Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[C:22]([NH:30][CH3:31])[C:23]([NH2:29])=[CH:24][CH:25]=4)[O:20][C:19]=3[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:39]OC(OC)OC.II>C(#N)C>[C:1]([O:5][C:6](=[O:38])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:27](=[O:28])[C:26]4[CH:25]=[CH:24][C:23]5[N:29]=[CH:31][N:30]([CH3:39])[C:22]=5[C:21]=4[O:20][C:19]=3[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CNc1c(N)ccc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc12
Reactant: COC(OC)OC
Agent: II
Solvent: CC#N
Product: Cn1cnc2ccc3c(=O)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)oc3c21
Reaction time: 1 h
Yield: 67.6 %

Procedure:
To a stirred solution of {1-[4-(7-amino-8-methylamino-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (95 mg, 0.19 mmol) in acetonitrile (3 mL) was added trimethylorthoformate (24 μL, 0.22 mmol) and iodine (5 mg, 0.02 mmol) at RT. After 1 hour, the reaction mixture was quenched with Na2S2O3. The resulting mixture was extracted with ethyl acetate (2×30 mL) and the combined organics washed with brine, dried (Na2SO4) and the solvents were removed in vacuo. The resulting residue was subjected to flash chromatography (SiO2, ethyl acetate) to give the title compound as a white solid (67 mg, 68%). LCMS (Method G): RT=3.63 min, [M+H]+=522.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:18]3[CH:19]=[N:20][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:22]=3)[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:4]=2[CH:3]=1.[CH2:30]([O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[NH2:39])[CH3:31]>>[C:26]([O:25][C:23]([N:21]1[CH:22]=[C:18]([C:9]2[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:4]3[CH:3]=[C:2]([NH:39][C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[O:32][CH2:30][CH3:31])[N:7]=[CH:6][C:5]=3[CH:8]=2)[CH:19]=[N:20]1)=[O:24])([CH3:27])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)n1cc(-c2cc3cnc(Br)cc3n2C(=O)OC(C)(C)C)cn1
Reactant: CCOc1ccccc1N
Product: CCOc1ccccc1Nc1cc2c(cn1)cc(-c1cnn(C(=O)OC(C)(C)C)c1)n2C(=O)OC(C)(C)C
Yield: 33 %

Procedure:
The title compound was prepared in 33% yield from compound (10) and 2-ethoxyphenylamine using the method described for Preparation 35. 1H-NMR (CDCl3, 500 MHz): δ 1.48 (t, J=6.94 Hz, 3H), 1.54 (s, 9H), 1.69 (s, 9H), 4.14 (q, J=6.94 Hz, 2H), 6.59 (d, J=0.63 Hz, 1H), 6.91-6.98 (m, 3H), 7.11 (br s, 1H), 7.70 (m, 1H), 7.83 (d, J=0.63 Hz, 1H), 7.91 (br d, J=8.20 Hz, 1H), 8.33 (d, J=0.63 Hz, 1H), 8.49 (s, 1H).
Reaction SMILES: I[CH2:2][CH:3]1[NH:9][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]1=2.[CH2:19]([O:26][C:27]1[CH:32]=[C:31](I)[CH:30]=[CH:29][C:28]=1[N:34]1[S:38](=[O:40])(=[O:39])[N:37]([CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:36](=[O:47])[CH2:35]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([O:26][C:27]1[CH:32]=[C:31]([CH:30]=[CH:29][C:28]=1[N:34]1[CH2:35][C:36](=[O:47])[N:37]([CH2:41][CH2:42][Si:43]([CH3:44])([CH3:45])[CH3:46])[S:38]1(=[O:39])=[O:40])[CH2:2][CH:3]1[NH:9][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]1=2)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1NC(CI)c2ccccc2-c2ccccc21
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(CC3NC(=O)c4ccccc4-c4ccccc43)cc2OCc2ccccc2)S1(=O)=O

Procedure:
The title compound is prepared from 7-iodomethyl-6,7-dihydro-dibenzo[c,e]azepin-5-one and 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one analogous to the method used in Example 57, step B.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:11]1([NH2:18])[CH2:16][CH2:15][CH:14]([NH2:17])[CH2:13][CH2:12]1.CN(C)C=O.C(=O)([O-])[O-].[Na+].[Na+]>O>[N+:8]([C:7]1[C:2]([NH:17][CH:14]2[CH2:15][CH2:16][CH:11]([NH2:18])[CH2:12][CH2:13]2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: NC1CCC(N)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: NC1CCC(Nc2ncccc2[N+](=O)[O-])CC1
Yield: 54.8 %

Procedure:
2-Chloro-3-nitropyridine (10 g, 63.3 mmol), cyclohexane-1,4-diamine (7.2 g, 63.3 mmol), anhydrous dimethylformamide (100 mL) and anhydrous sodium carbonate (13.4 g, 126 mmol) were combined with stirring under nitrogen. The reaction mixture was stirred at room temperature for 14 hours. It was poured into water and the resulting orange solid was filtered off and found to be N1-(3-nitropyridin-2-yl)cyclohexane-1,4-diamine (8.2 g, 34.7 mmol, 54.9% yield) which was used in the next step without further purification.
Reaction SMILES: [OH:1][CH:2]([C:9]1[O:10][CH:11]=[CH:12][CH:13]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:14](C1C=CC=CC=1Br)([CH3:16])[CH3:15]>>[OH:1][CH:2]([C:9]1[O:10][CH:11]=[CH:12][CH:13]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:14]([CH3:16])[CH3:15]
Reactant: OC(c1ccccc1)c1ccco1
Reactant: CC(C)c1ccccc1Br
Product: CC(C)c1ccccc1C(O)c1ccco1

Procedure:
(±) 2-(α-Hydroxy-2-isopropylbenzyl)furan (b.p. 110° C./0.15 mm.Hg) was prepared by the procedure hereinbefore described in (i) for the preparation of (±) 2-α-hydroxybenzylfuran but replacing the bromobenzene by 2-isopropylbromobenzene (described by Crawford and Stuart, J.C.S., 1952, 4445).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C@@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:19])=[N:6]2.[SH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[OH:35].C(=O)([O-])[O-].[K+].[K+]>[Cu]I>[OH:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[S:28][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C@@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:19])=[N:6]2
Reactant: Oc1ccccc1S
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nn2ccc(I)c2c(=O)n1-c1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C[C@H](NC(=O)OC(C)(C)C)c1nn2ccc(Sc3ccccc3O)c2c(=O)n1-c1ccccc1
Yield: 64 %

Procedure:
(S)-tert-Butyl (1-(5-iodo-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)carbamate (250 mg, 0.52 mmol) was treated with 2-mercaptophenol (80 μl, 0.80 mmol), potassium carbonate (110 mg, 0.8 mmol) and copper(I) iodide (150 mg, 0.79 mmol) according to the method described in Preparation 44. The crude was purified using SP1® Purification System (0%-25%, hexane-ethyl acetate) to give 252 mg (64% yield) to the title compound as an oil.
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH:12]1[NH:18][C:17](=[NH:19])[CH2:16][CH2:15][CH2:14][CH2:13]1)([O-])=O.[H][H]>C(O)C.[Rh]>[ClH:1].[ClH:1].[NH:19]=[C:17]1[NH:18][CH:12]([CH2:11][CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH:5]2[NH2:2])[CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: [H][H]
Reactant: N=C1CCCCC(Cc2ccccc2[N+](=O)[O-])N1
Agent: [Rh]
Agent: Cl
Solvent: CCO
Product: N=C1CCCCC(CC2CCCCC2N)N1
Temperature: 60 °C
Yield: 48.9 %

Procedure:
The product of Example 270 (0.262 g, 0.9 mmol) was dissolved in ethanol, treated with 5% Rhodium on Carbon under 60 psi of Hydrogen and warmed to 60° C. to give the title product (66 mg, 0.22 mmol).
Reaction SMILES: CC1(C)[O:6][C@@H:5]([CH2:7][CH2:8][NH:9][C:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[F:24])[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:41])([CH3:40])[CH2:37][CH2:38][NH2:39])[NH:13]2)=[O:11])[CH2:4][O:3]1.C(N(CC)CC)C.[C:50](Cl)(=[O:57])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.Cl>O1CCCC1>[OH:6][C@H:5]([CH2:4][OH:3])[CH2:7][CH2:8][NH:9][C:10]([CH:12]1[CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[F:24])[C:15]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:41])([CH3:40])[CH2:37][CH2:38][NH:39][C:50](=[O:57])[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[NH:13]1)=[O:11]
Reactant: CC(C)(CCN)CC1NC(C(=O)NCC[C@H]2COC(C)(C)O2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(CCNC(=O)c1ccccc1)CC1NC(C(=O)NCC[C@H](O)CO)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F

Procedure:
In a manner similar to the method described in Examples 122a and 122b, rac-(2R,3S,4R,5S)-5-(4-amino-2,2-dimethyl-butyl)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethyl]-amide (80 mg, 0.13 mmol) prepared in Example 121a was reacted with triethylamine and benzoyl chloride (22 mg, 0.16 mmol) in tetrahydrofuran, followed by the reaction with aqueous HCl solution in tetrahydrofuran to give rac-(2R,3S,4R,5S)-5-(4-benzoylamino-2,2-dimethyl-butyl)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a off white solid (57 mg, 90%)
Reaction SMILES: [CH3:1][C:2]1[N+:3]([O-])=[C:4]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=2)[O:5][C:6]=1[CH3:7].P(Cl)(Cl)([Cl:21])=O.N>C(Cl)(Cl)Cl>[Cl:21][CH2:1][C:2]1[N:3]=[C:4]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=2)[O:5][C:6]=1[CH3:7]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1oc(-c2ccc3ccccc3c2)[n+]([O-])c1C
Agent: N
Solvent: ClC(Cl)Cl
Product: Cc1oc(-c2ccc3ccccc3c2)nc1CCl
Temperature: 0 °C

Procedure:
40 g of 4,5-dimethyl-2-naphthalen-2-yloxazole 3-oxide are dissolved in 200 ml of chloroform, 16.7 ml of phosphorus oxychloride are added and the mixture is heated under reflux for 30 minutes. The reaction mixture is cooled to 0° C., a slightly alkaline pH is established using ammonia and the mixture is extracted three times with in each case 500 ml of ethyl acetate. The combined organic phases are washed with water and dried over MgSO4 and the solvent is then removed under reduced pressure. The residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate=80:1=>5:1. This gives 10.6 g of 4-chloromethyl-5-methyl-2-naphthalen-2-yloxazole as a colorless solid. C15H12ClNO (257.72), MS(ESI): 258 (M+H+).
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:16](=[O:17])[C:12]3([CH2:15][CH2:14][CH2:13]3)[N:11]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[C:20]([F:27])[CH:19]=3)[C:10]2=[S:28])=[CH:5][C:4]=1[C:29]([F:32])([F:31])[F:30])#[N:2].[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH2:39][CH2:40][NH2:41].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:16](=[O:17])[C:12]3([CH2:15][CH2:14][CH2:13]3)[N:11]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH:41][CH2:40][CH2:39][C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][N:33]=4)=[O:24])=[C:20]([F:27])[CH:19]=3)[C:10]2=[S:28])=[CH:5][C:4]=1[C:29]([F:32])([F:31])[F:30])#[N:2]
Reactant: NCCc1ccccn1
Reactant: N#Cc1ncc(N2C(=O)C3(CCC3)N(c3ccc(C(=O)O)c(F)c3)C2=S)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1ncc(N2C(=O)C3(CCC3)N(c3ccc(C(=O)NCCc4ccccn4)c(F)c3)C2=S)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.8 %

Procedure:
A mixture of 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluorobenzoic acid (Compound 224, 70 mg, 0.15 mmol), 2-(pyridin-2-yl)ethanamine (24 mg, 0.20 mmol), HATU (74 mg, 0.20 mmol), and DIEA (80 mL, 0.45 mmol) in DMF (3 mL) was stirred at room temperature overnight. The crude reaction mixture was purified by reverse phase HPLC (acetonitrile/water, 0.1% TFA). The fractions containing the desired compound were combined, acetonitrile was removed in vacuo, and the remaining aqueous layer was treated with a saturated solution of sodium bicarbonate. The aqueous layer was extracted with DCM (3×), the organics were combined, dried over sodium sulfate, and evaporated to dryness to afford 51 mg of 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluoro-N-(2-(pyridin-2-yl)ethyl)benzamide as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.22 (d, 1H), 8.75 (d, 1H), 8.66 (t, 1H), 8.52 (d, 1H), 7.82-7.70 (m, 2H), 7.47-7.22 (m, 4H), 3.65 (q, 2H), 3.01 (t, 2H), 2.68-2.62 (m, 2H), 2.54-2.43 (m, 2H), 2.03-1.93 (m, 1H), 1.60-1.57 (m, 1H). LCMS [M+1]+ 569.5.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:22])([CH3:21])[CH2:12][C:13]([OH:20])([C:16]([F:19])([F:18])[F:17])[CH:14]=O)[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.[CH3:23][O:24][C:25]([C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][C:33]=2[NH2:37])[N:28]=1)=[O:26]>C(O)(=O)C.C1(C)C=CC=CC=1>[CH3:23][O:24][C:25]([C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][C:33]=2[N:37]=[CH:14][C:13]([OH:20])([C:16]([F:19])([F:18])[F:17])[CH2:12][C:11]([C:4]2[C:5]3[O:9][CH2:8][CH2:7][C:6]=3[CH:10]=[C:2]([Cl:1])[CH:3]=2)([CH3:21])[CH3:22])[N:28]=1)=[O:26]
Reactant: CC(C)(CC(O)(C=O)C(F)(F)F)c1cc(Cl)cc2c1OCC2
Reactant: COC(=O)c1ccc2c(N)cccc2n1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COC(=O)c1ccc2c(N=CC(O)(CC(C)(C)c3cc(Cl)cc4c3OCC4)C(F)(F)F)cccc2n1

Procedure:
Analogously to Example 37, 160 mg (0.47 mmol) of 4-(5-chloro-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal is reacted with 116 mg (0.57 mmol) of 5-aminoquinoline-2-carboxylic acid methyl ester in 1.0 ml of concentrated acetic acid and 20 ml of toluene. After working-up and purification on silica gel with hexane-ethyl acetate (0–100%), 110 mg (45% of theory) of the product is obtained.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][NH:21][C:22](=[O:33])[C@H:23]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH3:24])=[O:19])C1C=CC=CC=1>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][NH:21][C:22](=[O:33])[C@H:23]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH3:24])=[O:19]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2O
Reaction time: 2 h
Yield: 100.2 %

Procedure:
To a solution of compound 275 (400 mg, 0.86 mmol) in 30 mL of MeOH was added 0.8 g of Pd/C (10%, wet). The mixture was hydrogenated at room temperature for 2 h. The catalyst was removed by filtration through a celite pad. The filtrate was concentrated to afford compound 276 as a colorless gum (320 mg, 99%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.C(Cl)Cl.[Cl:15][C:16]1[CH:17]=[C:18]([C:22]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=2)=[CH:23][C:24]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:25])[CH:19]=[CH:20][CH:21]=1>C(N(CC)CC)C>[Cl:38][C:34]1[CH:33]=[C:32]([C:22]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([Cl:15])[CH:17]=2)=[CH:23][C:24]([N:26]2[CH2:31][CH2:30][N:29]([C:7](=[O:8])[C:6]3[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:28][CH2:27]2)=[O:25])[CH:37]=[CH:36][CH:35]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: O=C(C=C(c1cccc(Cl)c1)c1cccc(Cl)c1)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)N2CCN(C(=O)C=C(c3cccc(Cl)c3)c3cccc(Cl)c3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
0.25 g of p-methoxybenzoyl chloride were added to 10 ml of a methylene chloride solution containing 0.529 g of 1-[3,3-bis(3-chlorophenyl)acryloyl]piperazine (prepared as described in Preparation 111) and 0.41 ml of triethylamine, whilst ice-cooling, and the mixture was stirred at room temperature for 1 hour. The mixture was then worked up and purified as described in Example 68 to give 0.682 g of the title compound as a powder.
Reaction SMILES: [O:1]=[C:2]1[O:6][CH2:5][C@:4]2([CH2:10][CH2:9][C@H:8]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])=[CH:13][CH:12]=3)[CH2:7]2)[NH:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:1]=[C:2]1[O:6][CH2:5][C@:4]2([CH2:10][CH2:9][C@H:8]([C:11]3[CH:12]=[CH:13][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:15][CH:16]=3)[CH2:7]2)[NH:3]1
Reactant: CC(C)(C)OC(=O)Cc1ccc([C@H]2CC[C@]3(COC(=O)N3)C2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)Cc1ccc([C@H]2CC[C@]3(COC(=O)N3)C2)cc1
Reaction time: 2 h

Procedure:
To a mixture of tert-butyl 2-(4-((5R,7S)-2-oxo-3-oxa-1-azaspiro[4.4]nonan-7-yl)phenyl)acetate (I-5A, 1 g, 3.02 mmol) in DCM (20 mL) was added TFA (10 mL). After 2 h, the solution was concentrated in vacuo and used as such for the subsequent step without further purification. HPLC retention time=0.65 min (Condition G); LC/MS M+1=276.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[C:9](O)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.B(F)(F)F>CC([O-])=O.[Na+]>[OH:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][C:8]=1[C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:16]
Reactant: O=C(O)c1ccccc1
Reactant: Oc1cccc(O)c1
Agent: CC(=O)[O-]
Agent: FB(F)F
Agent: [Na+]
Product: O=C(c1ccccc1)c1ccc(O)cc1O
Yield: 46.4 %

Procedure:
Resorcinol (1.10 g, 10.0 mmol) and benzoic acid (1.22 g, 1.01 eq.) were treated with BF3-etherate (7.55 mL, 6 eq.) and heated for 2 h to 95° C. After cooling the reaction mixture was carefully poured onto 500 mL of 10% aq. NaOAc solution, twofold extracted with AcOEt, washed with water, dried over sodium sulfate, and evaporated to dryness. Flash chromatography (SiO2, heptane/AcOEt=8/2), followed by direct crystallization after reducing the volume, afforded 0.994 g of the title compound as off-white crystals.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:3]=1.[C:19]([O:23][C:24](=[O:39])[C:25]([O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36](O)=[O:37])=[CH:31][CH:30]=1)([CH3:27])[CH3:26])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24](=[O:39])[C:25]([CH3:26])([O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36](=[O:37])[NH:8][C:7]2[C:2]([CH3:1])=[N:3][C:4]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([F:16])([F:18])[F:17])=[CH:11][CH:10]=3)=[CH:5][CH:6]=2)=[CH:31][CH:30]=1)[CH3:27])([CH3:21])([CH3:20])[CH3:22]
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CC(=O)O)cc1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1N
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1NC(=O)Cc1ccc(OC(C)(C)C(=O)OC(C)(C)C)cc1

Procedure:
A] In analogy to the procedures described in example 26B] and 124C], 2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylamine (example 125C]) was reacted with 2-(4-carboxymethyl-phenoxy)-2-methyl-propionic acid tert-butyl ester (example 124A]) to give 2-methyl-2-(4-{[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylcarbamoyl]-methyl}-phenoxy)-propionic acid tert-butyl ester, which was subsequently cleaved with trifluoroacetic acid to yield the title compound as colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C.O>[CH3:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[O:1][CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:10][C:9]2=[O:11]
Reactant: O=Cc1ccccc1
Reactant: CC(=O)c1cc(C)ccc1O
Solvent: CCO
Solvent: O
Product: Cc1ccc2c(c1)C(=O)CC(c1ccccc1)O2
Yield: 34 %

Procedure:
A mixture of 1-(2-hydroxy-5-methyl-phenyl)-ethanone (15 g, 0.10 mol), benzaldehyde (10.6 g, 0.10 mol) and borax (38 g, 0.10 mol) in ethanol (90 mL) and H2O (150 mL) was refluxed for one day. The reaction mixture was cooled, diluted with an equal volume of H2O and extracted with ether. The ether was dried over anhydrous Na2SO4, filtered, and evaporated to give 6-methyl-2-phenyl-chroman-4-one (8.1 g, 34%). 1H-NMR (CDCl3): 2.32 (s, 3H), 2.86 (d, 1H), 3.06 (t, 1H), 5.44 (d, 1H), 6.96 (d, 1H), 7.38 (d, 1H), 7.44 (m, 5H), 7.71 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[O:4].[CH3:17][CH:18]1[C:22](=[O:23])[CH2:21][CH2:20][O:19]1>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:22]2([OH:23])[CH2:21][CH2:20][O:19][CH:18]2[CH3:17])=[CH:8][C:9]=1[NH:10][C:11](=[O:16])[C:12]([F:13])([F:14])[F:15])=[O:4]
Reactant: COC(=O)c1sccc1NC(=O)C(F)(F)F
Reactant: CC1OCCC1=O
Product: COC(=O)c1sc(C2(O)CCOC2C)cc1NC(=O)C(F)(F)F

Procedure:
3-(2,2,2-Trifluoroacetylamino)thiophene-2-carboxylic acid methyl ester and 2-methyldihydrofuran-3-one were reacted by method M. The product with the molecular weight of 353.32 (C13H14F3NO5S) was obtained in this way; MS (ESI): 354 (M+H+).
Reaction SMILES: [CH2:1]([N:3]1[CH2:11][C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1)[CH3:2].O>COCCO.[Pd]>[CH2:1]([N:3]1[CH2:11][CH:10]2[CH:5]([NH:6][CH2:7][CH2:8][CH2:9]2)[CH2:4]1)[CH3:2]
Reactant: CCN1Cc2cccnc2C1
Agent: [Pd]
Solvent: COCCO
Solvent: O
Product: CCN1CC2CCCNC2C1
Temperature: 70 °C
Reaction time: 6 h
Yield: 72.1 %

Procedure:
To a solution of 6-ethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine (2.00 g) in glycol monomethyl ether was added a catalytic amount of 10% Pd/C. The suspension was heated to 70° C. and stirred for 6 h under H2 (2 MPa), then cooled to rt, and poured into 100 mL of water. The mixture was extracted with CH2Cl2 (50 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo to give the title compound as yellow oil (1.50 g, 70.00%). The crude product was used for the next step without further purification. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 155.0 (M+1).
Reaction SMILES: Cl.[C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10]N)=[CH:6][CH:5]=1)#[N:3].[C:12]([O:20][CH:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)(=O)C>[C:12]([O:20][CH:21]1[CH2:22][C:23]2[C:8]3[C:7](=[CH:6][CH:5]=[C:4]([C:2]#[N:3])[CH:9]=3)[NH:10][C:24]=2[CH2:25][CH2:26]1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#Cc1ccc(NN)cc1
Reactant: O=C1CCC(OC(=O)c2ccccc2)CC1
Agent: Cl
Solvent: CC(=O)O
Product: N#Cc1ccc2[nH]c3c(c2c1)CC(OC(=O)c1ccccc1)CC3
Yield: 47.9 %

Procedure:
4-Cyanophenyl hydrazine hydrochloride (20.2 g) and 4-benzoyloxycyclohexanone (25.9 g) were dissolved in glacial acetic acid (400 ml) and the mixture was heated under reflux for 1.5 hr. After allowing to cool, the mixture was filtered, and the filtrate was evaporated to dryness, and neutralized with aqueous sodium bicarbonate solution to give a solid precipitate, which was purified by chromatography (SiO2 ; hexane/ethyl acetate) to give 3-benzoyloxy-6-cyano-1,2,3,4-tetrahydrocarbazole (18 g). This product (11.6 g) was suspended in ethanol (230 ml) and treated with 2.5% aqueous potassium hydroxide solution (120 ml), and heated under reflux for 1 hr. The cooled mixture was neutralized with glacial acetic acid and evaporated to a solid residue, which was washed with water, and dried to give 3-hydroxy-6-cyano-1,2,3,4-tetrahydrocarbazole (6.6 g).