Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:37])[O:3][C:4]1[CH:5]=[C:6]([C:11]2[N:16]=[C:15]([CH3:17])[N:14]=[C:13]([N:18]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:12]=2)[C:7](F)=[N:8][CH:9]=1.[NH2:38][C:39]1[CH:40]=[CH:41][C:42]([O:45][CH3:46])=[N:43][CH:44]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[F:37][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]([C:11]2[N:16]=[C:15]([CH3:17])[N:14]=[C:13]([N:18]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[N:12]=2)[C:7]([NH:38][C:39]2[CH:44]=[N:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)=[N:8][CH:9]=1
Reactant: COc1ccc(N)cn1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(OC(F)F)cnc3F)n2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(OC(F)F)cnc3Nc3ccc(OC)nc3)n2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 60.6 %

Procedure:
A solution of 4-(5-(difluoromethoxy)-2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.030 g, 0.059 mmol) and 5-amino-2-methoxypyridine (Aldrich) (8.06 μL, 0.065 mmol), in THF (1 mL) was cooled to 0° C. under N2 and treated with lithium bis(trimethylsilyl)amide, 1.0 M solution in tetrahydriofuran (Aldrich) (0.039 mL, 0.235 mmol). The dark red mixture was stirred at 0° C. for 1 h and then partitioned between EtOAc and sat. NH4Cl. The aqueous layer was extracted with EtOAc (2×10 mL). The combined organic layers were washed with water, brine, dried over MgSO4 and concentrated. The crude product was purified by column chromatography (12 g, 10% to 20% EtOAc in hexanes) to give the product as a yellow solid (0.022 g). m/z (ESI, +ve ion) 616.0 (M+H)+. 1H NMR (300 MHz, CDCl3) δ 11.65 (s, 1H); 8.63 (br. s., 1H); 8.26 (s, 1H); 8.17 (br. s., 1H); 7.89 (d, J=8.77 Hz, 1H); 7.11-7.25 (m, 4H); 6.78-6.95 (m, 4H); 6.72 (d, J=8.77 Hz, 1H); 6.11-6.69 (m, 1H); 4.74-4.93 (m, 4H); 3.94 (s, 3H); 3.81 (d, J=8.48 Hz, 6H); 2.59 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([O:14]/C=C/C)[C@@H:12]([O:18]/C=C/C)[C@H:11]([O:22]/C=C/C)[C@@H:10]([CH2:26][O:27]/C=C/C)[NH:9]2)=[CH:4][C:3]=1[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH3:40])=[CH:34][CH:33]=1>C1COCC1.CC(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:18])[C@H:11]([OH:22])[C@@H:10]([CH2:26][OH:27])[NH:9]2)=[CH:4][C:3]=1[CH2:31][C:32]1[CH:33]=[CH:34][C:35]([O:38][CH2:39][CH3:40])=[CH:36][CH:37]=1
Reactant: C/C=C/OC[C@H]1N[C@@H](c2ccc(Cl)c(Cc3ccc(OCC)cc3)c2)[C@H](O/C=C/C)[C@@H](O/C=C/C)[C@@H]1O/C=C/C
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc([C@@H]3N[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Temperature: 70 °C
Yield: 46.2 %

Procedure:
Compound from Step G (15 mg, 0.026 mmol) was dissolved in a solution of THF/AcOH/1NHCl (0.2 ml:0.3 ml:0.15 ml) and heated to 70° C. for 30 minutes. The mixture was concentrated to give a pale yellow oil. Purification by preparative HPLC (sunfire C18, 30×100 mm, 5 μm, 10%-100% B over 15 minutes) afforded (2S,3S,4R,5R,6R)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-hydroxymethyl-piperidine-3,4,5-triol (5 mg, 0.012 mmol, 46%) as a white solid. MS (ES+) [M+H]+=408.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([OH:24])[CH2:15][C:16]2[C:21]([Cl:22])=[CH:20][N:19]=[C:18](Cl)[N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:26][S:27]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:29])=[O:28].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([OH:24])[CH2:15][C:16]2[C:21]([Cl:22])=[CH:20][N:19]=[C:18]([N:33]3[CH2:34][CH2:35][N:30]([S:27]([CH3:26])(=[O:29])=[O:28])[CH2:31][CH2:32]3)[N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(O)Cc2nc(Cl)ncc2Cl)CC1
Reactant: CS(=O)(=O)N1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(C(O)Cc2nc(N3CCN(S(C)(=O)=O)CC3)ncc2Cl)CC1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
A mixture of 4-[2-(2,5-dichloro-pyrimidin-4-yl)-1-hydroxy-ethyl]-piperidine-1-carboxylic acid tert-butyl ester (100 mg), 1-methanesulfonyl-piperazine hydrochloride (70 mg), potassium carbonate (100 mg), and N,N-dimethylformamide (1 mL) is stirred for 4 h at 60° C. After cooling to room temperature ethyl acetate is added. The organic phase is separated, washed with water and brine, dried over MgSO4, and concentrated in vacuo. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 50:50→0:100) to give the title compound. LC (method 7): tR=1.46 min; Mass spectrum (ESI+): m/z=504 [M+H]+.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([NH:10][C:11]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]4[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]4)=[CH:15][CH:14]=3)=[O:12])[CH:7]=[CH:6][C:5]=12.[Cl:32]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.CO>[Cl:32][C:3]1[N:4]2[CH:9]=[C:8]([NH:10][C:11]([C:13]3[CH:14]=[CH:15][C:16]([CH:19]4[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:24]4)=[CH:17][CH:18]=3)=[O:12])[CH:7]=[CH:6][C:5]2=[N:1][CH:2]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)Nc3ccc4nccn4c3)cc2)CC1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)Nc3ccc4ncc(Cl)n4c3)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of tert-butyl 4-(4-(imidazo[1,2-a]pyridin-6-ylcarbamoyl)phenyl)piperidine-1-carboxylate (0.015 g, 0.036 mmol) in chloroform (0.618 ml) and methanol (0.095 ml) was treated with N-chlorosuccinimide (5.24 mg, 0.039 mmol) and the reaction was stirred at ambient temperature for 16 hours. The reaction mixture was concentrated under a stream of warm nitrogen. The residue was purified by normal phase flash chromatography to provide the title compound. 1H NMR (500 MHz, methanol-d4) δ ppm 9.23 (s, 1H), 7.93 (d, J=8.3 Hz, 2H), 7.62-7.51 (m, 3H), 7.42 (d, J=8.3 Hz, 2H), 4.27-4.19 (m, 2H), 2.96-2.76 (m, 3H), 1.90-1.82 (m, 2H), 1.70-1.57 (m, 2H), 1.48 (s, 9H); MS (ESI(+)) m/e 455 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]#[C:18][CH3:19])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:2].Cl[CH2:22][CH2:23][N:24]([CH2:34][CH2:35]Cl)[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1>>[CH2:1]([O:3][C:4]([C:5]1([S:6]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][C:17]#[C:18][CH3:19])=[CH:13][CH:14]=2)(=[O:7])=[O:8])[CH2:35][CH2:34][N:24]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)[CH2:23][CH2:22]1)=[O:20])[CH3:2]
Reactant: COc1ccc(CN(CCCl)CCCl)cc1
Reactant: CC#CCOc1ccc(S(=O)(=O)CC(=O)OCC)cc1
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccc(OC)cc3)CC2)cc1

Procedure:
4-(4-but-2-ynyloxy-benzenesulfonyl)-1-(4-methoxy-benzyl)-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as outlined in Example 1. Starting from (4-but-2-ynyloxy-benzenesulfonyl)-acetic acid ethyl ester (2 g, 6.73 mmol) and bis-(2-chloro-ethyl)-(4-methoxy-benzyl)-amine (2.61 g, 8.75 mmol) and following the procedure as outlined in Example 1 (Step 6) 2.5 g of the product was isolated. Yield 2.5 g (77%); yellow oil; MS: 486 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:13])[C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2>C1C=CC=CC=1.[Ag]>[OH:1][CH2:2][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][O:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:13])[C:2](=[O:1])[CH:11]=1
Reactant: O=C1C=C(O)C(=O)c2ccccc21
Agent: [Ag]
Solvent: c1ccccc1
Product: O=C1C=C(OCCCCCCO)c2ccccc2C1=O
Yield: 100.8 %

Procedure:
A mixture of 6-bromohexanol-1 (4.5 g, 24.85 mmol) and the silver salt of 2-hydroxy-1,4-naphthoquinone (6.46 g, 23.01 mmol) in benzene (24 mL) was stirred for 48 h at 60° C. The reaction mixture was worked up as described for 502 and crystallized from hexane to afford a yellow solid (3.18 g, 50%). mp 96-98° C., 1H NMR (CDCl3) 8.12 (d, J=7.5 Hz, 1H), 7.87 (d, J=7.7 Hz, 1H), 7.70 (t, J=7.5 Hz, 1H), 7.58 (t, J=7.5 Hz, 1H), 5.95 (s, 1H), 4.15 (t, J=6.3 Hz, 2H), 3.69 (t, J=6.2 Hz, 2H), 1.92-1.97 (m, 2H), 1.3-1.8 (m, 7H)
Reaction SMILES: Cl.[OH:2][CH:3]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.[C:21]([C:29]1[CH:37]=[C:36]([Br:38])[CH:35]=[CH:34][C:30]=1[C:31](O)=[O:32])(=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[Br:38][C:36]1[CH:37]=[C:29]2[C:30](=[CH:34][CH:35]=1)[C:31](=[O:32])[N:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([S:13]([NH2:16])(=[O:14])=[O:15])=[CH:11][CH:12]=1)[C:4]([C:3](=[O:2])[CH2:17][CH2:18][CH2:19][CH3:20])=[C:21]2[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(O)c1ccc(Br)cc1C(=O)c1ccccc1
Reactant: CCCCC(O)CNCc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Product: CCCCC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(S(N)(=O)=O)cc1

Procedure:
In the same manner as in Example 452, Step 2, the title compound was synthesized from 4-[(2-hydroxyhexylamino)methyl]benzenesulfonamide hydrochloride and 2-benzoyl-4-bromobenzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8](I)=[CH:9][N:10]=[C:4]2[CH:3]=1.CC1(C)C(C)(C)OB([C:20]2[CH:21]=[C:22]([NH:26][C:27]([NH:29][CH2:30][C:31]([F:34])([F:33])[F:32])=[O:28])[CH:23]=[CH:24][CH:25]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:24]3[CH:23]=[C:22]([NH:26][C:27]([NH:29][CH2:30][C:31]([F:32])([F:33])[F:34])=[O:28])[CH:21]=[CH:20][CH:25]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1
Reactant: CC1(C)OB(c2cccc(NC(=O)NCC(F)(F)F)c2)OC1(C)C
Reactant: Clc1ccn2c(I)cnc2c1
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: COCCOC
Solvent: O
Product: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(Cl)ccn23)c1
Temperature: 80 °C

Procedure:
To a solution of 7-chloro-3-iodo-imidazo[1,2-a]pyridine (5.0 g, 17.8 mmol) in DME (350 ml) was added 1-[3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea (7.36 g, 21.4 mmol), 2M Na2CO3 (71.6 ml, 35.8 mmol) [reaction degassed by bubbling N2 through] followed by tetrakis(triphenylphosphine)palladium(0) (1.03 g, 0.89 mmol). The mixture was heated at 80° C. overnight, then diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The crude material was triturated with CH2Cl2 to afford the desired product as a beige solid. MS: [M+H]+ 389
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[NH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][N:18]=[CH:17]2.C(=O)([O-])O.[Na+]>CO>[NH:19]1[C:20]2[C:16](=[CH:15][C:14]([NH:13][CH:2]3[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]3)=[CH:22][CH:21]=2)[CH:17]=[N:18]1
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)C1CCC(Nc2ccc3[nH]ncc3c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 105.8 %

Procedure:
Ethyl 4-oxocyclohexanecarboxylate (0.85 g) and 5-aminoindazole (0.60 g) were dissolved in methanol (10 ml) thereto, and a borane-pyridine complex (0.81 ml) was added dropwise to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr. A saturated aqueous sodium hydrogencarbonate solution (10 ml) was then added thereto, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel [chloroform/methanol] to give the title compound (1.37 g) as substantially 1:1 enantiomers.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[CH3:10])[NH2:6].[N+]([C:14]1[CH:15]=C(S([O-])(=O)=O)C=C[CH:19]=1)([O-])=O.[Na+].S(O)(C)(=O)=O.OCC(CO)O.[OH-].[Na+]>O1CCOCC1>[CH3:10][C:9]1[CH:8]=[C:7]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[N:6]=[CH:15][CH:14]=[CH:19]2
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Reactant: COc1cc(N)ccc1C
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: OCC(O)CO
Product: COc1cc2ncccc2cc1C
Temperature: 150 °C
Yield: 98.2 %

Procedure:
Using a minimal amount of dioxane, 3-methoxy-4-methylaniline (5.00 g, 36.5 mmol) was slowly added to a mixture of sodium m-nitrobenzenesulfonate (6.62 g, 29.4 mmol), MsOH (20 mL), and FeSO4.7H2O (0.39 g, 1.4 mmol) in a 100 mL round bottom flask heated to an internal temperature of 145-155° C. Glycerol (10.75 g, 116.8 mmol) was then added dropwise via addition funnel while keeping the internal temperature at 145-155° C. After addition, the reaction was stirred in a 150° C. oil bath until LCMS indicated completion (4-6 h). After being cooled to rt, ice (20 g) was added, then the solution was neutralized with 10 N NaOH (calculated to same eq of MsOH) at a speed to keep the internal temperature below 40° C. A thick suspension appeared after addition, and this was extracted with EtOAc (50 mL×3). The organic layer was filtered through a Celite pad to remove insoluble black particles and then purified by flash column chromatography on silica gel to give the desired product (5.0 g, 79%). MS (ES) m/z 174.1 (M+H+).
Reaction SMILES: [CH2:1]([O:5][N:6]=[C:7]([C:13](=[O:15])[CH3:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:2]([CH3:4])[CH3:3].S(Cl)([Cl:19])(=O)=O>C(O)(=O)C>[CH2:1]([O:5][N:6]=[C:7]([C:13](=[O:15])[CH2:14][Cl:19])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:2]([CH3:3])[CH3:4]
Reactant: CCOC(=O)C(=NOCC(C)C)C(C)=O
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)C(=NOCC(C)C)C(=O)CCl
Yield: 65.5 %

Procedure:
Ethyl 2-iso-butoxyimino-3-oxobutyrate (syn isomer, 42 g.), acetic acid (42 ml.) and sulfuryl chloride (27.1 g.) were treated in a similar manner to that of Example F-(2) to give ethyl 2-iso-butoxyimino-4-chloro-3-oxobutyrate (syn isomer, 31.9 g.).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:25])=[C:11]([NH:13][C:14]([C:16]3[CH:24]=[C:23]4[C:19]([CH:20]=[CH:21][NH:22]4)=[CH:18][CH:17]=3)=[O:15])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[H-].[Na+].[CH:28](Br)([CH3:30])[CH3:29]>CN(C=O)C>[CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:25])=[C:11]([NH:13][C:14]([C:16]3[CH:24]=[C:23]4[C:19]([CH:20]=[CH:21][N:22]4[CH:28]([CH3:30])[CH3:29])=[CH:18][CH:17]=3)=[O:15])[CH:12]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc2cc[nH]c2c1
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc2ccn(C(C)C)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.6 %

Procedure:
To N-(5-(cyclopropylcarbamoyl)-2-methylphenyl)-1H-indole-6-carboxamide (0.05 g, 0.15 mmol, example 94, table 5) in DMF (0.5 mL) was added sodium hydride (60% dispersion, 0.030 g, 0.75 mmol) over a period of 3 min, at room temperature. After stirring at room temperature for 5 min. isopropyl bromide (21 μL, 0.225 mmol) is added and the contents stirred at room temperature for 1 h. The reaction mixture was quenched with 100 μL of methanol and subjected to reverse phase preparative HPLC (YMC S5 20×100 mm, 10 min. run, solvent A: 10% MeOH: 90% H2O: 0.1% TFA, solvent B: 90% MeOH, 10% H2O, 0.1% TFA). The desired fractions were collected, and concentrated using speedVac® Plus (SC250DDA) to yield the title compound (Example 224, 0.015 g). HPLC retention time (YMC S5 Combiscreen ODS; 4.6×50 mm (4 min. gradient); Solvent A=10% MeOH, 90% H2O, 0.2% H3PO4; solvent B=90% MeOH, 10% H2O, 0.2% H3PO4): 3.1 min. LCMS [M+H]+ 376.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[Br:9][C:10]1[CH:11]=[C:12]([CH:15]=[C:16]([Br:19])[C:17]=1[OH:18])[CH:13]=O>CO>[S:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:13]1[C:12]1[CH:11]=[C:10]([Br:9])[C:17]([OH:18])=[C:16]([Br:19])[CH:15]=1
Reactant: Nc1ccccc1S
Reactant: O=Cc1cc(Br)c(O)c(Br)c1
Solvent: CO
Product: Oc1c(Br)cc(-c2nc3ccccc3s2)cc1Br
Temperature: 25 °C
Yield: 16 %

Procedure:
In a methanol solvent, a solution including 2-aminothiophenol (1.0 eq.) and 3,5-dibromo-4-hydroxybenzaldehyde (1.0 eq.) was stirred at room temperature. The produced precipitate was filtered and the filtered product was washed with cold methanol to obtain Compound 27.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH:10]1([NH2:13])[CH2:12][CH2:11]1.C(N(CC)CC)C>C(#N)C>[Br:1][C:2]1[C:3]([NH:13][CH:10]2[CH2:12][CH2:11]2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: NC1CC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Clc1ncc(Br)c(NC2CC2)n1

Procedure:
In analogy to compound 1.1, a solution of 1.0 g (4.39 mmol) of 5-bromo-2,4-dichloro-pyrimidine in 15 ml of acetonitrile is reacted with 0.27 g (4.74 mmol) of cyclopropylamine in the presence of 0.74 ml (5.3 mmol) of triethylamine. Purification by chromatography (silica gel, ethyl acetate/hexane with ethyl acetate 0-100%) results in 0.76 g (70% of theory) of the product.
Reaction SMILES: C([O:8][NH:9][C:10]([C@H:12]1[CH2:17][N:16]([C:18]([N:20]([CH3:22])[CH3:21])=[O:19])[CH2:15][CH2:14][N:13]1[S:23]([N:26]1[CH2:31][CH2:30][CH:29]([C:32]2[C:40]3[C:35](=[C:36]([F:44])[C:37]([F:43])=[C:38]([F:42])[C:39]=3[F:41])[NH:34][CH:33]=2)[CH2:28][CH2:27]1)(=[O:25])=[O:24])=[O:11])C1C=CC=CC=1>[Pd].C(O)C.O1CCCC1>[OH:8][NH:9][C:10]([C@H:12]1[CH2:17][N:16]([C:18]([N:20]([CH3:21])[CH3:22])=[O:19])[CH2:15][CH2:14][N:13]1[S:23]([N:26]1[CH2:27][CH2:28][CH:29]([C:32]2[C:40]3[C:35](=[C:36]([F:44])[C:37]([F:43])=[C:38]([F:42])[C:39]=3[F:41])[NH:34][CH:33]=2)[CH2:30][CH2:31]1)(=[O:24])=[O:25])=[O:11]
Reactant: CN(C)C(=O)N1CCN(S(=O)(=O)N2CCC(c3c[nH]c4c(F)c(F)c(F)c(F)c34)CC2)[C@@H](C(=O)NOCc2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CN(C)C(=O)N1CCN(S(=O)(=O)N2CCC(c3c[nH]c4c(F)c(F)c(F)c(F)c34)CC2)[C@@H](C(=O)NO)C1
Reaction time: 0.75 h
Yield: 96 %

Procedure:
A solution of N-benzyloxy-4-(N,N-dimethylaminocarbonyl)-1-[4-(4,5,6,7-tetrafluoroindol-3-yl)piperidine-1-sulfonyl]piperazine-2-(R)-carboxamide (8.90 g, 13.97 mmol) [prepared as described in Step 6 above] in argon deoxygenated 80% ethanol/tetrahydrofuran (470 ml) was treated with 10% Pd/C (3.5 g) and stirred under a hydrogen atmosphere (1 atm) for 45 min. The reaction was degassed under argon, filtered through Celite, and the filtrate was concentrated in vacuo. Ethyl acetate (5 ml) was added and the solution was added dropwise to hexane (250 ml) with vigorous stirring. The solid was filtered to afford N-hydroxy-4-(N,N-dimethylaminocarbonyl)-1-[4-(4,5,6,7-tetrafluoroindol-3-yl)piperidine-1-sulfonyl]piperazine-2-(R)-carboxamide (96%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]([C:25]2S[CH:27]=[CH:28][N:29]=2)=[CH:4][CH2:3]1.FC(F)(F)S(O[C:37]1C2C=C(C#CC3C=CC(C(OCC)=O)=CC=3)C=CC=2C(C)(C)C[CH:46]=1)(=O)=O>>[CH3:1][C:2]1([CH3:30])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]([C:25]2[CH:46]=[CH:37][CH:27]=[CH:28][N:29]=2)=[CH:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(OS(=O)(=O)C(F)(F)F)=CCC3(C)C)cc1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2nccs2)=CCC3(C)C)cc1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccccn2)=CCC3(C)C)cc1

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(2-thiazolyl)naphth-2-yl)ethynyl]benzoate (Compound 67), 250.0 mg (0.52 mmol) of ethyl 4-[(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl]benzoate (Compound 66) was converted into the title compound (colorless solid) using 142.4 mg (1.045 mmol) of zinc chloride, 24.1 mg (0.02 mmol) of tetrakis(triphenylphosphine)palladium(0) and 2-lithiopyridine (prepared by the addition of 100.6 mg (0.97 ml, 1.57 mmol) of tert-butyllithium (1.5M solution in pentane) to a cold solution (−78° C.) of 123.8 mg (0.784 mmol) of 2-bromopyridine in 1.0 mL of THF).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[CH2:21][C:22](O)=[O:23])=[CH:11][CH:12]=2)[CH:7]=[N:6]1)[CH:2]([CH3:4])[CH3:3].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[N:67]1([C:73]2[CH:78]=[CH:77][C:76]([NH2:79])=[CH:75][CH:74]=2)[CH2:72][CH2:71][O:70][CH2:69][CH2:68]1.C(O)C(N)(CO)CO>C(Cl)(Cl)Cl>[CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[CH2:21][C:22]([NH:79][C:76]3[CH:75]=[CH:74][C:73]([N:67]4[CH2:68][CH2:69][O:70][CH2:71][CH2:72]4)=[CH:78][CH:77]=3)=[O:23])=[CH:11][CH:12]=2)[CH:7]=[N:6]1)[CH:2]([CH3:4])[CH3:3]
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: CC(C)Cn1ncc2cc(Oc3ccccc3CC(=O)O)ccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: NC(CO)(CO)CO
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CC(C)Cn1ncc2cc(Oc3ccccc3CC(=O)Nc3ccc(N4CCOCC4)cc3)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.3 %

Procedure:
To a solution of (15p) (0.04 g, 0.123 mmol), PyBOP (0.135 g, 0.26 mmol) and DIEA (0.02 mL, 0.12 mmol) in CHCl3 (2 ml), 4-morpholin-4-yl-phenylamine (0.044 g, 0.247 mmol) were added. The mixture was stirred at room temperature for 16 hours, treated with AP-trisamine resin (0.25 g, 2.49 mmol/g), and finally the solvent was removed under reduced pressure after filtration from the resin. The resulting residual was purified by chromatography (Sep-Pak, 10 g) with ether to provide the desired product (16p) (0.024 g, 40%). 1H NMR (400 MHz, CDCl3) δ 7.90 (s, 1H), 7.50 (br s, 1H), 7.45 (dd, J=7.83, 1.57 Hz, 1H), 7.39 (d, J=9.39 Hz, 2H), 7.31-7.26 (m, 3H), 7.23 (dd, J=7.83, 1.57 Hz, 1H), 7.15-7.09 (m, 2H), 6.86-6.79 (m, 3H), 4.17 (d, J=7.04 Hz, 2H), 3.86-3.82 (m, 4H), 3.80 (s, 2H), 3.11-3.06 (m, 4H), 2.41-2.29 (m, 1H), 0.95 (s, CH3), 0.94 (s, CH3); MS (APCI+) m/z 485.2 (M+H) was detected.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH2:6][C:7]([C:9]([F:12])([F:11])[F:10])=[O:8])=[O:5].CC(O[Na])=O.O.[Cl-].[C:20]1([N+:26]#[N:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[C:20]1([NH:26][N:27]=[C:6]([C:7](=[O:8])[C:9]([F:10])([F:11])[F:12])[C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: N#[N+]c1ccccc1
Agent: CC(=O)O[Na]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(=NNc1ccccc1)C(=O)C(F)(F)F
Yield: 60 %

Procedure:
7.3 ml (0.05 mol) of ethyl 3-oxo-4,4,4-trifluoroacetoacetate, 6 g (0.073 mol) of CH3COONa, 20 ml of water, 37.5 ml of ethanol and a solution of 0.05 mol of phenyldiazonium chloride were treated as described in preparation 2. The crude product was purified by chromatography on silica gel (hexane/Et2O 0%→25%) obtaining 8.65 g of the title compound. M.p.=78°-80° C.