Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[NH:12][CH2:13][C:14]([OH:16])=O.[CH2:19]([O:21][C@@H:22]1[CH2:26][N:25]([CH:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH2:24][C@H:23]1[NH:33]C(=O)CC1C(C(F)(F)F)=CC=CC=1C(N)=O)[CH3:20].F[C:51](F)(F)C1C=C(C=CC=1)C(NCC(O)=O)=O.C(Br)C=C.BrCC>>[CH2:19]([O:21][C@@H:22]1[CH2:26][N:25]([CH:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH2:24][C@H:23]1[NH:33][C:14](=[O:16])[CH2:13][NH:12][C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([C:2]([F:1])([F:18])[F:17])[CH:4]=2)[NH:8][N:7]=1)[CH:20]=[CH2:51]
Reactant: O=C(O)CNC(=O)c1cccc(C(F)(F)F)c1
Reactant: O=C(O)CNc1n[nH]c2ccc(C(F)(F)F)cc12
Reactant: CCO[C@@H]1CN(C2CCOCC2)C[C@H]1NC(=O)Cc1c(C(N)=O)cccc1C(F)(F)F
Solvent: C=CCBr
Solvent: CCBr
Product: C=CCO[C@@H]1CN(C2CCOCC2)C[C@H]1NC(=O)CNc1n[nH]c2ccc(C(F)(F)F)cc12

Procedure:
The title compound was synthesized in similar fashion to rel-N-(2-{([(3R,4R)-4-ethoxy-1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide {[5-(trifluoromethyl)-1H-indazol-3-yl]amino}acetic acid was substituted for {[3-(trifluoromethyl)benzoyl]amino}acetic acid, and allyl bromide was substituted for bromoethane, and was isolated as a white solid. 1H-NMR (DMSO-d6) δ: 1.18-1.35 (m, 2H), 1.60-1.70 (m, 2H), 2.06-2.16 (m, 1H), 2.23-2.31 (m, 1H), 2.38-2.44 (m, 1H), 2.74-2.84 (m, 2H), 3.18-3.28 (m, 2H), 3.72-3.87 (m, 6H), 3.92-4.08 (m, 2H), 5.02-5.19 (m, 2H), 5.73-5.87 (m, 1H), 6.70 (t, 1H), 7.39 (d, 1H), 7.48 (dd, 1H), 8.03 (d, 1H), 8.26 (s, 1H), 11.9 (s, 1H). MS m/z: 468 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[C:11]([CH2:14][C:15](=O)[CH3:16])(=[O:13])[CH3:12].[NH2:18][C:19]([NH2:21])=[S:20]>C(O)C.Cl>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]2[C:14]([C:11](=[O:13])[CH3:12])=[C:15]([CH3:16])[NH:21][C:19](=[S:20])[NH:18]2)=[CH:5][CH:4]=1
Reactant: CC(=O)CC(C)=O
Reactant: COc1ccc(C=O)cc1
Reactant: NC(N)=S
Agent: Cl
Solvent: CCO
Product: COc1ccc(C2NC(=S)NC(C)=C2C(C)=O)cc1
Reaction time: 4 h
Yield: 22.4 %

Procedure:
A solution of 12.1 ml (0.1 mol) of 4-methoxybenzaldehyde, 10.3 ml (0.1 mol) of acetylacetone and 9.13 g (0.12 mol) of thiourea in 30 ml of ethanol was treated with 10 drops of conc. hydrochloric acid and boiled under reflux while stirring for 4 h. The reaction mixture was concentrated and the residue was purified by column chromatography on silica gel (dichloromethane-methanol 98:2). Subsequent crystallization from ethanol gave 6.2 g (22%) of (RS)-1-[4-(4-methoxyphenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl]ethanone as a red-brown solid with m.p. 175° C.
Reaction SMILES: N#N.[N+:3]([C:6]1[CH:7]=[N:8][N:9]([CH2:11][C:12]2[O:16][N:15]=[C:14]([C:17](=[O:19])[CH3:18])[CH:13]=2)[CH:10]=1)([O-:5])=[O:4].[CH2:20](O)[CH2:21][OH:22].COC(OC)OC>C([O-])(O)=O.[Na+]>[CH3:18][C:17]1([C:14]2[CH:13]=[C:12]([CH2:11][N:9]3[CH:10]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=[N:8]3)[O:16][N:15]=2)[O:22][CH2:21][CH2:20][O:19]1
Reactant: OCCO
Reactant: CC(=O)c1cc(Cn2cc([N+](=O)[O-])cn2)on1
Agent: N#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COC(OC)OC
Product: CC1(c2cc(Cn3cc([N+](=O)[O-])cn3)on2)OCCO1
Temperature: 95 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and a Dean-Stark apparatus under inert atmosphere (N2), a solution of 1-[5-(4-nitro-pyrazol-1-ylmethyl)-isoxazol-3-yl]-ethanone (336 mg, 1.42 mmol) in ethylene glycol (1.59 mL, 28.45 mmol) was treated with trimethylorthoformate (0.31 mL, 2.84 mmol) followed by LiBF4 (27 mg, 0.29 mmol). The reaction mixture was heated at 95° C. overnight. Sat. aq. NaHCO3 (10 mL) was added and the mixture was extracted with EA (10 mL). The org. extracts were washed with brine (2×20 mL), dried over MgSO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (20:10 hept-EA) gave the title compound as a yellow oil. TLC: rf (20:10 hept-EA)=0.19. LC-MS-conditions 02: tR=0.86 min.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[C:10]([N:12]1[C@@H:19]([C:20]#[CH:21])[CH2:18][CH2:17][C@H:13]1[C:14]([OH:16])=O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:28]1CCOCC1.C(OC(Cl)=O)C(C)C.O1CCOCC1.OS([O-])(=O)=O.[K+]>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[C:10]([N:12]1[C@@H:19]([C:20]#[CH:21])[CH2:18][CH2:17][C@H:13]1[C:14]([NH2:28])=[O:16])=[O:11])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: C#C[C@H]1CC[C@@H](C(=O)O)N1C(=O)[C@@H](NC(=O)OC(C)(C)C)C1CCCC1
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: O
Product: C#C[C@H]1CC[C@@H](C(N)=O)N1C(=O)[C@@H](NC(=O)OC(C)(C)C)C1CCCC1
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (5R)-1-{(2S)-2-((tert-butoxycarbonyl)amino)-2-cyclopentylethanoyl}-5-ethynyl-L-proline (1.28 g, 3.38 mmol) in THF (25 mL) at −15° C. under nitrogen, was added 4-methylmorpholine (0.44 mL, 4.05 mmol), and isobutylchloroformate (0.5 mL, 3.72 mmol) over 2 minutes. The reaction mixture was stirred at −15° C. under nitrogen for 30 minutes, and a solution of 0.5 MNH3 in dioxane (34 mL, 16.90 mmol) was added. The reaction mixture diluted with water, the pH adjusted to 4 by the addition of 4% KHSO4 and extracted with ethyl acetate (3×). The combined extracts were washed with brine, dried (Na2SO4), filtered and evaporated. The residue was purified by flash column chromatography (5% MeOH/CH2Cl2) to provide the titled compound. MS (CI) m/e 364 (M+H)+.
Reaction SMILES: [CH3:1][C@:2]12[C:8]([CH3:10])([CH3:9])[C@H:5]([CH2:6][CH2:7]1)[C:4](=O)[C:3]2=O.COP([CH2:19][C:20]([CH:22]1[CH2:24][CH2:23]1)=O)(=O)OC.O.[NH2:26][NH2:27]>>[CH:22]1([C:20]2[N:26]=[N:27][C:3]3[C@@:2]4([CH3:1])[C:8]([CH3:10])([CH3:9])[C@@H:5]([C:4]=3[CH:19]=2)[CH2:6][CH2:7]4)[CH2:24][CH2:23]1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)C(=O)C2=O
Reactant: COP(=O)(CC(=O)C1CC1)OC
Reactant: NN
Solvent: O
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1nnc(C3CC3)cc12

Procedure:
colorless oil. MS (EI): 228.3 (M+). Prepared from (1R,4S)-1,7,7-trimethyl-bicyclo[2.2.1]heptane-2,3-dione, (2-Cyclopropyl-2-oxo-ethyl)-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9](Cl)(=[O:11])=[O:10].[NH2:14][CH2:15][CH2:16][OH:17].C(O)(=O)C>N1C=CC=CC=1>[C:1]1([CH3:13])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9]([OH:17])(=[O:11])=[O:10].[OH:17][CH2:16][CH2:15][NH:14][S:9]([C:2]1[C:3]([CH3:8])=[CH:4][C:5]([CH3:7])=[CH:6][C:1]=1[CH3:13])(=[O:11])=[O:10]
Reactant: NCCO
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: Cc1cc(C)c(S(=O)(=O)NCCO)c(C)c1
Product: Cc1cc(C)c(S(=O)(=O)O)c(C)c1
Yield: 171.3 %

Procedure:
84 g (0.4 mole) mesitylenesulphonyl chloride in 50 ml pyridine were added dropwise to a mixture of 12.2 g (0.2 mole) 2-aminoethanol and 20 ml pyridine at 0 ± 5° C. The reaction mixture was stored in a cooler (4° C.) overnight and then poured on ice. 30 ml acetic acid were added. The crystalline product was collected, washed with water and dried, giving 76 g of pale-yellow crystals of the title compound, m.p. 94° C.
Reaction SMILES: C(OC([N:8]1[C:19]2[C:11](=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]([C:20]([O:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)=[O:21])[CH2:13]3)[CH:10]=[CH:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[CH:10]1[C:11]2=[C:12]3[C:16](=[CH:17][CH:18]=[C:19]2[NH:8][CH:9]=1)[NH:15][CH:14]([C:20]([O:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=[O:21])[CH2:13]3
Reactant: CC(C)(C)OC(=O)n1ccc2c3c(ccc21)NC(C(=O)OCCc1ccc([N+](=O)[O-])cc1)C3
Solvent: O=C(O)C(F)(F)F
Product: O=C(OCCc1ccc([N+](=O)[O-])cc1)C1Cc2c(ccc3[nH]ccc23)N1

Procedure:
Two grams (4.43 mmol) of 14 are weighed into a round bottomed flask. Then, in a fume hood, 25 mL (325 mmol) of trifluroacetic acid is added, and the flask is capped and stirred. The solid dissolves in about a minute. The mixture is stirred for 1 hour, at which time deprotection will be done (HPLC can be used as a check). The acid is evaporated on a rotary evaporator (use a trap) and the product is dissolved in 100 mL of methylene chloride. This is extracted twice with 100 mL of half to ⅔ saturated sodium bicarbonate solution. The aqueous layers are back-extracted once with ˜50 mL of methylene chloride and this is combined with the rest. The organic layer is dried over sodium sulfate twice and evaporated to give a brown solid. If desired, this material can be recrystallized by diluting a very concentrated solution in methylene chloride with methanol and cooling. Yields approaching 100% are usually obtained. mp 192-194° C. 1H NMR (DMSO-d6) δ: 11.51 (s, 1H), 8.18 (d, J=8.5 Hz, 2H), 7.63 (d, J=8.5 Hz, 2H), 7.11 (d, J=8.5 1H), 6.80 (s, 1H), 6.70 (d, J=8.5 Hz), 5.03 (br s, 1H), 4.54 (t, J=6.4 Hz, 2H), 3.46 (t, J=8.6 Hz, 2H), 3.19 (m, 2H), 3.04 (t, J=8.6 Hz, 2H). Combustion Analysis: Calculated for C19H17N3O4: C,64.94%; H, 4.88%; N, 11.96%. Found: C, 65.50%; H, 4.70%; N, 11.64%
Reaction SMILES: [CH3:1][CH:2]([CH3:20])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:12][CH:13]=1)=[O:7].[Cl:21][C:22]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:23]=1[C:24](O)=[O:25].N12CCCN=C1CCCCC2.CN(C)CCCN=C=NCC>CN(C=O)C.CCOC(C)=O>[CH3:1][CH:2]([CH3:20])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:24](=[O:25])[C:23]3[CH:27]=[C:28]([Cl:31])[CH:29]=[CH:30][C:22]=3[Cl:21])[CH2:16][CH2:15]2)=[CH:12][CH:13]=1)=[O:7]
Reactant: O=C(O)c1cc(Cl)ccc1Cl
Reactant: CC(C)CCNC(=O)c1ccc(N2CCNCC2)nn1
Agent: CCN=C=NCCCN(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)CCNC(=O)c1ccc(N2CCN(C(=O)c3cc(Cl)ccc3Cl)CC2)nn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.8 %

Procedure:
A mixture of 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl)amide (0.255 mmol), 2,5-dichlorobenzoic acid (0.31 mmol), 1,8-diazabicylco[5.4.0]undec-7-ene (0.51 mmol) and 1-hydroxybenozotriazole hydrate (0.31 mmol) in DMF (2 mL) was stirred at ambient temperature for 15 min. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (0.31 mmol) was then added. The mixture was stirred at ambient temperature overnight, and then diluted with EtOAc (50 mL) and washed with aqueous saturated NaHCO3 (2×20 mL) and brine (2×20 mL). The organic extract was dried over anhydrous Na2SO4, concentrated, and purified by flash chromatography to give the title compound as a white solid (102 mg, 89% yield). 1H NMR (500 MHz, CDCl3) δ 8.07, 7.85, 7.32-7.40, 7.01, 4.01-4.08, 3.77-3.93, 3.35-3.55, 1.65-1.75, 1.52, 0.94. MS (ES+) m/z 450 (M).
Reaction SMILES: CS[C:3]1[S:4][C:5](=[CH:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][N:14]=[CH:13]3)[C:6](=[O:8])[N:7]=1.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][NH2:26].C(N(C(C)C)CC)(C)C>C(#N)C>[N:16]1[C:17]2[C:12](=[CH:11][C:10](/[CH:9]=[C:5]3/[C:6](=[O:8])[N:7]=[C:3]([NH:26][CH2:25][C:21]4[S:20][CH:24]=[CH:23][CH:22]=4)[S:4]/3)=[CH:19][CH:18]=2)[CH:13]=[N:14][CH:15]=1
Reactant: CSC1=NC(=O)C(=Cc2ccc3ncncc3c2)S1
Reactant: NCc1cccs1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C1N=C(NCc2cccs2)S/C1=C\c1ccc2ncncc2c1
Temperature: 145 °C

Procedure:
The suspension of 2-methylsulfanyl-5-quinazolin-6-ylmethylene-thiazol-4-one (example 1c, 58 mg, 0.2 mmol), thiophene methyl amine (45.3 mg, 0.4 mmol) and diisopropylethylamine (DIEA) (70 uL, 0.4 mmol) in acetonitrile (1 mL) was heated to 145° C. by microwave for 20 min. After cooling to room temperature, the solid was collected by filtration, washed with a small amount of acetonitrile and dried. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 0%-5% methanol in methylene chloride in 30 min) afforded 5-[1-quinazolin-6-yl-meth-(Z)-ylidene]-2-[(thiophen-2-ylmethyl)-amino]-thiazol-4-one as a light yellow solid: LC-MS m/e 353 (MH+).
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:12]/[C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)/[C:5](=[O:11])[NH:6]2.C([O-])([O-])=O.[Na+].[Na+].[Cl:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>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.COCCOC>[Cl:24][C:25]1[CH:30]=[C:29]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2/[C:4](=[CH:12]/[C:13]2[NH:14][CH:15]=[CH:16][CH:17]=2)/[C:5](=[O:11])[NH:6]3)[CH:28]=[CH:27][CH:26]=1
Reactant: O=C1Nc2cccc(I)c2/C1=C/c1ccc[nH]1
Reactant: OB(O)c1cccc(Cl)c1
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: COCCOC
Product: O=C1Nc2cccc(-c3cccc(Cl)c3)c2/C1=C/c1ccc[nH]1
Temperature: 25 °C
Yield: 91.1 %

Procedure:
A solution of (Z)-1,3-dihydro-4-iodo-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (30 mg, 0.089 mmol) (Starting Material 1), 2M aqueous Na2CO3 solution (89 μL , 0.178 mmol), (Ph3P)4Pd (5 mg, 0.004 mmol) (Aldrich), and 3-chlorophenylboronic acid (16 mg, 0.102 mmol) (Aldrich) in 3 mL of a 2:1 mixture of 1,2-dimethoxyethane:distilled water was heated at reflux under a nitrogen atmosphere for 16 h. The reaction mixture was allowed to cool to room temperature and then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 25% ethyl acetate-hexanes elution) to provide pure (Z)-4-(3-chlorophenyl)-1,3-dihydro-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (26 mg, 90%) as a yellow solid (mp 165-167° C.).
Reaction SMILES: Br.Br[CH2:3][C:4]1[N:8]([CH3:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]=1.[CH3:14][C:15]1[N:20]=[C:19]([SH:21])[N:18]=[C:17]([OH:22])[CH:16]=1.C(N(CC)CC)C>C(O)C>[CH3:14][C:15]1[N:20]=[C:19]([S:21][CH2:3][C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=3[N:5]=2)[N:18]=[C:17]([OH:22])[CH:16]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: Cn1c(CBr)nc2ccccc21
Agent: Br
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(O)nc(SCc2nc3ccccc3n2C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
A mixture of 2-(bromomethyl)-1-methyl-benzimidazole hydrobromide (6.8 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (740 mg, 5.2 mmol), and triethylamine (4 mL, 28.7 mmol) in absolute ethanol (30 mL) was stirred at room temperature overnight. The mixture was recovered, evaporated, and then co-evaporated with EtOAc (20 mL). The solid residue was treated with water (200 mL). The solid product was recovered by filtration, washed with water (2×20 mL), diethyl ether (2×20 mL), and hexanes (2×20 mL), and then dried in vacuo, affording 6-methyl-2-{[(1-methyl-1H-benzimidazol-2-yl)methyl]sulfanyl}pyrimidin-4-ol (1.3 g, 90% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.18 (s, 3H), 3.83 (s, 3H), 4.70 (s, 2H), 6.02 (s, 1H), 7.19 (m, 2H), 7.53 (m, 2H); M+ 287. The product was used without further purification.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:11][C:12]#[N:13])[CH:7]=[CH:8][C:9]=1[Cl:10].Cl/[CH:15]=[CH:16]\[CH2:17][CH2:18]Cl.O>CS(C)=O>[Cl:3][C:4]1[CH:5]=[C:6]([C:11]2([C:12]#[N:13])[CH2:18][CH:17]=[CH:16][CH2:15]2)[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Reactant: Cl/C=C\CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CC1(c2ccc(Cl)c(Cl)c2)CC=CC1
Temperature: 25 °C
Yield: 43 %

Procedure:
To ice-cold DMSO (100 mL) was added 60% NaH (1.0 g, 2.3 eq) in portions. The cooling bath was removed and the solution was stirred at ambient temperature for ten minutes. A solution of 2-(3,4-dichlorophenyl)acetonitrile (2.0 g, 10.75 mmol) in DMSO (50 mL) was added. The brown solution was stirred for 15 minutes before cis-1,4-dichlorobutene (1.0 mL, 0.9 eq) was added. The reaction mixture was stirred overnight and was then poured into water. The product was extracted with DCM. The organic layer was washed with brine, evaporated, diluted with 50% ethyl acetate in hexanes, washed with water, and evaporated. The residual oil was separated on silica to give the nitrile (966 mg, 43%) as a pale-brown oil. GCMS Rt=10.8 min m/z=237 (M+). 1H NMR (CDCl3, δ): 7.51 (d, J=2.3 Hz, 1H), 7.39 (d, J=8.5 Hz, 1H), 7.28 (dd, J=2.3, 8.5 Hz, 1H), 5.79 (s, 2H), 3.27 (d, J=14.7 Hz, 2H), 2.87 (d, J=14.7 Hz, 2H). 13C NMR (CDCl3, δ): 141.9, 133.2, 132.1, 131.0, 128.5, 127.6, 125.0, 124.0, 48.4.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](O)=[N:6][CH:7]=1.P(Cl)(Cl)([Cl:14])=O.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([Cl:14])=[N:6][CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cc(Br)cnc1O
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc(Br)cnc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In DMF (40 mL) was stirred 5-bromo-3-nitro-2-pyridinol (8.76 g, 40 mmol) and the solution treated dropwise with phosphorus oxychloride (28 mL). The solution warmed to 80° for 5 hours. The mixture was cooled to room temperature and carefully poured into a mixture of ice and water (400 mL). This mixture was stirred overnight to precipitate. The solid was collected by filtration, washed with water (2×100 mL) and dried at 65° C. on the high vacuum line for 3 hours to give the title compound. MS: M+−1=237.9 Da.
Reaction SMILES: [CH3:1][C@@:2]12[C:10](=[O:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH:13]=[C:14]3[CH2:19][C@@H:18]([OH:20])[CH2:17][CH2:16][C@:15]3([CH3:21])[C@H:5]1[CH2:4][CH2:3]2.[C:22]([O:26]O)(C)(C)[CH3:23].Cl[O-:29].[Ca+2].Cl[O-]>ClCCCl>[C:22]([O:20][C@H:18]1[CH2:17][CH2:16][C@@:15]2([CH3:21])[C:14](=[CH:13][C:12](=[O:29])[C@@H:6]3[C@@H:5]2[CH2:4][CH2:3][C@@:2]2([CH3:1])[C@H:7]3[CH2:8][CH2:9][C:10]2=[O:11])[CH2:19]1)(=[O:26])[CH3:23]
Reactant: CC(C)(C)OO
Reactant: [O-]Cl
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [Ca+2]
Solvent: ClCCCl
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC(=O)[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Temperature: 25 °C

Procedure:
DHEA-Ac (2, 1.1 gm., 0.0033 mol.) was dissolved in a mixture of 1,2-dichloroethane (10 ml) and tert-butyl hydroperoxide (70% aqueous solution from Aldrich, 3.0 ml, 0.023 mol). The mixture was stirred at room temperature and solid calcium hypochlorite (0.65 gm.) was added in very small portions over a period of seven hours. The aqueous layer was then separated and the organic layer was stirred with sodium sulfite solution (3.0 gm in 10 ml of water) for 3 hours at 40-45° C. and filtered over a small bed of celite. The aqueous yellow layer was removed and the organic layer was washed with half saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated on a rotary evaporator. The crude product was crystallized from methanol, afforded 3β-acetoxyandrost-5-en-7,17-dione (3) as a white solid, weight 0.38 gm.
Reaction SMILES: [F:1][C:2]([F:15])([C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1)[C:3]([F:6])([F:5])[F:4].C[CH:17]([C@@H:21]1[CH2:26][CH2:25][NH:24][C@H:23]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[CH2:22]1)[C:18]([O-:20])=[O:19].[CH3:37][C:38]([C:40]#[CH:41])=[CH2:39]>>[CH3:39][C:38](=[CH2:37])[C:40]#[C:41][C@@H:11]([N:24]1[CH2:25][CH2:26][C@@H:21]([CH2:17][C:18]([OH:20])=[O:19])[CH2:22][C@H:23]1[C:27]1[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:32]=1)[C:10]1[CH:13]=[CH:14][C:7]([C:2]([F:15])([F:1])[C:3]([F:6])([F:5])[F:4])=[CH:8][CH:9]=1
Reactant: O=Cc1ccc(C(F)(F)C(F)(F)F)cc1
Reactant: CC(C(=O)[O-])[C@@H]1CCN[C@H](c2ccc(C(F)(F)F)cc2)C1
Reactant: C#CC(=C)C
Product: C=C(C)C#C[C@H](c1ccc(C(F)(F)C(F)(F)F)cc1)N1CC[C@@H](CC(=O)O)C[C@H]1c1ccc(C(F)(F)F)cc1

Procedure:
The title compound was prepared from the aldehyde from Step 2, methyl{(2S,4R)-2-[4-(trifluoromethyl)phenyl]piperidin-4-yl}acetate (Example 114, Step 1) and 2-methylbut-1-en-3-yne as described in Example 116. M/Z (ES+) 560 (MH+). 1H NMR (400 MHz, CDCl3): δ 1.33 (1H, dq, J 5.2, 13.4), 1.46 (1H, q, J 11.9), 1.75 (1H, d, J 10.6), 1.94 (1H, d, J 13.4), 1.98-2.05 (4H, m), 2.23-2.36 (2H, m), 2.43-2.54 (2H, m), 3.69 (1H, dd, J 2.6, 11.1), 4.60 (1H, s), 5.32 (1H, quintet, J 1.6), 5.4 (1H, s), 7.54 (2H, d, J 8.2), 7.62 (4H, br s), 7.67 (2H, d, J 8.2).
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:7][CH:6]=[C:5]([C:8]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:9])[CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[CH3:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1O>C1COCC1>[N:10]1([C:8]([C:5]2[CH:4]=[C:3]([CH2:2][O:1][C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=3[CH3:47])[S:7][CH:6]=2)=[O:9])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: Cc1ccccc1O
Reactant: O=C(c1csc(CO)c1)N1CCCCC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccccc1OCc1cc(C(=O)N2CCCCC2)cs1
Reaction time: 8 h
Yield: 21.1 %

Procedure:
(5-Hydroxymethyl-thiophen-3-yl)-piperidin-1-yl-nnethanone (0.068 g, 0.3 mmol) was dissolved in THF (5 mL). Triphenylphosphine (0.3 mmol), diethylazodicarboxylate (0.3 mmol) and 2-methyl-phenol (0.3 mmol) were added and the reaction stirred overnight. The reaction was quenched with saturated aqueous ammonium chloride and the solvent was reduced under vacuum. The residue was partitioned between DCM and water and the organic solution separated, dried over magnesium sulphate, filtered and the solvent evaporated. The product was purified by HPLC, eluting with acetonitrile in water (0.1% formic acid). The fractions containing the desired product were concentrated under vacuum to give the title compound (20 mg). LCMS m/z 316.20 [M+H]+RT=11.75 min (Analytical Method 1). 1H NMR (400 MHz, CHCl3-d): δ 7.45 (s, 1H), 7.2-7.1 (m, 3H), 6.9 (m, 2H), 5.2 (s, 2H), 3.6 (m, 4H), 2.25 (s, 3H), 1.7-1.6 (m, 6H).
Reaction SMILES: C(N(CC)CC)C.[C:8]1([S:18]([NH:21][C@@H:22]([CH2:28][NH2:29])[C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:20])=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1.[Cl:30][C:31]1[C:36]([N+:37]([O-:39])=[O:38])=[C:35](Cl)[N:34]=[CH:33][N:32]=1.C1COCC1>CC(=O)OCC>[Cl:30][C:31]1[N:32]=[CH:33][N:34]=[C:35]([NH:29][CH2:28][C@H:22]([NH:21][S:18]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)(=[O:20])=[O:19])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:36]=1[N+:37]([O-:39])=[O:38]
Reactant: CCOC(=O)[C@H](CN)NS(=O)(=O)c1cccc2ccccc12
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](CNc1ncnc(Cl)c1[N+](=O)[O-])NS(=O)(=O)c1cccc2ccccc12
Temperature: -5 °C
Reaction time: 0.25 h

Procedure:
2.96 g (29.3 mmol) of triethylamine were added dropwise at −10° C. in the course of 5 minutes to 5.0 g (13.9 mmol) of ethyl (2S)-2-(naphthalene-1-sulfonylamino)-3-aminopropionate (EP 1070707 (EP 99114372.8)) and 2.84 g (14.6 mmol) of 4,6-dichloro-5-nitropyrimidine, dissolved in 140 ml of abs. THF. The mixture was stirred at −5° C. for 15 minutes and then at room temperature for 12 h. The reaction mixture was taken up in EA and extracted with a saturated aqueous NaCl solution, the organic phase was dried over MgSO4 and filtered, and the solvent was distilled off in vacuo. For purification, the residue was chromatographed over silica gel (EA/heptane 3:7). Yield: 6.38 g.