Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:21]=[CH:20][C:6]2[NH:7][C:8]3[S:9][C:10]4[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=4[C:12]=3[C:13]([NH2:15])=[N:14][C:5]=2[CH:4]=1.[CH3:22][O:23][CH2:24][CH2:25][C@H:26]1[CH2:31]N[CH2:29][CH2:28][NH:27]1>>[F:2][C:3]1[CH:21]=[CH:20][C:6]2[NH:7][C:8]3[S:9][C:10]4[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=4[C:12]=3[C:13]([N:15]3[CH2:29][CH2:28][NH:27][C@@H:26]([CH2:25][CH2:24][O:23][CH3:22])[CH2:31]3)=[N:14][C:5]=2[CH:4]=1
Reactant: NC1=Nc2cc(F)ccc2Nc2sc3ccccc3c21
Reactant: COCC[C@H]1CNCCN1
Agent: Cl
Product: COCC[C@H]1CN(C2=Nc3cc(F)ccc3Nc3sc4ccccc4c32)CCN1
Temperature: 115 °C
Reaction time: 24 h
Yield: 18 %

Procedure:
Following the method of Example 380 using 8-fluoro-11H-12-thia-6,11-diaza-dibenzo[a,f]azulen-5-ylamine hydrochloride (0.40 g, 1.3 mmol) and (S)-2-(2-methoxy-ethyl)-piperazine (0.36 g, 2.5 mmol), stirring at 115° C. for 24 hours, wash the separated organic layer with 0.1 N NaOH (2×), and extract the combined aqueous layers with ethyl acetate. Combine the organics and wash with a saturated solution of sodium chloride (3×), and then dry (sodium sulfate), filter, and concentrate under reduced pressure to a residue. Purify the residue by flash chromatography, eluting with a gradient of a solution of 5% 2M ammonia in methanol, in dichloromethane (in dichloromethane) to give the title compound (0.096 g). Mass spectrum (APCI+, m/e): 411 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3=[N:13][CH:14]=[N:15][C:16]([NH2:17])=[C:11]3[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:18][N:19]1[CH:23]=[CH:22][N:21]=[C:20]1[C:24](O)=[O:25].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C.CO>[NH2:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([C:4]3[CH:3]=[C:2]([NH:1][C:24]([C:20]4[N:19]([CH3:18])[CH:23]=[CH:22][N:21]=4)=[O:25])[CH:7]=[CH:6][CH:5]=3)[N:9]=[CH:10][C:11]=12
Reactant: Cn1ccnc1C(=O)O
Reactant: Nc1cccc(-n2ncc3c(N)ncnc32)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CO
Product: Cn1ccnc1C(=O)Nc1cccc(-n2ncc3c(N)ncnc32)c1
Reaction time: 0.17 h
Yield: 8.3 %

Procedure:
Title compound 11B, 1-(3-amino-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (30 mg, 1.1 eq, 0.13 mmol) was added to a solution 1-methyl-1H-imidazole-2-carboxylic acid (15 mg, 1.0 eq, 0.12 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (20 mg, 1.1 eq, 0.13 mmol), 1-hydroxybenzotriazole (16 mg, 1.0 eq, 0.12 mmol) in DMF (1 ml) which had been stirred for 10 minutes under an inert atmosphere. The reaction was stirred at room temperature for 18 hours, after which methanol (1 ml) was added, and the solvents were removed in vacuo. The residue was then triturated with methanol and the resultant solid was isolated by filtration to yield the title compound as a yellow solid (3 mg, 0.01 mmol, 8%). LCMS: [M+H]+=335, Rt=1.48 min, 94% purity.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]([CH3:17])=[CH:15][C:14]([O:18][CH:19]([C:24]3[CH:32]=[CH:31][C:27]([C:28]([OH:30])=O)=[CH:26][CH:25]=3)[CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:13][C:12]=2[CH3:33])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.Cl.[NH2:53][CH2:54][C:55]#[N:56]>C1COCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:12]([CH3:33])=[CH:13][C:14]([O:18][CH:19]([C:24]3[CH:25]=[CH:26][C:27]([C:28]([NH:56][CH2:55][C:54]#[N:53])=[O:30])=[CH:31][CH:32]=3)[CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:15][C:16]=2[CH3:17])=[CH:9][CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(OC(CC(C)C)c2ccc(C(=O)O)cc2)cc(C)c1-c1ccc(C(C)(C)C)cc1
Reactant: N#CCN
Agent: COc1nc(Cl)nc(OC)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: Cc1cc(OC(CC(C)C)c2ccc(C(=O)NCC#N)cc2)cc(C)c1-c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.2 %

Procedure:
4-[1-(4′-tert-Butyl-2,6-dimethyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoic acid (1.00 g, 2.25 mmol) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (593 mg, 3.38 mmol) is stirred in THF (25 mL) under nitrogen. N-Methyl morpholine (0.37 mL, 3.38 mmol) is added followed by addition of aminoacetonitrile hydrochloride (229 mg, 2.48 mmol) and the mixture stirred at room temperature for 24 h. The reaction is filtered and the resulting filtrate concentrated and purified by silica gel chromatography, eluting with hexanes using a gradient of 0-100% ethyl acetate to provide 806 mg (74%) of the titled compound as a white solid. 1H NMR.
Reaction SMILES: C1(O)C=C[C:4]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.C1(OC)C(=CC=C(C=1)CC=C)O>>[CH2:4]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH:3]=[CH2:2]
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Agent: C=CCc1ccc(O)c(OC)c1
Product: C=CCc1ccc(O)cc1

Procedure:
Polymerization was carried out in the same manner as in Example 18 except that 4,4'-biphenol and eugenol were replaced by the following bisphenol (BP-16) (21.9 g) ##STR110## and 4-allylphenol (1.6 g), to obtain a polycarbonate comprising the following repeating units and end groups in the following copolymerization ratios wherein bisphenol A, BP-16 and 4-allylphenol structures were present in a molar ratio of 82:15:3. ##STR111##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([O:12][CH3:13])=[O:11].[CH2:14](Br)[CH:15]=[CH2:16]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:16][CH:15]=[CH2:14])[C:10]([O:12][CH3:13])=[O:11]
Reactant: C=CCBr
Reactant: COC(=O)Cc1ccc(F)cc1Cl
Solvent: C1CCOC1
Product: C=CCC(C(=O)OC)c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a chilled (−78° C.) solution of lithium hexamethydisilylazide (27.1 mL, 1 M in THF, 27.1 mmol) in THF (30 mL) was added methyl 2-(2-chloro-4-fluorophenyl)acetate (5 g, 24.7 mmol) in THF (10 mL). After stirring for 0.5 hour, allyl bromide (2.4 mL, 27.1 mmol) was added in a single portion, the cooling bath removed and the reaction allowed to warm to room temperature (0.5 hour). The reaction was diluted with ethyl acetate, washed with water, brine, and the organic phase was dried with sodium sulfate and the solvent was evaporated in vacuo. The residue was purified by column chromatography on silica gel using n-heptane/ethyl acetate (v/v 1:0 to 9:1) as eluent. The title compound was obtained as a colourless liquid (6.0 g, 100%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:6]=2[N:7]=1.[NH2:32][C:33]1[CH:42]=[CH:41][C:36]([C:37]([NH:39][CH3:40])=[O:38])=[CH:35][C:34]=1[O:43][CH3:44].C(=O)([O-])[O-].[K+].[K+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:27]1([NH:26][C:4]2[C:5]3[C:10]([C:11]4[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=4)=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:6]=3[N:7]=[C:2]([NH:32][C:33]3[CH:42]=[CH:41][C:36]([C:37]([NH:39][CH3:40])=[O:38])=[CH:35][C:34]=3[O:43][CH3:44])[N:3]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CNC(=O)c1ccc(N)c(OC)c1
Reactant: C[Si](C)(C)CCOCn1cc(-c2ccc(O)cc2)c2c(NC3CCCC3)nc(Cl)nc21
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CNC(=O)c1ccc(Nc2nc(NC3CCCC3)c3c(-c4ccc(O)cc4)cn(COCC[Si](C)(C)C)c3n2)c(OC)c1
Temperature: 130 °C
Yield: 29.2 %

Procedure:
A mixture of 4-(2-chloro-4-(cyclopentylamino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenol (1 equiv), 4-amino-3-methoxy-N-methylbenzamide (1 equiv), potassium carbonate (2.5 equiv), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.2 equiv), and tris(dibenzylideneacetone)-dipalladium (0.2 equiv) in 1,4-dioxane (0.13 M) was purged with nitrogen and sealed. The reaction mixture was heated to 130° C. for 1.5 h. The reaction was filtered and solvents were removed under reduced pressure. The reaction mixture was loaded directly onto a silica gel column and purified using 15-100% ethyl acetate in hexanes, followed by 100% ethyl acetate. Fractions containing desired product were combined and volatile organic solvents were removed under reduced pressure to give the title compound (29.2% yield) as a brown oil. MS (ESI) m/z 603.5 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][NH2:8])=O.Cl.[CH3:13][NH:14][C:15](=NC)[CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[N:14]([CH3:13])[C:15]([CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20])=[N:8][N:7]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: C=CCCCC(=NC)NC
Reactant: NNC(=O)c1cccc(Cl)c1
Agent: Cl
Product: C=CCCCc1nnc(-c2cccc(Cl)c2)n1C

Procedure:
The title compound was prepared in analogy to Preparation 11 in 0.16 g yield starting from 3-chlorobenzhydrazide (0.52 g) and N,N′-dimethyl-5-hexenimidamide hydrochloride (0.48 g). MS (m/z): 262 [MH]+.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].[Br:9][C:10]1[C:11](Cl)=[N:12][CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1.O>O1CCCC1>[Br:9][C:10]1[C:11]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])=[N:12][CH:13]=[C:14]([C:16]([F:18])([F:17])[F:19])[CH:15]=1
Reactant: OCC(F)(F)F
Reactant: FC(F)(F)c1cnc(Cl)c(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: FC(F)(F)COc1ncc(C(F)(F)F)cc1Br
Reaction time: 0.33 h
Yield: 62.5 %

Procedure:
To 2,2,2-trifluoroethanol (1.4 mL, 19.2 mmol) in tetrahydrofuran (3 mL) was added sodium hydride (60% suspension in oil, 760 mg, 19.0 mmol) and the suspension formed was stirred for 20 minutes. 3-Bromo-2-chloro-5-trifluoromethylpyridine (1.0 g, 3.84 mmol) was then added and the solution stirred at room temperature for 16 hrs. Water (100 mL) was added and the mixture formed was extracted with ethyl acetate (2×100 mL). The extracts were dried (MgSO4) and concentrated to give the product as an oil (776 mg, 2.4 mmol, 62% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:15](=[O:17])[CH3:16].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>O1CCCC1.[Zn]>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:15]([OH:17])([CH3:16])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)CBr
Reactant: CC(=O)c1ccc(-c2ccc(F)cn2)cc1F
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)CC(C)(O)c1ccc(-c2ccc(F)cn2)cc1F
Temperature: 0 °C

Procedure:
A mixture of 1-[2-fluoro-4-(5-fluoropyridin-2-yl)phenyl]ethanone (3.6 g, 15.3 mmol) and ethyl bromoacetate (12.8 g, 76.5 mmol) in tetrahydrofuran (35 mL) was added dropwise to a refluxing suspension of zinc (Reike, activated) (5 g) in tetrahydrofuran (100 mL). After stirring at reflux for a further 15 min, the reaction was cooled, poured into ice water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (sodium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 10-50% ethyl acetate/hexane over 48 fractions afforded ethyl 3-[2-fluoro-4-(5-fluoropyridin-2-yl)phenyl]-3-hydroxybutanoate.
Reaction SMILES: N([O-])=O.[Na+].[Cl:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]([F:13])[C:7]=1N.C(OCC)C.[ClH:20]>O.[Cu]Cl>[Cl:20][C:7]1[C:6]([Cl:5])=[C:11]([CH3:12])[CH:10]=[CH:9][C:8]=1[F:13]
Reactant: Cl
Reactant: Cc1ccc(F)c(N)c1Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: Cc1ccc(F)c(Cl)c1Cl
Temperature: -5 °C
Reaction time: 0.08 h

Procedure:
Sodium nitrite (0.172 g, 2.5 mmol) was added to a stirred solution of 2-chloro-6-fluoro-3-methyl-phenylamine (0.400 g, 2.5 mmol) in water (20 ml) and 37% aqueous hydrogen chloride (5 ml) at −5° C. The mixture was stirred at −5° C. for 5 minutes and then added in one pot to a solution of copper (I) chloride (0.742 g, 7.5 mmol) in 37% aqueous hydrogen chloride (5 ml) whilst maintaining the temperature at −5 to 0° C. The reaction mixture was heated to 38° C. and stirred for 1 hr then the mixture was cooled and diethyl ether (20 ml) was added. The organic phase was separated and washed with 1N aqueous hydrogen chloride and then with water. The organic layer was then dried over sodium sulphate and concentrated in vacuo. The crude residue was purified by flash silica column chromatography, eluting with petroleum ether, to give 2,3-dichloro-1-fluoro-4-methylbenzene (0.090 g, 0.5 mmol) as a white solid.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[C:17]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]=O)=[CH:23][C:22]=1[N+:29]([O-:31])=[O:30])([CH3:20])([CH3:19])[CH3:18]>CCCCCC.CN(C)C=O.C(OCC)C>[C:17]([C:21]1[CH:26]=[CH:25][C:24](/[CH:27]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:23][C:22]=1[N+:29]([O-:31])=[O:30])([CH3:20])([CH3:18])[CH3:19]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CC(C)(C)c1ccc(C=O)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCOC(=O)/C=C/c1ccc(C(C)(C)C)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 57.1 %

Procedure:
8.0 g (0.18 mol) of sodium hydride (as a 55% w/w dispersion in mineral oil) was washed twice with hexane and suspended in 250 ml of dimethylformamide. A solution of 31 ml (0.16 mol) of ethyl diethylphosphonoacetate in 50 ml of dimethylformamide was then added, with ice-cooling, to the suspension, and the resulting mixture was stirred at room temperature for 40 minutes. At the end of this time, the mixture was ice-cooled and a solution of 27 g (0.13 mol) of 2-t-butyl-5-formyl-1-nitrobenzene [prepared as described in step (i) above] in 50 ml of dimethylformamide was added thereto over a period of 30 minutes, after which the mixture was stirred for 1 hour. The reaction mixture was then diluted with diethyl ether, and the diluted solution was washed with a 10% w/w aqueous solution of hydrochloric acid and with water, in that order, after which it was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 1:6 by volume mixture of ethyl acetate and hexane as the eluent, to give 20.6 g of the title compound as crystals, melting at 77-78° C. (from ethyl acetate-hexane).
Reaction SMILES: [CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]([CH3:19])[CH2:10][C:9]1=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1>O>[CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]([CH3:19])[CH:10]([CH2:29][C:28]2[CH:31]=[CH:32][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)[C:9]1=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CBr)cc1
Reactant: CC1=Nc2ccccc2N(Cc2ccccc2)C(=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(CC2C(=O)N(Cc3ccccc3)c3ccccc3N=C2C)cc1
Reaction time: 0.25 h
Yield: 74.6 %

Procedure:
To a solution of 1-benzyl-4-methyl-1,3-dihydro-1,5-benzodiazepin-2(2H)-one (3.0 g, 13.1 mmol) in N-dimethylformamide (20 mL) was added sodium hydride (content 60%, 0.51 g, 12.8 mmol). The mixture was stirred for 15 minutes, to which was added 4-methoxybenzylbromide (2.3 g, 11.5 mmol), and the mixture was stirred for further 30 minutes. The reaction mixture was diluted with water, which was extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The concentrate was crystallized from ethyl acetate-hexane to give 3.3 g of the titled compound. Yield 76%. m.p. 136°-137° C.
Reaction SMILES: [Cu][C:2]#[N:3].Br[C:5]1[C:14]2[CH2:13][CH2:12][N:11]([C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:10][CH:9]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:8]=2[S:7][CH:6]=1.CO>CN(C)C=O>[C:21]1([CH:9]2[C:8]3[S:7][CH:6]=[C:5]([C:2]#[N:3])[C:14]=3[CH2:13][CH2:12][N:11]([C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:10]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: N#C[Cu]
Reactant: O=C(N1CCc2c(Br)csc2C(c2ccccc2)C1)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Product: N#Cc1csc2c1CCN(C(=O)C(F)(F)F)CC2c1ccccc1

Procedure:
A mixture of copper (I) cyanide (0.45 g) and 3-bromo-8-phenyl-5,6,7,8-tetrahydro-6-trifluoroacetyl-4H-thieno[2,3-d]azepine (1.0 g) in dry dimethylformamide (10 ml) was heated under reflux for 5 hours. After allowing to cool to room temperature methanol (35 ml) was added and the mixture stirred vigorously, filtered and the filtrate evaporated to a yellow oil. Chromatography on silica eluting with diethylether gave the nitrile product, m.p. 107°.
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([Cl:19])[CH:17]=3)[NH:12][C:11]=2[C:20](O)=[O:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][N:24]1[CH:31]=[N:30][C:26]([CH2:27][CH2:28][NH2:29])=[CH:25]1>>[CH3:23][N:24]1[CH:25]=[C:26]([CH2:27][CH2:28][NH:29][C:20]([C:11]2[NH:12][C:13]3[C:18]([C:10]=2[S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:8])=[O:9])=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)=[O:21])[N:30]=[CH:31]1
Reactant: O=C(O)c1[nH]c2ccc(Cl)cc2c1S(=O)(=O)c1ccccc1
Reactant: Cn1cnc(CCN)c1
Product: Cn1cnc(CCNC(=O)c2[nH]c3ccc(Cl)cc3c2S(=O)(=O)c2ccccc2)c1

Procedure:
Reaction of 3-phenylsulfonyl-5-chloroindole-2-carboxylic acid with 1-methylhistamine under the conditions of Example 37 provides the title compound.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4](Br)=[N:5][N:6]=1.C([O-])([O-])=O.[K+].[K+].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.O>CN(C)C=O>[Br:1][C:2]1[S:3][C:4]([O:22][C:19]2[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)=[N:5][N:6]=1
Reactant: COc1ccc(O)cc1
Reactant: Brc1nnc(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Oc2nnc(Br)s2)cc1
Temperature: 90 °C
Yield: 98.2 %

Procedure:
2,5-dibromo-1,3,4-thiadiazole (2 g, 8.16 mmol), (prepared according to Example 1 as described in U.S. Pat. No. 5,847,149) was dissolved in N,N-dimethyl formamide (65 mL) and the resulting solution was treated with K2CO3 (1.69 g, 12.24 mmol) and 4-methoxyphenol (1.01 g, 8.16 mmol). The reaction mixture was heated at 90° C. for 1.5 hours, cooled to 25° C., poured into water (150 mL) and extracted with diethyl ether (2×150 mL) The combined organic layers were washed with 1N NaOH (1×100 mL), water (3×100 mL) and brine (1×100 mL), dried (Na2SO4), filtered and evaporated to provide 2.3 g of a light yellow oil. The residue was purified by flash chromatography on silica gel eluting with a solvent gradient from 1% to 14% ethyl acetate in hexanes to provide 1.86 g (79%) of the title compound, 1H NMR (300 MHz, DMSO-d6) δ ppm 7.40 (d, J=9.19 Hz, 2H) 7.04 (d, J=9.19 Hz, 2H) 3.79 (s, 3H); MS (APCI) m/z 289 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH2:11]O.S(Cl)([Cl:15])=O>ClCCl>[Cl:15][CH2:11][C:3]1[O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:2]=1[CH3:1]
Reactant: O=S(Cl)Cl
Reactant: Cc1c(CO)oc2ccccc12
Solvent: ClCCl
Product: Cc1c(CCl)oc2ccccc12
Reaction time: 2 h

Procedure:
To a solution of (3-methyl-benzofuran-2-yl)-methanol (1.12 g, 6.9 mmol) in 12 mL of dichloromethane was added 2.8 mL of thionyl chloride. The color of the reaction turned from pink initially to light yellow. After 2 h the reaction was worked up and 2-chloromethyl-3-methyl-benzofuran was obtained in quantitative yield. 1H NMR (400 MHz, CDCl3) δ ppm 2.3 (s, 3 H) 4.7 (s, 2 H) 7.2 (m, 1 H) 7.3 (m, 1 H) 7.5 (m, 1 H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[Cl:11][S:12](O)(=[O:14])=[O:13]>>[Cl:11][S:12]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[OH:1])[C:6]([OH:8])=[O:7])(=[O:14])=[O:13]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(O)c1ccc(O)cc1
Product: O=C(O)c1ccc(O)c(S(=O)(=O)Cl)c1
Temperature: 25 °C
Yield: 69 %

Procedure:
55 g of p-Hydroxybenzoic acid (I) (Aldrich) was added in small portions to 545 g of chlorosulfonic acid (Aldrich) while stirring at room temperature. After 18 hours the reaction mixture was poured in a thin stream upon crushed ice (5 liters). The product was filtered and the precipitate dissolved in ethyl acetate. The solution was then washed with brine, dried with magnesium sulfate, filtered and evaporated to yield 65 g of 3-chlorosulfonyl-4-hydroxybenzoic acid (II), m.p. 181°-182° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]([NH2:13])=[O:12])[CH:6]=[CH:7][CH:8]=1.[Cl:16][CH2:17][C:18]([CH2:20]Cl)=O>C1(C)C=CC=CC=1>[Cl:16][CH2:17][C:18]1[N:13]=[C:11]([CH:10]=[CH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:14])([F:15])[F:1])[CH:4]=2)[O:12][CH:20]=1
Reactant: NC(=O)C=Cc1cccc(C(F)(F)F)c1
Reactant: O=C(CCl)CCl
Solvent: Cc1ccccc1
Product: FC(F)(F)c1cccc(C=Cc2nc(CCl)co2)c1

Procedure:
2.0 g (9.3 mmol) 3-(3-Trifluoromethyl-phenyl)-acrylamide, 4.13 g (32.5 mmol) 1,3-dichloro acetone and 20.0 ml toluene were kept at reflux temperature for 16 h with continuous removal of water by use of a Dean-Stark trap. After removal of solvents in vacuo, the residue was purified by flash column chromatography (heptanes/ethyl acetate 2:1). Yield: 1.92 g (72%) 4-Chloromethyl-2-[2-(3-trifluoromethyl-phenyl)-vinyl]-oxazole as tan solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:10](=[O:25])[N:11]([CH3:24])[CH:12]=[C:13](B3OC(C)(C)C(C)(C)O3)[CH:14]=2)[CH:5]=[C:4]([CH3:26])[N:3]=1.Cl[C:28]1[CH:33]=[CH:32][N:31]=[C:30]([N:34]2[CH2:45][CH2:44][N:43]3[C:36](=[CH:37][C:38]4[CH2:39][C:40]([CH3:47])([CH3:46])[CH2:41][C:42]=43)[C:35]2=[O:48])[C:29]=1[CH:49]=[O:50].C([O-])(=O)C.[Na+].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C.O>[CH3:46][C:40]1([CH3:47])[CH2:39][C:38]2[CH:37]=[C:36]3[N:43]([CH2:44][CH2:45][N:34]([C:30]4[C:29]([CH:49]=[O:50])=[C:28]([C:13]5[CH:14]=[C:9]([NH:8][C:6]6[CH:5]=[C:4]([CH3:26])[N:3]=[C:2]([CH3:1])[N:7]=6)[C:10](=[O:25])[N:11]([CH3:24])[CH:12]=5)[CH:33]=[CH:32][N:31]=4)[C:35]3=[O:48])[C:42]=2[CH2:41]1
Reactant: CC1(C)Cc2cc3n(c2C1)CCN(c1nccc(Cl)c1C=O)C3=O
Reactant: Cc1cc(Nc2cc(B3OC(C)(C)C(C)(C)O3)cn(C)c2=O)nc(C)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: Cc1cc(Nc2cc(-c3ccnc(N4CCn5c(cc6c5CC(C)(C)C6)C4=O)c3C=O)cn(C)c2=O)nc(C)n1
Temperature: 100 °C
Yield: 79.7 %

Procedure:
A 100-mL round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 173b (250 mg, 0.70 mmol), 4-chloro-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridine-3-carbaldehyde 108a (240 mg, 0.70 mmol), Pd(dppf)Cl2 (57 mg, 0.071 mmol), sodium acetate (19 mg, 1.4 mmol), K3PO4 (316 mg, 1.4 mmol), water (0.5 mL), and acetonitrile (15 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 3 h. After this time the reaction was filtered and the filtrate was evaporated in vacuo. The resulting residue was recrystallized from ethyl acetate to afford 173c as a brown solid (300 mg, 80%). MS-ESI: [M+H]+ 538.3.