Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.Br[CH2:24][C:25]1[N:30]=[C:29]2[O:31][CH2:32][CH2:33][O:34][C:28]2=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:34]1[C:28]2[C:29](=[N:30][C:25]([CH2:24][NH:1][CH:2]3[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]4[C:19]5[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=5)[N:13]=[CH:12][C:11]4=[O:22])[CH2:6][CH2:7]3)=[CH:26][CH:27]=2)[O:31][CH2:32][CH2:33]1
Reactant: BrCc1ccc2c(n1)OCCO2
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCc4ccc5c(n4)OCCO5)CC3)c2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 37.5 %

Procedure:
To 5 mL of an N,N-dimethylformamide solution containing 170 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one and 130 mg of 6-bromomethyl-2,3-dihydro-1,4-dioxino[2,3-b]pyridine, 230 mg of potassium carbonate was added, and stirred at room temperature for 3 days. The solvent was removed under reduced pressure, and the residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel N, eluent; chloroform:methanol=5:1] to give 95.1 mg of 1-(2-(4-((2,3-dihydro-1,4-dioxino[2,3-b]pyridin-6-yl)methylamino)piperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one as a yellow oil.
Reaction SMILES: O.[C:2]1([CH3:19])[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[CH:27]([O:30][C:31](=[O:41])[C@H:32]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[NH2:33])([CH3:29])[CH3:28]>>[CH:27]([O:30][C:31](=[O:41])[C@H:32]([CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[NH:33][C:13](=[O:15])[C@@H:12]1[CH2:16][CH2:17][CH2:18][N:11]1[S:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:19])=[CH:7][CH:6]=1)(=[O:9])=[O:10])([CH3:29])[CH3:28]
Reactant: CC(C)OC(=O)[C@@H](N)Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N[C@@H](Cc2ccccc2)C(=O)OC(C)C)cc1

Procedure:
N-(Toluene-4-sulfonyl)-L-proline hydrate was coupled to phenylalanine isopropyl ester trifluoroacetate using the procedure described in Method 3 to give the title compound as an oil.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[NH2:14][C:15]1[S:16][CH:17]=[CH:18][N:19]=1>ClCCl.N1C=CC=CC=1>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:14][C:15]2[S:16][CH:17]=[CH:18][N:19]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: Nc1nccs1
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)c1ccc(S(=O)(=O)Nc2nccs2)cc1
Yield: 70 %

Procedure:
A solution of 4-acetyl-benzenesulfonyl chloride (50 mmol) and 2-aminothiazole (50 mmol) in dichloromethane and pyridine (300 mL, 8:2) was stirred for one day. After concentrated in vacuo, the residue was diluted with ethyl acetate (500 mL) and the solution was washed with 1N HCl solution, sat NaHCO3, dried over MgSO4, and concentrated in vacuo. The residue was recrystallized in ethyl acetate to give 4-acetyl-N-thiazol-2-yl-benzenesulfonamide (35 mmol) as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1.[P:13]([O:20]CC)([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]>>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])=[CH:5][CH:4]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1ccc(C(F)(F)F)cc1)OCC
Yield: 88.9 %

Procedure:
A mixture of 4-trifluoromethylbenzyl bromide (5.68 g, 23.8 mmol) and triethyl phosphite(10.4 g, 63 mmol) was heated at reflux under nitrogen for 5 hours. The excess triethyl phosphite was removed by distillation and the crude product was purified by distillation at 95° C. (0.07 mm Hg.) to give 6.27 g, 89% of the product as an oil. D.C.I.M.S.[MH+,297].
Reaction SMILES: C([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][C:13]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>Cl>[CH3:18][S:15]([C:13]1[CH:12]=[CH:11][C:8]2[CH2:9][CH2:10][NH:4][CH2:5][CH2:6][C:7]=2[CH:14]=1)(=[O:17])=[O:16]
Reactant: CC(=O)N1CCc2ccc(S(C)(=O)=O)cc2CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CS(=O)(=O)c1ccc2c(c1)CCNCC2
Temperature: 25 °C
Yield: 30.5 %

Procedure:
A solution of 3-acetyl-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine (1.75 g, 6.55 mmol) in 5 M hydrochloric acid was heated at reflux for 18 h. The reaction mixture was then cooled to room temperature, basified to pH=12 with potassium carbonate and the solvent evaporated in vacuo. The solid residue was then extracted with ethyl acetate (5×60 ml) and the combined organics dried (Na2SO4). The solvent was then evaporated in vacuo to give the title compound (450 mg, 32%) as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[CH3:10]N>CO.C(Cl)Cl>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][CH3:10]
Reactant: CN
Reactant: NCc1ccccc1Br
Solvent: ClCCl
Solvent: CO
Product: CNCc1ccccc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2-bromobenzylamine (9 g, 36.1 mmol) in MeOH (60 ml) was added dropwise over 30 min. to a solution of methylamine in MeOH (200 mL of a 2.0 M solution, 0.4 mol). The resulting solution was stirred at rt for 2 h and concentrated. The residue obtained was dissolved in DCM (100 mL) and successively washed with saturated aqueous sodium carbonate, dried over sodium sulphate, and concentrated. The resulting oil was distilled to afford the title compound (7 g, 95%) as a colorless oil (b.p. 110° C. at 0.1 mm Hg, LC/MS retention time=1.22 min.; M+=201.92 Column: Phenominex 4.6 mm×50 mm. Solvent A=10% MeOH, 90% H2O, 10 mM NH4Ac; Solvent B=90% MeOH, 10% H2O, 10 nM NH4Ac, Flow rate: 4 mL/min, Gradient: 0% B-100% B 4 min.).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([OH:13])[C@H:10]([OH:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])(=O)=O>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([O:13][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C@H:10]([O:14][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH3:20])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCCCCCCCCCCCOS(C)(=O)=O
Reactant: O[C@@H]1CN(Cc2ccccc2)C[C@H]1O
Product: CCCCCCCCCCCCCCCCCCO[C@@H]1CN(Cc2ccccc2)C[C@H]1OCCCCCCCCCCCCCCCCCC

Procedure:
Compound VI-12 (319 mg, 88.3%) was obtained in the same manner as that in Reference Example 5, by using (3R,4R)-1-benzylpyrrolidine-3,4-diol (Diverchim S. A.; 100 mg, 0.517 mmol) and octadecyl methanesulfonate (Nu-Chek Prep, Inc; 451 mg, 1.29 mmol).
Reaction SMILES: [CH3:1][CH:2]1[C:6](=[O:7])[O:5][C:4]2[CH2:8][C@H:9]([CH3:12])[CH2:10][CH2:11][C:3]1=2.CC1C2CCC(C)CC=2[O:16]C=1>>[OH:16][C:4]12[CH2:8][CH:9]([CH3:12])[CH2:10][CH2:11][C:3]1=[C:2]([CH3:1])[C:6](=[O:7])[O:5]2
Reactant: CC1C(=O)OC2=C1CC[C@@H](C)C2
Reactant: Cc1coc2c1CCC(C)C2
Product: CC1=C2CCC(C)CC2(O)OC1=O

Procedure:
The chemical structure of (6R)-4,5,6,7-tetrahydro-3,6-dimethyl-3H-benzo [b]furan-2-one is known. In fact, K. Schulte-Elte et al in Tetrahedron (1967), 23(6), 2583-2599 identified the compound of the formula (I) in a mixture of lactones resulting from the photooxidation of menthofuran. Furthermore, J. Hirsch et al in J. Org. Chem. (1967), 32(9), 2915-2916 also identified the lactone (I) from among other end products resulting from the hydrolysis of α,α′-dimethoxydihydromenthofuran. However, these authors specify that the lactone (I) oxidises very easily under the synthesis conditions described to give a hydroxylactone, 5,6,7,7a-tetrahydro-7a-hydroxy-3,6-dimethyl-4H-benzo[b]furan-2-one of the formula
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([O:13]CC)=[O:12])[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+]>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([OH:13])=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1ccccc1-c1cccc(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cccc(-c2ccccc2C(=O)O)c1

Procedure:
To a stirred solution of ethyl 2-(3-methoxyphenyl)benzoate from Step A (7.33 g, 28.6 mmol) in MeOH (200 mL) and water (30 mL) was added 1.0 N aq. NaOH (63 mL, 63 mmol) dropwise. The mixture was heated to reflux for 3 hours, then allowed to cool overnight. The solution was concentrated to remove most of the MeOH, cooled on ice, and 10% aq. citric acid (300 mL) was added. The resulting mixture was extracted with CH2Cl2 (3×250 mL), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the titled product as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH2:15])[C:9]=2[CH:8]=[N:7]1)[CH3:2].Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>C(=O)([O-])[O-].[Na+].[Na+]>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:15][C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)Cn1ncc2c1CCCC2N
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOC(=O)Cn1ncc2c1CCCC2NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
To a solution of (4-amino-4,5,6,7-tetrahydro-indazol-1-yl)-acetic acid ethyl ester (60 mg, 0.27 mmol) in 5% sodium carbonate (0.57 mL) and 1,4-1,4-dioxane (1 mL) was added benzyl chloroformate (58 uL, 0.40 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature slowly, and stirred overnight. The reaction mixture was partitioned between water (10 mL) and dichloromethane (20 mL×3). The combined organic layers were collected and dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (50% ethyl acetate in hexanes) to afford racemic (4-benzyloxycarbonylamino-4,5,6,7-tetrahydro-indazol-1-yl)-acetic acid ethyl ester (94.2 mg, 98.2%) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.54 (s, 1 H), 7.49-7.35 (m, 4 H), 5.18 (s, 2 H), 5.23 (s, 2 H), 4.92-4.80 (m, 3 H), 4.23 (dd, J=7.2 Hz, 2 H), 2.52 (m, 2 H), 2.05-1.88 (m, 4 H), 1.30 (t, J=7.2 Hz, 3 H). MS calcd. for C19H23N3O4 357, obsd. (ESI+) [(M+H)+] 358. The chrial separation (Gilson instrument: column: AS-H; flow rate: 15 mL/min; gradient: 55% hexane in propan-2-ol) gave ((R)-4-benzyloxycarbonylamino-4,5,6,7-tetrahydro-indazol-1-yl)-acetic acid ethyl ester (retention time 7.2 minutes) and ((S)-4-benzyloxycarbonylamino-4,5,6,7-tetrahydro-indazol-1-yl)-acetic acid ethyl ester (retention time 8.7 minutes). The recovery for both isomers together was 70%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH3:10])[CH:5]=[C:4]([O:18][CH2:19][CH:20]2[CH2:22][CH2:21]2)[CH:3]=1.[NH2:23][C:24]1[CH:29]=[N:28][CH:27]=[CH:26][N:25]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>C(OCC)(=O)C.O1CCOCC1>[CH:20]1([CH2:19][O:18][C:4]2[CH:3]=[C:2]([NH:23][C:24]3[CH:29]=[N:28][CH:27]=[CH:26][N:25]=3)[N:7]=[C:6]([NH:8][C@H:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[CH3:10])[CH:5]=2)[CH2:22][CH2:21]1
Reactant: C[C@H](Nc1cc(OCC2CC2)cc(Cl)n1)c1ccc(F)cc1
Reactant: Nc1cnccn1
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@H](Nc1cc(OCC2CC2)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 77.8 %

Procedure:
112 mg of (S)-6-chloro-4-(cyclopropylmethoxy)-N-[1-(4-fluorophenyl)ethyl]pyridine-2-amine, 43 mg of 2-aminopyrazine, 67 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 51 mg of sodium t-butoxide and 36 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added in turn to 2 ml of degassed 1,4-dioxane, and the mixture was stirred at 100° C. for 1.5 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 103 mg of the objective compound as brown powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[Li]CCCC.[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1>C1COCC1.CCOC(C)=O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([CH:19]([C:18]2[CH:21]=[CH:22][C:15]([F:14])=[CH:16][CH:17]=2)[OH:20])=[CH:3][CH:4]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Brc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC(c1ccc(F)cc1)c1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1,4-dibromobenzene (42.4 mmol, 10 g) in THF (100 mL) at −78° C. was added dropwise n-BuLi (42.4 mmol, 2 M in hexane). The mixture was stirred at −78° C. for 0.5 h., 4-fluorobenzaldehyde (42.4 mmol, 5.3 g) was added. The mixture was stirred at −78° C. for 1 h and then warmed to r.t. The reaction mixture was diluted with EtOAc, washed with NaHCO3 and brine. The organic extract was dried (anhyd. MgSO4) and concentrated under reduced pressure to give an oil. Chromatography gave the title compound.
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][C:9](=[O:17])[C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[S:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cu](C#N)[C:19]#[N:20].CN1CCCC1=O.N>S([O-])([O-])(=O)=O.[Cu+2].O>[C:19]([C:2]1[C:7]2[CH2:8][C:9](=[O:17])[C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[S:12][C:6]=2[CH:5]=[CH:4][CH:3]=1)#[N:20]
Reactant: N#C[Cu]C#N
Reactant: O=C1Cc2c(Cl)cccc2Sc2ccccc21
Agent: [Cu+2]
Agent: N
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CN1CCCC1=O
Product: N#Cc1cccc2c1CC(=O)c1ccccc1S2
Temperature: 200 °C
Reaction time: 8 h

Procedure:
The mixture of 2.6 g of 9-chloro-10,11-dihydro-11-oxo-dibenzo[b,f]thiepin, 2.0 g. of copper cyanide, 0.1 g of anhydrous copper sulfate and 50 ml of N-methyl pyrrolidone was heated with stirring at 200° C. overnight in a flask equipped with a tube packed with silica gel. After cooling, to the reaction mixture were added 100 ml of conc. aqueous ammonia and 200 ml of water, and the resulting mixture was extracted with benzene. The extract was washed with water, diluted hydrochloric acid and then water, which was dried over potassium sulfate and the solvent was evaporated therefrom. The residue thus obtained was chromatographed on 200 g of silica gel, and eluted with chloroform/methanol (50/1). 0.6 g of the starting material was recovered from a first eluate. Recrystallization of the residue of a second eluate from benzene gave 0.7 g of 9-cyano-10,11-dihydro-11-oxo-dibenzo[b,f]thiepin as pale yellow prismatic crystals having a melting point of 165°-167° C.
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=3)[C:14]2=[O:28])=[CH:9][CH:8]=1)C.[NH2:30][C:31](N)=[O:32]>>[O:28]=[C:14]1[CH:15]([C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:31]([NH:30][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[CH3:6])=[O:32])=[CH:21][CH:20]=2)[CH2:16][CH2:17][CH2:18][N:13]1[C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][C:4]([OH:3])=[O:29])=[CH:8][CH:9]=1
Reactant: NC(N)=O
Reactant: CCOC(=O)CCc1ccc(-n2cccc(-c3ccc([N+](=O)[O-])cc3)c2=O)cc1
Product: Cc1ccccc1NC(=O)Nc1ccc(C2CCCN(c3ccc(CCC(=O)O)cc3)C2=O)cc1

Procedure:
The title compound was prepared from 3-{4-[3-(4-nitrophenyl)-2-oxo-2H-pyridin-1-yl]phenyl}propionic acid ethyl ester which is prepared as described in Preparation 24 with subsequent hydrogenation, urea formation, and hydrolysis steps analogous to the procedures of Preparation 23, Preparation 9 and Example 1 respectively.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]([F:25])([F:24])[O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:21](=[O:22])[CH:20]=[CH:19][C:18]2=[O:23])=[CH:13][CH:12]=1.CO[CH2:28][N:29]([CH2:37][Si](C)(C)C)[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>ClCCl>[CH2:30]([N:29]1[CH2:37][CH:19]2[C:18](=[O:23])[N:17]([C:14]3[CH:15]=[CH:16][C:11]([O:10][C:9]([F:8])([F:24])[F:25])=[CH:12][CH:13]=3)[C:21](=[O:22])[CH:20]2[CH2:28]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: O=C1C=CC(=O)N1c1ccc(OC(F)(F)F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1C2CN(Cc3ccccc3)CC2C(=O)N1c1ccc(OC(F)(F)F)cc1
Reaction time: 3 h
Yield: 92 %

Procedure:
A solution of trifluoroacetic acid (0.89 g, 0.78 mmol) in dichloromethane was added at 4° C. to a stirred solution of 1-(4-(trifluoromethoxy)phenyl)-1H-pyrrole-2,5-dione (2.0 g, 7.8 mmol) and N-(methoxymethyl)(phenyl)-N-((trimethylsilyl)methyl)methanamine (2.2 g, 9.3 mmol) in dichloromethane (100 mL). After 3 h at room temperature, the solution was washed with saturated sodium bicarbonate (80 mL) and brine (80 mL) and dried over Na2SO4. After removal of dichloromethane, the residue was purified by column chromatography on silica gel with petroleum ether:ethyl acetate (10:1 to 5:1) to yield the title compound (2.8 g, 90%). 1H NMR (300 MHz, CDCl3): δ 7.46-7.41 (m, 5H), 7.38-7.31 (m, 4H), 4.19 (s, 2H), 3.89-3.87 (m, 2H), 3.67-3.65 (m, 2H), 3.21 (bs, 2H), LC-MS: [M+1]+ 390.9.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([NH2:9])=[C:4]([C:10]#[C:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[CH:3]=1.[CH2:19]([O:21][C:22](=[O:27])[CH2:23][C:24](Cl)=[O:25])[CH3:20]>>[CH2:19]([O:21][C:22](=[O:27])[CH2:23][C:24]([NH:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[C:10]#[C:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])=[O:25])[CH3:20]
Reactant: Nc1c(F)cc(Cl)cc1C#Cc1ccccc1Cl
Reactant: CCOC(=O)CC(=O)Cl
Product: CCOC(=O)CC(=O)Nc1c(F)cc(Cl)cc1C#Cc1ccccc1Cl

Procedure:
The title compound was prepared in analogy to example 29 step A from 4-chloro-2-(2-chloro-phenylethynyl)-6-fluoro-phenylamine (570 mg, 2.03 mmol) and chlorocarbonyl-acetic acid ethyl ester (460 mg, 3.05 mmol). White solid (440 mg, 55%) MS (ESI): 394 (M+H)+.
Reaction SMILES: C([O:5][C:6]1[CH:11]=[C:10]([C:12]2[CH:29]=[CH:28][C:15]([CH2:16][NH:17][C:18](=[O:27])[C:19]3[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:26])=[CH:14][CH:13]=2)[CH:9]=[CH:8][N:7]=1)(C)(C)C>C(O)=O>[Cl:26][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([Cl:25])[C:19]=1[C:18]([NH:17][CH2:16][C:15]1[CH:28]=[CH:29][C:12]([C:10]2[CH:9]=[CH:8][NH:7][C:6](=[O:5])[CH:11]=2)=[CH:13][CH:14]=1)=[O:27]
Reactant: CC(C)(C)Oc1cc(-c2ccc(CNC(=O)c3c(Cl)cccc3Cl)cc2)ccn1
Solvent: O=CO
Product: O=C(NCc1ccc(-c2cc[nH]c(=O)c2)cc1)c1c(Cl)cccc1Cl
Temperature: 40 °C
Reaction time: 3 h
Yield: 75.5 %

Procedure:
N-[4-(2-tert-Butoxy-pyridin-4-yl)-benzyl]-2,6-dichloro-benzamide was dissolved in 30 mL dichloromethone and 12 mL of 98% formic acid. The mixture was stirred at 40° C. for three hours after which the volatile components were evaporated under vacuum. The residue was triturated with ethyl acetate, filtered, washed with ethyl acetate and dried giving 2,6-dichloro-N-[4-(2-oxo-1,2-dihydro-pyridin-4-yl)-benzyl]-benzamide (4.34 g, 75.5% yield over two steps) as white powder. C19H14Cl2N2O2; MS m/z: 373 (MH+) 1H NMR (DMSO-d6): δ 11.56 (s, 1H), δ 9.21 (t, J=5.6 Hz, 1H), δ 7.67 (d, J=8.0 Hz, 2H), δ 7.46 (m, 6H), δ 6.57 (d, J=1.2 Hz, 1H), δ 6.49 (dd, J=6.8 Hz, J′=1.6 Hz, 1H), δ 4.50 (d, J=6.0 Hz, 2H.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:29])[CH2:14][NH:15][C:16]2[C:20]3[CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=[CH:24][C:19]=3[O:18][N:17]=2)[CH2:9]1.[CH:30]1([CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)[CH2:35][CH2:34][C:33](=O)[CH2:32][CH2:31]1>>[CH:30]1([CH:37]2[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]2)[CH2:35][CH2:34][CH:33]([N:8]2[CH2:11][CH:10]([NH:12][C:13](=[O:29])[CH2:14][NH:15][C:16]3[C:20]4[CH:21]=[C:22]([C:25]([F:27])([F:26])[F:28])[CH:23]=[CH:24][C:19]=4[O:18][N:17]=3)[CH2:9]2)[CH2:32][CH2:31]1
Reactant: O=C(CNc1noc2ccc(C(F)(F)F)cc12)NC1CNC1
Reactant: O=C1CCC(C2CCCCC2)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNc1noc2ccc(C(F)(F)F)cc12)NC1CN(C2CCC(C3CCCCC3)CC2)C1

Procedure:
The title compound was prepared as a white solid from reaction of (N-Azetidin-3-yl-2-(5-trifluoromethyl-benzo[d]isoxazol-3-ylamino)-acetamide TFA salt (as prepared in Example 1, Step D) and bicyclohexyl-4-one using the procedure described in Step E of Example 1.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][C:7]1=O)=[O:5])[CH3:2].[CH:12]1([NH2:17])[CH2:16][CH2:15][CH2:14][CH2:13]1.C([BH3-])#N.[Na+]>C(O)C.C(O)(=O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[NH:17][CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:5])[CH3:2]
Reactant: NC1CCCC1
Reactant: CCOC(=O)C1CCCC1=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C1CCCC1NC1CCCC1
Temperature: 50 °C
Reaction time: 16 h
Yield: 34.2 %

Procedure:
A solution of 2-oxo-cyclopentanecarboxylic acid ethyl ester (3.00 g, 19.2 mmol) in ethanol (20 mL) was treated with cyclopentylamine (1.90 mL, 19.2 mmol), sodium cyanoborohydride (2.42 g, 38.4 mmol), and glacial acetic acid (10 drops) and stirred for 16 h at 50° C. After cooling to 25° C. the solvent was removed in vacuo, the crude material was redissolved in ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate solution (100 mL). The aqueous layer was discarded and the organic layer was washed with 1.0 M aqueous hydrochloric acid solution (50 mL). The organic layer was discarded, 1.0 M aqueous sodium hydroxide solution (75 mL) was added and the aqueous layer was extracted with ethyl acetate (100 mL). The organic layer was dried over sodium sulfate, filtered and the solvent was removed in vacuo to afford the desired product, 2-cyclopentylamino-cyclopentanecarboxylic acid ethyl ester (1.48 g, 6.57 mmol, 34.2%), as a light yellow oil. LC-MS (ESI) calcd for C13H23NO2 225.17, found 226.2 [M+H+].
Reaction SMILES: [C:1]1(B(O)O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[C:15]1[CH:20]=[CH:19][C:18](Br)=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23].C(=O)([O-])[O-].[K+].[K+]>O.C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:22]([C:16]1[CH:17]=[C:18]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH:19]=[CH:20][C:15]=1[C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][CH:8]=1)([O-:24])=[O:23]
Reactant: OB(O)c1cccc2ccccc12
Reactant: O=[N+]([O-])c1cc(Br)ccc1Br
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: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1cc(-c2cccc3ccccc23)ccc1-c1cccc2ccccc12

Procedure:
2.4 g (2.1 mmol) of Pd(PPh3)4 are added to a well-stirred, degassed suspension of 67.8 g (190 mmol) of 1-naphthylboronic acid, 53.3 g (190 mmol) of 2,5-dibromonitrobenzene and 137.9 g (648.5 mmol) of potassium carbonate in a mixture of 250 ml of water and 250 ml of THF, and the mixture is heated under reflux for 20 h. After cooling, the organic phase is separated off, washed three times with 200 ml of water and once with 200 ml of saturated, aqueous sodium chloride solution, dried over magnesium sulfate and evaporated to dryness in vacuo in a rotary evaporator. The grey residue is recrystallised from hexane. The deposited crystals are filtered off with suction, washed with a little MeOH and subsequently dried in vacuo; yield: 86.1 g, 71% of theory; purity: 98.4% according to HPLC.