Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4](=[O:10])[C@H:5]([NH3+:9])[CH2:6][C:7]#[CH:8].Cl[C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[CH:14][N:13]=1>CS(C)=O>[N+:18]([C:17]1[C:12]([NH:9][C@H:5]([CH2:6][C:7]#[CH:8])[C:4]([O:3][CH3:2])=[O:10])=[N:13][CH:14]=[CH:15][CH:16]=1)([O-:20])=[O:19]
Reactant: C#CC[C@@H]([NH3+])C(=O)OC
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: [Cl-]
Solvent: CS(C)=O
Product: C#CC[C@@H](Nc1ncccc1[N+](=O)[O-])C(=O)OC
Reaction time: 120 h

Procedure:
(R)-1-methoxy-1-oxopent-4-yn-2-aminium chloride (6.16 g, 38 mmol) in DMSO (100 mL) added 2-chloro-3-nitropyridine (9.0 g, 56 mmol) and then 2-chloro-3-nitropyridine (9.0 g, 56 mmol). The reaction mixture was stirred for 5 d. EtOAC (500 mL) was added and the diluted reaction mixture was washed with 4×brine (200 mL), dried, evaporated to give 10 g of crude material which was purified by column chromatograph (silica gel, 20-100% hex/tolune, EtOAc) to give the title compound.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH:7]([NH:10][C:11]1[C:16]([C:17]#[N:18])=[CH:15][N:14]=[C:13]([S:19][CH3:20])[N:12]=1)([CH3:9])[CH3:8].S([O-])([O-])(=O)=O.[NH4+].[NH4+]>O1CCCC1>[NH2:18][CH2:17][C:16]1[C:11]([NH:10][CH:7]([CH3:9])[CH3:8])=[N:12][C:13]([S:19][CH3:20])=[N:14][CH:15]=1
Reactant: CSc1ncc(C#N)c(NC(C)C)n1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CSc1ncc(CN)c(NC(C)C)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.7 %

Procedure:
To a stirred 0° C. suspension of 5.9 g (156.3 mmol) of LAH in 200 mL of tetrahydrofuran is added dropwise a solution of 15.5 g (74.4 mmol) of 4-(isopropylamino)-2-(methylthio)-5-pyrimidinecarbonitrile in 500 mL of tetrahydrofuran. The reaction is allowed to warm slowly to room temperature overnight. The mixture is recooled to 0° C., and treated with a saturated solution of ammonium sulfate until there is no more effervescence. After stirring for another 15 minutes, the gray solids are filtered and washed six times with hot ethyl acetate. The combined organic washes are concentrated, and the residue is purified by chromatography in two portions on a 4×15 cm Biotage silica gel column that is eluted with 60:38:2 acetonitrile/dichloromethane/triethylamine followed by 60:33:5:2 acetonitrile/dichloromethane/methanol/triethylamine to obtain 12.9 g (82%) of the title compound as a yellow oil. Mass Spectrum (CI) (m+1)/z 213.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].Br[CH2:22][CH2:23][C:24]([N:26]([O:28][CH3:29])[CH3:27])=[O:25].[H-].[Na+].OS([O-])(=O)=O.[K+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:22][CH2:23][C:24]([N:26]([O:28][CH3:29])[CH3:27])=[O:25])[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCN1
Reactant: CON(C)C(=O)CCBr
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: CON(C)C(=O)CCN1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 65.4 %

Procedure:
A suspension of 10.02 g (32.00 mmol) of 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-[1,4]diazepan-5-one (intermediate 1A]) and 6.27 g (32.00 mmol) of 3-bromo-N-methoxy-N-methyl-propionamide (intermediate 2C]) in 225 ml of THF was treated at 0° C. with 1.54 g (35.20 mmol) of NaH (55% in oil) in two portions. The suspension was stirred 4 h at RT, cooled and treated again at 0° C. with 1.54 g (35.20 mmol) of NaH (55% in oil) in two portions. The reaction was warmed up to RT over night, treated a third time at 0° C. with 1.54 g (35.20 mmol) of NaH (55% in oil) in two portions and stirred for 30 min at 50° C. After 20 h at RT, the reaction was neutralized with cold aqueous 10% KHSO4 and extracted with EtOAc (3×). The organic phases were washed with aqueous saturated NaHCO3, aqueous 10% NaCl, dried over Na2SO4 evaporated and purified by flash silica gel column (CH2Cl2/MeOH 99:1 to 97.5:2.5) to yield 8.97 g (65%) of the title compound as an off-white foam. MS: 428.2 (MH+, 2Cl).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[N:12]=[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([OH:29])=O)[N:22]=3)[CH:10]=2)=[CH:5][CH:4]=1.S(Cl)([Cl:32])=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[N:12]=[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([Cl:32])=[O:29])[N:22]=3)[CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc(-c3ccccn3)nc(-c3cccc(C(=O)O)n3)c2)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(-c2cc(-c3ccccn3)nc(-c3cccc(C(=O)Cl)n3)c2)cc1

Procedure:
To 1 g of 4′-(4-methoxyphenyl)-2,2′:6′2″-terpyridine-6-carboxylic acid is added a solution of 1 mL of thionyl chloride in 25 mL of methylene chloride. The reaction mixture is heated gently for 1 hour, and the solvent and excess thionyl chloride are removed under reduced pressure. The crude product is triturated with anhydrous heptane and isolated by filtration under nitrogen.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23](I)=[CH:22][C:21]=1[F:29].COC1CCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH2:1]([S:8][C:9]1[CH:15]=[CH:14][C:12]([NH:13][C:23]2[CH:22]=[C:21]([F:29])[C:20]([Br:19])=[CH:25][C:24]=2[O:26][CH3:27])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(Br)c(F)cc1I
Reactant: Nc1ccc(SCc2ccccc2)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COC1CCCC1
Solvent: CCOC(C)=O
Product: COc1cc(Br)c(F)cc1Nc1ccc(SCc2ccccc2)cc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 104.5 %

Procedure:
A RBF was charged with 4-(benzylthio)-2-nitroaniline (13.72 g, 47.4 mmol), 1-bromo-2-fluoro-4-iodo-5-methoxybenzene (17.27 g, 52.2 mmol), Xantphos (1.372 g, 2.372 mmol), Pd2(dba)3 (1.086 g, 1.186 mmol), CPME (95 ml) and cesium carbonate (23.18 g, 71.2 mmol) were added. A reflux condenser was attached and the flask was lowered into a 90° C. heating bath. The mixture was stirred overnight. In the morning, the solid was scraped of the bottom of the flask, and an additional portion of cesium carbonate (23.18 g, 71.2 mmol) was added. The flask was returned to the heat with vigorous stirring for 3 h. After cooling, the mixture was diluted with EtOAc and filtered through celite with the aid of EtOAc. The filtrate was concentrated, and the residue was dissolved in DCM and loaded onto a pre-equilibrated 340-g SNAP Ultra column. The column was eluted with 0-30% EtOAc/Heptane. The material crashed out on the column, so the elution was changed to 0-50% EtOAc/Heptane with 10% DCM. The eluent was raised to 100% EtOAc, 20% DCM. Fractions containing product were combined and concentrated to give 22.96 g (>100% yield) of N-(4-(benzylthio)-2-nitrophenyl)-4-bromo-5-fluoro-2-methoxyaniline as a red solid that was 80-90% pure by LCMS. m/z (ESI) 563.0 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:8][CH2:9][C:10](=[O:14])[NH:11][C:12]=2[N:13]=1)([O-])=O>CO.Cl.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[O:8][CH2:9][C:10](=[O:14])[NH:11][C:12]=2[N:13]=1
Reactant: O=C1COc2ccc([N+](=O)[O-])nc2N1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Nc1ccc2c(n1)NC(=O)CO2

Procedure:
6-Nitro-2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one (1 g) was reduced under hydrogenolysis conditions using 10% Pd—C in methanol (50 mL) and 1N HCl solution (10 mL) at 50 psi for 2 h. The catalyst was filtered off and washed with methanol and 1N HCl solution. The filtrate was evaporated to give 6-amino-2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one.
Reaction SMILES: I[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:9]([O:15][CH3:16])(=[O:14])[CH2:10][C:11]([CH3:13])=O.C1(C2C(O)=CC=C3C=2C=CC=C3)C(O)=CC=C2C=1C=CC=C2.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.[Cu](I)I.C(OCC)(=O)C>[CH3:13][C:11]1[NH:8][C:3]2=[N:4][CH:5]=[CH:6][CH:7]=[C:2]2[C:10]=1[C:9]([O:15][CH3:16])=[O:14]
Reactant: Nc1ncccc1I
Reactant: COC(=O)CC(C)=O
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)c1c(C)[nH]c2ncccc12
Yield: 21.5 %

Procedure:
To a solution of 3-iodopyridin-2-amine (5.5 g, 25 mmol) in dimethylsulfoxide (40 mL) were added methyl acetoacetate (3.48 g, 30 mmol), copper iodide (476 mg, 2.5 mmol), 1,1′-binaphthyl-2,2′-diol (1.43 g, 5.0 mmol) and cesium carbonate (8.15 g, 2.5 mmol). The resultant mixture was stirred at 50° C. for 4 hours. To the reaction mixture was added ethyl acetate (400 mL). The organic phase was washed with brine (80 mL×3), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give crude product which was purified by column chromatography (petroleum ether/ethyl acetate=4:1) to afford methyl 2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (1.02 g, 21.4%) as a white solid. 1H NMR (300 MHz, CD3OD): δ 8.46-8.43 (m, 1H), 7.61-6.69 (m, 2H), 3.89 (s, 3H), 2.73 (s, 3H).
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][N:7]1[C:12]2[N:13]=[C:14]([O:17][CH3:18])[N:15]=[CH:16][C:11]=2[CH:10]=[CH:9][C:8]1=[O:19].FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH3:18][O:17][C:14]1[N:15]=[CH:16][C:11]2[CH:10]=[CH:9][C:8](=[O:19])[N:7]([CH2:6][CH:2]=[O:1])[C:12]=2[N:13]=1
Reactant: COc1ncc2ccc(=O)n(CC3OCCO3)c2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COc1ncc2ccc(=O)n(CC=O)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 126.1 %

Procedure:
To 0.20 g of 8-(1,3-dioxolan-2-ylmethyl)-2-methoxypyrido(2,3-d)pyrimidin-7(8H)-one, 5 mL of an 80% aqueous trifluoroacetic acid solution was added, and the mixture was stirred at room temperature for 8 hours. To the reaction mixture, a saturated aqueous sodium hydrogen carbonate solution and chloroform were added. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 0.21 g of (2-methoxy-7-oxopyrido(2,3-d)pyrimidin-8(7H)-yl)acetaldehyde as a yellow oily substance.
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6]C)=O)#[C-:2].[NH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>>[N+:1]([CH2:3][C:4]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:6])#[C-:2]
Reactant: [C-]#[N+]CC(=O)OC
Reactant: C1CCNCC1
Product: [C-]#[N+]CC(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Prepared in accordance with Method B with methyl isocyanoacetate (2.46 g, 24.63 mmol) and piperidine (3.22 mL, 37.85 mmol). The reaction mixture was stirred 1 h at RT and then concentrated. The residue was dissolved in dichloromethane (50 mL) and the organic layer was washed with 10% aqueous citric acid (2×25 mL), dried over MgSO4, filtered and evaporated. 2-Isocyano-1-(piperidin-1-yl)ethanone SLA 07116B was obtained as an orange solid (3.13 g, 83% yield).
Reaction SMILES: [C:1]([C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[CH2:11][CH:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]2)=[CH:5][C:4]=1[C:21]([F:24])([F:23])[F:22])#[N:2].Cl.[NH2:26][OH:27].C(=O)(O)[O-].[Na+]>C(O)(C)C>[OH:27][N:26]=[C:1]([C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[CH2:9][CH:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:11]2)=[CH:5][C:4]=1[C:21]([F:24])([F:23])[F:22])[NH2:2]
Reactant: NO
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(C#N)c(C(F)(F)F)c2)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)C1CN(Cc2ccc(C(N)=NO)c(C(F)(F)F)c2)C1
Reaction time: 16 h
Yield: 87.7 %

Procedure:
A solution of tert-butyl 1-(4-cyano-3-(trifluoromethyl)benzyl)azetidine-3-carboxylate (0.268 g, 0.787 mmol), hydroxylamine hydrochloride (0.109 g, 1.57 mmol), and sodium bicarbonate (0.265 g, 3.15 mmol) in isopropanol (2.2 mL) was stirred at 90° C. for 6.0 hrs. HPLC and LCMS indicated that the reaction was 69% complete. Additional hydroxylamine hydrochloride (0.109 g), sodium bicarbonate (0.265 g), and isopropanol (2.2 mL) were added, and heating was continued for 16 hrs. The isopropanol was removed under reduced pressure, and the reaction mixture was diluted with ethyl acetate and washed with water (2×), washed with brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded tert-butyl 1-(4-(N′-hydroxycarbamimidoyl)-3-(trifluoromethyl)benzyl)azetidine-3-carboxylate (0.258 g, 0.690 mmol, 88% yield) of a colorless, viscous oil. The compound had an HPLC ret. time=0.880 min.−Column: PHENOMENEX® S5 4.6×30 mm (2 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. MS M+1=374.10.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]([CH3:40])(/[C:10](=[N:17]\[O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27]N2C=C(C)OC2C2C=CC=CC=2)=[CH:22][CH:21]=1)/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]([O:7]CC)=[O:6].O.Cl.[O:43]1[CH2:47][CH2:46][CH2:45][CH2:44]1>CO>[CH3:40][C:4]([CH3:3])(/[C:10](=[N:17]\[O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:10]2[N:17]=[C:47]([C:46]3[CH:16]=[CH:11][CH:12]=[CH:44][CH:45]=3)[O:43][C:4]=2[CH3:3])=[CH:22][CH:21]=1)/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)C(C)(C)/C(=N\OCc1ccc(OCN2C=C(C)OC2c2ccccc2)cc1)c1ccccc1
Reactant: C1CCOC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(/c2ccccc2)C(C)(C)C(=O)O)cc1
Temperature: 25 °C
Yield: 52 %

Procedure:
Potassium hydroxide (1.83 g) was added to a solution of ethyl Z-2,2-dimethyl-3-[4-(5-methyl-2-phenyl-3-oxazolylmethoxy)benzyloxyimino]-3-phenylpropionate (265 mg) in tetrahydrofuran (3 ml)-water (3 ml)-methanol (6 ml), the mixture was heated to reflux for 3 days and cooled to room temperature. Dilute hydrochloric acid was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane to obtain Z-2,2-dimethyl-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-3-phenylpropionic acid (130 mg, yield 52%) as pale-yellow crystals. m.p. 142-143° C. (decomposition).
Reaction SMILES: [O:1]=[C:2]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([CH3:22])([CH3:21])[CH2:19][OH:20])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([CH3:12])([CH3:11])[CH2:9][OH:10].[BH4-].[Na+].C(OCC)(=O)C.Cl>C(O)(C)C.O>[CH3:21][C:18]([CH3:22])([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH:2]([OH:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([CH3:12])([CH3:11])[CH2:9][OH:10])[CH2:19][OH:20]
Reactant: CC(C)(CO)CCCCCC(=O)CCCCCC(C)(C)CO
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CC(C)(CO)CCCCCC(O)CCCCCC(C)(C)CO
Yield: 44.2 %

Procedure:
Under nitrogen atmosphere, a solution of 8-oxo-2,2,14,14-tetramethylpentadecane-1,15-diol (0.9 g, 2.5 mmol) in iso-propanol (10 mL) was added dropwise to a stirred suspension of sodium borohydride (0.1 g, 2.7 mmol) in iso-propanol (10 mL) at room temperature. The reaction progress was monitored by thin layer chromatography (silica, hexanes:ethyl acetate=1:1). Additional sodium borohydride was added after each hour (0.36 g, 10 mmol, six times). The reaction mixture was stirred for additional 20 h, hydrolyzed with water (10 mL), acidified with 1 N hydrochloric acid (25 mL) to pH 1, and extracted with dichloromethane (4×15 mL). The combined organic phases were washed with saturated sodium chloride solution (15 mL), dried over magnesium sulfate, and concentrated in vacuo to furnish the crude product (1.0 g) as a white solid in oil, which was purified by column chromatography (silica; hexanes, then hexanes:ethyl acetate=2:1 to 1:2) to give the pure product (0.35 g, 43%) as nice white crystals.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH:5]2[CH:14]=[CH:15][CH2:16][CH:4]2[CH2:3]1.C(O[CH:22](N(C)C)[N:23]([CH3:25])[CH3:24])(C)(C)C.O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:10]([O:9][C:7]([N:6]1[C:2](=[O:1])[C:3](=[CH:22][N:23]([CH3:25])[CH3:24])[CH:4]2[CH2:16][CH:15]=[CH:14][CH:5]12)=[O:8])([CH3:12])([CH3:13])[CH3:11]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: CC(C)(C)OC(=O)N1C(=O)CC2CC=CC21
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CN(C)C=C1C(=O)N(C(=O)OC(C)(C)C)C2C=CCC12
Temperature: 110 °C
Yield: 58 %

Procedure:
To a solution of tert-butyl 2-oxo-3,3a,4,6a-tetrahydrocyclopenta[b]pyrrole-1-carboxylate IV-1 (500 mg, 2.23 mmol) in toluene (11 mL) was added tert-butoxybis(dimethylamino)methane (1.39 mL, 6.71 mmol) The solution was heated for 2 h at 110° C. It was then cooled to room temperature, poured into water (20 mL), diluted with ethyl acetate (20 mL), and extracted 3 times. The combined organic layers were washed with brine, dried, concentrated and purified by flash chromatography (5% MeOH in CH2Cl2) giving the desired compound as a brown solid (367 mg, 58%); 1H NMR (400 MHz, CDCl3) 7.12 (1H, s), 5.99 (1H, m), 5.85 (1H, m), 4.91 (1H, d), 3.70 (1H, m), 3.03 (6H, s), 2.79 (1H, m), 2.40 (1H, dd), 1.54 (9H, s); LCMS (Method A): 0.83 min; ES+279 (M+H+).
Reaction SMILES: [OH:1][CH:2](CO)[CH2:3][N:4]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][CH2:6][C:5]1=[O:14].O>CO>[O:14]=[C:5]1[N:4]([CH2:3][CH:2]=[O:1])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: O=C1COc2ccccc2N1CC(O)CO
Solvent: CO
Solvent: O
Product: O=CCN1C(=O)COc2ccccc21
Yield: 84.9 %

Procedure:
Compound 1-3 (1.69 g, 7.58 mmol) was dissolved in MeOH (126 mL) and H2O (25 mL) in a 300 mL round bottom flask at rt, and treated with NalO4 (4.86 g, 23.0 mmol). After 2 hrs the solid was filtered, washing with methanol. The filtrate was concentrated to a white solid, taken up in dichloromethane (50 mL), washed with water (3×) and brine, then dried over sodium sulfate, and concentrated to give Compound 1-4 as a white solid (1.23 g, 83%, mp=97.1-98.0° C.). 1H NMR (500 MHz, CDCl3) δ 9.68 (s, 1H), 7.04-7.00 (m, 3H), 6.68-6.65 (m, 1H), 4.73 (s, 2H), 4.70 (s, 2H); 13C NMR (125 MHz, CDCl3) 195, 165.2, 145.3, 128.7, 124.7, 123.2, 117.6, 114.7, 67.6, 51.2; Anal Calcd. for C10H9NO3: C, 62.82; H, 4.74; N, 7.33. Found: C, 62.85; H, 4.46; N, 7.22.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][C:5]=1[C:13]([F:16])([F:15])[F:14])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.O[N:39]=[C:40]([C:42]1[C:43]2[CH2:44][CH2:45][CH:46]([OH:51])[C:47]=2[CH:48]=[CH:49][CH:50]=1)[NH2:41].[Na+].[Cl-]>CN(C=O)C>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]2[O:10][N:41]=[C:40]([C:42]3[CH:50]=[CH:49][CH:48]=[C:47]4[C:43]=3[CH2:44][CH2:45][CH:46]4[OH:51])[N:39]=2)=[CH:6][C:5]=1[C:13]([F:16])([F:15])[F:14])[CH3:2]
Reactant: CCOc1ccc(C(=O)O)cc1C(F)(F)F
Reactant: NC(=NO)c1cccc2c1CCC2O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CCOc1ccc(-c2nc(-c3cccc4c3CCC4O)no2)cc1C(F)(F)F
Temperature: 130 °C
Reaction time: 0.33 h
Yield: 51 %

Procedure:
In a microwave vial, a stirring solution of 4-ethoxy-3-(trifluoromethyl)benzoic acid (200 mg, 0.85 mmol) in DMF was treated with HOBt (151 mg, 1.11 mmol) and EDCI (212 mg, 1.11 mmol) at room temperature. The reaction was stirred for 20 min followed by addition, in a single portion, of N′,1-dihydroxy-2,3-dihydro-1H-indene-4-carboximidamide (213 mg, 1.11 mmol). The reaction was stirred for additional 30 min at room temperature and then heated to 130° C. for 35 min in the initiator. The reaction was diluted using a saturated solution of NaCl and extracted with EtOAc (80 ml×3). The organic phase was dried over Na2SO4 anhydrous and concentrated under reduced pressure. The product was purified by column chromatography using CH2Cl2:MeOH (9:1) to offer the product as white solid in 51% yield (200 mg).
Reaction SMILES: [CH2:1]([C:3]1[S:29][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][C:15]=3[F:28])[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].[CH3:30][C:31]1([CH3:43])[CH2:35][C:34]2[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][C:33]=2[O:32]1.C(N(CC)CC)C.N1C=CC=CC=1>ClCCl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:30][C:31]1([CH3:43])[CH2:35][C:34]2[CH:36]=[C:37]([N:9]3[C:10](=[O:11])[C:5]4[CH:4]=[C:3]([CH2:1][CH3:2])[S:29][C:6]=4[N:7]([CH2:13][C:14]4[CH:19]=[CH:18][C:17]([C:20]5[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=5)=[CH:16][C:15]=4[F:28])[C:8]3=[O:12])[CH:38]=[CH:39][C:33]=2[O:32]1
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3F)c2s1
Reactant: CC1(C)Cc2cc(B(O)O)ccc2O1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCc1cc2c(=O)n(-c3ccc4c(c3)CC(C)(C)O4)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3F)c2s1
Reaction time: 48 h
Yield: 79.4 %

Procedure:
To a suspension (20 mL) of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]-3′-fluorobiphenyl-2-carbonitrile (0.5 g), (2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)boronic acid (0.47 g), triethylamine (0.86 mL), pyridine (0.48 mL) and molecular sieves 4A (1 g) in dichloromethane was added copper(II) acetate (0.45 g) and the mixture was stirred for 2 days. The reaction mixture was diluted with ethyl acetate, insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow solid (0.54 g, 79%).
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:13][CH2:14][N:15]([CH2:20][CH2:21]Cl)[C:16]([CH3:19])([CH3:18])[CH3:17]>CS(C)=O.Cl>[C:16]([N:15]1[CH2:20][CH2:21][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:8]#[N:9])[CH2:13][CH2:14]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: N#CCc1ccccc1
Reactant: CC(C)(C)N(CCCl)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)N1CCC(C#N)(c2ccccc2)CC1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
A solution of phenyl acetonitrile (1.0 g, 8.54 mmol) in DMSO (8 mL) was treated with sodium hydride (0.717 g, 29.88 mmol) portionwise. The resulting-suspension was stirred at 23° C. for 30 minutes. N,N-bis(2-chloroethyl)-2-methylpropan-2-amine (2.20 g, 9.39 mmol) was then slowly added over 5 minutes, then the suspension was heated at 65° C. overnight. The reaction was then diluted with 1N hydrochloric acid and washed with ethyl acetate (2×). The aqueous phase was basified with sat. aq. sodium carbonate and extracted with ethyl acetate (3×). The combined extracts were washed with water (5×), dried over anhydrous magnesium sulfate, filtered and concentrated to give an oil (1.40 g, 68%) which solidified on standing and was used as such for the next reaction. 1H NMR (400 MHz, CDCl3) δ ppm: 2.10-2.17 (3H, m), 2.31-2.37 (1H, m), 2.42 (3H, s), 2.47-2.57 (2H, m), 3.01 (2G, d, J=12.6 Hz), 7.45 (2H, dd, J=4.55 and 1.52 Hz), 8.68 (2H, dd, J=4.55 and 1.77 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:18][C:17]([F:20])([F:19])[CH2:16][CH2:15][NH:14][C:13]2=[O:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([F:32])[C:25]=1[F:33]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([F:32])[C:25]=2[F:33])[C@@H:12]2[CH2:18][C:17]([F:19])([F:20])[CH2:16][CH2:15][NH:14][C:13]2=[O:21])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C1NCCC(F)(F)C[C@H]1NS(=O)(=O)c1ccc(Cl)cc1
Reactant: COc1ccc(CBr)c(F)c1F
Product: COc1ccc(CN([C@@H]2CC(F)(F)CCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)c(F)c1F

Procedure:
4-Chloro-N-((R)-5,5-difluoro-2-oxo-azepan-3-yl)-benzenesulfonamide was alkylated using 1-bromomethyl-2,3-difluoro-4-methoxy-benzene analogous to Example 1 to afford 4-chloro-N-(2,3-difluoro-4-methoxy-benzyl)-N-((R)-5,5-difluoro-2-oxo-azepan-3-yl)-benzenesulfonamide: