In-process HPLC taken after 5 hr 40 mins. showed compound 5b content of 0.09%, indicating completion of the reaction (in-process specification ≦1%). The contents of 200 L HP reactor were cooled to 25±5° C. While the 200 L reactor is cooling, closed all the valves of the PP1-R1000 reactor (2000 L GL reactor) and charged with process filtered water (550 Kg). The contents of the 200 L HP reactor were transferred to the 2000 L GL reactor over 15 minutes followed by rinsing the charging line with process filtered water (50 Kg). The contents of the 2000 L GL reactor were agitated for 2 hrs at 5±5° C. The filterable solids obtained were filtered onto PPF200 (GL nutsche filter) fitted with Mel-Tuf 1149-12 filter paper under vacuum. The wet filter cake was discharged and transferred into pre-lined vacuum trays with Dupont's fluorocarbon film (Kind 100 A). Clamped down the special oven paper (KAVON 992) over the vacuum trays containing the wet compound 6 and transferred to the vacuum oven tray dryer. The oven temperature was set to 55° C. and compound 6 dried to a constant weight for 12 hrs. The product 5c was discharged (12.70 Kg) in 76.5% yield (expected 85-95%). HPLC shows 98.96% purity and 1H NMR confirmed the structure for compound 5c. 1H NMR (DMSO): δ 11.10 (s, 1H), 7.36 (d, 1H), 6.78 (d, 2H), 6.75 (m, 1H), 6.56 (d, 2H), 6.20 (d, 1H), 5.18 (d, 2H), 2.76 (d, 3H).
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]1=[O:14].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.CCN(C(C)C)C(C)C>C(#N)C>[CH2:7]([N:4]1[CH2:5][CH2:6][CH:2]([N:26]2[CH2:27][CH2:28][CH:23]([C:20]3[CH:19]=[CH:18][C:17]([O:16][CH3:15])=[CH:22][CH:21]=3)[CH2:24][CH2:25]2)[C:3]1=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1C(Br)CCN1Cc1ccccc1
Reactant: COc1ccc(C2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc(C2CCN(C3CCN(Cc4ccccc4)C3=O)CC2)cc1
Yield: 75.3 %

Procedure:
A solution of 3-bromo-1-benzyl-pyrrolidin-2-one (1.4 g, 5.1 mmol)(intermediate 3), 4-(4-methoxyphenyl)-piperidine (0.98 g, 5.1 mmol) and DIPEA (3.6 mL, 20.6 mmol) in acetonitrile (15 mL) was heated at 90° C. for 18 h. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate (150 mL), washed with water and brine, and dried over sodium sulfate. The organic layer was concentrated to yield 2.1 g of crude product, which was purified by flash chromatography on silica gel (24 g) using 100% EtOAc to yield 1-benzyl-3-(4-(4-methoxyphenyl)piperidin-1-yl)pyrrolidin-2-one (1.4 g, 71%). 1H NMR: 400 MHz, DMSO-d6: δ ppm 1.51-1.65 (m, 2H) 1.66-1.77 (m, 2H) 1.86-1.98 (m, 1H) 2.02-2.12 (m, 1H) 2.27-2.45 (m, 2H) 2.66-2.83 (m, 2H) 2.99-3.23 (m, 3H) 3.45-3.54 (m, 1H) 3.72 (s, 3H) 4.29-4.46 (m, 2H) 6.85 (d, J=9.04 Hz, 2H) 7.16 (d, J=9.04 Hz, 2H) 7.19-7.24 (m, 2H) 7.28 (s, 1H) 7.32-7.39 (m, 2H). LCMS: R.T. 1.76 min. LCMS (ES-API), 365.2 m/z (M+H).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][C:5]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:11][C:4]=2[NH:3]1.Br[CH2:37][CH2:38][C:39]#[N:40].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:31]([O:30][C:29](=[O:35])[NH:28][C:24]1([C:21]2[CH:22]=[CH:23][C:18]([C:9]3[C:10]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[CH:11][C:4]4[N:3]([CH2:37][CH2:38][C:39]#[N:40])[C:2](=[O:1])[CH2:7][O:6][C:5]=4[N:8]=3)=[CH:19][CH:20]=2)[CH2:25][CH2:26][CH2:27]1)([CH3:32])([CH3:34])[CH3:33]
Reactant: N#CCCBr
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)CO4)cc2)CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(CCC#N)C(=O)CO4)cc2)CCC1

Procedure:
A mixture of tert-butyl 1-(4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutylcarbamate (100 mg, 0.212 mmol), 3-bromopropanenitrile (85 mg, 0.636 mmol) and potassium carbonate (88 mg) in DMF (4 ml) was heated at 80 degree for 16 h.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[CH:15]=[CH:16][CH:17]=[C:8]([C:9]=23)[S:7]1(=[O:19])=[O:18].Br.Br.[OH:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O.O1CCCC1>[OH:22][C:23]1[CH:24]=[CH:25][C:26]([N:29]2[CH2:34][CH2:33][N:32]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10]4[CH:11]=[CH:12][CH:13]=[C:14]5[CH:15]=[CH:16][CH:17]=[C:8]([C:9]=45)[S:7]3(=[O:19])=[O:18])[CH2:31][CH2:30]2)=[CH:27][CH:28]=1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCCl
Reactant: Oc1ccc(N2CCNCC2)cc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCCN1CCN(c2ccc(O)cc2)CC1
Temperature: 20 °C
Yield: 69.9 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(4-chlorobutyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (3 g), 4-(4-hydroxyphenyl)piperazine dihydrobromide (3.8 g) and sodium bicarbonate (2.8 g) in a mixture of dimethylformamide (30 cc) and tetrahydrofuran (20 cc). The mixture is heated for 5 hours at boiling point, then cooled to a temperature of about 20° C. After purification by recrystallization from boiling acetone (215 cc), 2-{4-[4-(4-hydroxyphenyl)-1-piperazinyl]butyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (3.1 g) is obtained, m.p. 195° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]([O:20][CH3:21])=[O:19].Cl>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[O:9][CH2:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)CBr
Reactant: Oc1c(F)cccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2,6-difluorophenol (25 g), potassium carbonate (39.5 g) and acetone (100 ml) was added dropwise with stirring at room temperature a solution of methyl bromoacetate (17.8 ml) in acetone (100 ml). After stirring at room temperature overnight, the reaction mixture was taken up in a mixture of conc. hydrochloric acid (40 ml) and ice water (500 ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure gave methyl 2,6-difluorophenoxyacetate (38 g) as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][N:3]=1.[C:9](#[N:13])[CH:10]([CH3:12])[CH3:11].C[Si]([N-][Si](C)(C)C)(C)C.NC1N=CC(C2C=CN=C(C3(C#N)CCOCC3)C=2)=NC=1C1ON=C(C2C=CC(CNC)=CC=2)C=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[I:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:10]([CH3:12])([CH3:11])[C:9]#[N:13])[CH:7]=1
Reactant: CC(C)C#N
Reactant: Clc1cc(I)ccn1
Agent: CNCc1ccc(-c2cc(-c3nc(-c4ccnc(C5(C#N)CCOCC5)c4)cnc3N)on2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C#N)c1cc(I)ccn1
Temperature: 0 °C
Reaction time: 3 h
Yield: 65.1 %

Procedure:
An oven-dried flask was evacuated and back-filled with nitrogen three times. The flask was charged with 2-chloro-4-iodo-pyridine (3 g, 12.53 mmol) and isobutyronitrile (865.9 mg, 1.125 mL, 12.53 mmol) in anhydrous toluene (30.00 mL). The reaction mixture was cooled to 0° C. and treated with bis(trimethylsilyl)azanide in tetrahydrofuran (sodium ion (1)) (12.53 mL of 1 M, 12.53 mmol) over a period of 5 minutes. The reaction mixture was allowed to warm to ambient temperature and stirred at this temperature for 3 hours. The reaction mixture was diluted with ethyl acetate and washed with 1 M hydrochloric acid. The aqueous layer was extracted with ethyl acetate (×3) and the combined organic extracts dried MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion, 80 g column) loaded with dichloromethane and eluted with 0 to 30% ethyl acetate/petroleum ether. Product fractions were combined and concentrated in vacuo to give the sub-title product as an off-white solid (2.22 g, 65% Yield). 1H NMR (400.0 MHz, DMSO-d6) δ 1.70 (s, 6H), 7.84 (dd, 1H), 7.98 (d, 1H) and 8.31 (d, 1H) ppm; LC/MS m/z 273.0 [M+H]+
Reaction SMILES: [CH:1](=[C:8]1/[N:9]=[C:10]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])[NH:11][C:12]/1=[O:13])/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1/[CH:30]=[CH:31]/[CH:32]=[O:33]>>[F:21][C:15]1[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=1[C:10]1[NH:11][C:12]2[O:13][C:32](=[O:33])[CH:31]([CH2:30][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[O:23][CH3:22])[CH:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:8]=2[N:9]=1
Reactant: COc1ccccc1/C=C/C=O
Reactant: O=C1NC(c2cc(F)ccc2F)=N/C1=C\c1ccccc1
Product: COc1ccccc1CC1C(=O)Oc2[nH]c(-c3cc(F)ccc3F)nc2C1c1ccccc1
Yield: 61 %

Procedure:
Prepared according to the general procedure using (Z)-4-benzylidene-2-(2,5-difluorophenyl)-1H-imidazol-5(4H)-one and (E)-3-(2-methoxyphenyl)acrylaldehyde. The unpurified residue was purified by flash chromatography using 15% EtOAc/hexanes to afford 10 as an off-white solid (81 mg, 61%). Analytical data for 10: 1H NMR (500 MHz, CDCl3) δ 9.34 (d, J=8.1 Hz, 1H), 7.89 (ddd, J=9.2, 6.0, 3.2 Hz, 1H), 7.38-7.29 (m, 3H), 7.27-7.21 (m, 1H), 7.09-7.00 (m, 3H), 7.00-6.92 (m, 1H), 6.91 (dd, J=7.6, 1.8 Hz, 1H), 6.86 (ap t, J=7.5 Hz, 2H), 4.06 (d, J=6.9 Hz, 1H), 3.84 (ddd, J=8.9, 6.9, 5.2 Hz, 1H), 3.80 (s, 3H), 3.26 (dd, J=14.2, 5.2 Hz, 1H), 2.49 (dd, J=14.2, 8.8 Hz, 1H); 13C NMR (CDCl3, 126 MHz) δ 169.4, 159.1 (d, JCF=243.7 Hz), 157.8, 155.3 (d, JCF=240.5 Hz), 148.9, 137.6, 136.1, 131.9, 129.1, 128.1, 128.0, 126.0, 120.2, 117.1 (dd, JCF=25.8, 8.7 Hz), 116.4 (dd, JCF=24.7, 9.4 Hz), 114.5 (dd, JCF=27.5, 3.0 Hz), 111.3 (d, JCF=2.9 Hz), 110.1, 55.2, 44.8, 39.0, 29.1; IR (film) cm−1 1773, 1637, 1482, 1464, 1243, 1173, 1122, 1101, 1030, 813, 765, 738, 700; LRMS (ESI): Mass calcd for [M+H]+ C26H21F2N2O3: 447.1. found 447.4; Enantiomeric ratio was measured by chiral phase HPLC (Chiralcel OD-H; 5% IPA/3% MeOH/hexanes 0.5 mL/min, 280 nm), Rt1 (minor)=32.2, Rt2 (major)=42.5 min; er=96:4.