Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:3][C:4](=[N:12][CH3:13])OC1C=CC=CC=1)#[N:2].[NH:14]1[CH2:16][CH2:15]1>>[C:1]([NH:3][C:4]([N:14]1[CH2:16][CH2:15]1)=[N:12][CH3:13])#[N:2]
Reactant: C1CN1
Reactant: CN=C(NC#N)Oc1ccccc1
Product: CN=C(NC#N)N1CC1
Yield: 57.7 %

Procedure:
N-Cyano-N'-methyl-O-phenylisourea (10.0 g, 0.0571 mol) was added in half-gram batches during 6 min to aziridine (7.926 g, 0.184 mol) cooled to 0° and stirred. A solution was formed, from which after 5 min a colourless solid crystallised out. The reaction mixture was stirred at 20° for 90 min. and then cooled to 0° to complete crystallisation. Filtration and washing the residue with cold ether gave crystalline N-cyano-N'-methyl-1-aziridinoamidine (4.09 g, 57%), m.p. 134°-135°, Rf 0.64-0.66 (silica, acetonitrile). Further product (1.78 g) was isolated from the ether washings, giving a total yield of 5.87 g, 82%.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][C:5]=1[CH2:17][N:18]([CH2:29][C:30]([O:32][CH3:33])=[O:31])S(C1C=CC(C)=CC=1)(=O)=O.C[O-].[Na+]>CO>[CH3:33][O:32][C:30]([C:29]1[N:18]=[CH:17][C:5]2[C:4]([C:3]=1[OH:2])=[CH:9][CH:8]=[C:7]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH:6]=2)=[O:31]
Reactant: COC(=O)CN(Cc1cc(Cc2ccccc2)ccc1C(=O)OC)S(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ncc2cc(Cc3ccccc3)ccc2c1O
Yield: 48.1 %

Procedure:
To a solution of crude 4-benzyl-2-{[methoxycarbonylmethyl-(toluene-4-sulfonyl)-amino]-methyl}-benzoic acid methyl ester (1.54 g) in methanol (1.75 mL) was added a solution of NaOMe (30 wt %) in methanol (1.75 mL) with stirring. After stirring for 5 h at ambient temperature the mixture was concentrated in vacuo and water (20 mL) was added. The pH of the mixture was adjusted to 7 to 8 by addition of 6N hydrochloric acid before the mixture was extracted with ethyl acetate (2×25 mL). The combined organic phases were then dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using hexanes:ethyl acetate=7:3 as the eluent to give the title compound as an off-white solid (451 mg); MS-(+)-ion: M+1=294.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13]CC)=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:16]1[CH2:21][CH:20]([CH3:22])[S:19](=[O:24])(=[O:23])[CH:18]([CH3:25])[CH2:17]1.CO.[OH-].[Na+]>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:16]1[CH2:17][CH:18]([CH3:25])[S:19](=[O:23])(=[O:24])[CH:20]([CH3:22])[CH2:21]1
Reactant: CCOC(=O)c1cc(Br)cc2c(C3CC(C)S(=O)(=O)C(C)C3)c[nH]c12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1CC(c2c[nH]c3c(C(=O)O)cc(Br)cc23)CC(C)S1(=O)=O
Temperature: 85 °C
Yield: 105.9 %

Procedure:
Ethyl 5-bromo-3-(2,6-dimethyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-indole-7-carboxylate (0.189 g, 0.441 mmol), was stirred in a methanol (5 mL)/water (3 mL) solution. 6M NaOH (0.735 mL, 4.41 mol, 10 eq) was added and the reaction was heated to 85° C. for 1.5 hours. LCMS analysis indicated the reaction was completed. The methanol was concentrated and the aqueous solution was acidified with 6M HCl. The resulting white solid was filtered and dried under vacuum to give 0.187 g (92%) of the title compound.
Reaction SMILES: [CH2:1]([C@H:4]1[O:9][CH2:8][O:7][C@@H:6]([CH2:10][C:11]#[N:12])[CH2:5]1)[CH:2]=C.[O:13]=[O+][O-]>ClCCl>[O:13]=[CH:2][CH2:1][C@H:4]1[O:9][CH2:8][O:7][C@@H:6]([CH2:10][C:11]#[N:12])[CH2:5]1
Reactant: O=[O+][O-]
Reactant: C=CC[C@@H]1C[C@H](CC#N)OCO1
Solvent: ClCCl
Product: N#CC[C@H]1C[C@@H](CC=O)OCO1
Temperature: 25 °C

Procedure:
A solution of (±)-cis-6-(2-propenyl)-1,3-dioxane-4-acetonitrile, 2.57 g (15.36 mmol), in 100 mL of dichloromethane is cooled to -78° C. under nitrogen. Ozone (Welsbach generator, flow rate 0.1, voltage=90V) is then passed through a fritted gas inlet tube into the solution until the blue color of ozone appears. The current is turned off, and oxygen bubbled through until the blue coor is discharged. Triphenylphosphine, 4.87 g (28.58 mmol), is added and the colorless solution is allowed to warm to room temperature. Flash chromatography provides after concentration in vacuo 2.3 g of pure (±)-cis-6-(2-oxo-ethyl)-1,3-dioxane-4-acetonitrile.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11](=[O:22])[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([Br:20])[C:13]=1F)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.BrC1C(F)=C(C=C(F)C=1F)C(CC(OCC)=O)=O.[NH2:41][C:42]1[C:47]([F:48])=[CH:46][C:45]([F:49])=[C:44]([NH:50][C:51]([CH3:54])([CH3:53])[CH3:52])[N:43]=1.NC(=C)C([O-])=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(Cl)(Cl)Cl>[Br:20][C:14]1[C:15]([F:19])=[C:16]([F:18])[CH:17]=[C:12]2[C:13]=1[N:41]([C:42]1[C:47]([F:48])=[CH:46][C:45]([F:49])=[C:44]([NH:50][C:51]([CH3:54])([CH3:53])[CH3:52])[N:43]=1)[CH:4]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:11]2=[O:22]
Reactant: CC(C)(C)Nc1nc(N)c(F)cc1F
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(Br)c1F
Agent: C=C(N)C(=O)[O-]
Agent: CCOC(=O)CC(=O)c1cc(F)c(F)c(Br)c1F
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(-c2nc(NC(C)(C)C)c(F)cc2F)c2c(Br)c(F)c(F)cc2c1=O
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
To 5 ml of chloroform solution of ethyl 3-ethoxy-2-(3-bromo-2,4,5-trifluorobenzoyl)acrylate prepared from 1.32 g of ethyl 3-bromo-2,4,5-trifluorobenzoylacetate by normal process was added 2-amino-6-(t-butylamino)-3,5-difluoropyridine until completion of the conversion into the aminoacrylate form was confirmed by monitoring the-reaction by TLC. The solution was concentrated under reduced pressure to obtain yellow solid residue. To this residue were added 1.2 g of anhydrous potassium carbonate and 2 ml of N,N-dimethylformamide, and the mixture was stirred at 90° C. for 15 minutes and allowed to cool. The solution was separated by adding 30 ml of chloroform and 300 ml of distilled water, and the chloroform layer was washed twice with 300 ml of distilled water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and allowed to stand. The precipitate was collected by filtration, washed with ethanol and diisopropylether successively to obtain 1.41 g of the title compound as a colorless powder.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:33])[CH2:6][C:7]1[C:15]2[C:10](=[N:11][C:12]([Cl:16])=[CH:13][CH:14]=2)[N:9]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][C:19]=2[C:28]([F:31])([F:30])[F:29])[C:8]=1[CH3:32]>C1COCC1.CO>[Cl:16][C:12]1[N:11]=[C:10]2[N:9]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][C:19]=3[C:28]([F:29])([F:31])[F:30])[C:8]([CH3:32])=[C:7]([CH2:6][C:5]([OH:33])=[O:4])[C:15]2=[CH:14][CH:13]=1
Reactant: COC(=O)Cc1c(C)n(Cc2ccc(S(C)(=O)=O)cc2C(F)(F)F)c2nc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(CC(=O)O)c2ccc(Cl)nc2n1Cc1ccc(S(C)(=O)=O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1M Aqueous NaOH (0.25 ml) is added to a stirring suspension of [6-chloro-1-(4-methanesulfonyl-2-trifluoromethyl-benzyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester: (0.01 g, 0.021 mmol) in 1:1 THF/MeOH (0.5 ml). The resulting suspension is sonicated and allowed to stir at room temperature overnight. The solvent is removed in vacuo and the crude solid is dissolved in water (0.5 ml) and acidified to pH 2-3 using 1 N HCl. The suspension which forms is filtered, washed with water (0.5 ml) and dried under high vacuum to yield the titled compound. (MH+ 461)
Reaction SMILES: [CH2:1]([C:3]1([CH2:19][CH3:20])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-])=O)[CH:10]=2)[N:5]([CH:15]([CH3:17])[CH3:16])[C:4]1=[O:18])[CH3:2]>CO.O1CCCC1.[Pd]>[NH2:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]([CH:15]([CH3:16])[CH3:17])[C:4](=[O:18])[C:3]2([CH2:19][CH3:20])[CH2:1][CH3:2]
Reactant: CCC1(CC)C(=O)N(C(C)C)c2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCC1(CC)C(=O)N(C(C)C)c2ccc(N)cc21
Reaction time: 4 h
Yield: 86.3 %

Procedure:
To a solution of 3,3-diethyl-1-isopropyl-5-nitro-1,3-dihydro-indol-2-one (12.6 g, 45.60 mmol) in methanol/tetrahydrofuran (THF) (1:1, 80 ml) palladium on charcoal (10%, 1.2 g) was added and the mixture hydrogenated at room temperature for 4 h. After filtration of the catalyst the solvent was evaporated and the residue triturated with iso-hexane to yield 9.7 g 5-amino-3,3-diethyl-1-isopropyl-1,3-dihydro-indol-2-one (39.37 mmol, 86%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:14]=[CH:13][N:12]=[C:11](NC(C3CC3)=O)[CH:10]=2)[C:5](=[O:21])[N:4]2[C:22]([C:27]3[CH:32]=[CH:31][CH:30]=C(F)C=3)([CH3:26])[NH:23][C:24](=[O:25])[C:3]=12.[O:34]1[CH2:39][CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH2:36][CH2:35]1.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[O:34]1[CH2:35][CH:36]=[C:37]([C:2]2[CH:7]=[C:6]([NH:8][C:9]3[CH:10]=[CH:11][N:12]=[CH:13][N:14]=3)[C:5](=[O:21])[N:4]3[C:22]4([CH2:26][CH2:30][CH2:31][CH2:32][CH2:27]4)[NH:23][C:24](=[O:25])[C:3]=23)[CH2:38][CH2:39]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: CC1(c2cccc(F)c2)NC(=O)c2c(Cl)cc(Nc3cc(NC(=O)C4CC4)ncn3)c(=O)n21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: O=C1NC2(CCCCC2)n2c1c(C1=CCOCC1)cc(Nc1ccncn1)c2=O
Temperature: 110 °C

Procedure:
A vial was charged with 8′-chloro-6′-(pyrimidin-4-ylamino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (1, 0.50 g, 1.44 mmol) and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2, 0.36 g, 1.73 mmol) in 1,4-dioxane (10 mL). Sodium carbonate (0.46 g, 4.33 mmol) was added followed by water (1.44 mL) and purged the mixture with argon for 10 min. [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (0.11 g, 0.144 mmol) was then added and purging was continued for 5 more min. The reaction was sealed and heated at 110° C. for 16 h. After completion of reaction by TLC and LCMS. Water (100 mL) was added and extracted with 10% methanol in dichloromethane (3×150 mL). The organics were washed with brine (1×100 mL). The organics were then separated and dried (sodium sulfate) before concentration to dryness. The crude was then purified by flash column chromatography eluting with 2-3% methanol in dichloromethane. The desired fractions were concentrated to dryness under vacuum to afford 8′-(3,6-dihydro-2H-pyran-4-yl)-6′-(pyrimidin-4-ylamino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (3) as an off white solid. Yield: 0.35 g, 61%; MS (ESI) m/z 394 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H), 9.41 (s, 1H), 8.78 (s, 1H), 8.61 (s, 1H), 8.43 (d, J=6.08 Hz, 1H), 7.44 (d, J=5.72 Hz, 1H), 5.75 (s, 1H), 4.18 (s, 2H), 3.79 (s, 2H), 3.05 (m, 2H), 2.45 (m, 2H), 1.84 (m, 6H), 1.56 (s, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24]([CH2:27][C:28]#[N:29])(=[O:26])=[O:25]>>[C:1]([C:5]1[CH:6]=[C:7](/[CH:8]=[C:27](/[S:24]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=2)(=[O:26])=[O:25])\[C:28]#[N:29])[CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: N#CCS(=O)(=O)c1ccccn1
Product: CC(C)(C)c1cc(/C=C(\C#N)S(=O)(=O)c2ccccn2)cc(C(C)(C)C)c1O

Procedure:
M34 was prepared with 3,5-di-t-butyl-4-hydroxybenzaldehyde and (pyrid-2-yl)sulfonyl acetonitrile under similar conditions as described for M26.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([F:29])[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].FC1C=CC=C2C=1OC(C1C=CC=CC=1)=C(I)C2=O>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:25](=[C:24]([F:29])[CH:23]=[CH:22][CH:21]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Agent: O=c1c(I)c(-c2ccccc2)oc2c(F)cccc12
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(F)cccc4c3=O)cc2)CCC1
Yield: 49 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 8-fluoro-3-iodo-2-phenyl-chromen-4-one (55 mg, 0.15 mmol) was reacted to give the title compound (36 mg, 49%). LCMS (Method A): RT=4.91 min, [M+H]+=486.
Reaction SMILES: C([O:8][C:9]1[CH:25]=[CH:24][N:12]2[C:13](=[O:23])[CH:14]=[C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:16]=[C:11]2[CH:10]=1)C1C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.CO>ClCCl>[OH:8][C:9]1[CH:25]=[CH:24][N:12]2[C:13](=[O:23])[CH:14]=[C:15]([N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)[N:16]=[C:11]2[CH:10]=1
Reactant: O=c1cc(N2CCOCC2)nc2cc(OCc3ccccc3)ccn12
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: O=c1cc(N2CCOCC2)nc2cc(O)ccn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.8 %

Procedure:
A solution of 8-benzyloxy-2-morpholinyl-4H-pyrido[1,2-a]pyrimidin-4-one (0.97 g, 2.9 mmol) in dichloromethane (50 ml) under nitrogen was treated dropwise with trifluoromethanesulfonic anhydride (1 ml, 6.0 mmol) and the mixture was stirred at RT overnight. Methanol (20 ml) was added and the solution stirred for a further 1 h, then the solution was evaporated to dryness. The residue was taken up in ethyl acetate, washed with brine, dried and then eluted through a silica column using a gradient of 0-5% methanol in ethyl acetate. The product was obtained as a brown powder (0.35 g)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][NH:24][CH:25]([CH3:27])[CH3:26])[CH:18]=3)[CH:14]=[CH:13][N:12]=2)[CH:5]=[CH:4][C:3]=1[OH:28].[CH3:29][C:30]1[N:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32](O)=[O:33]>>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=3)[CH2:23][N:24]([CH:25]([CH3:26])[CH3:27])[C:32](=[O:33])[C:31]3[CH:35]=[CH:36][CH:37]=[N:38][C:30]=3[CH3:29])[CH:14]=[CH:13][N:12]=2)[CH:5]=[CH:4][C:3]=1[OH:28]
Reactant: CC(C)NCc1cccc(-c2ccnc(NCCc3ccc(O)c(Cl)c3)n2)c1
Reactant: Cc1ncccc1C(=O)O
Product: Cc1ncccc1C(=O)N(Cc1cccc(-c2ccnc(NCCc3ccc(O)c(Cl)c3)n2)c1)C(C)C

Procedure:
2-Chloro-4-(2-{4-[3-(isopropylamino-methyl)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol (compound 132) was coupled with 2-methyl-nicotinic acid following procedure D2. LC-MS showed the product had the expected M+H+ of 516. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.7 (d, 1H)) 8.5 (m, 2H) 8.3 (d, 1H) 8.1 (s, 1H) 7.9 (m, 1H) 7.4 (m, 3H) 7.3 (m, 1H) 7.2 (m, 1H) 6.9 (d, 1H) 5.5 (s, br, 1H) 3.9 (s, 2H) 3.7 (m, 2H) 2.9 (m, 6H) 1.2 (d, 6H).
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][CH2:13][NH:14][C:15]2[C:16](=[O:32])[N:17]([C:28]([CH3:31])([CH3:30])[CH3:29])[S:18](=[O:27])(=[O:26])[C:19]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=O)=O)=CC=1.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35](O)[CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>CC#N>[C:28]([N:17]1[C:16](=[O:32])[C:15]([NH:14][CH2:13][CH2:12][O:11][C:35]2[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=2)=[C:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[S:18]1(=[O:27])=[O:26])([CH3:31])([CH3:30])[CH3:29]
Reactant: Cc1ccc(S(=O)(=O)OCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)cc1
Reactant: Oc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)N1C(=O)C(NCCOc2cccnc2)=C(c2ccccc2)S1(=O)=O
Temperature: 120 °C
Yield: 36.6 %

Procedure:
2-[(2-tert-Butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]ethyl 4-methylbenzenesulfonate (150 mg, 0.313 mmol) was dissolved in dry MeCN (3 mL) under nitrogen atmosphere. Pyridin-3-ol (33 mg, 0.345 mmol) was added followed by potassium carbonate (217 mg, 1.567 mmol). The reaction mixture was heated in a microwave reactor at 120° C. for 15 mins. Potassium carbonate was filtered off and the reaction mixture was evaporated to dryness in a vacuum centrifuge. The crude product was purified by preparative HPLC affording the title compound (46 mg, 35.7%). 1H NMR (CDCl3, 500 MHz): δ 1.74 (s, 9H), 3.30 (q, 2H), 3.92 (t, 2H), 5.64 (t, 1H), 7.12-7.14 (m, 1H), 7.22-7.24 (m, 1H), 7.46-7.48 (m, 3H), 7.53-7.55 (m, 2H), 8.26-8.28 (m, 2H); 13C NMR (CDCl3, 125 MHz): δ 27.84, 43.32, 61.90, 66.37, 108.51, 121.55, 124.15, 125.03, 129.09, 130.10, 131.69, 135.11, 137.90, 143.23, 154.51, 159.64; Mass Spectrum: M+H+ 402.1.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]2[CH:11]=[C:12]([NH:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]3[NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:13]=[N:14][C:15]=2[C:16]#[N:17])[CH:3]=1.[CH3:33][C:34]1[C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][O:36][N:35]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(OCC)(=O)C.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].O1CCOCC1>[C:16]([C:15]1[N:14]=[CH:13][C:12]([NH:18][C@@H:19]2[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]2[NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:11][C:10]=1[NH:9][C:4]1[CH:3]=[C:2]([C:38]2[C:34]([CH3:33])=[N:35][O:36][CH:37]=2)[CH:7]=[C:6]([CH3:8])[N:5]=1)#[N:17]
Reactant: Cc1cc(Cl)cc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)cnc2C#N)n1
Reactant: Cc1nocc1B1OC(C)(C)C(C)(C)O1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(-c2conc2C)cc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)cnc2C#N)n1
Temperature: 100 °C

Procedure:
To tert-butyl (1S,2R)-2-(5-(4-chloro-6-methylpyridin-2-ylamino)-6-cyanopyridin-3-ylamino)cyclohexylcarbamate (PrepEx 1.7) (50 mg, 0.11 mmol), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (27 mg, 0.13 mmol), and tricyclohexylphosphine (4 mg, 0.01 mmol) in a nitrogen purged vial was added dioxane (0.6 ml) and potassium phosphate tribasic (1.25 M in water, 0.26 ml, 0.33 mmol). The reaction mixture was purged with nitrogen, and then Pd2 dba3 (5 mg, 0.005 mmol) was added. The reaction vessel was sealed and heated at 100° C. for 1 hour. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with aqueous saturated sodium bicarbonate solution (10 mL). The organics were separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (5-50% ethyl acetate/hexanes, linear gradient) to give tert-butyl (1S,2R)-2-(6-cyano-5-(6-methyl-4-(3-methylisoxazol-4-yl)pyridin-2-ylamino)pyridin-3-ylamino)cyclohexylcarbamate. MS ESI calc'd. for C27H34N7O3 [M+H]+ 504. found 504.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][C:4]=1[O:5][CH2:6][C:7]([OH:9])=[O:8].N>[Ni].CO>[CH3:1][O:2][C:3]1[CH:13]=[C:12]([CH2:14][NH2:15])[CH:11]=[CH:10][C:4]=1[O:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: COc1cc(C#N)ccc1OCC(=O)O
Agent: [Ni]
Agent: N
Solvent: CO
Product: COc1cc(CN)ccc1OCC(=O)O

Procedure:
3.3 g of 2-(2-methoxy-4-cyanophenoxy)-acetic acid are hydrogenated in 90 ml of a 2:1 (by volume) mixture of methanol and 25% aqueous ammonia in the presence of 1.6 g of Raney nickel for 5 hours at room temperature under normal pressure. After filtering off the catalyst, it is washed with methanol and water and the filtrate is then concentrated to dryness. The resulting solid material is triturated with a small amount of water, filtered off and dried over P2O5 in an exsiccator.
Reaction SMILES: [Na].[Cl:2][C:3]1[C:4]([C:15]#[N:16])=[C:5]([C:9]([Cl:14])=[C:10]([Cl:13])[C:11]=1[Cl:12])[C:6]([OH:8])=[O:7].S(OC)(O[CH3:21])(=O)=O.[OH-].[Na+]>C(C(C)=O)C.O>[Cl:2][C:3]1[C:4]([C:15]#[N:16])=[C:5]([C:9]([Cl:14])=[C:10]([Cl:13])[C:11]=1[Cl:12])[C:6]([O:8][CH3:21])=[O:7]
Reactant: N#Cc1c(Cl)c(Cl)c(Cl)c(Cl)c1C(=O)O
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Solvent: CCC(C)=O
Product: COC(=O)c1c(Cl)c(Cl)c(Cl)c(Cl)c1C#N
Yield: 93 %

Procedure:
A reaction vessel is charged in succession with 360 g of water, 475 g of methyl ethyl ketone and 307 g (1.0 mole) of the sodium salt (dry) of 3,4,5,6-tetrachloro-2-cyanobenzoic acid. With stirring, the mixture is heated to 72°-74° C. and to the suspension so obtained are added, at this temperature and over 1 hour, 189 g of dimethyl sulfate (1.5 moles), while keeping the pH at 5.0-5.5 by the gradual addition of 66 g (0.5 mole) of 30% sodium hydroxide solution. The reaction mixture is then stirred for 1 hour at reflux temperature (72°-74° C.). Conventional working up affords a yield of 93% of theory of methyl 3,4,5,6-tetrachloro-2-cyanobenzoate, based on the sodium salt of 3,4,5,6-tetrachloro-2-cyanobenzoic acid.
Reaction SMILES: [CH2:1]([NH:9][C:10]([C@@H:12]1[CH2:14][C@H:13]1[C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:22]1(=[O:28])[O:27][C:25](=[O:26])[CH:24]=[CH:23]1>C1C=CC=CC=1>[CH2:1]([NH:9][C:10]([C@@H:12]1[CH2:14][C@H:13]1[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:28])/[CH:23]=[CH:24]\[C:25]([OH:27])=[O:26])=[CH:17][CH:16]=1)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCNC(=O)[C@@H]1C[C@H]1c1ccc(N)cc1
Reactant: O=C1C=CC(=O)O1
Solvent: c1ccccc1
Product: CCCCCCCCNC(=O)[C@@H]1C[C@H]1c1ccc(NC(=O)/C=C\C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a refluxing solution of 1.6 g. of trans-N-octyl-2-(4-aminophenyl)cyclopropanecarboxamide in 30 ml. of benzene was added 598 mg. of maleic anhydride all at once. Refluxing was continued for 10 minutes, and then the reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was recrystallized twice from ethanol to give 930 mg. of the title compound as a white solid, m.p. 178.5°-179.5° C. The IR spectrum (KBr disc) showed absorptions at 3280, 2925, 1725, 1640 and 1550 cm-1.
Reaction SMILES: C[C@H](P)[C]1[C](P(C2C3C(=CC=CC=3)C=CC=2)C2C3C(=CC=CC=3)C=CC=2)[CH][CH][CH]1.[CH2:30]([C:37]1[C:46]2[C:41](=[CH:42][CH:43]=[C:44]([O:47][CH3:48])[CH:45]=2)[CH2:40][CH2:39][C:38]=1[NH:49][C:50](=[O:53])[CH2:51][CH3:52])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[H][H]>[Rh+].ClC1CCCCC=CC=1.CO>[CH2:30]([C@H:37]1[C:46]2[C:41](=[CH:42][CH:43]=[C:44]([O:47][CH3:48])[CH:45]=2)[CH2:40][CH2:39][C@H:38]1[NH:49][C:50](=[O:53])[CH2:51][CH3:52])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCC(=O)NC1=C(Cc2ccccc2)c2cc(OC)ccc2CC1
Reactant: [H][H]
Agent: [Rh+]
Agent: C[C@H](P)[C]1[CH][CH][CH][C]1P(c1cccc2ccccc12)c1cccc2ccccc12
Agent: ClC1=CC=CCCCC1
Solvent: CO
Product: CCC(=O)N[C@@H]1CCc2ccc(OC)cc2[C@@H]1Cc1ccccc1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 15 %

Procedure:
Chlorocyclooctadiene rhodium(I) dimer (0.072 g, 0.292 mmol), Josiphos SL-J216-1 (0.197 g, 0.307 mmol), and N-(1-benzyl-7-methoxy-3,4-dihydronaphthalen-2-yl)propionamide (19.75 g, 61.4 mmol) were combined in a 500 ml SS pressure bottle, and the vessel was inerted with argon. Degassed methanol (200 ml) was added, the vessel was again inerted, then the mixture was stirred under 20 psig of argon at 50° C. for 20 min. The vessel was then pressurized with 60 psig of hydrogen and stirred at 55° C. for 14 hrs. HPLC analysis (YIYINADH.M, s.m. 9.08 min. with a 1.5 PA % impurity at 12.14 min., product enantiomers 9.45 and 13.41 min.) indicated 100% conversion and 95.6% ee. Crystallization from MeOH afforded the title compound (yield: 15%; ee: 99.5%).