Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].C([O-])([O-])=O.[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(C)=O>[CH2:17]([O:10][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[OH:1])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1ccc(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc(OCc2ccccc2)c(O)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 24.9 %

Procedure:
A mixture of 3,4-dihydroxybenzonitrile (540 mg, 4 mmol), K2CO3 (552 mg, 4 mmol) and benzyl bromide (476 mg, 4 mmol) in acetone (20 mL) was stirred at room temperature for 3 days. The mixture was evaporated under vacuum and subjected to flash column chromatography (2% MeOH in toluene-hexane, 2:1) to give the desired product (224 mg, 25%): MP 101° C.; 1H NMR (Acetone-d6, 500 MHz) δ 8.55 (s, 1H), 7.50 (d, 2H, J=7.3 Hz), 7.39 (dd, 2H, J=7.0 and 7.3), 7.34 (dd, 1H, J=7.0 and 7.3), 7.2 (m, complex, 3H), 5.25 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([NH:17][CH:18]([CH:20]([CH3:22])[CH3:21])[CH3:19])=[C:9]([C:12](=O)[CH2:13][CH2:14][CH3:15])[C:10]#[N:11].Cl.[O:24]([NH2:26])[CH3:25]>C(O)C.S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([NH:17][CH:18]([CH:20]([CH3:22])[CH3:21])[CH3:19])=[C:9]([C:12](=[N:26][O:24][CH3:25])[CH2:13][CH2:14][CH3:15])[C:10]#[N:11]
Reactant: CCCC(=O)C(C#N)=C(NC(C)C(C)C)c1ccccc1Cl
Reactant: CON
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCCC(=NOC)C(C#N)=C(NC(C)C(C)C)c1ccccc1Cl
Yield: 51 %

Procedure:
To a solution of 2-{(2-chlorophenyl)[(3-methylbutan-2-yl)amino]methylene}-3-oxohexanenitrile (0.300 g, 0.919 mmol, 1 eq.) in ethanol (6 ml) were added methoxylamine hydrochloride (0.314 g, 3.67 mmol, 4 eq.) followed by 2 drops of concentrated sulfuric acid. The reaction was microwaved (150° C., 22000 s, fixed hold, high absorption) and the solvent evaporated. The residual oil was triturated in ethyl acetate and washed with sat. aq. solution of NaCl. After drying over MgSO4 and concentration under vacuum, the residual oil was subjected to preparative HPLC to give 2-{(2-chlorophenyl)[(3-methylbutan-2-yl)amino]methylene}-3-(methoxyimino)hexanenitrile (0.163 g, 49% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:3]=1[C:4]([NH:6][CH:7]([CH2:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:30])[CH:17]=[CH:16]2)[C:8]([O:10]C)=[O:9])=[O:5].OS([O-])(=O)=O.[K+]>CC#N.O.[OH-].[Na+]>[Cl:1][C:2]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:3]=1[C:4]([NH:6][CH:7]([CH2:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:30])[CH:17]=[CH:16]2)[C:8]([OH:10])=[O:9])=[O:5]
Reactant: COC(=O)C(Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)NC(=O)c1c(Cl)cccc1Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C(NC(Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)C(=O)O)c1c(Cl)cccc1Cl

Procedure:
Methyl 2-[(2,6-dichlorobenzoyl)amino]-3-[2-(2,6-dichlorophenyl)-6-quinolinyl]propanoate 35 (0.2 g) is solubilized in CH3CN/H2O/NaOH 0.1N (4 ml/0.22 ml/3.65 ml). After 1 night at room temperature, 10% KHSO4 (9 ml) is added and CH3CN is evaporated. The resulting aqueous phase is extracted two times with AcOEt (2×12 ml). The organic phase is washed with brine, dried over MgSO4 and evaporated under vacuum. The residue is purified by silica gel chromatography using CH2Cl2/CH3OH/NH4OH cc (90/10/1) as eluent.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][C:9]([C:16]#[CH:17])=[CH:10][CH:11]=3)[C:6]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:18][CH2:19][CH2:20][CH3:21])[C:5]=2[CH:4]=1)#[CH:2].I[C:27]1[S:31][C:30]([CH:32]=[O:33])=[CH:29][CH:28]=1>C1(C)C=CC=CC=1.CCN(CC)CC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:22]([C:6]1([CH2:18][CH2:19][CH2:20][CH3:21])[C:7]2[CH:8]=[C:9]([C:16]#[C:17][C:27]3[S:31][C:30]([CH:32]=[O:33])=[CH:29][CH:28]=3)[CH:10]=[CH:11][C:12]=2[C:13]2[C:5]1=[CH:4][C:3]([C:1]#[C:2][C:27]1[S:31][C:30]([CH:32]=[O:33])=[CH:29][CH:28]=1)=[CH:15][CH:14]=2)[CH2:23][CH2:24][CH3:25]
Reactant: O=Cc1ccc(I)s1
Reactant: C#Cc1ccc2c(c1)C(CCCC)(CCCC)c1cc(C#C)ccc1-2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCC1(CCCC)c2cc(C#Cc3ccc(C=O)s3)ccc2-c2ccc(C#Cc3ccc(C=O)s3)cc21
Temperature: 40 °C
Reaction time: 0.17 h
Yield: 97.4 %

Procedure:
Air was removed from a solution of 2,7-diethynyl-9,9-dibutyl-9H-fluorene (0.150 g, 0.460 mmol) and 5-iodothiophene-2-carboxaldehyde (Wu, L.-H.; Chu, C.-S.; Janarthanan, N.; Hsu, C.-S. J. Polym. Res. 2000, 7, 125-134) (0.251 g, 1.06 mmol) in 6.5 mL of toluene/Et3N (4/1) by blowing argon for 20 min. Then CuI (7.0 mg, 0.0037 mmol) and Pd(PPh3)2Cl2 (27 mg, 0.0039 mmol) were added, and deaeration was continued for 10 min. Thereafter the mixture was stirred at 40° C. for 16 h. The solvent was removed under reduced pressure, and the crude product was purified by column chromatography (heptane/CH2Cl2 50:50 then 40:60) to yield 245 mg (97%) of 5,5′-(9,9-dibutyl-9H-fluorene-2,7-diyldi-2,1-ethynediyl)bis-2-thiophenecarboxaldehyde; 1H NMR (300.13 MHz, CDCl3) δ 9.80 (s, 2H), 7.61 and 7.26 (AX, JAX=3.9 Hz, 4H), 7.62 (d, J=8.5 Hz, 2H), 7.47 (d, J=8.5 Hz, 2H), 7.45 (s, 2H), 1.93 (m, 4H), 1.02 (m, 4H), 0.60 (t, J=7.3 Hz, 6H), 0.51 (m, 4H); 13C NMR (75.46 MHz, CDCl3) δ 182.4, 151.4, 143.9, 141.4, 136.1, 133.0, 132.5, 131.0, 126.0, 120.9, 120.4, 98.9, 82.6, 55.3, 40.1, 25.9, 23.0, 13.8; HRMS (ESI) calcd for C35H30O2S2 (M+·) m/z 546.16872. found 546.1687.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][NH:30][C:31](=[O:46])[C@H:32]([CH2:35][CH2:36][CH2:37][NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[NH:33][CH3:34])=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:28][CH2:29][NH:30][C:31](=[O:46])[C@H:32]([CH2:35][CH2:36][CH2:37][NH:38][C:39]([O:41][C:42]([CH3:44])([CH3:43])[CH3:45])=[O:40])[N:33]([C:18](=[O:20])[C@H:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([I:17])=[CH:15][CH:16]=2)[NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH3:34])=[CH:26][CH:27]=1
Reactant: CN[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)NCCc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)cc1)C(=O)O
Product: CN(C(=O)[C@H](Cc1ccc(I)cc1)NC(=O)OC(C)(C)C)[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)NCCc1ccc(F)cc1

Procedure:
Boc-4-iodophenylalanine and Nδ-Boc-Nα-methylornithine 2-(4-fluorophenyl)ethylamide were coupled by Procedure D: 1H NMR (400 MHz, CDCl3) δ1.38-1.51 (m, 20H), 1.82 (m, 1H), 1.90 (m, 1H), 2.78 (s, 3H), 2.80-2.97 (m, 4H), 3.00-3.17 (m, 2H), 3.28-3.44 (m, 2H), 4.63 (m, 1H), 4.97 (m, 1H), 6.94-6.99 (m, 4H), 7.11 (m, 1H), 7.18 (m, 1H), 7.58 (d, 1H), and 7.63 (dd, 1H).
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]([O:17][CH3:18])[C:6](=[O:16])[CH:7]=[C:8]1[C:12](=[O:13])[O:11][C:10](C)(C)[O:9]1>CO>[CH3:10][O:11][C:12](=[O:13])[C:8]([OH:9])=[CH:7][C:6](=[O:16])[N:5]([CH2:4][C:3]1[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:2]=1[F:1])[O:17][CH3:18]
Reactant: CON(Cc1ccc(F)cc1F)C(=O)C=C1OC(C)(C)OC1=O
Solvent: CO
Product: COC(=O)C(O)=CC(=O)N(Cc1ccc(F)cc1F)OC
Yield: 55 %

Procedure:
N-(2,4-Difluorobenzyl)-2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-methoxy-acetamide was treated with methanol as described in the preparation of Compound 44-D and gave the title ester as white crystals (55% yield); mp 104–105° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.73 (3H, s, OCH3), 3.89 (3H, s, OCH3), 4.87 (2H, s, NCH2), 6.45 (1H, s, CH), 6.8–6.9 (2H, m, aromatics), 7.31–7.37 (1H, m, aromatic). Anal. calcd for C13H13F2NO5: C, 51.83; H, 4.35; N, 4.65. Found: C, 51.68; H, 4.27; N, 4.53.
Reaction SMILES: [C:1]([C:9]1[CH:23]=[CH:22][CH:21]=[CH:20][C:10]=1[O:11][CH2:12][CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH-].[Li+]>>[C:1]([C:9]1[CH:23]=[CH:22][CH:21]=[CH:20][C:10]=1[O:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC#Cc1ccccc1OCCCC(=O)OCC
Agent: [Li+]
Agent: [OH-]
Product: CCCCCCC#Cc1ccccc1OCCCC(=O)O
Yield: 99 %

Procedure:
Ethyl 4-[2-(1-octynyl)-phenoxy]-butanoate, (250 mg, 0.79 mmole) was hydrolysed with 1 molar equivalent of lithium hydroxide using the same procedure as in example 9. Purification of the crude material by chromatography using silica gel, eluting with chloroform to chloroform/5% methanol afforded the title compound in 99% yield as a colourless oil.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[O:5][N:4]=1.C[O:19][C:20](=[O:33])[CH2:21][O:22][C:23]1[CH:28]=[C:27]([O:29][CH3:30])[C:26]([SH:31])=[CH:25][C:24]=1[CH3:32]>>[CH3:30][O:29][C:27]1[C:26]([S:31][CH2:2][C:3]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[O:5][N:4]=2)=[CH:25][C:24]([CH3:32])=[C:23]([CH:28]=1)[O:22][CH2:21][C:20]([OH:33])=[O:19]
Reactant: FC(F)(F)c1ccc(-c2cc(CCl)no2)cc1
Reactant: COC(=O)COc1cc(OC)c(S)cc1C
Product: COc1cc(OCC(=O)O)c(C)cc1SCc1cc(-c2ccc(C(F)(F)F)cc2)on1

Procedure:
The title compound was prepared in a manner analogous to Example 1F using 42C and 1D. MS m/z 468 (M+1).
Reaction SMILES: [F:1][CH:2]([F:26])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([F:25])[CH:16]=2)[CH:4]=1.[NH2:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([NH:34]O)=[NH:33])=[CH:30][N:29]=1>>[F:26][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]3[O:13][N:34]=[C:32]([C:31]4[CH:36]=[CH:37][C:28]([NH2:27])=[N:29][CH:30]=4)[N:33]=3)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:22])[F:24])=[C:17]([F:25])[CH:16]=2)[CH:4]=1
Reactant: N=C(NO)c1ccc(N)nc1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)c(F)c3)nc12
Product: Nc1ccc(-c2noc(-c3cnn4c(C(F)F)cc(-c5ccc(C(F)(F)F)c(F)c5)nc34)n2)cn1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(3-fluoro-4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.16) (188 mg, 0.5 mmol) and 6-amino-N-hydroxy-nicotinamidine (example B.4) (114 mg, 0.75 mmol) according to general procedure II. Obtained after flash chromatography on silica gel (ethyl acetate/heptane) and further purification by crystallization (dichloromethane/hexane) as a yellow solid (86 mg, 35%). MS (EI) 491.1 [(M)+]; mp 242° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:14]([N:15]([CH3:28])[C:16](=[O:27])[C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:29]1([C:32]([N:34]2[CH2:39][CH2:38][CH:37]([C:40](O)=[O:41])[CH2:36][CH2:35]2)=[O:33])[CH2:31][CH2:30]1>>[CH:29]1([C:32]([N:34]2[CH2:35][CH2:36][CH:37]([C:40]([N:11]3[CH2:12][CH2:13][C@@H:14]([N:15]([CH3:28])[C:16](=[O:27])[C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][CH:18]=4)[C@H:9]([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)[CH2:10]3)=[O:41])[CH2:38][CH2:39]2)=[O:33])[CH2:30][CH2:31]1
Reactant: CN(C(=O)c1ccc(C(F)(F)F)cc1)[C@@H]1CCNC[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)C1CCN(C(=O)C2CC2)CC1
Product: CN(C(=O)c1ccc(C(F)(F)F)cc1)[C@@H]1CCN(C(=O)C2CCN(C(=O)C3CC3)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1

Procedure:
Using the compound obtained in step 1 and 1-(cyclopropylcarbonyl)piperidine-4-carboxylic acid, and by the reaction and purification in the same manner as in Example 97, the title compound was obtained.
Reaction SMILES: [C:1]1([C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][C:8]=2[C:16]2[CH:25]=[CH:24][C:23]([O:26]C)=[C:22]3[C:17]=2[CH:18]=[CH:19][CH:20]=[N:21]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:28]1([C:34]2[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[O:36][C:35]=2[C:43]2[CH:52]=[CH:51][C:50]([OH:53])=[C:49]3[C:44]=2[CH:45]=[CH:46][CH:47]=[N:48]3)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Br[CH2:55][C:56]#[N:57]>>[C:1]1([C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][C:8]=2[C:16]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]3[C:17]=2[CH:18]=[CH:19][CH:20]=[N:21]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[C:28]1([C:34]2[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[O:36][C:35]=2[C:43]2[CH:52]=[CH:51][C:50]([O:53][CH2:55][C:56]#[N:57])=[C:49]3[C:44]=2[CH:45]=[CH:46][CH:47]=[N:48]3)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COc1ccc(-c2oc3ccccc3c2-c2ccccc2)c2cccnc12
Reactant: N#CCBr
Agent: Oc1ccc(-c2oc3ccccc3c2-c2ccccc2)c2cccnc12
Product: N#CCOc1ccc(-c2oc3ccccc3c2-c2ccccc2)c2cccnc12
Yield: 74 %

Procedure:
5-(3-Phenyl-1-benzofuran-2-yl)-8-hydroxy-quinoline was prepared as a solid (0.185 g, 99%) from 5-(3-phenyl-1-benzofuran-2-yl)-8-methoxy-quinoline according to the procedure described in the first part of Step 4 of Example 2; Mass spectrum (+ESI, [M+H]+) m/z 338. Reaction of 5-(3-phenyl-1-benzofuran-2-yl)-8-hydroxy-quinoline with bromoacetonitrile according to the procedure described in Step 2 of Example 1 afforded the title compound as a solid (0.148 g, 74%). Mass spectrum (+ESI, [M+H]+) m/z 377. 1H NMR (400 MHz, DMSO-d6): δ 8.90-8.96 (m, 1H), 8.19 (d, 1H, J=8.1 Hz), 7.71-7.81 (m, 3H), 7.39-7.65 (m,4H), 7.25-7.39 (m, 5H), and 5.48 ppm (s, 2H).
Reaction SMILES: C[Al](C)C.[CH3:5][CH:6]1[N:11]([CH3:12])[CH2:10][CH2:9][N:8]([C:13]2[S:17][C:16]([C:18]([O:20]CC)=O)=[CH:15][CH:14]=2)[CH2:7]1.Cl.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH2:34][O:35][C:36]2[CH:37]=[C:38]([NH2:41])[NH:39][N:40]=2)[CH:29]=[C:30]([O:32][CH3:33])[CH:31]=1.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[CH3:33][O:32][C:30]1[CH:29]=[C:28]([CH2:34][O:35][C:36]2[CH:37]=[C:38]([NH:41][C:18]([C:16]3[S:17][C:13]([N:8]4[CH2:9][CH2:10][N:11]([CH3:12])[CH:6]([CH3:5])[CH2:7]4)=[CH:14][CH:15]=3)=[O:20])[NH:39][N:40]=2)[CH:27]=[C:26]([O:25][CH3:24])[CH:31]=1
Reactant: COc1cc(COc2cc(N)[nH]n2)cc(OC)c1
Reactant: CCOC(=O)c1ccc(N2CCN(C)C(C)C2)s1
Agent: C[Al](C)C
Agent: Cl
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(COc2cc(NC(=O)c3ccc(N4CCN(C)C(C)C4)s3)[nH]n2)cc(OC)c1
Reaction time: 18 h
Yield: 7.6 %

Procedure:
2M Trimethylaluminium (1.250 ml, 2.50 mmol) in toluene, was added dropwise to a stirred solution of ethyl 5-(3,4-dimethylpiperazin-1-yl)thiophene-2-carboxylate (0.268 g, 1 mmol) and 5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine hydrochloride (0.286 g, 1.00 mmol) in toluene (7.14 ml) at 80° C. under nitrogen for 4 h and then at 70° C. for 18 h. Ethyl acetate (5 mL) was added to the reaction mixture followed by a solution of potassium sodium tartrate (5 mL, 20% aqueous). More ethyl acetate (50 mL) and water (25 mL) was added and the mixture was filtered through celite. The filtrate was transferred to a separating funnel and the aqueous layer removed. The ethyl acetate layer was washed with saturated brine and then dried over magnesium sulphate. After filtration the solvent was evaporated to give the crude product as a yellow gum. The crude product was purified by preparative LCMS, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (0.036 g, 7.63%) as a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:9]2[CH:10]=[C:11]([CH2:14]O)[CH:12]=[CH:13][C:8]=2[S:7][C:6]2[N:16]=[CH:17][CH:18]=[N:19][C:5]1=2.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:1][O:2][CH2:3][N:4]1[C:9]2[CH:10]=[C:11]([CH2:14][N:24]3[C:23](=[O:25])[C:22]4=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]4[C:20]3=[O:30])[CH:12]=[CH:13][C:8]=2[S:7][C:6]2[N:16]=[CH:17][CH:18]=[N:19][C:5]1=2
Reactant: COCN1c2cc(CO)ccc2Sc2nccnc21
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCN1c2cc(CN3C(=O)c4ccccc4C3=O)ccc2Sc2nccnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.3 %

Procedure:
A solution of 3.32 g of (10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)methanol, 2.12 g of phthalimide and 3.77 g of triphenylphosphine in tetrahydrofuran (50 ml) was ice-cooled and 2.24 ml of diethyl azodicarboxylate was dropped thereinto. After stirring at room temperature for 1 hour, the solvent was distilled off under reduced pressure and diethyl ether was added to the residue. Then it was subjected to ultrasonication and the crystals thus precipitated were taken up by filtration to thereby give 2.6 g of the title compound as pale yellow crystals.
Reaction SMILES: C([O:3][C:4](=O)[C@@:5]([NH2:24])([CH2:22][CH3:23])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:10][CH:9]=1)C.[BH3-][C:27]#N.[Na+]>ClCCl.C(O)=O>[CH2:22]([C@@:5]([NH:24][CH3:27])([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:10][CH:9]=1)[CH2:4][OH:3])[CH3:23]
Reactant: CCCCCCCOc1ccc(CC[C@](N)(CC)C(=O)OCC)cc1
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: O=CO
Solvent: ClCCl
Product: CCCCCCCOc1ccc(CC[C@](CC)(CO)NC)cc1

Procedure:
(R)-2-amino-2-ethyl-4-(4-heptyloxy-phenyl)-butyric acid ethyl ester (175 mg; 0.5 mmol) is dissolved in dichloromethane (2) and formic acid (100 μl), p-formaldehyde (100 μl; 30% in water) and NaBH3CN are added. After 1 hour at RT the reaction mixture is extracted with saturated aqueous NaHCO3 solution and the organic layer is dried over MgSO4 and purified on silica gel using n-hexanetethyl acetate (1/1→1/9) as mobile phase.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:12]2[NH:11][C:10]3[CH2:13][CH2:14][NH:15][C:16](=[O:17])[C:9]=3[C:8]=2[CH:7]=[CH:6][CH:5]=1.[CH3:18]I.O>CN(C=O)C>[F:3][C:4]1[C:12]2[N:11]([CH3:18])[C:10]3[CH2:13][CH2:14][NH:15][C:16](=[O:17])[C:9]=3[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: CI
Reactant: O=C1NCCc2[nH]c3c(F)cccc3c21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c2c(c3cccc(F)c31)C(=O)NCC2
Reaction time: 0.25 h

Procedure:
Sodium hydride (60% dispersion in oil; 196 mg) was added to a stirred suspension of 6-fluoro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one (500 mg) in dry DMF (10 ml) under nitrogen. After 30 min the solution was cooled (0°), and methyl iodide (0.153 ml) was added. After stirring for 15 min the suspension was poured into water 950 ml) and extracted with dichloromethane (3×25 ml). The combined, dried organic extracts were evaporated to give a solid (ca. 530 mg) which was purified by FCC eluting with System A (250:10:1) to give the title compound (130 mg), m.p. 242°.
Reaction SMILES: [CH3:1][C:2](=[CH2:9])[C:3]#[C:4][CH:5](O)[CH:6]=[CH2:7].[BrH:10]>>[Br:10][CH2:7][CH:6]=[CH:5][C:4]#[C:3][C:2]([CH3:1])=[CH2:9]
Reactant: C=CC(O)C#CC(=C)C
Reactant: Br
Product: C=C(C)C#CC=CCBr
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
An alcoholic solution of 6-methyl-1,6-heptadien-4-yn-3-ol is added dropwise to 40 ml of fuming HBr and the mixture stirred for 1.5 hours at room temperature. The reaction mixture is poured onto ice and extracted with hexane. The organic phase is repeatedly washed with aqueous NaCl, dried and concentrated on a rotary evaporator. The oily reaction product consists (according to NMR) of a 3:1 mixture of (E)- and (Z)-1-bromo-6-methyl-2,6-heptadien-4-yne and is directly employed for further reaction.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)=O.[N+]([O-])(O)=O.[F:17][C:18]([F:33])([O:22][C:23]1[CH:24]=[C:25]([NH:29][C:30]([NH2:32])=[NH:31])[CH:26]=[CH:27][CH:28]=1)[CH:19]([F:21])[F:20]>>[F:17][C:18]([F:33])([O:22][C:23]1[CH:24]=[C:25]([NH:29][C:30]2[N:32]=[C:5]([C:7]3[S:8][CH:9]=[CH:10][CH:11]=3)[CH:4]=[CH:3][N:31]=2)[CH:26]=[CH:27][CH:28]=1)[CH:19]([F:20])[F:21]
Reactant: CN(C)C=CC(=O)c1cccs1
Reactant: N=C(N)Nc1cccc(OC(F)(F)C(F)F)c1
Solvent: O=[N+]([O-])O
Product: FC(F)C(F)(F)Oc1cccc(Nc2nccc(-c3cccs3)n2)c1

Procedure:
In accordance with the eneral procedure described in Example 1, reaction of 100 mg (0.55 mmol) of 3-dimethylamino-1-(2-thienyl)-2-propen-1-one [described in EP-A-0 233 461] and 173 mg (0.55 mmol) of 3-(1,1,2,2-tetrafluoroethoxy)phenylguanidine nitrate gives N-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-4-(2-thienyl)-2-pyrimidine-amine; FAB-MS:370 (M+ +1), m.p. 115°-116°, Rf =0.95 (ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[H-].[Na+].Cl[CH2:14][C:15]1[C:16]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:32])=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:25]>CN(C=O)C>[Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH2:14][C:15]3[C:16]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[Cl:32])=[N:17][C:18]4[C:23]([CH:24]=3)=[CH:22][CH:21]=[CH:20][C:19]=4[CH3:25])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: Cc1cccc2cc(CCl)c(-c3ccccc3Cl)nc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc2cc(Cn3ccc4c(Cl)ncnc43)c(-c3ccccc3Cl)nc12
Reaction time: 2 h

Procedure:
A solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (280 mg, 1.1 eq) in DMF (3 mL) was treated with NaH (1.2 eq, 80 mg, 60%) and the reaction mixture was stirred at rt for 30 min before addition of 3-(chloromethyl)-2-(2-chlorophenyl)-8-methylquinoline (500 mg, 1.7 mmol) in DMF (2 mL). After 2 h at rt, the mixture was partitioned between EtOAc (50 mL) and H2O (30 mL), the layers were separated, and the aqueous layer was extracted with EtOAc (2×30 mL). The combined organic layers were dried (Na2SO4), concentrated and purified by flash chromatography (0% to 25% EtOAc/hexane) to provide 3-((4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-2-(2-chlorophenyl)-8-methylquinoline as a white foam. This material (60 mg, 0.14 mmol) was dissolved in EtOH (4 mL) and treated with NH3 gas for 3 min. The sealed tube was heated at 80° C. for 4 days. The reaction mixture was concentrated and purified by column chromatography on silica gel (eluent: DCM/MeOH, 20/1) to provide a white solid [PI3Kδ IC50=1968 nM]. 1H-NMR (DMSO-d6) δ 7.94 (s, 1H), 7.89 (s, 1H), 7.75 (t, J=7.8 Hz, 1H), 7.37-7.62 (m, 6H), 6.96 (s, 2H), 6.86 (d, J=3.6 Hz, 1H), 6.54 (d, J=3.5 Hz, 1H), 5.30 (d, J=5.9 Hz, 2H), 2.64 (s, 3H). Mass Spectrum (ESI) m/e=400 (M+1).
Reaction SMILES: [I-].[CH3:2][N+:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([OH:15])[CH:4]=1>CO>[CH3:2][N:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([OH:15])[CH2:4]1
Reactant: C[n+]1ccc(-c2ccccc2)c(O)c1
Agent: [I-]
Solvent: CO
Product: CN1C=CC(c2ccccc2)=C(O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.5 %

Procedure:
A mixture of 2 (4.03 g, 12.9 mmol) and IRA-OH (400) resin (20 mL) in MeOH was stirred at 25° C. for 1 h then the basic resin was filtered off and washed several time with MeOH. The resulting clear solution was concentrated under reduced pressure to afford the compound 3 (2.21 g, 92%) as a pale yellow solid used in the next step without further purification: mp 154-157° C.; 1H NMR (DMSO-d6) δ3.97 (s, 3H), 7.3-7.52 (m, 5H), 7.38 (d, 1H, J=7.5 Hz), 8.04 (d, 1H, J=8.1 Hz), 8.053 (s, 1H).