Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:7]([OH:19])/[CH:8]=[CH:9]/[CH:10]2[CH2:17][CH2:16][CH:15]3[CH:11]2[CH2:12][CH2:13][C:14]3=[O:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:20]([Si:24]([CH3:27])([CH3:26])Cl)([CH3:23])([CH3:22])[CH3:21].N1C=CN=C1.O>CN(C)C=O>[Si:24]([O:19][CH:7]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)/[CH:8]=[CH:9]/[CH:10]1[CH2:17][CH2:16][CH:15]2[CH:11]1[CH2:12][CH2:13][C:14]2=[O:18])([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:27])[CH3:26]
Reactant: O=C1CCC2C(/C=C/C(O)C3CCCCC3)CCC12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC(/C=C/C1CCC2C(=O)CCC12)C1CCCCC1
Yield: 96.8 %

Procedure:
A mixture of (E)-2-(3-cyclohexyl-3-hydroxyprop-1-enyl)bicyclo[3,3,0]octan-6-one (41 mg), prepared as described in Reference Example 13, and in the form of (±)-(E)-2β-(3-cyclohexyl-3α-hydroxyprop-1-enyl)bicyclo[3,3,0]octan-6-one, tert-butyldimethylchlorosilane (35 mg), and imidazole (29.5 mg) in dimethylformamide (0.25 ml) was stirred at ambient temperature for 3 hours. Water (2.5 ml) was added and the mixture was extracted with diethyl ether. The combined ethereal extracts were washed with saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulphate, and concentrated under reduced pressure to give (E)-2-(3-tert-butyldimethylsilyloxy-3-cyclohexylprop-1-enyl)bicyclo[3,3,0]octan-6-one (57 mg), in the form of (±)-(E)-2β-(3α-tert-butyldimethylsilyloxy-3-cyclohexylprop-1-enyl)bicyclo[3,3,0]octan-6-one.
Reaction SMILES: [OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.Br[C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([F:32])[CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.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>[F:32][C:26]1[CH:25]=[C:24]([C:8]2[CH:9]=[CH:10][C:5]([O:4][C@@H:3]([CH3:14])[C@H:2]([OH:1])[CH2:15][CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:6][CH:7]=2)[CH:31]=[CH:30][C:27]=1[C:28]#[N:29]
Reactant: N#Cc1ccc(Br)cc1F
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1
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: [Na+]
Solvent: CCO
Product: C[C@H](Oc1ccc(-c2ccc(C#N)c(F)c2)cc1)[C@H](O)CCc1cccnc1
Temperature: 90 °C
Yield: 56 %

Procedure:
Prepared according to the method described in Example 12b) from (1S,2R)-4-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy)benzeneboronic acid (0.20 g, Example 33), 4-bromo-2-fluorobenzonitrile (0.16 g), 2M aqueous sodium carbonate (0.76 ml) and tetrakis(triphenylphosphine)palladium (0) (0.03 g) in ethanol (3 ml) with heating at 90° C. for 4 hours. After work up, the residue was purified by normal-phase HPLC eluting with a gradient of 0-25% ethanol in dichloromethane to give the title compound as a gum (0.14 g)
Reaction SMILES: [OH:1][CH:2]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27]C=1)[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8].CCOC(/N=N/C(OCC)=O)=O.O[C:44]1[CH:53]=[CH:52][C:47]([C:48]([O:50][CH3:51])=[O:49])=[CH:46][CH:45]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C(OCC)C>[CH3:51][O:50][C:48]([C:47]1[CH:52]=[CH:53][C:44]([O:1][CH:2]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]2[CH:25]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8])=[CH:45][CH:46]=1)=[O:49]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: COC(=O)CCCCC(O)CCc1ccccc1OCCCCCc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)CCCCC(CCc1ccccc1OCCCCc1ccccc1)Oc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Over a period of 2 h, a solution of 100.0 mg (0.24 mmol) of methyl 6-hydroxy-8-{2-[(5-phenylpentyl)oxy]phenyl}octanoate from Ex. XXXIa and 63.32 mg (0.36 mmol) of DEAD in 2.5 ml of THF was added dropwise to a solution of 55.32 mg (0.36 mmol) of methyl 4-hydroxybenzoate and 95.36 mg (0.36 mmol) of triphenylphosphine in 2.5 ml of THF. The mixture was stirred at RT for 18 h, 40 ml of diethyl ether were added, the mixture was filtered and the solvent was removed. The product was purified chromatographically (silica gel, cyclohexane/EA 10:1). This gave 63.0 mg (47.5%) of a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1[N:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1/[CH:24]=[CH:25]/[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl>CO>[ClH:1].[CH3:8][C:7]1[C:2]([N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]=[C:16]2/[CH:24]=[CH:25]/[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Reactant: Cc1cccnc1Cl
Agent: Cl
Solvent: CO
Product: Cc1cccnc1-n1c(/C=C/c2ccccc2)nc2ccccc21

Procedure:
Free base of the titled compound was prepared from 2-styryl-1-benzimidazole and 2-chloro-3-methylpyridine according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method B). The free base was treated with a 10% methanol solution of hydrogen chloride and concentrated to dryness. The residue was recrystallized from ethyl acetate/n-hexane to give the titled compound.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:16](Br)[C:17]#[CH:18]>C(#N)C.C1(C)C=CC=CC=1>[CH2:18]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1)[C:17]#[CH:16]
Reactant: C#CCBr
Reactant: OCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC#N
Product: C#CCOc1ccc(CO)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
To a solution of 4-hydroxyl-benzyl alcohol 13 (2.5 g, 20 mmol) in acetonitrile (50 mL), K2CO3 (3.96 g, 200 mol %) was added at room temperature (see Scheme 4). After stirring for 1 h, the mixture was treated dropwise with an 80 wt % solution of propargyl bromide in toluene (3.27 g, 110 mol %) and the reaction mixture was heated to 50° C. for 48 h, cooled, filtered and concentrated under vacuum. The residue was purified by flash chromatography using an eluent of 100% to 30% hexane in AcOEt. Evaporation of the collected fractions gave propargyl ether 14 as a yellow liquid (3.12 g, 95.5%): 1H NMR (CDCl3) δ (ppm): 7.28 (d, 2H, Ph-H), 6.96 (d, 2H, Ph-H), 4.69 (d, 2H, PhCH2), 4.57 (s, 2H, CCH2O), 2.54 (t, 1H, OH), 2.39 (s, 1H, CH); 13C NMR (CD3OD) δ (ppm): 157.4, 134.53, 128.97, 115.34, 78.97, 76.04, 65.10, 56.24. Anal. Calcd for C10H10O2: C, 74.07; H, 6.17. Found: C, 73.64; H, 6.03.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:9][CH2:8][CH:7]=[CH:6]1)(=[O:3])[CH3:2].ClC1C=CC=CC=1.[OH-].CC(C)=O>CO>[C:1]([O:4][CH:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1C=CCC1
Agent: [OH-]
Solvent: CC(C)=O
Solvent: Clc1ccccc1
Solvent: CO
Product: CC(=O)OC1CCCC1
Temperature: 56 °C
Yield: 96 %

Procedure:
A solution of 1.80 g (0.014 mol) of 2-cyclopentenyl acetate in 3.80 g (0.12 mol) of methanol and 0.700 g of chlorobenzene (the internal standard for chromatographic analysis) was slowly passed through a jacketed column containing 20 ml of Dowex 1-X4 (an anion exchange resin of the quaternary ammonium type) in the hydroxide form in methanol. The column was maintained at 56° C. by refluxing acetone in the jacket. The resin was then rinsed with methanol, and the combined effluent and rinsings were analyzed by gas chromatography using a 6-ft. OV-17 column programmed from 80° to 220° C. The analysis showed that 2-cyclopentenol had been formed in 96% yield and essentially 100% efficiency. No by-products were observed.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[NH:10]1[CH:14]=[CH:13][N:12]=[C:11]1[CH:15]=O.C([BH3-])#N.[Na+].C(N(CC)CC)C>CO.[Cl-].[Zn+2].[Cl-]>[NH:10]1[CH:14]=[CH:13][N:12]=[C:11]1[CH2:15][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CCN2
Reactant: O=Cc1ncc[nH]1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: c1ccc2c(c1)CCN2Cc1ncc[nH]1
Temperature: 50 °C
Reaction time: 16 h
Yield: 50.8 %

Procedure:
To a solution of indoline (0.20 g, 1.68 mmol) in methanol (15 ml) were added sequentially imidazole-2-carboxaldehyde (0.24 g, 2.52 mmol), zinc chloride (0.92 g, 6.71 mmol) and sodium cyanoborohydride (0.32 g, 5.03 mmol). The reaction mixture was shaken at 50° C. for 16 hours, then triethylamine (0.5 ml) was added and the mixture shaken for a further 5 min. The resulting suspension was filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel (eluant: methanol/dichloromethane gradient) to yield the title compound as an off-white solid (0.17 g, 52%); MS (ISP): 200.3 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[N:12]=[C:13]3[CH:19]=[CH:18][N:17]([S:20]([C:23]4[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=4)(=[O:22])=[O:21])[C:14]3=[N:15][CH:16]=2)=O)=[CH:5][CH:4]=1.C(O)CC.CC1C=CC(S([NH:44][NH2:45])(=O)=O)=CC=1.N1CCOCC1>O1CCOCC1.Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:44]=[N:45][N:12]3[C:13]4[CH:19]=[CH:18][N:17]([S:20]([C:23]5[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=5)(=[O:21])=[O:22])[C:14]=4[N:15]=[CH:16][C:11]=23)=[CH:5][CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Reactant: COc1ccc(C(=O)c2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n2)cc1
Agent: Cl
Solvent: CCCO
Solvent: C1COCCO1
Solvent: C1COCCN1
Product: COc1ccc(-c2nnn3c2cnc2c3ccn2S(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 32.8 %

Procedure:
The (4-methoxyphenyl)(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanone (2.25 g, 5.52 mmol, prepared using AT from Preparation #AF.1) was dissolved in 1,4-dioxane (25 mL) and PrOH (5 mL) then treated with 4-methylbenzenesulfonohydrazide (1.08 g, 5.80 mmol). The mixture was heated to about 100° C. for about 2 h then it was treated with 1 drop concentrated HCl. The mixture was stirred about 1 h at about 100° C. and then the mixture was concentrated under reduced pressure. The material was dissolved in morpholine (15.0 mL, 172 mmol) then the mixture was heated to about 100° C. for about 15 min. The mixture was cooled to rt and concentrated on the under reduced pressure. The material was treated with water (100 mL) and EtOAc (˜40 mL). The mixture was stirred for about 10 min then filtered. The solids were washed with EtOAc (˜7 mL) then dried to a constant weight under vacuum at about 70° C. to give 3-(4-methoxyphenyl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,3]triazolo[1,5-a]pyrazine (0.760 g, 33%): LC/MS (Table 2, Method a) Rt=2.74 min; MS m/z 420 (M+H)+.
Reaction SMILES: [C:1](O)(=O)[CH2:2][C:3]([OH:5])=[O:4].[F:8][C:9]([F:19])([F:18])[C:10]1[CH:17]=[CH:16][C:13](C=O)=[CH:12][CH:11]=1.C(OC(=O)C)C.Cl>N1C=CC=CC=1.CCCCCC.N1CCCCC1>[F:8][C:9]([F:19])([F:18])[C:10]1[CH:17]=[CH:16][C:13]([CH:1]=[CH:2][C:3]([OH:5])=[O:4])=[CH:12][CH:11]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: C1CCNCC1
Solvent: CCCCCC
Solvent: c1ccncc1
Product: O=C(O)C=Cc1ccc(C(F)(F)F)cc1
Temperature: 105 °C
Yield: 119 %

Procedure:
Malonic acid (3.58 g, 0.03 mol) and piperidine (0.28 mL, 0.0028 mol) were added to a solution of 4-trifluoromethyl-benzaldehyde (5 g, 0.028 mol) in pyridine (50 mL) at room temperature under nitrogen atmosphere. The resulting mixture was refluxed at 105° C. for 20 minutes under nitrogen atmosphere. The reaction was monitored by TLC (50% ethylacetate in hexane). The reaction mixture was cooled to room temperature, followed by the addition of 6N HCl and filtered. The residue was washed with n-hexane (20 mL) and dried under reduced pressure to afford 7.2 g of the crude product which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]([CH3:28])[C:12]([C:14]1[S:27][C:17]2[C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1)=[O:13])[C:5]([OH:7])=O.[N:29]1([CH2:34][CH2:35][CH2:36][NH2:37])[CH:33]=[CH:32][N:31]=[CH:30]1>>[N:29]1([CH2:34][CH2:35][CH2:36][NH:37][C:5]([C:4]2[CH:8]=[CH:9][C:10]([N:11]([CH3:28])[C:12]([C:14]3[S:27][C:17]4[C:18]5[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=5[O:20][CH2:21][CH2:22][C:16]=4[CH:15]=3)=[O:13])=[C:2]([Cl:1])[CH:3]=2)=[O:7])[CH:33]=[CH:32][N:31]=[CH:30]1
Reactant: NCCCn1ccnc1
Reactant: CN(C(=O)c1cc2c(s1)-c1ccccc1OCC2)c1ccc(C(=O)O)cc1Cl
Product: CN(C(=O)c1cc2c(s1)-c1ccccc1OCC2)c1ccc(C(=O)NCCCn2ccnc2)cc1Cl

Procedure:
3-Chloro-4-(N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)benzoic acid and 3-(1H-imidazol-1-yl)propan-1-amine were reacted by a procedure similar to that to prepare 137 in Example 47 to give 229. MS: (ESI+) 521.1
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C@@H:11]1[C:15](=[CH:16][CH2:17][C:18](=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:14][CH2:13][C@@H:12]1[OH:25])[CH3:2].[CH3:27][Mg]Br>>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C@@H:11]1[C:15](=[CH:16][CH2:17][C:18]([OH:24])([CH3:27])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:14][CH2:13][C@@H:12]1[OH:25])[CH3:2]
Reactant: CCCCCC(=O)CC=C1CC[C@H](O)[C@@H]1CCCCCCC(=O)OCC
Reactant: C[Mg]Br
Product: CCCCCC(C)(O)CC=C1CC[C@H](O)[C@@H]1CCCCCCC(=O)OCC

Procedure:
Following the procedure of Example 16, 9α-hydroxy-15-oxo-12-prostenoic acid ethyl ester is reacted with methyl magnesium bromide to produce 9α,15-dihydroxy-15-methyl-12-prostenoic acid ethyl ester as a mixture of the 15-epimers, Rf = 0.29.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=2)[CH:17]=[CH:16][C:15]=1[S:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37](=[O:39])[CH3:38])=[CH:32][CH:31]=1>C(O)C>[Br:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][O:20][C:18]2[CH:17]=[CH:16][C:15]([S:29][C:30]3[CH:35]=[CH:34][C:33]([NH:36][C:37](=[O:39])[CH3:38])=[CH:32][CH:31]=3)=[C:14]([NH:13][C:2]3[C:3]4[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=4)[N:9]=[CH:10][CH:11]=3)[CH:19]=2)=[CH:23][CH:24]=1
Reactant: CC(=O)Nc1ccc(Sc2ccc(OCc3ccc(Br)cc3)cc2N)cc1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Solvent: CCO
Product: CC(=O)Nc1ccc(Sc2ccc(OCc3ccc(Br)cc3)cc2Nc2ccnc3nc(C)ccc23)cc1

Procedure:
The product from Example 1d (18 mg, 0.085 mmol) was reacted in ethanol (1 mL) with the product from Example 158a (37 mg, 0.085 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (26 mg, 42%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.97 (t, J=7.35 Hz, 3H) 1.67-1.92 (m, 2 H) 2.02 (s, 3 H) 2.99 (t, J=7.54 Hz, 2 H) 5.14 (s, 2 H) 6.30 (d, J=6.99 Hz, 1 H) 7.14 (d, J=8.46 Hz, 2 H) 7.16-7.26 (m, 2 H) 7.31-7.49 (m, 5 H) 7.53-7.66 (m, 2 H) 7.80 (d, J=8.46 Hz, 1 H) 8.37 (d, J=6.99 Hz, 1 H) 8.97 (d, J=8.82 Hz, 1 H) 9.97 (s, 1 H) 11.00 (s, 1 H) 14.37 (s, 1 H); MS (ESI+) m/z 615 (M+H)+.
Reaction SMILES: [NH:1]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C@H:2]([C:7](O)=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].NC(CC1C=CC=CC=1)C(O)C(NC(OC(C)(C)C)=O)CC1C=CC=CC=1.[NH2:47][CH:48]([CH:56]([OH:84])[CH:57]([NH:65][C:66](=[O:83])[C@H:67]([CH2:79][C:80](=[O:82])[NH2:81])[NH:68][C:69]([O:71][CH2:72][C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1)=[O:70])[CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>CO.C(Cl)(Cl)Cl>[C:69]([NH:68][C@H:67]([C:66]([NH:65][CH:57]([CH:56]([OH:84])[CH:48]([NH:47][C:7](=[O:8])[C@H:2]([CH2:3][C:4](=[O:6])[NH2:5])[NH:1][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[CH2:49][C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1)[CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)=[O:83])[CH2:79][C:80](=[O:82])[NH2:81])([O:71][CH2:72][C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1)=[O:70]
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)NC(Cc1ccccc1)C(O)C(N)Cc1ccccc1
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(O)C(N)Cc1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)NC(Cc1ccccc1)C(O)C(Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1
Yield: 75 %

Procedure:
Using the procedure of Example 55 but replacing Cbz-Val-OH with Cbz-Asn-OH and replacing the resultant compound of Example 11 with the resultant compound of Example 67 gave, after silica gel chromatography using methanol/chloroform, the desired compound (RF 0.4; 2.5% methanol/2% isopropylamine/chloroform) in 75% yield, m.p. 234°-236° C. (dec). Mass spectrum (M+H)+ =767.
Reaction SMILES: [NH2:1][C:2]1[CH2:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:5]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:4]=2[N:3]=1.[C:21]([C:27](OC)=[O:28])#[C:22][C:23]([O:25][CH3:26])=[O:24]>CO>[C:23]([C:22]1[N:3]2[C:4]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:5]=3[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[Cl:15])=[N:7][CH2:8][C:2]2=[N:1][C:27](=[O:28])[CH:21]=1)([O:25][CH3:26])=[O:24]
Reactant: NC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1
Reactant: COC(=O)C#CC(=O)OC
Solvent: CO
Product: COC(=O)c1cc(=O)nc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 21, 2-amino-7-chloro-5-(o-chlorophenyl)-3H-1,4-benzodiazepine was heated in methanol with dimethyl acetylenedicarboxylate to give 1-carbomethoxy-9-chloro-7-(o-chlorophenyl)pyrimido[1,2-a][1,4]benzodiazepin-3(5H)-one.
Reaction SMILES: C([Li])CCC.[C:6]1([C:12]2[N:13]=[CH:14][S:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl:17][C:18]1[CH:19]=[C:20]([N:33]2[C:38](=[O:39])[NH:37][C:36](=[O:40])[CH:35]=[N:34]2)[CH:21]=[CH:22][C:23]=1[C:24](=[O:32])[C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1.Cl>C(OCC)C.C1COCC1>[Cl:17][C:18]1[CH:19]=[C:20]([N:33]2[C:38](=[O:39])[NH:37][C:36](=[O:40])[CH:35]=[N:34]2)[CH:21]=[CH:22][C:23]=1[C:24]([C:25]1[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=1)([OH:32])[C:14]1[S:15][CH:16]=[C:12]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:13]=1
Reactant: c1ccc(-c2cscn2)cc1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(-n2ncc(=O)[nH]c2=O)cc1Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=c1cnn(-c2ccc(C(O)(c3ccc(Cl)cc3)c3nc(-c4ccccc4)cs3)c(Cl)c2)c(=O)[nH]1
Temperature: -70 °C
Reaction time: 1.5 h
Yield: 10.6 %

Procedure:
n-Butyl lithium (0.045 mol) was added at −70° C. under N2 flow to a solution of 4-phenyl-thiazole (0.045 mol) in diethyl ether (50 ml). The mixture was stirred at −70° C. for 90 minutes. A solution of 2-[3-chloro-4-(4-chlorobenzoyl)phenyl]-1,2,4-triazine-3,5-(2H,4H)-dione (0.015 mol) in THF (10 ml) was added at −70° C. The mixture was stirred at −70° C. for 1 hour, then poured out into ice water, neutralized with HCl 3N and extracted with EtOAc. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography oversilica gel (eluent: CH2Cl2/CH3OH 98/2). The desired fraction was repurified by HPLC (eluent: CH3OH/(NH4OAc 1% in H2O) 80/20). The pure fractions were collected and the solvent was evaporated, yielding 0.83 g (11%) of (±)-2-[3-chloro-4-[(4-chlorophenyl)hydroxy(4-phenyl-2-thiazolyl)methyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione (interm. 71).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:10](N(CC)CC)C.ClC1C=CC(S(ON2C3C=C(Cl)C=CC=3N=N2)(=O)=O)=CC=1.CO>C(Cl)(Cl)Cl>[C:1]([O:9][CH3:10])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCN(CC)CC
Reactant: CCCCCCC(=O)O
Agent: O=S(=O)(On1nnc2ccc(Cl)cc21)c1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCCCCC(=O)OC
Reaction time: 0.17 h

Procedure:
Heptanoic acid (1.30 g) is dissolved in chloroform (15 ml) and thereto are added triethylamine under ice-cooling and further 1-(p-chlorobenzenesulfonyloxy)-6-chloro-1,2,3-benzotriazole (3.44 g), and the mixture is stirred for 3 hours. To the solution are added methanol (0.61 ml) and triethylamine (1.40 ml), whereby exothermic reaction occurs. After stirring for 10 minutes, chloroform is distilled off and to the resulting residue are added water and ether. The ether layer is washed with water, an aqueous sodium hydrogen carbonate and water in order, dried over anhydrous magnesium sulfate and the solvent is distilled off to give methyl heptanoate (1.25 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[NH:14][C:13](=[O:15])[C:12]([CH3:17])([CH3:16])[C@@H:11]([OH:18])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[H-].[Na+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>C1COCC1>[F:8][C:6]1[CH:5]=[C:4]([C@H:9]2[N:14]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:13](=[O:15])[C:12]([CH3:16])([CH3:17])[C@@H:11]([OH:18])[CH2:10]2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: CC1(C)C(=O)N[C@H](c2cc(F)cc(F)c2)C[C@@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CN1C(=O)C(C)(C)[C@@H](O)C[C@H]1c1cc(F)cc(F)c1
Reaction time: 0.5 h

Procedure:
To a solution of cis-6-(3,5-difluorophenyl)-4-hydroxy-3,3-dimethylpiperidin-2-one from Step B (17.1 g, 67.0 mmol) in THF (400 mL) at 0° C. was added NaH (60% dispersion in oil, 4.91 g, 73.7 mmol). After 30 min, ethyl bromoacetate (8.20 mL, 73.7 mmol) was added. After 30 min, the reaction mixture was quenched with saturated aqueous NH4Cl (100 mL), diluted with H2O (700 mL) and brine (100 mL) and extracted with EtOAc (700 mL). The organic extract was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc-100:0 to 0:100, to give the alcohol as a mixture of four isomers. Additional purification was achieved by HPLC, using a ChiralPak AD column and eluting with hexane:EtOH:Et2NH-90:10:0.1. The first major peak to elute was a mixture of ethyl [(4S,6S)-6-(3,5-difluorophenyl)-4-hydroxy-3,3-dimethyl-2-oxopiperidin-1-yl]acetate and ethyl [(4S,6R)-6-(3,5-difluorophenyl)-4-hydroxy-3,3-dimethyl-2-oxopiperidin-1-yl]acetate (ca. 5:1). The second major peak to elute was a mixture of ethyl [(4R,6R)-6-(3,5-difluorophenyl)-4-hydroxy-3,3-dimethyl-2-oxopiperidin-1-yl]acetate and ethyl [(4R,6S)-6-(3,5-difluorophenyl)-4-hydroxy-3,3-dimethyl-2-oxopiperidin-1-yl]acetate (ca. 3:1). Further purification of the second major peak was achieved by SFC, using a ChiralPak AD column and eluting with CO2:MeOH:Et2NH-90:10:0.1, to give ethyl [(4R,6R)-6-(3,5-difluorophenyl)-4-hydroxy-3,3-dimethyl-2-oxopiperidin-1-yl]acetate, which eluted first, and ethyl [(4R,6S)-6-(3,5-difluorophenyl)-4-hydroxy-3,3-dimethyl-2-oxopiperidin-1-yl]acetate, which eluted second. Further purification of the first major peak was achieved by SFC, using a ChiralPak AD column and eluting with CO2:MeOH:Et2NH-90:10:0.1, to give ethyl [(4S,6R)-6-(3,5-difluorophenyl)-4-hydroxy-3,3-dimethyl-2-oxopiperidin-1-yl]acetate, which eluted first, and ethyl [(4S,6S)-6-(3,5-difluorophenyl)-4-hydroxy-3,3-dimethyl-2-oxopiperidin-1-yl]acetate, which eluted second, the title compound. MS: m/z=342 (M+1).