Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:11]([N:17]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[NH:27][C:28]([CH:30]3[CH2:32][CH2:31]3)=[O:29])[CH2:18]2)[CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:7]=[CH:8][C:9]=1[OH:10])[CH3:2].[CH2:33]([O:40][C:41]([CH:43]1[CH:48]([O:49][C:50](=[O:52])[CH3:51])[CH:47]([O:53][C:54](=[O:56])[CH3:55])[CH:46]([O:57][C:58](=[O:60])[CH3:59])[CH:45](OC(=N)C(Cl)(Cl)Cl)[O:44]1)=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.B(F)(F)F.CCOCC>ClCCl.CCOC(C)=O>[C:50]([O:49][C@H:48]1[C@H:47]([O:53][C:54](=[O:56])[CH3:55])[C@@H:46]([O:57][C:58](=[O:60])[CH3:59])[C@H:45]([O:10][C:9]2[CH:8]=[CH:7][C:6]([C@H:11]([N:17]3[CH2:18][C:19]4[C:24](=[C:23]([NH:27][C:28]([CH:30]5[CH2:31][CH2:32]5)=[O:29])[CH:22]=[CH:21][CH:20]=4)[C:25]3=[O:26])[CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:5][C:4]=2[O:3][CH2:1][CH3:2])[O:44][C@@H:43]1[C:41]([O:40][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:42])(=[O:52])[CH3:51]
Reactant: CC(=O)OC1C(OC(=N)C(Cl)(Cl)Cl)OC(C(=O)OCc2ccccc2)C(OC(C)=O)C1OC(C)=O
Reactant: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1O
Agent: FB(F)F
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1O[C@@H]1O[C@H](C(=O)OCc2ccccc2)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.4 %

Procedure:
A reaction mixture of (S)—N-(2-(1-(3-ethoxy-4-hydroxyphenyl)-2-(methylsulfonyl)ethyl)-3-oxoisoindolin-4-yl)cyclopropanecarboxamide (0.38 g, 0.83 mmol) and 3,4,5-triacetoxy-6-(2,2,2-trichloro-acetimidoyloxy)-tetrahydro-pyran-2-carboxylic acid benzyl ester (0.46 g, 0.83 mmol) in dichloromethane (40 mL) was chilled to −15° C. to −20° C., treated with BF3.OEt2 (0.10 mL, 0.83 mmol), and stirred for 2 hours at −15° C. to −20° C. After 2 hours, the reaction mixture was then allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with EtOAc (10 vol) then washed with saturated aqueous NaHCO3 (5 vol), 2% NaCl (5 vol), dried (MgSO4), and concentrated. The crude mixture was eluted through a 120 g ISCO column, 5% to 20% EtOAc/CH2Cl2. After concentration of the fractions, the product was dried under vacuum for 12 hours, which afforded (2S,3S,4S,5R,6S)-2-(benzyloxycarbonyl)-6-(4-((S)-1-(7-(cyclopropanecarboxamido)-1-oxoisoindolin-2-yl)-2-(methylsulfonyl)ethyl)-2-ethoxyphenoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (250 mg, 56% yield) as a light yellow solid: 1H-NMR (DMSO-d6): 10.4 (s, 1H), 8.26-8.23 (d, J=8 Hz, 1H), 7.53-7.48 (t, J=7 Hz, 1H), 7.39-7.31 (m, 5H), 7.20-7.18 (d, J=7 Hz, 1H), 7.13-7.12 (d, J=2 Hz, 1H), 7.09-7.07 (d, J=9 Hz, 1H), 6.95-6.92 (dd, J=1.8 Hz, 1H), 5.9-5.88 (dd, J=4, 10 Hz, 1H), 5.44-5.37 (overlapping d and t, Jd=8 Hz, Jt=10 Hz, 2H), 5.17-5.03 (m, 4H), 4.70-4.63 (m, 2H), 4.38-4.30 (m, 1H), 4.21-4.15 (d, J=18 Hz, 1H), 4.08-3.95 (m, 3H), 3.04 (s, 3H), 2.00 (s, 3H), 1.97 (s, 3H), 1.81-1.76 (m, 4H), 1.32-1.27 (t, J=7 Hz, 3H), 0.89-0.86 (d, J=6 Hz, 4H). HPLC: Waters Nova-Pak C18 column, 150×3.9 mm, 4 μm; Gradient CH3CN/0.1% aq H3PO4 10/90 to 90/10 in 20 min, 1.0 mL/min, tR 14.022 min, 98.5 AP at 240 nm.
Reaction SMILES: O=[C:2]([CH2:8][C:9](=[O:11])[CH3:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].Cl.[NH2:13]O.C(=O)(O)[O-].[Na+]>C(O)C>[CH3:10][C:9]1[O:11][N:13]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:8]=1
Reactant: CCOC(=O)C(=O)CC(C)=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc(C)on1
Yield: 56.2 %

Procedure:
A mixture of ethyl 2,4-dioxovalerate (25 ml, 178 mmol), hydroxylamine hydrochloride (13.7 g, 197 mmol) and sodium bicarbonate (15.4 g, 183 mmol) in ethanol (125 ml) were heated at reflux for 2.5 h, cooled and the solvent removed under reduced pressure. The residue was taken up in chloroform and washed with water, the organic layer separated and dried (MgSO4). Solvent removal and distillation under reduced pressure gave the desired product (15.44 g, 100 mmol, 56%); b.p. 82°-86° C. at 0.5 mm Hg; νmax (film) 3120, 2980, 2930, 1730, 1600, 1450, 1270, 1200, 1100, 1020, 915, 830, 780 cm-1 ; δH (CDCl3) 1.40(3H,t,J 7 Hz, OCH2CH3), 2.50(3H,s,CH3 -5), 4.40(2H,q,J 7 Hz, OCH2CH3), 6.40(1H,s,CH-4).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[NH:11][C:12](=[O:21])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1.[NH4+].[Cl-].C(Cl)CCl.CC[N:30](CC)CC>CN(C=O)C>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](=[O:7])[NH2:30])=[CH:4][C:3]=1[NH:11][C:12](=[O:21])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1
Reactant: CCN(CC)CC
Reactant: COc1ccc(C(=O)Nc2cc(C(=O)O)ccc2N)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2cc(C(N)=O)ccc2N)cc1
Yield: 30 %

Procedure:
A solution of 108 (200 mg, 0.70 mmol), NH4Cl (74 mg, 1.40 mmol), HOBT-hydrate (104 mg, 0.77 mmol), EDC (119 mg, 0.77 mmol) and Et3N (0.29 ml, 2.1 mmol) in DMF (3 ml) was stirred for 16 h at room temperature. The solvent was evaporated, ethyl acetate was added and the organic layer was washed successively with saturated solutions of NH4Cl, NaHCO3 and NaCl, dried over MgSO4, filtered and concentrated. The crude product was triturated in ethyl acetate and filtered to give the title compound 109 (60 mg, 30%). 1H NMR: (DMSO) δ (ppm): 9.57 (s, 1H), 7.96 (d, J=8.8 Hz, 2H), 7.67 (d, J=2.2 Hz, 1H), 7.59 (sb, 1H), 7.52 (dd, J=8.2, 2.0 Hz, 1H), 7.02 (d, J=8.8 Hz, 2H), 6.90 (sb, 1H), 6.72 (d, J=8.4 Hz, 1H), 5.41 (s, 2H), 3.83 (s, 3H). MS: (calc.) 285.1; (obt.) 286.1 (MH)+.
Reaction SMILES: C[N:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.Cl.[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[C:23]2[CH2:29][CH2:30][NH2:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[C:23]2[CH2:29][CH2:30][NH:31][C:7](=[O:9])[C:6]1[CH:5]=[CH:4][C:3]([NH:2][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:11][CH:10]=1
Reactant: CN(c1ccccc1)c1ccc(C(=O)O)cc1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(Nc2ccccc2)cc1
Yield: 14.2 %

Procedure:
A solution of 4-(methyl(phenyl)amino)benzoic acid (0.045 g, 0.198 mmol), 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.046 g; 0.198 mmol), HATU (0.083 g; 0.217 mmol) and N,N-diisoproylethylamine (0.085 mL; 0.495 mmol) in DMF (3 mL), was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulphate, the organic layer was washed with sodium carbonate, brine, dried and concentrated in vacuo. The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.011 g (14%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:16])[CH2:2][CH2:3][CH3:4].[CH2:17]([O:19][C:20]([CH:22]([O:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Br)=[CH:32][CH:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:21])[CH3:18]>>[CH2:1]([C:5]1[N:14]([CH2:34][C:33]2[CH:36]=[CH:37][C:30]([O:29][CH:22]([C:20]([O:19][CH2:17][CH3:18])=[O:21])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:31][CH:32]=2)[C:13](=[O:15])[C:12]2[C:7](=[C:8]([CH3:16])[CH:9]=[CH:10][CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)C(Oc1ccc(CBr)cc1)c1ccccc1
Reactant: CCCCc1nc(=O)c2cccc(C)c2[nH]1
Product: CCCCc1nc2c(C)cccc2c(=O)n1Cc1ccc(OC(C(=O)OCC)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 1a from 2-n-butyl-8-methyl-quinazolin-4(1H)-one and 4-(α-ethoxycarbonylbenzyloxy)benzylbromide.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH2:10].[F:11][C:12]1[CH:13]=[C:14]([B:21]([OH:23])[OH:22])[CH:15]=[C:16]([F:20])[C:17]=1[CH:18]=O.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1.CCOC(C)=O>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][CH2:18][C:17]1[C:16]([F:20])=[CH:15][C:14]([B:21]([OH:23])[OH:22])=[CH:13][C:12]=1[F:11]
Reactant: NC1Cc2ccccc2C1
Reactant: O=Cc1c(F)cc(B(O)O)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: OB(O)c1cc(F)c(CNC2Cc3ccccc3C2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2,3-dihydro-1H-inden-2-amine (0.780 mL, 5.99 mmol), (3,5-difluoro-4-formylphenyl)boronic acid (1.0 g, 5.99 mmol) and acetic acid (0.710 mL, 12.0 mmol) in THF (12 mL) was stirred at room temperature for 1 hr. To the solution was added NaBH(OAc)3 (3.81 g, 18.0 mmol) and the mixture stirred at room temperature for 16 hr. The mixture was diluted with EtOAc then washed with satd Na2CO3. The combined layers were filtered and the filter cake washed with H2O and EtOAc to give {4-[(2,3-dihydro-1H-inden-2-ylamino)methyl]-3,5-difluorophenyl}boronic acid as a beige glass. LC/MS (method A) tR 0.48 min; m/z 304 (M+H).
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:6][C@@H:7]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N:25]([CH3:36])[C:26]([NH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:27])[CH:20]=2)=[CH:15][CH:14]=1)[C:8]([O:10]C)=[O:9])[CH:4]=[CH2:5].C1COCC1.CO.O>C(O)(=O)C>[CH2:3]([O:6][C@@H:7]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N:25]([CH3:36])[C:26]([NH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:27])[CH:20]=2)=[CH:15][CH:14]=1)[C:8]([OH:10])=[O:9])[CH:4]=[CH2:5]
Reactant: C=CCO[C@@H](Cc1ccc(-c2cccc(N(C)C(=O)NCCCCCCC)c2)cc1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: C=CCO[C@@H](Cc1ccc(-c2cccc(N(C)C(=O)NCCCCCCC)c2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.5 %

Procedure:
56 mg (1.4 mmol, 3 eq) of sodium hydroxide are added to a solution of 200 mg (0.47 mmol, 1 eq) of methyl (S)-2-allyloxy-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoate in 2 ml of 9/1 THF/methanol. The reaction mixture is stirred at ambient temperature for 3 hours. The reaction is halted by the addition of 2 ml of water and 0.5 ml of acetic acid, and then extraction is carried out with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated and then the residue is chromatographed on silica gel (dichloromethane/methanol 90/10). 152 mg of 2(S)-allyloxy-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic acid are obtained in the form of an oil. Yield=78%.
Reaction SMILES: [Na].Cl[CH2:3][C:4]([OH:6])=[O:5].O.[CH2:8]([OH:12])[CH2:9][CH2:10][CH3:11]>>[C:4]([OH:6])(=[O:5])[CH2:3][O:12][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCO
Reactant: O=C(O)CCl
Agent: [Na]
Solvent: O
Product: CCCCOCC(=O)O
Temperature: 25 °C

Procedure:
Sodium metal (16 g) was added to 92.5 ml of butanol and heated at reflux under nitrogen. After the sodium had reacted, chloroacetic acid (32.9 g) in 40 ml of butanol was added dropwise and then heated at reflux for twenty hours. The mixture, upon cooling to room temperature, was added to 1300 ml of water and extracted four times with 250-ml portions of diethyl ether. The aqueous phase was acidified to about pH 2 with aqueous hydrochloric acid and again extracted four times with 250-ml portions of diethyl ether. The organic extracts were combined and dried over sodium sulfate, filtered, and concentrated in vacuo. Distillation afforded the title compound as an oil. Structure assignment was supported by the proton nmr spectrum.
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].[NH2:20][C:21]1[CH:22]=[CH:23][C:24]2[O:28][C:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:26][C:25]=2[CH:36]=1>CC#N>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]([NH:20][C:21]2[CH:22]=[CH:23][C:24]3[O:28][C:27]([C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])=[CH:26][C:25]=3[CH:36]=2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)OC(=O)c1cc2cc(N)ccc2o1
Reactant: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: CC#N
Product: CCCCN1C(=O)C(Nc2ccc3oc(C(=O)OC(C)(C)C)cc3c2)=C(c2ccccc2)S1(=O)=O
Temperature: 160 °C

Procedure:
A mixture of 2-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (1.000 g, 3.336 mmol), tert-butyl 5-amino-1-benzofuran-2-carboxylate (0.778 g, 3.336 mmol) and TEA (0.340 ml, 2.471 mmol) in MeCN (5 ml) was heated in a microwave reactor at 160° C. for 1.5 h.
Reaction SMILES: [CH3:1][N:2]([CH3:34])[CH2:3][CH:4]([OH:33])[CH2:5][N:6]1[C:18]2[C:17]3[N:19]([CH3:26])[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=4[C:16]=3[C:15]3[C:27](=[O:32])N(C)[C:29](=[O:30])[C:14]=3[C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2.[OH-:35].[K+]>>[CH3:34][N:2]([CH3:1])[CH2:3][CH:4]([OH:33])[CH2:5][N:6]1[C:18]2[C:17]3[N:19]([CH3:26])[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=4[C:16]=3[C:15]3[C:27](=[O:32])[O:30][C:29](=[O:35])[C:14]=3[C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2
Reactant: [OH-]
Reactant: CN(C)CC(O)Cn1c2ccccc2c2c3c(c4c5ccccc5n(C)c4c21)C(=O)N(C)C3=O
Agent: [K+]
Product: CN(C)CC(O)Cn1c2ccccc2c2c3c(c4c5ccccc5n(C)c4c21)C(=O)OC3=O

Procedure:
950 mg (2.1 mmol) (±)-12-(3-dimethylamino-2-hydroxy-1-propyl)-6,7,12,13-tetrahydro-6,13-dimethyl-5,7-dioxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole are heated under reflux for 16 hours in 150 ml 15% methanolic potassium hydroxide solution. The solution is evaporated to one half, mixed with 100 ml of water and weakly acidified with semi-concentrated hydrochloric acid. The precipitate obtained is filtered off, stirred with 50 ml 5% sodium hydrogen carbonate solution, again filtered and dried. (±)-12-(3-Dimethylamino-2-hydroxy-1-propyl)-6,7,12,13-tetrahydro-13-methyl-5,7-dioxo-indolo[2,3-a]furano[3,4-c]carbazole is obtained in the form of a yellow amorphous powder.
Reaction SMILES: [S:1]1[C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=[CH:2]1.Cl[C:10]([C:12]1[CH:13]=[C:14]([CH:18]([CH3:21])[C:19]#[N:20])[CH:15]=[CH:16][CH:17]=1)=[O:11].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[S:1]1[C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=[C:2]1[C:10]([C:12]1[CH:13]=[C:14]([CH:18]([CH3:21])[C:19]#[N:20])[CH:15]=[CH:16][CH:17]=1)=[O:11]
Reactant: c1cc2ccsc2s1
Reactant: CC(C#N)c1cccc(C(=O)Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C#N)c1cccc(C(=O)c2cc3ccsc3s2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.2 %

Procedure:
A mixture of thieno[2,3-b]thiophene (23.8 g) and 2-(3-chloroformyl-phenyl)propionitrile (29.6 g) is added dropwise to a suspension of anhydrous aluminium chloride (50 g) in methylene chloride (425 cc). After 16 hours at 25° C., the reaction mixture is heated under reflux for 40 minutes and then, after cooling, distilled water (600 cc) and 12 N hydrochloric acid (50 cc) are added. The organic phase is decanted and the aqueous phase is extracted twice with methylene chloride (total 200 cc). The combined methylene chloride solutions are washed three times with distilled water (total 1500 cc), and then stirred with 5 N aqueous sodium hydroxide solution (50 cc) for 2 hours at 25° C. The organic phase is decanted, washed four times with distilled water (total 2000 cc) and dried over anhydrous sodium sulphate, decolourizing charcoal (5 g) is added, and the organic phase is filtered and evaporated. The residue obtained (43.6 g) is chromatographed on a column (4.8 cm diameter, 47 cm height) containing silica gel (410 g). Elution is carried out with methylene chloride (total 1500 cc). The first fraction (500 cc) is discarded, whilst the two following fractions are combined and concentrated to dryness. 2-{3-(Thieno[2,3-b]thien-2-yl)carbonylphenyl}propionitrile (16.9 g) is obtained in the form of an oil. Rf=0.60 (silica gel chromatographic plate; solvent: methylene chloride).
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([OH:10])[C:5]([C:6]#[N:7])=[C:4]([F:11])[CH:3]=1.C([O-])(=O)C.[K+].C(Cl)Cl.Cl[C:21]1[CH:26]=[C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][C@H:28]2[CH3:33])[N:24]=[C:23]([NH:34][CH3:35])[N:22]=1.C([O-])([O-])=O.[K+].[K+]>C(OCC)(=O)C.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].O1CCOCC1>[F:11][C:4]1[CH:3]=[C:2]([C:21]2[CH:26]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][C@H:28]3[CH3:33])[N:24]=[C:23]([NH:34][CH3:35])[N:22]=2)[CH:9]=[C:8]([OH:10])[C:5]=1[C:6]#[N:7]
Reactant: CNc1nc(Cl)cc(N2CCOC[C@H]2C)n1
Reactant: N#Cc1c(O)cc(Br)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CNc1nc(-c2cc(O)c(C#N)c(F)c2)cc(N2CCOC[C@H]2C)n1
Temperature: 100 °C
Reaction time: 4 h
Yield: 93.7 %

Procedure:
To a 20-mL screw-cap vial was added 4-bromo-2-fluoro-6-hydroxybenzonitrile (500 mg, 2.315 mmol), bis-pinacolato diboron (705 mg, 2.78 mmol), potassium acetate (568 mg, 5.79 mmol), PdCl2(dppf).CH2Cl2 adduct (95 mg, 0.116 mmol), and 1,4-dioxane (8 mL). The vial was capped and stirred for 4 h at 100° C. on a stirrer hot-plate. The reaction mixture was allowed to cool, then was diluted with ethyl acetate (50 mL) and washed with water (20 mL). The organic layer was dried over Na2SO4 and concentrated. The residue was added to a 20 mL microwave vial and 4-chloro-N-methyl-6-[(3R)-3-methyl-4-morpholinyl]-2-pyrimidinamine (0.279 g, 1.15 mmol), PdCl2(dppf).CH2Cl2 adduct (0.047 g, 0.058 mmol), K2CO3 (2 M, 1.725 mL, 3.45 mmol), and 1,4-dioxane (6 mL) were added. The resulting mixture was heated at 140° C. for 10 minutes in a microwave reactor. The organic layer was separated and the aqueous was diluted with water (10 mL), neutralized with 0.1 N HCl (pH paper), then extracted with EtOAc (3×50 mL). The organics were combined, and then dried over Na2SO4. The dried solution was concentrated, then purified by flash chromatography 0-10% CH3OH in CH2Cl2 (24 g column, dry-loaded) to afford the title compound (0.37 g) as a brown solid. LC-MS (ES) m/z=344 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[O:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=2[CH2:22][NH2:23])[CH2:16][CH2:15]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.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]>[Cl:13][C:5]1[CH:4]2[CH:9]([CH:10]=[CH:11][C:2]([NH:23][CH2:22][C:21]3[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=3[N:17]3[CH2:18][CH2:19][O:14][CH2:15][CH2:16]3)=[CH:3]2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: NCc1ccccc1N1CCOCC1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: O=C1NN=C(Cl)C2C=C(NCc3ccccc3N3CCOCC3)C=CC12
Yield: 10.2 %

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (1.227 g, 4.728 mmol), (2-morpholino)benzylamine (1.00 g, 5.201 mmol), Pd2(dba)3 (450 mg, 0.491 mmol), rac-BINAP (883 mg, 1.418 mmol) and NaOtBu (1.17 g, 12.175 mmol) in DMA (20 mL) was heated at 80° C. for 1.5 h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO3, brine and dried (Na2SO4). Chromatography (Hexanes/EtOAc) afforded 4-chloro-6-(2-morpholin-4-yl-benzylamino)-4a,8a-dihydro-2H-phthalazin-1-one (180 mg) as a white solid. 1H (400 MHz, d6-DMSO) δ: 2.90 (m, 4H), 3.79 (m, 4H), 4.46 (d, 2H), 6.66 (bs, 1H), 7.04 (t, 1H), 7.15 (m, 2H), 7.24 (m, 1H), 7.35 (d, 1H), 7.77 (t, 1H), 7.90 (d, 1H), 12.32 (s, 1H) ppm; m/z (M+1) 371.23.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][CH:19]=[C:6]2[C:7]([N:9]([CH:12]3[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]3)[C:10](=[O:11])[C:5]=12)=[O:8])([O-])=O.[N-:22]=[N+:23]=[N-].[Na+]>CS(C)=O>[N:1]([C:4]1[CH:21]=[CH:20][CH:19]=[C:6]2[C:7]([N:9]([CH:12]3[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]3)[C:10](=[O:11])[C:5]=12)=[O:8])=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1c2cccc([N+](=O)[O-])c2C(=O)N1C1CCC(O)CC1
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=Nc1cccc2c1C(=O)N(C1CCC(O)CC1)C2=O
Temperature: 80 °C
Reaction time: 6 h
Yield: 90.8 %

Procedure:
A mixture of 2.9 g (0.01 mol) of 4-(3-nitrophthalimidyl)-cyclohexanol and 0.9 g (0.013 mol) of sodium azide in 20 ml of dimethylsulphoxide is stirred for 6 hours at 80° C. and then evaporated in vacuo at the same temperature. The residue is diluted with 20 ml of water. The product which has separated out is filtered off with suction, washed with 5 ml of water and dried for 24 hours at 80° C. in a drying cabinet. 2.6 g (91% of theory) of 4-(3-azidophthalimidyl)-cyclohexanol are obtained; melting point 155° C. (with decomposition). IR spectrum (KBr): 1775 cm-1 and 1710 cm-1 (CO--N--CO); 2130 cm-1 (N3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.Br[CH2:18][CH2:19][CH2:20][Cl:21].Cl>C1COCC1.CCCCCC.C(OCC)(=O)C>[Cl:21][CH2:20][CH2:19][CH2:18][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[C:9]([OH:11])=[O:10]
Reactant: ClCCCBr
Reactant: O=C(O)Cc1cccc(F)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(O)C(CCCCl)c1cccc(F)c1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
A solution of 3-fluorophenylacetic acid (500 mg) in THF (15 mL) was stirred at −78° C. for 5 minutes. A 2.66 M solution of n-butyl lithium in hexane (2.44 mL) was added, and the reaction solution was stirred at −78° C. for three hours. Thereafter, the reaction solution was stirred at 0° C. for one hour, 1-bromo-3-chloropropane was added, and the reaction solution was stirred at room temperature for 17 hours. Thereafter, ethyl acetate and 1 N aqueous hydrochloric acid were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 734 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[CH:17]=[CH:16][C:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15][C:9]=2[CH:8]=1)=[O:6])[C:2]#[CH:3].[C:18]([OH:21])(=[O:20])C>C([O-])(=O)C.[Hg+2].C([O-])(=O)C>[C:7]([O:21][C:18]([N:13]1[CH2:12][CH2:11][C:10]2[CH:16]=[CH:17][C:7]([C:5]3[O:6][C:2]([CH3:3])=[CH:1][N:4]=3)=[CH:8][C:9]=2[CH2:15][CH2:14]1)=[O:20])([CH3:17])([CH3:8])[CH3:5]
Reactant: CC(=O)O
Reactant: C#CCNC(=O)c1ccc2c(c1)CCNCC2
Agent: CC(=O)[O-]
Agent: [Hg+2]
Product: Cc1cnc(-c2ccc3c(c2)CCN(C(=O)OC(C)(C)C)CC3)o1

Procedure:
A mixture of 2,3,4,5-tetrahydro-1H-3-benzazepine-7-carboxylic acid prop-2-ynyl amide (3.8 g) and mercury (II) acetate (350 mg) in glacial acetic acid was heated under reflux for 1.5 h. After cooling, the solvent was removed in vacuo and the residue partitioned between EtOAc (200 ml) and saturated NaHCO3 solution (100 ml). The aqueous layer was re-extracted with EtOAc and the combined organic layers dried and evaporated in vacuo. The residue was purified using silica gel chromatography (gradient elution, hexane/EtOAc) to give the title compound (2.35 g) as a colourless oil.
Reaction SMILES: FC1C=CC([S:8]([Cl:11])(=[O:10])=[O:9])=CC=1OC.N[C:15]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:16]=1[C:17]#[N:18]>>[Cl:23][C:21]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([S:8]([Cl:11])(=[O:10])=[O:9])[CH:22]=1
Reactant: N#Cc1ccc(Cl)cc1N
Reactant: COc1cc(S(=O)(=O)Cl)ccc1F
Product: N#Cc1ccc(Cl)cc1S(=O)(=O)Cl

Procedure:
The titled compound is prepared analogously 4-fluoro-3-methoxy-benzenesulfonyl chloride (Intermediate 102a) by replacing 4-fluoro-3-methoxyaniline with 2-amino-4-chloro-benzonitrile.