Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21](O)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH:47]([CH:50]1[CH2:54][CH2:53][CH2:52][NH:51]1)([CH3:49])[CH3:48].C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:51]2[CH2:52][CH2:53][CH2:54][CH:50]2[CH:47]([CH3:49])[CH3:48])=[O:22])=[CH:15]3)=[O:11])[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CC(C)C1CCCN1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)O)cc3c2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C1CCCN1C(=O)c1cc2cc(C(=O)N3CCN(C(C)C)CC3)ccc2[nH]1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 2-isopropylpyrrolidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18](OS(OCC)(=O)=O)[CH3:19]>CO>[CH2:18]([N:7]1[C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[N:4]=[C:3]1[CH2:2][OH:1])[CH3:19]
Reactant: CCOS(=O)(=O)OCC
Reactant: OCc1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCn1c(CO)nc2ccccc21

Procedure:
99.2 mg (0.67 mmol) 2-hydroxymethylbenzimidazole was dissolved in 3 ml methanol. Potassium carbonate (103.1 g, 0.75 mmol) and diethylsulfate (442 μl 3.38 mmol) were added to the reaction mixture. Solution was stirred and refluxed overnight. The reaction mixture was then evaporated to dryness and purified on silica using gradient elution (chloroform to 5% methanol in chloroform) to obtain white crystals of 1-ethyl-2-hydroxymethylbenzimidazole, 41 mg (32%).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24]([C:28]#[N:29])[CH:23]=3)=[CH:17][C:16]=2F)=[O:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].NC1C=CC(OC2C=CN=C(C(=[S:45])N)C=2)=CC=1>>[C:1]([C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:12](=[O:13])[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24]([C:28](=[S:45])[NH2:29])[CH:23]=3)=[CH:17][CH:16]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NC(=S)c1cc(Oc2ccc(N)cc2)ccn1
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccnc(C#N)c3)cc2F)ncn1
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccnc(C(N)=S)c3)cc2)ncn1

Procedure:
The title compound was prepared in the same manner as described for 1-(6-tert-butylpyrimidin-4-yl)-3-[4-(2-cyanopyridin-4-yloxy)-2-fluorophenyl]urea, replacing 4-(4-amino-3-fluorophenoxy)pyridine-2-car-bonitrile for 4-(4-aminophenoxy)pyridine-2-thioamide. 1H-NMR (DMSO-d6) δ 10.32 (broad s, 1H), 10.20 (broad s, 1H), 10.13 (s, 1H), 9.93 (broad s, 1H), 9.72 (s, 1H), 8.74 (d, J=1.2 Hz, 1H), 8.46 (d, J=5.7 Hz, 1H), 7.95 (d, J=2.1 Hz, 1H), 7.67 (d, J=1.2 Hz, 1H), 7.64 to 7.60 (m, 2H), 7.21 to 7.17 (m, 2H), 7.12 (dd, J=5.7, 3.0 Hz, 1H), 1.26 (s, 9H); LC-MS m/z 423 [M+H]+, RT=3.39 min.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([OH:8])[CH:2]=1.[OH:9][C:10]1[CH:11]=[C:12]2[C:17](=O)[O:16][C:14](=[O:15])[C:13]2=[CH:19][CH:20]=1.O.Cl>N1C=CC=CC=1>[OH:9][C:10]1[CH:11]=[C:12]2[C:17](=[O:16])[N:7]([C:6]3[CH:5]=[CH:4][C:3]([OH:8])=[CH:2][CH:1]=3)[C:14](=[O:15])[C:13]2=[CH:19][CH:20]=1
Reactant: O=C1OC(=O)c2cc(O)ccc21
Reactant: Nc1ccc(O)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=C1c2ccc(O)cc2C(=O)N1c1ccc(O)cc1

Procedure:
In a stirred dry flask under N2, to a solution of 54.5 g p-aminophenol (0.5 mole) in 500 ml dry pyridine was added over 10 min at room temperature 82.0 g powdered 4-hydroxyphthalic anhydride (0.31 mole) and the mixture refluxed 5 hr. This black solution was cooled, poured into 1500 ml water, acidified with HCl, filtered, washed, and dried. M.P. 302°-304° C. Recrystallization was unnecessary. Yield 104 g, 82%.
Reaction SMILES: [F:1][C:2]1[C:10]([N+:11]([O-])=O)=[CH:9][CH:8]=[C:7]([F:14])[C:3]=1[C:4]([OH:6])=[O:5].[H][H]>[C].[Pd].CO>[NH2:11][C:10]1[C:2]([F:1])=[C:3]([C:7]([F:14])=[CH:8][CH:9]=1)[C:4]([OH:6])=[O:5]
Reactant: [H][H]
Reactant: O=C(O)c1c(F)ccc([N+](=O)[O-])c1F
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(F)c(C(=O)O)c1F
Yield: 93 %

Procedure:
A solution of 2,6-difluoro-3-nitrobenzoic acid and 10% palladium carbon added to 10 ml of methanol was stirred in a hydrogen atmosphere at room temperature for 2 hours. The catalyst was filtered off and then the solvent was removed under a reduced pressure to obtain the desired product (Yield: 93%) as a white solid.
Reaction SMILES: C[O-].[Na+].[CH2:4]([O:6][CH:7]([O:10][CH2:11][CH3:12])[C:8]#[N:9])[CH3:5].[C:13](=O)=[O:14]>CO>[CH2:4]([O:6][CH:7]([O:10][CH2:11][CH3:12])[C:8](=[NH:9])[O:14][CH3:13])[CH3:5]
Reactant: CCOC(C#N)OCC
Reactant: O=C=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCOC(OCC)C(=N)OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 92 %

Procedure:
To a solution of sodium methoxide (3.54 ml of a 25% wt. solution in methanol, 15.5 mmol) in methanol (80 ml) was added diethoxyacetonitrile (215 ml, 155 mmol) and the reaction mixture stirred for 4 hours at room temperature. Solid carbon dioxide was added and most of the methanol was removed in vacuo. Diethyl ether (30 ml) was added and the sodium carbonate removed by filtration. The residue was concentrated to afford methyl diethoxyacetimidate as a colourless oil (22 g, 92% yield) which was used with no further purification.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][N:7]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][C:11]=2[Cl:21])[C:8]=1[CH3:9])(O)=O.S(Cl)(Cl)=O.S(N)([NH2:29])(=O)=O>S1(CCCC1)(=O)=O>[C:1]([C:4]1[CH:5]=[N:6][N:7]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][C:11]=2[Cl:21])[C:8]=1[CH3:9])#[N:29]
Reactant: Cc1c(C(=O)O)cnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: NS(N)(=O)=O
Solvent: O=S(Cl)Cl
Solvent: O=S1(=O)CCCC1
Product: Cc1c(C#N)cnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Yield: 97.8 %

Procedure:
By the method of Example 5, Step C, 117.0 g (0.3451 mole) of 4-carboxy-5-methyl-1-(2,6-dichloro-4-trifluoromethylphenyl)-1H-pyrazole was reacted with 205.3 g (1.73 moles) of thionyl chloride and 45.1 g (0.47 mole) of sulfamide in 390 mL of sulfolane, yielding 108 g of 4-cyano-5-methyl-1-(2,6-dichloro-4-trifluoromethylphenyl)-1H-pyrazole. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[N:16]1([C:22]([C:24]2[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=2)=[O:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(N(CC)CC)C>ClCCl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:27]1[CH:26]=[CH:25][C:24]([C:22]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[O:23])=[CH:29][CH:28]=1)(=[O:5])=[O:4]
Reactant: O=C(c1ccc(O)cc1)N1CCOCC1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(OS(=O)(=O)C(F)(F)F)cc1)N1CCOCC1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
1.23 ml (7.24 mmol) of trifluoromethanesulphonic anhydride are slowly added dropwise to a solution, cooled to −10° C., of 1.0 g (4.83 mmol) of 4-(4-morpholinylcarbonyl)phenol and 2.02 ml (14.48 mmol) of triethylamine in 20 ml of dichloromethane. The mixture is stirred at −10° C. for 30 min and then at 0° C. for 30 min. It is washed successively with 10% strength sodium bicarbonate solution, water and saturated sodium chloride solution, dried over sodium sulphate and concentrated in vacuo, and the residue is dried under high vacuum. 1.71 g (94.6% of theory) of the title compound are obtained.
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:33]=[CH:32][C:23]([O:24][C:25]2[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=2)=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[CH2:35][CH2:36][N:37]1[C:41](=[O:42])[C:40]2=[CH:43][CH:44]=[CH:45][CH:46]=[C:39]2[C:38]1=[O:47]>>[CH2:1]([N:8]([CH2:19][C:20]1[CH:33]=[CH:32][C:23]([O:24][C:25]2[CH:26]=[C:27]([CH:28]=[CH:29][CH:30]=2)[O:31][CH2:35][CH2:36][N:37]2[C:38](=[O:47])[C:39]3[C:40](=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:41]2=[O:42])=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(N(Cc2ccccc2)Cc2ccc(Oc3cccc(O)c3)cc2)cccc1[N+](=O)[O-]
Reactant: O=C1c2ccccc2C(=O)N1CCO
Product: Cc1c(N(Cc2ccccc2)Cc2ccc(Oc3cccc(OCCN4C(=O)c5ccccc5C4=O)c3)cc2)cccc1[N+](=O)[O-]

Procedure:
The product from Example 61F and N-(2-hydroxyethyl)-phthalimide were processed as described in Example 62A to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](OCC#C)=[CH:5][C:4]=1[C:13]1[NH:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[N:21]=1.C([O-])(=O)/[CH:23]=[CH:24]/[C:25]([O-])=[O:26]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:26][CH2:25][C:24]#[CH:23])[CH:6]=[CH:5][C:4]=1[C:13]1[NH:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[N:21]=1
Reactant: O=C([O-])/C=C/C(=O)[O-]
Reactant: C#CCOc1ccc(OC)c(-c2nc3cnccc3[nH]2)c1
Product: C#CCOc1ccc(-c2nc3cnccc3[nH]2)c(OC)c1

Procedure:
2-(2-Methoxy-5-propargyloxyphenyl)imidazo(4,5-c)-pyridine, fumarate, m.p. 210°.
Reaction SMILES: [Mg].II.C(Br)C.[C:7]1([C:13]#[CH:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[O:15]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=[O:26])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1.Cl>[O:15]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]([OH:26])[C:14]#[C:13][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Reactant: C#Cc1ccccc1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: CCBr
Solvent: C1CCOC1
Product: OC(C#Cc1ccccc1)c1cccc(Oc2ccccc2)c1
Temperature: 0 °C
Yield: 98.7 %

Procedure:
The alcohol required for the preparation of the pyrethroid is prepared as follows: ##STR12## A reaction vessel is charged with 14.6 g of magnesium filings together with a trace of iodine crystals. 73.6 g of ethyl bromide in 25 ml of tetrahydrofuran are then added dropwise such that the tetrahydrofuran boils gently under reflux. The Grignard solution formed is added dropwise at 0°-5° C. to a solution of 62.1 g of phenylacetylene in 250 ml of tetrahydrofuran and the mixture is stirred until the evolution of gas ceases. The resultant solution is cooled to 0° C. and 99 g of 3-phenoxybenzaldehyde are added dropwise such that the temperature does no exceed +5° C. The reaction mixture is stirred overnight at room temperature and then cooled to a temperature in the range from 0° to +5° C. About 100 g of ice are added, whereupon a precipitate forms which is dissolved in 100 ml of concentrated HCl. The aqueous solution is extracted with three 150 ml portions of ether and the extracts are washed with NaHCO3 solution and then dried over Na2SO4. The ether is distilled off by rotary evaporation, affording as residue 148 g of 3-phenoxy-α-phenylethynylbenzyl alcohol with a refractive index of nD23 =1.6238 and with an NMR spectrum as shown in FIG. 2. The yield is 98.8 % of theory.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[NH:7][C:8]3[CH:17]=[CH:16][CH:15]=[N:14][C:9]=3[N:10]([C:11](Cl)=[O:12])[C:4]=2[CH:3]=1.[CH2:21]([N:23]([CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[CH2:33][CH2:34][NH2:35])[CH2:24][CH3:25])[CH3:22].Cl>C(#N)C>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[NH:7][C:8]3[CH:17]=[CH:16][CH:15]=[N:14][C:9]=3[N:10]([C:11]([NH:35][CH2:34][CH2:33][N:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH:27]3[CH2:26][N:23]([CH2:21][CH3:22])[CH2:24][CH3:25])=[O:12])[C:4]=2[CH:3]=1
Reactant: CCN(CC)CC1CCCCN1CCN
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2cc(Cl)ccc21
Agent: Cl
Solvent: CC#N
Product: CCN(CC)CC1CCCCN1CCNC(=O)N1c2cc(Cl)ccc2C(=O)Nc2cccnc21
Yield: 33 %

Procedure:
Prepared analogously to Example 2 from 9-chloro-11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and (-)-2-[2-[(diethylamino)methyl]-piperidin-1-yl]ethanamine in a yield of 33% of theory. Colourless crystals, m.p. 169°-170° C. (acetonitrile); [α]D20 =-11.92° (dilute hydrochloric acid).
Reaction SMILES: C([N:8]1[CH2:21][CH2:20][C:19]2[C:18]3[CH:17]=[C:16]([S:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)(=[O:24])=[O:23])[CH:15]=[CH:14][C:13]=3[N:12]([CH2:31][CH3:32])[C:11]=2[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[CH2:31]([N:12]1[C:13]2[CH:14]=[CH:15][C:16]([S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:24])=[O:23])=[CH:17][C:18]=2[C:19]2[CH2:20][CH2:21][NH:8][CH2:9][CH2:10][C:11]1=2)[CH3:32]
Reactant: CCn1c2c(c3cc(S(=O)(=O)c4ccccc4)ccc31)CCN(Cc1ccccc1)CC2
Agent: [Pd]
Solvent: CO
Product: CCn1c2c(c3cc(S(=O)(=O)c4ccccc4)ccc31)CCNCC2

Procedure:
A mixture of 3-benzyl-6-ethyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (Step I, 107 mg, 0.241 mmol) in methanol (20 mL, 1 drop concentrated hydrochloric acid) is treated with palladium on carbon (10%, 32 mg) and hydrogenated at 25 psi for 48 hr. The resulting mixture is filtered, rinsing with methanol and methylene chloride, and the filtrate is concentrated to a solid. The solid is purified via chromatography (10 g SG; methanol/methylene chloride/ammonium hydroxide, 20/79/1) to give the title compound, mp=224°, dec.; IR (drift) 2982, 2935, 2743, 1473, 1449, 1312, 1300, 1151, 1091, 819, 768, 728, 691, 647 and 623 cm−1; NMR (300 MHz, DMSO-d6) 8.09, 7.85-7.95, 7.45-7.65, 4.20, 2.95-3.25 and 1.15 δ; MS (EI) m/z 354 (M+), 312, 170, 167, 153, 143, 114, 78, 76 and 51; HRMS (FAB) calculated for C20H23N2O2S=355.1480, found 355.1488.
Reaction SMILES: N.[CH2:2]([O:4][C:5](=[O:24])[CH2:6][C:7]([C:22]#[N:23])([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1)[CH2:8][C:9](OCC)=[O:10])[CH3:3]>[Ni].C(O)C>[CH2:2]([O:4][C:5](=[O:24])[CH2:6][C:7]1([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:8][C:9](=[O:10])[NH:23][CH2:22]1)[CH3:3]
Reactant: CCOC(=O)CC(C#N)(CC(=O)OCC)c1ccc(Cl)c(Cl)c1
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CCOC(=O)CC1(c2ccc(Cl)c(Cl)c2)CNC(=O)C1
Reaction time: 20 h

Procedure:
Combine Raney nickel (24 lb) and an aqueous concentrated ammonia solution (19 lb). Add a solution of 3-cyano-3-(3,4-dichlorophenyl)pentanedioic acid diethyl ester (15 lb) and ethanol (117 lb) in a pressure reactor. Hydrogenate at 200 psi and 35° C. After 20 hours, cool, vent the vessel, purge with nitrogen, and filter. Rinse the solids with ethanol. Evaporate the filtrate in vacuo to give a residue. Crystallize the residue by dissolving in ethyl acetate and triturate the solution with heptane to give a solid. Collect the solid to give the title compound. Elemental Analysis calculated for C14H15Cl2NO3: C 53.18; H 4.78; N 4.43; Found: C 53.18; H 4.72; N 4.46.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]3[N:13]([CH2:16][C@@H:17]4[CH2:22][N:21]([C:23]5[N:28]=[CH:27][C:26]([C:29]6[CH:30]=[N:31][N:32]([CH:34]7[CH2:39][CH2:38][N:37](C(OC(C)(C)C)=O)[CH2:36][CH2:35]7)[CH:33]=6)=[CH:25][N:24]=5)[CH2:20][CH2:19][O:18]4)[N:14]=[N:15][C:10]3=[N:9][CH:8]=2)[CH:4]=[N:3]1.[ClH:47]>C(Cl)Cl.O1CCOCC1>[ClH:47].[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]3[N:13]([CH2:16][C@H:17]4[O:18][CH2:19][CH2:20][N:21]([C:23]5[N:28]=[CH:27][C:26]([C:29]6[CH:30]=[N:31][N:32]([CH:34]7[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]7)[CH:33]=6)=[CH:25][N:24]=5)[CH2:22]4)[N:14]=[N:15][C:10]3=[N:9][CH:8]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(-c6cnn(C7CCN(C(=O)OC(C)(C)C)CC7)c6)cn5)CCO4)c3n2)cn1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cn1cc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(-c6cnn(C7CCNCC7)c6)cn5)CCO4)c3n2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
(S)-tert-butyl 4-(4-(2-(2-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate 463 mg (0.74 mmol) was dissolved in methylene chloride 20 ml, and 4 M HCl (excess) dissolved in 1,4-dioxane 20 ml was added and then charged with nitrogen, followed by stirring at room temperature for 18 hours. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove methylene chloride and dioxane, thereby giving a yellow solid 493 mg (100%).
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([N:8]=[C:9]=[S:10])=[C:5]([C:11]([O:13]C)=O)[CH:4]=1)[CH3:2].[CH3:15][C:16]1[N:20]([CH2:21][CH2:22][CH2:23][NH2:24])[CH:19]=[N:18][CH:17]=1>>[CH2:1]([C:3]1[S:7][C:6]2[NH:8][C:9](=[S:10])[N:24]([CH2:23][CH2:22][CH2:21][N:20]3[C:16]([CH3:15])=[CH:17][N:18]=[CH:19]3)[C:11](=[O:13])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc(C(=O)OC)c(N=C=S)s1
Reactant: Cc1cncn1CCCN
Product: CCc1cc2c(=O)n(CCCn3cncc3C)c(=S)[nH]c2s1

Procedure:
The compound was synthesized starting from methyl 5-ethyl-2-isothiocyanatothiophene-3-carboxylate (0.1 g, 0.44 mmol) and 3-(5-methyl-1H-imidazol-1-yl)propan-1-amine (5) (0.06 g, 0.44 mmol) as described above.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11]([F:16])[C:12]=3[C:14]#[CH:15])[C:7](=[O:18])[C:6]([C:19]([O:21]CC)=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.O.S(=O)(=O)(O)O>C(O)(=O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11]([F:16])[C:12]=3[C:14]#[CH:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: C#Cc1c(F)c(F)cc2c(=O)c(C(=O)OCC)cn(C3CC3)c12
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: C#Cc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 25 °C
Yield: 60.7 %

Procedure:
10.3 g of ethyl 1-cyclopropyl-8-ethinyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate are refluxed for 4 hours in a mixture of 100 ml of glacial acetic acid, 8 ml of water and 3 ml of concentrated sulphuric acid. After cooling to room temperature, the solid is filtered off with suction, washed with water and dried. In this way, 5.7 g of 1-cyclopropyl-8-ethinyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (62% of theory) are obtained.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4]#[N:5].[NH:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:10][C:7]1[CH:8]=[CH:9][C:2]([N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: c1nc[nH]n1
Reactant: N#Cc1cc(F)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1cc(F)ccc1-n1cncn1
Temperature: 80 °C

Procedure:
A mixture of 2,5-difluorobenzonitrile (500 mg, 3.6 mmol), 1,2,4-triazole (273 mg, 3.9 mmol) and Cs2CO3 (1.27 g, 3.9 mmol) in DMF (10 mL) was heated at 80° C. for 2 days. The solvent was removed under reduced pressure. The residue was partitioned between H2O and EtOAc. The layers were separated and the aqueous layer extracted with EtOAc (×3). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated to give the title compound as an off white solid (596 mg) along with a minor bis-alkylated byproduct. 1H NMR (400 MHz, CDCl3): δ 8.71 (s, 1H), 8.19 (s, 1H), 7.75–7.98 (m, 1H), 7.48–7.57 (m, 2H).
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[CH3:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1>>[CH3:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][C:12]=1[N+:6]([O-:9])=[O:7]
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
Conc. sulfuric acid (25 ml; 0.5 equiv.) was added over a period of 10 minutes to nitric acid at 0° C. (69-72%; 25 ml; 0.5 equiv.). The resulting mixture was stirred for 30 minutes at 0° C. Conc. sulfuric acid (75 ml; 1.5 equiv.) was added at room temperature, over a period of 20 minutes, to 4-methylbenzoic acid (50 g; 1 equiv.). The resulting suspension was cooled to 0° C., and the nitrating acid was added thereto over a period of 45 minutes. The resulting reaction mixture was stirred for 1 hour at 10-20° C. When the conversion was complete, the reaction mixture was poured onto ice-water and the resulting white solid was filtered out and dried. 4-Methyl-3-nitrobenzoic acid (66.5 g; 82.7%) was obtained in the form of a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N+:14]([O-])=O)[C:8]([O:12][CH3:13])=[C:9]([Cl:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].O.O.Cl[Sn]Cl.O>Cl>[C:1]([C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([O:12][CH3:13])=[C:7]([NH2:14])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(Cl)cc(C(C)(C)C)cc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Product: COc1c(N)cc(C(C)(C)C)cc1Cl
Temperature: 90 °C
Reaction time: 2 h
Yield: 72.4 %

Procedure:
5-tert-Butyl-1-chloro-2-methoxy-3-nitro-benzene (157 mg, 0.646 mmol) was dissolved in 3 mL concentrated HCl and SnCl2.2H2O (0.874 g, 3.87 mmol) was added. The reaction was stirred at 90° C. for 2 hrs, after which water was added and the product extracted into diethyl ether. The organic layer was dried over MgSO4 and concentrated. The residue was purified by column chromatography (2/1 Hex/EtOAc) to yield 100 mg of final product. Calculated mass=213. Observed mass=214
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][CH2:7][C:8]1[NH:9][CH:10]=[CH:11][N:12]=1.[F:16]C1C=CC(O)=CC=1>>[F:16][C:15]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]2[NH:9][CH:10]=[CH:11][N:12]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: COc1cccc(OCc2ncc[nH]2)c1
Product: Fc1ccc(OCc2ncc[nH]2)cc1

Procedure:
2-(4-Fluoro-phenoxymethyl)-1H-imidazole was prepared following a similar procedure for the preparation of 2-(3-Methoxy-phenoxymethyl)-1H-imidazole (see Example 18) using 4-fluorophenol in place of 3-methoxyphenol to provide a white solid (1.69 g, 85% for 2 steps); ESI MS m/z 193 [C10H9FN2O+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH:13]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)O)[C:10]([CH3:21])=[N:9]2)=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([NH:31][CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])=[O:30])=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH:13]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([C:29]([NH:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:30])=[CH:27][CH:28]=3)[CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:10]([CH3:21])=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1nn(-c2ccc(Cl)cc2)cc1C(O)C1CCCCC1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Product: Cc1nn(-c2ccc(Cl)cc2)cc1C(Nc1ccc(C(=O)NCCC(=O)O)cc1)C1CCCCC1
Yield: 57.3 %

Procedure:
Using [1-(4-chlorophenyl)-3-methyl-1H-pyrazol-4-yl](cyclohexyl)methanol (0.46 g) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (0.35 g) synthesized in Example 1(2) and in the same manner as in Example 1(7), the title object compound (0.42 g, 57%) was obtained as a white solid.