Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:30]1[CH:31]=[C:32]([NH:36][C:37](=[O:39])[CH3:38])[CH:33]=[CH:34][CH:35]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(OCC)(=O)C.CC(O)(C)C>[C:37]([NH:36][C:32]1[CH:31]=[C:30]([NH:1][C:2]2[CH:14]=[C:13]([CH2:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=[CH:11][C:3]=2[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[CH:35]=[CH:34][CH:33]=1)(=[O:39])[CH3:38]
Reactant: CC(=O)Nc1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1N
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: CC(=O)Nc1cccc(Nc2cc(CCc3ccccc3)ccc2C(=O)OC(C)(C)C)c1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To 2-methyl-2-propanol 2.5 mL solution of tert-butyl 2-amino-4-phenethylbenzoate 0.12 g were added cesium carbonate 0.26 g, N-(3-bromophenyl)acetamide 0.13 g, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 10 mg, tris(dibenzylideneacetone)dipalladium(0) 4.0 mg and palladium acetate 2.0 mg at room temperature, and it was stirred at 80° C. for 4 hours. Tris(dibenzylideneacetone)dipalladium(0) 4.0 mg, palladium acetate 2.0 mg and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 10 mg were added to it, and it was stirred at 80° C. for 12 hours. Cesium carbonate 0.26 g, N-(3-bromophenyl)acetamide 0.13 g, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 10 mg, tris(dibenzylideneacetone)dipalladium(0) 4.0 mg and palladium acetate 2.0 mg were added to it, and it was stirred at 80° C. for 5 hours and 30 minutes. After the reaction mixture was cooled to room temperature, ethyl acetate and water were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=2:1] to give tert-butyl 2-((3-(acetamido)phenyl)amino)-4-phenethylbenzoate.
Reaction SMILES: CC(C)(C)[C@H:3]([NH:8][C:9]([N:11]1[C:19]2[CH2:18][CH2:17][N:16]([CH3:20])[CH2:15][C:14]=2[C:13]([C:21]2[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:22]=2F)=[N:12]1)=[O:10])[C:4]([NH:6]C)=[O:5].FC1[CH:34]=[C:35]([C:40]2C3CN(C(OC(C)(C)C)=O)CCC=3NN=2)[CH:36]=CC=1F.N[C@H](C(N)=O)CC(C)C>>[NH2:6][C:4](=[O:5])[C@@H:3]([NH:8][C:9]([N:11]1[C:19]2[CH2:18][CH2:17][N:16]([CH3:20])[CH2:15][C:14]=2[C:13]([C:21]2[CH:22]=[CH:23][C:24]([F:28])=[C:25]([F:27])[CH:26]=2)=[N:12]1)=[O:10])[CH2:34][CH:35]([CH3:40])[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(F)c(F)c3)c2C1
Reactant: CNC(=O)[C@@H](NC(=O)n1nc(-c2cc(F)c(F)cc2F)c2c1CCN(C)C2)C(C)(C)C
Agent: CC(C)C[C@H](N)C(N)=O
Product: CC(C)C[C@H](NC(=O)n1nc(-c2ccc(F)c(F)c2)c2c1CCN(C)C2)C(N)=O

Procedure:
Compound 49 was prepared according to the procedure described for the synthesis of compound 37 by replacing intermediate 19 with intermediate 15, and replacing tert-leucine methylamide with L-leucine amide. 1H NMR (CDCl3) δ 7.49-7.58 (m, 2H), 7.34-7.38 (m, 1H), 7.18-7.24 (m, 1H), 4.50 (m, 1H), 3.58 (s, 2H), 3.20 (s, 2H), 2.27 (s, 3H), 2.53 (s, 3H), 1.71-1.82 (m, 3H), 0.88-0.99 (m, 6H). LCMS (+ESI) m/z=406.3 [M+H]+.
Reaction SMILES: C1(S[C:8]2[S:9][C:10]([CH2:13][N:14]3[C:19](=[N:20][N+:21]([O-:23])=[O:22])[N:18]([CH3:24])[CH2:17][O:16][CH2:15]3)=[CH:11][N:12]=2)C=CC=CC=1.[ClH:25].ClCl>ClC1C=CC=CC=1>[Cl:25][C:8]1[S:9][C:10]([CH2:13][N:14]2[C:19](=[N:20][N+:21]([O-:23])=[O:22])[N:18]([CH3:24])[CH2:17][O:16][CH2:15]2)=[CH:11][N:12]=1
Reactant: CN1COCN(Cc2cnc(Sc3ccccc3)s2)C1=N[N+](=O)[O-]
Reactant: Cl
Agent: ClCl
Solvent: Clc1ccccc1
Product: CN1COCN(Cc2cnc(Cl)s2)C1=N[N+](=O)[O-]
Reaction time: 2 h

Procedure:
183 g of 3-(2-phenylthiothiazol-5-yl-methyl)-5-methyl-4-nitroimino-perhydro-1,3,5-oxadiazine are introduced over a period of 5 minutes, with stirring, into a mixture of 300 g of hydrochloric acid (32%) and 150 g of chlorobenzene. 124 g of chlorine are introduced at 20° C. over a period of 4 hours. After 2 hours, excess chlorine is removed by the introduction of nitrogen, and the phases are then separated. The aqueous phase is adjusted to pH 5 with sodium hydroxide solution (30%) and then filtered, and the filtration residue is washed with water and dried in vacuo at 50° C. The title product is obtained in a purity of 97%.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N+:8]([O-])=[C:9]2[Cl:12])=[CH:4][CH:3]=1.[OH-].[Na+].O=P(Cl)(Cl)[Cl:18]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([Cl:18])[N:8]=[C:9]2[Cl:12])=[CH:4][CH:3]=1
Reactant: [O-][n+]1ccc2ccc(Br)cc2c1Cl
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: Clc1cc2ccc(Br)cc2c(Cl)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
7-Bromo-1-chloroisoquinoline 2-oxide (1.43 g, 5.56 mmol) and POCl3 (20 mL) were heated at reflux for 2 h. The reaction mixture was cooled and carefully poured onto a mixture of ice/water (500 g), stirred for 1 h and the pH adjusted to 10.0 with 10M NaOH. The mixture was extracted with chloroform (2×100 mL) and the chloroform extracts washed with brine, dried over MgSO4, filtered and concentrated to give the title compound (1.40 g). LRMS (M+H)+=276.0.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br:11][C:12]1[CH:17]=[C:16]([CH3:18])[C:15]([SH:19])=[C:14]([CH3:20])[CH:13]=1.[Cl:21][C:22]1[N:27]=[C:26]([CH3:28])[C:25]([N+:29]([O-:31])=[O:30])=[C:24](Cl)[N:23]=1>C1COCC1>[Br:11][C:12]1[CH:17]=[C:16]([CH3:18])[C:15]([S:19][C:24]2[C:25]([N+:29]([O-:31])=[O:30])=[C:26]([CH3:28])[N:27]=[C:22]([Cl:21])[N:23]=2)=[C:14]([CH3:20])[CH:13]=1
Reactant: Cc1nc(Cl)nc(Cl)c1[N+](=O)[O-]
Reactant: Cc1cc(Br)cc(C)c1S
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(Br)cc(C)c1Sc1nc(Cl)nc(C)c1[N+](=O)[O-]
Temperature: -100 °C
Reaction time: 2 h

Procedure:
A solution of LiHMDS in THF (77 mmol) is added to a mixture of 4-bromo-2,6-dimethylbenzenethiol (70 mmol) in THF (100 ml) at −78° C. over 15 minutes and the mixture stirred for an additional 2 hours. The mixture is cooled with liquid nitrogen to around −100° C. and a solution of 2,6-dichloro-4-methyl-5-nitropyrimidine (84 mmol) in THF (50 ml) is added rapidly. The reaction is maintained at around −100° C. for 1 hour and then allowed to warm to room temperature. The mixture is filtered and the isolated solid washed with ethanol. The filtrate may be concentrated and crystallized to obtain additional compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5](Cl)=[O:6].[CH3:12][NH:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26].CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([N:13]([CH3:12])[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26])=[O:6]
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Reactant: CNc1cnccc1-c1ccccc1C
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1cc(Cl)cc(Cl)c1
Reaction time: 8 h
Yield: 87 %

Procedure:
3,5-Dichlorobenzoyl chloride (85 mg, 0.40 mmol, CAS RN 2905-62-6) was added to a solution of methyl-(4-o-tolyl-pyridin-3-yl)-amine (40 mg, 0.20 mmol, example 1, intermediate a) and DIPEA (70 μL, 0.40 mmol) in THF (1 mL). The reaction mixture was stirred overnight, filtered and all volatiles removed. The resulting oil was purified by flash chromatography on silica gel eluting with 33-50% EtOAc in n-hexane to yield the product as a waxy solid (65 mg, 87%). MS (ESI): m/z=470.0 [M+H]+.
Reaction SMILES: OC1C(=O)NN=C(CCC2C=CC=CC=2)C=1.C([O:24][C:25]1[N:26]=[N:27][C:28]([C:39]#[C:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][C:42]=2[F:51])=[CH:29][C:30]=1[O:31]CC1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[F:51][C:42]1[CH:43]=[C:44]([C:47]([F:49])([F:50])[F:48])[CH:45]=[CH:46][C:41]=1[CH2:40][CH2:39][C:28]1[CH:29]=[C:30]([OH:31])[C:25](=[O:24])[NH:26][N:27]=1
Reactant: Fc1cc(C(F)(F)F)ccc1C#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: O=c1[nH]nc(CCc2ccccc2)cc1O
Solvent: C1CCOC1
Product: O=c1[nH]nc(CCc2ccc(C(F)(F)F)cc2F)cc1O
Yield: 29 %

Procedure:
Prepared as described for 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-{2-[2-fluoro-4-(trifluoromethyl)phenyl]-ethynyl}pyridazine (Intermediate 70) except that THF was used as the solvent. The reaction was filtered through diatomaceous earth flushing with further tetrahydrofuran and concentrated in vacuo. The residue was purified by column chromatography (silica C18 cartridge; eluting with 0-65% acetonitrile in water with acid modifier). The appropriate fractions were combined and concentrated in vacuo to remove the acetonitrile before the aqueous portion was extracted with ethyl acetate (×2), dried (MgSO4) and concentrated in vacuo. The resulting solid was recrystallised from a mixture of methyl tert-butyl ether and heptane to afford 6-{2-[2-fluoro-4-(trifluoromethyl)phenyl]ethyl}-4-hydroxy-2,3-dihydropyridazin-3-one as a cream solid (29% yield).
Reaction SMILES: [CH2:1]([C:3]1[S:4][CH:5]=[C:6]([C:8]([N:10]2[CH2:15][C:14]3([CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)[O:13][CH2:12][CH2:11]2)=[O:9])[N:7]=1)[CH3:2].Cl.CC(OC)(C)C>CC(O)C>[CH2:1]([C:3]1[S:4][CH:5]=[C:6]([C:8]([N:10]2[CH2:15][C:14]3([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[O:13][CH2:12][CH2:11]2)=[O:9])[N:7]=1)[CH3:2]
Reactant: CCc1nc(C(=O)N2CCOC3(CCN(C(=O)OC(C)(C)C)CC3)C2)cs1
Agent: Cl
Solvent: CC(C)O
Solvent: COC(C)(C)C
Product: CCc1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Temperature: 49 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
To a solution of tert-butyl 4-(2-ethylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (limiting reagent) (step a) in iPrOH (3 volumes) was added hydrogen chloride (2 molar equivalents of a 5-6N solution in iPrOH). The reaction mixture was heated and stirred at 49° C. (internal) for 18 hr before being cooled to 22° C. TBME (4.3 volumes) was added and the suspension was stirred at 22° C. for 3 days. The solid was collected by filtration, washed with TBME (3.5 volumes) and air dried for 2 days to give an off white solid. Yield 95% of theoretical.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:58][C@H:59]1[CH:64]2[CH2:65][CH2:66][N:61]([CH2:62][CH2:63]2)[CH2:60]1>>[CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:58][C@H:59]5[CH:64]6[CH2:65][CH2:66][N:61]([CH2:62][CH2:63]6)[CH2:60]5)=[O:29])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N[C@@H]1CN2CCC1CC2
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)N[C@@H]2CN3CCC2CC3)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and (S)-(−)-3-aminoquinuclidine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10-1.42 (m, 3 H) 1.57-1.92 (m, 12 H) 2.71-89 (m, 4 H) 2.96 (m, 1 H) 3.13 (m, 1 H) 3.31 (s, 3 H) 3.95 (s, 3 H) 3.97-4.10 (m, 2 H) 4.45 (m, 1 H) 7.47 (d, J=8.0 Hz, 1 H) 7.50 (s, 1 H) 7.93 (s, 1 H) 8.19 (d, 1 H) 8.21 (s, 1 H) 8.26 (d, J=8.0 Hz, 1 H). [M+H] calculated for C29H37F2N7O3, 570; found 570.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])=[CH:10][CH:9]=1)=[O:6].[OH-].[NH4+:26]>>[F:23][C:17]1[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=1[CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[CH2:4][C:3]([NH2:26])=[O:2])=[CH:9][CH:10]=1
Reactant: [NH4+]
Reactant: COC(=O)CC(=O)Nc1ccc(OCc2ccc(F)cc2F)cc1
Agent: [OH-]
Product: NC(=O)CC(=O)Nc1ccc(OCc2ccc(F)cc2F)cc1
Yield: 49 %

Procedure:
Prepared in analogy to example 3 from N-[4-(2,4-difluoro-benzyloxy)-phenyl]-malonamic acid methyl ester and ammonium hydroxide. Yield=49%. Colorless solid. MS: m/e=321.1 (M++H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH2:9][CH2:8]2)(=[O:3])[CH3:2].[Br:14]Br>C(O)(=O)C.O>[C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[Br:14])[CH2:10][CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: BrBr
Reactant: CC(=O)Nc1ccc2c(c1)CCC2
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1cc2c(cc1Br)CCC2
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 80 %

Procedure:
To a solution of 5-acetylaminoindane (53.0 g, 0.30 mol) in glacial acetic acid (1 L) at 10° C. was added dropwise over a period of 1 h a solution of bromine (19.0 mL, 0.37 mol). The mixture was further stirred at 10° C. for 15 min, and was then diluted with water until no more precipitate formed. The precipitate was collected, washed with water and dried under vacuum to give 61 g (80%) of the title compound.
Reaction SMILES: CN([CH:4]([CH3:15])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[F:14])=O)C.[NH2:16]/[C:17](/[CH3:24])=[CH:18]\[C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[F:14][C:8]1[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=1[C:5]1[CH:4]=[CH:15][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:17]([CH3:24])[N:16]=1
Reactant: CCOC(=O)/C=C(/C)N
Reactant: CC(C(=O)c1ccc(F)cc1F)N(C)C
Product: CCOC(=O)c1ccc(-c2ccc(F)cc2F)nc1C

Procedure:
The title compound was prepared from dimethylamino-(2,4-difluorophenyl)-propan-1-one and ethyl 3-aminocrotonate using the general procedure outlined in D18. 1H NMR (250 MHz, CDCl3) δ (ppm): 8.25 (d, 1H), 8.13 (dt, 1H), 7.67 (dd, 1H), 6.86-7.05 (m, 2H), 4.40 (q, 2H), 2.90 (s, 3H), 1.41 (t, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=2[OH:16])=[CH:4][CH:3]=1.[C:17]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])[NH:18][NH2:19].CN(C)C1C2C(=CC=CC=2N(C)C)C=CC=1>>[C:22]([O:21][C:17]([NH:18][NH:19][C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=2[OH:16])=[CH:4][CH:3]=1)=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: COc1ccc(-c2ccc(Cl)nn2)c(O)c1
Reactant: CC(C)(C)OC(=O)NN
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Product: COc1ccc(-c2ccc(NNC(=O)OC(C)(C)C)nn2)c(O)c1

Procedure:
i. A mixture of 6-chloro-3-(2-hydroxy-4-methoxyphenyl)-pyridazine, t-butyl carbazate and 1,8-bis-(dimethylamino)-naphthalene was heated for 2 hours to give 6-(2-t-butyloxycarbonylhydrazino)-3-(2-hydroxy-4-methoxyphenyl)pyridazine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH3:18])=[C:6]([CH:16]=1)[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)=[O:8].Br[C:20]1C=CC(OC)=CC=1C>>[Br:1][C:2]1[C:3]([CH3:20])=[CH:4][C:5]([O:17][CH3:18])=[C:6]([CH:16]=1)[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)=[O:8]
Reactant: COc1ccc(Br)c(C)c1
Reactant: COc1ccc(Br)cc1C(=O)c1ccc(C)cc1
Product: COc1cc(C)c(Br)cc1C(=O)c1ccc(C)cc1

Procedure:
Employing the same general procedure as for the preparation 5-bromo-2-methoxy-4'-methylbenzophenone (Compound H), 780 mg (3.9 mmol) of 4-bromo-1-methoxy-3-methylbenzene (Compound E) was converted into the title compound using 260 mg (1.9 mmol) of aluminum chloride, 0.6 mL (0.7 g, 4.7 mmol) of p-toluoyl chloride and 17 mL of dichloromethane. Purification by flash chromatography (silica, 5% ethyl acetate in hexane) gave the title compound as a white solid.
Reaction SMILES: O.[OH-].[Li+].[F:4][C:5]1[CH:10]=[CH:9][C:8](/[C:11](=[N:22]/[O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]3[N:34]=[C:35]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[O:36][C:37]=3[CH3:38])=[CH:27][CH:26]=2)/[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]C)=[O:19])=[CH:7][CH:6]=1.O.Cl>O1CCCC1.CO>[F:4][C:5]1[CH:6]=[CH:7][C:8](/[C:11](=[N:22]/[O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]3[N:34]=[C:35]([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[O:36][C:37]=3[CH3:38])=[CH:27][CH:26]=2)/[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:9][CH:10]=1
Reactant: COC(=O)CCCCCC/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1ccc(F)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\CCCCCCC(=O)O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.1 %

Procedure:
Lithium hydroxide monohydrate (157 mg) was added to a solution of methyl E-8-(4-fluorophenyl)-8-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]octanoate (700 mg) in tetrahydrofuran (10 ml)-water (4 ml)-methanol (4 ml) and stirred at room temperature for 3 hours. 1N hydrochloric acid (3.8 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-8-(4-fluorophenyl)-8-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]octanoic acid (608 mg, yield 89%) as colorless crystals. m.p. 79-80° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([F:20])[CH:10]=1.[Br:21]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>CN(C)C=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:21])=[CH:4][C:3]=1[NH:8][C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([F:20])[CH:10]=1
Reactant: CCOC(=O)c1ccc(Nc2ccccc2N)cc1F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Nc2cc(Br)ccc2N)cc1F
Reaction time: 2 h
Yield: 68.2 %

Procedure:
179 mg ethyl 4-(2-amino-phenylamino)-2-fluoro-benzoate (compound in Production Example 332) was dissolved in 4 mL N,N-dimethylformamide, and 116 mg N-bromosuccinimide was added thereto under ice-cooling and stirred for 2 hours. An aqueous sodium thiosulfate solution and an aqueous sodium bicarbonate solution were added thereto and stirred for 1 hour, and the reaction mixture was extracted with ethyl acetate. The extract was purified by NH silica gel chromatography (ethyl acetate/hexane), to give 157 mg of the title compound as a red oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](Br)=[C:10]([NH2:13])[N:9]=[C:8]([CH:14]2[CH2:16][CH2:15]2)[N:7]=1)=[O:5])[CH3:2].[CH3:17][Sn](C)(C)C>ClCCCl.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>[CH2:1]([O:3][C:4]([C:6]1[C:11]([CH3:17])=[C:10]([NH2:13])[N:9]=[C:8]([CH:14]2[CH2:16][CH2:15]2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(C2CC2)nc(N)c1Br
Reactant: C[Sn](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCCl
Product: CCOC(=O)c1nc(C2CC2)nc(N)c1C
Temperature: 150 °C
Yield: 49.9 %

Procedure:
6-Amino-5-bromo-2-cyclopropylpyrimidine-4-carboxylic acid ethyl ester (300 mg, 1.05 mmol; see WO 2005/063721 A1 for preparation), tetramethyltin (937 mg, 5.24 mmol), and bis(triphenylphosphine)palladium(II) dichloride (74 mg, 0.105 mmol) were combined in 5 mL of 1,2-dichloroethane and heated in a CEM microwave reactor at 150° C. for 20 min. The resulting reaction mixture was filtered and concentrated. The product was purified by flash chromatography on silica gel (ethyl acetate/hexane gradient) followed by a purification by reverse phase chromatography to yield the title compound (116 mg, 50% yield): mp 130-132° C.: 1H NMR (DMSO-d6) δ 6.85 (br s, 2H), 4.27 (q, 2H), 1.94 (s, 3H), 1.87 (m, 1H), 1.28 (t, 3H), 0.84 (d, 4H).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([CH2:5][C:6](=O)[CH3:7])=O.[CH3:11][NH:12][NH2:13]>>[CH3:11][N:12]1[C:6]([CH3:7])=[CH:5][C:3]([C:2]([F:10])([F:9])[F:1])=[N:13]1
Reactant: CNN
Reactant: CC(=O)CC(=O)C(F)(F)F
Product: Cc1cc(C(F)(F)F)nn1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.1 %

Procedure:
Into 100 ml of an ethanolic solution of 25 g (0.16 mol) of trifluoroacetylacetone, there was added dropwise 7.4 g (0.16 mol) of methylhydrazine. After stirring at room temperature for 3 hours, the mixture was left to stand overnight and the solvent was evaporated to give 19.2 g of 1,5-dimethyl-3-trifluoromethylpyrazole as an oil. Following then the procedures as Reference example 1, this product was allowed to react with chlorosulfonic acid and then with thionyl chloride to obtain 29 g of 1,5-dimethyl-3-trifluoromethylpyrazole-4-sulfonyl-chloride, which was in turn reacted with aqueous ammonia (28%) in tetrahydrofuran to give 21.5 g of 1,5-dimethyl-3-trifluoromethylpyrazole-4-sulfonamide melting at 204°-206° C.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]#[N:5].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([SH:13])=[CH:9][CH:8]=1.[OH-].[Na+]>O>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:2][CH2:3][C:4]#[N:5])=[CH:9][CH:8]=1
Reactant: N#CCCCl
Reactant: Sc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N#CCCSc1ccc(Cl)cc1

Procedure:
10 ml of β-chloropropionitrile (0.13 mol) are added, whilst stirring at 70°-80° C, to a solution of 17.4 g (0.12 mol) of p-chlorothiophenol and 4.8 g of sodium hydroxide pellets in 50 ml of water. The mixture is kept at 80° C for half an hour. After cooling, it is extracted with ether and the extract is washed with water and dried. 22.5 g of 3-(p-chlorophenylthio)-propionitrile. Melting point = 53-54° C.
Reaction SMILES: [H-].[Na+].C([O:5][C:6](=[O:33])[C:7]([CH3:32])([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH:18]2[CH2:22][NH:21][C:20](=[O:23])[N:19]2[CH3:24])=[CH:11][CH:10]=1)C.[CH:34]([C:37]1[CH:44]=[CH:43][C:40]([CH2:41]Cl)=[CH:39][CH:38]=1)([CH3:36])[CH3:35]>CN(C=O)C>[CH:34]([C:37]1[CH:44]=[CH:43][C:40]([CH2:41][N:21]2[CH2:22][CH:18]([CH2:17][CH2:16][O:15][C:12]3[CH:11]=[CH:10][C:9]([CH2:8][C:7]([CH3:32])([O:25][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:6]([OH:33])=[O:5])=[CH:14][CH:13]=3)[N:19]([CH3:24])[C:20]2=[O:23])=[CH:39][CH:38]=1)([CH3:36])[CH3:35]
Reactant: CC(C)c1ccc(CCl)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CNC(=O)N2C)cc1)Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)c1ccc(CN2CC(CCOc3ccc(CC(C)(Oc4ccccc4)C(=O)O)cc3)N(C)C2=O)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 69.1 %

Procedure:
To a cooled (0° C.) suspension of NaH (24 mg, 0.60 mmol, 60% w/w in mineral oil) in DMF (1 ml) is added a solution of 2-Methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-phenoxy-propionic acid ethyl ester (128 mg, 0.30 mmol) in DMF (1.5 ml). After 5 minutes, the reaction mixture is removed from the cooling bath and stirred while warming to ambient temperature over 45 minutes. After the solution is cooled again to 0° C., 4-isopropylbenzyl chloride (126 mg, 0.75 mmol) is added in a single portion, the cooling bath removed, and the mixture stirred for 50 minutes. The reaction mixture is quenched with 1N HCl and extracted with ethyl acetate (2×). The organic extracts were washed with water, brine, dried (Na2SO4), and concentrated to an oil. The crude product is dissolved in ethanol (4 ml), treated with 5N NaOH (1.5 ml), and stirred for 24 hours at ambient temperature. The mixture is poured into 1N HCl, then extracted with ethyl acetate (2×20 ml). The combined ethyl acetate extracts were washed with water, brine, dried (Na2SO4), and concentrated to an oil which is purified by MS/LC to provide a foam (110 mg, 69%).