Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[N:4]([CH3:14])[C:3]=1[C:15]([O:17]C)=O.[NH2:19][C:20]1[C:21](=[O:28])[C:22]([OH:27])=[CH:23][CH:24]=[CH:25][CH:26]=1>C1(C)C(C)=CC=CC=1>[OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:12])(=[O:13])[N:4]([CH3:14])[C:3]=1[C:15]([NH:19][C:20]1[C:21](=[O:28])[C:22]([OH:27])=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:17]
Reactant: COC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1C
Reactant: Nc1ccccc(O)c1=O
Solvent: Cc1ccccc1C
Product: CN1C(C(=O)Nc2ccccc(O)c2=O)=C(O)c2ccccc2S1(=O)=O
Temperature: 25 °C
Yield: 90.4 %

Procedure:
A mixture of methyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (2.95 g) and 2-amino-7-hydroxy-2,4,6-cycloheptatrien-1-one (1.5 g) in xylene (103 ml) was refluxed for 52 hours. The reaction mixture was cooled to room temperature. The crystals were collected by filtration and washed successively with N,N-dimethylformamide and chloroform to give 4-hydroxy-N-(7-hydroxy-1-oxo-2,4,6-cycloheptatrien-2-yl)-2-methyl-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide (3.7 g).
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][N:18]3[C:23]2[CH:28]=[CH:27][N:26]=[C:25](S(C)(=O)=O)[N:24]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.[NH2:34][CH:35]1[CH2:40][CH2:39][CH:38]([NH:41][S:42]([CH3:45])(=[O:44])=[O:43])[CH2:37][CH2:36]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Si:1]([O:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][N:18]3[C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:34][CH:35]3[CH2:40][CH2:39][CH:38]([NH:41][S:42]([CH3:45])(=[O:44])=[O:43])[CH2:37][CH2:36]3)[N:24]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)NC1CCC(N)CC1
Reactant: CC(C)(C)[Si](C)(C)OC1CCN(c2cccc3c2ccn3-c2ccnc(S(C)(=O)=O)n2)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)(C)[Si](C)(C)OC1CCN(c2cccc3c2ccn3-c2ccnc(NC3CCC(NS(C)(=O)=O)CC3)n2)C1
Yield: 73.3 %

Procedure:
4-[3-(t-Butyl-dimethylsilyloxy)pyrrolidin-1-yl]-1-(2-methylsulfonyl-pyrimidin-4-yl)-1H-indole (about 160 mg, 0.35 mmol), N-(4-amino-cyclohexyl)-methanesulfonamide hydro-chloride (743 mg, 3.255 mmol) and DIEA (0.169 mL, 4.32 mmol) were mixed in NMP (7 mL) under Ar at 130° C. for 2.5 h. The reaction mixture was washed with NH4Cl/H2O and extracted into EtOAc (6×15 mL), and further washed with H2O (6×30 mL). The solvent was removed in vacuo to yield N-[4-(4-{4-[3-(t-butyl-dimethylsilanyloxy)-pyrrolidin-1-yl]-indol-1-yl}-pyrimidin-2-ylamino)-cyclohexyl]-methanesulfonamide (150 mg).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH2:8][CH3:9])[N:5]=[CH:4][C:3]=1[C:10]#[N:11].S(=O)(=O)(O)[OH:13].C(=O)([O-])[O-].[Na+].[Na+]>O>[NH2:1][C:2]1[N:6]([CH2:7][CH2:8][CH3:9])[N:5]=[CH:4][C:3]=1[C:10]([NH2:11])=[O:13]
Reactant: O=S(=O)(O)O
Reactant: CCCn1ncc(C#N)c1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCCn1ncc(C(N)=O)c1N
Temperature: 90 °C
Yield: 95 %

Procedure:
A solution of 5-amino-4-cyano-1-n-propylpyrazole (J. Med. Chem., 1968, 11, 79; 4.0 g, 0.0027 mol) in a mixture of concentrated sulphuric acid (30 ml) and water (3 ml) was heated at 90° C. for 1 hour. The cool reaction mixture was poured into ice/water (70 g) and the resulting mixture basified with solid sodium carbonate to pH 8. The aqueous solution thus obtained was extracted with ethyl acetate (5×100 ml), the combined extracts dried (Na2SO4) and the solvent removed by evaporation under vacuum to give the title compound as a pale yellow solid (4.25 g, 95%). A sample was obtained as colourless crystals, m.p. 183-185° C., by crystallisation from methanol-diethyl ether. Found: C, 50.39; H, 6.94; N, 33.21. C7H12N4O requires C, 49.99; H, 7.19; N, 33.31%.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:10][C:11]2[C:19]([N:20]=1)=[CH:18][C:17]1[C:16](=[O:21])[N:15]([CH:22]3[CH2:27][CH2:26][N:25]([CH2:28][CH3:29])[CH2:24][CH2:23]3)[C:14](=[O:30])[C:13]=1[CH:12]=2.[NH2:31][CH2:32][C@@H:33]([OH:44])[CH2:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][C:37]=1[CH3:43].CCN(CC)CC>CCO>[CH3:43][C:37]1[CH:38]=[C:39]([CH3:42])[CH:40]=[CH:41][C:36]=1[O:35][CH2:34][C@H:33]([OH:44])[CH2:32][NH:31][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:10][C:11]2[C:19]([N:20]=1)=[CH:18][C:17]1[C:16](=[O:21])[N:15]([CH:22]3[CH2:27][CH2:26][N:25]([CH2:28][CH3:29])[CH2:24][CH2:23]3)[C:14](=[O:30])[C:13]=1[CH:12]=2
Reactant: CCN1CCC(N2C(=O)c3cc4nc(-c5c(Cl)cc[nH]c5=O)[nH]c4cc3C2=O)CC1
Reactant: Cc1ccc(OC[C@H](O)CN)c(C)c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCN1CCC(N2C(=O)c3cc4nc(-c5c(NC[C@@H](O)COc6ccc(C)cc6C)cc[nH]c5=O)[nH]c4cc3C2=O)CC1
Temperature: 95 °C

Procedure:
To a solution of 2-(4-chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(1-ethyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione (143 mg, 0.336 mmol) and (R)-1-amino-3-(2,4-dimethyl-phenoxy)-propan-2-ol (78 mg, 0.403 mmol) in EtOH (200 mL) was added Et3N (5.35 mL, 38.4 mmol) and the mixture was heated at 95° C. for 16.5 h and then concentrated. Chromatography of the crude with CH2Cl2/MeOH/28% aqueous NH4OH (160:10:1) (65 mg, 33%). 1H NMR (DMSO-d6) δ 1.02 (t, J=6 Hz, 3H), 1.63 (m, 2H), 1.83 (m, 2H), 2.19 (s, 3H, CH3), 2.21 (s, 3H, CH3), 2.29-2.40 (4H), 2.98 (m, 2H), 3.53 (m, 1H), 3.70 (m, 1H), 3.91-4.08 (3H), 4.18 (m, 1H), 5.52 (d, J=4 Hz, 1H, NH), 6.23 (d, J=7 Hz, 1H), 6.83 (d, J=7 Hz, 1H), 6.91 (d, J=7 Hz, 1H), 6.97 (s, 1H), 7.38 (d, J=7 Hz, 1H), 7.65 (s, 1H), 8.09 (br s, 1H), 10.95 (br s, 1H, NH), 11.08 (br s, 1H, NH); ESI-MS m/z 585.5 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][O:12][C:11](=[O:14])[N:10]([CH2:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][C:20](=[O:25])[CH:19]4SC)[N:9]=2)=[CH:4][CH:3]=1>C(O)(=O)C.[Zn]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][O:12][C:11](=[O:14])[N:10]([CH2:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][C:20](=[O:25])[CH2:19]4)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CSC1C(=O)Nc2ccc(CN3N=C(c4ccc(Cl)cc4)COC3=O)cc21
Agent: [Zn]
Solvent: CC(=O)O
Product: O=C1Cc2cc(CN3N=C(c4ccc(Cl)cc4)COC3=O)ccc2N1
Reaction time: 6 h

Procedure:
Powdered Zn (157.3 mmoles) is added to a solution of the compound obtained in Step F (15.73 mmoles) in glacial acetic acid (150 ml). The reaction mixture is stirred for 6 hours and then filtered. The filtrate is evaporated to dryness and then taken up in water (200 ml) and DCM (400 ml). The phases are separated and the aqueous phase is extracted with DCM; the organic phases are combined. The organic phase obtained is washed with water and then with saturated NaCl solution, dried over sodium sulphate, filtered and evaporated to dryness. The residue obtained is recrystallised from ethanol to yield the title product.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([CH3:11])=[CH:6][CH:5]=2.[C:12]([C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:23]=1[N:22]=[CH:21][CH:20]=[C:19]2Cl)#[N:13].Cl>O1CCOCC1>[C:12]([C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:23]=1[N:22]=[C:21]([C:10]1[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([CH3:11])[CH:8]=3)[NH:3][C:2]=1[CH3:1])[CH:20]=[CH:19]2)#[N:13]
Reactant: Cc1ccc2[nH]c(C)cc2c1
Reactant: N#Cc1cccc2c(Cl)ccnc12
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc2[nH]c(C)c(-c3ccc4cccc(C#N)c4n3)c2c1

Procedure:
The sub-title compound was prepared by the method of Example 40 step a, using 2,5-dimethyl indole and 8-cyano-4-chloroquinoline and 1 molar equivalent of 4M HCl in dioxane.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13].C(Cl)(=O)C([Cl:19])=O>ClCCl.CN(C=O)C>[Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:19])=[O:8])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(CBr)c(C(F)(F)F)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(CBr)c(C(F)(F)F)c1

Procedure:
1.00 g of 4-(bromomethyl)-3-(trifluoromethyl)benzoic acid was dissolved in dichloromethane (q.s.), then 2 drops of anhydrous N,N′-dimethylformamide were added. Then 2 ml of oxalyl chloride was added dropwise to the mixture. The reaction mixture was reacted at room temperature for 5 h, and concentrated to provide the product.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=[C:6]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[CH:5]=2)[CH2:3][CH2:2]1.[Cl:28][C:29]1[CH:34]=[C:33](I)[CH:32]=[CH:31][N:30]=1>C([Mg]Cl)(C)C.[Cl-].[Cl-].[Zn+2]>[Cl:28][C:29]1[CH:34]=[C:33]([C:8]2[CH:7]=[C:6]([C:18]3[CH:19]=[CH:20][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:22][CH:23]=3)[CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[N:9]=2)[CH:32]=[CH:31][N:30]=1
Reactant: Clc1cc(I)ccn1
Reactant: O=S(=O)(Oc1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CC2)n1)C(F)(F)F
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Zn+2]
Product: FC(F)(F)c1ccc(-c2cc(-c3ccnc(Cl)c3)nc(C3CC3)c2)cc1

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 6-cyclopropyl-4-(4-trifluoromethyl-phenyl)-pyridin-2-yl ester (example A.34) (2.7 g, 7.0 mmol), commercially available 2-chloro-4-iodo-pyridine [CAS No. 153034-86-7] (1.62 g, 6.8 mmol) and i-PrMgCl/ZnCl2 according to the general procedure IVc protocol a. Obtained as a white solid (0.75 g, 30%). MS (ISP) 375.2 [(M+H)+] and 377.1 [(M+2+H)+].
Reaction SMILES: [NH2:1][C:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:13]=2)=[N:5]S(=O)[N:3]=1.[ClH:26]>CO.C(O)C>[ClH:26].[ClH:26].[ClH:26].[N:19]1([CH2:18][C:14]2[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=2)[O:11][CH2:10][CH2:9][CH2:8][NH:7][C:6](=[NH:5])[C:2](=[NH:1])[NH2:3])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: NC1=NS(=O)N=C1NCCCOc1cccc(CN2CCCCC2)c1
Agent: Cl
Solvent: CCO
Solvent: CO
Product: N=C(N)C(=N)NCCCOc1cccc(CN2CCCCC2)c1
Yield: 82.6 %

Procedure:
A suspension of 3-amino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole 1-oxide (17.1 g; 47.0 mmoles) [prepared according to published U.K. patent application No. 2,067,987] in 450 mL of methanol was treated with 38 mL of concentrated HCl. The resultant solution was stirred for 3 hours at ambient temperature. Concentration of the solution followed by azeotropic removal of water with absolute ethanol gave colorless crystals. These were suspended in 200 mL of absolute ethanol, filtered and dried under vacuum to give 16.6 g (82.6%) of the title compound, m.p. 205°-222° C. (dec.). Recrystallization from 50% methanol-ethyl acetate gave an analytical sample, m.p. 206°-216° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][NH:23][CH3:24])[C:8]([F:11])=[CH:9][CH:10]=1.Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][C:13]=2[CH2:22][N:23]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH3:24])[C:8]([F:11])=[CH:9][CH:10]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1F
Product: COC(=O)Cc1ccc(F)c(-c2ccc(C(F)(F)F)cc2CN(C)C(=O)OCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 7, Step 1, using the following starting materials: (6-fluoro-2′-methylaminomethyl-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and benzyl chloroformate.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[O:6][CH2:7][C:8]1[N:9]=[C:10]([C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)[O:11][C:12]=1[CH3:13].[CH2:22]([N:29]1[CH:33]=[C:32]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:31]([OH:39])=[N:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:22]([N:29]1[CH:33]=[C:32]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:31]([O:39][CH2:2][C:3]2[CH:21]=[CH:20][CH:19]=[C:5]([O:6][CH2:7][C:8]3[N:9]=[C:10]([C:14]4[O:15][CH:16]=[CH:17][CH:18]=4)[O:11][C:12]=3[CH3:13])[CH:4]=2)=[N:30]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1O
Reactant: Cc1oc(-c2ccco2)nc1COc1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1cccc(OCc2nc(-c3ccco3)oc2C)c1
Temperature: 80 °C
Reaction time: 15 h
Yield: 78.6 %

Procedure:
A mixture of 4-(3-chloromethylphenoxy)methyl-2-(2-furyl)-5-methyl-1,3-oxazole (2.04 g), ethyl 1-benzyl-3-hydroxy-1H-pyrazole-4-carboxylate (1.50 g), potassium carbonate (0.84 g) and N,N-dimethylformamide (50 mL) was stirred at 80° C. for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:2, v/v) to give ethyl 1-benzyl-3-[(3-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazole-4-carboxylate as colorless crystals (2.46 g, yield 79%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 92-93° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:20][CH2:19]1.[Cl:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[C:32]([O:45][CH3:46])[C:31]=1[OH:47]>>[Cl:29][C:30]1[CH:35]=[C:34]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[C:5]3[NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([N:24]3[CH2:25][CH2:26][CH2:27][CH2:28]3)[CH2:20][CH2:19]2)[CH:33]=[C:32]([O:45][CH3:46])[C:31]=1[OH:47]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Reactant: O=C(c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](N2CCCC2)CC1)C1CC1
Product: COc1cc(-c2ccc3ncc(C(=O)C4CC4)c(N[C@H]4CC[C@H](N5CCCC5)CC4)c3c2)cc(Cl)c1O

Procedure:
Following general procedure D, {6-bromo-4-[trans-4-(pyrrolidin-1-yl)cyclohexylamino]quinolin-3-yl}(cyclopropyl)methanone (25 mg, 0.150 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (43 mg, 0.150 mmol) to afford the desired product (20 mg, 67%), as a yellow-brown solid: 1H NMR (500 MHz, CD3OD) δ 9.14 (s, 1H), 8.34 (d, J=1.9 Hz, 1H), 8.03 (dd, J=8.7, 1.9 Hz, 1H), 7.92 (d, J=8.7 Hz, 1H), 7.29 (d, J=2.1 Hz, 1H), 7.22 (d, J=2.0 Hz, 1H), 4.15 (t, J=10.6 Hz, 1H), 3.99 (s, 3H), 3.16 (s, 4H), 2.94 (s, 1H), 2.89-2.79 (m, 1H), 2.38 (d, J=12.5 Hz, 2H), 2.28 (d, J=11.9 Hz, 2H), 1.99 (s, 4H), 1.70-1.50 (m, 4H), 1.23-1.17 (m, 2H), 1.13-1.06 (m, 2H); ESI MS m/z 520 [C30H34ClN3O3+H]+; HPLC 98.7% (AUC), tR=10.99 min.
Reaction SMILES: [CH:1]([C:4]1[C:12]2[O:11][CH2:10][C:9]([CH3:14])([CH3:13])[C:8]=2[CH:7]=[C:6]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:5]=1[CH3:24])([CH3:3])[CH3:2].[CH2:25]([Li])CCC.IC.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[C:1]([C:4]1[C:12]2[O:11][CH2:10][C:9]([CH3:13])([CH3:14])[C:8]=2[CH:7]=[C:6]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:5]=1[CH3:24])([CH3:25])([CH3:3])[CH3:2]
Reactant: [Li]CCCC
Reactant: COc1ccc(Nc2cc3c(c(C(C)C)c2C)OCC3(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: COc1ccc(Nc2cc3c(c(C(C)(C)C)c2C)OCC3(C)C)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
A stirred solution of 7-isopropyl-5-[(4-methoxy-phenyl)-amino]-3,3,6-trimethyl-2,3-dihydro-benzofuran (Compound 52, 0.2 g, 0.615 mmol) in 5 mL of anhydrous tetrahydrofuran under argon, was cooled to -78° C. and treated with 1.6M solution of n-butyllithium in hexanes (0.77 mL, 1.23 mmol). The resulting green reaction mixture was stirred for 0.5 hour at -78° C. and then treated drop wise with iodomethane (0.5 mL, 6.15 mmol) that was passed through a bed of potassium carbonate. The yellow reaction mixture was allowed to warm to room temperature, recooled to 0° C., quenched with saturated ammonium chloride solution and extracted with diethylether. The organic extract was dried over anhydrous sodium sulfate, filtered and evaporated to a residue which was subjected to flash column chromatography to afford the title compound (0.11 5 g, 51%) as a pale yellow oil. 1H NMR (300 MHz, CDCl3): δ 6.80 (d, 2H, J=9.1 Hz), 6.74 (s, 1H), 6.45 (d, 2H, J=9.1 Hz), 4.24 (s, 2H), 3.77 (s, 3H), 3.60 (br m, 2H), 3.25 (heptet, 1H, J=7.0 Hz), 2.12 (s, 3H), 1.38 (d, 6H, J=7.0 Hz), 1.32 (s, 6H), 1.24 (t, 6H, J=7.0 Hz).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([O:10][C@H:11]1[CH2:15][NH:14][CH2:13][C@H:12]1[NH:16][C:17]1[C:22]([CH2:23][CH3:24])=[N:21][C:20]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=2[CH3:33])=[C:19]([CH2:34][CH3:35])[N:18]=1)[CH3:9]>>[CH2:8]([O:10][C@H:11]1[CH2:15][N:14]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:13][C@H:12]1[NH:16][C:17]1[C:22]([CH2:23][CH3:24])=[N:21][C:20]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=2[CH3:33])=[C:19]([CH2:34][CH3:35])[N:18]=1)[CH3:9]
Reactant: Brc1ccccn1
Reactant: CCO[C@H]1CNC[C@H]1Nc1nc(CC)c(-c2ccc(OC)cc2C)nc1CC
Product: CCO[C@H]1CN(c2ccccn2)C[C@H]1Nc1nc(CC)c(-c2ccc(OC)cc2C)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(3R,4S)-4-ethoxy-1-(1,3-thiazol-2-yl)pyrrolidin-3-yl}-3,6-diethylpyrzin-2-amine but substituting 2-bromopyridine and starting with N-[(3R,4S)-4-ethoxypyrrolidin-3-yl]-3,6-diethyl-5-(4-methoxy-2-methylphenyl)pyrazin-2-amine provided the title compound as an amorphous solid. 1H NMR (CDCl3) δ 1.15, 1.31, 2.14, 2.49, 2.71, 3.42, 3.54, 3.78, 3.85, 4.07, 4.28, 4.92, 5.21, 6.50˜6.66, 6.79, 6.84, 7.12, 8.20; IR (diffuse reflectance) 2969, 2405 (w), 2351 (w), 2337 (w), 2212 (w), 2015 (w), 1599 (s), 1560, 1482 (s), 1474 (s), 1442 (s), 1392, 1385, 1242, 769 cm−1 HRMS (ESI) calcd for C27H35N5O2+H1 462.2869. found 462.2859.
Reaction SMILES: [N:1]1([C:10]2[N:18]=[C:17](Cl)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH:20]([CH2:24][CH2:25][OH:26])[CH2:21][CH2:22][OH:23]>CS(C)=O>[N:1]1([C:10]2[N:18]=[C:17]([N:20]([CH2:24][CH2:25][OH:26])[CH2:21][CH2:22][OH:23])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: OCCNCCO
Reactant: Clc1nc(-n2cnc3ccccc32)c2nc[nH]c2n1
Solvent: CS(C)=O
Product: OCCN(CCO)c1nc(-n2cnc3ccccc32)c2nc[nH]c2n1
Temperature: 120 °C
Yield: 7042.7 %

Procedure:
200 mg of product obtained in stage 1 above are mixed with 3 ml of DMSO and 0.388 mg (5 equivalents) of diethanolamine, and the mixture is then heated at 120° C. for approximately 48 hours. The mixture is allowed to return to ambient temperature. Purification is carried out by chromatography on silica with a CH2Cl2-MeOH—NH4OH: 90-9-1 mixture for eluent. Evaporation is carried out and a paste is formed in methylene chloride. Partial drying and drying under vacuum at 50° C. are carried out. 88.2 mg of expected product are obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH2:11]([N:13]([CH2:28][CH3:29])[CH2:14][CH2:15][O:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([CH:26]=O)=[CH:20]2)[CH3:12].N1CCCCC1>C(O)C>[CH2:28]([N:13]([CH2:11][CH3:12])[CH2:14][CH2:15][O:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([CH:26]=[C:3]1[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]1=[O:10])=[CH:20]2)[CH3:29]
Reactant: O=C1Cc2ccccc2N1
Reactant: CCN(CC)CCOc1ccc2[nH]c(C=O)cc2c1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCOc1ccc2[nH]c(C=C3C(=O)Nc4ccccc43)cc2c1
Temperature: 100 °C
Yield: 66.6 %

Procedure:
A mixture of oxindole (26 mg, 0.2 mmol), 5-(2-diethylamino-ethoxy)-1H-indole-2-carbaldehyde (50 mg, 0.2 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated at 100° C. for 2 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 50 mg (67%) of the title compound.
Reaction SMILES: [C-:1]#[N:2].[K+].C1(C)C=CC(S(O[CH2:14][C@H:15]2[CH2:23][C@@H:22]3[C@@H:18]([CH2:19][N:20]([C:24](=[O:35])[C@H:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[O:33][CH3:34])[CH3:26])[CH2:21]3)[C@@:17]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[F:43])([OH:36])[CH2:16]2)(=O)=O)=CC=1>CS(C)=O.ClCCl>[C:1]([CH2:14][C@@H:15]1[CH2:23][C@@H:22]2[C@@H:18]([CH2:19][N:20]([C:24](=[O:35])[C@H:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])[CH3:26])[CH2:21]2)[C@@:17]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[F:43])([OH:36])[CH2:16]1)#[N:2]
Reactant: COc1ccccc1[C@H](C)C(=O)N1C[C@@H]2C[C@H](COS(=O)(=O)c3ccc(C)cc3)C[C@@](O)(c3ccccc3F)[C@@H]2C1
Reactant: [C-]#N
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: COc1ccccc1[C@H](C)C(=O)N1C[C@@H]2C[C@@H](CC#N)C[C@@](O)(c3ccccc3F)[C@@H]2C1
Temperature: 50 °C
Reaction time: 18 h
Yield: 149.6 %

Procedure:
0.35 g of potassium cyanide is added at room temperature to a solution of 1.55 g of (3aS,4S,6S,7aR)-6-p-toluenesulphonyloxymethyl-4-(2-fluorophenyl)-2-[(S)-2-(2-methoxyphenyl)propionyl]perhydroisoindol-4-ol in 15 cm3 of dimethyl sulphoxide. The reaction mixture is stirred at 50° C. for 18 hours and then diluted with 100 cm3 of dichloromethane, and the organic phase is washed with twice 50 cm3 of water then with 50 cm3 of saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). Recrystallization from diisopropyl ether gives 1.74 g of (3aS,4S,6S,7aR)-6-cyanomethyl-4-(2-fluorophenyl)-2-[(S)-2-(2-methoxyphenyl)propionyl]perhydroisoindol-4-ol in the form of white crystals melting at 182° C.
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:6])[CH2:4][CH3:5].[F:7][C:8]1[C:9](I)=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:20][CH:21]=[CH:22][CH:23]=1>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[F:7][C:8]1[C:9]([C:1]#[C:2][CH:3]([OH:6])[CH2:4][CH3:5])=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C1Nc2ccc(F)c(I)c2/C1=C/c1ccc[nH]1
Reactant: C#CC(O)CC
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(O)C#Cc1c(F)ccc2c1/C(=C/c1ccc[nH]1)C(=O)N2

Procedure:
Using Method C above, 1-pentyn-3-ol (58.9 mg, 0.7 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (100 mg, 0.28 mmol) (Starting Material 5, supra) using (Ph3P)4Pd (32 mg) and CuI (5.3 mg) as catalyst in DMF (5 mL) and Et3N (5 mL) as solvent at 85° C. for 10 h to yield rac-(Z)-1,3-Dihydro-5-fluoro-4-(3-hydroxy-1-pentynyl)-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 64 mg, 70%).
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[S:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[Si]([O:28][CH2:29][CH:30]1[CH:34]([CH2:35][O:36][Si](C(C)(C)C)(C)C)[CH2:33][C:32]([CH2:44]Br)=[CH:31]1)(C(C)(C)C)(C)C>>[OH:28][CH2:29][CH:30]1[CH:34]([CH2:35][OH:36])[CH2:33][C:32]([CH2:44][N:8]2[C:9]([S:10][C:11]3[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]2=[O:19])=[CH:31]1
Reactant: CC(C)(C)[Si](C)(C)OCC1C=C(CBr)CC1CO[Si](C)(C)C(C)(C)C
Reactant: Cc1cc(C)cc(Sc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: Cc1cc(C)cc(Sc2c(C(C)C)c(=O)[nH]c(=O)n2CC2=CC(CO)C(CO)C2)c1
Yield: 17.9 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenylthio)-2,4-pyrimidinedione and [3,4-di(t-butyldimethylsilyloxymethyl)cyclopent-1-en-1-yl]methyl bromide were reacted by the same method with example 28 to obtain the titled compound (51 mg).