Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N:12]4[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]4=[O:19])=[CH:8][N:7]3[C:20]=2[CH3:21])[CH2:3][CH2:2]1.[F:22][C:23]([F:32])([F:31])[C:24]1[S:28][C:27]([CH2:29]O)=[CH:26][CH:25]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1.O>[CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N:12]4[CH:17]=[CH:16][C:15]([O:18][CH2:29][C:27]5[S:28][C:24]([C:23]([F:32])([F:31])[F:22])=[CH:25][CH:26]=5)=[CH:14][C:13]4=[O:19])=[CH:8][N:7]3[C:20]=2[CH3:21])[CH2:3][CH2:2]1
Reactant: Cc1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cn12
Reactant: OCc1ccc(C(F)(F)F)s1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C2CC2)nc2ccc(-n3ccc(OCc4ccc(C(F)(F)F)s4)cc3=O)cn12
Yield: 20.2 %

Procedure:
To a solution of 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (100 mg), (5-(trifluoromethyl)thiophen-2-yl)methanol (130 mg) and tributylphosphine (0.27 ml) in THF (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (269 mg) at 60° C., and the mixture was heated at the same temperature for 2 h. The mixture was poured into water, and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, concentrated, and purified by NH silica gel column chromatography (hexane/EtOAc), followed by silica gel column chromatography (EtOAc/MeOH). The resulting solid was purified by preparative HPLC (C18, mobile phase: H2O/CH3CN (0.1% TFA included)). The desired fraction was neutralized with saturated NaHCO3 solution, and extracted with EtOAc. The organic layer was separated, dried over MgSO4 and concentrated in vacuo to give the title compound (32.0 mg) as a white solid.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([S:14]([OH:17])(=[O:16])=[O:15])=[CH:6][CH:5]=1.[N:18]([O-])=O.[Na+].[ClH:22]>O>[ClH:22].[NH:3]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([S:14]([OH:17])(=[O:15])=[O:16])=[CH:6][CH:5]=1)[NH2:18]
Reactant: O=N[O-]
Reactant: Nc1ccc(S(=O)(=O)O)c2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NNc1ccc(S(=O)(=O)O)c2ccccc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
4 g of NaOH are added to a suspension of 22.33 g of 4-amino-1-naphthalenesulphonic acid in 125 ml of water. The mixture is cooled to 0° C. and 2 ml of concentrated NaOH are added, followed by 7.5 g of sodium nitrite and 125 g of ice to maintain the temperature at 0° C. The suspension thereby obtained is poured into 75 ml of concentrated HCl cooled beforehand to 0° C., and left stirring for 2 hours 15 minutes at this temperature. The reaction mixture is added slowly to a solution, cooled beforehand to -10° C., of 55 g of stannous chloride dihydrate in 50 ml of concentrated HCl and 25 ml of water. After one night, the expected product is obtained by filtration, rinsing with 1N HCl and with water, m=23.96 g.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15].C1(C)C=CC(S([NH:31][NH:32]S(C2C=CC(C)=CC=2)(=O)=O)(=O)=O)=CC=1>C1COCC1>[N+:31](=[CH:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15])=[N-:32]
Reactant: O=C(CBr)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)NNS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: [N-]=[N+]=CC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.7 %

Procedure:
DBU (7.5 mL, 50.2 mmol) was added dropwise to a solution of 2-bromo-1-phenylethanone (2.0 g, 10.05 mmol) and N,N′-bis(p-toluenesulfonyl)hydrazine (6.8 g, 20.1 mmol) in dry THF (30 mL) at 0° C. The reaction mixture was stirred at 0° C. for 30 min, and quenched with aqueous saturated NaHCO3 solution. The organic product was extracted with EtOAc and the combined extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluant 10-15% EtOAc in petroleum ether) to get 2-diazo-1-phenylethanone (1.2 g, yield 82%) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 7.78-7.76 (m, 2H), 7.56-7.53 (m, 1H), 7.48-7.43 (m, 2H), 5.91 (s, 1H).
Reaction SMILES: Cl.[Cl-].[CH3:3][NH+:4]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)[CH3:5]>C(OCC)C>[CH3:3][N:4]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=1)[CH3:5]
Reactant: C[NH+](C)CCCCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Cl-]
Solvent: CCOCC
Product: CN(C)CCCCc1ccc([N+](=O)[O-])cc1

Procedure:
The solid thus formed was added portion-wise over one hour to a stirred solution of 275 ml. of a 0.94 molar solution of borane in tetrahydrofuran. Following complete addition of the solid, the reaction mixture was heated at reflux for twelve hours, and then cooled to 0° C. in an ice bath. The reaction mixture was diluted by the dropwise addition of 75 ml. of 2 N hydrochloric acid. The reaction solvent was then removed by evaporation under reduced pressure, and the residue was dissolved in 100 ml. of concentrated hydrochloric acid and heated at reflux for one hour. The acidic mixture then was cooled and made alkaline by the addition of 5 N sodium hydroxide. The alkaline solution was extracted several times with diethyl ether, and the ethereal extracts were combined, washed with water and dried. Removal of the solvent by evaporation under reduced pressure afforded 18.4 g. of N,N-dimethyl-4-(4-nitrophenyl)butylamine. The amine thus formed was dissolved in diethyl ether containing hydrogen chloride, whereupon a solid precipitate formed. Crystallization of the precipitate from 150 ml. isopropanol afforded 18.1 g. of N,N-dimethyl-4-(4-nitrophenyl)butylaminium chloride. M.P. 143°-145° C.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[O:19]1[C:23]2[CH:24]=[CH:25][C:26]([C:28]3[CH:36]=[C:35]4[C:31]([C:32]([NH:46][C:47](=[O:51])[CH2:48][CH2:49][CH3:50])=[N:33][N:34]4OCOCC[Si](C)(C)C)=[CH:30][CH:29]=3)=[CH:27][C:22]=2CO1.[C:52](OCC)(=[O:54])C>O1CCCC1>[O:19]1[C:23]2[CH:24]=[CH:25][C:26]([C:28]3[CH:36]=[C:35]4[C:31]([C:32]([NH:46][C:47](=[O:51])[CH2:48][CH2:49][CH3:50])=[N:33][NH:34]4)=[CH:30][CH:29]=3)=[CH:27][C:22]=2[O:54][CH2:52]1
Reactant: CCOC(C)=O
Reactant: CCCC(=O)Nc1nn(OCOCC[Si](C)(C)C)c2cc(-c3ccc4c(c3)COO4)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCCC(=O)Nc1n[nH]c2cc(-c3ccc4c(c3)OCO4)ccc12
Temperature: 67 °C

Procedure:
2 cm3 of tetrabutylammonium fluoride as a 1M solution in tetrahydrofuran are added to 600 mg of N-[6-(benzodioxol-5-yl)-1-[[2-(trimethylsilyl)ethoxy]methoxy]-1H-indazol-3-yl]butanamide, described previously, in 12 cm3 of tetrahydrofuran. The medium is then maintained at 67° C. for 16 hours. The mixture is then allowed to return to 19° C. and 60 μm3 of ethyl acetate are added, after which it is washed with 30 cm3 of saturated aqueous sodium hydrogen carbonate solution and then with 2×30 cm3 of distilled water and finally with 30 cm3 of saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulphate, filtered through a sinter funnel and evaporated under reduced pressure (2 kPa; 45° C.). The residue obtained is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 15-40 μm; diameter 3 cm), eluting with a cyclohexane/ethyl acetate mixture (60/40 by volume) and collecting 15 cm3 fractions. The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). After drying (90 Pa; 50° C.), 260 mg of N-[6-(1,3-benzodioxol-5-yl)-1H-indazol-3-yl]butanamide are obtained in the form of a white solid melting at 240° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([O:27][CH2:28][CH2:29][NH2:30])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].C(N(CC)CC)C.[C:39](OC(=O)C)(=[O:41])[CH3:40]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([O:27][CH2:28][CH2:29][NH:30][C:39](=[O:41])[CH3:40])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: Cc1cc(F)ccc1-c1nc(OCCN)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCCOc1nc(-c2ccc(F)cc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 0 °C

Procedure:
The product of Example 131 (61 mg, 0.14 mmol)was dissolved in CH2Cl2 (2 mL) and stirred at 0° C. under Ar. Triethylamine (0.1 mL) was added followed by the addition of acetic anhydride (0.2 g, 2 mmol). The reaction was allowed to slowly warm to 23° and stir for 18 h. The solvents were removed in vacuo, and the residue was flash chromatographed eluted with 10-30% EtOAc/CH2Cl2 to give the title compound as a white-amorphous solid. mp 75-79°, LC MS m/z=469 (MH+) Retention time=1.95 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4](=[CH:9][C:10]1[CH:11]=[C:12]2[C:16](=[C:17]([CH3:19])[CH:18]=1)[NH:15][N:14]=[CH:13]2)[CH2:5][C:6]([OH:8])=[O:7]>C(OCC)(=O)C.CO.[Pd]>[CH3:1][O:2][C:3](=[O:20])[CH:4]([CH2:9][C:10]1[CH:11]=[C:12]2[C:16](=[C:17]([CH3:19])[CH:18]=1)[NH:15][N:14]=[CH:13]2)[CH2:5][C:6]([OH:8])=[O:7]
Reactant: COC(=O)C(=Cc1cc(C)c2[nH]ncc2c1)CC(=O)O
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)C(CC(=O)O)Cc1cc(C)c2[nH]ncc2c1
Yield: 100 %

Procedure:
A suspension of 2-(7-methyl-1H-indazol-5-ylmethylene)-succinic acid 1-methyl ester (0.4440 g, 1.62 mmol) and 10% Pd/C (0.04 g) in ethyl acetate (15 mL) and methanol (5 mL) was hydrogenated in a Parr apparatus overnight at 50 psi. The reaction mixture was filtered through a pad of celite and the filtrate evaporated to give the desired product as a yellow solid (100%). Mass spec.: 277 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](O)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[NH3:21]>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH2:21])=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: N
Product: NC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and ammonia (0.24 mL, 0.5 M in THF, 0.12 mmol). The title compound was obtained as a solid (4.5 mg, 12.8% yield). MS m/z: 347.80, 349.80 [M+H]+.
Reaction SMILES: [NH:1]1[C:8](=[O:9])[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].S(=O)(=O)(O)O.[CH3:15]O>>[OH:3][C:2]1[N:4]=[C:5]([OH:6])[CH:7]=[C:8]([O:9][CH3:15])[N:1]=1
Reactant: CO
Reactant: O=C1CC(=O)NC(=O)N1
Agent: O=S(=O)(O)O
Product: COc1cc(O)nc(O)n1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a suspension of barbituric acid (51.2 g) in methanol (1 L) was added concentrated sulfuric acid (80 mL) in a dropwise manner over 20 minutes, and the mixture was stirred at room temperature for 22 hours. The crystals were collected by filtration. The collected crystals were washed with methanol, cold water and diethyl ether successively, and dried under reduced pressure to give 2,4-dihydroxy-6-methoxypyrimidine (52.9 g). To a mixture of fuming nitric acid (20 mL) and concentrated sulfuric acid (10 mL) was added 2,4-dihydroxy-6-methoxypyrimidine (14.2 g) slowly at around 15° C., and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added ice water (150 mL), and the mixture was stirred at room temperature for 30 minutes. The crystals were collected by filtration. The collected crystals were washed with water, and dried under reduced pressure to give the title compound (7.4 g).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[ClH:25].Cl.[CH3:27][C@H:28]1[C:36]2[C:35]([N:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)=[N:34][CH:33]=[N:32][C:31]=2[C@H:30]([OH:43])[CH2:29]1.C(OC([N:51]([CH:65]([CH3:67])[CH3:66])[CH2:52][C:53]([C:58]1[CH:63]=[CH:62][C:61]([Cl:64])=[CH:60][CH:59]=1)([OH:57])[C:54](O)=[O:55])=O)(C)(C)C>C(Cl)Cl>[Cl:64][C:61]1[CH:60]=[CH:59][C:58]([C:53]([OH:57])([CH2:52][NH:51][CH:65]([CH3:66])[CH3:67])[C:54]([N:40]2[CH2:39][CH2:38][N:37]([C:35]3[C:36]4[C@H:28]([CH3:27])[CH2:29][C@@H:30]([OH:43])[C:31]=4[N:32]=[CH:33][N:34]=3)[CH2:42][CH2:41]2)=[O:55])=[CH:63][CH:62]=1.[ClH:25]
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCNCC3)c21
Reactant: CC(C)N(CC(O)(C(=O)O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CC(C)NCC(O)(C(=O)N1CCN(c2ncnc3c2[C@H](C)C[C@H]3O)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
HBTU (37 mg, 0.098 mmol) was added to a solution of (5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (30 mg, 0.098 mmol) and 3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)-2-hydroxypropanoic acid (35 mg, 0.098 mmol) in DCM (5 mL) and TEA (1 mL). The mixture was stirred at room temperature for 1 hour. The solvent was removed, and the residue was subject to column chromatography, eluted by DCM/MeOH (40:1). The resulting product was treated with HCl (4M, 2 mL) to afford 2-(4-chlorophenyl)-2-hydroxy-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one as HCl salt (22 mg, 48%).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)[N:9]=[N:10][C:5]2=[N:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:27]([O:29][CH2:30][CH3:31])=[CH2:28])CCC>CN(C=O)C.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>[CH2:30]([O:29][C:27]([C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)[N:9]=[N:10][C:5]2=[N:4][CH:3]=1)=[CH2:28])[CH3:31]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Brc1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=C(OCC)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 61.6 %

Procedure:
To a degassed solution of 6-((6-bromo-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)quino-line (2.50 g, 5.86 mmol) in DMF (20 mL), was added Pd(Ph3P)4 (0.542 g, 0.469 mmol) and the solution was stirred for 20 min at room temperature. Then tributyl(1-ethoxyvinyl)stannane (2.117 g, 5.86 mmol) was added. The reaction was heated to 100° C. until LC-MS showed the reaction was complete. The reaction mixture was filtered through celite and the filtrate was washed with water, dried over Na2SO4, and concentrated. The resulting crude product was purified by silica gel column chromatography with gradient Hex:EA to give 6-((6-(1-ethoxyvinyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)quinoline (1.2 g, 62%). 1H-NMR (400 MHz, CDCl3) δ ppm 9.19 (s, 1H), 8.94 (m, 1H), 8.20 (m, 1H), 7.99 (s, 1H), 7.89 (d, 1H), 7.548 (m, 1H), 6.12 (s, 2H), 5.61 (d, 1H), 4.61 (d, 1H), 4.05 (q, 2H), 1.51 (t, 3H). LCMS (method B): [MH]+=360, tR=2.40 min.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.C(N(CC)C(C)C)(C)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37].C([O-])(O)=O.[Na+]>ClCCl>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][S:36]([CH3:35])(=[O:38])=[O:37])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: CS(=O)(=O)Cl
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Temperature: 25 °C

Procedure:
To a stirred mixture of Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (30 mg, 0.0818 mmol, Eq: 1.00) in dichloromethane (500 μl) was added at room temperature N,N-diisopropylethylamine (31.6 mg, 42.7 μl, 245 μmol, Eq: 3) and methanesulfonyl chloride (14.1 mg, 123 μmol). The mixture was allowed to stir at room temperature over night. The crude reaction diluted with 5 mL sat NaHCO3 and extracted with DCM (2×10 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 10 g, 0% to 10% MeOH in DCM) to yield the title compound as an white solid (16.2 mg, 48.5%), MS (ISP) m/z=409.3 [(M+H)+].
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[NH2:18][C:19]1[C:24]2[O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:23]=2[CH:22]=[CH:21][C:20]=1[O:32][CH3:33]>>[CH3:33][O:32][C:20]1[CH:21]=[CH:22][C:23]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[O:25][C:24]=2[C:19]=1[NH:18][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: COc1ccc2c(oc3ccccc32)c1N
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Product: COc1ccc2c(oc3ccccc32)c1Nc1cc(C(F)(F)F)nc(-c2cccnc2)n1

Procedure:
The title compound was prepared from 4-chloro-2-(3-pyridinyl)-6-trifluoromethylpyrimidine (50 mg, 0.192 mmol) and 4-amino-3-methoxydibenzofuran (61 mg, 0.288 mmol) similar to Example 185 and was isolated as a solid (6 mg, 7%). 1H NMR (CDCl3): 9.73 (brs, 1H), 8.88 (d, J=7.8 Hz, 1H), 8.77 (brs, 1H), 7.89 (m, 1H), 7.19-7.59 (m, 6H), 7.02 (s, 1H), 4.05 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Br[CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CC#N>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13]
Reactant: Oc1ccccc1Br
Reactant: CC(C)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)CCOc1ccccc1Br
Temperature: 80 °C

Procedure:
A round-bottomed flask was charged with commercially available 2-bromophenol (43 g, 0.25 mol), 1-bromo-3-methylbutane (41 mL, 0.33 mol), potassium carbonate (0.38 mol), and 200 mL of CH3CN. The resulting slurry was heated to 80° C. for 18 h. Upon completion, the mixture was cooled down to the room temperature, filtered, and concentrated down under reduced pressure. Vacuum distillation of the residue resulted in 1-bromo-2-(isopentyloxy)benzene (56 g, 93%, b.p. 82° C. at 10 mm Hg) as a colorless liquid. 1H NMR (400 MHz, CDCl3): δ 7.55 (d, 1H), 7.25 (t, 1H), 6.90 (d, 1H), 6.80 (t, 1H), 4.05 (t, 2H), 1.97-1.85 (m, 1H), 1.78-1.70 (m, 2H), 0.98 (d, 6H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH:9]=[O:10])=[C:4]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:3]=1.[Sn](C)(C)(C)[CH3:18]>CN(C=O)C.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>[NH2:1][C:2]1[N:7]=[C:6]([CH3:18])[C:5]([CH:9]=[O:10])=[C:4]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:3]=1
Reactant: CCCCCNc1nc(N)nc(Cl)c1C=O
Reactant: C[Sn](C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCCCCNc1nc(N)nc(C)c1C=O
Temperature: 100 °C

Procedure:
To the product from step (i) (20 g) in DMF (200 ml), Pd(PPh3)4 (2 g) was added followed by SnMe4 (20 ml) and the mixture heated at 100° C. for 16 h. The solvent was evaporated and the residue partitoned between EtOAc and brine, the organics were dried and solvent removed. The product was purified by silica chromatography to give the subtitle compound, 14.4 g.
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)([CH3:3])[CH3:2].[CH3:16][CH:17](Br)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(=O)([O-])[O-].[Na+].[Na+].C(O)C>O>[CH:1]([O:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH:17]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:16])=[CH:11][CH:10]=1)([CH3:3])[CH3:2]
Reactant: CC(C)OCCCNc1ccc(N)cc1
Reactant: CCCCCCC(C)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCCCC(C)Nc1ccc(NCCCOC(C)C)cc1

Procedure:
A mixture of 50 g. of N-(3-isopropoxypropyl)-p-phenylenediamine, 50 g. of 2-octyl bromide, 200 ml. of 2N sodium carbonate and 1 liter of ethanol is stirred for 18 hours at 60°C. The reaction mixture is treated with 1 liter of water and extracted with 1 liter of ether. The ether layer is separated, washed with 1200 ml. of water, dried over sodium sulfate and evaporated in vacuo. A mixture of the residue in ether is treated with hydrogen chloride gas to yield the title product in dihydrochloride salt form, m.p. 200°-202°C.
Reaction SMILES: [Na].[F:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[NH:7][CH:8]=1.[CH2:10](Br)[CH:11]=[CH2:12]>CO>[CH2:12]([N:5]1[CH:4]=[C:3]([F:2])[CH:8]=[N:7][C:6]1=[O:9])[CH:11]=[CH2:10]
Reactant: O=c1ncc(F)c[nH]1
Reactant: C=CCBr
Agent: [Na]
Solvent: CO
Product: C=CCn1cc(F)cnc1=O
Yield: 48 %

Procedure:
The sodium salt of 5-fluoropyrimid-2-one (0.01 mol) was dissolved in methanol (100 ml) and allyl bromide (0.015 mol) added gradually at room temperature and the reaction allowed to proceed until neutral pH had been reached. The reaction mixture was then concentrated at reduced pressure and the residue extracted with chloroform (100 ml). The chloroform solution was washed with water (2×5 ml) and dried before evaporation; Yield 48%, m.p. 88°-90° C. after recrystallisation from acetone: (Found: C, 55.10; H, 4.80. Calc. for C7H7FN2O: C, 54.56; H, 4.58.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][NH2:8].[CH2:9]([CH2:11][CH2:12][CH2:13][C:14](CC([O-])=O)=[O:15])[CH3:10]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:14](=[O:15])[CH2:13][C:12]([CH2:11][CH2:9][CH3:10])=[N:8]1
Reactant: NNc1ccccn1
Reactant: CCCCCC(=O)CC(=O)[O-]
Product: CCCC1=NN(c2ccccn2)C(=O)C1

Procedure:
From the reaction of 2-pyridylhydrazine and ethylbutyrylacetate, 2,4-dihydro-2-(2-pyridyl)-5-propyl-3H-pyrazol-3-one is obtained. Subsequent reaction with 2-ethylaniline yields 4-(2-ethylanilinomethylene)-2,4-dihydro-2-(2-pyridyl)-5-propyl-3H-pyrazol-3-one, Mp 151° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][C:11]=2[Cl:25])=[O:9])[CH:7]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([N:35]=[C:36]=[O:37])[CH:32]=[CH:33][CH:34]=1>N1C=CC=CC=1>[Cl:25][C:11]1[CH:12]=[C:13]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])[CH:14]=[CH:15][C:10]=1[C:8]([C:6]1[CH:7]=[C:2]([NH:1][C:36]([NH:35][C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([O:28][CH3:27])[CH:30]=2)=[O:37])[CH:3]=[CH:4][C:5]=1[CH3:26])=[O:9]
Reactant: COc1cccc(N=C=O)c1
Reactant: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Solvent: c1ccncc1
Product: COc1cccc(NC(=O)Nc2ccc(C)c(C(=O)c3ccc(Nc4ccc(F)cc4F)cc3Cl)c2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Compound 494 (0.03 g, 0.08 mmol) was dissolved in pyridine (0.2 mL) and 3-methoxyphenyl isocyanate (0.016 mL, 0.12 mmol) was added. The solution was stirred at room temperature for 1.5 h. Work up as described in the preparation of compound 259. The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 2:3 as the eluent. This afforded the title compound as a slightly coloured solid. 13C NMR (CD3OD) δ 198.3, 161.7, 161.0 (dd), 157.9 (dd), 155.3, 151.2, 141.6, 141.2, 138.3, 136.2, 135.0, 132.7, 132.6, 130.6, 128.7, 127.4 (dd), 126.0 (dd), 122.8, 121.1, 116.7, 113.0, 112.7, 112.6 (dd), 109.5, 106.3, 105.8 (dd), 55.7, 19.7