Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[NH:2][C:3]([N:5]([CH2:9]CC)[CH2:6][CH2:7][CH3:8])=[O:4].C=O.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[O:17]1[CH2:18][CH2:19][N:14]([CH2:9][N:5]([CH2:6][CH2:7][CH3:8])[C:3]([NH2:2])=[O:4])[CH2:15][CH2:16]1.[CH3:9][N:5]([CH2:6][CH2:7][CH3:8])[C:3]([NH2:2])=[O:4]
Reactant: CCCN(CCC)C(=O)NC
Reactant: C1COCCN1
Agent: C=O
Product: CCCN(C)C(N)=O
Product: CCCN(CN1CCOCC1)C(N)=O

Procedure:
1 mol of N-methyl dipropylurea and 1 mol of formol in aqueous 30% solution are mixed. To this solution 1 mol of morpholine is slowly added while cooling. The stirring is maintained one hour after the end of the N-methyl dipropylurea addition. After evaporation to dryness a crystalline product is obtained which melts at 110°C. The yield of the reaction is 98%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[CH:13]=O.Cl.[NH2:16]O.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]#[N:16]
Reactant: COc1ccc2c(c1)c(C=O)cn2C
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(C#N)cn2C
Yield: 70.9 %

Procedure:
5-Methoxy-1-methyl-1H-indole-3-carbaldehyde [76 g, Reference Example 2(a)] and hydroxylamine hydrochloride (55.9 g) were stirred together in dimethylformamide (900 mL) under reflux for 1 hour. The mixture was allowed to cool, then poured into water and then extracted with ethyl acetate. The combined extracts were washed with water then evaporated to give the title compound (53 g) as a pale brown solid, m.p. 100-104° C. 1H NMR [(CD3)2SO]: δ 8.17 (1H, s); 7.54 (1H, d, J=9.0 Hz); 7.09 (1H, d, J=2.4 Hz); 6.97 (1H, dd, J=9.0 and 2.4 Hz); 3.82 and 3.84 (6H, s).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([O:12][CH3:13])=[C:7]([CH3:14])[CH:6]=1)(=[O:3])[CH3:2].[Br:15]Br>C(O)(=O)C>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([O:12][CH3:13])=[C:7]([CH3:14])[C:6]=1[Br:15])(=[O:3])[CH3:2]
Reactant: COc1c(C)cc(NC(C)=O)cc1C
Reactant: BrBr
Solvent: CC(=O)O
Product: COc1c(C)cc(NC(C)=O)c(Br)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.4 %

Procedure:
4-Acetamido-2,6-dimethylanisole (7, 8.6 g, 44.3 mmol) and acetic acid (30 mL) were placed in a round-bottom flask under an argon atmosphere. Bromine (2.7 mL, 44.3 mmol) was added dropwise to the solution, after which the reaction mixture was stirred at room temperature for about 3 h, and then concentrated. The residue was diluted with methylene chloride and carefully washed sequentially with saturated aq. sodium bicarbonate and brine, and dried (MgSO4). Removal of solvents gave a brown-colored solid which was recrystallized from methylene chloride-hexanes to yield 4-acetamido-3-bromo-2,6-dimethylanisole (10.3 g, 85% yield) as an off-white solid, mp 152°-153° C. Spectral data: 1H NMR: δ 2.18 (s, 3H), 2.24 (s, 3H), 2.35 (s, 3H), 3.66 (s, 3H), 7.55 (br s, 1H), 7.9 (s, 1H); 13C NMR: δ 16.1, 16.8, 24.6, 60.1, 114.5, 122.0, 130.5, 131.3, 131.5, 153.6, 168.1; CI-HRMS: calcd. for C11H15BrNO2 (M+H+) 272.0286, fnd. 272.0284.
Reaction SMILES: C(S[C:4]1[S:5][C:6](=[CH:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([OH:30])([CH3:29])[CH3:28])=[CH:23][C:22]=2[C:31]([F:34])([F:33])[F:32])[N:15]=[CH:14]3)[C:7](=[O:9])[N:8]=1)C.[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][C@@H:43]1[CH2:48][OH:49])=[O:41])([CH3:38])([CH3:37])[CH3:36]>>[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][N:45]([C:4]2[S:5][C:6](=[CH:10][C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[N:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([OH:30])([CH3:29])[CH3:28])=[CH:23][C:22]=3[C:31]([F:33])([F:32])[F:34])[N:15]=[CH:14]4)[C:7](=[O:9])[N:8]=2)[CH2:44][C@@H:43]1[CH2:48][OH:49])=[O:41])([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1CO
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(C)(C)O)cc3C(F)(F)F)c2)S1
Product: CC(C)(C)OC(=O)N1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(C)(C)O)cc4C(F)(F)F)c3)S2)C[C@@H]1CO

Procedure:
(2R)-2-Hydroxymethyl-4-(5-{1-[4-(1-hydroxy-1-methyl-ethyl)-2-trifluoromethyl-benzyl]-1H-indazol-5-ylmethylene}-4-oxo-4,5-dihydro-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester was prepared from 2-Ethylsulfanyl-5-{1-[4-(1-hydroxy-1-methyl-ethyl)-2-trifluoromethyl-benzyl]-1H-indazol-5-ylmethylene}-thiazol-4-one and (2R)2-Hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester following General Procedure C.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[O:15]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16]1.C(#N)C1C=CC=CC=1.[O:31]1CCC[CH2:32]1>O>[C:32]([C:16]1[O:15][CH:19]=[CH:18][C:17]=1[C:20]([OH:22])=[O:21])(=[O:31])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C1CCOC1
Reactant: O=C(O)c1ccoc1
Reactant: C1CCCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: N#Cc1ccccc1
Solvent: O
Product: O=C(O)c1ccoc1C(=O)c1ccccc1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
Lithium diisopropyl amide (276 mL, 0.4 mol of a 1.5M cyclohexane solution) was added dropwise over 45 minutes under nitrogen atmosphere at -78° C. to -55° C. to a stirred solution of 3-furoic acid (22.4 g, 0.2 mol) in tetrahydrofuran (70 mL). After one hour, the temperature was raised to -10° C. for 1/2 hour. The yellow solution was recooled to -78° C. and benzonitrile (20.6 g, 0.2 mol) was added over 1/4 hour. After one hour at -78° C., the temperature was brought to 0° C. over 21/2 hours. Following a one hour period at 0° C., the reaction was diluted with cold water (200 mL). The tetrahydrofuran was removed in vacuo. The residue was acidified with hydrochloric acid to pH 5 and was left at room temperature over night. The x s mixture was further acidified to pH 3 and the precipitated tan solid was extracted into ether (600 mL). The ether extract was washed with saturated NaCl solution, dried over Na2SO4, filtered and concentrated in vacuo. The product (26.0 g) was recrystallized from n-butyl chloride (100mL) and petroleum ether (100 mL). Weight of light tan solid recovered was 20.5 g.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[N:6][CH:7]=[CH:8][C:9]=2[O:10][CH:11]([CH3:14])[CH2:12][F:13])[CH2:3][CH2:2]1.[N+:15]1([O-])C=CC=C[CH:16]=1.CN(C)C(Cl)=O.C[Si](C#N)(C)C>ClCCl>[CH:1]1([C:4]2[C:9]([O:10][CH:11]([CH3:14])[CH2:12][F:13])=[CH:8][C:7]([C:16]#[N:15])=[N:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: [O-][n+]1ccccc1
Reactant: CC(CF)Oc1ccncc1C1CC1
Agent: CN(C)C(=O)Cl
Agent: C[Si](C)(C)C#N
Solvent: ClCCl
Product: CC(CF)Oc1cc(C#N)ncc1C1CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 21.2 %

Procedure:
To a solution of 3-cyclopropyl-4-(2-fluoro-1-methyl-ethoxy)pyridine (example 287b, 6.26 g, 32.1 mmole) in dichloromethane (100 mL) was added m-cpba 77% (10.8 g, 48.1 mmole) and the reaction was stirred at room temperature for 16 hours. Reaction mixture was diluted with dichloromethane and extracted with a 1M aqueous solution of sodium bicarbonate. Organic phase was collected and the aqueous phase was back-extracted with dichloromethane. Combined organic phases were dried over magnesium sulfate and evaporated down to dryness. The crude pyridine-oxide intermediate (6.97 g) was used without any purification. To a solution of the crude pyridine-oxide (6.97 g, 33.0 mmole) in dichloromethane (110 mL) was added dimethylcarbamoylchloride (CAN 79-44-7, 5.32 g, 4.55 mL, 49.5 mmole) and trimethylsilylcyanide (8.18 g, 10.3 mL, 82.5 mmole). The reaction mixture was stirred at room temperature for 16 hours and the reaction was quenched by addition of a 1M aqueous solution of sodium bicarbonate. The bi-phasic mixture was vigorously stirred for 10 minutes and then poured into a separatory funnel. The organic phase was extracted and collected. The aqueous phase was back-extracted with dichloromethane. Combined organic phases were dried over magnesium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a gradient of heptane and ethyl acetate to yield the title compound (1.5 g, 21%). MS (ESI, m/z): 221.6 (M+H+).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:20])[N:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:9](=[O:12])[NH:10][N:11]=1)=[O:5])C.[OH-].[Na+]>C1COCC1.CO>[F:19][C:16]1[CH:17]=[CH:18][C:13]([N:8]2[C:7](=[O:20])[C:6]([C:4]([OH:5])=[O:3])=[N:11][NH:10][C:9]2=[O:12])=[CH:14][CH:15]=1
Reactant: CCOC(=O)c1n[nH]c(=O)n(-c2ccc(F)cc2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1n[nH]c(=O)n(-c2ccc(F)cc2)c1=O

Procedure:
4-(4-Fluoro-phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid ethyl ester (300 mg, 1 mmol) in THF (3 mL) and MeOH (7 mL) was added 5M NaOH (2 mL, 2 mmol). The mixture was stirred at rt for 1h and was concentrated. Water was added and the mixture was extracted with ether. The aq. layer was made acidic with HCl at 0° C. and was extracted with EtOAc and concentrated. LCMS m/z=274 (M+Na); 1H NMR (DMSO) δ: 13.03 (s, 1H), 7.35-7.30 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[N:13][CH:14]=[N:15][C:16]([NH2:17])=[C:11]3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[S:23](Cl)(=[O:25])=[O:24].C(N(C(C)C)CC)(C)C.CN(C=O)C>CO>[NH2:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][S:23]([C:19]4[S:18][CH:22]=[CH:21][CH:20]=4)(=[O:25])=[O:24])=[CH:3][CH:4]=3)[N:9]=[CH:10][C:11]=12
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: Nc1ccc(-n2ncc3c(N)ncnc32)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Nc1ncnc2c1cnn2-c1ccc(NS(=O)(=O)c2cccs2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 56.3 %

Procedure:
Title compound 11A, 1-(4-amino-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (36 mg, 1.1 eq, 0.16 mmol), 2-thiophenesulphonylchloride (29 mg, 1.0 eq, 0.16 mmol) and diisopropylethylamine (28 μl, 1.0 eq, 0.16 mmol) were added to DMF (1 ml) and the mixture was stirred for 15 hours at room temperature under an inert atmosphere. Methanol was then added (1 ml) and the solvents were removed in vacuo. The resultant residue was purified by semi-preparative HPLC to yield the title compound as a white solid (35 mg, 0.09 mmol, 75%). LCMS: [M+H]+=373, Rt=1.60 min, 100% purity.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH2:7])[CH:4]=[N:3]1.N1(/[C:13](/[NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[N:14]\[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])C=CC=N1>CC#N>[CH3:1][N:2]1[CH:6]=[C:5]([NH:7]/[C:13](/[NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[N:14]\[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:4]=[N:3]1
Reactant: CC(C)(C)OC(=O)/N=C(/NC(=O)OC(C)(C)C)n1cccn1
Reactant: Cn1cc(N)cn1
Solvent: CC#N
Product: Cn1cc(N/C(=N\C(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cn1
Reaction time: 20 h
Yield: 92.1 %

Procedure:
1-methyl-1H-pyrazol-4-amine (11.7 g, 0.12 mol) was added portion-wise to a solution of di-tert-butyl [(Z)-1H-pyrazol-1-ylmethylylidene]biscarbamate (17.5 g, 0.056 mol) in MeCN (100 mL). The mixture was stirred for 20 hrs then filtered to afford the title compound (17.5 g, 91% yield) as a crude solid which was used as is in the next step.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH3:6])[CH2:3][OH:4].C(N([CH2:12][CH3:13])CC)C.C(Cl)Cl.[C:17]1(C)[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>>[OH:4][CH2:3][C@@H:2]([NH:1][S:23]([C:20]1[CH:21]=[CH:22][C:17]([CH2:12][CH3:13])=[CH:18][CH:19]=1)(=[O:25])=[O:24])[CH2:5][CH3:6]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCN(CC)CC
Reactant: CC[C@H](N)CO
Solvent: ClCCl
Product: CCc1ccc(S(=O)(=O)N[C@@H](CC)CO)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
(2S)-2-Aminobutan-1-ol (2.1 mL, 22 mmol) and triethylamine (3.8 mL, 27 mmol) were dissolved in methylene chloride (30 mL, 500 mmol) and the solution was stirred at 0° C. for 5 minutes. Then, p-toluenesulfonyl chloride (4.3 g, 22 mmol) was added and the reaction mixture was stirred and permitted to warm to room temperature. The reaction was quenched with water and the phases were separated. The aqueous phase was extracted with 1×50 mL of DCM. The combined organic phases were washed with 1N HCl (50 mL), sat. NaHCO3 (50 mL) and brine (50 mL), dried with Magnesium sulfate, filtered and concentrated to give a white solid. The crude material was crystallized in ether/hexane to give (S)—N-(1-hydroxybutan-2-yl)-4-ethylbenzenesulfonamide as a white solid: 1H NMR (400 MHz, DMSO) δ 7.69 (d, J=8.2 Hz, 2H), 7.38 (t, J=9.0 Hz, 3H), 4.62 (t, J=5.6 Hz, 1H), 3.24 (dd, J=10.3, 5.2 Hz, 1H), 3.18-3.02 (m, 1H), 2.92 (dd, J=7.9, 4.2 Hz, 1H), 1.61-1.39 (m, 1H), 1.19 (dd, J=14.5, 7.1 Hz, 1H), 0.63 (t, J=7.4 Hz, 3H); LC-MS: m/z=244 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:13][C:12]3=[N:14][CH:15]=[C:16](I)[N:11]3[N:10]=2)=[CH:4][CH:3]=1.[C:18]([NH:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)(=[O:20])[CH3:19].C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1.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.C(OCC)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:13][C:12]3=[N:14][CH:15]=[C:16]([C:25]4[CH:26]=[CH:27][C:22]([NH:21][C:18](=[O:20])[CH3:19])=[CH:23][CH:24]=4)[N:11]3[N:10]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)Nc1ccc(B(O)O)cc1
Reactant: Fc1ccc(Nc2nn3c(I)cnc3s2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOCC
Product: CC(=O)Nc1ccc(-c2cnc3sc(Nc4ccc(F)cc4)nn23)cc1
Temperature: 140 °C
Yield: 15.1 %

Procedure:
(4-Fluoro-phenyl)-(5-iodo-imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-amine (0.065 g, 0.18 mmol) was suspended in 1,4-dioxane (1 mL) at room temperature, and Argon was bubbled into the mixture while dichlorobis(triphenylphosphine)-palladium(II) (13 mg, 0.018 mmol), 4-acetamidophenylboronic acid (37 mg, 0.21 mmol), cesium carbonate (118 mg, 0.36 mmol) and water (1 mL) were added. The mixture was deoxygenated for 10 minutes and heated under microwave irradiation at 140° C. for 30 minutes. On cooling, the mixture was diluted with dichloromethane (5 mL), adsorbed in silica and purified by column chromatography (Biotage™/Flash, silica, methanol:dichloromethane 0.4:9.6 to 1.5:8.5). The product obtained was treated with diethylether (7 mL) and filtered to give N-{4-[2-(4-fluoro-phenylamino)-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]-phenyl}-acetamide as an off-white solid (10 mg, 15% yield).
Reaction SMILES: [H][H].[C:3]1([CH:9]2[C:21]3[NH:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]=3[CH2:12][CH2:11][N:10]2[CH2:22][C:23]([O:25]CC2C=CC=CC=2)=[O:24])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O1CCCC1.C(Cl)Cl>[Pd].CO>[C:3]1([CH:9]2[C:21]3[NH:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]=3[CH2:12][CH2:11][N:10]2[CH2:22][C:23]([OH:25])=[O:24])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(CN1CCc2c([nH]c3ccccc23)C1c1ccccc1)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CN1CCc2c([nH]c3ccccc23)C1c1ccccc1
Reaction time: 3 h
Yield: 24.9 %

Procedure:
A catalytic amount of 10% w/w palladium on charcoal was added under a stream of hydrogen to a solution of 260.2 mg (0.656 mmol) of benzyl (1-phenyl-1,2,3,4-tetrahydro-β-carbolin-2-yl)acetate, as obtained in Example 71, in 2 ml each of methanol and of tetrahydrofuran, and hydrogenation was allowed to proceed for 3 hours. The palladium on charcoal catalyst was removed from the reaction mixture by filtration, and the solvent was removed by evaporation under reduced pressure to give 0.32 g of a crude mixture. The resulting residue was subjected to column chromatography using 5 g of silica gel with a 19:1 by volume mixture of methylene chloride and methanol as the eluent, to yield 0.05 g of the title compound as a pale yellow powder, melting at 157°-164° C. (with decomposition).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[Li+].[Cl-].Br[CH2:16][C:17](=[CH2:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19].C([Cu])#N>C1COCC1>[F:1][C:2]1[C:3]([CH2:23][C:17](=[CH2:16])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1
Reactant: COc1ccc(F)cc1[N+](=O)[O-]
Reactant: C=C(CBr)C(=O)OCC
Agent: N#C[Cu]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(Cc1c(F)ccc(OC)c1[N+](=O)[O-])C(=O)OCC
Temperature: -50 °C
Reaction time: 1 h
Yield: 66.7 %

Procedure:
4-Fluoro-1-methoxy-2-nitrobenzene (21) (171 mg, 1.0 mmol) in THF (2 mL) was added to a solution of TMPZnCl.LiCl (2) (1.3 M in THF, 0.85 mL, 1.1 mmol) at 25° C. and the reaction mixture was then stirred at this temperature for 6 h according to TP 2. After cooling down to −50 ° C., ethyl 2-(bromomethyl)acrylate (230 mg, 1.2 mmol) and CuCN.2LiCl (1.0 M solution in THF, 5 drops) were added at −40° C. and the resulting mixture was stirred at the same temperature for 1 h. The reaction mixture was quenched with a sat. aq. NH4Cl solution (20 mL), extracted with diethyl ether (3×50 mL) and dried over anhydrous Na2SO4. After filtration, the solvent was evaporated in vacuo. Purification by flash-chromatography (CH2Cl2/n-pentane, 1:3) furnished compound 23 (189 mg, 67%) as a colourless oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([C:39]#[N:40])[CH:34]=3)=[CH:29][CH:28]=2)([CH2:14][O:15][C:16]2[NH:20][C:19]3[CH:21]=[C:22]([Cl:26])[C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl.C1(C)C=CC=CC=1>[Cl:26][C:22]1[C:23]([Cl:25])=[CH:24][C:18]2[NH:17][C:16]([O:15][CH2:14][C:11]3([C:27]4[CH:28]=[CH:29][C:30]([C:33]5[CH:38]=[CH:37][CH:36]=[C:35]([C:39]#[N:40])[CH:34]=5)=[CH:31][CH:32]=4)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[N:20][C:19]=2[CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2nc3cc(Cl)c(Cl)cc3[nH]2)(c2ccc(-c3cccc(C#N)c3)cc2)CC1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(-c2ccc(C3(COc4nc5cc(Cl)c(Cl)cc5[nH]4)CCNCC3)cc2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a solution of 0.015 g of 4-(3′-cyano-biphenyl-4-yl)-4-(5,6-dichloro-1H-benzoimidazol-2-yloxymethyl)-piperidine-1-carboxylic acid tert-butyl ester 53 (0.026 mmol) in 3 mL of dichloromethane at 0° C. was added 1 mL of trifluoroacetic acid. The mixture was stirred at 0° C. for 2 h then diluted with 10 mL of toluene and concentrated by rotary evaporation. The resulting residue was dissolved in 25 m) of ethyl acetate and washed with 10% aqueous NaHCO3 and saturated brine. The organic extracts were dried over Na2SO4, filtered and concentrated by rotary evaporation to give the crude product which was purified by reverse phase preparative HPLC to give 0.0113 g of the desired product 4′-[4-(5,6-dichloro-1H-benzoimidazol-2-yloxymethyl)-piperidin-4-yl]-biphenyl-3-carbonitrile 54 as a pale foam. 1H NMR (300 MHz, CDCl3/CD3OD): δ 7.85-7.75 (t, 1H), 7.72-7.70 (dt, 1H), 7.57-7.41 (m, 6H), 7.30(s, 2H), 5.19 (s, 2H), 4.31 (s, 2H), 3.33-3.25 (m, 2H), 2.90-2.82 (d, 2H), 2.47-2.34 (m, 2H), MS (ESI): Calcd m/z for C26H22Cl2N4O.H+=477.1. Found m/z=476.7/478.7 [(M+1)+/(M+3)+].
Reaction SMILES: C([O:4]C1C=CC(C[C:12]([OH:14])=[O:13])=CC=1Cl)C=C.[NH2:16][C@H:17]([C:23]([OH:25])=[O:24])[CH2:18][CH2:19][CH2:20][CH2:21][NH2:22]>C(O)C.O>[C:12](=[O:14])=[O:13].[C:23](=[O:24])([OH:4])[OH:25].[NH2:16][C@H:17]([C:23]([OH:25])=[O:24])[CH2:18][CH2:19][CH2:20][CH2:21][NH2:22]
Reactant: C=CCOc1ccc(CC(=O)O)cc1Cl
Agent: NCCCC[C@H](N)C(=O)O
Solvent: CCO
Solvent: O
Product: O=C(O)O
Product: O=C=O

Procedure:
226.6 g of 4-allyloxy-3-chlorophenylacetic acid are dissolved in 1200 ml of 25% ethyl alcohol. Separately 146 g of lysine are dissolved in water which is then, saturated with CO2, so as to obtain a 30% solution of lysine carbonate.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].C(N(CC)CC)C.[S:12]1[CH:16]=[CH:15][C:14]2[CH:17]([N:21]=[C:22]=[O:23])[CH2:18][CH2:19][CH2:20][C:13]1=2>C(Cl)Cl>[CH3:2][O:3][NH:4][C:22]([NH:21][CH:17]1[C:14]2[CH:15]=[CH:16][S:12][C:13]=2[CH2:20][CH2:19][CH2:18]1)=[O:23]
Reactant: O=C=NC1CCCc2sccc21
Reactant: CON
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CONC(=O)NC1CCCc2sccc21
Temperature: 15 °C
Reaction time: 0.33 h

Procedure:
A mixture of 5 grams of methoxyamine hydrochloride in 60 ml. of methylene chloride is stirred and cooled to 15° C., and 6 grams of triethylamine in 15 ml. of methylene chloride is added. After 20 minutes of stirring, 5.38 grams of 4,5,6,7-tetrahydrobenzo[b]thien-4-yl isocyanate is added dropwise. After stirring an additional 0.5 hour at 15° C. to 20° C., the mixture is stirred at room temperature for 0.5 hour. The mixture is then filtered, and the filtrate is washed with water and saturated sodium bicarbonate solution. The filtrate is dried (magnesium sulfate) and evaporated to dryness to afford the title compound which is recrystallized from acetone/hexane to give the product with melting point 138.5° C. to 141° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[NH:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[N:8](COCC[Si](C)(C)C)[CH:7]=[C:6]([C:29]#[N:30])[C:5]2=[O:31].N1C=CN=[CH:33]1>C(O)=O>[N:15]1([CH2:14][CH2:13][N:12]2[C:11]3[C:2](=[CH:3][C:4]4[C:5](=[O:31])[C:6]([C:29]#[N:30])=[CH:7][NH:8][C:9]=4[CH:10]=3)[N:1]=[CH:33]2)[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)c(=O)c2cc(N)c(NCCN3CCOCC3)cc21
Reactant: c1c[nH]cn1
Solvent: O=CO
Product: N#Cc1c[nH]c2cc3c(cc2c1=O)ncn3CCN1CCOCC1
Yield: 49.4 %

Procedure:
A mixture of 422 mg (0.95 mmol) of 6-amino-7-{[2-(4-morpholinyl)ethyl]amino}-4-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,4-dihydro-3-quinolinecarbonitrile, 258.7 mg (3.80 mmol) of imidazole in 6 mL of 96% formic acid is refluxed for 6.5 hours. After cooling, the mixture is concentrated under reduced pressure and the residue is diluted with water. Undissolved solid is filtered off and washed with water. The combined filtrate and water washes are brought to pH 8 with 28% ammonium hydroxide aqueous solution. The precipitate is collected by filtration and washed with water. After drying in vacuo, this yields 190.0 mg of the crude product as a yellow solid. The crude product is purified by flash chromatography (elution with methylene chloride, then a gradient of 99:1 to 88:12 methylene chloride/methanol) to give 151.6 mg (49.3%) of the pure product as an off-white solid, mp>270° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[C:21]3[N:22]=[CH:23][N:24]=[C:25]([C:26]4[C:34]5[O:33][CH2:32][O:31][C:30]=5[CH:29]=[CH:28][C:27]=4[O:35][CH2:36][CH:37]4[CH2:39][CH2:38]4)[C:20]=3[NH:19][CH:18]=2)=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.CC(O)C.[ClH:44].C(OC)(C)(C)C>O1CCOCC1>[ClH:44].[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[C:21]3[N:22]=[CH:23][N:24]=[C:25]([C:26]4[C:34]5[O:33][CH2:32][O:31][C:30]=5[CH:29]=[CH:28][C:27]=4[O:35][CH2:36][CH:37]4[CH2:38][CH2:39]4)[C:20]=3[NH:19][CH:18]=2)=[O:16])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Solvent: COC(C)(C)C
Product: O=C(NC1CCNCC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Temperature: 80 °C

Procedure:
4-({1-[4-(5-Cyclopropylmethoxy-1,3-benzodioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl]-methanoyl}-amino)-piperidine-1-carboxylic acid tert-butyl ester from example A86 (4.02 g; 7.5 mmol) is dissolved in warm (40-70° C.) 2-propanol (37.5 mL). After addition of 4M HCl in dioxane (7.5 mL) the stirred reaction mixture is heated to 80° C. for two hours. Tert-butylmethylether (150 mL) is added to the reaction mixture while still warm (40-70° C.). After cooling in an ice bath the precipitated product is collected, washed with tert-butylmethylether and dried in high vacuo at 50° C. to yield 3.35 g of the title compound as bright yellow solid.