Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:15][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>C(O)C>[CH2:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH:2]([OH:1])[CH2:15][N:27]2[CH2:26][CH2:25][N:24]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[O:17][CH3:16])[CH2:29][CH2:28]2)=[CH:6][CH:7]=1)[C:12](=[O:14])[CH3:13]
Reactant: CC(=O)Cc1ccc(OCC2CO2)cc1
Reactant: COc1ccccc1N1CCNCC1
Solvent: CCO
Product: COc1ccccc1N1CCN(CC(O)COc2ccc(CC(C)=O)cc2)CC1
Yield: 61.2 %

Procedure:
30.0 g of 4-(2,3-epoxypropoxy)-phenylacetone and 25.6 g of 2-methoxyphenyl-piperazine are heated under reflux in 300 ml of ethanol for 3 hours. The solvent is then distilled off. The residue is made to crystallise with ethyl acetate/hexane. 32.5 g of 1-[4-(propan-2-on-yl)-phenoxy]-3-[4-(2-methoxyphenyl)-piperazin-1-yl]-propan-2-ol are obtained.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]([C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][C:22](OC)=[O:23])[CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.Cl>O1CCCC1.[Cl-].[Na+]>[O:7]([C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][CH2:22][OH:23])[CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)CCc1cccc(Oc2ccccc2)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: OCCCc1cccc(Oc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 96.5 %

Procedure:
Lithium aluminium hydride (60 cm3 of a 1M solution in tetrahydrofuran) was added dropwise over a period of 10 minutes to a stirred solution of methyl 3-(3-phenoxyphenyl)propanoate (25.6 g) in tetrahydrofuran (30 cm3) whilst the temperature was maintained at 0° C. by external cooling. Stirring was continued for a further 45 minutes after which the mixture was allowed to warm up to the ambient temperature (ca. 22° C.). Iced water was added carefully to the mixture which was then acidified with dilute hydrochloric acid at pH2. The mixture was diluted with saturated sodium chloride solution and extracted with diethyl ether (×4) and with ethyl acetate. The combined extracts were dried over anhydrous sodium sulphate and concentrated by evaporation of the solvent under reduced pressure to yield 3-(3-phenoxyphenyl)propan-1-ol (22 g, 100% by gas-liquid chromatography) as a colourless oil.
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][C:39]([NH:42][C:43](=[O:45])[CH3:44])=[CH:38][CH:37]=2)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].Cl.N1C=CC=CC=1>>[OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][C:39]([NH:42][C:43](=[O:45])[CH3:44])=[CH:38][CH:37]=2)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: CC(=O)Nc1ccc(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(-c2ccc(C(O)(c3c[nH]cn3)C(C)C)cc2)cc1
Yield: 20.6 %

Procedure:
By the reaction in the same manner as in Example 4-(iii) using N-{4′-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl][1,1′-biphenyl]-4-yl}acetamide (601 mg) and pyridine hydrochloride (0.17 g), the title compound (73 mg) was obtained as colorless powder crystals.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[C:6]([CH:21]=[CH:22][CH:23]=1)[O:7][CH2:8][C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])#[N:2]>N.[Ni]>[NH3:2].[NH2:2][CH2:1][CH2:3][C:4]1[CH:5]=[C:6]([CH:21]=[CH:22][CH:23]=1)[O:7][CH2:8][C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]([O:16][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cccc(CC#N)c1
Agent: [Ni]
Agent: N
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cccc(CCN)c1
Reaction time: 20 h
Yield: 112.6 %

Procedure:
A mixture of tert-butyl (2R)-2-{[3-(cyanomethyl)phenoxy]methyl}-1-pyrrolidinecarboxylate (preparation 133) (2.70 g, 8.54 mmol), and Raney® nickel (400 mg) in saturated ethanolic ammonia solution (100 ml), was hydrogentaed at 60 psi and room temperature for 20 hrs. The reaction mixture was filtered through a glass microfibre filter, and the filtrate evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol:0.88 ammonia (95:5:0.5 to 90:10:1) to afford the title compound, (1.54 g, 56%).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.CN(C)[CH:9]=[CH:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)=O>C(O)(=O)C>[CH3:20][O:19][C:15]1[CH:14]=[C:13]([C:11]2[N:3]3[N:4]=[CH:5][N:6]=[C:2]3[N:1]=[CH:9][CH:10]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: COc1cccc(C(=O)C=CN(C)C)c1
Reactant: Nc1nc[nH]n1
Solvent: CC(=O)O
Product: COc1cccc(-c2ccnc3ncnn23)c1

Procedure:
A mixture of 2.54 g. of 3-amino-1,2,4-triazole and 6.15 g. of 3-dimethylamino-3'-methoxyacrylophenone in 25 ml. of glacial acetic acid is refluxed for 6 hours. The resulting mixture is worked up as described in Example 54 to give the product of the Example, m.p. 163°-165° C.
Reaction SMILES: [F:1][C@:2]1([CH3:19])[C@H:6]([OH:7])[C@@:5]([F:10])([CH2:8][OH:9])[O:4][C@H:3]1[N:11]1[CH:16]=[CH:15][C:14](=[O:17])[NH:13][C:12]1=[O:18].C([Mg]Cl)(C)(C)C.Cl[C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]=1[O:37][P:38](=[N:40][C@@H:41]([CH3:48])[C:42]([O:44][CH:45]([CH3:47])[CH3:46])=[O:43])=[O:39].CO>C1COCC1>[CH:45]([O:44][C:42](=[O:43])[C@@H:41]([N:40]=[P:38]([O:37][C:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:35]=[CH:36][C:27]=1[O:9][CH2:8][C@:5]1([F:10])[C@@H:6]([OH:7])[C@:2]([F:1])([CH3:19])[C@H:3]([N:11]2[CH:16]=[CH:15][C:14](=[O:17])[NH:13][C:12]2=[O:18])[O:4]1)=[O:39])[CH3:48])([CH3:46])[CH3:47]
Reactant: CC(C)OC(=O)[C@H](C)N=[P+]([O-])Oc1c(Cl)ccc2ccccc12
Reactant: C[C@]1(F)[C@H](n2ccc(=O)[nH]c2=O)O[C@](F)(CO)[C@H]1O
Agent: CC(C)(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)OC(=O)[C@H](C)N=[P+]([O-])Oc1c(OC[C@@]2(F)O[C@@H](n3ccc(=O)[nH]c3=O)[C@](C)(F)[C@@H]2O)ccc2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 62.3 %

Procedure:
To a solution of chiral 1-((2R,3R,4S,5S)-3,5-difluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione (150 mg, 539 μmol) prepared in Preparation 6 in THF (24 ml) was added a THF solution (Aldrich, 1 M) of tert-butylmagnesium chloride (1.35 mL, 1.35 mmol) dropwise. The mixture was stirred at room temperature for 15 min, followed by the addition of THF solution (0.5 M) of (2S)-isopropyl 2-(chloro(naphthalen-1-yloxy)phosphorylamino)propanoate (2.7 mL, 1.35 mmol). The reaction mixture was stirred at room temperature for 1 h, then additional THF solution (Aldrich, 1 M) of tert-butylmagnesium chloride (0.68 mL, 0.68 mmol) and THF solution (0.5 M) of (2S)-isopropyl 2-(chloro(naphthalen-1-yloxy)phosphorylamino)propanoate (1.35 mL, 0.68 mmol) were added. The reaction mixture was then stirred at room temperature for 3 h. Methanol (6 mL) was added to quench the reaction. The mixture was purified by flash chromatography (silica gel, 0-15% MeOH in DCM) and dried in vacuo to give the title compound as a white solid (0.2 g, 62%).
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][Si](C)(C)C)=[O:11])(OCC)=O)C.C([Li])CCC.[N+:22]([C:25]1[CH:54]=[C:53]([N+:55]([O-:57])=[O:56])[CH:52]=[CH:51][C:26]=1[O:27][CH2:28][C:29]([F:50])([F:49])[C:30]([F:48])([F:47])[C:31]([F:46])([F:45])[C:32]([F:44])([F:43])[CH2:33][O:34][C:35]1[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=1)([O-:24])=[O:23]>O1CCCC1.CCCCCC.O>[N+:22]([C:25]1[CH:54]=[C:53]([N+:55]([O-:57])=[O:56])[CH:52]=[CH:51][C:26]=1[O:27][CH2:28][C:29]([F:49])([F:50])[C:30]([F:47])([F:48])[C:31]([F:45])([F:46])[C:32]([F:43])([F:44])[CH2:33][O:34][C:35]1[CH:36]=[CH:37][C:38]([CH:39]=[CH:9][C:10]([OH:12])=[O:11])=[CH:41][CH:42]=1)([O-:24])=[O:23]
Reactant: O=Cc1ccc(OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)COc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc1
Reactant: CCOP(=O)(CC(=O)O[Si](C)(C)C)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: O=C(O)C=Cc1ccc(OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)COc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc1
Reaction time: 2 h

Procedure:
To a mixture of trimethylsilyl diethylphosphonoacetate (2.97 g) in anhydrous tetrahydrofuran (100 mL) at 0° C. is added 1.6 M solution of butyllithium in hexane (6.9 mL). The reaction is stirred for 2 hrs. at room temperature and then treated with 4-[6-(2,4-dinitrophenoxy)-2,2,3,3,4,4,5,5-octaflurohexyloxy]benzaldehyde (5.32 g) in anhydrous tetrahydrofuran (30 mL). The mixture is stirred for a further 2 hrs., diluted with water and extracted with ethyl ether. The extracts are washed with water and brine, dried (MgSO4), concentrated, and purified by crystallization to give 4-[6-(2,4-dinitrophenoxy)-2,2,3,3,4,4,5,5-octaflurohexyloxy]cinnamic acid. The acid is converted to the methyl ester by treatment with diazomethane in ether solution.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][C@H:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([OH:32])=[O:31])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[C:4]([Cl:34])[N:3]=1.Cl.[NH2:36][OH:37].C([O-])(O)=O.[Na+]>>[Cl:34][C:4]1[CH:5]=[C:6](/[C:8](=[N:36]/[OH:37])/[CH2:9][C@H:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([OH:32])=[O:31])=[CH:28][CH:29]=3)=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:7]=[C:2]([Cl:1])[N:3]=1
Reactant: NO
Reactant: Cc1ccccc1[C@H](CC(=O)c1cc(Cl)nc(Cl)c1)c1ccc(-c2ccc(C(=O)O)cc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1[C@H](C/C(=N\O)c1cc(Cl)nc(Cl)c1)c1ccc(-c2ccc(C(=O)O)cc2)cc1

Procedure:
In analogy to example 132, step 6, from (R)-4′-(3-(2,6-dichloropyridin-4-yl)-3-oxo-1-o-tolylpropyl)biphenyl-4-carboxylic acid and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as an off-white foam, MS (ESI−): m/z=503.09 ([M−H]−, 1Cl).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[N:11]1[CH2:22][CH2:21][C:14]2([C:19](=[O:20])[NH:18][CH2:17][CH2:16][CH2:15]2)[CH2:13][CH2:12]1.[H-].[Na+].Cl[CH2:26][C:27]1[CH:28]=[C:29]([C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)[CH:30]=[CH:31][CH:32]=1>C1COCC1>[N:35]1[CH:36]=[CH:37][CH:38]=[C:33]([C:29]2[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=2)[CH2:26][N:18]2[CH2:17][CH2:16][CH2:15][C:14]3([CH2:21][CH2:22][N:11]([C:2]4[CH:3]=[N:4][C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[N:1]=4)[CH2:12][CH2:13]3)[C:19]2=[O:20])[CH:34]=1
Reactant: ClCc1cccc(-c2cccnc2)c1
Reactant: O=C1NCCCC12CCN(c1cnc3ccccc3n1)CC2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1N(Cc2cccc(-c3cccnc3)c2)CCCC12CCN(c1cnc3ccccc3n1)CC2
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 44.9 %

Procedure:
To a stirred solution of 9-(quinoxalin-2-yl)-2,9-diazaspiro[5.5]undecan-1-one (0.035 g, 0.12 mmol) in dry THF (4.0 mL), NaH (0.014 g, 0.36 mmol) was added at rt and the mixture was stirred for 10 min. 3-(3-Chloromethyl-phenyl)-pyridine (0.05 g, 0.24 mmol) was then added and the reaction mixture was heated to 60° C. for 6 h. The mixture was quenched with 1 ml saturated aqueous NH4Cl solution, diluted with 50 ml water and the resulting mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with water and brine. The organic layer was dried over Na2SO4, filtered and concentrated to obtain the crude product. Preparative HPLC purification furnished the title compound as a pale yellow sticky solid (0.025 g, 46%). [1H-NMR (CDCl3, 300 MHz): δ 8.84-8.81 (m, 1H), 8.66-8.58 (m, 2H), 7.92-7.81 (m, 2H), 7.72-7.65 (m, 1H), 7.35-7.61 (m, 6H), 4.68 (s, 2H), 4.31-4.20 (m, 2H), 3.70-3.55 (m, 2H), 3.31 (t, 2H), 2.43-2.29 (m, 2H), 1.96-1.82 (m, 4H), 1.75-1.63 (dt, 2H); HPLC RtA=4.635 min (96%); LCMS RtC=0.395, [M+H]+=464.0].
Reaction SMILES: [CH3:1][C:2]12[O:10][CH:6]([CH:7]([CH3:9])[O:8]1)[CH2:5][CH2:4][CH:3]2[OH:11].[CH2:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O1CCCC(O)C1>>[CH3:1][C:2]12[O:10][CH:6]([CH:7]([CH3:9])[O:8]1)[CH2:5][CH2:4][CH:3]2[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC1OC2(C)OC1CCC2O
Reactant: ClCc1ccccc1
Agent: OC1CCCOC1
Product: CC1OC2(C)OC1CCC2OCc1ccccc1

Procedure:
18A was treated with benzyl chloride, by the procedure described for treatment of 1A, to give 18, as a liquid, b.p.: 145° C., 0.06 Torr.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:15][CH:14]([CH3:16])[C:13]2[C:12]3[C:17](=O)[CH2:18][CH:19]([C:20]([F:23])([F:22])[F:21])[C:11]=3[S:10][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].[BH4-].[Na+].Cl.Cl[Sn]Cl>CCO.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:15][CH:14]([CH3:16])[C:13]2[C:12]3[CH2:17][CH2:18][CH:19]([C:20]([F:22])([F:23])[F:21])[C:11]=3[S:10][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2sc3c(c2C(C)C1)C(=O)CC3C(F)(F)F
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [BH4-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)N1CCc2sc3c(c2C(C)C1)CCC3C(F)(F)F
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
The product of step (d) (mixture of diastereomers, 234 mg, 1.54 mmol) was dissolved in 5 mL EtOH and treated with NaBH4 (117 mg, 3.1 mmol). After stirring for 15 minutes, the reaction was quenched with HOAc and diluted with water (10 mL). The product was extracted into DCM (2×25 mL) and the extracts were concentrated to dryness. The crude residue was dissolved in HOAc (8 mL) and concentrated HCl (4 mL) and treated with SnCl2 (1.4 g, 6.2 mmol). After heated to 80° C. for 1 hour, the reaction was cooled and diluted with water (15 mL). The product was extracted into DCM (3×25 mL) and the extracts were dried over MgSO4 and concentrated to dryness. The diastereomers were separated by HPLC (Novapak C-18, 19×300 mm, 55% CH3CN/water, 10 mL/min) to give diastereomer 1 (rt=23.0 min) and diastereomer 2 (rt=24.2 min) giving approximately 20 mg of each diastereomer.
Reaction SMILES: C([O:4][CH:5]([C:7]1[CH:8]=[CH:9][C:10]2[O:15][CH:14]=[C:13]([C:16]#[N:17])[C:12](=[O:18])[C:11]=2[CH:19]=1)[CH3:6])(=O)C.[OH-].[Na+].Cl>>[OH:4][CH:5]([C:7]1[CH:8]=[CH:9][C:10]2[O:15][CH:14]=[C:13]([C:16]#[N:17])[C:12](=[O:18])[C:11]=2[CH:19]=1)[CH3:6]
Reactant: CC(=O)OC(C)c1ccc2occ(C#N)c(=O)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(O)c1ccc2occ(C#N)c(=O)c2c1
Temperature: 25 °C
Reaction time: 1.33 h

Procedure:
A mixture of 1.43 parts of 6-(1-acetoxyethyl)-4-oxo-4H-1-benzopyran-3-carbonitrile and 25 parts by volume of 1N-sodium hydroxide is stirred at room temperature for 80 minutes. After being acidified with 1N-hydrochloric acid, the reaction mixture is extracted with ethyl acetate. The ethyl acetate layer is washed with water and dried on Na2SO4. The ethyl acetate is distilled off and the resulting residue is recrystallized from ethyl acetate. The procedure yields 0.790 part of 6-(1-hydroxyethyl)-4-oxo-4H-1-benzopyran-3-carbonitrile as colorless crystals. Melting point: 147°-148° C
Reaction SMILES: [ClH:1].C[O:3][CH:4](OC)[C:5]1[NH:6][C:7]2[N:8]([CH:25]=[CH:26][N:27]=2)[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].CC(C)=O>O>[ClH:1].[CH2:14]([O:13][C:11]([C:10]1[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[N:8]2[CH:25]=[CH:26][N:27]=[C:7]2[NH:6][C:5]=1[CH:4]=[O:3])=[O:12])[CH3:15]
Reactant: CCOC(=O)C1=C(C(OC)OC)Nc2nccn2C1c1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)C1=C(C=O)Nc2nccn2C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10 ml of 6N hydrochloric acid is added to a solution of 4.4 g of 7-dimethoxymethyl-6-ethoxycarbonyl-5-(3-nitrophenyl)-5,8-dihydroimidazo[1,2-a]pyrimidine in mixture of 10 ml of acetone and 10 ml of water and the mixture is stirred at room temperature for an hour, and then allowed to stand overnight. The solvent is distilled off under reduced pressure below 40° C. to give 4 g of 6-ethoxycarbonyl-7-formyl-5-(3-nitrophenyl)-5,8-dihydroimidazo[1,2-a]pyrimidine hydrochloride, melting at 228° C. with decomposition.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([OH:12])=[CH:9]2)=[CH:4][CH:3]=1.S(OCC)(O[CH2:17][CH3:18])(=O)=O.C([O-])([O-])=O.[K+].[K+]>C(#N)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][C:8]([O:12][CH2:17][CH3:18])=[CH:7][CH:6]=2)[CH:11]=1
Reactant: Oc1ccc2ccc(Br)cc2c1
Reactant: CCOS(=O)(=O)OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC#N
Product: CCOc1ccc2ccc(Br)cc2c1
Yield: 89 %

Procedure:
To a solution of 7-bromo-naphth-2-ol (1.0 g, 4.5 mmol, prepared according to patent WO 0146187 A1) in acetonitrile (10 ml) was added diethyl sulfate (1.04 g, 6.7 mmol), K2CO3 (0.92 g) and tetrabutylammonium bromide (10 mg). The reaction mixture was refluxed for 1 hour, poured on water and extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered and the solvent was removed under reduced pressure to provide 2-bromo-7-ethoxynaphthalene (89%), MS: m/e=252 (M+).
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:21]4[CH2:26][CH2:25][NH:24][C@@H:23]([CH2:27][OH:28])[CH2:22]4)=[N:18][C:17]3=[O:29])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH:40]1([C:43](Cl)=[O:44])[CH2:42][CH2:41]1>>[F:39][C:2]([F:38])([F:1])[C:3]1[CH:33]=[C:32]([C:34]([F:37])([F:35])[F:36])[CH:31]=[CH:30][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:21]4[CH2:26][CH2:25][N:24]([C:43]([CH:40]5[CH2:42][CH2:41]5)=[O:44])[C@@H:23]([CH2:27][OH:28])[CH2:22]4)=[N:18][C:17]3=[O:29])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: O=C1N=C(N2CCN[C@@H](CO)C2)SC1=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1
Reactant: O=C(Cl)C1CC1
Product: O=C1N=C(N2CCN(C(=O)C3CC3)[C@@H](CO)C2)SC1=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1

Procedure:
5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[4-(cyclopropylcarbonyl)-3-(R)-(hydroxymethyl)piperazin-1-yl]-1,3-thiazol-4(5H)-one was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-(R)-hydroxymethyl-piperazin-1-yl)-thiazol-4-one (example 139) and Cyclopropanecarbonyl chloride.
Reaction SMILES: [Br:1][C:2]1[C:12]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[C:11]([Br:19])[CH:10]=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].[OH-].[Na+]>C1COCC1.O>[Br:1][C:2]1[C:12]([O:13][CH2:14][C:15]([F:16])([F:17])[F:18])=[C:11]([Br:19])[CH:10]=[CH:9][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)c1ccc(Br)c(OCC(F)(F)F)c1Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(Br)c(OCC(F)(F)F)c1Br
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1.380 g (3.40 mmol) of ethyl 2,4-dibromo-3-(2,2,2-trifluoroethoxy)benzoate were dissolved in a mixture of 15 ml of THF and 15 ml of water, and 0.150 g (3.47 mmol) of NaOH was added. The mixture was stirred at RT for 12 h and concentrated to completion. The residue was taken up in water, and 6 N HCl was added. The precipitate was filtered off with suction and dried. This gave 2-chloro-2,4-dibromo-3-(2,2,2-trifluoroethoxy)benzoic acid in the form of a white solid.
Reaction SMILES: [CH2:1]([C@H:8]1[C@H:12]([CH2:13][CH:14]([NH:29][C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][N:23]=3)=[CH:18][CH:17]=2)[O:11]C(C)(C)[N:9]1C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.Cl>C1COCC1>[NH2:9][C@@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@@H:12]([OH:11])[CH2:13][CH:14]([NH:29][C:30](=[O:31])[O:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][N:23]=2)=[CH:20][CH:21]=1
Reactant: Cc1ccc(-c2ccc(CC(C[C@@H]3OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]3Cc3ccccc3)NC(=O)OCc3ccccc3)cc2)nc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(-c2ccc(CC(C[C@H](O)[C@@H](N)Cc3ccccc3)NC(=O)OCc3ccccc3)cc2)nc1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A solution containing the product from Example 128C (0.322 g, 0.496 mmol) in a mixture of THF (5 mL), methanol (5 mL), and aqueous HCl (5 mL, 1 N) was stirred at 60° C. for 16 hours. The solvent was removed under reduced pressure to give the title compound as the hydrochloride salt.
Reaction SMILES: C([NH:4][C:5]1[N:9]([CH2:10][C:11]([O:13]CC)=[O:12])[N:8]=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6]=1[C:22]#[C:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=O)C.[OH-].[Na+:31]>C(O)C>[NH2:4][C:5]1[N:9]([CH2:10][C:11]([O-:13])=[O:12])[N:8]=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6]=1[C:22]#[C:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Na+:31]
Reactant: CCOC(=O)Cn1nc(-c2ccccc2)c(C#Cc2ccccc2)c1NC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1c(C#Cc2ccccc2)c(-c2ccccc2)nn1CC(=O)[O-]
Temperature: 80 °C

Procedure:
A mixture of ethyl 2-[5-acetamido-3-phenyl-4-(2-phenylethynyl)pyrazol-1-yl]acetate (13 g, 34 mmol), ethanol (150 mL) and 25% aq. NaOH solution (150 mL) was stirred and heated to 80° C. for 8 h and cooled to room temperature. Upon cooling, a precipitate formed. The precipitate was filtered and washed with cooled mixture of ethyl acetate/water (1:1). The solid was further triturated with diethyl ether, filtered and dried to provide 9.8 g of the title compound.
Reaction SMILES: [NH2:1][C:2](=[N:31]O)[C:3]1[CH:4]=[C:5]([NH:20][C:21](=[O:30])[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:6]([NH:9][C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:7][CH:8]=1.O1CCCC1.Cl.[H][H]>C(O)C.[Pd].O>[NH2:31][C:2](=[NH:1])[C:3]1[CH:4]=[C:5]([NH:20][C:21](=[O:30])[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:6]([NH:9][C:10](=[O:19])[C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=O)Nc2ccc(C(N)=NO)cc2NC(=O)c2ccc(OC)cc2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2ccc(C(=N)N)cc2NC(=O)c2ccc(OC)cc2)cc1
Reaction time: 12 h
Yield: 35.8 %

Procedure:
To a stirred solution 4-[(amino)(hydroxyimino)methyl]-N1,N2-bis(4-methoxybenzoyl)-1,2-benzenediamine (0.50 g, 1.2 mmol), tetrahydrofuran (5 mL), water (25 mL), and 1 N aqueous hydrochloric acid (1.4 mL) in ethanol (50 mL) was added 10% palladium-on-carbon (250 mg). The vessel was placed under vacuum and the atmosphere was replaced with hydrogen (1 bar). After 12 h, the balloon was removed and the mixture was filtered through diatomaceous earth and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium chloride solution, dried (magnesium sulfate), filtered, and concentrated in vacuo to give 180 mg (35%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C@H:4]([CH:11]([CH3:13])[CH3:12])[N:5]=[C:6]([O:9][CH3:10])[CH2:7][N:8]=1.[Br:14][C:15]1[C:22]([F:23])=[CH:21][C:18]([CH2:19]Br)=[C:17]([F:24])[CH:16]=1>>[CH3:1][O:2][C:3]1[C@H:4]([CH:11]([CH3:13])[CH3:12])[N:5]=[C:6]([O:9][CH3:10])[C@@H:7]([CH2:19][C:18]2[CH:21]=[C:22]([F:23])[C:15]([Br:14])=[CH:16][C:17]=2[F:24])[N:8]=1
Reactant: COC1=N[C@@H](C(C)C)C(OC)=NC1
Reactant: Fc1cc(CBr)c(F)cc1Br
Product: COC1=N[C@H](Cc2cc(F)c(Br)cc2F)C(OC)=N[C@H]1C(C)C
Yield: 88 %

Procedure:
The title compound (1.61 g) was prepared from 0.865 g (4.7 mmol) of (2S)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine and 1.5 g (5.2 mmol) of 4-bromo-2,5-difluorobenzyl bromide using the procedure described for Intermediate 2, Step A. 1H NMR (400 MHz, CDCl3) δ 7.21 (m, 1H), 6.97 (m, 1H), 4.25 (m, 1H), 3.78 (s, 3H), 3.70-3.64 (m, 4H), 3.25-3.18 (m, 1H), 2.96-2.90 (m, 1H), 2.25-2.16 (m, 1H), 1.01 (d, 3H, J=8 Hz), 0.65 (d, 3H, J=8 Hz).