Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:12][CH3:13])[C:4]1[N:9]=[C:8]([Cl:10])[CH:7]=[C:6](Cl)[N:5]=1)[CH3:2].[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C(O)C>[CH2:12]([N:3]([CH2:1][CH3:2])[C:4]1[N:5]=[C:6]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:7]=[C:8]([Cl:10])[N:9]=1)[CH3:13]
Reactant: CCN(CC)c1nc(Cl)cc(Cl)n1
Reactant: C1CNCCN1
Solvent: CCO
Product: CCN(CC)c1nc(Cl)cc(N2CCNCC2)n1

Procedure:
2-Diethylamino-4,6-dichloropyrimidine (10 g) is reacted with piperazine (14.45 g) in ethanol (200 ml) at reflux for 2 hr. The mixture is concentrated and the product isolated by silica gel chromatography giving 2-diethylamino-4-piperazino-6-chloropyrimidine. The 2-diethylamino-4-piperazino-6-chloropyrimidine (8 g) and N-methylpiperazine (8 g) is heated neat at 70° for 16 hr. Then water (2.5 ml) is added and the mixture is heated at 100° for 50 hr. The mixture is chromatographed on silica gel, the appropriate fractions are pooled and concentrated to give the title compound, NMR (CDCl3) 1.15, 2.80, 2.85, 2.90, 3.30, 3.70 and 4.95 δ.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:8]([CH2:9][CH3:10])=[N:7][C:6]2[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:5]=2[C:4]=1[NH:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.CC(OC([N:30]1[CH2:35][CH2:34][N:33]([CH2:36][C:37]2[CH:38]=[C:39]([C:43]3[C:48]([F:49])=[CH:47][CH:46]=[C:45]([CH2:50][NH:51][S:52]([C:55]4[CH:56]=[C:57]([CH:61]=[CH:62][CH:63]=4)[C:58](O)=[O:59])(=[O:54])=[O:53])[CH:44]=3)[CH:40]=[CH:41][CH:42]=2)[CH2:32][CH2:31]1)=O)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl>[CH2:14]([N:11]1[C:6]2=[N:7][C:8]([CH2:9][CH3:10])=[C:3]([CH2:2][NH:1][C:58](=[O:59])[C:57]3[CH:61]=[CH:62][CH:63]=[C:55]([S:52]([NH:51][CH2:50][C:45]4[CH:44]=[C:43]([C:39]5[CH:40]=[CH:41][CH:42]=[C:37]([CH2:36][N:33]6[CH2:34][CH2:35][NH:30][CH2:31][CH2:32]6)[CH:38]=5)[C:48]([F:49])=[CH:47][CH:46]=4)(=[O:54])=[O:53])[CH:56]=3)[C:4]([NH:16][CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[C:5]2[CH:13]=[N:12]1)[CH3:15]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3cc(CNS(=O)(=O)c4cccc(C(=O)O)c4)ccc3F)c2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(S(=O)(=O)NCc2ccc(F)c(-c3cccc(CN4CCNCC4)c3)c2)c1
Temperature: 25 °C
Reaction time: 21 h
Yield: 32.7 %

Procedure:
To a solution of 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-amine (0.0195 g, 0.0641 mmol) in DCM (0.64 mL) was added 3-{[({3′-[(4-{[(1,1-dimethyl ethyl)oxy]carbonyl}-1-piperazinyl)methyl]-6-fluoro-3-biphenylyl}methyl)amino]sulfonyl}benzoic acid (0.0374 g, 0.0641 mmol), HBTU (0.0365 g, 0.0962 mmol), Et3N (0.018 mL, 0.128 mmol). The result mixture was stirred at room temperature for 21 h before it was concentrated and purified using a Gilson HPLC (w/TFA). The HPLC fraction was concentrated on a GeneVac EZ-2 evaporator at 45° C. (de-Boc completed during evaporation), basified with an amine cartridge to afford 0.0161 g (33%) of the title compound. LC-MS m/z 769 (M+H)+; 1H-NMR (400 MHz, MeOD) δ ppm 1.41 (t, J=7.30 Hz, 3 H) 1.49 (t, J=7.05 Hz, 3 H) 1.86 (q, J=9.90 Hz, 2 H) 2.09 (d, J=12.34 Hz, 2 H) 3.17 (q, J=7.39 Hz, 2 H) 3.46-3.59 (m, J=12.59 Hz, 8 H) 3.67 (t, J=11.33 Hz, 2 H) 4.04 (d, J=11.83 Hz, 2 H) 4.16 (s, 2 H) 4.30-4.39 (m, 1 H) 4.41 (s, 2 H) 4.48 (q, J=6.88 Hz, 2 H) 4.70 (s, 2 H) 7.04 (t, J=9.44 Hz, 1 H) 7.18-7.27 (m, 1 H) 7.34 (d, J=7.05 Hz, 1 H) 7.50-7.58 (m, 3 H) 7.60-7.68 (m, 2 H) 7.98 (d, J=7.55 Hz, 1 H) 8.08 (d, J=7.81 Hz, 1 H) 8.30 (d, J=13.60 Hz, 2 H).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[C:5]([CH:9]1CC2O[CH:10]1C=C2)(OC)=[O:6]>>[CH2:1]([NH:4][C:5](=[O:6])[CH:9]=[CH2:10])[CH2:2][NH:3][C:5](=[O:6])[CH:9]=[CH2:10]
Reactant: COC(=O)C1CC2C=CC1O2
Reactant: NCCN
Product: C=CC(=O)NCCNC(=O)C=C
Temperature: 140 °C
Reaction time: 8 h

Procedure:
7.2 parts 30% methanolic Na-methylate solution are added to 15 parts ethylenediamine. 77 parts 2-carbomethoxy-7-oxabicyclo(2,2,1)hept-5-ene are added drop-wise at 30° C. during cooling. Recrystallisation is then allowed to proceed overnight and the crystalline mass is dissolved in 400 parts chloroform, and neutralised with 4 parts concentrated hydrochloric acid. 50 parts water are added, the organic phase separated off, and the aqueous phase extracted 5 times with 50 parts chloroform in each instance. The combined organic phases are reduced in a rotary evaporator at a bath temperature of 90° C. and under a vacuum of 20 Torr. The residue is heated in a vacuum of 10 Torr to 110° to 120° C. (bath temperature 140° C.). On conclusion of the furane separation the sedimentation temperature increases to 140° C. After cooling, the product is dissolved in hot n-butanol, filtered, and allowed to recrystallise at 0° C. 27 g N,N'-ethylenebisacrylamide with a melting point of 150° to 155° C. is obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[CH2:7][C@@H:8]([CH2:20][S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:23])=[O:22])[NH:9]C(OCC1C=CC=CC=1)=O)([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)(=O)C.[Pd]>[C:1]([O:5][C:6](=[O:30])[CH2:7][C@@H:8]([CH2:20][S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:23])=[O:22])[NH2:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C[C@@H](CS(=O)(=O)c1ccccc1)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)C[C@H](N)CS(=O)(=O)c1ccccc1
Yield: 98.7 %

Procedure:
A mixture of N-(benzyloxycarbonyl)-3(S)-phenylsulfonylmethy-β-alanine tert-butyl ester (0.44 g) and 10% Pd—C (0.1 g, 50% wet) in acetic acid (5 ml) was hydrogenated at 1 atmospheric pressure of hydrogen for 1 hour. The catalyst was filtered off and the filtrate was evaporated in vacuo. The residue was dissolved in ethyl acetate and washed with saturated aqueous NaHCO3 solution. The organic layer was dried over MgSO4 and evaporated in vacuo to give 3(S)-phenylsulfonylmethy-βalanine tert-butyl ester (0.3 g) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]([O:14][CH3:15])=[CH:12][C:6]2[S:7][C:8]([CH:10]=O)=[CH:9][C:5]=2[CH:4]=1.[C:16]([CH:18]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:17]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:13]([O:14][CH3:15])=[CH:12][C:6]2[S:7][C:8](/[CH:10]=[CH:18]/[C:16]#[N:17])=[CH:9][C:5]=2[CH:4]=1
Reactant: COc1cc2cc(C=O)sc2cc1OC
Reactant: N#CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: COc1cc2cc(/C=C/C#N)sc2cc1OC
Yield: 84.2 %

Procedure:
A mixture of 5,6-dimethoxybenzo[b]thiophene-2-carboxaldehyde (8.14 g) and cyanomethylene triphenylphosphorane (22.06 g) in dry toluene (270 ml) was stirred and heated to reflux for 1 hour. The reaction mixture was then evaporated to dryness and the residue was dissolved in a mixture of dichloromethane (50 ml) and toluene (50 ml) and passed through a column of coarse silica (0.2-0.5 mm, Merck, 600 g). The column eluted with toluene:ethyl acetate (4:1 v/v). The appropriate fractions were combined and evaporated to dryness and the residue was crystallised from dichloromethane:diethyl ether to give pure (E)-3-(5,6-dimethoxy-benzo[b]thiophene-2-yl)-2-propenenitrile (7.56 g), m.p. 154°-158° C.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][CH2:6][C:7]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=[CH:9][N:8]=1.C(N(CC)CC)C>O1CCCC1>[C:1]([NH:5][CH2:6][C:7]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=[CH:9][N:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: NCc1ncccc1OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NCc1ncccc1OCc1ccccc1
Temperature: 25 °C

Procedure:
Add dropwise with stirring a solution of 3.5 ml acetyl chloride in 50 ml THF (tetrahydrofuran) to a cooled solution of 10 gm of 2-aminomethyl-3-phenylmethoxypyridine and 7.1 ml triethylamine in 125 ml THF. Warm to room temperature and stir an additional hour. Remove triethylamine hydrochloride by filtration and evaporate the filtrate under reduced pressure. Recrystallize the residue from toluene to obtain 2-acetamidomethyl-3-(phenylmethoxy)pyridine, mp 94°-96°.
Reaction SMILES: [C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:2]([C:7]([N:9]2[CH2:13][C@H:12]([OH:14])[CH2:11][C@H:10]2[CH2:15][N:16]2C(=O)C3C(=CC=CC=3)C2=O)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.O.NN>CO>[NH2:16][CH2:15][C@@H:10]1[CH2:11][C@@H:12]([OH:14])[CH2:13][N:9]1[C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:8]
Reactant: O=C1c2ccccc2C(=O)N1C[C@@H]1C[C@@H](O)CN1C(=O)c1ccccc1-c1ccccc1
Agent: NN
Solvent: O
Solvent: CO
Product: NC[C@@H]1C[C@@H](O)CN1C(=O)c1ccccc1-c1ccccc1
Temperature: 70 °C
Reaction time: 4 h
Yield: 66 %

Procedure:
A mixture of the above mentioned 2-(((2S,4R)-1-(biphenylcarbonyl)-4-hydroxypyrrolidin-2-yl)methyl)isoindoline-1,3-dione (˜5.6 mmol) and hydrazine monohydrate (0.65 mL, 10 mmol) in MeOH was stirred at 70° C. for 4 h. The resulting white suspension was cooled to rt, filtered and the filtrate was concentrated in vacuo to a white solid, which was purified by column chromatography on silica gel (100% MeOH) to provide ((2S,4R)-2-(aminomethyl)-4-hydroxypyrrolidin-1-yl)(biphenyl-2-yl)methanone as a white solid (1.1 g, 66% yield over two steps. MS (ESI) 297.05 (M+H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Br:12])[CH:8]=2)[CH:3]=1.[C:13]1(B(O)O)[C:26]2[C:27]3=[C:28]4[C:23](=[CH:24][CH:25]=2)[CH:22]=[CH:21][CH:20]=[C:19]4[CH:18]=[CH:17][C:16]3=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[Br:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([C:20]1[C:19]3[C:28]4=[C:27]5[C:16](=[CH:17][CH:18]=3)[CH:15]=[CH:14][CH:13]=[C:26]5[CH:25]=[CH:24][C:23]4=[CH:22][CH:21]=1)[CH:11]=[CH:10]2
Reactant: Brc1ccc2cc(Br)ccc2c1
Reactant: OB(O)c1ccc2ccc3cccc4ccc1c2c34
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Brc1ccc2cc(-c3ccc4ccc5cccc6ccc3c4c56)ccc2c1
Temperature: 90 °C
Yield: 48.1 %

Procedure:
A mixture of 12.1 g (42.4 mmol) of 2,6-dibromonaphthalene, 10.43 g (42.4 mmol) of Pyren-1-ylboronic acid, 0.5 g (0.424 mmol) of Tetrakis(triphenylphosphine)palladium, 32 ml of 2M Na2CO3, 80 ml of EtOH and 160 ml toluene was degassed and placed under nitrogen, and then heated at 90° C. for 24 h. After the reaction finish, the mixture was allowed to cool to room temperature. The organic layer was extracted with ethyl acetate and water, dried with anhydrous magnesium sulfate, the solvent was removed and the residue was purified, by column chromatography on silica (hexane-dichloromethane) to give product 8.3 g (48%) as a white solid.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].[NH2:32][CH2:33][C:34]([NH:36][CH3:37])=[O:35].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:31])([F:29])[F:30])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:32][CH2:33][C:34]([NH:36][CH3:37])=[O:35])=[O:4]
Reactant: CNC(=O)CN
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CNC(=O)CNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 18 %

Procedure:
2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-Va, 60 mg, 0.139 mmol), 2-amino-N-methylacetamide (12.26 mg, 0.139 mmol), 4-methylmorpholine (56.3 mg, 0.556 mmol), and HATU (68.8 mg, 0.181 mmol) were added to DMF (1 mL). The mixture was stirred for 1 h before it was purified by prep HPLC (PHENOMENEX® Luna 5u 21×250 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 30 min, 25 mL/min, 220 nM, product retention=29.4 min) to provide 2-hydroxy-N-(2-(methylamino)-2-oxoethyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (13 mg, 0.025 mmol, 18.02% yield) as a single enantiomer. LCMS=502.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.10-8.25 (2 H, m), 7.53-7.82 (7 H, m), 5.20 (1 H, s), 3.77-4.01 (2 H, m), 2.75 (3 H, s); HPLC peak RT=8.4 min (Method A).
Reaction SMILES: [CH:1]([C:4]1[O:8][CH:7]=[N:6][C:5]=1[C:9]([O:11]C)=[O:10])([CH3:3])[CH3:2].[OH-].[K+]>CO.O>[CH:1]([C:4]1[O:8][CH:7]=[N:6][C:5]=1[C:9]([OH:11])=[O:10])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ncoc1C(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)c1ocnc1C(=O)O
Temperature: 25 °C
Yield: 85 %

Procedure:
23.1 g of 5-isopropyl-4-methoxycarbonyloxazole are dissolved in a mixture of 200 ml of methanol and 200 ml of water, and 15.3 g of potassium hydroxide are added thereto. The mixture is stirred at room temperature over night, and condensed under reduced pressure to remove methanol. The residue is dissolved in water and the aqueous solution is adjusted to pH 2-3 with conc. hydrochloric acid. Said solution is extracted with ethyl acetate, and the extract is washed with water, dried and then evaporated to remove solvent. 18 g of 5-isopropyl-4-oxazolecarboxylic acid are obtained. Yield: 85.3%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([N:11]2[C:16](=[O:17])[C:15]([CH3:18])=[N:14][C:13]3[CH:19]=[CH:20][CH:21]=[N:22][C:12]2=3)[CH:8]=[CH:9][CH:10]=1)=[O:4].[Br:23]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)Cl>[Br:23][CH2:18][C:15]1[C:16](=[O:17])[N:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=2)[C:12]2[N:22]=[CH:21][CH:20]=[CH:19][C:13]=2[N:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cccc(-n2c(=O)c(C)nc3cccnc32)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cccc(-n2c(=O)c(CBr)nc3cccnc32)c1
Yield: 74.7 %

Procedure:
A mixture of 4-(3-methoxycarbonylphenyl)-2-methyl-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (5.02 g), N-bromosuccinimide (4.0 g) and benzoyl peroxide (0.50 g) in chloroform (60 ml) was stirred under reflux for 2 hours. The mixture was concentrated and chromatographed on silica gel column (1% methanol in chloroform) to give 2-bromomethyl-4-(3-methoxycarbonylphenyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (4.75 g).
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:17][CH3:18])=[C:4]([C:9]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[BrH:19].BrBr>C(O)(=O)C>[CH3:1][C:2]1[C:3]([O:17][CH3:18])=[C:4]([C:9]([C:11]2([Br:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: COc1c(C)cc(C)cc1C(=O)C1CCCCC1
Reactant: Br
Agent: BrBr
Solvent: CC(=O)O
Product: COc1c(C)cc(C)cc1C(=O)C1(Br)CCCCC1
Temperature: 0 °C

Procedure:
285.2 Grams of cyclohexyl 3,5-dimethyl-2methoxyphenyl ketone was dissolved in 800 ml of acetic acid. To the solution was added 8 ml of 47% hydrobromic acid and then a solution prepared by dissolving 212 g of bromine in 100 ml of acetic acid was added thereto dropwise with ice-cooling and stirring. After stirring at room temperature for 2 hours, the reaction mixture was poured into ice water, followed by extraction with 2 liters of ethyl acetate. The extract was washed with water and then with a saturated aqueous sodium chloride solution and then dried with anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to obtain 363.6 g of 1-bromocyclohexyl 3,5-dimethyl-2-methoxyphenyl ketone.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=3)[CH:10]=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:18]([C:25]1[CH:30]=[CH:29][N:28]=[CH:27][C:26]=1[CH:31]=[CH:32][C:33](O)=[O:34])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[O:18]([C:25]1[CH:30]=[CH:29][N:28]=[CH:27][C:26]=1/[CH:31]=[CH:32]/[C:33]([NH:17][C:14]1[CH:15]=[C:16]2[C:11]([CH:10]=[N:9][N:8]2[CH2:7][CH2:6][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:12][CH:13]=1)=[O:34])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(O)C=Cc1cnccc1Oc1ccccc1
Reactant: Nc1ccc2cnn(CCN3CCCC3)c2c1
Product: O=C(/C=C/c1cnccc1Oc1ccccc1)Nc1ccc2cnn(CCN3CCCC3)c2c1

Procedure:
According to the procedure for Example 49, 1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-6-ylamine and 3-(4-phenoxy-pyridin-3-yl)-acrylic acid were processed to provide the title compound. MS (DCI/NH3) MS m/z 454 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ ppm 1.84 (m, 2 H), 2.01 (m, 2 H), 3.07 (m, 2 H), 3.54 (m, 2 H), 3.73 (m, 2 H), 4.71 (t, J=6.08 Hz, 2 H), 6.88 (m, 1 H), 7.20 (m, 5 H), 7.45 (m, 2 H), 7.62 (m, 1 H), 7.75 (m, 1 H), 8.13 (m, 2 H), 8.40 (m, 2 H), 9.62 (br s, N H).
Reaction SMILES: Br[C:2]1[C:3](=[O:11])[N:4]([CH3:10])[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[CH2:12]([NH:19][CH2:20][CH2:21][C:22]1[CH:36]=[CH:35][C:25]([O:26][C:27]([CH3:34])([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:24][CH:23]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>>[CH3:8][N:6]1[C:5](=[O:9])[N:4]([CH3:10])[C:3](=[O:11])[C:2]([N:19]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:20][CH2:21][C:22]2[CH:36]=[CH:35][C:25]([O:26][C:27]([CH3:34])([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:24][CH:23]=2)=[N:7]1
Reactant: CCCCCCCNCCc1ccc(OC(C)(C)C(=O)OCC)cc1
Reactant: Cn1nc(Br)c(=O)n(C)c1=O
Product: CCCCCCCN(CCc1ccc(OC(C)(C)C(=O)OCC)cc1)c1nn(C)c(=O)n(C)c1=O

Procedure:
Compound 112 (oil) is prepared from triazine 1b and from intermediate 14a according to synthesis method 1.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][S:18]([C:21]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[CH:24]=[CH:23][CH:22]=4)(=[O:20])=[O:19])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[H][H]>CO.[Pd].C(OCC)C>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][S:18]([C:21]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[CH:24]=[CH:23][CH:22]=4)(=[O:20])=[O:19])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: CN1CC=C(c2c[nH]c3ccc(NS(=O)(=O)c4cccc5ccccc45)cc23)CC1
Agent: [Pd]
Solvent: CO
Solvent: CCOCC
Product: CN1CCC(c2c[nH]c3ccc(NS(=O)(=O)c4cccc5ccccc45)cc23)CC1
Yield: 64.8 %

Procedure:
To a solution of 417 mg (1 mMol) of N-[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl]naphthalene-1-sulphonamide in 50 ml of methanol are added 100 mg of 5% palladium on carbon. The mixture is hydrogenated at ambient temperature at an initial hydrogen pressure of 3 atmospheres for 20 hours. The reaction mixture is filtered and the filtrate is concentrated at reduced pressure to provide a crude that is suspended in ethyl ether, yielding 272 mg (65%) of N-[3-(1-methyl-piperidin-4-yl)-1H-indol-5-yl]naphthalene-1-sulphonamide as a solid with m.p.=254–256° C.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.[CH2:8]([O:10][C:11]([C:13]1[C:14]([CH2:37]Cl)=[N:15][C:16]2[C:21]([C:22]=1[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=1)=[CH:20][C:19]([O:33][CH3:34])=[C:18]([O:35][CH3:36])[CH:17]=2)=[O:12])[CH3:9].O>CN(C)C=O>[CH2:8]([O:10][C:11]([C:13]1[C:14]([CH2:37][N:3]2[CH:7]=[N:6][CH:5]=[N:4]2)=[N:15][C:16]2[C:21]([C:22]=1[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=1)=[CH:20][C:19]([O:33][CH3:34])=[C:18]([O:35][CH3:36])[CH:17]=2)=[O:12])[CH3:9]
Reactant: CCOC(=O)c1c(CCl)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(Cn2cncn2)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 52.8 %

Procedure:
Oily sodium hydride (60%, 0.323 g) was added to a solution of 1H-1,2,4-triazole (0.558 g) in N,N-dimethylformamide (30 ml), followed by stirring at room temperature for 15 minutes. Then 2-chloromethyl-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylic acid ethyl ester (3.0 g) was added. After stirring at 80° C. for 1 hour, the reaction mixture was poured over water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and then dried (MgSO4), after which the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with chloroform-methanol (40:1, v/v) to yield 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-(1,2,4-triazol- 1-ylmethyl)quinoline-3-carboxylic acid ethyl ester (1.7 g, 53%), which was then recrystallized from ethyl acetate-hexane to yield a colorless prismatic crystal having a melting point of 176 to 177° C.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:19][C:20]3[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=3[Br:28])=[N:14][CH:15]=[N:16]2)=[C:11]([O:29][CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:10]=1)C1C=CC=CC=1.FC(F)(F)C(O)=O>>[Br:28][C:21]1[CH:22]=[CH:23][C:24]([O:26][CH3:27])=[CH:25][C:20]=1[NH:19][C:13]1[C:12]2[C:17](=[CH:18][C:9]([OH:8])=[CH:10][C:11]=2[O:29][CH:30]2[CH2:31][CH2:32][NH:33][CH2:34][CH2:35]2)[N:16]=[CH:15][N:14]=1
Reactant: COc1ccc(Br)c(Nc2ncnc3cc(OCc4ccccc4)cc(OC4CCNCC4)c23)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Br)c(Nc2ncnc3cc(O)cc(OC4CCNCC4)c23)c1
Temperature: 80 °C

Procedure:
A mixture of 7-benzyloxy-4-(2-bromo-5-methoxyanilino)-5-piperidin-4-yloxyquinazoline (0.35 g) and trifluoroacetic acid (6 ml) was stirred and heated to 80° C. for 5 hours. The mixture was evaporated and the residue was dissolved in water (12 ml). The solution was basified to pH8 by the addition of sodium bicarbonate. The resultant precipitate was isolated, washed with water and with ethyl acetate and dried under vacuum. There was thus obtained the title compound (0.26 g); NMR Spectrum: (DMSOd6) 1.95–2.15 (m, 2H), 2.32 (d, 2H), 3.05 (t, 2H), 3.3–3.4 (m, 2H), 3.8 (s, 3H), 5.0 (r, 1H), 6.75 (m, 2H), 6.85 (s, 1H), 7.6 (d, 1H), 7.98 (s, 1H), 8.4 (s, H), 9.58 (s, 1H); Mass Spectrum: M+H+ 445 and 447.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([C:9]([F:12])([F:11])[F:10])[C:5]([F:13])=[C:4]([F:14])[C:3]=1[N:15]1[C:19]([NH:20][C:21]([CH3:23])=[O:22])=[CH:18][CH:17]=[N:16]1.S(Cl)([Cl:27])(=O)=O>C(Cl)Cl>[Cl:27][C:18]1[CH:17]=[N:16][N:15]([C:3]2[C:4]([F:14])=[C:5]([F:13])[C:6]([C:9]([F:12])([F:10])[F:11])=[C:7]([F:8])[C:2]=2[F:1])[C:19]=1[NH:20][C:21]([CH3:23])=[O:22]
Reactant: CC(=O)Nc1ccnn1-c1c(F)c(F)c(C(F)(F)F)c(F)c1F
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CC(=O)Nc1c(Cl)cnn1-c1c(F)c(F)c(C(F)(F)F)c(F)c1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94.9 %

Procedure:
A solution of 0.80 gram (0.0023 mole) of 1-(2,3,5,6-tetrafluoro-4-trifluoromethylphenyl)-5-methylcarbonylaminopyrazole (Step C of Example 1) in 25 mL of methylene chloride was cooled to -5° C. Sulfuryl chloride (9.35 gram, 0.0026 mole) was added dropwise during a two minute period. After the addition was complete, the reaction mixture was allowed to warm to room temperature and was stirred for 1.5 hours. The reaction mixture was diluted with methylene chloride and washed in succession with an aqueous, saturated sodium bicarbonate solution and water. The organic phase was evaporated under reduced pressure to yield 0.82 gram of 4-chloro-1-(2,3,5,6-tetrafluoro-4-trifluoromethylphenyl)-5-methylcarbonylaminopyrazole as a white solid, m.p. 45°-47° C. The nmr spectrum was consistent with the proposed structure.