Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][CH:15]([CH3:17])[CH3:16])[C@H:10]([C:18]([CH3:26])([CH3:25])[O:19][SiH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][O:28][CH2:29][CH2:30][CH2:31][O:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][C:41]=1[O:42][CH3:43])[C:36](O)=[O:37].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>C(Cl)Cl.O.CC#N>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:15]([CH3:16])[CH3:17])[C:36](=[O:37])[C:35]2[CH:39]=[CH:40][C:41]([O:42][CH3:43])=[C:33]([O:32][CH2:31][CH2:30][CH2:29][O:28][CH3:27])[CH:34]=2)[C@H:10]([C:18]([CH3:26])([CH3:25])[O:19][SiH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)NC[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C(C)(C)O[SiH2]C(C)(C)C
Reactant: COCCCOc1cc(C(=O)O)ccc1OC
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C(C)(C)O[SiH2]C(C)(C)C)C(C)C)ccc1OC

Procedure:
The title compound is prepared in a similar manner as described for Example 9/reaction step G, from ((3S*,4R)-3-(tert-butyl-dimethyl-silanyloxymethyl)-4-(isopropylamino-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (22.9 g, 59.1 mmol), 3-(3-methoxy-propoxy)-4-methoxy-benzoic acid (15.6 g, 65.1 mmol), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (16.6 g, 65.1 mmol) and triethylamine (19.6 mL, 237 mmol) in CH2Cl2 (0.6 L) as a yellowish oil. MS: 609.4 [M+H]+; tR (HPLC, C18 column, 5-100% CH3CNIH2O/6 min, 100% CH3CN/23 min, CH3CN and H2O containing 0.1% TFA, flow: 1 mL/min): 7.06 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([OH:18])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[N:19]1([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][C:16]([NH:32][C:29]3[CH:28]=[CH:27][C:26]([CH2:25][N:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)=[CH:31][CH:30]=3)=[O:18])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: Nc1ccc(CN2CCCCC2)cc1
Reactant: O=C(O)COc1ccc(-c2ccc(Cl)cc2)cc1
Product: O=C(COc1ccc(-c2ccc(Cl)cc2)cc1)Nc1ccc(CN2CCCCC2)cc1

Procedure:
The product was prepared according to general working method I from (4′-chloro-biphenyl4-yloxy)-acetic acid (137a) and 4-piperidin-ylmethyl-phenylamine.
Reaction SMILES: C1(S([CH2:10][C:11]2[N:15]=[C:14]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)[NH:13][N:12]=2)(=O)=O)C=CC=CC=1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH:27]=[CH:28][C:29]#[N:30]>>[O:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[C:14]1[N:15]=[C:11]2[CH:10]=[C:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=3)[CH:28]=[C:29]([NH2:30])[N:12]2[N:13]=1
Reactant: N#CC=Cc1ccccn1
Reactant: O=S(=O)(Cc1n[nH]c(-c2ccco2)n1)c1ccccc1
Product: Nc1cc(-c2ccccn2)cc2nc(-c3ccco3)nn12

Procedure:
The title compound, MS m/e (%): 278 (M+H+, 100), was prepared in accordance with the general method of example 1 from 3-benzenesulfonylmethyl-5-furan-2-yl-1H-[1,2,4]triazole and 3-(2-pyridinyl)-2-propenenitrile.
Reaction SMILES: [N:1]([CH:4]([C:6]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[C:14]2[C:9]([CH:10]=[CH:11][N:12]=[N:13]2)=[C:8]([Cl:23])[CH:7]=1)[CH3:5])=[N+]=[N-].O.CP(C)C>O1CCCC1.C(OCC)(=O)C>[Cl:23][C:8]1[CH:7]=[C:6]([CH:4]([NH2:1])[CH3:5])[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[C:14]2[C:9]=1[CH:10]=[CH:11][N:12]=[N:13]2
Reactant: CC(N=[N+]=[N-])c1cc(Cl)c2ccnnc2c1-c1cccc(F)c1
Agent: CP(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(N)c1cc(Cl)c2ccnnc2c1-c1cccc(F)c1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
A solution of peak 1 of 7-(1-azidoethyl)-5-chloro-8-(3-fluorophenyl)cinnoline (0.57 g, 1.7 mmol) from step N, in tetrahydrofuran (9.3 mL) and water (1.8 mL) was treated with 1 M of trimethylphosphine in tetrahydrofuran (2.1 mL, 2.1 mmol) and stirred at 20° C. for 30 minutes. The reaction mixture was diluted with ethyl acetate, washed with brine, dried with sodium sulfate, filtered, and concentrated to give the desired product (quantitative). This material was used without further purification. LCMS for C16H14ClFN3 (M+H)+: m/z=302.1; Found: 301.9.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:21])[CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)=[C:4]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:3]=1.C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[O:44]1[CH:48]=[CH:47][N:46]=[C:45]1[C:49](Cl)=O>CN(C=O)C>[CH3:18][O:17][C:15](=[O:16])[C:14]1[CH:19]=[CH:20][C:11]([CH2:10][C:9]2[C:8](=[O:21])[C:5]3[C:4](=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:49]=2[C:45]2[O:44][CH:48]=[CH:47][N:46]=2)=[CH:12][CH:13]=1
Reactant: O=C(Cl)c1ncco1
Reactant: COC(=O)c1ccc(CCC(=O)c2ccc(Cl)cc2Nc2ccccc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cc2c(-c3ncco3)n(-c3ccccc3)c3cc(Cl)ccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 2.6 %

Procedure:
Separately, in a 100 mL round-bottomed flask, methyl 4-(3-(4-chloro-2-(phenylamino)phenyl)-3-oxopropyl)benzoate (898 mg, 2.28 mmol) was combined with THF to give a yellow solution. A 1.0 M solution of NaHMDS in THF (5.7 ml, 5.7 mmol) was added. The reaction mixture was stirred at room temperature for 15 minutes. A heterogeneous mixture of oxazole-2-carbonyl chloride from above, THF (5 mL), DMF (500 μL) was added dropwise to the reaction mixture. The mixture was stirred at room temperature overnight. The reaction flask was cooled to 0° C., then the reaction was quenched with water. The resulting heterogeneous mixture was extracted with ethyl acetate, and the organic phase was dried over MgSO4, filtered, then concentrated. The crude product was dissolved in methylene chloride, then concentrated over silica gel. The silica gel supported crude product was loaded onto a 80 gram analogix column. Flash chromatography (15% EtOAc-hexanes→55% EtOAc-hexanes) provided 4-(7-Chloro-2-oxazol-2-yl-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-benzoic acid methyl ester (28 mg, 2.6%) as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[C:18]1([C:24]2[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([C:24]2[CH:25]=[CH:26][C:27]([C:28]([NH:1][C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[NH:7][CH:6]=[C:5]4[CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[O:29])=[CH:31][CH:32]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc(-c5ccccc5)cc4)cc23)CC1

Procedure:
Reacting 12.0 mg (0.05 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole with 20.0 mg (0.10 mMol) 4-phenylbenzoic acid at 70° C., 10.0 mg (49%) of the title compound were recovered.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[C:20]1[N:25]=[C:24]([CH:26]=O)[CH:23]=[CH:22][CH:21]=1.[CH:28]([C:31]1[CH:37]=[CH:36][CH:35]=[C:34]([CH:38]([CH3:40])[CH3:39])[C:32]=1[NH2:33])([CH3:30])[CH3:29]>C(O)C>[CH:38]([C:34]1[CH:35]=[CH:36][CH:37]=[C:31]([CH:28]([CH3:30])[CH3:29])[C:32]=1[N:33]=[CH:26][C:24]1[CH:23]=[CH:22][CH:21]=[C:20]([C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:18]=[CH:19][C:10]=2[CH2:9][NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[N:25]=1)([CH3:40])[CH3:39]
Reactant: Cc1ccccc1NCc1ccc2ccccc2c1-c1cccc(C=O)n1
Reactant: CC(C)c1cccc(C(C)C)c1N
Solvent: CCO
Product: Cc1ccccc1NCc1ccc2ccccc2c1-c1cccc(C=Nc2c(C(C)C)cccc2C(C)C)n1

Procedure:
A mixture of 1.50 g (4.26 mmol) of 6-(2-{[(2-methylphenyl)amino]methyl}-1-naphthyl) pyridine-2-carbaldehyde and 0.75 g (4.26 mmol) of 2,6-diisopropylaniline in 15 ml of dry ethanol was refluxed for 3 h. Crystals precipitated from this mixture at 0° C. were collected, washed by 3×5 ml of cold ethanol, and dried in vacuum. Yield 1.92 g (88%) of yellowish crystalline solid. Anal. calc. for C36H37N3: C, 84.50; H, 7.29; N, 8.21. Found: C, 84.73; H, 7.41; N, 8.02. 1H NMR (CDCl3): 8.35 (m, 1H, 8-H in naphthyl), 8.33 (s, 1H, CH═N), 7.98 (m, 1H, 4-H in Py), 7.92 (d, J=8.6 Hz, 1H, 4-H in naphthyl), 7.89 (m, 1H, 5-H in naphthyl), 7.68 (d, J=8.6 Hz, 1H, 3-H in naphthyl), 7.57 (m, 1H, 3-H in Py), 7.40-7.50 (m, 3H, 5-H in Py and 6,7-H in naphthyl), 6.98-7.17 (m, 5H, 3,4,6-H in 2,6-disopropylphenyl and 3,5-H in ortho-tolyl), 6.61 (m, 1H, 4-H in ortho-tolyl), 6.53 (m, 1H, 6-H in ortho-tolyl), 4.29 (m, 2H, CH2N), 3.93 (br. s, 1H, NH), 2.96 (sept, J=6.8 Hz, 2H, CHMe2), 2.06 (s, 3H, Me in ortho-tolyl), 1.16 (d, J=6.8 Hz, 6H, CHMeMe′), 1.15 (d, J=6.8 Hz, 6H, CHMeMe').
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[CH2:13]([N:16]1[CH:20]=[CH:19][N:18]=[CH:17]1)[C:14]#[CH:15].C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.C(N(CC)CC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N:16]1([CH2:13][C:14]#[C:15][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]3)[CH:20]=[CH:19][N:18]=[CH:17]1
Reactant: O=C1CCc2cc(Br)ccc2N1
Reactant: C#CCn1ccnc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: O=C1CCc2cc(C#CCn3ccnc3)ccc2N1

Procedure:
A mixture of 11.6 mg of cuprous iodide, 86 mg of bis (triphenylphosphine) palladium (II) dichloride, 1.5 g of 6-bromo-3,4-dihydrocarbostyril and 774 mg of N-propargylimidazole was stirred in a mixture of 10 ml of pyridine and 2 ml of triethylamine at 100° C. for 48 hours under nitrogen. The reaction was then treated with 10 ml of saturated aqueous potassium carbonate and extracted with a solution of 10% methanol in methylene chloride. The extract was dried over anhydrous sodium sulfate, the solvent removed under reduced pressure and the residue chromatographed on silica gel eluting with 4% methanol in methylene chloride, yielding 6-[3-(imidazol-1-yl)-prop-1-yn-1-yl]-3,4-dihydrocarbostyril, m.p. 164°-168° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:10])=[C:4]([CH2:8][OH:9])[CH:5]=[CH:6][CH:7]=1.FC(F)(F)[C:13]([O-])=[O:14].[Tl+].C(O)(C(F)(F)F)=O.[Cl-].[Li+].[O-2].[Mg+2]>[Pd](Cl)Cl.CCOC(C)=O.CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:13](=[O:14])[O:9][CH2:8][C:4]=2[C:3]=1[F:10]
Reactant: O=C([O-])C(F)(F)F
Reactant: OCc1cccc(Br)c1F
Agent: Cl[Pd]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: O=C1OCc2c1ccc(Br)c2F
Reaction time: 16 h

Procedure:
To a flask charged with (3-bromo-2-fluorophenyl)methanol (840 mg, 4.1 mmol) and a stir bar was added added thallium trifluoroacetate (2.3 g, 4.3 mmol) and TFA (4.0 mL) at 0° C. The mixture was allowed to stir for 16 hours. LC showed no SM left at that point. The volatiles were removed under reduced pressure, and the residue was dissolved in DCM and concentrated twice to affect azeotropic removal of all TFA. After pumping the residue under high vacuum for 20 minutes, palladium chloride (73 mg, 0.41 mmol), lithium chloride (350 mg, 8.2 mmol), magnesium oxide (330 mg, 8.2 mmol), and MeOH (15 mL) were added to the flask. The mixture was treated under an atmosphere of CO for 2 hours. To this mixtue was added EtOAc to precipitate all the inorganic solids. The crude solution was filtered through a Celite® pad, and the filtrate was collected, adsorbed onto silica gel, and purified by silica gel chromatography. Removal of solvents gave rise to 5-bromo-4-fluoro-2-benzofuran-1(3H)-one. LC-MS (IE, m/z): 231 [M+1]+;
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH2:8][OH:9])[CH:6]=1.[F:17][C:18]1[CH:19]=[C:20]([CH2:25][C:26]([NH:28][C@@H:29]([CH2:33][CH2:34][CH3:35])[C:30](O)=[O:31])=[O:27])[CH:21]=[C:22]([F:24])[CH:23]=1>>[F:16][C:13]1[CH:14]=[CH:15][C:10]([CH:7]([N:5]2[CH:6]=[C:2]([NH:1][C:30](=[O:31])[C@@H:29]([NH:28][C:26](=[O:27])[CH2:25][C:20]3[CH:21]=[C:22]([F:24])[CH:23]=[C:18]([F:17])[CH:19]=3)[CH2:33][CH2:34][CH3:35])[N:3]=[CH:4]2)[CH2:8][OH:9])=[CH:11][CH:12]=1
Reactant: CCC[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: Nc1cn(C(CO)c2ccc(F)cc2)cn1
Product: CCC[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C(CO)c2ccc(F)cc2)cn1

Procedure:
2-(4-amino-1H-imidazol-1-yl)-2-(4-fluorophenyl)ethanol was reduced and coupled with (S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid (U.S. Ser. No. 11/078,898 filed Mar. 11, 2005) to afford the title compound: MS 475 m/z (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]3[N:22]=[CH:23][C:24]([C:25](O)=[O:26])=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[CH3:28][S:29]([C:32]1[CH:33]=[C:34]([NH2:38])[CH:35]=[CH:36][CH:37]=1)(=[O:31])=[O:30].Cl>>[CH3:28][S:29]([C:32]1[CH:33]=[C:34]([NH:38][C:25]([C:24]2[CH:23]=[N:22][N:15]3[C:16]([C:18]([F:19])([F:20])[F:21])=[CH:17][C:12]([C:4]4[CH:5]=[CH:6][C:7]([C:8]([F:10])([F:9])[F:11])=[C:2]([Cl:1])[CH:3]=4)=[N:13][C:14]=23)=[O:26])[CH:35]=[CH:36][CH:37]=1)(=[O:30])=[O:31]
Reactant: CS(=O)(=O)c1cccc(N)c1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)c(Cl)c3)nc12
Agent: Cl
Product: CS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)c(Cl)c4)nc23)c1

Procedure:
The title compound was prepared from 5-(3-chloro-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.17) and 3-methanesulfonyl-phenylamine [commercially available as hydrochloride] according to general procedure II. Yellow solid. MS (ISP) 561.1 [(M+H)+]; mp 268° C.
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:20])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[CH:14]=[C:13]([NH2:17])[N:12]([CH3:18])[C:11]1=[O:19])(=[O:3])[CH3:2].[CH3:21][C:22](=O)[CH2:23][C:24](=O)[CH3:25]>>[C:1]([O:4][C@H:5]([CH3:20])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[C:14]2[C:22]([CH3:21])=[CH:23][C:24]([CH3:25])=[N:17][C:13]=2[N:12]([CH3:18])[C:11]1=[O:19])(=[O:3])[CH3:2]
Reactant: CC(=O)CC(C)=O
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)cc(N)n(C)c1=O
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(C)cc(C)nc2n(C)c1=O
Temperature: 145 °C

Procedure:
A mixture of (R)-3-(5-acetoxyhexyl)-6-amino-1-methyluracil (250 mg, 0.88 mmol), 2,4-pentanedione (2 ml, 19.5 mmol) and xylenes (3 ml) was heated to 145° C. for 18 hours. The mixture was concentrated under reduced pressure followed by coevaporation with toluene (2×5 ml) to remove the remaining 2,4-pentanedione to provide crude (R)-3-(5-acetoxyhexyl)-1,5,7-trimethylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([F:11])[C:3]=1[Si:12]([CH3:15])([CH3:14])[CH3:13]>CO.[C].[Pd]>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([F:11])[C:3]=1[Si:12]([CH3:14])([CH3:13])[CH3:15])[NH2:8]
Reactant: C[Si](C)(C)c1c(F)cc([N+](=O)[O-])cc1F
Agent: [Pd]
Solvent: CO
Product: C[Si](C)(C)c1c(F)cc(N)cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.1 %

Procedure:
A mixture of (2,6-difluoro-4-nitrophenyl)trimethylsilane (3.5 g, 15.13 mmol) and 10% palladium-carbon (350 mg, 0.16 mmol, 50% wet) in MeOH (70 mL) was stirred at room temperature for 5 hr under hydrogen atmosphere (1 atm). The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent; ethyl acetate/hexane) to give 3,5-difluoro-4-(trimethylsilyl)aniline (2.50 g, 12.42 mmol, 82%) as a pale-yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([N:15](C(OCC(Cl)(Cl)Cl)=O)[C@H:16]([C:18]([OH:20])=O)[CH3:17])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2].[CH2:29]([O:31][C:32](=[O:56])[C@@H:33]1[CH2:37][C:36](=[CH:38][C:39](=[O:55])[C:40]2[CH:45]=[CH:44][C:43]([O:46][CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])=[C:42]([Cl:53])[C:41]=2[Cl:54])[CH2:35][NH:34]1)[CH3:30].C(N(CC)CC)C>C(Cl)Cl>[CH2:29]([O:31][C:32](=[O:56])[C@@H:33]1[CH2:37][C:36](=[CH:38][C:39](=[O:55])[C:40]2[CH:45]=[CH:44][C:43]([O:46][CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])=[C:42]([Cl:53])[C:41]=2[Cl:54])[CH2:35][N:34]1[C:18](=[O:20])[C@@H:16]([NH:15][C@H:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH3:17])[CH3:30]
Reactant: CCOC(=O)COc1ccc(C(=O)C=C2CN[C@H](C(=O)OCC)C2)c(Cl)c1Cl
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N(C(=O)OCC(Cl)(Cl)Cl)[C@@H](C)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)COc1ccc(C(=O)C=C2C[C@@H](C(=O)OCC)N(C(=O)[C@H](C)N[C@@H](CCc3ccccc3)C(=O)OCC)C2)c(Cl)c1Cl

Procedure:
The acid chloride from 6.7 g (14.7 mmol) of N-((1S)-1-ethoxycarbonyl-3-phenylpropyl)-N-(2,2,2-trichloroethoxycarbonyl)alanine (Example 7A) is dissolved in 25 ml CH2Cl2 and added dropwise to a solution of 6.3 g (14.6 mmol) of 4-(2,3-dichloro-4-((ethoxycarbonyl)-methoxy)benzoyl)methylene proline ethyl ester and 1.6 g (15.8 mmol) of triethylamine in 100 ml CH2Cl2. Further reaction and purification as in example 7A gives the desired amide.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:20]2[C@@H:29]3[C@@H:24]([CH2:25][CH:26]=[CH:27][CH2:28]3)[C:23](=[O:30])[N:22]([CH:31]3[CH2:36][CH2:35][N:34](C4C=CC([N+]([O-])=O)=CC=4)[CH2:33][CH2:32]3)[N:21]=2)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19].O>C(OCC)C>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:20]2[C@@H:29]3[C@@H:24]([CH2:25][CH:26]=[CH:27][CH2:28]3)[C:23](=[O:30])[N:22]([CH:31]3[CH2:36][CH2:35][N:34]([CH2:8][C:5]4[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=4)[CH2:33][CH2:32]3)[N:21]=2)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19]
Reactant: COc1ccc(C2=NN(C3CCN(c4ccc([N+](=O)[O-])cc4)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC
Reactant: ClCc1ccncc1
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: COc1ccc(C2=NN(C3CCN(Cc4ccncc4)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC
Reaction time: 0.5 h

Procedure:
Prepared from starting compound A1 and 4-picolylchloride hydrochloride as described for compound 11. After the addition of 100 ml of water, 20 ml of diethyl ether is added and the resulting mixture stirred for 30 min. The precipitate is filtered off and dried. M. p. 196-197° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([O:19]C)=[O:18])=[CH:14][CH:15]=2)[N:10]([CH:21]([CH3:23])[CH3:22])[N:9]=1.[OH-].[Na+].Cl>CO.O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([OH:19])=[O:18])=[CH:14][CH:15]=2)[N:10]([CH:21]([CH3:23])[CH3:22])[N:9]=1
Reactant: COC(=O)c1ccc2c(-c3ccccc3Cl)nn(C(C)C)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)n1nc(-c2ccccc2Cl)c2ccc(C(=O)O)cc21
Temperature: 50 °C
Reaction time: 18 h
Yield: 97.1 %

Procedure:
To a solution of methyl 3-(2-chlorophenyl)-1-isopropyl-1H-indazole-6-carboxylate (57.7 mg, 0.18 mmol) in methanol (1.1 mL) and tetrahydrofuran (0.7 mL) was added sodium hydroxide (1.0 M, 1.10 mL, 1.10 mmol). The mixture was heated to 50° C. and stirred for 18 h. The mixture was cooled to ambient temperature and 1.0 M hydrochloric acid (ca 1.1 mL) was added until pH<3. The mixture was extracted with ethyl acetate (3×10 mL). The combined organic layer was washed with saturated aqueous sodium chloride (1×7 mL), dried over sodium sulfate, filtered and concentrated to give the title compound (55.0 mg): LC-MS [M+1]=315.0.
Reaction SMILES: [CH3:1][C:2]([OH:16])([CH3:15])[CH2:3][C:4]1[N:5]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[CH:6]=[CH:7][N:8]=1.C1C(=O)N([Br:24])C(=O)C1>CN(C=O)C>[Br:24][C:7]1[N:8]=[C:4]([CH2:3][C:2]([CH3:1])([OH:16])[CH3:15])[N:5]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(O)Cc1nccn1C1CCCCO1
Solvent: CN(C)C=O
Product: CC(C)(O)Cc1nc(Br)cn1C1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.2 %

Procedure:
To a solution of 2-methyl-1-[1-(tetrahydro-pyran-2-yl)-1H-imidazol-2-yl]-propan-2-ol (1.12 g, 5 mmol) in DMF (10 mL) at −78° C. was added NBS (0.72 g, 4 mmol) in DMF (pre-cooled to −78° C.). The reaction mixture was warmed to r.t. slowly and stirred at r.t. overnight. The solvent was removed under vacuum and purified by neutral Al2O3 column chromatography (CH2Cl2: MeOH=100:1) to give 0.5 gm of 1-[4-bromo-1-(tetrahydro-pyran-2-yl)-1H-imidazol-2-yl]-2-methyl-propan-2-ol (34%). 1H NMR (CDCl3, 400 MHz): δ 7.03 (s, 1H), 5.13 (dd, J=2.6, 9.6 Hz, 1H), 4.05-4.02 (m, 1H), 3.68-3.62 (m, 1H), 2.82 (d, J=12.0 Hz, 2H), 2.01-1.89 (m, 4H), 1.92 (m, 1H), 1.69-1.60 (m, 3H), 1.24 (m, 6H)
Reaction SMILES: [N:1]1([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][CH2:7]2)[CH2:3][CH2:2]1.C=O.[C:27](O)(=O)C.C([BH3-])#N.[Na+].C([O-])(O)=O.[Na+]>CO>[CH3:27][N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:4]2([CH2:3][CH2:2][N:1]([C:15]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:16])[CH2:6][CH2:5]2)[CH2:7]1
Reactant: O=C(OCc1ccccc1)N1CCC2(CC1)CNc1ccccc12
Reactant: CC(=O)O
Agent: C=O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: CO
Product: CN1CC2(CCN(C(=O)OCc3ccccc3)CC2)c2ccccc21
Temperature: 25 °C
Yield: 75.1 %

Procedure:
To a 0° C. solution of benzyl spiro[indoline-3,4′-piperidine]-1′-carboxylate (1.15 g, 3.56 mmol), formaldehyde (37% aqueous solution, 1.44 mL, 17.83 mmol) and acetic acid (1.02 mL, 17.83 mmol) in methanol (25 mL) is added sodium cyanoborohydride (0.67 g, 10.68 mmol). The reaction mixture is allowed to warm to room temperature overnight. The pH of the mixture is adjusted to approximately 8 with 10% NaHCO3 solution and extracted with EtOAc (3×50 mL). The combined extracts are washed with water (50 mL) and brine (50 mL), dried, filtered, and evaporated to dryness. The crude material is purified by silica gel chromatography, eluting with hexane:ethyl acetate (85:15) to give the title compound as an off-white solid (0.9 g, 75%). ESI/MS m/z 337.2 (M+H)+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([C:11]2[N:16]=[C:15]([C:17]#[N:18])[CH:14]=[CH:13][CH:12]=2)[N:9]=[C:8]([C:19]([F:22])([F:21])[F:20])[CH:7]=1>C1COCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([C:11]2[N:16]=[C:15]([CH2:17][NH2:18])[CH:14]=[CH:13][CH:12]=2)[N:9]=[C:8]([C:19]([F:21])([F:20])[F:22])[CH:7]=1
Reactant: N#Cc1cccc(-n2nc(C(F)(F)F)cc2-c2ccco2)n1
Solvent: C1CCOC1
Product: NCc1cccc(-n2nc(C(F)(F)F)cc2-c2ccco2)n1
Temperature: 21 °C
Reaction time: 3 h
Yield: 122.8 %

Procedure:
To a stirred solution of 46 (65 mg, 0.214 mmol) in THF (1.068 mL) was added 1M BH3 in THF (1.1 mL, 1.1 mmol). The resulting solution was allowed to stir at 21° C. for 3 hours. The excess BH3-THF was destroyed by the careful addition of MeOH. The solvent was evaporated, the residue dissolved in HCl/EtOH and the mixture was heated to reflux for 2 hours and then evaporated to dryness. The title product 47 (81 mg, 99% yield) was isolated as a pale yellow oil. LRMS (ESI): calc. 308.3; found 309.2 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]2[S:7](=[O:17])[C:8]([C:14]([OH:16])=O)=[C:9]([O:10][CH:11]([CH3:13])[CH3:12])[C:5]=2[CH:4]=1.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]2[S:7](=[O:17])[C:8]([C:14]([NH:27][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:16])=[C:9]([O:10][CH:11]([CH3:12])[CH3:13])[C:5]=2[CH:4]=1
Reactant: NCc1ccccc1
Reactant: COc1ccc2c(c1)C(OC(C)C)=C(C(=O)O)S2=O
Product: COc1ccc2c(c1)C(OC(C)C)=C(C(=O)NCc1ccccc1)S2=O
Yield: 2.7 %

Procedure:
Following a procedure analogous to Example 28, Preparation B, 200 mg (0.71 mmol) of 5-methoxy-3-(1-methylethoxy)benzo[b]thiophene-2-carboxylic acid-1-oxide and 388 μL (3.55 mmol) of benzylamine gives 7 mg (52%) of 5-methoxy-3-(1-methylethoxy)-N-(phenylmethyl)benzo[b]thiophene-2-carboxamide-1-oxide as a yellow gum.