Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH2:6]([N:9]1[C:13]([CH3:14])=[C:12]([CH3:15])[N:11]=[CH:10]1)[CH:7]=[CH2:8].CN(C)CCN(C)C.[Cl:24][C:25]1[CH:39]=[CH:38][C:28]([C:29]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)=[O:30])=[CH:27][CH:26]=1.C(=O)=O>CCCCCC.O1CCCC1.O>[Cl:24][C:25]1[CH:39]=[CH:38][C:28]([C:29]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)([C:10]2[N:9]([CH:6]=[CH:7][CH3:8])[C:13]([CH3:14])=[C:12]([CH3:15])[N:11]=2)[OH:30])=[CH:27][CH:26]=1
Reactant: C=CCn1cnc(C)c1C
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: CN(C)CCN(C)C
Agent: O=C=O
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC=Cn1c(C(O)(c2ccc(Cl)cc2)c2ccc(Cl)cc2)nc(C)c1C
Reaction time: 2 h

Procedure:
In the course of one hour, 40 ml. (0.085 mol) of a 20% butyl lithium solution in n-hexane were added dropwise with stirring, under a nitrogen atmosphere at -60° C. to a solution of 10.4 g (0.0765 mol) of 1-allyl-4,5-dimethyl-imidazole and 9.3 g (0.080 mol) of N,N,N',N'-tetramethylethylenediamine in 125 ml. of anhydrous tetrahydrofuran. Stirring was continued for another two hours at -60° C. and then 19.5 g (0.078 mol) of 4,4'-dichlorobenzophenone in 100 ml of anhydrous tetrahydrofuran were added dropwise. The reaction mixture was kept standing overnight at room temperature and then 15 ml. of water and some pieces of solid carbon dioxide were added. The mixture was filtered and the filtrate was concentrated. The residue was extracted with a mixture of diethyl ether and 2 N hydrochloric acid. The aqueous phase was made alkaline with potassium carbonate and extracted with diethyl ether. The extract was dried over sodium sulphate and concentrated. The residue was extracted again with 2 N hydrochloric acid and diethyl ether and the aqueous phase was made alkaline again with potassium carbonate. The solid matter formed was filtered off and dissolved in boiling petroleum ether (boiling range 60°-80° C.). The undissolved material was filtered off and the petroleum ether was distilled off. The residue was taken up in a very small amount of diethyl ether. The solution was cooled in a mixture of carbon dioxide and acetone and the precipitate was filtered off. α,α-Bis(p-chlorophenyl)-4,5-dimethyl-1-(1-propenyl)imidazole-2-methanol was obtained. Melting point 127°-128° C.
Reaction SMILES: [CH3:1][C:2]([C@H:4]1[C@@H:8]2[C@@H:9]3[C@@:22]([CH3:25])([CH2:23][CH2:24][C@@:7]2([CH2:31][OH:32])[CH2:6][CH2:5]1)[C@@:21]1([CH3:26])[C@@H:12]([C@:13]2([CH3:30])[C@@H:18]([CH2:19][CH2:20]1)[C:17]([CH3:28])([CH3:27])[C@@H:16]([OH:29])[CH2:15][CH2:14]2)[CH2:11][CH2:10]3)=[CH2:3].[C:33]1([CH3:43])[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>N1C=CC=CC=1>[CH3:25][C@:22]12[C@:21]3([CH3:26])[CH2:20][CH2:19][C@H:18]4[C:17]([CH3:27])([CH3:28])[C@@H:16]([OH:29])[CH2:15][CH2:14][C@:13]4([CH3:30])[C@H:12]3[CH2:11][CH2:10][C@@H:9]1[C@@H:8]1[C@@:7]3([CH2:31][O:32][C@H:4]1[C:2]([CH3:1])([CH3:3])[CH2:5][CH2:6]3)[CH2:24][CH2:23]2.[S:39]([C:36]1[CH:37]=[CH:38][C:33]([CH3:43])=[CH:34][CH:35]=1)([O-:29])(=[O:41])=[O:40]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C=C(C)[C@@H]1CC[C@]2(CO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: c1ccncc1
Product: CC1(C)CC[C@]23CC[C@]4(C)[C@H](CC[C@@H]5[C@@]6(C)CC[C@H](O)C(C)(C)[C@@H]6CC[C@]54C)[C@H]2[C@H]1OC3
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 0 °C
Yield: 142.3 %

Procedure:
Betulin (3 g) and p-toluenesulfonyl chloride (2.52 g) were placed in dry pyridine (70 ml) at 3-5° C. After 72 hours at 3-5° C. the solution was poured into 100 ml of cracked ice and the resulting precipitate was washed with water (2×50 ml), 1% HCl (50 ml) and water (2×50 ml) and dried in an oven. Chromatography on a silica column (Ether:Hexane=25:75) gave 2.96 g of allobetulin tosylate as white crystals mp. 180-182.6° C. (dec); IR (KBr) 2944, 2864, 1489, 1451, 1363, 1337, 1174, 1098, 1036, 925, 905, 875, 812, 685, 560 cm−1; 1H NMR (CDCl3) δ 7.8(D, 2H, benz-Tos), 7.37(D, 2H, benz-Tos), 4.22(DD, 1H, 3H), 3.76(D, 1H, 28H, J=11 Hz), 3.52(S, 1H, 19H), 3.39(D, 1H, 28H, J=11 Hz), 2.44(S, 3H, Tos-Me), 0.8, 0.8, 0.83, 0.92, 0.93, 0.96, 0.99, (all S, 7×3H, 23-, 24-, 25-, 26-, 27-, 29-, 30-Me), 0.6-1.86(complex CH—, CH2—, 25H); 13C NMR (CDCl3) δ 144.46, 135.08, 129.88, 129.88, 127.83, 127.83, 91.18, 88.10, 71.42, 55.93, 51.1, 46.98, 41.65, 40.9, 40.76, 38.95, 38.84, 37.16, 36.92, 36.46, 34.29, 33.97, 32.90, 29.03, 27.98, 26.59, 26.43, 25.04, 24.76, 21.86, 21.23, 18.47, 16.67, 16.43, 15.87, 13.69.
Reaction SMILES: C([C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:7]=[CH:6][C:5]=1[O:15][CH2:16][CH2:17][CH2:18][CH3:19])(=O)C.[C:20]([O:23]CC)(=[O:22])[CH3:21].C(OO)(=O)C>O>[C:20]([O:23][C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:7]=[CH:6][C:5]=1[O:15][CH2:16][CH2:17][CH2:18][CH3:19])(=[O:22])[CH3:21]
Reactant: CCCCOc1ccc(OCCCC)c(C(C)=O)c1
Reactant: CCOC(C)=O
Agent: CC(=O)OO
Solvent: O
Product: CCCCOc1ccc(OCCCC)c(OC(C)=O)c1
Temperature: 40 °C
Reaction time: 18 h

Procedure:
Next, 67.1 [g] of 2-acetyl-1,4-di-n-butoxybenzene was added to 54 [ml] of ethyl acetate, 83 [ml] of 40 [wt %] peracetic acid was dripped in at 40° C., and the reaction was carried out while stirring at 40° C. for 18 hours. The reaction liquor was poured into 700 [ml] of water at room temperature, and extracted twice with 300 [ml] of ethyl acetate. The extraction solvent (i.e. the ethyl acetate solution) was washed with water, and concentrated by evaporating off the ethyl acetate solvent under reduced pressure. Concentration of the extraction solution was continued until there was almost no further evaporation of ethyl acetate (i.e., almost no further ethyl acetate remained in the extraction solution). Subsequently, the separated crystals were filtered off using filter paper, washed with a small amount of ethyl acetate, and dried to obtain 53.0 [g] of 2-acetoxy-1,4-di-n-butoxybenzene.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[F:21][C:22]1[CH:30]=[CH:29][C:25]([CH2:26][CH2:27][NH2:28])=[CH:24][CH:23]=1.[BH4-].[Na+]>CO>[F:21][C:22]1[CH:30]=[CH:29][C:25]([CH2:26][CH2:27][NH:28][CH2:1][C:3]2[CH:18]=[CH:17][C:6]([O:7][C:8]3[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=3)=[C:5]([O:19][CH3:20])[CH:4]=2)=[CH:24][CH:23]=1
Reactant: COc1cc(C=O)ccc1Oc1cnc(C(N)=O)cn1
Reactant: NCCc1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(CNCCc2ccc(F)cc2)ccc1Oc1cnc(C(N)=O)cn1
Reaction time: 8 h
Yield: 53.7 %

Procedure:
Place 5-(4-formyl-2-methoxyphenoxy)pyrazine-2-carboxamide (Example 719, Part A) (0.700 g, 2.56 mmol), 4-fluorophenethylamine (0.374 g, 2.69 mmol) and 3 Å molecular sieves in a vial. Add methanol (12.8 mL), cap and stir overnight. Add NaBH4 (0.0969 g, 2.56 mmol) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 5% to 20% (2.0 M NH3 in methanol) in ethyl acetate over 45 minutes. Concentrate the fraction containing the product then add EtOAc (100 mL). Wash the organic solution with 1.0 N NaOH (2× 25 mL), dry it over Na2SO4, filter and concentrate. Dissolve the product in ether:dichloromethane (5:1) (25 mL), add hexanes (20 mL), and then concentrate to about a quarter of the volume. Filter the precipitate to give the title compound (0.545 g, 53.4%): TOF MS ES+ 397.2 (M+H)+, HRMS calcd for C21H22N4O3F 397.1676 (M+H)+, found 397.1689, time 0.38 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=11.2 min, 100% purity.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[NH:6][CH:7]=[C:8]([CH3:10])[CH:9]=1)=[O:4].[NH2:13][C:14]1[C:15]([CH3:20])=[CH:16][CH:17]=[CH:18][CH:19]=1.C(N(CC)CC)C>CCCCCC>[CH3:10][C:8]1[CH:9]=[C:5]([C:3]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])=[O:4])[NH:6][CH:7]=1
Reactant: Cc1ccccc1N
Reactant: Cc1c[nH]c(C(=O)C(Cl)(Cl)Cl)c1
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: Cc1c[nH]c(C(=O)Nc2ccccc2C)c1
Temperature: 80 °C
Reaction time: 75 h
Yield: 45 %

Procedure:
A solution of 2,2,2-trichloro-1-(4-methyl-1H-pyrrol-2-yl)ethanone (2 g, 8.8 mmol) in a mixture of o-toluidine (1.76 mL, 16.5 mmol) and triethylamine (2.1 mL, 15.07 mmol) under argon was heated to 80° C. with stirring during 75 h. Afterwards, the reaction mixture was concentrated to dryness giving a residue that was treated with hexane and the resulting solid filtered to afford 848 mg of the title compound (45% yield).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[S:12][CH2:11][CH2:10][C:5]21OCC[O:6]2.C1COCC1.O>C(O)(=O)C>[CH3:1][O:2][CH2:3][CH:4]1[C:5](=[O:6])[CH2:10][CH2:11][S:12]1
Reactant: COCC1SCCC12OCCO2
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: COCC1SCCC1=O
Yield: 114 %

Procedure:
A solution of 0.16 g (0.84 mmol) of compound from Step C, 3.2 ml THF, 3.2 ml H2O, and 4.8 ml acetic acid was heated at 70° C. for 48 hours. The cooled mixture was concentrated and the residue was dissolved in ethyl acetate, (50 ml) washed with saturated sodium bicarbonate solution (10 ml) and brine, dried, filtered, and concentrated to give 0.14 g of an oil. The oil was flash chromatographed on silica gel eluting with hexane:ether (3:1) to give 0.090 g (75%) product as an oil; NMR (deuteriochloroform): δ 3.7 (m, 2H), 3.5 (m, 1H), 3.37 (S, 3H), 2.05 (m, 1H), 1.95 (m, 1H), 2.65 (t, 2H).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[CH:10][CH:11]=2)[CH:6]=[CH:5][N:4]=1.C(N(CC)CC)C.[C:27]([O:31][C:32](=O)[O-:33])([CH3:30])([CH3:29])[CH3:28]>ClCCl>[C:27]([O:31][C:32]([N:17]1[CH2:18][CH2:19][CH:14]([O:13][C:9]2[CH:8]=[C:7]3[C:12](=[CH:11][CH:10]=2)[C:3]([Cl:2])=[N:4][CH:5]=[CH:6]3)[CH2:15][CH2:16]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)[O-]
Reactant: Clc1nccc2cc(OC3CCNCC3)ccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(Cl)nccc3c2)CC1
Reaction time: 8 h
Yield: 73.8 %

Procedure:
1.23 g (4.11 mmol) of 1-Chloro-6-(piperidin-4-yloxy)-isoquinoline hydrochloride (161) were dissolved in 50 ml of dichloromethane and 0.85 ml (6.15 mmol) of triethylamine were added. At 0° C. a solution of 1.09 g (5.0 mmol) of tert-butyl-carbonate in 10 ml dichloromethane was added dropwise and the mixture was allowed to stand at room temperature overnight. For working up, the mixture was washed twice with H2O, dried over magnesium sulfate and evaporated, to yield 1.1 g of the desired product, which could be used without further purification. Rt=1.86 min (Method #4). Detected mass: 363.1/365.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=2)[NH2:19])[CH:5]=[CH:4][N:3]=1.[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[S:28](Cl)(=[O:30])=[O:29]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:19][S:28]([C:24]3[S:23][CH:27]=[CH:26][CH:25]=3)(=[O:30])=[O:29])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CC(C)c1nc(-c2cccc(N)c2)c(-c2ccnc(Cl)n2)s1
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3cccs3)c2)c(-c2ccnc(Cl)n2)s1
Yield: 87.8 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14, using 3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]aniline (600 mg, 1.8 mmol) and thiophene-2-sulfonyl chloride (331 mg, 1.1 mmol) the title compound was obtained (760 mg, 87.8% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.27 (d, J=5.3 Hz, 1H), 7.51-7.57 (m, 2H), 7.29-7.38 (m, 2H), 7.20-7.27 (m, 2H), 7.13-7.17 (br, 1H), 6.98-7.03 (m, 1H), 6.88 (d, J=5.3 Hz, 1H), 3.27-3.37 (m, 1H), 1.43 (d, J=7.1 Hz, 6H). MS (ES+): 477 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.[CH3:10][CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][N:12]1[C:21]1[N:30]=[C:29]([Cl:31])[C:28]2[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=2[N:22]=1>CN(C)C=O>[ClH:31].[CH3:9][C:4]1[CH:3]=[C:2]([F:1])[CH:8]=[CH:7][C:5]=1[NH:6][C:29]1[C:28]2[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=2[N:22]=[C:21]([N:12]2[CH2:13][CH2:14][C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]2[CH3:10])[N:30]=1
Reactant: CC1c2ccccc2CCN1c1nc(Cl)c2c(n1)CCCC2
Reactant: Cc1cc(F)ccc1N
Solvent: CN(C)C=O
Product: Cc1cc(F)ccc1Nc1nc(N2CCc3ccccc3C2C)nc2c1CCCC2
Product: Cl
Yield: 31.1 %

Procedure:
After 4-fluoro-2-methylaniline(0.3 ml, 2.7 mmol) was added to a mixture solution of 2-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-4-chloro-5,6,7,8-tetrahydroquinazoline(0.35 g, 1.1 mmol) and dimethylformamide(5 ml), 0.15 g of the titled compound was obtained in accordance with the same procedure as in Step 4 of Example 57.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([OH:16])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.[CH2:42]([O:44][C:45](=[O:48])[CH2:46][NH2:47])[CH3:43]>CN(C=O)C.O>[CH2:42]([O:44][C:45](=[O:48])[CH2:46][NH:47][C:14](=[O:16])[C:13]1[CH:17]=[CH:18][CH:19]=[C:11]([OH:10])[CH:12]=1)[CH3:43]
Reactant: O=C(O)c1cccc(O)c1
Reactant: CCOC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
DIPEA (375 μL, 2.17 mmol) was added drop wise to 3-hydroxy benzoic acid (100 mg, 0.72 mmol) in DMF (4 mL). EDCI (208 mg, 1.09 mmol) and HOBT (117 mg, 0.87 mmol) were added consecutively and after 15 mins, glycine ethyl ester HCl (120 mg, 0.87 mmoles) was added. The resulting mixture was stirred at room temperature overnight. Water was then added, and the product was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford (3-Hydroxy-benzoyl amino)-acetic acid ethyl ester in quantitative yield.
Reaction SMILES: P(Br)(Br)[Br:2].[CH3:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[CH3:15])[CH2:9][CH2:10]O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl.O>[CH3:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[CH3:15])[CH2:9][CH2:10][Br:2]
Reactant: BrP(Br)Br
Reactant: Cc1ccc(CCO)cc1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ccc(CCBr)cc1C
Temperature: 25 °C

Procedure:
Phosphorus tribromide (0.82 g) was added dropwise to a solution of 3,4-dimethylphenethyl alcohol (1.27 g--see Preparation 17) in carbon tetrachloride (10 ml). The mixture was heated under reflux for 2.5 hours then cooled to room temperature and basified (pit 8) by the dropwise addition of 10% aqueous sodium carbonate (5 ml). The mixture was then diluted with water (20 ml) and extracted with dichloromethane (3×50 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give the title compound as a colourless oil, yield, 0.5g.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C@@H:5]2[C@@H:7]([CH3:11])[CH2:8][C:9](=[O:10])[C@@H:4]2[O:3]1.CC(C[AlH]CC(C)C)C.CO.O>C(Cl)Cl>[CH3:1][C:2]1([CH3:12])[O:6][C@@H:5]2[C@@H:7]([CH3:11])[CH2:8][C@H:9]([OH:10])[C@@H:4]2[O:3]1
Reactant: C[C@H]1CC(=O)[C@@H]2OC(C)(C)O[C@H]12
Agent: CC(C)C[AlH]CC(C)C
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: C[C@H]1C[C@H](O)[C@@H]2OC(C)(C)O[C@@H]21
Temperature: -78 °C
Reaction time: 4 h

Procedure:
(3aR,6S,6aR)-2,2,6-trimethyldihydro-3aH-cyclopenta[d][1,3]dioxol-4(5H)-one (6-1) (490 mg, 2.7 mmol, 1 equiv) was dissolved in dry DCM (55 mL) and 3A molecular sieves were added. The mixture was cooled to −78° C. and DIBAL (4.1 mL, 4.1 mmol, 1.5 equiv, 1.0M in heptane) was added dropwise. The resulting mixture stirred at the same temperature for 4 hours. Upon disappearance of the starting material, MeOH (6 mL) was added to quench the reaction. Water (10 mL) was added and the mixture was filtered through celite washing with DCM (2×30 mL). The organic layer was separated, dried over MgSO4, filtered and concentrated to afford (3aS,4S,6S,6aR)-2,2,6-trimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ol (6-2) as a colorless oil. 1H NMR (500 MHz, CDCl3): δ 4.50 (t, J=6.0 Hz, 1H); 4.27 (d, J=5.5 Hz, 1H); 4.12 (quin, J=6.0 Hz, 1H); 2.46 (d, J=8.5 Hz, 1H); 2.15 (quirt, J=4.5 Hz, 1H); 1.85 (m, 1H); 1.64 (dq, J=12.5, 3.0 Hz, 1H); 1.49 (s, 3H); 1.34 (s, 3H); 0.93 (d, J=8.0 Hz, 3H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[Br:12][C:13]1[CH:14]=[C:15]([CH:23]=[CH:24][CH:25]=[O:26])[CH:16]=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20].N1CC[O:30][CH2:29]C1>>[Br:12][C:13]1[CH:14]=[C:15]([CH:23]2[C:8]3[C:7](=[CH:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:10][CH:9]=3)[O:11][CH:25]([OH:26])[CH2:24]2)[CH:16]=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20].[CH3:29][OH:30]
Reactant: COc1cc(C=CC=O)cc(Br)c1OC
Reactant: C1COCCN1
Reactant: CC(=O)Nc1cccc(O)c1
Product: CO
Product: COc1cc(C2CC(O)Oc3cc(NC(C)=O)ccc32)cc(Br)c1OC
Yield: 26 %

Procedure:
The title compound was prepared following the procedure as in Example 18 from 3-acetamido phenol (13 mg; 0.086 mmol) and 3-(3-bromo-4,5-dimethoxy-phenyl)-propenal (25 mg; 0.09 mmol) using morpholine (15 μl; 0.17 mmol) as a base in reluxing methanol (1 ml) (7 h) (yield: 26%). 1H NMR (acetone-d6): 9.06 (s, 1H), 7.36 and 7.34 (broad s each, 1H), 6.89-7.01 (m, 3H), 6.57-6.62 (overlapping d, J=8.4 Hz; 1H), 6.14 (d, J=6.6 Hz) and 6.11 (d, J=4.1 Hz) (1H), 5.62 (broad s) and 5.48-5.50 (m) (1H), 4.19-4.26 (overlapping dd, J=6.2, 11.1 Hz; 1H), 3.85, 3.83 and 3.79 (s each, 6H); 2.34 (broad dd, J=5.9, 12.9 Hz) and 2.09-2.18 (m) (2H), 2.04 (s overlapping with acetone-signal).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:4]=[C:5]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:6]2[C:7](=[O:9])[CH:8]=1.[Br:15]N1C(=O)CCC1=O.C(O)(=O)C.O>C(Cl)Cl>[Br:15][C:8]1[C:7](=[O:9])[N:6]2[C:10]([CH3:14])=[CH:11][CH:12]=[CH:13][C:5]2=[N:4][C:3]=1[CH2:2][Cl:1]
Reactant: Cc1cccc2nc(CCl)cc(=O)n12
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O
Product: Cc1cccc2nc(CCl)c(Br)c(=O)n12
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
A mixture of 2-(chloromethyl)-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (3.5648 g, 17.09 mmol), N-bromosuccinimide (3.35 g, 18.79 mmol), and acetic acid (48.2 mL, 843 mmol) was stirred at rt. After 4.5 h, the mixture was poured into water (200 mL) and the resulting precipitate was collected by filtration, washed with water (200 mL), and dried to give an orange solid. The orange solid was dissolved in DCM (100 mL), dried over Na2SO4, filtered, and concd under reduced pressure to give 3-bromo-2-(chloromethyl)-6-methyl-4H-pyrido[1,2-a]-pyrimidin-4-one as an orange solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 7.76 (1 H, dd, J=9.0, 7.0 Hz), 7.47-7.52 (1 H, m), 7.04-7.09 (1 H, m), 4.71 (2 H, s), 2.95 (3 H, s); Mass Spectrum (ESI) m/e=288.9 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:17])=[C:4]([CH3:16])[C:5]2[O:9][CH:8]([CH2:10][CH2:11][CH2:12]O)[S:7][C:6]=2[C:14]=1[CH3:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:37]I.O>C1C=CC=CC=1.N1C=CC=CC=1>[OH:1][C:2]1[C:3]([CH3:17])=[C:4]([CH3:16])[C:5]2[O:9][CH:8]([CH2:10][CH2:11][CH2:12][I:37])[S:7][C:6]=2[C:14]=1[CH3:15]
Reactant: Cc1c(C)c2c(c(C)c1O)SC(CCCO)O2
Reactant: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: Cc1c(C)c2c(c(C)c1O)SC(CCCI)O2
Reaction time: 0.5 h

Procedure:
3.0 g of 3-(5-hydroxy-4,6,7-trimethyl-1,3-benzoxathiole-2-yl)propanol (prepared as described in Example 71) were dissolved in a mixture of 40 ml of benzene and 4 ml of pyridine, after which 6.2 g of triphenylphosphine were dissolved in the mixture. After the dissolution, 6.0 g of iodine was added to the solution all at once. The reaction temperatures of the mixture rose to 45° C. The reaction was allowed to continue for another 30 minutes at room temperature, and then the reaction mixture was poured into water and extracted with benzene. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The resulting crude reaction product was subjected to silica gel Lobar column chromatography, and the title compound, melting at 72°-75° C. was obtained from the fraction eluted with benzene.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)[NH:8][N:7]=1)=[O:5])[CH3:2].[CH3:22]I.[OH-].[K+]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:22])[N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)[CH:10]=1)=[O:5])[CH3:2].[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)[N:8]([CH3:22])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(-c2ccc(OC(F)(F)F)cc2)[nH]n1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Product: CCOC(=O)c1cc(-c2ccc(OC(F)(F)F)cc2)n(C)n1
Product: CCOC(=O)c1cc(-c2ccc(OC(F)(F)F)cc2)nn1C

Procedure:
In analogy to the procedure described for example 2 a], 5-(4-trifluoromethoxy-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester was reacted with methyl iodide in the presence of potassium hydroxide to to give 2-methyl-5-(4-trifluoromethoxy-phenyl)-2H-pyrazole-3-carboxylic acid ethyl ester as white crystals and 1-methyl-5-(4-trifluoromethoxy-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester as yellow oil.
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][C@@H:9]([CH3:38])[C:10]([NH:12][C@@H:13]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)[C:14]([NH:16][C@@H:17]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:18]([C@:20]1([CH3:23])[CH2:22][O:21]1)=[O:19])=[O:15])=[O:11].[O:39]1[CH2:44][CH2:43][N:42]([CH2:45][C:46](O)=[O:47])[CH2:41][CH2:40]1.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:23][C@:20]1([C:18](=[O:19])[C@@H:17]([NH:16][C:14](=[O:15])[C@@H:13]([NH:12][C:10](=[O:11])[C@@H:9]([NH:8][C:46](=[O:47])[CH2:45][N:42]2[CH2:43][CH2:44][O:39][CH2:40][CH2:41]2)[CH3:38])[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:22][O:21]1
Reactant: O=C(O)CN1CCOCC1
Reactant: C[C@H](N)C(=O)N[C@@H](Cc1ccccn1)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@]1(C)CO1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](NC(=O)CN1CCOCC1)C(=O)N[C@@H](Cc1ccccn1)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@@]1(C)CO1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36.5 %

Procedure:
To (S)-2-((S)-2-aminopropanamido)-N-((S)-1-((S)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)-3-(pyridin-2-yl)propanamide TFA salt (0.601 mmol assumed) was added morpholinoacetic acid (174 mg, 1.20 mmol), HOBt (130 mg, 0.962 mmol), HBTU (365 mg, 0.962 mmol) and DMF (3 mL). The mixture was cooled to 0° C. and DIEA (0.627 mL, 3.61 mmol) was added. The reaction mixture was stirred at ambient temperature for 30 min then quenched with sodium bicarbonate (sat.), extracted with ethyl acetate (2×), dried with sodium sulfate, filtered, and concentrated. Purification by column chromatography (3:1 DCM/ethyl acetate+0-15% methanol) provided (S)-N-((S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)-2-((S)-2-(2-morpholinoacetamido)propanamido)-3-(pyridin-2-yl)propanamide (121 mg, 37%) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 8.39 (ddd, J=4.9, 1.8, 0.9 Hz, 1H), 7.89 (d, J=6.7 Hz, 2H), 7.60 (ddt, J=7.7, 5.6, 1.8, 1.8 Hz, 2H), 7.25-7.09 (m, 5H), 7.09-6.99 (m, 2H), 4.88-4.65 (m, 2H), 4.47 (p, J=7.1, 7.1, 7.0, 7.0 Hz, 1H), 3.88-3.61 (m, 4H), 3.34-3.23 (m, 2H), 3.14 (dd, J=15.2, 6.3 Hz, 1H), 3.08-2.94 (m, 3H), 2.88 (d, J=5.0 Hz, 1H), 2.76 (dd, J=14.1, 7.9 Hz, 1H), 2.66-2.42 (m, 4H), 1.45 (s, 3H), 1.35 (d, J=7.1 Hz, 3H). MS (EI) for C29H37N5O6, found 552.4 (MH+).