Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[S:8][C:7]([CH2:9][O:10][C:11]2[C:12]([F:21])=[C:13]([C:17]([F:20])=[CH:18][CH:19]=2)[C:14]([NH2:16])=[O:15])=[N:6][C:5]=1[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[CH:2]=[CH2:3]>CO>[F:21][C:12]1[C:11]([O:10][CH2:9][C:7]2[S:8][C:4]([CH2:1][CH2:2][CH3:3])=[C:5]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[N:6]=2)=[CH:19][CH:18]=[C:17]([F:20])[C:13]=1[C:14]([NH2:16])=[O:15]
Reactant: C=CCc1sc(COc2ccc(F)c(C(N)=O)c2F)nc1-c1ccc(OC)cc1
Solvent: CO
Product: CCCc1sc(COc2ccc(F)c(C(N)=O)c2F)nc1-c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 239 %

Procedure:
To a solution of 3-[5-allyl-4-(4-methoxy-phenyl)-thiazol-2-ylmethoxy]-2,6-difluoro-benzamide (0.1 g, 0.02 mmol) in 5 ml of anhydrous methanol was added dry 50 mg of dry Pd—C. The reaction mixture was stirred at 25° C. for 12 h under hydrogen atmosphere. The reaction mixture was filtered over the bed of celite. The filtrate was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (230-400μ) using ethyl acetate/hexane (50:50) as the eluent to provide the title compound as white solid (0.02 g, 2%). 1H NMR (DMSO-d6, 400 MHz); δ 0.92 (t, 3H, J=7.2 Hz), 1.63-1.65 (m, 2H), 2.8 (t, 2H, J=7.6 Hz (o-coupling), 3.79 (s, 3H), 5.47 (s, 2H), 7.02 (d, 2H, J=8.8 Hz (o-coupling), 7.11 (m, 1H), 7.42 (m, 1H), 7.53 (d, 2H, J=8.8 Hz (o-coupling), 7.88 (s, 1H), 8.16 (s, 1H), 8.38 (d, 1H, J=8.4 Hz (O-coupling). MS ES+ (419.14), HPLC (method 5) Rt=16.58 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6](/[CH:8]=[N:9]/[C:10]([CH3:13])([CH3:12])C)[CH:7]=1.[CH2:15]([OH:19])CC#C.C(NC(C)C)(C)C>C1(C)C=CC=CC=1.C(Cl)Cl.[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>[Br:1][C:2]1[CH:7]=[C:6]2[C:5]([CH:13]=[C:10]([CH2:12][CH2:15][OH:19])[N:9]=[CH:8]2)=[CH:4][CH:3]=1
Reactant: C#CCCO
Reactant: CC(C)(C)/N=C/c1cc(Br)ccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: OCCc1cc2ccc(Br)cc2cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The product from Example 15D (1.3 g, 3.6 mmol), 3-butyn-1-ol (0.3 g, 4.3 mmol), CuI (0.04 g, 0.2 mmol), and PdCl2(PPh3)2 (0.08 g, 0.1 mmol) were combined in toluene (15 mL). The mixture was treated with diisopropylamine (0.54 g, 5.3 mmol) and stirred at room temperature for 4 hours. The mixture was then treated with additional CuI (0.07 g, 0.4 mmol) and heated at 100° C. for 4 hours. The mixture was allowed to cool to room temperature, diluted with 30 mL CH2Cl2, and filtered. The filtrate was washed with 2×10 mL 15% NaCl and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 10:90 MeOH:CHCl3) to provide the title compound. 1H NMR (CDCl3, 400 MHz) δ 9.08 (s, 1H), 8.09 (d, J=4 Hz, 1H), 7.73 (dd, J=8, 4 Hz, 1H), 7.63 (d, J=8 Hz, 1H), 7.48 (s, 1H), 4.08 (t, J=4 Hz, 2H), 3.92 (s, 1H), 3.15 (t, J=4 Hz, 2H). 13C NMR (CDCl3, 100 MHz) δ 153.8, 150.3, 134.5, 133.8, 129.4, 127.6, 120.0, 118.6, 62.3, 39.4. MS (DCl/NH3) 252, 254 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][CH2:10][NH:9][CH2:8]2)[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[N:3]=1.[C:17]([O:21][C:22]([NH:24][C@H:25]([CH2:30][C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=1)[CH2:26][C:27](O)=[O:28])=[O:23])([CH3:20])([CH3:19])[CH3:18].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:1][C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][CH2:10][N:9]([C:27](=[O:28])[CH2:26][C@H:25]([NH:24][C:22](=[O:23])[O:21][C:17]([CH3:18])([CH3:19])[CH3:20])[CH2:30][C:31]3[CH:40]=[CH:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:32]=3)[CH2:8]2)[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[N:3]=1
Reactant: Cc1nc2ccccc2n1C1CCCNC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccc2ccccc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1nc2ccccc2n1C1CCCN(C(=O)C[C@@H](Cc2ccc3ccccc3c2)NC(=O)OC(C)(C)C)C1

Procedure:
(2-methyl-1-(piperidin-3-yl)-1H-benzo[d]imidazole (0.486 mmoles, 0.160 g) was added to a 10 mL round-bottomed flask equipped for stirring under nitrogen. DMF (4 mL), (R)-3-(tert-butoxycarbonylamino)-4-(naphthalen-2-yl)butanoic acid (0.486 mmoles, 0.140 g) and N-methylmorpholine (1.94 mmoles, 0.214 mL) were then added and the solution was allowed to stir at rt for 5 min. HATU (0.534 mmoles, 0.204 g) was added and the resultant solution was stirred at room temperature for 3 hr. The reaction solution was then directly purified by preparative LC/MS (35-95% CH3CN in H2O). The resultant fractions were collected and the solvent was removed in-vacuo affording (R)-tert-butyl 4-(3-(2-methyl-1H-benzo[d]imidazol-1-yl)piperidin-1-yl)-1-(naphthalen-2-yl)-4-oxobutan-2-ylcarbamate (1354) as a clear oil. ESI-MS: raiz 527.5 (M+H)+.
Reaction SMILES: CC1[C:7]([CH2:8]Cl)=[C:6]([CH3:10])[C:5]([CH3:11])=[C:4]([CH3:12])[C:3]=1[CH3:13]>C1COCC1>[CH3:13][CH:3]1[C:4]([CH3:12])=[C:5]([CH3:11])[C:6]([CH3:10])=[C:7]1[CH3:8]
Reactant: Cc1c(C)c(C)c(CCl)c(C)c1C
Solvent: C1CCOC1
Product: CC1=C(C)C(C)C(C)=C1C
Temperature: -20 °C
Reaction time: 48 h
Yield: 117.4 %

Procedure:
A 250 ml roundbottom flask equipped with a condenser, stirrer, thermometer and dropping funnel with nitrogen inlet was charged with 100 ml THF in which pentamethylbenzyl chloride (19.8 g, 0.10 mol) was dissolved. The solution was cooled to -20° C. and sodium cyclopentadienyl (60 ml, 2.0 M in THF) was added; the solution was stirred for 48 hours at 22° C. GC analysis showed 90% conversion to pentamethylcyclopentadienyl. A precipitate was filtered off and the solvent was evaporated. The remaining residue was recrystallized from hot dichloromethane/petroleum ether. After recrystallization, pentamethylcyclopentadiene (16 g) was obtained. The product was characterized by GC, GC-MS, 13C and 1H NMR.
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9](CC1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4CCN(C(OCC)=O)C[CH2:35]4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.[CH2:45](N)[CH3:46].NC1C=CC=CC=1>>[CH:6]12[N:7]([C:13]3[N:18]=[C:17]([C:19]4[CH:20]=[CH:21][C:22]([NH:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[CH:23][CH:24]=4)[N:16]=[C:15]4[N:31]([CH2:34][CH3:35])[N:32]=[CH:33][C:14]=34)[CH:8]([CH2:45][CH2:46]1)[CH2:9][O:12][CH2:5]2
Reactant: CCN
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Agent: NC(N)=O
Solvent: Nc1ccccc1
Product: CCNC(=O)Nc1ccc(-c2nc(N3C4CCC3COC4)c3cnn(CC)c3n2)cc1

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing ethylamine (2M in THF) as the aniline component. (46%, MS=422.4 (M+H))
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1.C(Cl)(=O)C([Cl:17])=O.CN(C=O)C>C(Cl)Cl>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:17])=[O:8])=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4-(Trifluoromethyl)benzoic acid (2.45 g, 12.9 mmol) dissolved in DCM (30 ml), cooled to 0° C. and added oxalyl chloride (3.4 ml, 38.6 mmol). Catalytic amount of DMF was added to this mixture and stirred at rt for 30 mins. After 30 mins, DCM removed on rotavapour and co-distilled the residue two times with DCM to obtain 4-(trifluoromethyl)benzoyl chloride quantitatively. 2-Hydroxy-3-amino-5-bromopyridine (2.4 g, 11.1 mmol) dissolved in DCM (15 ml) and added Pyridine (1.74 g, 22 mmol) under nitrogen atmosphere. This mixture stirred at rt for 30 mins and added 4-(trifluoromethyl)benzoyl chloride (2.4 g, 13.3 mmol). After continuing stirring at rt for 30 mins, reaction mass diluted with water and extracted with DCM. DCM removed on rotavapour to obtain the crude. Crude was purified on column using 60-120 mesh silica gel and a gradient mixture of MeOH and DCM (2:98) as eluent to afford the titled compound (2.1 g) as a brown solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.43 (bs, 1H), 9.58 (s, 1H), 8.37 (d, J 2.6, 1H), 8.09 (d, J 8.2, 2H), 7.91 (d, J 8.2, 2H), 7.48 (d, J 2.6, 1H).
Reaction SMILES: [H-].[Na+].CS(C)=O.[Cl:7][C:8]1[CH:9]=[C:10]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:11]=[CH:12][C:13]=1[Cl:14].[C:23]([O:27][C:28]([N:30]1[CH2:34][CH2:33][CH:32](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>C(OCC)(=O)C>[C:23]([O:27][C:28]([N:30]1[CH2:34][CH2:33][CH:32]([N:15]([C:10]2[CH:11]=[CH:12][C:13]([Cl:14])=[C:8]([Cl:7])[CH:9]=2)[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: Fc1ccc(Nc2ccc(Cl)c(Cl)c2)cc1
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)C2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(N(c2ccc(F)cc2)c2ccc(Cl)c(Cl)c2)C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 17.5 %

Procedure:
Sodium hydride (0.19 g, 60% in oil) was added to 10 ml of dimethyl sulfoxide (DMSO) and stirred at 60° C. for one hour. Subsequently, 1.0 g of (3,4-dichlorophenyl)-(4-fluorophenyl)amine was added to the mixture and stirred at 60° C. for one hour. A DMSO solution containing 2.0 g of 3-(toluene-4-sulfonyloxy)pyrrolidine-1-carboxylic acid tert-butyl ester was gradually added to the mixture and stirred at 60° C. for 15 hours. Ethyl acetate was added to the reaction solution. The solution was then washed with water, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=20:1). The eluent solvent was distilled off under reduced pressure to thereby obtain 0.29 g of oily brown 3-[(3,4-dichlorophenyl)-(4-fluorophenyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][C:2]1([C:5]2[NH:6][CH:7]=[CH:8][C:9](=O)[CH:10]=2)[CH2:4][CH2:3]1.P(Br)(Br)([Br:14])=O.C([O-])(O)=O.[Na+]>>[Br:14][C:9]1[CH:8]=[CH:7][N:6]=[C:5]([C:2]2([CH3:1])[CH2:4][CH2:3]2)[CH:10]=1
Reactant: O=P(Br)(Br)Br
Reactant: CC1(c2cc(=O)cc[nH]2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Product: CC1(c2cc(Br)ccn2)CC1
Temperature: 85 °C
Reaction time: 0.25 h

Procedure:
A mixture of 2-(1-methyl-cyclopropyl)-1H-pyridin-4-one (Step 1.5) (13.4 mmol) and POBr3 (14.74 mmol) was stirred for 15 min at 85° C. and then 15 min at 120° C. After cooling slightly, the reaction mixture was poured into a saturated solution of NaHCO3 and extracted with CH2Cl2 (2×). The combined organic phases were washed with a saturated solution of NaHCO3, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography to afford the title compound as a brown oil. HPLC: tR=4.11 min (method B); LC-MS: tR=2.39 min, [M+H]+ 212/214; TLC: Rf=0.31 (CH2Cl2).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[N:23]([S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:26])=[O:25])[C:16]4[N:17]=[CH:18][CH:19]=[C:20]([CH:21]=O)[C:15]=4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:34][CH3:35].Cl.[NH2:37][OH:38]>N1C=CC=CC=1.O.ClCCl>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[N:23]([S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:26])=[O:25])[C:16]4[N:17]=[CH:18][CH:19]=[C:20]([CH:21]=[N:37][OH:38])[C:15]=4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:34][CH3:35]
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(C=O)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Reactant: NO
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: COc1cc2c(nc1OC)c(-c1cc3c(C=NO)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Temperature: 50 °C

Procedure:
To a solution of 1 g of [2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde in 50 cm3 of pyridine, at a temperature in the region of 20° C., is added 0.46 g of hydroxylamine hydrochloride. The reaction medium is heated at 50° C. for 24 hours. The reaction medium is concentrated under reduced pressure. The residue obtained is taken up in 20 cm3 of water and 50 cm3 of dichloromethane. After separation of the phases by settling, the organic phase is dried over magnesium sulfate, filtered and then concentrated under reduced pressure. 0.510 g of [2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-carbaldehyde oxime is obtained with the following characteristics:
Reaction SMILES: C1O[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=3[C:18]#[N:19])[CH2:7][CH2:6]2)[O:4]C1C.C(O)(=O)C>Cl>[C:18]([C:12]1[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=1[N:8]1[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]1)#[N:19]
Reactant: CC1COC2(CCN(c3ccc(F)cc3C#N)CC2)O1
Agent: Cl
Solvent: CC(=O)O
Product: N#Cc1cc(F)ccc1N1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 39 (1.483 g, 5.36 mmol) in 6N aqueous HCl (25 mL) was treated with acetic acid (50 mL) at room temperature. The mixture was stirred at room temperature (3 d). The solvent was removed in vacuo and the residue dissolved in dichloromethane and sodium carbonate solution. The aqueous layer was extracted with three additional portions of dichloromethane and the combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. PCTLC (SiO2, 6 mm, 20% EtOAc-80% hexane) afforded the title compound (40).
Reaction SMILES: C(OC(=O)N([C@H]1[C@H](C2C=CC(Cl)=C(Cl)C=2)CN(CC2C=CC=CC=2)C1)C)(C)(C)C.C(O[C:35](=O)[N:36]([C@@H:38]1[C@@H:42]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[C:45]([Cl:50])[CH:44]=2)[CH2:41][N:40]([C:51]([CH:53]2[CH2:58][CH2:57][N:56]([C:59]([C:61]3([CH3:64])[CH2:63][CH2:62]3)=[O:60])[CH2:55][CH2:54]2)=[O:52])[CH2:39]1)C)(C)(C)C>>[Cl:50][C:45]1[CH:44]=[C:43]([C@H:42]2[C@H:38]([NH:36][CH3:35])[CH2:39][N:40]([C:51]([CH:53]3[CH2:58][CH2:57][N:56]([C:59]([C:61]4([CH3:64])[CH2:62][CH2:63]4)=[O:60])[CH2:55][CH2:54]3)=[O:52])[CH2:41]2)[CH:48]=[CH:47][C:46]=1[Cl:49]
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Agent: CN(C(=O)OC(C)(C)C)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)c(Cl)c1
Product: CN[C@@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of rac-[(3R,4S)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester (example 1, e) the title compound was prepared from [(3S,4R)-1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester through cleavage of the benzyl group. And, in analogy to the procedure described for the synthesis of rac-{(3R,4S)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid tert-butyl ester (example 1, f) the Boc-protected title compound was prepared from the intermediately built [(3S,4R)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester and 1-(1-Methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid. The title compound was subsequently isolated after acidic cleavage of the Boc group with TFA. MS m/e: 438.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].CC(C)([O-])C.[Na+].Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([C:23]#[N:24])[CH:18]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([C:23]#[N:24])[CH:18]=2)=[CH:4][C:3]=1[F:9]
Reactant: Nc1ccc(O)cc1F
Reactant: N#Cc1cc(Cl)ccn1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cc(Oc2ccc(N)c(F)c2)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.9 %

Procedure:
A teflon capped vial was charged with 4-amino-3-fluorophenol (0.291 g, 2.29 mmol) and anhydrous DMF (2.3 mL). The resultant solution was de-gassed in vacuo and backfilled with argon (3×). The vial was treated with sodium tert-butoxide (0.27 g, 2.41 mmol) under argon and quickly capped. The reaction mixture was stirred at RT for 1 h. After addition of 4-chloropicolinonitrile (0.317 g, 2.29 mmol) and K2CO3 (0.174 g, 1.26 mmol), the vial was de-gassed again and heated in a 90° C. oil bath overnight. The reaction mixture was diluted with EtOAc (60 mL) and washed with brine (25 mL). The aqueous phase was back-extracted with EtOAc (50 mL). The combined organic layers were washed with brine (25 mL), dried (MgSO4), concentrated in vacuo and purified by chromatography to afford 4-(4-amino-3-fluorophenoxy)picolinonitrile (0.162 g, 31% yield) as a colorless oil. 1H NMR (DMSO-d6) δ 8.56 (d, J=5.6 Hz, 1H), 7.62 (d, J=2.0 Hz, 1H), 7.14 (dd, J=6.0, 2.8 Hz, 1H), 7.03 (dd, J=11.6, 2.4 Hz, 1H), 6.88-6.77 (m, 2H), 5.25 (s, 2H); MS (ESI) m/z: 230.0 (M+H+).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=1.[Na+].[CH3:17][S:18]([O-:20])=[O:19]>CO>[CH3:17][S:18]([CH2:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=1)(=[O:20])=[O:19]
Reactant: O=[N+]([O-])c1cc(CCl)cc(C(F)(F)F)c1
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CS(=O)(=O)Cc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 92.2 %

Procedure:
A solution of 1-chloromethyl-3-nitro-5-trifluoromethyl-benzene (520 mg; 2.170 mmol) and methanesulfinic acid sodium salt (664 mg; 6.511 mmol) in Methanol (10 ml) of was refluxed overnight. The reaction was then cooled to room temperature and the product precipitated was filtered and diluted with dichloromethane. The solid was removed and the organic phase was concentrated in vacuo 520 mg (2 mmol; 85% yield) of 1-methylsulfonylmethyl-3-nitro-5-trifluoromethyl-benzene were obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[C:9]2[CH2:13][C:14]#[N:15])([O-:3])=[O:2].O>O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[C:9]2[CH2:13][CH2:14][NH2:15])([O-:3])=[O:2]
Reactant: N#CCc1c[nH]c2c([N+](=O)[O-])cccc12
Solvent: O
Solvent: C1CCOC1
Product: NCCc1c[nH]c2c([N+](=O)[O-])cccc12
Reaction time: 20 h

Procedure:
Dissolve in a 500 mL round bottom flask equipped with magnetic stirring, and a nitrogen inlet, (7-nitro-1H-indol-3-yl)-acetonitrile (5.27 g, 26 mmol) in dry tetrahydrofuran (150 mL). Treat the solution with 1M BH3:THF (55 mL, 55 mmol) and stir at room temperature. After 20 hours, quench the reaction by the cautious dropwise addition of water (9 mL) and stir until foaming and gas evolution has stopped. Concentrate the mixture to dryness in vacuo, redissolve in 1 N HCl (300 ml) and extracte with ethyl acetate. Basify the aqueous phase 5 N NaOH and extract with ethyl acetate. Pool the ethyl acetate extracts and dry over sodium sulfate and concentrate in vacuo to give the title compound as an orange-brown solid: 1H NMR (400 MHz, dmso-d6): 11.66 (br s, 1H) 8.07 (t, 2H, J=7.6 Hz), 7.32 (s, 1H), 7.20 (t, 1H, J=8.0 Hz) 2.79–2.83 (m, 4H), MS (APCI):m/e 189.0 (M-NH2).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:10](=[CH:11][C:12]=1[CH3:13])[C:8](=[O:9])[CH:7]=[CH:6][C:5]2=[O:14].[Br:15]Br.C([O-])(=O)C.[Na+].O>C(O)(=O)C>[Br:15][C:6]1[C:5]([C:4]2[C:10]([C:8](=[O:9])[CH:7]=1)=[CH:11][C:12]([CH3:13])=[C:2]([CH3:1])[CH:3]=2)=[O:14]
Reactant: Cc1cc2c(cc1C)C(=O)C=CC2=O
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc2c(cc1C)C(=O)C(Br)=CC2=O
Reaction time: 2 h

Procedure:
A solution of 6,7-dimethyl naphtho-1,4-quinone (20.0 g.; 0.107 mole) in glacial acetic acid (250 ml) was stirred during the dropwise addition of bromine (5.6 ml; 17.2 g; 0.107 mole) in acetic acid (10 ml.) at 15° C and allowed to stir at this temperature for a further 2 hours. Anhydrous sodium acetate (20 g) was added and the mixture stirred at 100° C for 11/2 hours after an initial half hour period at room temperature; cooled, poured into water (2.5 l) and the yellow bromo product filtered off. It had m.p. (ethanol, chloroform) 156°-159° C. (Found; C, 53.47; H, 3.39; Br. 30.23; C12H9BrO2 requires; C, 54.36; H, 3.42; Br, 30.14%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:19])=[C:4]([C:10]([O:16][CH2:17][CH3:18])=[C:11]([CH:13](Cl)[CH3:14])[CH:12]=1)[C:5]([NH:7][CH2:8][CH3:9])=[O:6].[I:20][C:21]1[C:29]2[C:24](=[N:25][CH:26]=[N:27][C:28]=2[NH2:30])[NH:23][N:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>CN(C)C=O.CCOCC>[NH2:30][C:28]1[N:27]=[CH:26][N:25]=[C:24]2[N:23]([CH:13]([C:11]3[C:10]([O:16][CH2:17][CH3:18])=[C:4]([C:3]([CH3:19])=[C:2]([Cl:1])[CH:12]=3)[C:5]([NH:7][CH2:8][CH3:9])=[O:6])[CH3:14])[N:22]=[C:21]([I:20])[C:29]=12
Reactant: CCNC(=O)c1c(C)c(Cl)cc(C(C)Cl)c1OCC
Reactant: Nc1ncnc2[nH]nc(I)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCNC(=O)c1c(C)c(Cl)cc(C(C)n2nc(I)c3c(N)ncnc32)c1OCC
Temperature: 140 °C
Yield: 61.6 %

Procedure:
A mixture of 3-chloro-5-(1-chloroethyl)-6-ethoxy-N-ethyl-2-methylbenzamide (130 mg, 0.43 mmol), 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (120 mg, 0.47 mmol), cesium carbonate (210 mg, 0.64 mmol) and potassium iodide (7.1 mg, 0.043 mmol) in N,N-dimethylformamide (1 mL) was heated at 140° C. for 1 h. The mixture was diluted with ether, washed with water, and concentrated. The residue was purified on silica gel (eluting with 0 to 100% EtOAc in hexanes) to give the desired product (0.14 g, 62%). LCMS calculated for C19H23ClIN6O2 (M+H)+: m/z=529.1; Found: 528.9.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[CH:13]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)[CH2:16][C:17]([OH:19])=[O:18].N1CCCCC1.N1C=CC=CC=1>C(OCC)C>[C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[CH:13]=[CH:16][C:17]([OH:19])=[O:18])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1cnccc1-c1ccccc1
Reactant: O=C(O)CC(=O)O
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1cnccc1-c1ccccc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 64.3 %

Procedure:
A mixture of 4.3 g of 4-phenyl-3-pyridinecarbaldehyde [cf. Heterocycles, 14, 813 (1980)], 2.5 g of malonic acid, 0.5 ml of piperidine, and 6 ml of pyridine is stirred at 100° C. for 2 hours. After cooling, 50 ml of diethyl ether is added, and the resulting precipitate is collected. The obtained solid is washed with water and dried to give 3.4 g of the title compound.