Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[C:5]=1[NH2:6])([CH3:3])[CH3:2].C[Al](C)C.[Br:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([CH3:27])[CH:26]=1)[C:22]#[N:23].ClCCl.CO>C1(C)C=CC=CC=1.CCCCCC>[Br:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([CH3:27])[CH:26]=1)[C:22](=[NH:23])[NH:6][C:5]1[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:10][CH:9]=[CH:8][C:7]=1[CH:11]([CH3:13])[CH3:12]
Reactant: Cc1cc(Br)cc(C#N)c1
Reactant: CC(C)c1cccc(C(C)C)c1N
Agent: C[Al](C)C
Solvent: CO
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1cc(Br)cc(C(=N)Nc2c(C(C)C)cccc2C(C)C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 250 mL 3-neck round bottom flask was added 2,6-diisopropylaniline (2.365 g, 13.34 mmol) and 70 mL toluene. The solution was cooled in an ice bath under nitrogen and trimethylaluminum (2.0 M in toluene, 9.34 mL, 18.68 mmol) was added dropwise via dropping funnel. The reaction mixture was stirred at room temperature for 2 hours. Next, 3-bromo-5-methylbenzonitrile (3.4 g, 17.34 mmol) in 30 mL toluene was added and the reaction mixture was heated to 70° C. overnight under nitrogen. The reaction mixture was cooled in an ice bath and was poured onto a stirring slurry of silica gel in 2:1 dichloromethane/methanol (v/v). The silica gel was filtered off and washed with dichloromethane and methanol. The filtrate was evaporated leaving a solid. Hexane was added to the solvent and the solid was filtered off and washed with hexane (2.92 g, 59%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1.[C:13]([O-])([O-])=O.[K+].[K+].CI>O1CCCC1>[CH3:13][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCOc2cc(O)ccc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: COc1ccc2c(c1)OCCC2=O
Temperature: 70 °C
Yield: 72.2 %

Procedure:
7-Hydroxy-2,3-dihydrochromen-4-one (4.47 g, 27.2 mmol) was diluted with tetrahydrofuran (40 mL) followed by the addition of K2CO3 (5.64 g, 40.8 mmol) and MeI (2.55 mL, 40.8 mmol). The reaction was heated at 70° C. for 5 hours. The reaction was allowed to cool and loaded onto a Biotage 40M cartridge running a gradient 5% ethyl acetate/hexanes to 75% to yield the title compound (3.5 g, 72.1% yield).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].[CH2:31]([CH:33]1[CH2:35][O:34]1)[CH3:32]>C(O)(C)C>[Cl:3][C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:35][CH:33]([OH:34])[CH2:31][CH3:32])[CH2:21][CH2:20]2)[CH2:13][CH2:12]1
Reactant: CCC1CO1
Reactant: Clc1cccc(N2CCN(CCC3CCNCC3)CC2)c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CCC(O)CN1CCC(CCN2CCN(c3cccc(Cl)c3Cl)CC2)CC1
Reaction time: 0.5 h
Yield: 48.3 %

Procedure:
A suspension of 0.41 g (1 mmol) of 1-(2,3-dichlorophenyl)-4-(2-piperidin-4-ylethyl)piperazine, dihydrochloride in 25 mL of isopropanol and 0.29 g (2.1 mmol) of potassium carbonate is stirred for 30 minutes then 0.08 g (1.1 mmol of 2-ethyloxirane is added. The suspension is stirred to reflux overnight. The precipitate is filtered and the solution is concentrated under reduced pressure. The residue is dissolved in ethyl acetate, washed with water and with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified over 10 g of silica gel (dichloromethane/methanol 90/10) to give 0.2 g (50%) of 1-(4-{2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl}piperidin-1-yl)butan-2-ol as an oil that crystallizes upon standing.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[N:3]=1.[N:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:11]([C:7]1[CH:6]=[C:5]2[C:10]([C:2]([C:25]3[CH:26]=[CH:27][N:22]=[CH:23][CH:24]=3)=[N:3][N:4]2[CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])=[CH:9][CH:8]=1)([O-:13])=[O:12]
Reactant: C[Si](C)(C)CCOCn1nc(I)c2ccc([N+](=O)[O-])cc21
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: C[Si](C)(C)CCOCn1nc(-c2ccncc2)c2ccc([N+](=O)[O-])cc21
Temperature: 120 °C
Yield: 83.1 %

Procedure:
To a microwave vial was added 3-iodo-6-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (1.2 g, 2.9 mmol, WO 2010/027500, Intermediate 57, Step B), pyridine-4-boronic acid (0.704 g, 5.72 mmol), and Pd(PPh3)4 (0.165 g, 0.143 mmol), 1,4-dioxane (25 mL) and an aqueous solution of Na2CO3 (2 M, 6.3 mL, 12.6 mmol). The vial was sealed and the mixture was heated in a microwave at about 120° C. for about 40 min. The mixture was diluted with EtOAc (100 mL) and water (25 mL) and the layers separated. The aqueous layer was extracted with EtOAc (15 mL). The combined extracts were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (80 g silica gel) eluting with 20 to 80% EtOAc/heptane to provide 6-nitro-3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (0.893 g, 84%): LC/MS (Table 2, Method c) Rt=3.02 min.; MS m/z: 371 (M+H)+.
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][C:21]3[CH:24]=[CH:25][S:26][C:20]=3[CH:19]=2)=[CH:8]1)(C)(C)C.Cl.[Cl:28][CH2:29][CH2:30][N:31]1[CH2:36][CH:35]([CH3:37])[O:34][CH:33]([CH3:38])[CH2:32]1>>[ClH:28].[CH3:38][CH:33]1[O:34][CH:35]([CH3:37])[CH2:36][N:31]([CH2:30][CH2:29][O:17][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][C:21]4[CH:24]=[CH:25][S:26][C:20]=4[CH:19]=2)=[CH:8][C:7]3=[N:6][OH:5])[CH2:32]1
Reactant: CC(C)(C)ON=c1cc(-c2cc3sccc3cn2)oc2ccc(O)cc12
Reactant: CC1CN(CCCl)CC(C)O1
Agent: Cl
Product: CC1CN(CCOc2ccc3oc(-c4cc5sccc5cn4)cc(=NO)c3c2)CC(C)O1

Procedure:
6-[2-(2,6-Dimethyl-morpholin-4-yl)-ethoxy]-2-thieno[3,2-c]pyridin-6-yl-chromen-4-one oxime, hydrochloride was prepared in 48% overall yield using the method described in example 127, starting from 6-Hydroxy-2-thieno[3,2-c]pyridin-6-yl-chromen-4-one O-tert-butyl-oxime (example 127B) and 4-(2-Chloro-ethyl)-2,6-dimethyl-morpholine hydrochloride (JACS 1949, 500-505; US2006/14948).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[Cl:13]N1C(=O)CCC1=O>C(#N)C>[Cl:13][C:12]1[CH:11]=[C:5]([CH:4]=[CH:3][C:2]=1[NH2:1])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: CC#N
Product: CCOC(=O)c1ccc(N)c(Cl)c1

Procedure:
To a solution of ethyl 4-aminobenzoate (16 g.) in dry acetonitrile (200 ml.) at 60° was added N-chlorosuccinimide (13.35 g.) over 30 minutes. When the exothermic reaction had subsided the mixture was heated to reflux for 4 hours. After cooling the acetonitrile was removed under vacuum and the residue dissolved in dichloromethane. This was washed with 5% sodium hydroxide solution (2×100 ml.), brine and the organic layer dried over anhydrous magnesium sulphate. Evaporation yielded a solid that was purified by column chromatography on silica eluting with 10% ether/hexane.
Reaction SMILES: C(CC[O:5][C:6]([C:8]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C:12]([C:21](=[O:38])[NH:22][CH2:23][CH2:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:11]([CH3:39])[NH:10][C:9]=1[CH3:40])=[O:7])#N.[OH-].[Na+].Cl>CO>[Cl:20][C:16]1[CH:15]=[C:14]([CH:13]2[C:12]([C:21](=[O:38])[NH:22][CH2:23][CH2:24][CH:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[C:11]([CH3:39])[NH:10][C:9]([CH3:40])=[C:8]2[C:6]([OH:7])=[O:5])[CH:19]=[CH:18][CH:17]=1
Reactant: CC1=C(C(=O)NCCC(c2ccccc2)c2ccccc2)C(c2cccc(Cl)c2)C(C(=O)OCCC#N)=C(C)N1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1=C(C(=O)O)C(c2cccc(Cl)c2)C(C(=O)NCCC(c2ccccc2)c2ccccc2)=C(C)N1
Temperature: 25 °C
Reaction time: 7.5 h

Procedure:
275 mg (0.500 mmol) of 4-(3-chlorophenyl)-2,6-dimethyl-5-(3,3-diphenylpropylcarbamoyl)-1,4-dihydropyridine-3-carboxylic acid 2-cyanoethyl ester was dissolved in 10 ml of methanol. 1 ml of 1 N aqueous sodium hydroxide solution was added and stirred at room temperature for 7.5 hours. After adding 2 N hydrochloric acid, methanol was evaporated under reduced pressure. Water was added to the residue, and precipitates thus formed were taken by the filtration, then washed with water and hexane/ethyl acetate (3/1) and dried under reduced pressure to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[C:34]([C:38](Cl)=[O:39])=[CH:33][CH:32]=[CH:31]2>CN(C1C=CN=CC=1)C.ClCCl>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[C:34]([C:38]([NH:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:10])[F:11])[CH:5]=[CH:6][C:7]=1[F:8])=[O:39])=[CH:33][CH:32]=[CH:31]2
Reactant: COc1cc2nccc(Oc3ccc4c(C(=O)Cl)cccc4c3)c2cc1OC
Reactant: Nc1cc(C(F)(F)F)ccc1F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc4c(C(=O)Nc5cc(C(F)(F)F)ccc5F)cccc4c3)c2cc1OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Into a 16×100 mm vial was added 3-amino-4-fluorobenzotrifluoride (100 mg, 0.563 mmol), and dichloromethane (1 mL). To this was added 1.5 mL of a stock solution that is both 0.25M 6-(6,7-dimethoxyquinolin-4-yloxy)-1-naphthoyl chloride and 0.5M DMAP in dichloromethane. Reactions was stirred 24 h at RT. The mixture loaded directly onto silica column. Purified using 0 to 100% EtOAc in hexane. Best fractions were pooled, concentrated under reduced pressure to afford the title compound as a yellow oil. MS (ESI, pos. ion) m/z: 537 (M+1). Mass Calc'd for C29H20F4N2O4: 536.47.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.[Br:16][C:17]1[S:21][C:20]([C:22]2[O:23][CH:24]=[C:25]([CH2:27]Cl)[N:26]=2)=[CH:19][C:18]=1[CH3:29]>>[Br:16][C:17]1[S:21][C:20]([C:22]2[O:23][CH:24]=[C:25]([CH2:27][O:1][C:2]3[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]4[CH:15]=[CH:14][N:13]=[CH:12]4)=[CH:4][CH:3]=3)[N:26]=2)=[CH:19][C:18]=1[CH3:29]
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Reactant: Cc1cc(-c2nc(CCl)co2)sc1Br
Product: Cc1cc(-c2nc(COc3ccc(CCCn4ccnc4)cc3)co2)sc1Br
Yield: 77 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 2-(5-bromo-4-methyl-2-thienyl)-4-chloromethyloxazole to give 2-(5-bromo-4-methyl-2-thienyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole. The yield was 77%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 92-93° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4].Br[CH2:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([F:31])[CH:29]=2)[CH:24]=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([F:31])[CH:29]=3)[CH:24]=[CH:23][CH:22]=2)[C:7]2[C:12]([C:13]=1[CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4]
Reactant: Fc1ccc2cccc(CBr)c2c1
Reactant: COC(=O)Cc1c(C(=O)OC)[nH]c2ccccc12
Product: COC(=O)Cc1c(C(=O)OC)n(Cc2cccc3ccc(F)cc23)c2ccccc12

Procedure:
Using general procedure B, 3-methoxycarbonylmethyl-1H-indole-2-carboxylic acid methyl ester (prepared according to Lit. 2) was coupled with 1-bromomethyl-7-fluoro-naphthalene (from Example 49.3.) to give 1-(7-fluoro-naphthalen-1-ylmethyl)-3-methoxycarbonylmethyl-1H-indole-2-carboxylic acid methyl ester which was hydrolyzed as described in the general procedure B (Exp. 2.2) to the title compound as a white solid. MS: 375.9 ([M−H]−).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH2:12]2)=[O:10])[CH2:4][CH2:3]1.[N:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:20]1([S:17]([N:13]2[CH2:14][CH2:15][CH2:16][C@H:11]([C:9]([NH:8][CH:5]3[CH2:6][CH2:7][CH:2]([O:1][C:29]4[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=4)[CH2:3][CH2:4]3)=[O:10])[CH2:12]2)(=[O:19])=[O:18])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Oc1ccncc1
Reactant: O=C(N[C@H]1CC[C@H](O)CC1)[C@H]1CCCN(S(=O)(=O)c2ccccc2)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(NC1CCC(Oc2ccncc2)CC1)[C@H]1CCCN(S(=O)(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 6.3 %

Procedure:
Under a nitrogen atmosphere, to a mixture of (3S)-N-(trans-4-hydroxycyclohexyl)-1-(phenylsulfonyl)piperidine-3-carboxamide (25 mg, 0.068 mmol), 4-pyridinol (9.7 mg, 0.10 mmol), and triphenylphosphine (26.8 mg, 0.10 mmol) in tetrahydrofuran (0.5 mL) was added a solution of diethyl azodicarboxylate (16 μL, 0.10 mmol) in tetrahydrofuran (0.1 mL). The mixture was stirred at r.t. overnight. The product was purified with prep. HPLC. 1.9 mg product was obtained, yield: 6.3%. LCMS: m/z 444.2 (M+H)+; 887.2 (2M+Na)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:14])=[C:4]([C:8](=[O:13])[CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+]>C1COCC1.O>[Br:1][C:2]1[C:3]([CH3:14])=[C:4]([CH:8]([OH:13])[CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:6][CH:7]=1
Reactant: CCCCC(=O)c1cccc(Br)c1C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCC(O)c1cccc(Br)c1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 69.5 %

Procedure:
To a solution of 1-(3-bromo-2-methylphenyl)-1-pentanone (706 mg, 2.77 mmol) in anhydrous THF (12 mL) under nitrogen at 0° C. was added sodium borohydride (209 mg, 5.53 mmol) in water (8 mL) and the resulting mixture stirred at 0° C. for 2 h. Additional sodium borohydride (105 mg, 2.77 mmol) was then added, along with more THF (40 mL), and the resulting mixture stirred at 0° C. for an additional 30 min. The reaction mixture was then partitioned between EtOAc (50 mL) and water (50 mL), the layers separated, and the aqueous re-extracted with EtOAc (50 mL). The combined organic solution was then dried (Na2SO4) filtered, and reduced under vacuum. Purification by SPE (silica, 20 g cartridge), eluted with cyclohexane:EtOAc (gradient 99:1 to 19:1) afforded the title compound as a colourless oil (495 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[CH:8]=[C:7]([Cl:16])[C:3]=1[C:4]([OH:6])=O.Cl.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][NH2:26])=[CH:21][CH:20]=1.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][NH:26][C:4](=[O:6])[C:3]2[C:7]([Cl:16])=[CH:8][C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[CH:10][C:2]=2[Cl:1])=[CH:21][CH:20]=1
Reactant: COCCOc1cc(Cl)c(C(=O)O)c(Cl)c1
Reactant: NCc1ccc(Br)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COCCOc1cc(Cl)c(C(=O)NCc2ccc(Br)cc2)c(Cl)c1
Temperature: 25 °C

Procedure:
2,6-Dichloro-4-(2-methoxyethoxy)benzoic acid (0.1 g, 0.23 mmol), (4-bromophenyl)methanamine hydrochloride (0.1 g, 0.27 mmol), 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (HATU) (0.17 g, 0.27 mmol), and triethylamine (0.15 mL, 0.7 mmol) were combined in DMF (3 mL) and then stirred at room temperature until reaction was completed. The reaction mixture was diluted with ethyl acetate and washed with water and twice with a saturated sodium bicarbonate solution. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuum. The solid resulting was used for next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([O:17][C@@H:18]([CH3:22])[CH2:19][O:20][CH3:21])[CH:16]=1)[C:5]([NH:7][C:8]1[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=1)=[O:6].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.C([O-])(=O)C1C=CC=CC=1.[K+].[CH3:51][C:52]([C:54]1[CH:59]=[CH:58][C:57](F)=[CH:56][CH:55]=1)=[O:53]>CN1C(=O)CCC1>[C:52]([C:54]1[CH:59]=[CH:58][C:57]([O:1][C:2]2[CH:3]=[C:4]([CH:14]=[C:15]([O:17][C@@H:18]([CH3:22])[CH2:19][O:20][CH3:21])[CH:16]=2)[C:5]([NH:7][C:8]2[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=2)=[O:6])=[CH:56][CH:55]=1)(=[O:53])[CH3:51]
Reactant: COC[C@H](C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Reactant: CC(=O)c1ccc(F)cc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Agent: O=C([O-])c1ccccc1
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(C)=O)cc2)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 200 °C
Yield: 49.8 %

Procedure:
A mixture of 3-hydroxy-5-[(1S)-2-methoxy-(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide (400 mg, 1.31 mmol), PS-BEMP (2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diaza-phosphorine, polymer-bound, loading 2.2 mmol/g) (894 mg, 1.97 mmol), potassium benzoate (210 mg, 1.31 mmol) and 4-fluoroacetophenone (0.160 mL, 1.31 mmol) in NMP (10 mL) was heated to 200° C. in a ‘Smith Creator’ microwave for 1 hour. The polymer supported base was filtered off and the resin washed with ethyl acetate (100 mL). The organic phase was partioned with water (100 mL) at which point brine had to be added to resolve the layers. The aqueous phase was washed twice with ethyl acetate (50 mL) and then discarded. The combined organic extracts were Washed with saturated aqueous lithium chloride solution (2×100 mL), 2M sodium hydroxide solution (2×100 mL), water (2×100 mL), brine (100 mL) and dried (MgSO4). The volatiles were removed and the resulting oil purified by on silica, eluting with 0-100% ethyl acetate in iso-hexane, to give the desired product as a colourless foam (276 mg).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6](Cl)[C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.ClCCl.CO>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: C1CNCCN1
Reactant: Fc1ccc(C(Cl)c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Yield: 78.3 %

Procedure:
To 14.32 g (60 mmol) of said 4,4'-difluorobenzhydryl chloride were added 10.46 g (90 mmol) of anhydrous sodium carbonate, 25.84 g (300 mmol) of piperazine and 52 ml of dry chloroform, and the mixture was heated under reflux. To the reaction mixture was added dropwise over 45 minutes 14.32 g (60 mmol) of 4,4'-difluorobenzhydryl chloride in 13 ml of dry chloroform. The mixture was heated under reflux for 18 hours and filtered. The filtrate was washed successively with water and a saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. There was obtained a residue, which was subjected to column chromatography on silica gel to give 13.49 g (47 mmol) of 4,4'-difluorobenzhydryl piperazine from eluates of dichloromethane-methanol (10:1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:14](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Brc1ccc(N2CCNCC2)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1CCN(c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
1-(4-Bromo-phenyl)-piperazine (1 g, 4.1 mmol) and potassium carbonate (1.8 g, 3 eq) in DMF (15 ml) treated with methyl iodide (250 μl, 1.1 equivalents), solution stirred at room temperature overnight. Reaction quenched with deionised water (10 ml), extracted with ethyl acetate. Organic phase washed with sodium hydrogen carbonate to remove any dimethylated impurity, dried and solvent removed to give 1-(4-Bromo-phenyl)-4-methyl-piperazine in 73% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[C:11]([OH:17])[C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19]OS(OC)(=O)=O.[OH-].[Na+].O1CCOCC1>O>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[C:11]([O:17][CH3:19])[C:10]=1[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(OCc2ccccc2)ccc(C=O)c1O
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1c(C=O)ccc(OCc2ccccc2)c1C
Temperature: 90 °C
Reaction time: 6 h

Procedure:
A mixture of 4-benzyloxy-2-hydroxy-3-methyl-benzaldehyde (1.57 g, 6.49 mmol), dimethylsulfate (1.04 ml, 10.9 mmol), NaOH (1.02 g, 25.5 mmol), 1,4-dioxane (20 mL) and water (10 mL) was stirred at 90° C. for 6 h. The reaction mixture was cooled to RT, water (100 mL) was added, extracted with EtOAc (150 mL). The extract was washed with brine (100 mL), dried over Na2SO4 and evaporated. The residue was purified on SiO2 (25 g) column, hexane to toluene. Yield 1.20 g (4.68 mmol, 72%), white solid. 1H NMR (300 MHz, DMSO): δ 10.11 (s, 1H), 7.64 (d, J=8.9 Hz, 1H), 7.49-7.32 (m, 5H), 7.05 (d, J=8.9 Hz, 1H), 5.24 (s, 2H), 3.81 (s, 3H), 2.14 (s, 3H).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:15]=[C:14]([NH2:16])[CH:13]=[CH:12][N:11]=1>C(#N)C>[Cl:9][C:10]1[CH:15]=[C:14]([NH2:16])[C:13]([I:1])=[CH:12][N:11]=1
Reactant: Nc1ccnc(Cl)c1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: Nc1cc(Cl)ncc1I
Temperature: 25 °C
Yield: 28.8 %

Procedure:
N-Iodosuccinimide (24.75 g, 110.0 mmol) was added to a solution of 2-chloro-pyridin-4-ylamine (12.85 g, 100.0 mmol) in acetonitrile (400 mL) and the mixture stirred and held at reflux overnight. Upon cooling to room temperature the solvent was removed in vacuo and residue partitioned between EtOAc (250 mL), saturated sodium thiosulfate (100 mL) and water (250 mL). The organic layer was separated, washed with water (2×250 mL), separated and the solvent removed in vacuo to afford an orange oil that was subjected to column chromatography on silica. Gradient elution with 30-50% EtOAc in petrol afforded a pale orange solid that was rinsed with 25% EtOAc in petrol (80 mL). Solids were collected by filtration and sucked dry to afford the title compound (7.32 g) as an off-white solid. The mother liquors were concentrated to dryness in vacuo and the residues subjected to column chromatography on silica. Elution with 30-50% EtOAc in petrol afforded further pure material (1.90 g). Combined yield: (9.22 g, 36%) 1H NMR (DMSO-d6) 8.20 (1H, s), 6.64 (1H, s), 6.50 (2H, br s). MS: [M+H]+ 255.
Reaction SMILES: [Br:1][CH2:2][C:3]([OH:5])=[O:4].[CH3:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12]O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Br:1][CH2:2][C:3]([O:5][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH3:6])=[O:4]
Reactant: O=C(O)CBr
Reactant: COCCOCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COCCOCCOC(=O)CBr

Procedure:
A solution of 13.9 g (0.1 mmol) of bromoacetic acid in 40 ml of toluene was treated with 11.8 ml (0.1 mol) of diethylene glycol monomethyl ether and 0.8 g of p-toluenesulphonic acid monohydrate. The mixture was heated under reflux on a water separator until water no longer separated. The reaction mixture was washed in succession with water, saturated sodium bicarbonate solution and water. The organic phase was dried over sodium sulphate and concentrated. Flash chromatography of the residue on 500 g of silica gel (elution agent methylene chloride/ether 4:1) yielded 2-(2-methoxyethoxy)ethyl bromoacetate as a pale yellow oil.