Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH:12]([CH3:16])[N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[CH:26]=[C:27]([C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1)[CH3:28].N1CCC[C@H]1C(O)=O>CN(C=O)C.[Cu]I.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:26]=[C:27](/[C:29]3[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=3)\[CH3:28])[C:6]3[CH2:11][CH:12]([CH3:16])[N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CC1Cc2[nH]c3ccc(Cl)cc3c2CN1C
Reactant: CC(=CBr)c1ccncc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(Cl)ccc31)CN(C)C(C)C2)c1ccncc1
Temperature: 140 °C

Procedure:
8-Chloro-2,3-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (117 mg, 0.5 mmol) and potassium phosphate (212 mg, 1 mmol) were mixed in DMF and the suspension was purged with nitrogen. The suspension was heated at 140° C. for 10 min. In a separate round bottomed flask, 4-(1-bromoprop-1-en-2-yl)pyridine (107.83 mg, 0.55 mmol), L-proline (11.5 mg, 0.1 mmol) and Copper (I) iodide (9.5 mg, 0.05 mmol) were mixed in DMF, the suspension was purged with nitrogen, and heated at 90° C. for 5 min. at which point it became a clear solution. The contents in the two reaction flasks were mixed and the reaction mixture was heated overnight at 90° C. The contents were cooled to RT and poured into water The precipitate obtained was filtered, dried and purified by silica gel chromatography (100-200 mesh, neutralized with aqueous ammonia) eluting with 0-10% MeOH-DCM as eluent. Compound was further purified by HPLC. 1H NMR (CD3OD, freebase) δ (ppm): 8.60 (d, 2H), 7.70 (d, 2H), 7.45 (s, 1H), 7.30 (s, 1H), 7.10 (s, 2H), 4.05 (d, 1H), 3.80 (d, 1H), 3.10 (m, 1H), 2.95 (m, 1H), 2.65 (m, 1H), 2.60 (s, 3H), 2.0 (s, 3H), 1.30 (d, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][N:5]([CH2:8][CH2:9][O:10][CH3:11])[C:4](=[O:12])[CH:3]=1.[I:13][C:14]1[N:15]=[C:16]([CH3:20])[NH:17][C:18]=1[CH3:19]>>[I:13][C:14]1[N:15]=[C:16]([CH3:20])[N:17]([C:2]2[CH:7]=[N:6][N:5]([CH2:8][CH2:9][O:10][CH3:11])[C:4](=[O:12])[CH:3]=2)[C:18]=1[CH3:19]
Reactant: COCCn1ncc(Cl)cc1=O
Reactant: Cc1nc(I)c(C)[nH]1
Product: COCCn1ncc(-n2c(C)nc(I)c2C)cc1=O

Procedure:
The title compound, light yellow waxy solid, MS: m/e=375.2 (M+H+), was prepared in accordance with the general method of example 23b from 5-Chloro-2-(2-methoxy-ethyl)-2H-pyridazin-3-one and 4-iodo-2,5-dimethyl-1H-imidazole.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.[NH2:27][CH2:28][CH2:29][O:30][C:31]1[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=1>C(Cl)(Cl)Cl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:27][CH2:28][CH2:29][O:30][C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=2)=[O:11])=[CH:12][CH:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc(OCCN)cc1
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(OCCNC(=O)c2ccc(C(C)(C)C)cc2)cc1
Yield: 91.9 %

Procedure:
p-tert-Butylbenzoic acid (5.35 g) and 3.34 g of triethylamine were dissolved in 70 ml of chloroform and 3.26 g of ethyl chloroformate was dropped into the above mixture with stirring and cooling at 0° to 5° C. After the dropping, the mixture was stirred at the same temperature for 30 minutes and, after addition of 5.86 g of methyl 4-(2-aminoethoxy)benzoate thereto, the mixture was stirred for 6 hours more. The reaction solution was washed with 10% hydrochloric acid, saturated potassium carbonate solution, and water, dried with anhydrous magnesium sulpahte, concentrated in vacuo, and the residue was crystallised with n-hexane to give 9.8 g of crystals which were further recrystallised from ethyl acetate to give 7.64 g (yield: 71.65%) of the product, m.p. 112°-114° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:7]2[CH:8]=[C:9]([C:12]3[S:16][C:15]([C:17]#[N:18])=[CH:14][C:13]=3[CH3:19])[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=O)[O:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:21])[C:7]2[CH:8]=[C:9]([C:12]3[S:16][C:15]([C:17]#[N:18])=[CH:14][C:13]=3[CH3:19])[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[S:31])[O:3]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1cc(C#N)sc1-c1ccc2c(c1)C(C)(C)OC(=O)N2
Solvent: Cc1ccccc1
Product: Cc1cc(C#N)sc1-c1ccc2c(c1)C(C)(C)OC(=S)N2
Temperature: 25 °C
Yield: 51.6 %

Procedure:
To a solution of 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-4-methylthiophene-2-carbonitile (5 g, 16.7 mmol) in anhydrous toluene was added, at room temperature under a blanket of nitrogen, Lawesson's reagent (6 g, 14.8 mmol). The reaction mixture was heated at reflux for 2 hrs, allowed to cool to room temperature, and solvent was removed in vacuo. The residue was purified by a silica gel column chromatography (THF:hexane/1:3) to yield the title compound as a yellowish solid (2.4 g, 46%): mp 211-212° C.; 1H-NMR (DMSO-d6) δ 12.3 (s, 1H), 7.88 (s, 1H), 7.46-7.52 (m, 2H), 7.16 (d, 1H, J=8.3 Hz), 2.30 (s, 3H), 1.68 (s, 6H); MS (ESI) m/z 313 [M−H]−; Anal. Calcd. For C16H14N2OS2; C, 61.12; H, 4.49; N, 8.91. Found: C, 60.91; H, 4.48; N, 8.66.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19](=[O:20])[CH2:18][CH:17]([C:21]([OH:23])=O)[CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][NH2:25]>>[CH3:24][NH:25][C:21]([CH:17]1[CH2:18][C:19](=[O:20])[N:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:11]=2)[CH2:16]1)=[O:23]
Reactant: CN
Reactant: O=C(O)C1CC(=O)N(c2ccc(OCc3ccccc3)cc2)C1
Product: CNC(=O)C1CC(=O)N(c2ccc(OCc3ccccc3)cc2)C1
Yield: 73 %

Procedure:
The title compound is prepared in analogy to Example 20d) from (RS)-1-(4-benzyloxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid and methylamine. Yield: 73% of a slightly yellow solid. MS: m/e=325.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:18][C:17]([F:20])([F:19])[CH2:16][CH2:15][NH:14][C:13]2=[O:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([CH2:35]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([CH2:35][N:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:9])=[O:10])[C@@H:12]2[CH2:18][C:17]([F:19])([F:20])[CH2:16][CH2:15][NH:14][C:13]2=[O:21])[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: O=C1NCCC(F)(F)C[C@H]1NS(=O)(=O)c1ccc(Cl)cc1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Product: CC(C)(C)OC(=O)N1CCC(CN([C@@H]2CC(F)(F)CCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)CC1

Procedure:
4-Chloro-N-((R)-5,5-difluoro-2-oxo-azepan-3-yl)-benzenesulfonamide was alkylated using 4-(toluene-4-sulfonyloxymethyl)-piperidine-1-carboxylic acid tert-butyl ester analogous to Example 1 to afford 4-{[(4-chloro-benzenesulfonyl)-((R)-5,5-difluoro-2-oxo-azepan-3-yl)-amino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:16][O:17][CH3:18].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:16][O:17][CH3:18])=[CH:4][CH:3]=1
Reactant: COCCl
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1ccc(Br)cc1
Reaction time: 2 h

Procedure:
In DMF (255 ml) was dissolved 4-bromophenol (51.0 g). To the mixture was added at room temperature potassium carbonate (81.5 g) and then was added dropwise chloromethylmethyl ether (44.8 ml), and the mixture was stirred for 2 hours. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=8/1) to give 1-bromo-4-(methoxymethoxy)benzene (61.4 g). In ether (240 ml) was dissolved 1-bromo-4-(methoxymethoxy)benzene (30 g). To the mixture was added dropwise at −78° C. 1.6M n-butyllithium/hexane (90.7 ml), and the mixture was stirred for 1 hour. To the mixture was added dropwise a solution of trimethyl borate (43.1 g) in THF (43 ml), and the mixture was stirred for 30 minutes and warmed to room temperature. To the mixture was added water (150 ml), and the mixture was stirred for 15 minutes. The reaction mixture was extracted with ethyl acetate. Under reduced pressure, the solvent was evaporated, and the residue was stirred in methanol/water (2/1, 1000 ml) for 3 days. Under reduced pressure, methanol was removed, and the residue was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was washed with hexane/isopropylether to give 4-(methoxymethoxy)phenyl borate (2.4 g). 1H-NMR (200 MHz, CDCl3) δ 3.51 (3H, s), 5.26 (2H, s), 7.14 (2H, d, J=8.4 Hz), 8.15 (2H, d, J=8.4 Hz).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:11]3[CH2:12][N:13](C(=O)C)[CH2:14][CH2:15][C:10]3(N3CCCC3)[O:9][N:8]=2)=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[OH-].[Na+]>O>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[C:11]3[CH2:12][NH:13][CH2:14][CH2:15][C:10]=3[O:9][N:8]=2)=[CH:5][CH:6]=1
Reactant: CC(=O)N1CCC2(N3CCCC3)ON=C(c3ccncc3)C2C1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1cc(-c2noc3c2CNCC3)ccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-(3-(Pyridin-4-yl)-7a-(pyrrolidin-1-yl)-3a,4,7,7a-tetrahydroisoxazolo[4,5-c]pyridin-5(6H)-yl)ethanone (0.63 g, 2 mmol) was initially introduced into water (14 ml) and sulfuric acid (95%, 14 ml) was added. The reaction mixture was refluxed for 5 hours, cooled with an ice bath, neutralized with sodium hydroxide solution (5 mol/l) and concentrated in vacuo. Ethyl acetate (10 ml) was added to the residue and the suspension was stirred at room temperature for 30 minutes. The precipitate was filtered out with suction and the mother liquor was extracted with ethyl acetate (4×20 ml). The combined organic phases were dried (MgSO4) and concentrated in vacuo. The yield was 0.34 g (84%). [The regiochemistry was assigned in analogy to AM1-AM4.]
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[CH2:13]([OH:15])[CH3:14].[ClH:16]>C(Cl)(Cl)Cl>[ClH:16].[CH2:13]([O:15][C:7](=[NH:8])[C:6]1[CH:9]=[CH:10][C:3]([C:2]([F:11])([F:12])[F:1])=[CH:4][CH:5]=1)[CH3:14]
Reactant: CCO
Reactant: N#Cc1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=N)c1ccc(C(F)(F)F)cc1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
A solution of 4-trifluoromethyl-benzonitrile (5.16 g, 30.2 mmol) and ethanol (1.39 ml, 30.2 mmol) in chloroform (15 ml) was saturated with a dry stream of HCl gas for 15 min. at −5° C. and the mixture allowed to stand 1 week at 4° C. The product was precipitated with ether, and the suspension stirred for 30 min. at −15°C., then filtered and washed with ether. The solid product was dried at r.t. under high vacuum overnight to afford the title compound (7.1 g, 28 mmol, 93% yield) as a white solid. MS: m/e=217 (M+), 172 (M+-EtOH)
Reaction SMILES: [C:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(Cl)(Cl)Cl.ClC1C=C(C=CC=1)C(OO)=[O:22]>O>[C:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]2[O:22][CH2:10]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: C=Cc1ccc(OC(C)=O)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(=O)Oc1ccc(C2CO2)cc1
Reaction time: 24 h
Yield: 83.7 %

Procedure:
30 g of 4-acetoxy styrene and 1 L of chloroform were added into a 2 L reactor, and was stirred and cooled in iced water. 47 g of 3-chloroperoxybenzoicacid were added into the cooled solution, and the reaction was carried out at room temperature for 24 hours. After completion of the reaction, the 3-chlorobenzoicacid (by-product) was removed by filtering the product, and then the residual 3-chlorobenzoicacid was removed by washing 2 times with saturated sodium sulfite aqueous solution, 1 time with saturated sodium bicarbonate aqueous solution, 1 time with saturated sodium chloride aqueous solution, and 1 time with distilled water. Next, the product was dried with magnesium sulfate, and chloroform was removed under reduced pressure, and then the product was vacuum dried for 1 day to obtain 27.6 g of the pure 4-acetoxy styreneoxide.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:20]2[C:15](=[C:16]([O:21][CH3:22])[CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)[N:12]=1>>[CH3:29][C:27]1[NH:26][N:25]=[C:24]([NH:23][C:13]2[N:12]=[C:11]([O:1][C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=3)[C:20]3[C:15]([CH:14]=2)=[C:16]([O:21][CH3:22])[CH:17]=[CH:18][CH:19]=3)[CH:28]=1
Reactant: COc1cccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc12
Reactant: N#Cc1ccc(O)cc1
Product: COc1cccc2c(Oc3ccc(C#N)cc3)nc(Nc3cc(C)[nH]n3)cc12

Procedure:
Similar procedure as described in example 10 was used, starting from 4-hydroxy-benzonitrile and (1-chloro-5-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give 4-[3-(5-methyl-1H-pyrazol-3-ylamino)-5-methoxy-isoquinolin-1-yloxy]-benzonitrile. LC-MS m/e 372(MH+).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.Cl.[Cl:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22](Cl)=[O:23])[CH:17]=1>C1COCC1.CCOC(C)=O>[Cl:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]([NH:4][CH:1]2[CH2:3][CH2:2]2)=[O:23])[CH:17]=1
Reactant: NC1CC1
Reactant: O=C(Cl)c1cc(Cl)ccn1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CC1)c1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 116 %

Procedure:
A 0° C. solution of cyclopropylamine (0.645 g, 11.30 mmol) and DIEA (1.973 mL, 11.30 mmol) in THF (15 mL) was treated with 4-chloropicolinoyl chloride hydrochloride (0.8 g, 3.77 mmol) in one portion, stirred at RT for 2 h, diluted with EtOAc and washed with satd. NaHCO3, then brine. The organic layer was dried over Na2SO4 and concentrated to dryness to afford 4-chloro-N-cyclopropylpicolinamide (0.86 g, 116%). 1H NMR (400 MHz, DMSO-d6): δ 8.83 (d, J=5.0 Hz, 1H), 8.58 (d, J=5.3 Hz, 1H), 7.99 (d, J=2.1 Hz, 1H), 7.74 (dd, J=5.3, 2.2 Hz, 1H), 2.89-2.88 (m, 1H), 0.68-0.66 (m, 4H); MS (ESI) m/z: 197.1 (M+H+).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[N:3]=1.[CH2:17]([OH:21])[CH2:18][CH2:19][CH3:20].[H-].[Na+]>CN(C=O)C.CCOC(C)=O.O>[CH2:17]([O:21][C:2]1[C:7]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[N:3]=1)[CH2:18][CH2:19][CH3:20]
Reactant: O=C(O)C=Cc1ccc(C(F)(F)F)nc1Cl
Reactant: CCCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCOc1nc(C(F)(F)F)ccc1C=CC(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 46 %

Procedure:
To a suspension of 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (40 mg, 0.158 mmol) and 1-butanol (0.029 ml, 0.316 mmol) in DMF (2 mL) was added NaH (19 mg, 0.47 mmol) at 0° C. The mixture was stirred for 12 hours at room temperature. The residue was diluted with EtOAc and water. The organic layer was washed with 1N HCl, saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was column-chromatographed to give 3-(2-butoxy-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (21 mg, 92%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH:13]([OH:15])[CH3:14])=O)(C)(C)C.C(O)(C(F)(F)F)=O.[N+:23]([C:26]1[CH:33]=[CH:32][C:29](CBr)=[CH:28][CH:27]=1)([O-:25])=[O:24].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[N+:23]([C:26]1[CH:33]=[CH:32][C:29]([CH2:6][N:8]2[CH2:12][CH2:11][CH2:10][CH:9]2[CH:13]([OH:15])[CH3:14])=[CH:28][CH:27]=1)([O-:25])=[O:24]
Reactant: CC(O)C1CCCN1C(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(O)C1CCCN1Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(1-Hydroxy-ethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (1.0 g, 4.6 mmol) in CH2Cl2 is cooled to 0° C. and TFA (2.5 mL) is added dropwise. The mixture is allowed to stir at room temperature overnight. All the volatiles were removed and CH3CN (20 mL) is added. After addition of 4-nitrobenzyl bromide (1.25 g, 5.78 mmol) and K2CO3 (2.0 g, 14.4 mmol), the mixture is stirred at room temperature for 5 hours.
Reaction SMILES: [C:1]1([C:7]2[N:16]=[C:15]([C:17]([O:19]CC)=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:22]1[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]1.C([Li])CCC>CCCCCC.O1CCCC1>[C:1]1([C:7]2[N:16]=[C:15]([C:17]([N:22]3[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]3)=[O:19])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC1CCNCC1
Reactant: CCOC(=O)c1nc(-c2ccccc2)nc2ccccc12
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(c1nc(-c2ccccc2)nc2ccccc12)N1CCC(O)CC1

Procedure:
The procedure of Example 24 is followed using ethyl 2-phenylquinazoline-4-carboxylate (2 g), piperidin-4-ol (1.4 g), a 1.6M solution of butyllithium in hexane (18 ml) and tetrahydrofuran (30 ml) as the starting materials. After recrystallisation from a mixture of methanol and methylene chloride, 1-[(2-phenylquinazolin-4-yl)-carbonyl]-piperidin-4-ol (2.1 g), melting at 209° C., is obtained.
Reaction SMILES: [N:1]1[N:2]=[N:3][N:4]2[CH:9]=[C:8]([C@@H:10]3[CH2:12][O:11]3)[CH:7]=[CH:6][C:5]=12.[CH3:13][C:14]1([CH3:19])[CH2:17][CH:16]([NH2:18])[CH2:15]1>C(O)C>[CH3:13][C:14]1([CH3:19])[CH2:17][CH:16]([NH:18][CH2:12][C@@H:10]([C:8]2[CH:7]=[CH:6][C:5]3[N:4]([N:3]=[N:2][N:1]=3)[CH:9]=2)[OH:11])[CH2:15]1
Reactant: c1cc2nnnn2cc1[C@@H]1CO1
Reactant: CC1(C)CC(N)C1
Solvent: CCO
Product: CC1(C)CC(NC[C@H](O)c2ccc3nnnn3c2)C1
Yield: 104 %

Procedure:
A solution of (R)-2-(tetrazolo[1,5-a]pyrid-6-yl)oxirane (375 mg, 2.31 mmol) and (3,3-dimethylcyclobutyl)amine (1.14 g, 11.5 mmol) in 0.8 ml of absolute ethanol was heated at 70° C. in a sealed reaction vessel for 3 hours. The reaction mixture was concentrated and the residue was purified by preparative Tlc on silica gel (90:10:1 methylene chloride:methanol:NH4OH) to give 628 mg of product; Analysis: Calc'd. for C13H19N5O:
Reaction SMILES: [OH-].[K+].[CH2:3]([S:5][C:6]1[NH:11][C:10](=[O:12])[C:9]([CH2:13][CH2:14][OH:15])=[C:8]([CH3:16])[N:7]=1)[CH3:4].I[CH3:18].O>CS(C)=O>[CH2:3]([S:5][C:6]1[N:11]([CH3:18])[C:10](=[O:12])[C:9]([CH2:13][CH2:14][OH:15])=[C:8]([CH3:16])[N:7]=1)[CH3:4]
Reactant: CI
Reactant: CCSc1nc(C)c(CCO)c(=O)[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCSc1nc(C)c(CCO)c(=O)n1C
Temperature: 65 °C
Reaction time: 1 h
Yield: 46.7 %

Procedure:
Potassium hydroxide (8.4 g) was added to a solution of intermediate 2 (33 g) in dimethyl sulfoxide (150 ml). The mixture was stirred for 1 hour at 60-70 ° C. The mixture was cooled to 20° C. and iodomethane (21.3 g) was added dropwise. The reaction mixture was stirred overnight at RT. The mixture was poured out into water and extracted with toluene. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was crystallized from 4-methyl-2-pentanone and the precipitate was filtered off and dried, yielding 16 g (46%) of 2-(ethylthio)-5-(2-hydroxy-ethyl)-3,6-dimethyl-4(3H)-pyrimidinone (intermediate 3).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:22][C:23]([CH3:25])=O.C(Br)C=C>O>[CH2:25]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:14][CH:15]=1)[CH:23]=[CH2:22]
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C=CCBr
Product: C=CCOc1ccc(C(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
To start with, a three-necked flask was charged with commercially available 4-hydroxybenzophenone (39.6 g) and potassium carbonate (28 g), followed by argon substitution. Subsequently, dehydrated acetone (120 ml) was added, followed by well stirring, and then allyl bromide (18.6 ml) was added. Stirring was performed at 60° C. for 8 hours. After that, the mixture was cooled to a room temperature, and pure water was added, followed by stirring. Extraction with diethylether (100 ml) was performed twice. Extraction-and-washing with a 10% NaOH solution (100 ml) was performed twice, followed by drying over sodium sulfate. The solvent was removed by using an evaporator to obtain a pale yellow residue. The residue was recrystallized from methanol, followed by suction filtration, and then drying in vacuum was performed to obtain 4-allyloxybenzophenone (hereinafter referred to as ABP) which was a pure product (weight: 43.7 g, yield: 91.9%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([CH2:8][NH:9][C:10]([C@@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]1[CH2:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][OH:29])=[CH:24][CH:23]=1)(=[O:21])=[O:20])=[O:11])#[N:7].C(N(C(C)C)CC)(C)C>ClCCl>[C:6]([CH2:8][NH:9][C:10]([C@@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]1[CH2:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][O:29][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:24][CH:23]=1)(=[O:20])=[O:21])=[O:11])#[N:7]
Reactant: CS(=O)(=O)Cl
Reactant: N#CCNC(=O)[C@@H]1CCCC[C@H]1CS(=O)(=O)c1ccc(CO)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCc1ccc(S(=O)(=O)C[C@@H]2CCCC[C@H]2C(=O)NCC#N)cc1
Temperature: 5 °C
Reaction time: 8 h

Procedure:
Methanesulfonyl chloride (0.140 mL, 1.81 mmol) was added dropwise to a stirred solution of trans-N-cyanomethyl-2-(4-hydroxymethylbenzenesulfonylmethyl)-cyclohexanecarboxamide (0.576 g, 1.645 mmol) and diisopropylethylamine (0.344 mL, 1.97 mmol) in dichloromethane (5 mL) chilled to 5° C. The ice bath was removed and the reaction was allowed to proceed with stirring overnight. The reaction was not complete, so additional diisopropylethylamine (0.172 ml, 1.0 mmol) was added, followed by additional methanesulfonyl chloride (0.070 mL, 0.90 mmol). The reaction was allowed to stir an additional hour at ambient temperature. Dichloromethane (100 mL) was added and the solution was washed with water, 1N HCl, and then saturated aqueous sodium bicarbonate. The organic layer was dried with magnesium sulfate, filtered, and concentrated by rotary evaporation to yield trans-methanesulfonic acid 4-[2-(cyanomethyl-carbamoyl)-cyclohexylmethanesulfonyl]-benzyl ester as a white solid.