Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:22]([O:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][N:32]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>>[CH2:15]([O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[N:6]=[N:7][C:2]([C:34]3[CH:33]=[N:32][C:31]([O:30][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:36][CH:35]=3)=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCCCCCCCOc1ccc(B(O)O)cn1
Reactant: Clc1ccc(-c2ccc(OCc3ccccc3)cc2)nn1
Product: CCCCCCCCOc1ccc(-c2ccc(-c3ccc(OCc4ccccc4)cc3)nn2)cn1
Yield: 69.3 %

Procedure:
In accordance with scheme D, 14 g (47.2 mmol) of 6-chloro-3-(4-benzyloxyphenyl)pyridazine are reacted analogously to Example 4a with 11.8 g (47.2 mmol) of 2-octyloxypyridine-5-boronic acid to give 15.3 g of 3-(4-benzyloxyphenyl)-6-(6-octyloxypyridin-3-yl)pyridazine.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[NH:26][CH:25]=[CH:24]5)[N:17]=3)[S:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]1([C:7]2[CH:8]=[C:9]([C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[N:26]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:25]=[CH:24]5)[N:17]=3)[S:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCBr
Reactant: FC(F)(F)c1sc(-c2nc(-c3ccc4[nH]ccc4c3)no2)cc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCn1ccc2cc(-c3noc(-c4cc(-c5ccccc5)c(C(F)(F)F)s4)n3)ccc21

Procedure:
5-{5-[4-phenyl-5-(trifluoromethyl)-2-thienyl]-1,2,4-oxadiazol-3-yl}-1H-indole (D2) (600 mg), ethyl 3-bromopropanoate (374 μl), caesium carbonate (950 mg) and DMF were heated at 140° C. for 1 hour in a microwave reactor. A further 1 eq. of ethyl 3-bromopropanoate (187 μl) was added and the mixture heated for 30 minutes. The reaction mixture was then evaporated, dissolved in DCM and filtered to give the title compound (650 mg) as a brown solid. δH (CDCl3, 400 MHz): 1.21 (3H, t), 2.85 (2H, t), 4.13 (2H, q), 4.50 (2H, t), 6.61 (1H, d), 7.22 (1H, d), 7.44-7.52 (6H, m), 7.89-7.92 (1H, m), 7.98-8.02 (1H, m), 8.45-8.46 (1H, m). MS (ES): C26H20F3N3O3S requires 511; found 512 (MH+).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([C:7]1[CH:14]=[CH:13][C:10]([CH2:11]Br)=[CH:9][CH:8]=1)#[N:6]>CN(C=O)C.O>[N:1]([CH2:11][C:10]1[CH:13]=[CH:14][C:7]([C:5]#[N:6])=[CH:8][CH:9]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(CBr)cc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(CN=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.2 %

Procedure:
Sodium azide (Aldrich, 3.5 g, 54 mmol) was added to a solution of p-cyanobenzyl bromide (Aldrich, 10 g, 51 mmol) in DMF (100 ml), and the resulting mixture was stirred at ambient temperature for 5 hours. The reaction mixture was then diluted with water (350 ml) and extracted with ether (2×100 ml). Combined organic layers were washed with brine and dried (MgSO4). Removal of solvent gave the title compound (8 g, 96%). 1H NMR (CDCl3): δ 4.42 (s, 2H), 7.41 (d, 2H, J=8.1 Hz), 7.65 (d, 2H, J=8.1 Hz).
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([O:9][C:10]2[N:14]([CH3:15])[N:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:6]=[N:7][CH:8]=1.P(Br)(Br)([Br:22])=O.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Br:22][C:3]1[CH:4]=[C:5]([O:9][C:10]2[N:14]([CH3:15])[N:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:6]=[N:7][CH:8]=1
Reactant: COc1cnnc(Oc2cc(C(F)(F)F)nn2C)c1
Reactant: O=P(Br)(Br)Br
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cn1nc(C(F)(F)F)cc1Oc1cc(Br)cnn1
Yield: 46.8 %

Procedure:
5-Methoxy-3-[[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]oxy]pyridazine(Compound No. 5, 5.0 g, 0.0182 mole) and phosphorus oxybromide (5.7 g, 0.02 mole) were refluxed under N2 in toluene (100 mL) for 3.5 hours. The mixture was poured into ethyl acetate and extracted 2×200 mL with water. The organic layer was then extracted with saturated sodium bicarbonate, brine, dried (MgSO4), filtered and evaporated in vacuo to give a crude oil. The oil was purified by chromatography on silica gel to give 5-bromo-3-[[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5yl]oxy]pyridazine (2.75 g, 47% yield) as a brown solid which was used directly in the following step.
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](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[F:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[CH2:24][CH2:25][NH2:26]>>[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]([NH:26][CH2:25][CH2:24][C:23]2[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=2[F:21])=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: NCCc1ccccc1F
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(NCCc1ccccc1F)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (150 mg, 0.41 mmol) and 2-fluoro-phenethylamine (67.9 mg, 0.49 mmol). The title compound was obtained as a solid (35 mg, 18% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.98 (2H, m), 8.97 (1H, m), 8.37 (1H, s), 7.27 (2H, m), 7.16 (2H, m), 3.44 (2H, m), 2.82 (2H, m). MS m/z: 470.00, 472.01 [M+H]+.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][N:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[CH2:2]1.Cl.[NH2:15][OH:16]>>[O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][N:7]2[CH2:12][CH2:11][C:10](=[N:15][OH:16])[CH2:9][CH2:8]2)[CH2:2]1
Reactant: NO
Reactant: O=C1CCN(CC2CCOC2)CC1
Agent: Cl
Product: ON=C1CCN(CC2CCOC2)CC1

Procedure:
1-(3-Tetrahydrofuranylmethyl)-4-piperidone oxime is prepared from 1-(3-tetrahydrofuranylmethyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.[N+:9]([O-])([OH:11])=[O:10]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[C:4]([CH3:8])[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1cccc(F)c1
Product: Cc1cc(F)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of 200 g of 3-fluorotoluene and 670 ml of concentrated nitric acid was heated at 50°-55° for 8 hours; after standing overnight, the reaction mixture was poured into 1200 ml of ice-water. The organic layer was separated, and the aqueous layer was extracted three times with ether; the organic fraction and the ethereal extracts were combined, washed once with water and saturated sodium chloride solution. The combined organic fraction was dried over magnesium sulfate, filtered, and evaporated under reduced pressure to give a yellow oil. This crude product was distilled using a 30-cm vacuum-jacketed column filled with glass helices to yield 192.7 g of 5-fluoro-2-nitrotoluene, bp 74.5°-77°/4 mm.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[F:28][C:29]([F:39])([F:38])[O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[NH2:37]>>[NH2:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:23])([CH3:24])[C@:12]([C:15]2[CH:20]=[C:19]([NH:37][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[O:30][C:29]([F:28])([F:38])[F:39])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: Nc1ccccc1OC(F)(F)F
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Br)ccc2F)N=C1NC(=O)OC(C)(C)C
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Nc3ccccc3OC(F)(F)F)ccc2F)N=C1N

Procedure:
The coupling of [(S)-4-(5-bromo-2-fluoro-phenyl)-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (intermediate E8) and o-(trifluoromethoxy)phenylamine according to procedure A followed by deprotection yielded the title compound as a white solid. MS (ESI): m/z=439.3 [M+H]+.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[N:16]1([C:22](=[O:24])[CH3:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>CN(C)C=O.CCOC(C)=O>[C:22]([N:16]1[CH2:21][CH2:20][N:19]([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:18][CH2:17]1)(=[O:24])[CH3:23]
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(c2ccc(C=O)cc2)CC1
Temperature: 130 °C
Reaction time: 16 h
Yield: 63.8 %

Procedure:
To a solution of 4-fluorobenzaldehyde (5 g, 40.2 mmol) in N,N-dimethylformamide (130 mL) was added potassium carbonate (8.35 g, 60.4 mmol) and 1-piperazin-1-ylethanone (10.3 g, 80.5 mmol) and the reaction was stirred at 130° C. for 16 hours. The reaction was then cooled to ambient temperature, diluted with EtOAc and washed with water (×2) and brine. The organic layer was then dried with MgSO4, concentrated and purified by silica gel column chromatography (0-10% methanol in dichloromethane) to give 4-(4-acetylpiperazin-1-yl)benzaldehyde (5.96 g, 64% yield). LCMS (m/z) ES+ 233 [M+1]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[N+:12]([C:15]1[CH:16]=[C:17]([OH:24])[CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])([O-:14])=[O:13]>C(Cl)Cl.[OH-].[Na+]>[N+:12]([C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[O:24][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1)([O-:14])=[O:13]
Reactant: Clc1ccnc2ccccc12
Reactant: O=[N+]([O-])c1ccc(O)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(Oc2ccnc3ccccc23)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
4-Chloroquinoline (4.3 g, 26.3 mmol) and 3,4-dinitrophenol (41.5 g, 24.4 mmol) were heated at 150° C. for 30 min. The mixture was cooled to RT and the residue was dissolved in CH2Cl2. The mixture was diluted in NaOH 2 M and extracted with CH2Cl2. The organic phase was dried, filtered and evaporated. The residue was diluted in EtOAc and filtered through a silica pad. The solvent was removed to give the title compound as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([NH2:10])[CH2:7][N:6]1[CH2:11][CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:4].[OH:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[C:28](O)=[O:29]>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([NH:10][C:28]([C:19]2[CH:20]=[CH:21][C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:18]=2[OH:17])=[O:29])[CH2:7][N:6]1[CH2:11][CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@H](N)CN1CCC(C)(C)C
Reactant: O=C(O)c1ccc2ccccc2c1O
Product: COC(=O)[C@@H]1C[C@H](NC(=O)c2ccc3ccccc3c2O)CN1CCC(C)(C)C

Procedure:
(2S,4S)-1-(3,3-Dimethyl-butyl)-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic acid methyl ester was prepared from (2S,4S)-4-amino-1-(3,3-dimethyl-butyl)-pyrrolidine-2-carboxylic acid methyl ester and 1-hydroxy-naphthalene-2-carboxylic acid in an analogous manner to example 1. MS calcd. for C23H31N2O4 [(M+H)+] 399.0, obsd. 399.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]([OH:13])=[O:12])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21]O)=[CH:19][CH:18]=1)([O-:16])=[O:15].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21][O:12][C:11](=[O:13])[CH2:10][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH3:9])=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CN(CC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
Subsequently, to a solution of (N-t-butoxycarbonyl-N-methyl-amino)acetic acid (2.52 g, 13.3 mmol) and p-nitrobenzyl alcohol (4.07 g, 26.6 mmol) in methylene chloride (125 ml) were added WSC (5,10 g, 26.6 mmol) and 4-dimethylaminopyridine (252 mg, 1.33 mmol) in an ice bath under an atmosphere of nitrogen, and the mixture was stirred at room temperature overnight. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (1:1) as the eluant to afford (N-t-butoxycarbonyl-N-methyl-amino)acetic acid p-nitrobenzyl ester (4.30 g, yield 88%) as a pale yellow oil.
Reaction SMILES: [O-]CC.[Na+].[Na].[CH3:6][CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH2:18]=[C:19]1[C:24](=[O:25])[CH:23]2[CH2:26][CH2:27][N:20]1[CH2:21][CH2:22]2>C(O)C.C(O)(=O)C>[O:25]=[C:24]1[CH:23]2[CH2:26][CH2:27][N:20]([CH2:21][CH2:22]2)[CH:19]1[CH2:18][C:7]([CH3:6])([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: C=C1C(=O)C2CCN1CC2
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(C)(CC1C(=O)C2CCN1CC2)C(=O)OCC
Reaction time: 16 h

Procedure:
Ethanolic sodium ethoxide, previously prepared from 2.9 g of metallic sodium and 100 ml of ethanol, was added to diethyl methyl-malonate, 50 g, and the mixture was refluxed for 30 min. then cooled to 5°. A solution of 2-methylenequinuclidin-3-one, 39.4 g, in ethanol, 50 ml, was then added dropwise and with stirring. After 16 hrs. at room temperature, the resulting solution was neutralized with acetic acid then subjected to evaporation at reduced pressure. Water, 100 ml was added and the mixture was extracted with chloroform. Evaporation of this solvent gave diethyl (3-oxo quinuclidin-2-yl)-methyl-methylmalonate, 72 g (81%), m.p., 58.4° (from petroleum ether). A solution of the foregoing compound, 72 g, in ethanol, 50 ml, was treated at 5° and with stirring with a solution of sodium borohydride, 3.55 g, in ethanol, 600 ml. The borohydride solution was added in small increments over a period of six hours. After 20 hours, the mixture was neutralized with concentrated hydrochloric acid, then subjected to evaporation at reduced pressure. The residue was taken up in 200 ml of water and extracted with chloroform. Evaporation of this solvent left a syrupy residue, 55 g, which consisted of the compound diethyl (3-hydroxyquinucldin-2-yl)methyl-methylmalonate; its methiodide salt, prepared with methyl iodide in acetone, has a m.p. of 228.2°.
Reaction SMILES: C(OC([N:8]1[CH2:26][CH2:25][CH:11]2[N:12]([CH3:24])[C:13]3[C:14]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:16]([OH:19])=[CH:17][C:18]=3[CH:10]2[CH2:9]1)=O)(C)(C)C.Br[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:24][N:12]1[C:13]2[C:14]([C:20]([F:21])([F:23])[F:22])=[CH:15][C:16]([O:19][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)=[CH:17][C:18]=2[CH:10]2[CH2:9][NH:8][CH2:26][CH2:25][CH:11]12
Reactant: CN1c2c(cc(O)cc2C(F)(F)F)C2CN(C(=O)OC(C)(C)C)CCC21
Reactant: BrCc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1c2c(cc(OCc3ccccn3)cc2C(F)(F)F)C2CNCCC21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
8-Hydroxy-5-methyl-6-trifluoromethyl-1,3,4,4a,5,9b-hexahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester (1.0 eq.), bromomethylpyridine (2.0 eq.), and K2CO3 (4.0 eq.) were dissolved in anhydrous DMF(0.3 M). The mixture was stirred under Ar at rt for 24 h. Same work up and deprotection procedure were followed as described in Example 74 Method A and B to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[H-].[Na+].Br[C:14]1[N:19]=[CH:18][C:17]([Br:20])=[CH:16][N:15]=1>C1COCC1>[Br:20][C:17]1[CH:16]=[N:15][C:14]([O:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[N:19][CH:18]=1
Reactant: OCCc1ccc(F)cc1
Reactant: Brc1cnc(Br)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1ccc(CCOc2ncc(Br)cn2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.1 %

Procedure:
To a solution of 2-(4-fluorophenyl)ethanol (0.566 g) in THF (10 mL) was added NaH (0.269 g). The mixture was stirred at room temperature for 2 hours, before 2,5-dibromopyrimidine (0.8 g) was added. The mixture was stirred at room temperature for 16 h. The reaction was quenched with water and extracted with EtOAc (2×20 mL). The organic layers were combined, dried over MgSO4 and concentrated under vacuum. The residue was purified by silica gel column (Hex/EtOAc=100:5) to give 5-bromo-2-(4-fluorophenethoxy)pyrimidine (0.7 g). LCMS (M+H)=297.0.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][CH3:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH:20][C:21](=[O:40])[CH2:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:32]=[N:33][C:34]([CH:37]3[CH2:39][CH2:38]3)=[CH:35][CH:36]=2)[CH:26]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:37]1([C:34]2[N:33]=[CH:32][C:31]([C:27]3[CH:26]=[C:25]([C:23]4[CH2:22][C:21](=[O:40])[NH:20][C:9]5[CH:10]=[C:11]([C:16]([F:18])([F:19])[F:17])[C:12]([CH2:14][CH3:15])=[CH:13][C:8]=5[N:7]=4)[CH:30]=[CH:29][CH:28]=3)=[CH:36][CH:35]=2)[CH2:38][CH2:39]1
Reactant: CCc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccc(C4CC4)nc3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccc(C4CC4)nc3)c1)=N2

Procedure:
The title compound was prepared from (2-{3-[3-(6-cyclopropyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-5-ethyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M205) (201 mg, 0.35 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (98 mg, 62%).
Reaction SMILES: [N:1]1([CH2:5][CH2:6][C:7]2[N:11]([CH3:12])[N:10]=[N:9][C:8]=2[CH2:13][OH:14])[CH2:4][CH2:3][CH2:2]1.Cl[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]2=[N:26][N:27]=[C:28]([C:29]3[CH:33]=[C:32]([CH3:34])[O:31][N:30]=3)[N:18]2[N:17]=1>>[N:1]1([CH2:5][CH2:6][C:7]2[N:11]([CH3:12])[N:10]=[N:9][C:8]=2[CH2:13][O:14][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]3=[N:26][N:27]=[C:28]([C:29]4[CH:33]=[C:32]([CH3:34])[O:31][N:30]=4)[N:18]3[N:17]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: Cn1nnc(CO)c1CCN1CCC1
Reactant: Cc1cc(-c2nnc3c4ccccc4c(Cl)nn23)no1
Product: Cc1cc(-c2nnc3c4ccccc4c(OCc4nnn(C)c4CCN4CCC4)nn23)no1

Procedure:
The reaction was carried out according to Example 1 step 4 using [5-(2-(azetidin-1-yl)ethyl)-1-methyl-1H-[1,2,3]triazol-4-yl]methanol (103 mg, 0.53 mmol) and 6-chloro-3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[3,4-α]phthalazine (150 mg, 0.53 mmol). The crude residue was purified by column chromatography on silica using 2% MeOH/CH2Cl2 containing 1% NH3 to yield, after recrystallisation from CH2Cl2/iso-hexanes, the desired phthalazine (104 mg, 44%). 1H NMR (360 MHz, CDCl3) δ 8.68 (1H, d, J=7.9 Hz), 8.19 (1H, d, J=7.9 Hz), 7.95 (1H, t, J=7.9 Hz), 7.78 (1H, t, J=7.9 Hz), 6.95 (1H, s), 5.75 (2H, s), 4.07 (3H, s), 3.11 (4H, t, J=6.9 Hz), 2.84 (2H, t, J=7.1 Hz), 2.65-2.50 (5H, m), 1.99 (2H, quintet, J=6.9 Hz). m/z (ES+) 446 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:19]=[C:18]([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:17]=[CH:16][C:4]=1[O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1.N1C=CC=CC=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl.Cl>[C:24]([O:23][C:21](=[O:22])[CH2:20][C:18]1[CH:17]=[CH:16][C:4]([O:5][C:6]2[CH:7]=[CH:8][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:14][CH:15]=2)=[C:3]([CH2:2][NH:1][S:35]([CH3:34])(=[O:37])=[O:36])[CH:19]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: COC(=O)c1ccc(Oc2ccc(CC(=O)OC(C)(C)C)cc2CN)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(Oc2ccc(CC(=O)OC(C)(C)C)cc2CNS(C)(=O)=O)cc1
Reaction time: 12 h
Yield: 67.7 %

Procedure:
The product of step B (1.87 g, 5.03 mmol) was diluted with methylene chloride (2 mL) followed by the addition of pyridine (0.489 mL, 6.04 mmol) and methanesulfonyl chloride (0.779 mL, 10.1 mmol). After stirring for 12 hours, the reaction mixture was diluted with methylene chloride and 2N HCl, the layers were separated and the organic layer was dried over MgSO4, filtered and concentrated. The material was purified using a biotage 40M cartridge eluting with hexanes:ethyl acetate (1:1) to yield methyl 4-(4-(2-tert-butoxy-2-oxoethyl)-2-(methylsulfonamidomethyl)phenoxy)benzoate (1.53 g, 67.6% yield) as a clear oil.
Reaction SMILES: [O:1]=[C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][C:4]#[N:5].[S:12]1CC(O)S[CH2:14][CH:13]1O.C(NCC)C>C(O)C>[NH2:5][C:4]1[S:12][CH:13]=[CH:14][C:3]=1[C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:1]
Reactant: N#CCC(=O)c1ccccc1
Reactant: OC1CSC(O)CS1
Solvent: CCNCC
Solvent: CCO
Product: Nc1sccc1C(=O)c1ccccc1
Temperature: 50 °C
Yield: 41.3 %

Procedure:
Following a procedure described in J. Med. Chem. 2002, 45, 382-389; 1.45 g (10 mmol) 3-oxo-3-phenyl-propionitrile, 0.76 g (5.0 mmol) [1,4]dithiane-2,5-diol, 0.40 ml (10 mmol) diethylamine and 5 ml ethanol were charged in a sealed tube. The reaction mixture was heated at 50° C. for 6 h. The tube was then placed in a fridge (about 4° C.) for the night, and the product was collected by filtration and dried under vacuum to afford 0.42 g (23%) (2-amino-thiophen-3-yl)-phenyl-methanone as a light brown crystals. ES-MS m/e (%): 204 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=2[CH:27]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH2:29]([O:31][C:32](=[O:44])[C:33]1[CH:38]=[CH:37][C:36](Cl)=[N:35][C:34]=1[C:40]([F:43])([F:42])[F:41])[CH3:30].C1N2CCN(CC2)C1>>[CH2:29]([O:31][C:32](=[O:44])[C:33]1[CH:38]=[CH:37][C:36]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:28])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19]4[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=4[CH:27]=3)[C:11]([F:12])([F:13])[F:14])=[C:2]([Cl:1])[CH:7]=2)=[N:35][C:34]=1[C:40]([F:41])([F:42])[F:43])[CH3:30]
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Reactant: CCOC(=O)c1ccc(Cl)nc1C(F)(F)F
Agent: C1CN2CCN1CC2
Product: CCOC(=O)c1ccc(Oc2ccc(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c(Cl)c2)nc1C(F)(F)F

Procedure:
In analogy to Example 62, step 1, 6-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 56, Step 4) was reacted with 6-chloro-2-trifluoromethyl-nicotinic acid ethylester and DABCO (17 h, r.t.) to give the title compound as a white solid. MS (m/e)=633.2 [M+H+].
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3]1=[O:16].[O:17]=[C:18]1[N:27]([CH:28]2[CH2:33][CH2:32][N:31]([C:34](Cl)=[O:35])[CH2:30][CH2:29]2)[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19]1>>[CH2:9]([N:4]1[CH2:5][CH2:6][CH2:7][CH2:8][C@@H:2]([NH:1][C:34]([N:31]2[CH2:32][CH2:33][CH:28]([N:27]3[CH2:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[NH:19][C:18]3=[O:17])[CH2:29][CH2:30]2)=[O:35])[C:3]1=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: N[C@@H]1CCCCN(Cc2ccccc2)C1=O
Reactant: O=C(Cl)N1CCC(N2Cc3ccccc3NC2=O)CC1
Product: O=C(N[C@@H]1CCCCN(Cc2ccccc2)C1=O)N1CCC(N2Cc3ccccc3NC2=O)CC1

Procedure:
The title compound was prepared with (3R)-3-amino-1-benzylazepan-2-one and 4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)piperidine-1-carbonyl chloride using a similar procedure to Example 16. MS 476.2645 (M+1).