Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:33][C:34]([F:45])([F:44])[C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([C:39]3[CH:38]=[CH:37][CH:36]=[C:35]([C:34]([F:45])([F:44])[F:33])[CH:40]=3)[C:18]([C:23]([N:25]3[CH2:30][CH2:29][S:28](=[O:31])(=[O:32])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCS(=O)(=O)CC1)n2-c1cccc(C(F)(F)F)c1)N1CCN(C2CCCC2)CC1
Yield: 40 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone (example 34), 3-(trifluoromethyl)phenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light yellow solid (40%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[O:20][C:21]([CH3:24])=[N:22][N:23]=3)=[CH:15][CH:14]=2)[CH:3]=1.[C:25]([C:28]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)([CH3:30])[CH3:29])([OH:27])=[O:26].C([O-])([O-])=O.[Cs+].[Cs+].O>COCCOC.C(#N)C>[CH3:9][O:8][C:6]1[N:7]=[C:2]([C:33]2[CH:32]=[C:31]([C:28]([CH3:30])([CH3:29])[C:25]([OH:27])=[O:26])[CH:36]=[CH:35][CH:34]=2)[CH:3]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[O:20][C:21]([CH3:24])=[N:22][N:23]=3)=[CH:15][CH:14]=2)[N:5]=1
Reactant: CC(C)(C(=O)O)c1cccc(B(O)O)c1
Reactant: COc1nc(Cl)cc(NCCc2ccc(-c3nnc(C)o3)cc2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Solvent: CC#N
Product: COc1nc(NCCc2ccc(-c3nnc(C)o3)cc2)cc(-c2cccc(C(C)(C)C(=O)O)c2)n1
Reaction time: 3 h
Yield: 25.3 %

Procedure:
A mixture of (6-chloro-2-methoxy-pyrimidin-4-yl)-{2-[4-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenyl]-ethyl}-amine (0.16 g, 0.46 mmol), 3-(1-carboxy-1-methyl-ethyl)-phenyl boronic acid, [125 mg, 0.6 mmol, see Example 49(b), step 2], and Cs2CO3 (0.37 g, 1.15 mmol) in ethylene glycol dimethyl ether (8 mL), acetonitrile (10 mL), and water (2 mL) is degassed by bubbling with Argon gas for 5 minutes, and treated with 1,1′-bis(diphenylphosphino)ferrocene palladium(II) chloride (20 mg) at room temperature. After 3 h at 85° C., the mixture is diluted with water (15 mL), and extracted with EtOAc (2×15 mL). The extracts are dried (MgSO4), filtered, and concentrated. The residue is chromatographed on SiO2 eluting with 80% EtOAc in heptane to afford 2-[3-(2-methoxy-6-{2-[4-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenyl]-ethylamino}-pyrimidin-4-yl)-phenyl]-2-methyl-propionic acid [55 mg, Example 68]. LCMS: RT=1.82 minutes; MS: 474 (M+H); 1H NMR (300 MHz, CDCl3) □ 7.98-7.81 (4H, m), 7.5-7.27 (4H, m), 6.33 (1H, s), 3.97 (3H, s), 3.72-3.6 (2H, m), 2.92 (2H, t, J=6.5 Hz), 2.6 (3H, s), 1.6 (6H, s).
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][S:7][C:8](=[NH:10])[NH2:9].[CH2:11]([O:13][C:14](=[O:22])[C:15](=O)[CH2:16][C:17](=O)[CH2:18][CH3:19])[CH3:12]>C(O)C>[CH2:11]([O:13][C:14]([C:15]1[CH:16]=[C:17]([CH2:18][CH3:19])[N:9]=[C:8]([S:7][CH3:6])[N:10]=1)=[O:22])[CH3:12]
Reactant: CSC(=N)N
Reactant: CCOC(=O)C(=O)CC(=O)CC
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCOC(=O)c1cc(CC)nc(SC)n1
Yield: 56.1 %

Procedure:
A solution of S-methylisothiourea sulphate (874 mg, 4.65 mmol) and 2,4-dioxohexanoic acid ethyl ester (800 mg, 4.65 mmol) in ethanol (4 mL) is heated to 80° C. for 48 h. The reaction mixture is then filtered, evaporated and purified by prep. TLC (using heptane/EA 1/1 as eluent) to give 590 mg of 6-ethyl-2-methylsulfanyl-pyrimidine-4-carboxylic acid ethyl ester as a yellow oil; LC-MS: tR=0.91 min, [M+H]+=227.22. 1H NMR (D6-DMSO): δ 1.24 (t, J=7.5 Hz, 3H), 1.34 (t, J=7.0 Hz, 3H), 2.56 (s, 3H), 2.81 (q, J=7.5 Hz, 2H), 4.37 (q, J=7.0 Hz, 2H), 7.58 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.C(N(CC)CC)C.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][O:8][S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=2)(=[O:25])=[O:24])[CH2:4][O:3]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1(C)OCC(CO)O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC2COC(C)(C)O2)cc1
Reaction time: 0.5 h

Procedure:
2,2-Dimethyl-4-hydroxymethyl-1,3-dioxolan (3.96 g, 30 mmol) and triethyl amine (5 mL) were dissolved in CH2Cl2 (50 mL). p-Toluenesulphonyl chloride (3.8 g, 20 mmol) was added. The solution was stirred for 3 h after which 4-dimethylaminopyridine (0.05 g, 0.04 mmol) was added. The solution was stirred for 0.5 h after which the solution was concentrated in vacuo. The residue was taken up in CH2Cl2 and the organic phase was washed with H2O, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography to afford the title compound.
Reaction SMILES: N[NH:2][C:3]([C:5]1[CH:6]=[C:7](B(O)O)[CH:8]=[CH:9][CH:10]=1)=[O:4].Cl[C:15]1[CH:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=1.[IH:22]>>[I:22][C:15]1[CH:20]=[C:19]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([C:3]([NH2:2])=[O:4])[CH:6]=2)[N:18]=[CH:17][N:16]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: NNC(=O)c1cccc(B(O)O)c1
Reactant: I
Product: NC(=O)c1cccc(-c2cc(I)ncn2)c1

Procedure:
The compound was prepared according to Example 1 using 3-aminocarbamoylphenylboronic acid and 4,6-dichloropyrimidine. The resultant chloro compound was converted to iodo with hydroiodic acid as described in the general procedure.
Reaction SMILES: [ClH:1].[CH3:2][NH:3][S:4](/[CH:7]=[CH:8]/[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[C:18]1[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH:23]=1)(=[O:6])=[O:5].C>CN(C=O)C.CO.[Pd]=O>[ClH:1].[CH3:2][NH:3][S:4]([CH2:7][CH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH:18]1[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]1)(=[O:5])=[O:6]
Reactant: CNS(=O)(=O)/C=C/c1ccc2[nH]cc(C3=CCN(C)CC3)c2c1
Agent: O=[Pd]
Agent: Cl
Solvent: CO
Solvent: CN(C)C=O
Product: CNS(=O)(=O)CCc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Reaction time: 24 h

Procedure:
A mixture of (E)-N-methyl-2-[3-(1,2,3,6-tetrahydro-1-methyl-4-pyridinyl)-1H-indol-5-yl]ethenesulphonamide hydrochloride (500 g) and 10% palladium oxide on charcoal (50% wet paste, 700g added as three charges) in DMF (3L), water (3L) and methanol (1.5L) was hydrogenated at atmospheric pressure over 24 hr. The suspension was filtered and the filter cake washed with water (500 mL). The filtrate was concentrated to approximately 2L by distillation in vacuo. Ethyl acetate (5L) was added over 10 mins and the mixture cooled to 5°. The product was filtered off, washed with ethyl acetate (1L) and dried in vacuo at 45° overnight (453 g, 90.1% of theory). Recrystallisation from hot water (1.36L) afforded white crystals (324.0 g, 71.2% of theory).
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[S:12][C:11]([S:13]([NH:16][CH:17]2[CH:23]3[CH2:24][CH2:25][CH:18]2[CH2:19][C:20]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][C:21]=2[CH2:22]3)(=[O:15])=[O:14])=[CH:10][CH:9]=1.[CH3:32][O:33][CH2:34]Cl.O>C1COCC1>[Cl:7][C:8]1[S:12][C:11]([S:13]([N:16]([CH:17]2[CH:23]3[CH2:24][CH2:25][CH:18]2[CH2:19][C:20]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][C:21]=2[CH2:22]3)[CH2:32][O:33][CH3:34])(=[O:15])=[O:14])=[CH:10][CH:9]=1
Reactant: COCCl
Reactant: N#Cc1ccc2c(c1)CC1CCC(C2)C1NS(=O)(=O)c1ccc(Cl)s1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COCN(C1C2CCC1Cc1cc(C#N)ccc1C2)S(=O)(=O)c1ccc(Cl)s1
Reaction time: 0.33 h
Yield: 99.8 %

Procedure:
Potassium t-butoxide (1.0M in THF; 1.33 ml, 1.33 mmol) was added to a solution of 5-chloro-N-(2-cyano-5,6,7,8,9,10-hexahydro-6,9-methanobenzo[a][8]annulen-11-yl)thiophene-2-sulfonamide (Example 176) (350 mg, 0.89 mmol) in THF (10 ml) and stirred for 20 mins. Chloromethyl methyl ether (108 μl, 1.42 mmol) was added and the reaction stirred overnight at RT. More reagents were added as necessary until the reaction was complete by NMR. The reaction mixture was poured into water (25 ml) and extracted with ethyl acetate (2×25 ml). The combined organic layers were washed with brine, dried over MgSO4 and evaporated to give 5-chloro-N-(2-cyano-5,6,7,8,9,10-hexahydro-6,9-methanobenzo[a][8]annulen-11-yl)-N-(methoxymethyl)thiophene-2-sulfonamide (388 mg, quant.).
Reaction SMILES: O.NN.[F:4][C:5]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH3:18])=[C:11]2[C:6]=1[C:7](=[O:41])[C:8]([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1)=[CH:9][N:10]2[CH2:19][CH2:20][CH2:21][N:22]1C(=O)C2C(=CC=CC=2)C1=O>C(O)C>[NH2:22][CH2:21][CH2:20][CH2:19][N:10]1[C:11]2[C:6](=[C:5]([F:4])[CH:14]=[CH:13][C:12]=2[O:15][CH2:16][CH2:17][CH3:18])[C:7](=[O:41])[C:8]([C:33]2[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=2)=[CH:9]1
Reactant: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(CCCN3C(=O)c4ccccc4C3=O)c12
Agent: NN
Solvent: O
Solvent: CCO
Product: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(CCCN)c12
Yield: 93.9 %

Procedure:
Hydrazine hydrate (0.62 ml, 12.8 mmol) was added to an ethanol solution (60 ml) of 2-{3-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]propyl}isoindole-1,3-dione (2.0 g, 3.88 mmol) and heated under reflux for 4 hours. The resulting mixture was concentrated under reduced pressure, a 5N aqueous sodium hydroxide solution was added to the thus-obtained residue, and then the resulting mixture was subjected to extraction using dichloromethane. The thus-obtained organic layer was sequentially washed with water and an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure, giving a yellow oily 1-(3-aminopropyl)-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one (1.4 g, yield: 94%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][NH2:40])=[CH:33][C:32]=2[CH3:41])=[C:28]([CH:42]([CH3:44])[CH3:43])[NH:27][N:26]=1)(=[O:3])[CH3:2].[CH2:45]([O:52][C:53]([N:55]1[CH2:60][CH2:59][N:58]([C:61](=[O:68])[C:62]([C:65](O)=[O:66])([CH3:64])[CH3:63])[CH2:57][CH2:56]1)=[O:54])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O.C(N(CC)CC)C>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][NH:40][C:65](=[O:66])[C:62]([C:61]([N:58]3[CH2:59][CH2:60][N:55]([C:53]([O:52][CH2:45][C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)=[O:54])[CH2:56][CH2:57]3)=[O:68])([CH3:64])[CH3:63])=[CH:33][C:32]=2[CH3:41])=[C:28]([CH:42]([CH3:44])[CH3:43])[NH:27][N:26]=1)(=[O:3])[CH3:2]
Reactant: CC(C)(C(=O)O)C(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCN)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCNC(=O)C(C)(C)C(=O)N3CCN(C(=O)OCc4ccccc4)CC3)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 39.7 %

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-aminoethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole (0.5 g) in N,N-dimethylformamide (10 mL) were added 1-benzyloxycarbonyl-4-[2-carboxy-2-(methyl)propionyl]piperazine (0.28 g), 1-hydroxybenzotriazole (0.22 g), triethylamine (0.18 mL) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.46 g), and the mixture was stirred at room temperature for 2 days. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, water and brine successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=30/1) to give 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{2-[2-{[4-(benzyloxycarbonyl)piperazin-1-yl]-carbonyl}-2-(methyl)propionylamino]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole (0.3 g). This material was dissolved in methanol (4 mL). To the solution was added sodium methoxide (28% methanol solution, 0.06 mL), and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added acetic acid (0.035 mL), and the resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1-5/1) to give the title compound (0.23 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([C:11]2([OH:27])[C:15]3=[N:16][CH:17]=[CH:18][C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:14]3[C:13](=[O:26])[O:12]2)[N:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C)C=O>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([C:11]([C:15]2[N:16]=[CH:17][CH:18]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]=2[C:13]([O:26][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:12])=[O:27])[N:6]=1
Reactant: COc1cc(OC)nc(C2(O)OC(=O)c3c(-c4ccccc4)ccnc32)n1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(C(=O)c2nccc(-c3ccccc3)c2C(=O)OCc2ccccc2)n1
Temperature: 0 °C
Yield: 81.6 %

Procedure:
0.5 g of 7-(4,6-dimethoxypyrimidin-2-yl)-7-hydroxy-4-phenylfuro[3,4-b]pyridin-5(7H)one was dissolved in 10 ml of N,N-dimethylformamide, and 0.2 g of potassium carbonate was added thereto. Then, the reaction solution was stirred sufficiently. 0.23 g of benzyl bromide was added dropwise to the reaction solution at room temperature, and the reaction solution was stirred for one day. The reaction solution was poured into ice water and extracted with ethyl acetate. The extract was sufficiently washed with water and then dried over anhydrous magnesium sulfate. The solvent was distilled off, and the resulting crude crystals were washed with isopropyl ether to obtain 0.5 g (yield 80%) of the desired compound. m.p.: 124°-126° C.
Reaction SMILES: Cl.[NH2:2][NH:3][C:4]([NH2:6])=[O:5].[C:7](=[O:10])([O-])O.[K+].C(O)C.[CH2:15]([O:17][C:18](=O)[C:19]#C)[CH3:16]>O>[CH2:15]([O:17][C:18](=[N:2][NH:3][C:4]([NH2:6])=[O:5])[CH2:19][CH:7]=[O:10])[CH3:16]
Reactant: C#CC(=O)OCC
Reactant: NNC(N)=O
Reactant: O=C([O-])O
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOC(CC=O)=NNC(N)=O
Reaction time: 4 h

Procedure:
11.15 g (0.1 mole) semicarbazide hydrochloride are dissolved in 10 ml water in a three neck 100 ml round flask with stirrer and thermometer and 10.0 g (0.1 mole) potassium hydrogen carbonate are added and then 10 ml ethanol are employed to thin. To this during 5 minutes are added drop by drop 9.8 g (0.1 mole) propiolic acid ethyl ester. The reaction temperature is kept for 4 hours at about 30° C. and a thick crystal paste forms slowly. After standing over night the product is cooled down in an ice bath and thinned with 10 ml water. The crystals are sucked off, are washed with 10 ml water and dried in vacuo at 40° C. to constant weight.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[C:17]([OH:25])(=[O:24])[C:18]([CH2:20][C:21](O)=[O:22])=[CH2:19]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([N:16]3[C:21](=[O:22])[CH2:20][CH:18]([C:17]([OH:25])=[O:24])[CH2:19]3)=[CH:14][CH:15]=2)=[CH:6][CH:7]=1
Reactant: Nc1ccc(CCc2ccc(Cl)cc2)cc1
Reactant: C=C(CC(=O)O)C(=O)O
Product: O=C(O)C1CC(=O)N(c2ccc(CCc3ccc(Cl)cc3)cc2)C1

Procedure:
In an analogous manner to that described in Example 36c), the reaction of 4-[2-(4-chloro-phenyl)-ethyl]-phenylamine with itaconic acid yields the (RS)-1-{4-[2-(4-chloro-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylic acid as an off-white solid; MS: m/e=342 (M−H)+.
Reaction SMILES: [CH2:1]([NH:3][C:4]([CH:6]1[NH:19][CH:18]=[C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:9]2[NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:8]=2[CH2:7]1)=[O:5])[CH3:2].[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>>[CH2:1]([NH:3][C:4]([CH:6]1[N:19]([C:30](=[O:31])[C:29]2[CH:33]=[CH:34][C:26]([F:25])=[CH:27][CH:28]=2)[CH:18]=[C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:9]2[NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:8]=2[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCNC(=O)C1Cc2c([nH]c3ccccc23)C(C(=O)OCC)=CN1
Reactant: O=C(Cl)c1ccc(F)cc1
Product: CCNC(=O)C1Cc2c([nH]c3ccccc23)C(C(=O)OCC)=CN1C(=O)c1ccc(F)cc1

Procedure:
The title compound was prepared in a manner similar to that described in Example 2A by using ethyl 2-ethylcarbamoyl-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylate and 4-fluorobenzoyl chloride; 1H-NMR (CDCl3): δ 10.21 (1H, br s), 8.27 (1H, s), 7.71-7.79 (3H, m), 7.53 (1H, m), 7.36 (1H, d), 7.20 (1H, m), 7.11 (2H, m), 6.11 (1H, d), 5.32 (1H, t), 4.21 (2H, m), 3.87 (1H, dd), 3.20 (1H, dd), 2.86-3.06 (2H, m), 1.18 (3H, t), 0.57 (3H, t); MS (ES): 450 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[O:17]C(=O)C.F[C:22](F)(F)[C:23](O)=O.CO[CH2:30][N:31]([Si](C)(C)C)C>C1(C)C=CC=CC=1>[CH3:30][N:31]1[CH2:23][CH2:22][C@@H:9]([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[OH:17])[C@@H:8]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1]
Reactant: COCN(C)[Si](C)(C)C
Reactant: CC(=O)Oc1ccc(Cl)cc1/C=C/c1ccccc1Br
Reactant: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CN1CC[C@@H](c2cc(Cl)ccc2O)[C@@H]1c1ccccc1Br
Reaction time: 0.5 h
Yield: 96 %

Procedure:
trans-2-Bromo-2′-acetoxy-5′-chlorostilbene (26 g, 73 mmol) was slurried in toluene (91 ml) at 33° C. Trifluoroacetic acid (200 microliters) was added. The N-methoxymethyl-N-trimethylsilyl-N-methylamine (14.5 g; 89.7 mmol) was added to the reaction mixture over 90 minutes. After addition, the reaction was washed with water (25 ml). The toluene was removed by vacuum distillation. Ethanol (30 ml) was added and removed under reduced pressure. The oil was dissolved in methanol (90 ml). Potassium hydroxide (5 grams in 25 ml water)) was added. The product began to precipitate immediately. After 30 minutes, the pH was adjusted to 8-9 with 3N HCl (8 ml). Added water (10 ml) and cooled to less than 10° C. Filtered and washed with 1:1 methanol:water. Dried in vacuum to 26.0 grams (96% yield). Purity according to HPLC is 98% a/a.
Reaction SMILES: [CH:1]1([CH2:4][C:5]2[C:6]([OH:15])=[C:7]([CH:11]=[CH:12][C:13]=2[OH:14])[C:8]([NH2:10])=[O:9])[CH2:3][CH2:2]1.[C:16]([O:19][CH2:20]C)(=[O:18])[CH3:17].[CH3:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>>[NH2:10][C:8]([C:7]1[CH:11]=[CH:12][C:13]([O:14][CH2:6][CH2:7][CH2:8][O:9][C:24]2[CH:23]=[CH:22][C:27]3[CH2:4][CH2:5][CH:13]([CH2:12][CH2:17][C:16]([O:19][CH3:20])=[O:18])[O:14][C:26]=3[C:25]=2[CH2:2][CH2:1][CH3:3])=[C:5]([CH2:4][CH:1]2[CH2:3][CH2:2]2)[C:6]=1[OH:15])=[O:9]
Reactant: CCCCCC
Reactant: NC(=O)c1ccc(O)c(CC2CC2)c1O
Reactant: CCOC(C)=O
Product: CCCc1c(OCCCOc2ccc(C(N)=O)c(O)c2CC2CC2)ccc2c1OC(CCC(=O)OC)CC2

Procedure:
The compound of Example 66 and the compound of Example 3 are coupled under the conditions outlined in Example 60. Chromatography of the crude phenolic ester on silica gel using ethyl acetate/hexane (3:7) as eluant affords the product.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:6](=[O:7])[CH2:5][C:4]([CH3:9])([CH3:8])[O:3]1.[H-].[Na+].[CH2:13]([OH:15])C.C(OCC)=O>CCOCC.O>[OH:15][CH:13]=[C:5]1[C:4]([CH3:9])([CH3:8])[O:3][C:2]([CH3:10])([CH3:1])[C:6]1=[O:7]
Reactant: CCO
Reactant: CC1(C)CC(=O)C(C)(C)O1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC=O
Solvent: CCOCC
Solvent: O
Product: CC1(C)OC(C)(C)C(=CO)C1=O
Temperature: 0 °C
Yield: 79 %

Procedure:
Mercuric oxide (600 mg) was dissolved in 200 mL of water containing 2 mL of concentrated H2SO4. Solid 2,5-dimethyl-3-hexyne-2,5-diol (50.0g, 352 mmol) was added and the solution was heated until the homogeneous solution turned cloudy. Heating was stopped and the flask was stirred in a room temperature water bath for 30 min. The solution was distilled and 250 mL of distillate was collected (more H2O was added). The biphasic material was taken up into ether, separated, washed with brine, dried over MgSO4, filtered, evaporated and distilled (150° C.) to give 44.5 g (89%) of dihydro-2,2,5,5-tetramethyl-3(2H)-furanone as a water-white oil. Dihydro-2,2,5,5-tetramethyl-3(2H)furanone (32.1 g, 226 mmol) in 50 mL of ether was added dropwise to a suspension of sodium hydride (18.1 g of 60%, 453 mmol) in 400 mL of ether containing two drops of ethanol and 36.5 mL (453 mmol) of ethyl formate stirred at 0° C. After stirring overnight at room temperature, the reaction mixture was taken up into water, washed with additional ether, acidified with 6N HCl and extracted into ether. The combined ether layers were washed with water and brine, dried over MgSO4, decolorized with charcoal, filtered through celite and evaporated. The solid residue was recrystallized from a small volume of ether and a large quantity of hexanes. The solid was isolated by filtration and dried to give 30.4 g (79%) of 4-hydroxymethylene-dihydro-2,2,5,5-tetramethyl-3(2H)-furanone as an off-white solid. Ethylenediamine (1.15 mL, 17.4 mmol) was added to a solution of 4-hydroxymethylene-dihydro-2,2,5,5-tetramethyl-3(2H)furanone (5.9 g, 34.7 mmol) in 40 mL of THF. This solution was refluxed for one hour. The solvents were evaporated under high vacuum with moderate heating. The solid residue was slurried in 50 mL of cold ether and filtered to give 5.3 g (76%) of off-white solid. Recrystallization from 50 mL of THF followed by drying at 70° C. (1 Torr) for 6 hours gave 4.0 g of 1,2-bis[dihydro-2,2,5,5-tetramethyl3(2H)furanone-4-methyleneamino]ethane as a white solid: Anal. Calc'd for C20H32N2O4 : C, 65.93; H, 8.79; N, 7.69. Found: C, 65.68; H, 8.90; N, 7.65.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH:13]3[CH2:15][C:16](=O)[CH2:17][CH:12]3[C:11]2=[O:19])=[CH:6][CH:5]=1.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl>[CH2:22]([NH:29][CH:16]1[CH2:17][CH:12]2[C:11](=[O:19])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:20])=[CH:5][CH:6]=3)[CH2:14][CH:13]2[CH2:15]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C1CC2CN(c3ccc(OC(F)(F)F)cc3)C(=O)C2C1
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1C2CC(NCc3ccccc3)CC2CN1c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 64 %

Procedure:
To a solution of 2-(4-Trifluoromethoxy-phenyl)-hexahydro-cyclopenta[c]pyrrole-1,5-dione (0.5 g, 1.6 mmol) and benzylamine (0.34 g, 3.2 mmol) in dichloromethane (10 mL) were added NaBH(AcO)3 (1.0 g, 4.7 mmol). The mixture was stirred for 6 h at ambient temperature. The mixture was extracted with dichloromethane (2×15 mL), washed with brine (30 mL), dried over anhydrous Na2SO4. The solvent was removed, and the crude product was purified by silica column (MeOH/dichloromethane=1/30) to yield the title compound (0.4 g, 63%). 1H NMR (300 MHz, CDCl3): δ 7.67-7.63 (m, 2H), 7.32-7.07 (m, 7H), 4.08 (t, 1H, J=9.3 Hz), 3.76-3.56 (m, 3H), 3.34-3.31 (m, 1H), 3.16-3.09 (m, 1H), 2.88-2.83 (m, 1H), 2.21-2.02 (m, 3H), 1.65-1.58 (m, 1H).