Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]([CH:19]=[O:20])=[CH:17][CH:16]=[CH:15][C:10]=1[C:11](OC)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl.[Cl:24][C:25]1[CH:26]=[N+:27]([O-:50])[CH:28]=[C:29]([Cl:49])[C:30]=1[CH2:31][C@@H:32]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH:41]([F:43])[F:42])=[C:36]([O:44][CH2:45][CH:46]2[CH2:48][CH2:47]2)[CH:35]=1)[OH:33].Cl.CN(C)CCCN=C=NCC>C1COCC1.CO.CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:18]([CH:19]=[O:20])=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([O:33][C@H:32]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH:41]([F:43])[F:42])=[C:36]([O:44][CH2:45][CH:46]2[CH2:48][CH2:47]2)[CH:35]=1)[CH2:31][C:30]1[C:29]([Cl:49])=[CH:28][N+:27]([O-:50])=[CH:26][C:25]=1[Cl:24])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: COC(=O)c1cccc(C=O)c1OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: O=Cc1cccc(C(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)c1OCc1ccccc1
Reaction time: 0.5 h
Yield: 90.2 %

Procedure:
A solution of methyl 2-(benzyloxy)-3-formylbenzoate (598 mg, 2.21 mmol) in THF (4 mL) and MeOH (2 mL) and a solution of 4 N NaOH (1.10 mL, 4.43 mmol) was added at 0° C. and the reaction mixture stirred for 30 minutes. 2N HCl was then added at 0° C. to adjust the pH to ˜2. After concentration in vacuo, the residue was azeotroped with toluene to dryness. The crude solid was dissolved in DMF (4.4 mL). To half of this solution (2.2 mL, 1.1 mmol) was added (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (553 mg, 1.32 mmol), 4-(dimethylamino)-pyridine (67 mg, 0.55 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (422 mg, 2.2 mmol and the resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with DCM (100 mL), the organic phase washed with sat. NaHCO3 (2×50 mL). The phases were separated over a hydrophobic frit and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-100% EtOAc in isohexane to give the title compound as a white solid (784 mg, 54% over two steps).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@@H:10]3[O:19][C@@H:9]3[C:8]=2[CH:20]=1)([O-:3])=[O:2].[F:21][C:22]([F:38])([F:37])[C:23]1[CH:28]=[CH:27][C:26]([NH:29][CH2:30][C:31]2[N:32]=[N:33][N:34]([CH3:36])[N:35]=2)=[CH:25][CH:24]=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@H:10]([OH:19])[C@@H:9]([N:29]([C:26]3[CH:25]=[CH:24][C:23]([C:22]([F:38])([F:37])[F:21])=[CH:28][CH:27]=3)[CH2:30][C:31]3[N:32]=[N:33][N:34]([CH3:36])[N:35]=3)[C:8]=2[CH:20]=1)([O-:3])=[O:2]
Reactant: Cn1nnc(CNc2ccc(C(F)(F)F)cc2)n1
Reactant: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H]2O[C@H]21
Product: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H](N(Cc2nnn(C)n2)c2ccc(C(F)(F)F)cc2)[C@H]1O
Yield: 16 %

Procedure:
The same procedure as step 3 of example 1 was accomplished, except for using the epoxide compound (300 mg, 1.07 mmol) obtained in step 1 of example 2 and N-(4-trifluoromethylphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine. The crude product was purified by silica gel column chromatography (developing solvent-n-hexane:ethyl acetate=2:1), to give desired compound (92 mg, yield: 16%).
Reaction SMILES: CN(C=[N:5][S:6]([CH2:9][CH:10]([CH:13]([CH3:15])[CH3:14])[CH2:11][OH:12])(=[O:8])=[O:7])C.Cl[C:17]1[C:18]([CH3:26])=[CH:19][C:20]2[N:21]([N:23]=[CH:24][N:25]=2)[N:22]=1>>[CH:13]([CH:10]([CH2:9][S:6](=[O:7])(=[O:8])[NH2:5])[CH2:11][O:12][C:17]1[C:18]([CH3:26])=[CH:19][C:20]2[N:21]([N:23]=[CH:24][N:25]=2)[N:22]=1)([CH3:14])[CH3:15]
Reactant: Cc1cc2ncnn2nc1Cl
Reactant: CC(C)C(CO)CS(=O)(=O)N=CN(C)C
Product: Cc1cc2ncnn2nc1OCC(CS(N)(=O)=O)C(C)C

Procedure:
Using 3-(N,N-dimethylaminomethylene)aminosulfonyl-2-isopropyl-1-propanol and 6-chloro-7-methyl[1,2,4]triazolo[1,5-b]pyridazine, the same reaction as in Example 6 was conducted to produce the title compound. m.p. 196°-197° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]([F:23])([F:22])[F:21])=[C:6]([CH:19]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16](I)=[CH:17][C:9]1=2.[CH2:24]([O:26][C:27]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)=[O:28])[CH3:25]>>[CH2:24]([O:26][C:27](=[O:28])[C:29]1[CH:34]=[CH:33][C:32]([C:16]2[CH:15]=[N:14][C:10]3[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]4[CH:19]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[C:20]([F:23])([F:22])[F:21])[C:9]=3[CH:17]=2)=[CH:31][CH:30]=1)[CH3:25]
Reactant: FC(F)(F)c1ccc(Cl)cc1CN1CCNc2ncc(I)cc21
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Product: CCOC(=O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1

Procedure:
1-[5-Chloro-2-(trifluoromethyl)benzyl]-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (7.0 g) was reacted with 4-ethoxycarbonyl phenyl boronic acid as in General Procedure 4A. The title compound was obtained as a yellow solid (71% yield). M.p.=154° C., LCMS: m/z=476.04 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.40, (t, 3H), 3.49 (m, 2H), 3.71 (m, 2H), 4.35 (q, 2H), 4.61 (s, 2H), 5.72 (bs, 1H), 6.62 (s, 1H), 7.44 (m, 3H), 7.50 (s, 1H), 7.63 (d, 1H), 7.72 (s, 1H), 8.07 (d, 2H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)=[N:13][N:14]3[C:19]=2[CH:18]=[CH:17][CH:16]=[N:15]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].I[CH2:28][CH3:29].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:28]([O:26][C:23]1[CH:22]=[CH:21][C:20]([C:12]2[C:11]([C:8]3[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=3)=[C:19]3[N:14]([N:15]=[CH:16][CH:17]=[CH:18]3)[N:13]=2)=[CH:25][CH:24]=1)[CH3:29]
Reactant: CCI
Reactant: CS(=O)(=O)c1ccc(-c2c(-c3ccc(O)cc3)nn3ncccc23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1ccc(-c2nn3ncccc3c2-c2ccc(S(C)(=O)=O)cc2)cc1

Procedure:
4-[3-(4-methanesulfonyl-phenyl)-pyrazolo[1,5-b]pyridazin-2-yl]-phenol (663 mg, 1.82), iodoethane (1 eq) and potassium carbonate (2 eq) in acetonitrile (30 ml ) were heated at reflux under nitrogen for 18 h. The cooled reaction mixture was partitioned between water (30 ml) and ethyl acetate (30 ml). The organic phase was collected, dried and purified by chromatography to give the title compound (547 mg) as a cream foam.
Reaction SMILES: Cl[C:2]([F:7])([F:6])C([O-])=O.[Na+].C(=O)([O-])[O-].[K+].[K+].[F:15][C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:17]=1[OH:25]>CN(C=O)C.O>[F:6][CH:2]([F:7])[O:25][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([N+:22]([O-:24])=[O:23])[C:16]=1[F:15]
Reactant: O=C([O-])C(F)(F)Cl
Reactant: O=[N+]([O-])c1cccc(O)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cccc(OC(F)F)c1F
Temperature: 110 °C
Reaction time: 6 h

Procedure:
To a mixture of sodium 2-chloro-2,2-difluoroacetate (7.14 g, 46.8 mmol) and potassium carbonate (3.50 g, 25.3 mmol) in DMF (10 mL) and water (2.5 mL) at 110° C. was added a solution of 2-fluoro-3-nitrophenol (2 g, 12.65 mmol) in DMF (10 mL) and the mixture was stirred at 110° C. for 6 h. After cooling down, the mixture was quenched with water and extracted with EtOAc. The organic layer was then washed with water, brine and dried over Na2SO4, filtered and concentrated. The crude material was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 1:1). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.79 (td, 1H), 7.45 (t, 1H), 5.15 (m, 1H), 7.44 (m, 1H). tR (HPLC conditions f): 2.09 min.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)[N:3]=1.O.[NH2:23][NH2:24]>>[NH:23]([C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)[N:3]=1)[NH2:24]
Reactant: NN
Reactant: Cn1cnc2c(Nc3ccc([N+](=O)[O-])cc3)nc(Cl)nc21
Solvent: O
Product: Cn1cnc2c(Nc3ccc([N+](=O)[O-])cc3)nc(NN)nc21

Procedure:
Was prepared according to Example 8 from (2-chloro-9-methyl-9H-purin-6-yl)-(4-nitro-phenyl)-amine and hydrazine monohydrate.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.Cl.[NH2:20][CH:21]([CH:26]1[CH2:28][CH2:27]1)[CH2:22][C:23]([NH2:25])=[O:24]>>[NH2:25][C:23](=[O:24])[CH2:22][CH:21]([NH:20][C:10]([C:7]1[CH:6]=[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:9][N:8]=1)=[O:12])[CH:26]1[CH2:28][CH2:27]1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Reactant: NC(=O)CC(N)C1CC1
Agent: Cl
Product: NC(=O)CC(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)C1CC1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 48c) and 3-amino-3-cyclopropylpropanamide hydrochloride (CAN 1354953-76-6) as starting materials and isolated (50 mg, 35%); MS (ESI, m/z): 372.5 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=2)=[CH:11][C:10]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1>CO>[CH2:27]([O:26][C:10]1[CH:11]=[C:12]([CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([NH2:23])=[CH:21][CH:22]=2)[CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=[N+]([O-])c1ccc(C=Cc2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)cc1
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(CCc2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)cc1
Yield: 65.5 %

Procedure:
The 1,2-dibenzyloxy-4-[2-(4-nitrophenyl)ethenyl]benzene (10 g, 22 mmole) is dissolved in methanol (50 ml), THF (100 ml) and reacted with Ra--N1 (1.5 g). Reduction under a pressure of 512 psi at 19.5° C. affords 5.9 g (60%) of 4-[-2-(-3,4-dibenzyloxyphenyl)ethyl]benzenamine, mp 97°-101° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C1COCC1>[CH3:24][S:25]([O:16][CH2:15][CH2:14][N:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:13][CH2:12]1)(=[O:27])=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCN(CCO)CC1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(CCOS(C)(=O)=O)CC1

Procedure:
A solution of tert-butyl-4-(2-hydroxyethyl)-piperazine-1-carboxylate (Maybridge, 0.29 g, 1.2 mmol), triethylamine (0.56 mL, 4.1 mmol), and methanesulfonyl chloride (0.15 mL, 1.9 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.[CH3:13][NH:14][O:15][CH3:16].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl.O>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([N:14]([O:15][CH3:16])[CH3:13])=[O:5]
Reactant: CNOC
Reactant: Nc1ccc(Cl)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CON(C)C(=O)c1cc(Cl)ccc1N
Temperature: 25 °C
Reaction time: 12 h
Yield: 59.2 %

Procedure:
A solution of 2-amino-5-chlorobenzoic acid (5.0 g, 29.1 mmol), N,O-dimethylhydroxylamine hydrochloride (3.1 g, 32.0 mmol), and HOBt (3.9 g, 29.1 mmol) in CH2Cl2 (100 mL) was cooled to 0° C. and treated with EDCI (17.3 g, 87.3 mmol). The reaction was stirred at 25° C. for 12 h, diluted with H2O, and extracted with EtOAc. The organics were dried (Na2SO4), filtered, and concentrated. Chromatography (SiO2, 1:1 Hex/EtOAc) gave 8 (3.7 g, 60%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([O:17]CC3C=CC=CC=3)[CH:16]=[C:11]2[CH:10]=[C:9]1[C:25]([N:27]1[CH2:32][CH2:31][C:30]([F:34])([F:33])[CH2:29][CH2:28]1)=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C>CO>[C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([OH:17])[CH:16]=[C:11]2[CH:10]=[C:9]1[C:25]([N:27]1[CH2:32][CH2:31][C:30]([F:34])([F:33])[CH2:29][CH2:28]1)=[O:26])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1c(C(=O)N2CCC(F)(F)CC2)cc2cc(OCc3ccccc3)cnc21
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)n1c(C(=O)N2CCC(F)(F)CC2)cc2cc(O)cnc21
Reaction time: 0.25 h
Yield: 77.8 %

Procedure:
To the solution of 0.3 g (0.64 mmol) 5-benzyloxy-2-(4,4-difluoro-piperidine-1-carbonyl)-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester in 3 ml methanol and 4 ml ethyl acetate 45 mg palladium on activated charcoal (10%) was added and the suspension was hydrogenated at 1.3 bar for 15 min. The suspension was filtered over Dicalite Speed Plus®(Aldrich), the filtercake was washed with ethyl acetate and methanol and the filtrate evaporated. The residue was purified by flash column chromatography on silica gel with ethyl acetate:n-heptane (2:1) as eluant to give 0.19 g (78%) of the desired compound as a colorless solid.
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH2:6][CH:5]=[CH:4][CH2:3]1.[NH2:11][C@@H:12]([CH2:30][O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1)=[O:14]>>[CH2:32]([O:31][CH2:30][C@H:12]([NH:11][C:8](=[O:10])[CH2:7][N:2]1[CH2:3][CH:4]=[CH:5][CH2:6]1)[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1)=[O:14])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: O=C(O)CN1CC=CC1
Agent: Cl
Product: O=C(CN1CC=CC1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 65.6 %

Procedure:
Proceeding as in Example 1, but substituting 2-(2,5-dihydro-1H-pyrrol-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 214, (S)-3-(benzyloxy)-2-(2-(2,5-dihydro-1H-pyrrol-1-yl)acetamido)-N-(4-(4-fluorophenoxy)phenyl)propanamide (25.7 mg, 65.6%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.21 (s, 1H), 7.96 (d, 1H), 7.60 (d, 2H), 7.27-7.32 (m, 5H), 7.21 (m, 2H), 6.98-7.04 (m, 4H), 4.72 (m, 1H), 4.52 (s, 2H), 3.69-3.74 (m, 2H), 3.30 (s, 2H), 3.13 (d, 1H), 2.56 (d, 2H), 1.72 (s, 1H). MS (EI) for C28H28FN3O4. found 490.5 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH3:13])([CH3:12])[CH2:4][CH2:3]1.[Cl-].[Al+3].[Cl-].[Cl-].[Cl:19][CH2:20][C:21](Cl)=[O:22]>C(Cl)Cl>[Cl:19][CH2:20][C:21]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[C:5]([CH3:13])([CH3:12])[CH2:4][CH2:3][C:2]2([CH3:14])[CH3:1])=[O:22]
Reactant: O=C(Cl)CCl
Reactant: CC1(C)CCC(C)(C)c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc(C(=O)CCl)ccc21
Reaction time: 8 h

Procedure:
A solution of 68 g (0.36 mole) of 1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene in 200 ml of methylene chloride was added dropwise at 0°-5° C. to a solution of 72 g (0.55 mole) of anhydrous aluminum chloride and 0.7 g (0.36 mole) of chloroacetyl chloride in 270 ml of dry methylene chloride. Stirring was then carried out overnight at room temperature. The mixture was poured onto ice/water and extracted with methylene chloride, and the organic phase was washed several times with water, dried over sodium sulfate and evaporated down. 92.2 g of 6-chloroacetyl-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene remained as an oil. The structure was determined by H-NMR spectroscopy.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][N:9]=[N+:10]=[N-:11])[CH2:3][CH2:2]1.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].[C:25]([C:27]1[CH:32]=[CH:31][C:30]([S:33]([N:36]2[CH:40]=[CH:39][C:38](/[CH:41]=[CH:42]/[C:43]([NH:45][O:46][CH:47]3[CH2:52][CH2:51][CH2:50][CH2:49][O:48]3)=[O:44])=[CH:37]2)(=[O:35])=[O:34])=[CH:29][CH:28]=1)#[CH:26].C(Cl)Cl>O.CC(O)(C)C>[O:48]1[CH2:49][CH2:50][CH2:51][CH2:52][CH:47]1[O:46][NH:45][C:43](=[O:44])/[CH:42]=[CH:41]/[C:38]1[CH:39]=[CH:40][N:36]([S:33]([C:30]2[CH:29]=[CH:28][C:27]([C:25]3[N:11]=[N:10][N:9]([CH2:8][CH2:7][N:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)[CH:26]=3)=[CH:32][CH:31]=2)(=[O:35])=[O:34])[CH:37]=1
Reactant: C#Cc1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)NOC3CCCCO3)c2)cc1
Reactant: [N-]=[N+]=NCCN1CCOCC1
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: O=C(/C=C/c1ccn(S(=O)(=O)c2ccc(-c3cn(CCN4CCOCC4)nn3)cc2)c1)NOC1CCCCO1
Yield: 27 %

Procedure:
To a stirred mixture of 2-morpholino-ethylazide (0.30 mmol) in water (2 ml) are added CuSO4 pentahydrate (0.02 mmol), sodiumascorbate (0.04 mmol) and (E)-3-[1-(4-Ethynyl-benzenesulfonyl)-1H-pyrrol-3-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (0.30 mmol) in t-BuOH (1 ml) at room temperature. The reaction mixture is stirred over night. After addition of DCM the organic phase is separated, evaporated under reduced pressure and purified by prep. HPLC yielding 0.081 mmol of the title compound.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][C:7]=1[O:15][CH3:16].FC(F)(F)C(OI(C1C=CC=CC=1)OC(=O)C(F)(F)F)=[O:20].O.CC(O)=O>CC#N>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH2:13][OH:20])=[CH:8][C:7]=1[O:15][CH3:16]
Reactant: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Solvent: O
Solvent: CC#N
Solvent: CC(=O)O
Product: COc1cc(C(=O)CO)ccc1OCCCCl
Yield: 32.8 %

Procedure:
A solution of 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (4.3 g, 17.7 mmol), [bis(trifluoroacetoxy)iodo]benzene (15.6 g, 36.2 mmol), H2O (18 ml), CH3CO2H (2.8 ml) and CH3CN (90 ml) was refluxed for 3 hours. The CH3CN was removed under reduced pressure and the resulting yellow liquid was partitioned between H2O and CH2Cl2. The biphasic mixture was filtered, the organic phase collected, washed with saturated NaHCO3 solution and concentrated to afford 1.5 g of an amorphous brown solid. The solid was flash chromatographed on silica gel, eluting the column with 5% EtOAc/CH2Cl2. Concentration of similar fractions afforded 0.7 g of the compound as a pale yellow solid, m.p. 99°-101° C.
Reaction SMILES: [CH2:1]([N:5]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=1)[C:6](=[O:28])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]2[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=2[C:20]([O:22]C)=[O:21])=[CH:11][CH:10]=1)[CH:2]([CH3:4])[CH3:3].O.[OH-].[Li+]>C1COCC1>[CH2:1]([N:5]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]([F:37])([F:38])[F:39])=[CH:34][CH:35]=1)[C:6](=[O:28])[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][O:17][C:18]2[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=2[C:20]([OH:22])=[O:21])=[CH:13][CH:14]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)c1ccccc1OCCc1ccc(OCC(=O)N(Cc2ccc(C(F)(F)F)cc2)CC(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CN(Cc1ccc(C(F)(F)F)cc1)C(=O)COc1ccc(CCOc2ccccc2C(=O)O)cc1
Yield: 56 %

Procedure:
Methyl 2-{2-[4-(2-{isobutyl[4-(trifluoromethyl)benzyl]amino}-2-oxoethoxy)phenyl]-ethoxy}benzoate (0.242 g, 0.455 mmol) was dissolved in a mixture of THF (freshly distilled)/water (2/1, 3 ml), lithium hydroxide (0.218 g, 0.909 mmol) was added. The reaction was performed in a single node microwave oven (5 min, 150 deg). THF was removed by evaporation. Water was added (10 ml) and the basic water phase was washed with diethyl ether (2×10 ml). Addition of HCl (2 ml, 1 M, pH 1). The water phase was extracted with two portions of DCM (20 ml), the organic phase was dried (MgSO4) and the solvent was removed by evaporation to give 0.135 g of 2-{2-[4-(2-{isobutyl[4-(trifluoromethyl)benzyl]amino}-2-oxoethoxy)phenyl]ethoxy}benzoic acid (yield 57.3%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH2:22])[CH:10]=[CH:11][C:12]=2[O:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[CH:5][CH:4]=[N:3]1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29].C(N(CC)CC)C>C1COCC1>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28]([NH:22][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[CH:8]=1)=[O:29]
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: Cn1nccc1-c1cc(N)ccc1OCCN1CCOCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)Nc2ccc(OCCN3CCOCC3)c(-c3ccnn3C)c2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50.4 %

Procedure:
A mixture of 3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenylamine (120 mg, 0.40 mmole), 3-methoxy-benzoyl chloride (81 mg, 0.48 mmole), and triethylamine (0.1 mL, 0.79 mmole) in 5 mL THF was stirred at room temperature for 10 minutes. The mixture was purified by HPLC to give the title compound as a white solid (TFA salt, 88 mg, 51%). 1H NMR (Acetone-d6, 400 MHz) 2.99-3.21 (m, 2H), 3.22-3.45 (m, 2H), 3.66 (t, J=4.80 Hz, 2H), 3.75 (s, 3H), 3.85 (s, 3H), 3.79-3.89 (m, 4H), 4.58 (t, J=4.80 Hz, 2H), 6.29 (d, J=2.02 Hz 1H), 7.13 (dd, J=8.34, 2.53 Hz, 1H), 7.22 (d, J=8.84 Hz, 1H), 7.42 (t, J=7.83 Hz, 1H), 7.47 (d, J=1.77 Hz, 1H), 7.52 (t, J=1.77 Hz, 1H), 7.56 (d, J=7.07 Hz, 1H), 7.80-7.83 (m, 1H), 7.91-7.96 (m, 1H), 9.54 (s, NH). Exact mass calculated for C24H28N4O4 436.2. found 437.5 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:27])=[C:6]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:17]=3[CH:18]=[CH:19][C:20]([CH3:26])=[N:21]4)[CH2:12][CH2:11]2)[CH:7]=1.[NH:28]1[CH2:32][CH2:31][NH:30][C:29]1=[O:33]>>[F:27][C:5]1[CH:4]=[CH:3][C:2]([N:28]2[CH2:32][CH2:31][NH:30][C:29]2=[O:33])=[CH:7][C:6]=1[CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[CH:18]=[CH:19][C:20]([CH3:26])=[N:21]3)[CH2:12][CH2:11]1
Reactant: O=C1NCCN1
Reactant: Cc1ccc2c(N3CCN(CCc4cc(Br)ccc4F)CC3)cccc2n1
Product: Cc1ccc2c(N3CCN(CCc4cc(N5CCNC5=O)ccc4F)CC3)cccc2n1
Yield: 35 %

Procedure:
The title compound was prepared in 35% yield according to the general procedure for the preparation of amides, ureas and carbamates (Method A) starting from 5-{4-[2-(5-bromo-2-fluorophenyl)ethyl]-1-piperazinyl}-2-methylquinoline and 2-imidazolidone.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:5]([O:7][CH3:8])=[O:6].[F:15][C:16]([F:26])([F:25])[O:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21].C(N(CC)C(C)C)(C)C>CS(C)=O.C(OCC)(=O)C>[N+:12]([C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[NH:21][C:20]1[CH:22]=[CH:23][CH:24]=[C:18]([O:17][C:16]([F:15])([F:25])[F:26])[CH:19]=1)([O-:14])=[O:13]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: Nc1cccc(OC(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc([N+](=O)[O-])c(Nc2cccc(OC(F)(F)F)c2)c1
Yield: 34.8 %

Procedure:
A solution of methyl 3-fluoro-4-nitrobenzoate (4.66 g, 23.4 mmol), 3-trifluoromethoxyaniline (4.98 g, 28.1 mmol) and N,N-diisopropylethylamine (4.84 mL, 28.1 mmol) in dimethyl sulfoxide (30 mL) was stirred at 120° C. overnight. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from hexane/tetrahydrofuran to give the title compound (2.90 g, yield 35%) as red crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:3]=1[N+:18]([O-:20])=[O:19].[Cl:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH2:24].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH:24][C:2]1[C:3]([N+:18]([O-:20])=[O:19])=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:5]=[C:6]([S:8][CH2:9][CH2:10][CH3:11])[N:7]=1
Reactant: CCCSc1nc(Cl)c([N+](=O)[O-])c(N2CCOCC2)n1
Reactant: Nc1ccccc1Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CCCSc1nc(Nc2ccccc2Cl)c([N+](=O)[O-])c(N2CCOCC2)n1
Temperature: 55 °C

Procedure:
A mixture of the product from step (i) (1 g), 2-chloroaniline (0.4 g) and N,N-diisopropylethylamine (0.404 g) in isopropylalcohol (12ml) was heated at 55° C. for 14 h. The mixture was cooled and the isopropylalcohol decanted off. Yield 0.82 g