Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].C(N(CC)CC)C.Cl[Si](C)(C)C.[CH:20]1([C:25](Cl)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21]1>ClCCl.O>[CH:20]1([C:25]([NH:1][CH:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4])=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C(Cl)C1CCCC1
Reactant: CCC(N)C(=O)O
Agent: C[Si](C)(C)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(NC(=O)C1CCCC1)C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
35 g (339 mmol) 2-aminobutanoic acid and 75.6 g (747 mmol) triethylamine are suspended in 300 ml of dichloromethane and stirred at 0° C. 81 g (747 mmol) chlorotrimethylsilane are added dropwise, then the mixture is stirred for 1 hour at room temperature and for 1 hour at 40° C. After cooling down to −10° C., 45 g (339 mmol) cyclopentanecarbonyl chloride are added slowly. The reaction mixture is stirred for 2 hours at −10° C. and then for 1 hour at room temperature. At 0° C., 50 ml of water are added. The mixture is diluted with water and dichloromethane, filtered and the solid product washed with water/dichloromethane 9:1, toluene and diethylether.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[N:11]2[CH2:30][CH2:31][N:32]([CH:35]([CH3:37])[CH3:36])[C:33](=[O:34])[C:10]=12)C1C=CC=CC=1.OS(O)(=O)=O>C(O)(=O)C>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][C:12]2[N:11]3[CH2:30][CH2:31][N:32]([CH:35]([CH3:37])[CH3:36])[C:33](=[O:34])[C:10]3=[C:9]([OH:8])[C:14](=[O:15])[N:13]=2)=[C:18]([C:24]2[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=2)[CH:19]=1
Reactant: CC(C)N1CCn2c(Cc3ccc(Cl)cc3-c3ccncc3)nc(=O)c(OCc3ccccc3)c2C1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(C)N1CCn2c(Cc3ccc(Cl)cc3-c3ccncc3)nc(=O)c(O)c2C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 34.7 %

Procedure:
To a stirred solution of 9-benzyloxy-6-(4-chloro-2-pyridin-4-yl-benzyl)-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (387) (50 mg, 0.097 mmol) in acetic acid (2 mL), concentrated H2SO4 (0.001 mL, 0.019 mmol) was added and the reaction mixture was stirred for 4 h at room temperature (monitored by LC-MS). From the reaction, volatiles were removed and the residue was quenched with ice c old water (5 mL). Aqueous saturated NaHCO3 was added to adjust the pH up to 8. The quenched mass was extracted with ethyl acetate (2×15 mL). The combined organic part was dried and concentrated and the resulting residue was purified by preparative HPLC to get 6-(4-chloro-2-pyridin-4-yl-benzyl)-9-hydroxy-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (388) (14.3 mg, 31.45%) as an off-white solid.
Reaction SMILES: FC1C=CC(CCCC(C2C=C(O)C3C4CC(C)CCC=4C(C)(C)OC=3C=2)C)=CC=1.C([O:34][C:35]1[C:44]2[C:43]3[CH2:45][CH:46]([CH3:50])[CH2:47][C:48](=[O:49])[C:42]=3[C:41]([CH3:52])([CH3:51])[O:40][C:39]=2[CH:38]=[C:37]([CH:53]([CH3:64])[CH2:54][CH2:55][CH2:56][C:57]2[CH:62]=[CH:61][C:60]([F:63])=[CH:59][CH:58]=2)[CH:36]=1)(=O)C>>[F:63][C:60]1[CH:59]=[CH:58][C:57]([CH2:56][CH2:55][CH2:54][CH:53]([C:37]2[CH:36]=[C:35]([OH:34])[C:44]3[C:43]4[CH2:45][CH:46]([CH3:50])[CH2:47][C:48](=[O:49])[C:42]=4[C:41]([CH3:52])([CH3:51])[O:40][C:39]=3[CH:38]=2)[CH3:64])=[CH:62][CH:61]=1
Reactant: CC(=O)Oc1cc(C(C)CCCc2ccc(F)cc2)cc2c1C1=C(C(=O)CC(C)C1)C(C)(C)O2
Agent: CC1CCC2=C(C1)c1c(O)cc(C(C)CCCc3ccc(F)cc3)cc1OC2(C)C
Product: CC1CC(=O)C2=C(C1)c1c(O)cc(C(C)CCCc3ccc(F)cc3)cc1OC2(C)C

Procedure:
3-(4-p-fluorophenyl-1-methylbutyl)-1-hydroxy-7,8,9,10-tetrahydro-6,6,9-trimethyl-6H-dibenzo[ b,d]pyran, prepared as disclosed in Winn et al. U.S. Pat. No. 3,901,926, is converted to the 1-acetoxy compound according to the procedure of Example 1, the 1-acetoxy compound is converted to 1-acetoxy-3-(4-p-fluorophenyl-1-methylbutyl)-7-oxo-7,8,9,10-tetrahydro-6,6,9-trimethyl-6H-dibenzo[ b,d]pyran according to Example 2 and this compound upon hydrolysis according to Example 3 gives 3-(4-p-fluorophenyl-1-methylbutyl)-1-hydroxy-7-oxo-7,8,9,10-tetrahydro-6,6,9-trimethyl-6H-dibenzo[ b,d]pyran.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]([NH:12][C:13]([CH:15]1[C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]([O:23][C:24]2[C:33]3[C:28](=[CH:29][C:30]([O:34][CH3:35])=[CH:31][CH:32]=3)[N:27]=[C:26]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:25]=2)[CH2:16]1)=[O:14])[CH2:9][CH2:10][CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:42][O:43][C:44](=[O:60])[CH:45]([NH:52][C:53](=[O:59])[CH:54]([NH2:58])[CH:55]([CH3:57])[CH3:56])[CH:46]1[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CO.C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:7])[C@@H:8]([NH:12][C:13]([C@H:15]1[CH2:16][C@H:17]([O:23][C:24]2[C:33]3[C:28](=[CH:29][C:30]([O:34][CH3:35])=[CH:31][CH:32]=3)[N:27]=[C:26]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:25]=2)[CH:18]=[C:19]1[C:20](=[O:22])[NH:58][C@H:54]([C:53](=[O:59])[NH:52][C@@H:45]([CH:46]1[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51]1)[C:44]([O:43][CH3:42])=[O:60])[CH:55]([CH3:57])[CH3:56])=[O:14])[CH2:9][CH2:10][CH3:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(NC(=O)C(N)C(C)C)C1CCCCC1
Reactant: CCC[C@H](NC(=O)C1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)C=C1C(=O)O)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: CO
Product: CCC[C@H](NC(=O)[C@H]1C[C@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)C=C1C(=O)N[C@H](C(=O)N[C@H](C(=O)OC)C1CCCCC1)C(C)C)C(=O)OC(C)(C)C
Yield: 7.5 %

Procedure:
The acid 11 (0.051 g, 0.087 mmol) and (2-amino-3-methyl-butyrylamino)-cyclohexyl-acetic acid methyl ester (0.054 g, 0.21 mmol) were dissolved in DMF (1.5 mL) and cooled in an ice-bath. DIPEA (16 mg, 0.12 mmol) and HATU (47 mg, 0.13 mmol) were added. After two and a half hours the mixture was co-concentrated with toluene and methanol and then purified by flash column chromatography (toluene/ethyl acetate 3:1). Further purification was performed on HPLC (90% MeOH+0.2% TEA). This gave after co-concentration the two diastereomers 19a (9.4 mg, 13%) and 19b (5.3 mg, 7%) as slightly yellow syrups. After lyophilisation 19a and 19b were collected as white powders:
Reaction SMILES: [OH-].[Na+:2].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([NH:14][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[N:25][CH:24]=3)[CH:18]=2)=[O:16])=[C:8]([CH:13]=1)[C:9]([O:11]C)=[O:10]>C1COCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([NH:14][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[N:25][CH:24]=3)[CH:18]=2)=[O:16])=[C:8]([CH:13]=1)[C:9]([O-:11])=[O:10].[Na+:2]
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)c1cccc(-c2cncc3ccccc23)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)cc1C(=O)[O-])c1cccc(-c2cncc3ccccc23)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 98 %

Procedure:
20 mL of THF and 1.6 mL of 1N aqueous sodium hydroxide solution were added to 360 mg (0.86 mmol) of methyl 5-chloro-2-({[3-(isoquinolin-4-yl)phenyl]carbonyl}amino)benzoate, and the mixture was stirred at room temperature for one day. THF was distilled off under reduced pressure and water-washing was performed by adding water, thereby giving 360 mg of the target sodium 5-chloro-2-({[3-(isoquinolin-4-yl)phenyl]carbonyl}amino)benzoate (yield: 98%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:16][C:6]2[C:7](=[O:15])[CH:8]=[C:9]([O:13]C)[C:10](=[O:12])[NH:11][C:5]=2[CH2:4][CH:3]1[CH3:17].B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][CH:2]1[CH2:16][C:6]2[C:7](=[O:15])[CH:8]=[C:9]([OH:13])[C:10](=[O:12])[NH:11][C:5]=2[CH2:4][CH:3]1[CH3:17]
Reactant: COc1cc(=O)c2c([nH]c1=O)CC(C)C(C)C2
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC1Cc2[nH]c(=O)c(O)cc(=O)c2CC1C
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a stirred suspension of 7,8-dimethyl-3-methoxy-6,7,8,9-tetrahydro1H-1-benzazepine-2,5-dione (90.0 mg, 382 μmol) in dry CH2Cl2 (2 mL, distilled from CaH2) under N2, there was added a solution of BBr3 in CH2Cl2 (1.0 mL, 1M, Aldrich) in one portion over 5 seconds at rt. A green precipitate immediately formed. The reaction was allowed to stir under N2 at rt for 45 min. The reaction was added to saturated NaHCO3 (15 mL) and the resulting orange solution was allowed to stir for 15 min. The solution was extracted with CH2Cl2 (2×4 mL). The aqueous solution was acidified with coned HCl (pH 2), the resulting precipitate collected by filtration and washed to neutrality with water (6×2 mL). Crystallization from 95% EtOH yielded pale beige needles (56 mg, 67%, pure by 1H NMR, consists of a probable mixture of cis- and trans-isomers (85:15)); mp 242°-243° C. (dec.); 1H NMR (DMSO-d6) δ0.80 (t, J=7.5 Hz, 6H), 1.79 (m, 2H), 2.03 (dd, J=7.5, 17.7 Hz, 1H), 2.21 (dd, J=6.0, 18.0 Hz, 1H), 2.35 (dd, J=5.1, 17.7 Hz, 1H), 2.58, (dd, J=5.4, 18.0 Hz, 1H), 6.29 (s, 1H), 10.15 (bs, 1H), 10.82 (s, 1H), the minor isomer displays a methyl resonance at δ0.92 (t, J=5.7 Hz); IR (KBr) 3314 (m), 1676 (m), 1664 (m), 1613 (m), 1550 (s), Anal. Calcd for C12H15NO3 : C, 65.14, H, 6.83, N, 6.33. Found: C, 65.47; H, 6.87; N, 6.32.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[N:5]=[C:6]([N:11]([CH3:32])[C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:31])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=4)[CH:15]=[CH:16][CH:17]=3)[N:7]=[CH:8][C:9]=2[N:10]=1.Cl.[N:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40](Cl)=[O:41])[CH:35]=1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:29]([C:26]([C:22]1[CH:21]=[C:20]([C:19]([NH:18][C:14]2[CH:13]=[C:12]([N:11]([CH3:32])[C:6]3[N:7]=[CH:8][C:9]4[N:10]=[C:2]([NH:1][C:40]([C:36]5[CH:35]=[N:34][CH:39]=[CH:38][CH:37]=5)=[O:41])[S:3][C:4]=4[N:5]=3)[CH:17]=[CH:16][CH:15]=2)=[O:31])[CH:25]=[CH:24][CH:23]=1)([CH3:27])[CH3:28])#[N:30]
Reactant: CN(c1cccc(NC(=O)c2cccc(C(C)(C)C#N)c2)c1)c1ncc2nc(N)sc2n1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CN(c1cccc(NC(=O)c2cccc(C(C)(C)C#N)c2)c1)c1ncc2nc(NC(=O)c3cccnc3)sc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.1 %

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-d]pyrimidin-5-yl)(methyl)amino]phenyl)-3-(1-cyano-1-methylethyl)benzamide (150 mg, 338 μmol) produced in Example D5(i) in pyridine (4 mL) was added pyridine-3-carbonyl chloride hydrochloride (362 mg, 2.03 mmol), and the mixture was stirred at room temperature for 3 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (30 mL), and the mixture was extracted with ethyl acetate (30 mL, 10 mL). The combined organic layer was washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=35/65→15/85), and the fractions containing the object product were concentrated under reduced pressure. The obtained residue was recrystallized from methanol, ethyl acetate and hexane to give the title compound (78 mg, 42%) as a orange crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27](O)=[O:28])[CH:5]=[CH:6][CH:7]=1.[NH2:30][CH2:31][CH:32]([CH2:35][OH:36])[CH2:33][OH:34].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>C(Cl)Cl>[OH:34][CH2:33][CH:32]([CH2:35][OH:36])[CH2:31][NH:30][C:27]([CH:9]1[CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:25])([CH3:24])[CH3:26])[NH:10]1)=[O:28]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Reactant: NCC(CO)CO
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: ClCCl
Product: CC(C)(C)CC1NC(C(=O)NCC(CO)CO)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.1 %

Procedure:
A mixture of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.20 mmol), 2-aminomethyl-propane-1,3-diol (31.5 mg, 0.3 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2Cl2 (2 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by reverse phase chromatography (20-95% of ACN/water) to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-hydroxy-2-hydroxymethyl-propyl)-amide (31.2 mg, 30.9%) as an off-white powder. HRMS (ES+) m/z Calcd for C26H31Cl2N3O3S+H [(M+H)+]: 504.455. found: 504.1815.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][CH2:14]Br.[H-].[Na+].CC(O)C>CCOCC.CS(C)=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:9]#[N:10])[CH2:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: BrCCCBr
Reactant: N#CCc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Solvent: CCOCC
Product: N#CC1(c2ccc(F)cc2)CCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.4 %

Procedure:
A solution of 3.00 g (22.2 mmol) of 4-fluorophenylacetonitrile and 4.93 g (24.4 mmol) of 1,3-dibromopropane in 15 mL of ether was added dropwise into 1.17 g (48.8 mmol) of NaH in 60 mL of DMSO. The temperature was held between 250 and 35° by water bath cooling. The mixture was stirred at room temperature for 18 hours. The mixture was cooled in ice water and 3 mL of 2-propanol was added dropwise, followed by the addition of 50 mL of water. The mixture was extracted with hexane (3×100 mL), and the combined extracts were washed with water (3×75 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated to yield 2.35 g (61%) product as colorless oil. 1H NMR (CDCl3) δ 2.03-2.16 (m, 1H), 2.38-2.53 (m, 1H), 2.58-2.67 (m, 21), 2.80-2.90 (m, 2H), 7.11 (dd, J=9.0, 8.4 Hz, 2H), 7.41 (dd, J=9.1, 5.1 Hz, 2H). 13C NMR (CDCl3) 17.3, 35.0, 39.9, 116.1 (d, J=21.5 Hz), 124.5, 127.7, 135.9, 162.5 (d, J=230 Hz).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].Br[C:8]1[N:13]=[CH:12][C:11]([C:14]([N:16]2[CH2:21][CH2:20][CH:19]([C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[CH2:18][CH2:17]2)=[O:15])=[CH:10][CH:9]=1>>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([C:22]([CH:19]2[CH2:18][CH2:17][N:16]([C:14]([C:11]3[CH:10]=[CH:9][C:8]([N:1]4[CH2:5][CH2:4][CH2:3][C:2]4=[O:6])=[N:13][CH:12]=3)=[O:15])[CH2:21][CH2:20]2)=[O:30])=[CH:28][CH:27]=1
Reactant: O=C1CCCN1
Reactant: O=C(c1ccc(Cl)cc1)C1CCN(C(=O)c2ccc(Br)nc2)CC1
Product: O=C(c1ccc(Cl)cc1)C1CCN(C(=O)c2ccc(N3CCCC3=O)nc2)CC1
Yield: 50.7 %

Procedure:
Using pyrrolidin-2-one (102 mg) and (6-bromopyridin-3-yl)[4-(4-chlorobenzoyl)piperidin-1-yl]methanone (408 mg) described in Preparation Example 190 and by the reaction and treatment in the same manner as in Example 1, the title compound (209 mg) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27](=[O:31])[CH2:28][CH2:29][OH:30])=[CH:22][CH:21]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15](=[O:19])[CH2:16][CH2:17][OH:18])=[CH:10][CH:9]=2)[CH:7]=1.[C:32]([OH:37])(=O)[C:33]([CH3:35])=[CH2:34]>>[CH3:34][C:33](=[CH2:35])[C:32]([O:30][CH2:29][CH2:28][C:27]([O:26][C:23]1[CH:24]=[CH:25][C:20]([C:4]2[CH:3]=[C:2]([O:1][C:32](=[O:37])[C:33]([CH3:35])=[CH2:34])[CH:7]=[C:6]([C:8]3[CH:9]=[CH:10][C:11]([O:14][C:15](=[O:19])[CH2:16][CH2:17][O:18][C:32](=[O:37])[C:33]([CH3:35])=[CH2:34])=[CH:12][CH:13]=3)[CH:5]=2)=[CH:21][CH:22]=1)=[O:31])=[O:37]
Reactant: O=C(CCO)Oc1ccc(-c2cc(O)cc(-c3ccc(OC(=O)CCO)cc3)c2)cc1
Reactant: C=C(C)C(=O)O
Product: C=C(C)C(=O)OCCC(=O)Oc1ccc(-c2cc(OC(=O)C(=C)C)cc(-c3ccc(OC(=O)CCOC(=O)C(=C)C)cc3)c2)cc1

Procedure:
In analogy to step 2 of Example 1, 3-hydroxy-propionic acid-5′-hydroxy-4″-(3-hydroxy-propionyloxy)-[1,1′;3′,1″]terphenyl-4-yl ester and methacrylic acid are reacted to give 2-methyl-acrylic acid-4,4″-bis-[3-(2-methylacryloyloxy)-propionyloxy]-[1,1′;3′,1″]terphenyl-5′-yl ester as colourless crystals, m.p. 88° C.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH2:9][CH:10]=O)=[CH:7][CH:6]=[CH:5][C:4]=1[C:12]1[S:16][C:15]([C:17]2[CH:18]=[CH:19][C:20]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH:24]=2)[C:22]#[N:23])=[N:14][CH:13]=1)[CH3:2].C(O)(=O)C.C([O-])(=O)C.[Na+].[NH:38]1[CH2:41][CH:40]([C:42]([O:44][CH3:45])=[O:43])[CH2:39]1>C(O)C>[C:22]([C:21]1[CH:24]=[C:17]([C:15]2[S:16][C:12]([C:4]3[C:3]([CH2:1][CH3:2])=[C:8]([CH2:9][CH2:10][N:38]4[CH2:41][CH:40]([C:42]([O:44][CH3:45])=[O:43])[CH2:39]4)[CH:7]=[CH:6][CH:5]=3)=[CH:13][N:14]=2)[CH:18]=[CH:19][C:20]=1[O:25][CH:26]([CH3:28])[CH3:27])#[N:23]
Reactant: COC(=O)C1CNC1
Reactant: CCc1c(CC=O)cccc1-c1cnc(-c2ccc(OC(C)C)c(C#N)c2)s1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCc1c(CCN2CC(C(=O)OC)C2)cccc1-c1cnc(-c2ccc(OC(C)C)c(C#N)c2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of 5-{5-[2-ethyl-3-(2-oxoethyl)phenyl]-1,3-thiazol-2-yl}-2-[(1-methylethyl)oxy]benzonitrile (D76) (150 mg), acetic acid (0.044 mL) and sodium acetate (63 mg) in ethanol (20.00 mL) stirred under nitrogen at room temperature was added methyl 3-azetidinecarboxylate (175 mg) in one charge. The reaction mixture was stirred at room temperature for 30 min, then the solvent was evaporated in vacuo. The residue was dissolved in dichloromethane (DCM) (20 mL), sodium triacetoxyborohydride (204 mg) was added to the mixture. The reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate (100 mL) and saturated brine (30 mL). The organic phase was dried over sodium sulphate and evaporated in vacuo to give the crude product methyl 1-{2-[3-(2-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-2-ethylphenyl]ethyl}-3-azetidinecarboxylate (D83) (188 mg). The crude product was used for next step without further purification. MS (ES): C28H31N3O3S requires 489. found 490.2 (M+H+).
Reaction SMILES: CCCCCC.[H-].[K+].[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[CH:13]2.[CH:19]([N:22]=[C:23]=[S:24])([CH3:21])[CH3:20]>C1COCC1>[CH:19]([NH:22][C:23]([N:15]1[C:16]2[C:12](=[CH:11][C:10]([Cl:9])=[CH:18][CH:17]=2)[CH:13]=[CH:14]1)=[S:24])([CH3:21])[CH3:20]
Reactant: CC(C)N=C=S
Reactant: Clc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)NC(=S)n1ccc2cc(Cl)ccc21
Reaction time: 1 h
Yield: 61.7 %

Procedure:
A stirred slurry of hexane washed potassium hydride (0.87 g, 21.8 mmol) in 50 mL of dry THF was treated portionwise with 5-chloroindole (3.3 g, 21.8 mmol). The mixture was heated at reflux until a clear solution was obtained. A solution of isopropyl isothiocyanate (2.2 g, 21.8 mmol) in 5 mL THF was slowly added and stirring was continued for 1 hour. The solvent was evaporated and the residue partitioned between EtOAc and 1N HCl. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The amber solids were recrystallized from EtOH to provide 3.4 g of the title compound as a tan solid, m.p. 135° C. (62% of theory).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:16](Cl)(=[O:18])[CH3:17].CO>C(Cl)Cl>[C:16]([NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:18])[CH3:17]
Reactant: NCc1ccccc1
Reactant: CC(=O)Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
10 g of benzylamine was dissolved in 200 ml of methylene chloride followed by the addition of 26 ml of triethylamine and dropwise addition of 7.3 ml of acetyl chloride at 0° C. After stirring for 1 hour at room temperature, 2 ml of methanol was added to the reaction system at 0° C. followed by 120 ml of water and separation of the phases. The aqueous layer was extracted with 100 ml of chloroform, and the resulting organic layer was concentrated after drying with anhydrous sodium sulfate to obtain 8.55 g of the target compound (yield: 61%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][C:5]2[O:9][C:8](=[O:10])[CH2:7][C:6]=2[CH:11]=1.[H-].C([Al+]CC(C)C)C(C)C.S(=O)(=O)(O)O>O1CCCC1.C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][C:5]2[O:9][CH:8]([OH:10])[CH2:7][C:6]=2[CH:11]=1
Reactant: O=C1Cc2cc(Cl)c(N3CCCCC3)cc2O1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)(O)O
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: OC1Cc2cc(Cl)c(N3CCCCC3)cc2O1
Reaction time: 0.5 h

Procedure:
A solution of 251 mg (1.00 mmole) of 5-chloro-6-(piperidin-1-yl)-benzofuran-2(3H)-one in 5 ml of absolute tetrahydrofuran is cooled to -78° under a nitrogen atmosphere, 0.84 ml (1.00 mmole) of a 20% diisobutyl aluminium hydride solution in toluene is added and the whole is stirred for 30 minutes at -78°. 2 ml of 2N sulphuric acid are then added and the whole is stirred for 15 minutes at -40°. The reaction mixture is diluted with water and extracted with methylene chloride. The organic phases are washed with water, combined, dried over sodium sulphate and concentrated in a vacuum rotary evaporator. 5-chloro-2-hydroxy-6-(piperidin-1-yl)-2,3-dihydrobenzofuran is obtained in the form of an oil which is used for the following reactions without purification. Rf [silica gel, chloroform/ethyl acetate (3:1)]=0.48.
Reaction SMILES: [C:1]([N:9]1[CH2:26][CH2:25][C:13]2[N:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][C:22]=4[C:12]=2[CH2:11][CH2:10]1)[C:17](=[O:24])[CH2:16][CH2:15]3)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[C:1]([N:9]1[CH2:26][CH2:25][CH:13]2[N:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][C:22]=4[CH:12]2[CH2:11][CH2:10]1)[CH:17]([OH:24])[CH2:16][CH2:15]3)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCn2c3c(c4cccc1c42)CCN(C(=O)c1ccccc1)CC3
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=C(c1ccccc1)N1CCC2c3cccc4c3N(CCC4O)C2CC1
Temperature: 25 °C
Yield: 83.9 %

Procedure:
A solution of 10-benzoyl-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinolin-4-one (1.46 g, 4.24 mmol) in ethanol (40 mL) was cooled to 0° C. under N2. Added sodium borohydride (0.32 g, 8.46 mmol) and allowed to warm slowly to room temperature. Concentrated under reduced pressure to approximately 10 mL, diluted with H2O, and extracted with CH2Cl2. The combined organic extracts were washed with saturated aqueous NaCl, dried over Na2SO4, decanted, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography with EtOAc/heptanes (2:1) to give 1.24 g (84%) of the title compound as a yellow foam. 1H NMR (CDCl3) δ 7.42, 7.33, 7.12-7.02, 5.10, 4.13, 4.02, 3.68, 3.21, 2.92, 2.38, 2.23, 1.80; IR (drift) 1627, 1614, 1475, 1466, 1457, 1448, 1429, 1372, 1360, 1329, 1292, 1268, 785, 747, 706 cm−1; MS (ESI) 369.1 (M++Na).