Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[C:9]([C:24]#[N:25])[N:8]([C@@H:26]3[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[OH-:38].[Na+]>COCCO.O>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:15][CH:16]=3)=[C:9]([C:24](=[O:38])[NH2:25])[N:8]([C@@H:26]3[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](n2c(C#N)c(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Reactant: [OH-]
Agent: [Na+]
Solvent: COCCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@@H](n2c(C(N)=O)c(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Temperature: 125 °C
Yield: 100.5 %

Procedure:
A mixture of (R)-tert-butyl 3-(4-amino-6-cyano-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (101) (290 mg, 0.58 mmol) and NaOH (290 mg, 7 mmol) in 2-methoxyethanol/H2O (8 mL/2 mL) was sealed in a microwave tube. The reaction mixture was purged with N2 (3×) and heated at 125° C. in a microwave reactor for 45 min. After cooling down to r.t., the reaction was diluted with water, and the resulting solid was filtered, washed with water, dried under vacuum. (R)-tert-Butyl 3-(4-amino-6-carbamoyl-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (125) (300 mg, quant.) was obtained as a brown solid. LC-MS (ESI): m/z (M+1) 515.0.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:22]([Cl:23])=[C:21]3[C:17]([CH2:18][N:19]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[C:20]3=[O:24])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:31]1([CH:37]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:38]CBr)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[Cl:23][C:22]1[CH:21]=[C:17]2[C:16](=[CH:15][C:14]=1[N:11]1[CH2:12][CH2:13][N:8]([CH2:6][CH2:38][CH:37]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:9][CH2:10]1)[C:20](=[O:24])[N:19]([CH:25]1[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1)[CH2:18]2
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2Cl)C(=O)N(C2CCCCC2)C3)CC1
Reactant: BrCCC(c1ccccc1)c1ccccc1
Product: O=C1c2cc(N3CCN(CCC(c4ccccc4)c4ccccc4)CC3)c(Cl)cc2CN1C1CCCCC1

Procedure:
In the same manner as in Example 47, the title compound was prepared from 6-[4-(t-butoxycarbonyl)piperazin-1-yl]-5-chloro-2-cyclohexyl-2,3-dihydro-1H-isoindol-1-one obtained in Example 45 and 3,3-diphenylpropyl bromide.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[CH2:4][CH2:5][CH2:6][CH3:7].F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[C:19]([F:22])([F:21])[F:20]>C1COCC1>[N+:16]([C:13]1[CH:14]=[CH:15][C:10]([O:8][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[C:11]([C:19]([F:22])([F:21])[F:20])[CH:12]=1)([O-:18])=[O:17]
Reactant: CCCCCO
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCOc1ccc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
NaH (0.7 g, 17.5 mmol) is added to a solution of 1-pentanol (5 ml) in dry THF (25 ml). After stirring at room temperature for 30 min, 3.50 g (16.7 mmole) of 1-fluoro-4-nitro-2-trifluoromethylbenzene is added, and stirring is continued at room temperature overnight. The reaction is quenched with water and extracted with ethylacetate, dried over sodium sulfate and evaporated to dryness. The residue is purified by chromatography on silica gel, eluted with 33% dichloromethane/hexane. Removal of solvent provides 4-nitro-1-pentyloxy-2-trifluoromethyl-benzene as pale yellow oil.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH3:12])(=[O:4])[C:2]#[CH:3].C([Li])CCC.[CH2:18]1[O:28][C:27]2[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][C:20]=2[O:19]1.[Cl-].[NH4+]>O1CCCC1>[OH:24][CH:23]([C:22]1[CH:25]=[CH:26][C:27]2[O:28][CH2:18][O:19][C:20]=2[CH:21]=1)[C:3]#[C:2][C:1]([O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH3:12])=[O:4]
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: C#CC(=O)OCCOCCOC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCCOCCOC(=O)C#CC(O)c1ccc2c(c1)OCO2
Reaction time: 0.17 h

Procedure:
A solution of 6.9 g (40 mmol) of 2-(2-methoxyethoxy)-ethyl propiolate in 60 ml of tetrahydrofuran was treated at -78° under argon with 25 ml of n-butyllithium (1.6M in hexane). The mixture was stirred at -78° for 10 minutes and then a solution of 6 g (40 mmol) of 3,4-methylenedioxy-benzaldehyde in 60 ml of tetrahydrofuran was added within 30 minutes. The reaction mixture was stirred at -78° for a further 30 minutes then brought to room temperature and treated with 100 ml of saturated ammonium chloride solution The aqueous phase was extracted twice with ether. The combined organic phases were washed in succession with saturated sodium chloride solution and with water, dried over sodium sulphate and concentrated. The residue was purified by flash chromatography on 600 g of silica gel (elution agent methylene chloride/ether 4:1). There was obtained 2-(2-methoxyethoxy)ethyl 4-hydroxy-4-[3,4(methylenedioxy)phenyl]-2 -butynoate as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[O:12])=[CH:7][CH:6]=1)=[O:4].CCOCC.[C:18]1([Mg]Br)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>O1CCCC1>[OH:12][CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:8]1[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=1
Reactant: Br[Mg]c1ccccc1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(O)c2ccccc2)cc1
Reaction time: 0.2 h

Procedure:
25.2 g (154 mmol) of methyl terephthalaldehydate was dissolved in 200 ml of tetrahydrofuran. 51.2 ml(154 mmol) of a 2M ether solution of phenyl magnesium bromide was added dropwise thereto under cooling in a sodium chloride-ice bath with stirring for 12 minutes and the mixture was stirred for further 20 minutes. Dilute hydrochloric acid was added to the resulting reaction mixture, then the obtained mixture was extracted twice with ethyl acetate. After the organic phase was washed with brine and dried (MgSO4), the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=6:1 (v/v)) to obtain 31.7 g (131 mmol) of methyl α-hydroxy-α-phenyl-p-toluate as a pale yellow oily substance. Its spectroscopic data are as follows:
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9](=O)[CH3:10].[OH-:12].[K+].O.NN>C(O)CO>[OH:12][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[CH2:9][CH3:10]
Reactant: CC(=O)c1cccn1CCBr
Reactant: [OH-]
Agent: NN
Agent: [K+]
Solvent: OCCO
Solvent: O
Product: CCc1cccn1CCO
Temperature: 200 °C
Reaction time: 1.5 h

Procedure:
A mixture containing 2-bromoethyl-2-acetyl-1H-pyrrole (8.2 g), ethylene glycol (45 mL), 85% potassium hydroxide pellets (8.91 g) and 80% hydrazine hydrate (6.76 mL) was stirred at 200° C. for about 1.5 hr along with simultaneous distillation of volatile materials. The product obtained was extracted with ethyl acetate (2×100 mL). The ethyl acetate layer was washed with water (100 mL), dried over sodium sulfate, filtered and evaporated. The crude product obtained was purified by column chromatography (silica gel 100-200), using ethyl acetate:pet. ether (8:2) as an eluent to obtain 2.2 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[F:9].BrC1[C:16]([CH:17]([OH:19])C)=C(Cl)C(F)=CC=1>>[Br:1][C:2]1[C:3]([F:9])=[CH:4][CH:5]=[C:6]([Cl:8])[C:7]=1[CH:17]([OH:19])[CH3:16]
Reactant: CC(O)c1c(Br)ccc(F)c1Cl
Reactant: Fc1ccc(Cl)cc1Br
Product: CC(O)c1c(Cl)ccc(F)c1Br

Procedure:
Starting from 2-bromo-4-chloro-1-fluorobenzene, the procedure for 1-(6-bromo-2-chloro-3-fluorophenyl)ethanol was followed, except column chromatography required a less polar solvent system for product elution (CH2Cl2:Heptane 3:1→1:0→neat EtOAc). Additionally, preparative TLC purification was also required to obtain pure product. 1H NMR (400 MHz, CDCl3) δ=1.65 (d, J=6.8 Hz, 3H), 2.98 (br s, 1H), 5.59 (q, J=6.8 Hz, 1H), 7.01 (dd, J=8.7, 7.5 Hz, 1H), 7.32 (dd, J=8.7, 4.9 Hz, 1H). MS (ES+): m/z 275.99/277.96 [MNa+]. HPLC: tR=3.23 min (ZQ3, polar—5 min).
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:5]=[N:6][CH:7]=[N:8][CH:9]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[CH:19])=[CH:14][C:13]=1[Cl:20].N>>[Cl:20][C:13]1[CH:14]=[C:15]([C:18]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[N:8][CH:9]=3)[CH:19]=2)[CH:16]=[CH:17][C:12]=1[Cl:11]
Reactant: C#Cc1ccc(Cl)c(Cl)c1
Reactant: ON=C(Cl)c1cncnc1
Agent: N
Product: Clc1ccc(-c2cc(-c3cncnc3)no2)cc1Cl

Procedure:
The titled compound was prepared as the hydrochloride salt according to Method CB using the product of Example 44B (79 mg, 0.5 mmol) and 1,2-dichloro-4-ethynylbenzene (Aldrich, 86 mg, 0.5 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.86-7.96 (m, 3H), 8.20 (d, J=1.7 Hz, 1H), 9.31 (s, 2H), 9.36 (s, 1H) ppm; MS (DCI/NH3) m/z 294 (M+H)+, 292 (M+H)+.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)=[CH:8][C:6]=1[NH2:7])[CH2:2][CH3:3].[CH:21](=O)[CH3:22].OOS([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:13]1[C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=[C:12]1[C:9]1[CH:10]=[CH:11][C:5]2[N:4]([CH2:1][CH2:2][CH3:3])[C:21]([CH3:22])=[N:7][C:6]=2[CH:8]=1
Reactant: CCCNc1ccc(-c2nc3ccccc3o2)cc1N
Reactant: CC=O
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCn1c(C)nc2cc(-c3nc4ccccc4o3)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.9 %

Procedure:
To a solution of 2-(2-n-propylaminoanilin-5-yl)benzoxazole (see Working Example 50-1) (148 mg, 0.554 mmol) in dimethylformamide (3 mL) was added an aqueous solution of acetaldehyde (approx. 90%, 104 μL, 1.66 mmol) and oxone (341 mg, 0.554 mmol), and this was stirred at room temperature for 3 hours. After the reaction was complete, aqueous potassium carbonate solution was added, this was filtered and washed with water. The crystals obtained were purified by silica gel column chromatography to yield the title compound (46.6 mg, 29% yield) as gray crystals.
Reaction SMILES: [NH2:1][C:2]([N:4]1[C:8](O)([C:9]([F:12])([F:11])[F:10])[CH:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=[N:5]1)=[S:3].Br[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][CH3:30])=O>C(O)C>[CH3:30][O:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:21]1[N:1]=[C:2]([N:4]2[C:8]([C:9]([F:12])([F:11])[F:10])=[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=[N:5]2)[S:3][CH:20]=1
Reactant: COc1ccccc1C(=O)CBr
Reactant: CCOC(=O)C1C=NN(C(N)=S)C1(O)C(F)(F)F
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2nc(-c3ccccc3OC)cs2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of ethyl 1-(aminocarbonothioyl)-5-hydroxy-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazole-4-carboxylate (470 mg, 1.65 mmol, prepared according to J. Comb. Chem. 2002, 4, 23-32) and 2-bromo-2′-methoxyacetophenone (377 mg, 1.65 mmol) in ethanol (8 mL) was heated at 80° C. After 1 h, the mixture was allowed to cool to ambient temperature, then was concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 55% EtOAc in hexanes) provided the title compound as an off-white solid: LCMS m/z 398.5 [M+H]+; 1H NMR (500 MHz, CD3OD) δ 8.26 (dd, J=7.6, 1.6 Hz, 1H), 8.13 (s, 1H), 8.03 (s, 1H), 7.37 (ddd, J=8.9, 6.5, 1.8 Hz, 1H), 7.12-7.01 (m, 2H), 4.42 (q, J=7.0 Hz, 2H), 4.02 (s, 3H), 1.42 (tr=7.0 Hz, 3H).
Reaction SMILES: O[CH2:2][N:3]1[C:8](=[O:9])[N:7]2[CH:10]=[N:11][C:12]([C:13]([NH2:15])=[O:14])=[C:6]2[N:5]=[N:4]1.Br[CH2:17][C:18]#[C:19]C.C1CCN2C(=NCCC2)CC1.Cl>C(#N)C>[CH2:2]([N:3]1[C:8](=[O:9])[N:7]2[CH:10]=[N:11][C:12]([C:13]([NH2:15])=[O:14])=[C:6]2[N:5]=[N:4]1)[C:17]#[C:18][CH3:19]
Reactant: NC(=O)c1ncn2c(=O)n(CO)nnc12
Reactant: CC#CCBr
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC#CCn1nnc2c(C(N)=O)ncn2c1=O
Reaction time: 0.5 h

Procedure:
To a cooled solution of 3-(Hydroxymethyl)-4-oxo-3,4-dihydroimidazo[5,1-][1,2,3,5]tetrazine-8-carboxamide (MM-001) (1 equiv) in acetonitrile (0.17 M concentration substrate in solvent) was added the 1-bromo-2-butyne (4 equivs) and DBU (1.4 equivs). The mixture was stirred at this temperature for 30 minutes whereupon it was acidified with 1 N HCl. The mixture was extracted with EtOAc (3×1 reaction volume). The combined organic extracts were combined, dried (MgSO4), filtered and concentrated in vacuo to give an oily residue which was then precipitated from Et2O and washed with further Et2O to give the title compound. 1H NMR (400 MHz, d6-DMSO) δ ppm: 8.84 (1H, s), 7.82 (1H, s), 7.70 (1H, s), 5.08 (2H, q, J=2.4 Hz), 1.84 (3H, t, J=2.4 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]=12)=O.Cl.[NH2:14][CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22].C([O-])(=O)C.[Na+]>C(O)(=O)C>[O:22]=[C:16]1[CH:15]([N:14]2[C:8](=[O:9])[C:3]3[C:4](=[CH:10][CH:11]=[CH:12][C:2]=3[Cl:1])[C:5]2=[O:7])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1
Reactant: O=C1OC(=O)c2c(Cl)cccc21
Reactant: NC1CCC(=O)NC1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1CCC(N2C(=O)c3cccc(Cl)c3C2=O)C(=O)N1

Procedure:
2-(2,6-Dioxo(3-piperidyl))-4-chloroisoindoline-1,3-dione was prepared by the procedure of Example 1 from 3-chlorophthalic anhydride (0.40 g, 2.2 mmol), 3-aminopiperidine-2,6-dione hydrogen chloride (0.36 g, 2.2 mmol) and sodium acetate (0.19 g, 2.4 mmol) in acetic acid (10 mL). The product was a white solid (0.44 g, 69% yield); mp, 290.0-291.5° C.; 1H NMR (DMSO-d6) δ 2.05-2.11 (m, 1H, CHH), 2.49-2.64 (m, 2H, CH2), 2.64-2.92 (m, 1H, CHH), 5.17 (dd, J=5.2, 12.7 Hz, 1H, NCH), 7.86-7.94 (m, 3H, Ar), 11.17 (br s, 1H, NH); 13C NMR (DMSO-d6) δ 21.83, 30.91, 49.12, 122.41, 126.94, 129.84, 133.52, 136.11, 136.39, 164.77, 165.76, 169.73, 172.77; Anal Calcd for C13H9N2O4Cl: C, 53.35; H, 3.10; N, 9.57; Cl, 12.11. Found: C, 53.37; H, 2.94; N, 9.30, Cl, 11.97.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH2:4][CH2:3]1.[Br-].[CH2:14]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:15][CH3:16].CC(C)([O-])C.[K+]>C1COCC1>[CH:14](=[C:2]1[CH2:7][CH2:6][CH:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH2:4][CH2:3]1)[CH2:15][CH3:16]
Reactant: CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)CC1CCC(=O)CC1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCC=C1CCC(CC(=O)OC)CC1
Temperature: -10 °C

Procedure:
64.4 g of methyl (4-oxocyclohexyl)acetate and 137.9 g of propyltriphenylphosphonium bromide were introduced into 500 ml of THF, and the mixture was cooled to -10° C. with stirring under nitrogen. A solution of 40.17 g of potassium tert-butoxide in 400 ml of THF was then added dropwise with stirring at the same temperature, and the mixture was then stirred at RT for a further 2 h. Conventional work-up gave methyl (4-propylidenecyclohexyl)acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH2:18]([N:20]([CH2:35][CH3:36])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=O)[NH:28][C:27]=1[CH3:34])=[O:25])[CH3:19]>C(O)C.N1CCCCC1>[CH2:35]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[NH:12][C:11]2=[O:17])[NH:28][C:27]=1[CH3:34])=[O:25])[CH3:36]
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Reactant: O=C1Cc2c(cccc2-c2ccc(Cl)cc2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(Cl)cc4)c32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 48.4 %

Procedure:
To a solution of 4-(4-chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (69.0 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide 5-[4-(4-chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide as a yellow solid (59.4 mg, 48%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.CC(C)=[O:17].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O.OS(O)(=O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:17])=[O:10])=[C:4]([C:11]([F:12])([F:13])[F:14])[CH:3]=1
Reactant: OCCc1ccc(Cl)cc1C(F)(F)F
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: O=C(O)Cc1ccc(Cl)cc1C(F)(F)F
Reaction time: 0.42 h

Procedure:
To a solution of 2-(4-chloro-2-trifluoromethylphenyl)-ethanol in acetone (50 mL) at 0° C. was added dropwise a solution of Jones reagent (40.3 mL of a 2.67 M solution in H2SO4). After 25 min, the mixture was poured onto Et2O/H2O and the layers were separated. The organic layer was washed with H2O and brine, dried (MgSO4) and the solvent was removed in vacuo. The resultant orange solid was crystallized from hexane and heptane to furnish the title compound as a solid which showed: 1H NMR (300 MHz, CDCl3) δ 7.67 (d, 1H, J=2.0Hz), 7.51 (dd, 1H, J=2.0, 8.0Hz), 7.34 (d, 1H, J=8.0Hz), 3.84 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=O)=[CH:4][CH:3]=1.[CH3:16][C@H:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:18][NH2:19]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][NH:19][CH2:18][C@@H:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:16])=[CH:4][CH:3]=1
Reactant: C[C@@H](CN)c1ccccc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Product: Cc1noc(-c2ccc(Br)cc2)c1CNC[C@H](C)c1ccccc1

Procedure:
Prepared according to the procedure described in Example 67, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde and (R)-(+)-β-methylphenethylamine.
Reaction SMILES: [CH3:1][S:2][CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[N+:12]([O-:14])=[O:13])[NH:5][C:4]1=[O:15].[Cl:16]N1C(=O)CCC1=O>C(Cl)Cl>[Cl:16][C:3]1([S:2][CH3:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[N+:12]([O-:14])=[O:13])[NH:5][C:4]1=[O:15]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CSC1C(=O)Nc2cccc([N+](=O)[O-])c21
Solvent: ClCCl
Product: CSC1(Cl)C(=O)Nc2cccc([N+](=O)[O-])c21

Procedure:
A solution of 3-methylthio-4-nitrooxindole (1.58 g, 7 mmol) and N-chlorosuccinimide (1.20 g, 9 mmol) in 100 ml of methylene chloride was stirred at room temperature for 48 hours. The solvent was removed in vacuo, yielding crude 3-chloro-3-methylthio-4-nitrooxindole. The residue was dissolved in 25 ml of tetrahydrofuran and added rapidly in a vigorously stirred slurry of red mercuric oxide (1.52 g, 7 mmol) and boron trifluoride etherate (1.00 g, 7 mmol) in 100 ml of 50 percent aqueous tetrahydrofuran. After stirring for 3 hours, the solution was filtered through a Celite pad which was then washed with copious amounts of chloroform. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated. The residue was chromatographed on silica gel. Elution with chloroform-ethanol (9:1) gave 4-nitroisatin (535 mg, 40%), mp 248°-250° (dec) (recrystallized from ethanol); ir (KBr) 3200 (NH), 1750 (C=O), 1710 (C=O), 1520 (NO2) and 1350 cm-1 (NO2); nmr (DMSO-d6)τ-1.30 (1H, b s, NH), 2.20-2.80 (m, 3H, aryl H).
Reaction SMILES: C([O:3][C:4](=[O:21])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[N:7][C:6]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)C.O.[OH-].[Li+].Cl>O1CCCC1>[Cl:20][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[Cl:19])[O:12][C:6]1[N:7]=[CH:8][C:9]([F:11])=[CH:10][C:5]=1[C:4]([OH:21])=[O:3]
Reactant: CCOC(=O)c1cc(F)cnc1Oc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(F)cnc1Oc1ccc(Cl)c(Cl)c1
Reaction time: 7 h
Yield: 98.4 %

Procedure:
2-(3,4-Dichloro-phenoxy)-5-fluoro-nicotinic acid ethyl ester (4.9 g, 14.8 mmol, see preparation 72) was dissolved in tetrahydrofuran (50 ml). Water (27 ml) and lithium hydroxide (1.56 g, 37.1 mmol) were added and the mixture was stirred vigorously for 7 hours. The reaction mixture was acidified to pH5 by addition of 2 M hydrochloric acid and the mixture was partitioned between ethyl acetate (200 ml) and water (200 ml). The aqueous layer was acidified to pH 3 by addition of 2 M hydrochloric acid and the phases were separated. The aqueous phase was extracted with ethyl acetate (2-fold 50 ml) and the combined organic solutions were dried over magnesium sulphate and concentrated in-vacuo to give 2-(3,4-dichloro-phenoxy)-5-fluoro-nicotinic acid as a white solid (4.4 g).
Reaction SMILES: [H-].[Na+].[O:3]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:24]3[C:23]([NH2:25])=[N:22][CH:21]=[N:20][C:19]=3[NH:18][CH:17]=2)=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]1[C:39](=[O:40])[C:38]2=[CH:41][CH:42]=[CH:43][CH:44]=[C:37]2[C:36]1=[O:45]>CN(C)C=O>[O:3]([C:10]1[CH:11]=[CH:12][C:13]([C:16]2[C:24]3[C:23]([NH2:25])=[N:22][CH:21]=[N:20][C:19]=3[N:18]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]3[C:39](=[O:40])[C:38]4=[CH:41][CH:42]=[CH:43][CH:44]=[C:37]4[C:36]3=[O:45])[CH:17]=2)=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Nc1ncnc2[nH]cc(-c3ccc(Oc4ccccc4)cc3)c12
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2CCCCCCCCN1C(=O)c2ccccc2C1=O

Procedure:
Sodium hydride (120 mg of a 60% dispersion in mineral oil) was added to a solution of 5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (906 mg) in dry dimethylformamide (30 ml) with stirring under nitrogen. The mixture was stirred for 30 minutes under nitrogen and then N-(8-bromooctyl)phthalimide (1.4 g) in dimethyl-formamide (5 ml) was added. The mixture was stirred at ambient temperature for 18 hours under nitrogen and then partitioned between water and ethyl acetate. The ethyl acetate layer was separated and purified by flash column chromatography using ethyl acetate as the mobile phase to give 5-(4-phenoxyphenyl)-7-(8-phthalimidooctyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine, m.p. 85-86° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][N:24]2[C:29]([CH:31]2[CH2:36][CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32]2)=[O:30])=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][N:24]2[C:29]([CH:31]2[CH2:36][CH2:35][CH2:34][NH:33][CH2:32]2)=[O:30])=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)N2CCCCC2C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCCCN1C(=O)C1CCCNC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.2 %

Procedure:
1-(1-tert-butoxycarbonylpiperidine-3-carbonyl)-piperidine-2-carboxylic acid [4-phenyl-1(3-phenyl-propyl)-butyl]-amide (81) (1.35 g; 2.29 mmol) is dissolved in methylene chloride (40 mL) at ambient temperature. Trifluoroacetic acid (20 mL) is added in a slow stream, and the solution is stirred for 4 hours at ambient temperature. The solution is concentrated in vacuo at 40° C. The residue is dissolved in methylene chloride (200 mL) and poured onto saturated sodium bicarbonate solution. The pH is adjusted to 9 with saturated potassium carbonate solution. The mixture is shaken the layers separated. The water layer is extracted with methylene chloride (3×50 mL). The combined organic extracts are washed with water, dried over MgSO4, filtered, and concentrated in vacuo affording the desired product (1.09 g) as an oil.