Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH2:11][N:10]([C:15](OC(C)(C)C)=O)[CH2:9][CH2:8]2)=[O:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH2:11][N:10]([CH3:15])[CH2:9][CH2:8]2)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)CCN(C(=O)OC(C)(C)C)C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)CCN(C)C2
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
To 3,4-dihydro(1H)isoquinoline-2,6-dicarboxylic acid 2-(tert-butyl) ester 6-methyl ester (WO00/09480) (344 mg) dissolved in methylene chloride (6 mL), under ice cooling, trifluoroacetic acid (3 mL) was added, followed by stirring for 30 minutes. The reaction mixture was concentrated, and diluted with chloroform. The resultant mixture was neutralized with saturated aqueous sodium hydrogencarbonate, followed by extracting with chloroform/methanol (4/1). The resultant organic layer was dried over sodium sulfate anhydrate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (chloroform:methanol=20:1→1:1), to thereby give 1, 2, 3, 4-tetrahydroisoquinoline-6-carboxylic acid methyl ester (154 mg). This material was dissolved in methylene chloride (5 mL), and formalin (90.6 μL) was added thereto at room temperate, followed by stirring for 10 minutes. Under ice cooling, acetic acid (46 μL) and sodium triacetoxyborohydride (269 mg) were added thereto. The mixture was stirred at room temperature for 105 minutes, and neutralized with saturated aqueous sodium hydrogencarbonate. The resultant mixture was extracted with chloroform. The organic layer was dried over sodium sulfate anhydrate, and concentrated under reduced pressure, to thereby give the title compound (162 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[S:12][C:11]([C:13]([NH2:15])=[O:14])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C1(C)C=CC(S(O[CH2:26][CH2:27][Cl:28])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:28][CH2:27][CH2:26][O:1][C:2]1[CH:3]=[C:4]([C:8]2[S:12][C:11]([C:13]([NH2:15])=[O:14])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1ccc(-c2cccc(O)c2)s1
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)c1ccc(-c2cccc(OCCCl)c2)s1

Procedure:
5-(3-Hydroxyphenyl)-2-thiophenecarboxamide (0.31 g, 1.41 mmol), 2-chloroethyl p-toluenesulfonate (1.327 g, 5.65 mmol) and potassium carbonate (0.782 g, 5.65 mmol) in 20 ml of acetonitrile were heated to reflux for 15 h. The reaction mixture was concentrated in vacuo and purified by silica gel column chromatography (50 to 80% ethyl acetate in hexanes) to give the title compound as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:10])[CH2:4][C:5]([CH3:9])([CH3:8])[CH:6]=[CH2:7].[Cl:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1.[Sn](Cl)(Cl)(Cl)Cl>C(Cl)Cl>[CH3:9][C:5]1([CH3:8])[CH:6]([CH2:7][C:16]([C:15]2[CH:19]=[CH:20][C:12]([Cl:11])=[CH:13][CH:14]=2)=[O:17])[O:2][C:3](=[O:10])[CH2:4]1
Reactant: C=CC(C)(C)CC(=O)OC
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC1(C)CC(=O)OC1CC(=O)c1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
71 g (0.5 mol) of 3,3-dimethyl-4-pentenoic acid methyl ester were added dropwise to a mixture of 87.5 g (0.5 mol) of p-chlorobenzoyl chloride and 130.3 g (0.5 mol) of tin tetrachloride at 20° C., while cooling with ice. After being left to stand overnight, the reaction mixture had solidified. It was taken up in methylene chloride, the methylene chloride mixture was filtered and the filtrate was extracted by shaking with dilute hydrochloric acid. After drying and stripping off the solvent in vacuo, 111.1 g of crude product (about 83%), which crystallized completely, were obtained. Recrystallization from 120 ml of ethanol gave 3,3-dimethyl-4-(4'-chloro-phenacyl)-γ-butyrolactone of melting point 76°-80° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[C:6](=[O:7])[N:5]([C:8]2[CH:9]=[CH:10][C:11]([O:19][C:20]([F:23])([F:22])[F:21])=[C:12]([NH:14][C:15](=[O:18])[CH2:16]Cl)[CH:13]=2)[C:4](=[O:24])[N:3]1[CH2:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[CH3:1][C:2]1([CH3:32])[C:6](=[O:7])[N:5]([C:8]2[CH:9]=[CH:10][C:11]([O:19][C:20]([F:23])([F:22])[F:21])=[C:12]([NH:14][C:15](=[O:18])[CH2:16][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[CH:13]=2)[C:4](=[O:24])[N:3]1[CH2:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1
Reactant: CC1(C)C(=O)N(c2ccc(OC(F)(F)F)c(NC(=O)CCl)c2)C(=O)N1Cc1ccncc1
Reactant: C1COCCN1
Product: CC1(C)C(=O)N(c2ccc(OC(F)(F)F)c(NC(=O)CN3CCOCC3)c2)C(=O)N1Cc1ccncc1

Procedure:
50 mg N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl-imidazolidin-1-yl)-2-trifluoromethoxy-phenyl]-2-chloro-acetamide (raw material, as described above) owere dissolved in 2 ml morpholine and heated for 1 h to 50° C. Subsequently, the mixture was poured on ice and extracted with ethylacetate. The combined organic phases were evaporated to dryness and the residue was purified by flash chromoatography (Silica gel, methylene chloride:methanol=1.98:22.95:5) Yield: 20 mg
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[CH3:20][N:21]1[CH:25]=[CH:24][N:23]=[C:22]1[C:26]([OH:30])([C:28]#[CH:29])[CH3:27]>>[F:19][C:3]1[C:2]([C:29]#[C:28][C:26]([OH:30])([C:22]2[N:21]([CH3:20])[CH:25]=[CH:24][N:23]=2)[CH3:27])=[CH:18][C:6]2[C:7]3[N:8]([CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Reactant: C#CC(C)(O)c1nccn1C
Product: Cn1ccnc1C(C)(O)C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2
Yield: 16 %

Procedure:
Similar to as described in General Procedure G 10-bromo-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 2-(1-methyl-1H-imidazol-2-yl)but-3-yn-2-ol to give the titled compound as an off-white solid (22 mg, 16%).
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:10])=[O:9].C([Li])CCC.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[C:31]2[O:35][CH2:34][O:33][C:32]=12)[CH:28]=[O:29].[Cl-].[NH4+]>O1CCCC1>[OH:29][CH:28]([C:27]1[CH:26]=[C:25]([O:24][CH3:23])[C:32]2[O:33][CH2:34][O:35][C:31]=2[CH:30]=1)[C:16]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:8]([NH:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:17])(=[O:9])=[O:10]
Reactant: Cc1ccccc1NS(=O)(=O)c1ccccc1
Reactant: COc1cc(C=O)cc2c1OCO2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc(C(O)c2ccccc2S(=O)(=O)Nc2ccccc2C)cc2c1OCO2
Temperature: -72 °C
Reaction time: 3 h

Procedure:
To tetrahydrofuran (200 mL) was added N-o-tolyl-benzenesulfonamide (4.95 g, 20 mmol). After cooling to −72° C., a solution of n-butyllithium (1.6 M, 25 mL in hexane) was added, and the mixture was stirred for 3 hours at −72° C. A solution of 3-methoxy-4,5-methylenedioxybenzaldehyde (3.60 g, 20 mmol) in tetrahydrofuran (70 mL) was added, and the mixture was stirred and warmed to 0° C. over 1.5 hours. The mixture was poured into 200-mL saturated ammonium chloride solution, and the organic phase was decanted. The solvent was evaporated in vacuo and the residue was suspended in ethyl ether, washed with saturated sodium bicarbonate and brine solutions. The solution was dried over anhydrous magnesium sulfate, filtered, and evaporated to give a syrup which was chromatographed on 500 g silica gel eluted with a mixture of ethyl acetate and hexane (35:65). The appropriate fractions were concentrated in vacuo and crystallized giving a solid, 4.15 g, 48.6%o yield, mp 155-158° C. NMR spectra and elemental analysis were consistent with the structure.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[C:7]([S:13][CH2:14][C:15](OC)=[O:16])=[N:6][CH:5]=1>C(O)(=O)C.[Fe]>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[N:6][C:7]2[S:13][CH2:14][C:15](=[O:16])[NH:10][C:8]=2[CH:9]=1)=[O:19]
Reactant: COC(=O)CSc1ncc(C(=O)OC)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: COC(=O)c1cnc2c(c1)NC(=O)CS2
Temperature: 60 °C
Yield: 108.5 %

Procedure:
The ester (a) (1.0 g) in acetic acid (50 mL) was treated with iron powder (10 g) and the mixture was stirred and heated at 60° C. for 1 hour, cooled and filtered. The filtrate was evaporated, treated with sodium bicarbonate solution and extracted with warm chloroform. It was dried (anhydrous sodium sulfate) and evaporated to give a white solid (0.85 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:12][C:13]([C:16]([OH:28])([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:17](OC)=[O:18])=[N:14][N:15]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[OH-].[Na+].[F:31][C:32]1[CH:37]=[CH:36][C:35]([C@H:38]([N:40]=[C:41]=[O:42])[CH3:39])=[CH:34][CH:33]=1>C1COCC1.C(OCC)(=O)C>[CH2:21]([C:16]1([C:13]2[NH:12][C:11]([C:5]3[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:15][N:14]=2)[O:28][C:41](=[O:42])[N:40]([C@@H:38]([C:35]2[CH:34]=[CH:33][C:32]([F:31])=[CH:37][CH:36]=2)[CH3:39])[C:17]1=[O:18])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)C(O)(Cc1ccccc1)c1nnc(-c2cc(OC)cc(OC)c2)[nH]1
Reactant: C[C@@H](N=C=O)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(OC)cc(-c2nnc(C3(Cc4ccccc4)OC(=O)N([C@H](C)c4ccc(F)cc4)C3=O)[nH]2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2-[5-(3,5-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl]-2-hydroxy-3-phenylpropanoate (7 mg) in 1 mL of THF was added NaOH (4 mg) and (R)-1-fluoro-4-(1-isocyanatoethyl)benzene (15 mg). The resulting mixture was stirred at ambient temperature overnight. The resulting mixture was diluted with ethyl acetate, and then quenched with water. The organic layer was concentrated and purified by reverse phase HPLC (YMC Pro-C18 column, gradient elution, 30% to 100% acetonitrile/water with 0.1% TFA) to give the title compound. LC/MS 517.2 (M+1). IC50 value=C rating.
Reaction SMILES: [CH:1]1([C:8]2[CH:17]=[CH:16][C:11]3[NH:12][C:13](=[O:15])[O:14][C:10]=3[CH:9]=2)[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][CH2:26][CH2:27][NH2:28].Cl>>[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][CH2:26][CH2:27][NH:28][C@H:4]1[CH2:5][CH2:6][C@H:1]([C:8]2[CH:17]=[CH:16][C:11]3[NH:12][C:13](=[O:15])[O:14][C:10]=3[CH:9]=2)[CH2:2][CH2:3]1
Reactant: NCCCc1ccccc1F
Reactant: O=C1CCC(c2ccc3[nH]c(=O)oc3c2)CC1
Agent: Cl
Product: O=c1[nH]c2ccc([C@H]3CC[C@H](NCCCc4ccccc4F)CC3)cc2o1

Procedure:
Coupling of ketone 5 and 3-(2-fluorophenyl)-1-propylamine, using the method given in Example 1, gave 6-{trans-4-[3-(2-fluorophenyl)propylamino]-cyclohexyl}-3H-benzoxazol-2-one (1.7 g, 45%) as the HCl salt: 1H NMR (500 MHz, DMSO-d6): δ 11.50 (s, 1H), 8.86 (s, 2H), 7.34 (t, J=8 Hz, 1H), 7.35-7.26 (m, 1H), 7.19-7.15 (m, 3H), 7.02-6.97 (m, 2H), 3.10-3.03 (m, 1H), 2.98-2.92 (m, 2H), 2.72 (dd, J=8, 8 Hz, 2H), 2.57-2.50 (m, 1H), 2.18-2.13 (m, 2H), 1.98-1.92 (m, 2H), 1.89-1.85 (m, 2H), 1.57-1.46 (m, 4H).
Reaction SMILES: Br[CH2:2][S:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.CC(C)([O-])C.[K+].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1>CN(C=O)C>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([S:3][CH2:2][O:24][C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=2)=[CH:5][CH:6]=1
Reactant: Clc1ccc(SCBr)cc1
Reactant: Oc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ccc(OCSc2ccc(Cl)cc2)cc1
Temperature: 25 °C

Procedure:
1-Bromomethylthio-4-chlorobenzene (20 mmol) in DMF (10 ml) was added with stirring at room temperature to a solution prepared from potassium tert-butoxide (20 mmol) and 4-chlorophenol (20 mmol) in DMF (50 ml). The resultant mixture was stirred at 80° C. for 1 h, the solvent was then distilled off, the residue triturated with water, the residual material extracted with chloroform, the dried (MgSO4) chloroform solution evaporated and the residue distilled; yield 3.65 g (64%), b.p. 135°-140° C./0.01 mmHg. 1H NMR (CDCl3): δ 5.29 (CH2), 6,6-7.4 (Ph's). MS [70 eV, m/Z (rel. int.)]; 2.84 (3,M), 159(36), 157 (100), 111 (15), 105 (13), 75 (21).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[N:5]([C:13]1[CH:18]=[C:17](Cl)[N:16]=[C:15]([NH2:20])[C:14]=1[N+:21]([O-:23])=[O:22])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].[F:25][C:26]1[CH:27]=[N:28][NH:29][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([O:3][C:4](=[O:24])[N:5]([C:13]1[CH:18]=[C:17]([N:28]2[CH:27]=[C:26]([F:25])[CH:30]=[N:29]2)[N:16]=[C:15]([NH2:20])[C:14]=1[N+:21]([O-:23])=[O:22])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2]
Reactant: Fc1cn[nH]c1
Reactant: CCOC(=O)N(Cc1ccccc1)c1cc(Cl)nc(N)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)N(Cc1ccccc1)c1cc(-n2cc(F)cn2)nc(N)c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
(2-Amino-6-chloro-3-nitro-pyridin-4-yl)-benzyl-carbamic acid ethyl ester (100mg, 0.285 mmol), 4-fluoropyrazole (24.5 mg, 0.285 mmol) and potassium carbonate (118 mg 0.855 mmol) were stirred together in 5 mL of acetonitrile, under nitrogen. Heated the reaction to reflux for 3 hours and then allowed to cool to ambient temperature over night.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1[CH2:10][C:11]([OH:13])=O.S(Cl)([Cl:16])=O>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1[CH2:10][C:11]([Cl:16])=[O:13]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1cc(Cl)cc(Cl)c1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(Cl)Cc1cc(Cl)cc(Cl)c1Cl

Procedure:
A suspension of 6.0 grams (0.023 mole) of 2,3,5-trichlorophenylacetic acid in about 125 mL of carbon tetrachloride was stirred, and 5 mL of thionyl chloride was added. The reaction mixture was then warmed to reflux, where it was stirred for about 30 minutes. After this time the reaction mixture was concentrated under reduced pressure, yielding 6.4 grams of 2,3,5-trichlorophenylacetyl chloride.
Reaction SMILES: [H-].[Na+].[CH3:3][C@@H:4]1[CH2:9][C@H:8]([OH:10])[CH2:7][CH2:6][N:5]1[C@@H:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:12].I[CH3:20].O>CN(C=O)C>[CH3:20][O:10][C@@H:8]1[CH2:7][CH2:6][N:5]([C@@H:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH3:12])[C@H:4]([CH3:3])[CH2:9]1
Reactant: CI
Reactant: C[C@@H]1C[C@H](O)CCN1[C@H](C)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CO[C@@H]1CCN([C@H](C)c2ccccc2)[C@H](C)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Sodium hydride (710 mg, 17.7 mmol; 60% dispersion in mineral oil) was added to a solution of (2R,4R)-2-methyl-1-((R)-1-phenylethyl)piperidin-4-ol (1.95 g, 8.87 mmol) in DMF (47 mL) at 0° C. After 15 min, iodomethane (666 μL, 10.7 mmol) was added and the solution was allowed to warm to room temperature. After 1 h, water was slowly added at 0° C. The aqueous phase was extracted with a 4:1 mixture of EtOAc/n-heptane (3×). The combined organic layers were washed with brine (3×), dried over anhydrous sodium sulfate, filtered, and concentrated under reduce pressure. The residue was purified via FCC (0-30% EtOAc/heptane) to give the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 7.49 (d, J=7.8 Hz, 2H), 7.35 (t, J=7.6 Hz, 2 H), 7.21-7.28 (m, 1 H), 4.33 (q, J=6.8 Hz, 1 H), 3.36 (s, 3 H), 3.11-3.22 (m, 1 H), 2.59-2.71 (m, 1 H), 2.49 (dt, J=11.9, 3.8 Hz, 1 H), 1.99-2.16 (m, 2 H), 1.85 (d, J=12.1 Hz, 1 H), 1.33-1.42 (m, 1 H), 1.28 (d, J=7.1 Hz, 4 H), 1.25 (d, J=6.3 Hz, 3 H); MS (ESI+) m/z 234.2 (M+H)+; [α]25D-49.17 (c 1.0, MeOH).
Reaction SMILES: Cl.[C:2]([O:6][CH2:7][C@@H:8]([C:10]([N:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[C:17]#[N:18])=[O:11])[NH2:9])([CH3:5])([CH3:4])[CH3:3].[C:19](=O)([O:27]C1C=CC([N+]([O-])=O)=CC=1)[O:20][CH:21]([O:23][C:24](=[O:26])[CH3:25])[CH3:22].C(N(CC)CC)C>ClCCl>[C:24]([O:23][CH:21]([O:20][C:19]([NH:9][C@H:8]([C:10]([N:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[C:17]#[N:18])=[O:11])[CH2:7][O:6][C:2]([CH3:5])([CH3:3])[CH3:4])=[O:27])[CH3:22])(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC[C@H](N)C(=O)N1CCC[C@H]1C#N
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC(C)OC(=O)N[C@@H](COC(C)(C)C)C(=O)N1CCC[C@H]1C#N
Yield: 34.5 %

Procedure:
A solution of (2S)-1-(O′-tert-butylserinyl)pyrrolidine-2-carbonitrile hydrochloride (30 mg, 0.11 mmol; prepared according to Jenkins et al., WO95/15309), α-acetoxyethyl p-nitrophenyl carbonate (32 mg, 0.12 mmol; prepared according to Alexander et al., J. Med. Chem. 31, 318, 1988) and triethylamine (20 mg, 0.20 mmol) in dichloromethane (25 ml) was stirred at room temperature for 18 hours. After this time the solvent was removed in vacuo and the residue was taken up in ethyl acetate (70 ml). This solution was washed with 0.3M KHSO4, sat. NaHCO3, water and brine, dried (Na2SO4) and evaporated. The residue was purified by flash chromatography (eluant EtOAc:Pet. Ether 60–80° C.; 4:6) yielding a white solid identified as the title compound (14 mg, 0.038 mmol, 35%).
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:42])[CH2:9][CH2:10][C@H:11]([C@@H:13]2[C@:30]3([CH3:31])[C:16]([C:17]4[CH2:18][CH2:19][C@@H:20]5[C@:25]([C:27]=4[CH2:28][CH2:29]3)([CH3:26])[CH2:24][CH2:23][C@H:22]([O:32][Si](C(C)(C)C)(C)C)[C:21]5([CH3:41])[CH3:40])=[CH:15][CH2:14]2)[CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>C(O)C>[C:1]1([NH:7][C:8](=[O:42])[CH2:9][CH2:10][C@H:11]([C@@H:13]2[C@:30]3([CH3:31])[C:16]([C:17]4[CH2:18][CH2:19][C@@H:20]5[C@:25]([C:27]=4[CH2:28][CH2:29]3)([CH3:26])[CH2:24][CH2:23][C@H:22]([OH:32])[C:21]5([CH3:41])[CH3:40])=[CH:15][CH2:14]2)[CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](CCC(=O)Nc1ccccc1)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)[C@@H]1CC3
Agent: Cl
Solvent: CCO
Product: C[C@H](CCC(=O)Nc1ccccc1)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3β-tert-Butyldimethylsilyloxy-4,4-dimethyl-5α-chola-8,14-dien-24-oic acid-N-phenyl amide (50 mg) is dissolved in 5 ml of ethanol, 0.2 ml of 6N hydrogen chloride is added and the mixture is stirred at room temperature overnight. After aqueous work-up and crystallization from methanol the title compound is obtained. (36 mg). H-NMR (CDCl3, 400 MHz): δ=7.53 (2H, d); 7.33 (2H, t); 7.18 (1H, s); 7.12 (1H, t); 5.36 (1H, s); 3.26 (1H, m). MS: Calculated: 475.7. Found: 475.4.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[OH:13].Br[C:15]#[N:16].[OH-].[Na+]>O>[NH2:16][C:15]1[O:13][C:3]2[CH:4]=[C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: N#CBr
Reactant: CC(C(=O)O)c1ccc(N)c(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C(=O)O)c1ccc2nc(N)oc2c1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To a stirred solution of 2-(4-Amino-3-hydroxy-phenyl)-propionic acid (1.02 g) in H2O was added BrCN (648 mg) at room temperature. After stirred for 40 h at room temperature, the reaction mixture was neutralized with 30% aq. NaOH to pH 6-7 and then stirred for 1 hour. The solid was filtered, washed with water and dried under reduced vacuum to afford the product as yellow solid. (760 mg, 65.5%)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[F:17])[N:3]=1.C1N2CC[N:20](CC2)[CH2:19]1.C(#N)C>[C-]#N.C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:19]#[N:20])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[F:17])[N:3]=1
Reactant: Nc1nc(Cl)nc(Nc2cccc(F)c2F)n1
Reactant: C1CN2CCN1CC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [C-]#N
Solvent: CCOC(C)=O
Solvent: CC#N
Product: N#Cc1nc(N)nc(Nc2cccc(F)c2F)n1
Reaction time: 1 h
Yield: 44.4 %

Procedure:
To 2-amino-4-chloro-6-(2,3-difluorophenylamino)-[1,3,5]triazine (Intermediate 55, 1.0 g, 3.89 mmol) was added DABCO (540 mg, 4.67 mmol), tetra n-butylammonium cyanide (1.15 g, 4.28 mmol) and anhydrous acetonitrile (15 mL). The reaction mixture was stirred at 50 C for 1 h, diluted with 50 mL ethyl acetate, extracted with 1M aq. citric acid (2×50 mL), water (2×50 mL), saturated brine (50 mL) and dried further over anhydrous sodium sulfate. Evaporation of the solvent gave a red gum which was purified by column chromatography on silica eluting with DCM-2% ethyl acetate to give the desired compound (429 mg, 69%). Method B HPLC-MS: MH+ requires m/z=249. Found: m/z=249, Rt=1.64 min (91%).
Reaction SMILES: [NH2:1][CH2:2][C:3]#[N:4].Cl.[C:6]([N:10]=[C:11]=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>O1CCCC1>[C:3]([CH2:2][NH:1][C:11]([NH:10][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:12])#[N:4]
Reactant: CC(C)(C)N=C=O
Reactant: N#CCN
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)NCC#N

Procedure:
To a stirring mixture of 18.7 g (0.2 mole) aminoacetonitrile·HCl in 300 ml. dry tetrahydrofuran under a nitrogen atmosphere, there is added 20.4 g. (0.2 mole) t-butyl isocyanate (97%), followed by 28 ml. (0.2 mole) triethylamine. The resulting mixture is heated at reflux for five hours, cooled and the tetrahydrofuran removed at reduced pressure. The solid is recrystallized from ethyl acetate to give N-cyanomethyl-N'-(1,1-dimethylethyl)urea, m.p. 128°-32° (Anal. Calcd. for C7H13N3O: C: 54.17, H: 8.44, N: 27.07; Found: C: 53.84, H: 8.33, N: 26.86.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[NH2:15])[N:11]=[CH:10][CH:9]=[N:8]2)=[O:4].[Cl:16]N1C(=O)CCC1=O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([Cl:16])[C:14]=1[NH2:15])[N:11]=[CH:10][CH:9]=[N:8]2)=[O:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1cc2nccnc2cc1N
Solvent: CN(C)C=O
Product: COC(=O)c1cc2nccnc2c(Cl)c1N
Temperature: 95 °C
Reaction time: 0.25 h
Yield: 88.7 %

Procedure:
2.07 g (10.2 mmol) 7-amino-quinoxaline-6-carboxylic acid methyl ester and 1.36 g (10.2 mmol) N-chloro-succinimide is suspended in 5 ml DMF and heated at a temperature of 95° C. during 30 min. After cooling, the mixture is poured into 150 ml ice water. The mixture is stirred 15 min and filtered. The compound is dried and crystallised in hexane to give 2.15 g (88%) of the title compound. m.p.: 182-184° C.
Reaction SMILES: [CH:1]([C:3]1[C:8]([CH:9]([N:13]([CH3:23])[C:14](=[O:22])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:10]([CH3:12])[CH3:11])=[CH:7][N:6]=[CH:5][N:4]=1)=O.Cl.[NH2:25][OH:26].C([O-])(=O)C.[K+].O>CO>[OH:26][N:25]=[CH:1][C:3]1[C:8]([CH:9]([N:13]([CH3:23])[C:14](=[O:22])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:10]([CH3:12])[CH3:11])=[CH:7][N:6]=[CH:5][N:4]=1
Reactant: CC(C)C(c1cncnc1C=O)N(C)C(=O)Cc1ccccc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)C(c1cncnc1C=NO)N(C)C(=O)Cc1ccccc1
Yield: 43.1 %

Procedure:
1.0 g (3.2 mmol) of N-(1-(4-formylpyrimidin-5-yl)-2-methylpropyl]-N-methylphenylacetamide was dissolved in 30 ml of methanol, and 0.45 g (6.5 mmol) of hydroxylamine hydrochloride and 0.63 g (6.4 mmol) of potassium acetate were added and reacted at room temperature for 1 hour. After completion of the reaction, the product was poured into water and extracted with ethyl acetate. The organic layer was washed with an aqueous sodium hydrogencarbonate solution, an aqueous citric acid solution, water and an aqueous sodium chloride solution, in this order, dried and concentrated, and the obtained oily product was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:1 to ethyl acetate) to obtain 0.45 g (yield: 43%) of N-[1-(4-hydroxyiminomethylpyrimidin-5-yl)-2-methylpropyl]-N-methylphenylacetamide as colorless crystals (melting point: 171-172° C.).