Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C:5]([NH2:20])=[CH:4][CH:3]=1.[C:21](N1C=CN=C1)(N1C=CN=C1)=[O:22]>C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:20][C:21](=[O:22])[N:8]([CH2:9][CH2:10][CH2:11][O:12][Si:13]([C:16]([CH3:17])([CH3:19])[CH3:18])([CH3:14])[CH3:15])[C:6]=2[CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)[Si](C)(C)OCCCNc1cc(Br)ccc1N
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCCn1c(=O)[nH]c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
5-Bromo-N1-(3-((tert-butyldimethylsilyl)oxy)propyl)benzene-1,2-diamine (1.8 g, 5.14 mmol) was dissolved in dry THF (50 mL) and 1,1′-carbonyl-diimidazole (0.92 g, 5.65 mmol) was added. The dark brown solution was stirred at room temperature under nitrogen overnight. The mixture was diluted with ethyl acetate and washed with water then brine and dried over anhydrous magnesium sulfate. After filtration and concentration the crude product was chromatographed on silica gel eluting with 5-50% ethyl acetate in hexanes to give 6-bromo-1-(3-((tert-butyldimethylsilyl)oxy)propyl)-1H-benzo[d]imidazol-2(3H)-one as a purple oily foam (1.14 g, 2.96 mmol).
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH:6]([OH:12])[CH2:7][NH:8][CH2:9][CH2:10][CH3:11])[CH:2]=[CH2:3].C(N(CC)CC)C.[Cl:20][CH2:21][C:22](Cl)=[O:23]>C(Cl)Cl>[CH2:1]([O:4][CH2:5][CH:6]([OH:12])[CH2:7][N:8]([CH2:9][CH2:10][CH3:11])[C:22](=[O:23])[CH2:21][Cl:20])[CH:2]=[CH2:3]
Reactant: C=CCOCC(O)CNCCC
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCOCC(O)CN(CCC)C(=O)CCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1-allyloxy-3-n-propylamino-2-propanol (95.2 g.) in a mixture of dry methylene chloride (275 ml.), and triethylamine (80 ml.) is cooled to between -5°C. and 0°C. and a solution of chloroacetylchloride (42 ml.) in methylene chloride (60 ml.) is added dropwise with stirring during 2 hours. The mixture is allowed to warm to ambient temperature (18°-20°C.) and stirred at this temperature for 18 hours. The solution is washed with 2N hydrochloric acid (2 × 100 ml.) and then with water (100 ml.) and dried (MgSO4). Removal of the solvent under reduced pressure gives N-(3-allyloxy-2-hydroxypropyl)-N-n-propyl-α-chloroacetamide (119.7 g.) as an oil which is used without further purification.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([CH2:15][O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:13][CH:12]=[CH:11][C@H:10]1[OH:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.Br.C(=O)([O-])[O-:28].[Na+].[Na+]>C1COCC1>[CH2:1]([O:8][C@H:9]([C@@H:14]([CH2:15][O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[OH:13])[C@H:10]([OH:24])[CH2:11][CH:12]=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O[C@@H]1C=CO[C@H](COCc2ccccc2)[C@H]1OCc1ccccc1
Agent: Br
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=CC[C@@H](O)[C@H](OCc1ccccc1)[C@H](O)COCc1ccccc1
Temperature: 25 °C
Yield: 63 %

Procedure:
4,6-di-O-benzyl-D-glucal (4.9 mmol) was dissolved in THF (60 mL). 48% Water solution of hydrobromic acid (0.4 mL) was added and the reaction mixture was stirred at room temperature. After reaction was completed, water (250 mL) was added, and pH of obtained solution was adjusted to 8 using saturated sodium carbonate. Water solution was then extracted with ethyl acetate (3×100 mL). Combined water extracts were washed with water until neutral, and dried over anhydrous sodium sulfate. Solids and solvents were removed and crude product was purified by column chromatography (SilicaGel 60) using hexanes:ethyl acetate as eluents. Pure 4,6-di-O-benzyl-2-deoxy-D-glucose (3.1 mmol, yield 63%) was obtained.
Reaction SMILES: [C:1]([CH:7]([OH:13])[CH2:8][CH:9]([OH:12])[CH2:10][OH:11])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].N1C=CN=C1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>C(Cl)Cl.O>[Si:19]([CH:10]([OH:11])[CH:9]([OH:12])[CH2:8][CH:7]([C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])[OH:13])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)C(=O)C(O)CC(O)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)C(=O)C(O)CC(O)C(O)[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.4 %

Procedure:
To a solution of 1 (70 g, 0.368 mol) in CH2Cl2 (2.0 L) is added imidazole (31.3 g, 0.46 mol) and tert-butyldimethylsilyl chloride (58.2 g, 0.386 mol) and stirred at room temperature for 3 h. The reaction mixture is diluted with water, the organic layer separated and washed with water and brine and then dried over MgSO4. After filtration, the filtrate is concentrated and the residue is purified on a silica gel column using ethyl acetate:hexanes as eluent to give 91.2 g (81%) of product as an oil: 1H NMR (DMSO-d6): δ 4.66 (d, J=5.2 Hz, 1H), 4.14-3.90 (m, 2H), 3.54-3.25 (m, 3H), 1.84-1.72 (m, 1H), 1.51-1.39 (m, 1H), 1.10 (s, 9H), 0.83 (s, 9H), 0.01 (s, 6H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:14][CH3:15])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]=O)=[CH:8][CH:7]=1.N1CCCCC1.[I-:22].[CH3:23][N+:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:30]>CO>[I-:22].[CH3:23][N+:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH:30]=[CH:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH:3]([O:14][CH3:15])[O:2][CH3:1])=[CH:7][CH:8]=1
Reactant: Cc1cccc[n+]1C
Reactant: COC(COc1ccc(C=O)cc1)OC
Agent: [I-]
Solvent: CO
Solvent: C1CCNCC1
Product: COC(COc1ccc(C=Cc2cccc[n+]2C)cc1)OC

Procedure:
In 7 ml of methanol were dissolved 1.61 of N-methyl-α-picolinium iodide and 1.70 g of p-formylphenoxyacetaldehyde dimethyl acetal. The resultant mixture, after addition thereto of 0.3 ml of piperidine, was refluxed for four hours. When the reaction solution was cooled, there ensued precipitation of crystals. The crystals were recovered, washed with a small amount of cooled methanol and washed thoroughly with acetone. Thus, there was obtained 2.11 g of 1-methyl-2-{p-(2,2-dimethoxyethoxy)-styryl}-pyridinium iodide having a melting point of 192° to 197° C. By following the same procedure, but using the n-methyl-α-picolinium iodide in combination with m-formylphenoxyacetaldehyde dimethylacetal and n-methyl-γ-picolinium p-tolunesulfonate in combination with p-formylphenoxyacetaldehyde dimethylacetal, as the raw materials, there were respectively obtained 1-methyl-2-{m-(2,2-dimethoxyethoxyl)-styryl}-pyridinium iodide having a melting point of 181° to 186° C., 1-methyl-2-{o-(2,2-dimethoxyethoxy)-styryl}-pyridinium iodide having a melting point of 169° to 173° C., and 1-methyl-4-{p-(2,2-dimethoxyethoxy)-styryl}-pyridinium p-toluenesulfonate having a melting point of 219° to 226° C.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[C:3]([S:7](Cl)(=[O:9])=[O:8])[CH:2]=1.[CH3:12][O:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[OH:21].C(N(CC)CC)C>C(Cl)Cl>[CH3:11][C:1]1[CH:2]=[C:3]([S:7]([O:21][C:15]2[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=2[O:13][CH3:12])(=[O:9])=[O:8])[CH:4]=[CH:5][CH:6]=1
Reactant: COc1cc(C)ccc1O
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C)ccc1OS(=O)(=O)c1cccc(C)c1
Temperature: 25 °C
Yield: 98.3 %

Procedure:
A solution of m-toluenesulfonyl chloride (0.53 g, 2.78 mmol) and 2-methoxy-4-methylphenol (0.38 g, 2.75 mmol) in DCM (10 mL) was treated with triethylamine (0.5 mL, 3.6 mmol) and stirred at ambient temperature. After 18 hours the reaction was concentrated in vacuo, the residue dissolved in 1:1 hexane:DCM, filtered, and the filtrate evaporated under high vacuum giving the title compound as a white solid (0.79 g, 99%). 1H NMR (300 MHz, CDCl3) δ 7.72 (hr s, 1H), 7.66 (br d, 1H, J=7.2 Hz), 7.45 (br d, 1H, J=7.2 Hz), 7.38 (t, 1H, J=7.6 Hz), 7.00 (d, 1H, J=8.1 Hz), 6.67 (m, 1H), 3.54 (s, 3H), 2.42 (s, 3H), 2.31 (s, 3).
Reaction SMILES: [F:1][C:2]1[C:3]([O:20][CH3:21])=[CH:4][C:5]2[O:19][CH2:18][C:8]3([C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[NH:10][C:9]3=[O:17])[C:6]=2[CH:7]=1.Br.Br[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.BrCC1CCCCO1>>[F:1][C:2]1[C:3]([O:20][CH3:21])=[CH:4][C:5]2[O:19][CH2:18][C:8]3([C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[C:9]3=[O:17])[C:6]=2[CH:7]=1
Reactant: BrCc1ccccn1
Reactant: COc1cc2c(cc1F)C1(CO2)C(=O)Nc2ccccc21
Agent: Br
Agent: BrCC1CCCCO1
Product: COc1cc2c(cc1F)C1(CO2)C(=O)N(Cc2ccccn2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 5-fluoro-6-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, and 2(bromomethyl)pyridine hydrobromide to replace 2-(bromomethyl)tetrahydro-2H-pyran, 5-fluoro-6-methoxy-1′-(pyridin-2-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (77%) as a colorless solid: mp 142-144° C.; 1H NMR (300 MHz, CDCl3) δ 8.59-8.53 (m, 1H), 7.65 (ddd, J=7.7, 7.7, 1.7 Hz, 1H), 7.28-7.10 (m, 4H), 7.01 (dd, J=7.5, 7.5 Hz, 1H), 6.88 (d, J=7.8 Hz, 1H), 6.60 (d, J=6.8 Hz, 1H), 6.52 (d, J=10.1 Hz, 1H), 5.20 (d, J=15.8 Hz, 1H), 5.03-4.90 (m, 2H), 4.72 (d, J=9.0 Hz, 1H), 3.86 (s, 3H); 13C NMR (75 MHz, CDCl3) δ177.3, 157.2 (d), 155.4, 149.6, 149.3, 149.1, 149.0, 146.1, 142.1, 137.1, 131.8, 129.0, 123.8, 123.6, 122.8, 121.6, 119.0 (d), 110.7, 110.4, 109.6, 96.3, 80.5, 58.1, 56.4, 46.0; MS (ES+) m/z 377.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([Mg]Br)=[CH:17][CH:16]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:18]2[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=2)([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
To a stirred solution of 1-t-butoxycarbonyl-3-pyrrolidinone (0.57 g, 3.23 mmol) in THF (10 mL) was added 4-chlorophenyl magnesium bromide (1.0 M, 5.2 mL) under the protection of argon at 0° C. The reaction was stirred at room temperature for 1 hour then quenched by the addition of saturated aqueous NH4OH (8 mL). The aqueous layer was extracted with EtOAc (50 mL×2), dried over MgSO4 and concentrated in vacuo. Chromatographic purification on silica gel (Hexane/EtOAc=3/1) provided 0.57 g 1-t-butoxycarbonyl -3-(4-chlorophenyl)-3-hydroxypyrrolidine (60%). m/z 298 (m+1)
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:16])=[C:4]([C:11]([O:13]CC)=O)[C:5](=[O:10])[N:6]([CH3:9])[C:7]=1[CH3:8].[NH2:17][C:18]1[N:19]=[N:20][C:21]([Cl:24])=[CH:22][CH:23]=1.BrC1C=CC=CC=1>CCCCCC>[Cl:24][C:21]1[N:20]=[N:19][C:18]([NH:17][C:11]([C:4]2[C:5](=[O:10])[N:6]([CH3:9])[C:7]([CH3:8])=[C:2]([Cl:1])[C:3]=2[OH:16])=[O:13])=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1c(O)c(Cl)c(C)n(C)c1=O
Reactant: Nc1ccc(Cl)nn1
Solvent: Brc1ccccc1
Solvent: CCCCCC
Product: Cc1c(Cl)c(O)c(C(=O)Nc2ccc(Cl)nn2)c(=O)n1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.4 %

Procedure:
168 mg of ethyl 5-chloro-1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylate and 82 mg of 3-amino-6-chloropyridazine were added to 1.5 ml of bromobenzene, and the mixture was stirred for 4 hours under heat refluxing. The reaction mixture was cooled to room temperature, and n-hexane was added to the reaction mixture. The resulting solid was collected by filtration, washed with a mixture of t-butyl methyl ether and n-hexane, and dried to obtain 180 mg of N-(6-chloro-3-pyridazinyl)-5-chloro-1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxamide (hereafter, referred to as present compound 17) represented by the formula:
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][C:5](=O)[CH2:4][C:3]1=[O:9].[Br:11][C:12]1[C:13]([OH:21])=[C:14]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[CH:15]=O.[NH2:22][C:23]1[CH:27]=[CH:26][NH:25][N:24]=1>>[Br:11][C:12]1[C:13]([OH:21])=[C:14]([CH:15]2[C:4]3[C:3](=[O:9])[C:2]([CH3:10])([CH3:1])[CH2:7][CH2:6][C:5]=3[NH:22][C:23]3=[CH:27][CH:26]=[N:25][N:24]23)[CH:17]=[C:18]([Cl:20])[CH:19]=1
Reactant: Nc1cc[nH]n1
Reactant: CC1(C)CCC(=O)CC1=O
Reactant: O=Cc1cc(Cl)cc(Br)c1O
Product: CC1(C)CCC2=C(C1=O)C(c1cc(Cl)cc(Br)c1O)n1nccc1N2

Procedure:
4,4-Dimethyl-1,3-cyclohexanedione, 3-bromo-5-chloro-2-hydroxybenzaldehyde and 3-aminopyrazole were processed as described in General Procedure A to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][C:4]=1[Cl:10].Cl[C:12](OC1C=CC([N+]([O-])=O)=CC=1)=[O:13].C(N(C(C)C)CC)(C)C.[Cl:33][C:34]1[CH:43]=[C:42]2[C:37]([C:38]([N:44]3[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)=[CH:39][CH:40]=[N:41]2)=[CH:36][CH:35]=1>>[Cl:10][C:4]1[CH:5]=[C:6]([NH:7][C:12]([N:47]2[CH2:48][CH2:49][N:44]([C:38]3[C:37]4[C:42](=[CH:43][C:34]([Cl:33])=[CH:35][CH:36]=4)[N:41]=[CH:40][CH:39]=3)[CH2:45][CH2:46]2)=[O:13])[CH:8]=[CH:9][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(N)cc1Cl
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(NC(=O)N2CCN(c3ccnc4cc(Cl)ccc34)CC2)cc1Cl

Procedure:
As described for example 78, 4-methoxy-3-chloro-aniline, p-nitrophenyl chloroformate, diisopropylethyl amine, and 7-chloro-4-piperazinylquinoline are reacted to afford the product. LC-MS: 431 (M++1). 1H NMR (CDCl3) δ 8.78 (d, 1H), 8.05 (s, 1H), 7.95 (d, 1H), 7.50 (d, 1H), 7.45 (s, 1H), 7.22 (d, 1H), 6.90 (m, 2H), 6.38 (s, 1H), 3.85 (s, 3H), 3.80 (m, 4H), 3.25 (m, 4H).
Reaction SMILES: CO[C:3]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)=[C:4]([C:7]#[N:8])[C:5]#[N:6].[Br:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][C:24]=1[NH:32][NH2:33]>C(O)C>[NH2:6][C:5]1[N:32]([C:24]2[CH:25]=[C:26]([N+:29]([O-:31])=[O:30])[CH:27]=[CH:28][C:23]=2[Br:22])[N:33]=[C:3]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)[C:4]=1[C:7]#[N:8]
Reactant: NNc1cc([N+](=O)[O-])ccc1Br
Reactant: COC(=C(C#N)C#N)c1ccc(Oc2ccccc2)cc1
Solvent: CCO
Product: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn(-c2cc([N+](=O)[O-])ccc2Br)c1N
Temperature: 70 °C
Reaction time: 8 h
Yield: 20.8 %

Procedure:
To a solution of 2-(methoxy(4-phenoxyphenyl)methylene)malononitrile (392 mg, 1.42 mmol) in ethanol (30 mL) was added (2-bromo-5-nitrophenyl)hydrazine (300 mg, 1.29 mmol) in one portion, then the mixture was stirred at 70° C. under N2 overnight. The mixture was concentrated to dryness and chromatographed on 5 g of silica gel using PE/EA (10/1 to 2/1) as eluant to afford 128 mg (21%) of 5-amino-1-(2-bromo-5-nitrophenyl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile as a yellow solid. MS (ESI) m/e [M+1]+ 476, 478.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([C:19]#[N:20])[CH2:18][CH2:17][CH2:16]2)=[CH:11][C:10]=1[O:21][CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C.[N+:30]([O-])([OH:32])=[O:31]>C(O)(=O)C>[CH2:1]([O:8][C:9]1[C:10]([O:21][CH3:22])=[CH:11][C:12]([C:15]2([C:19]#[N:20])[CH2:18][CH2:17][CH2:16]2)=[C:13]([N+:30]([O-:32])=[O:31])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C2(C#N)CCC2)ccc1OCc1ccccc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: COc1cc(C2(C#N)CCC2)c([N+](=O)[O-])cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 91.8 %

Procedure:
A solution of 1-(4-(benzyloxy)-3-methoxyphenyl)cyclobutanecarbonitrile (5 g, 17.04 mmol), from Step 1, in acetic acid (20 mL)/acetic anhydride (20 mL) was cooled in an ice bath to 0° C. and treated slowly with 65% nitric acid (2.54 mL, 34.1 mmol). The reaction was stirred at 0° C. for 20 min, poured into ice and extracted with EtOAc. Organic layer was washed with saturated aqueous NaHCO3 and water. Organic layer was dried (MgSO4), filtered and concentrated. Purification by flash chromatography (silica gel, 5-50% EtOAc/hexane) afforded 1-(4-(benzyloxy)-5-methoxy-2-nitrophenyl)cyclobutanecarbonitrile (5.29 g, 92%). MS (ESI) m/z 339 (M+H)+.
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5]1[CH:12]=[C:11]([O:13][CH2:14][CH3:15])[CH:10]=[CH:9][C:6]=1[C:7]#[N:8])[CH3:3].[CH2:16]([OH:18])[CH3:17]>>[ClH:1].[CH2:2]([O:4][C:5]1[CH:12]=[C:11]([O:13][CH2:14][CH3:15])[CH:10]=[CH:9][C:6]=1[C:7](=[NH:8])[O:18][CH2:16][CH3:17])[CH3:3]
Reactant: CCO
Reactant: CCOc1ccc(C#N)c(OCC)c1
Agent: Cl
Product: CCOC(=N)c1ccc(OCC)cc1OCC
Temperature: 25 °C
Reaction time: 288 h
Yield: 95 %

Procedure:
Hydrogen chloride gas was passed through a solution of 2,4-diethoxybenzonitrile (1.86 g, 9.7 mmol) in absolute ethanol (20 mL) in a pressure tube for 1 h at −10° C. The tube was sealed and stirred at room temperature for 12 d. Evaporation of the solvents and trituration of the residue in diethyl ether gave ethyl 2,4-diethoxy-benzimidate hydrochloride (2.53 g, 95%).
Reaction SMILES: [C:1]([O:20][CH2:21][C@@H:22]([OH:35])[CH2:23][CH2:24][O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][C:37](C)([O-])[CH3:38].[K+].C(Br)C=C>C1COCC1.CCCCCC>[C:1]([O:20][CH2:21][C@@H:22]([O:35][CH2:38][CH:37]=[CH2:36])[CH2:23][CH2:24][O:25][CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccc(COCC[C@H](O)COC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C=CCBr
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CCO[C@@H](CCOCc1ccc(OC)cc1)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 98.8 %

Procedure:
To a solution of Compound 5 (10 grams, 21.4 mmoles) in dry THF (250 ml), a solution of 1M of potassium t-butoxide (Aldrich) (27.8 ml, 27.8 mmoles) in THF was added, under argon atmosphere. The mixture was stirred at room temperature for 5 minutes and, thereafter, allyl bromide (Aldrich) (7.4 ml, 85.5 mmoles) was added. The mixture was stirred for 18 hours at 55° C. The solvent was thereafter evaporated to dryness and the residue was extracted with ethyl acetate (250 ml) and washed with water and brine. The organic layer was dried over sodium sulfate and the solvent was removed under reduced pressure. The resulting yellowish oily residue was purified by silica gel chromatography, using 1:2 (v:v) ethyl acetate:hexane as eluent, 10.75 grams (99% yield) of Compound 6 were obtained as an oil.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-].O>C1C=CC=CC=1>[OH:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=2)=[O:9])=[CH:11][CH:12]=1
Reactant: COc1ccc(C(=O)c2ccc(I)cc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: c1ccccc1
Product: O=C(c1ccc(O)cc1)c1ccc(I)cc1
Temperature: 0 °C
Yield: 94.5 %

Procedure:
A mixture of (4-Iodophenyl)[4-(methyloxy)phenyl]methanone (142) (1.50 g, 4.44 mmol) and AlCl3 (2.40 g, 17.74 mmol) were refluxed in benzene (50 mL) for 1.5 h and then cooled to 0° C. in an ice bath. Water (50 mL) was added slowly, and the mixture was extracted with ether (2×100 mL). The combined ethereal extracts were washed with water, brine, and dried over Na2SO4. Concentration and trituration with hot hexanes afforded 1.36 g (95%) of the title compound as light brown solid. 1H NMR (400 MHz, CDCl3): δ 5.37 (br s, 1H), 6.90 (d, J=8.6 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H), 7.75 (d, J=8.6 Hz, 2H), 7.83 (d, J=8.5 Hz, 2H). LCMS (ESI): m/z, 325 (M+H)+, 323 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[C:9]([OH:11])=O)[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.C(Cl)CCl.[CH3:40][CH:41]([CH3:44])[CH2:42][NH2:43]>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[C:9]([NH:43][CH2:42][CH:41]([CH3:44])[CH3:40])=[O:11])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)CN
Reactant: CC(C(=O)O)c1ccc(-c2ccccc2)c(F)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CNC(=O)C(C)c1ccc(-c2ccccc2)c(F)c1
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a solution of 2-(2-fluorobiphenyl-4-yl)propanoic acid (Aldrich) (172.3 mg), HOBt (133.2 mg, 1.4 eq) and triethylamine (196.5 mL, 2 eq) in dichoromethane (7 mL) was added at room temparature EDC (270.4 mg, 2.0 eq). The reaction was stired at room temperature for 30 minutes and 2-methylpropan-1-amine (0.1 mL, 1.5 eq) was added. The solution was stirred overnight then diluted with dichlorometahne and washed successively with aqueous NaHCO3, water, aqoueous HCL (1N), water, dried over MGSO4, filtered and evaporated. Chromatogarphy on silica gel (eluent:ethyl acetate/hexane 1:1) afforded 170 mg of 2-(2-fluorobiphenyl-4-yl)-N-isobutylpropanamide. Yield: 80%. 1H NMR (500 MHz, CDCl3): δ 0.83-0.79 (d, 6H), 1.55-1.56 (d, 3H), 1.69-1.74 (m, 1H), 3.04-3.07 (m, 2H), 3.56-3.58 (m, 1H), 5.4 (s br, 1H), 7.11-7.16 (m, 2H), 7.37-7.46 (m, 4H), 7.53-7.55 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[N:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:29]([Br:32])[CH:30]=[CH2:31].Br>C(OCC)(=O)C.O.CN(C)C=O>[BrH:32].[CH2:31]([N:20]1[CH2:19][CH2:18][N:17]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:9]=2)[CH2:22][CH2:21]1)[CH:30]=[CH2:29]
Reactant: C=CCBr
Reactant: Fc1ccc(-n2nc(N3CCNCC3)c3ccccc32)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: C=CCN1CCN(c2nn(-c3ccc(F)cc3)c3ccccc23)CC1
Reaction time: 16 h
Yield: 32.7 %

Procedure:
A mixture of 5.0 g of 1-(4-fluorophenyl)-3-(1-piperazinyl)-1H-indazole, 2.6 g of potassium carbonate, 2.2 g of allyl bromide, and 75 ml of dimethylformamide was stirred at 70°-75° for 16 hours, and then at ambient temperature for 48 hours. The mixture was poured into water and the aqueous mixture was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated to produce an oil. The oil was dissolved in ethyl acetate and a saturated solution of hydrogen bromide in ethyl acetate was added, dropwise, until the solution was acidic. A precipitate was formed and collected. Recrystallization of the precipitate from ethanol gave 2.3 g (33%) of 3-[4-(2-propenyl)-1-piperazinyl)-1-(4-fluorophenyl)-1H-indazole hydrobromide.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]C.[CH:13]([OH:15])=O.OO.CO.S(=O)(=O)(O)[OH:21]>>[CH2:13]([OH:15])[CH:11]([OH:21])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: C=CCCCCCCCCCC
Reactant: O=CO
Reactant: O=S(=O)(O)O
Agent: OO
Solvent: CO
Product: CCCCCCCCCCC(O)CO
Temperature: 100 °C
Reaction time: 0.75 h

Procedure:
168.3 g (1.0 mol) of 1-dodecene and 73.6 g (1.6 mol) of formic acid were mixed. This mixture was heated to 100° C. and then 115.7 g (1.7 mol) of 50% strength hydrogen peroxide solution were added dropwise over a period of 2 hours. The mixture was then stirred at 100° C. for 45 min. 64.1 g (2 mol) of methanol and 0.1 g of concentrated sulfuric acid were added, and the mixture was heated under reflux for 30 min and then the methyl formate, methanol and water were removed by distillation under atmospheric pressure. A >99% pure main fraction was isolated after the subsequent workup by distillation. The freshly distilled target product had an unpleasant, pungent odor.