Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]1(/[CH:25]=[CH:26]/[C:27](O)=[O:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:27](=[O:28])/[CH:26]=[CH:25]/[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)/C=C/c1ccccc1
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)/C=C/c3ccccc3)cn2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-phenyl-acrylic acid.
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[C:20]([NH2:22])=[O:21])[CH2:14][CH2:13]2)=[CH:4]1.[F:29][C:30]([F:43])([F:42])[C:31]1[CH:32]=[C:33]([CH:39]=[CH:40][CH:41]=1)/[CH:34]=[CH:35]/[C:36](O)=[O:37]>>[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([CH:23]3[CH2:24][CH2:25][N:26]([C:36](=[O:37])/[CH:35]=[CH:34]/[C:33]4[CH:39]=[CH:40][CH:41]=[C:31]([C:30]([F:42])([F:43])[F:29])[CH:32]=4)[CH2:27][CH2:28]3)[C:20]([NH2:22])=[O:21])[CH2:14][CH2:13]2)=[CH:4]1
Reactant: O=C(O)/C=C/c1cccc(C(F)(F)F)c1
Reactant: NC(=O)C(NC1CCC(c2c[nH]c3ccccc23)CC1)C1CCNCC1
Agent: Cl
Product: NC(=O)C(NC1CCC(c2c[nH]c3ccccc23)CC1)C1CCN(C(=O)/C=C/c2cccc(C(F)(F)F)c2)CC1

Procedure:
The title compound was prepared from the product of Example 1, step J (142 mg, 0.333 mmol), and trans-3-(trifluoromethyl)-cinnamic acid, by the method of Example 1, step K, giving a gold solid that was mostly the more polar cyclohexyl diastereomer by LCMS. Mass spectrum (LCMS, ESI pos.) calcd. for C31H35F3N4O2: 553 (M+H). Found: 553.2.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]([NH2:14])=[O:13])=[N:4][C:5](S(C)(=O)=O)=[N:6][CH:7]=1.[CH3:15][C@H:16]1[CH2:24][C:23]2[C:18](=[CH:19][C:20]([CH3:25])=[CH:21][CH:22]=2)[C@@H:17]1[NH2:26].C(N(CC)CC)C>CN(C)C(=O)C>[Cl:1][C:2]1[C:3]([C:12]([NH2:14])=[O:13])=[N:4][C:5]([NH:26][C@H:17]2[C:18]3[C:23](=[CH:22][CH:21]=[C:20]([CH3:25])[CH:19]=3)[CH2:24][C@@H:16]2[CH3:15])=[N:6][CH:7]=1
Reactant: Cc1ccc2c(c1)[C@H](N)[C@@H](C)C2
Reactant: CS(=O)(=O)c1ncc(Cl)c(C(N)=O)n1
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: Cc1ccc2c(c1)[C@H](Nc1ncc(Cl)c(C(N)=O)n1)[C@@H](C)C2
Yield: 17.4 %

Procedure:
0.30 g (1.27 mmol) of 5-chloro-2-(methylsulfonyl)pyrimidine-4-carboxamide, 0.25 g (1.53 mmol) of (1R,2S)-2,6-dimethyl-2,3-dihydro-1H-indene-1-amine and 0.28 g (2.54 mmol) of triethylamine in 1.5 ml of N,N-dimethylacetamide are heated in a closed cuvette in the microwave at 120° C. for 45 minutes (Biotage Initiator, http://www.biotage.com/DynPage.aspx?id=22001). The crude mixture obtained in this manner is applied to silica gel and purified by column chromatography using the mobile phase heptane/ethyl acetate. Concentration gives initially 0.07 g of 5-chloro-2-{[(1R,2S)-2,6-dimethyl-2,3-dihydro-1H-inden-1-yl]amino}pyrimidine-4-carboxamide (wax-like) and then 0.252 g of 5-{[(1R,2S)-2,6-dimethyl-2,3-dihydro-1H-inden-1-yl]amino}-2-(methylsulfonyl)pyrimidine-4-carboxamide (yield 52% at a purity of 95%).
Reaction SMILES: Cl.[C:2]1([C:8]([C:10]2[CH:11]=[N:12][C:13]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[N:14][CH:15]=2)=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:23]1[N:28]=[CH:27][N:26]=[C:25]([NH:29][C:30]2[CH:31]=[N:32][N:33]([CH2:35][C@H:36]3[O:41][CH2:40][CH2:39][N:38]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:37]3)[CH:34]=2)[N:24]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[C:8]([C:10]1[CH:15]=[N:14][C:13]([N:16]2[CH2:21][CH2:20][N:19]([C:23]3[N:28]=[CH:27][N:26]=[C:25]([NH:29][C:30]4[CH:31]=[N:32][N:33]([CH2:35][C@H:36]5[O:41][CH2:40][CH2:39][N:38]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:37]5)[CH:34]=4)[N:24]=3)[CH2:18][CH2:17]2)=[N:12][CH:11]=1)(=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1cnc(N2CCNCC2)nc1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cn2cc(Nc3ncnc(Cl)n3)cn2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCO[C@H](Cn2cc(Nc3ncnc(N4CCN(c5ncc(C(=O)c6ccccc6)cn5)CC4)n3)cn2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.4 %

Procedure:
To a mixture of phenyl(2-(piperazin-1-yl)pyrimidin-5-yl)methanone HCl salt (141.6 mg, 0.38 mmol) and (S)-tert-butyl 2-((4-(4-chloro-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate (150 mg, 0.38 mmol) in dioxane (10 mL) was added diisopropylethylamine (1 mL), and the reaction was stirred at room temperature overnight. LCMS showed the reaction was completed. The solvents were removed under reduced pressure, and the residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=1:1) to give (S)-tert-butyl 2-((4-(4-(4-(5-benzoylpyrimidin-2-yl)piperazin-1-yl)-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate (230 mg, 95%) as a yellowish solid. (MS (ES+) C31H37N11O4 requires: 627, found: 573 [M-56+H]+.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]CC2C=CC=CC=2)=[CH:11][C:10]=1[CH:23]([CH3:33])[CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)C1C=CC=CC=1.C(O)C.Cl.[H][H]>C(OCC)(=O)C.[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH:23]([CH3:33])[CH2:24][CH2:25][O:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(CCOc1ccccc1)c1cc(OCc2ccccc2)ccc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(CCOc1ccccc1)c1cc(O)ccc1O
Reaction time: 2 h

Procedure:
A solution of 3-(2,5-dibenzyloxyphenyl)-1-phenoxybutane (14.7 g., 133.5 mM) in a mixture of ethyl acetate (110 ml.), ethanol (110 ml.) and concentrated hydrochloric acid (0.7 ml.) is hydrogenated for 2 hours under 60 p.s.i. hydrogen in the presence of 10% palladium-on-carbon (1.5 g.). Removal of the catalyst by filtration and concentration of the filtrate gives an oil. The oil is purified by chromatography on silica gel (100 g.) and eluting with benzene-ethyl acetate consisting of 0-10% ethyl acetate. The middle fractions are combined and concentrated to give the title product.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[C:3](=[O:7])[CH2:4][C:5]#[N:6].[OH-].[Na+].[NH2:12]O.Cl.Cl>O>[C:2]([C:3]1[O:7][N:6]=[C:5]([NH2:12])[CH:4]=1)([CH3:9])([CH3:8])[CH3:1]
Reactant: NO
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)c1cc(N)no1
Temperature: 25 °C
Yield: 77.4 %

Procedure:
4,4-dimethyl-3-oxopentanenitrile (3 g, 23.97 mmol) was dissolved in distilled water, stirred, and added with NaOH (1.06 g, 26.4 mmol) and NH2OH.HCl (1.83 g, 26.4 mmol). The reaction solution was stirred for about 30 minutes at room temperature. The reaction mixture was calibrated to yield pH in a range of 8 to 9 by adding an aqueous solution of 1 N NaOH, followed by further stirring for 10 hours or more at 50° C. The reaction mixture was washed 2 to 3 times with carbon tetrachloride, and aqueous layer was calibrated to yield pH in a range of 4 to 5 by adding concentrated HCl. The reaction mixture was further stirred for about 3 hours at 50° C. The reaction mixture was cooled to room temperature, and calibrated to yield pH 12 by adding an aqueous solution of 1 N NaOH. The resulting solid was filtered under reduced pressure, and washed with distilled water. The filtered solid was dried with warm wind in an oven (40° C.) for 3 hours or more to obtain the title compound (2.6 g, 77%).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([CH2:14][N:15]1[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:17]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:16]1)[CH:8]=[CH:7]2.Cl[CH2:34][C:35]1[C:36]([CH3:41])=[N:37][CH:38]=[CH:39][CH:40]=1.O>CN(C)C=O>[CH3:41][C:36]1[C:35]([CH2:34][O:3][C:4]2[CH:5]=[C:6]3[C:11](=[CH:12][CH:13]=2)[CH:10]=[C:9]([CH2:14][N:15]2[CH:19]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:17]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:16]2)[CH:8]=[CH:7]3)=[CH:40][CH:39]=[CH:38][N:37]=1
Reactant: Cc1ncccc1CCl
Reactant: CCOC(=O)CCc1cn(Cc2ccc3cc(O)ccc3c2)cc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc3cc(OCc4cccnc4C)ccc3c2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95.1 %

Procedure:
Sodium hydride (60%, oily, 80.0 mg) was added to a solution of ethyl 3-[1-(6-hydroxy-2-naphthylmethyl)-4-phenyl-3-pyrrolyl]propionate (799 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 15 minutes. 3-Chloromethyl-2-methylpyridine (283 mg) was added to the mixture, which was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatograpy, and ethyl 3-[1-[6-(2-methyl-3-pyridylmethoxy)-2-naphthylmethyl]-4-phenyl-3-pyrrolyl]propionate (959 mg, yield: 95%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: [N:1]1[C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=[C:3]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:2]=1.[NH2:16][C@@H:17]([CH3:34])[CH2:18][N:19]1[CH:23]=[CH:22][C:21]([C:24]2[CH:31]=[C:30]([F:32])[C:27]([C:28]#[N:29])=[C:26]([Cl:33])[CH:25]=2)=[N:20]1.CN(C=O)C>C(Cl)Cl>[Cl:33][C:26]1[CH:25]=[C:24]([C:21]2[CH:22]=[CH:23][N:19]([CH2:18][C@@H:17]([NH:16][C:7]([C:6]3[N:1]=[CH:2][C:3]([C:10]4[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=4)=[CH:4][CH:5]=3)=[O:9])[CH3:34])[N:20]=2)[CH:31]=[C:30]([F:32])[C:27]=1[C:28]#[N:29]
Reactant: O=C(O)c1ccc(-c2cccnc2)cn1
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1ccc(-c2cccnc2)cn1
Yield: 22.7 %

Procedure:
The title compound was prepared using the procedure described in Example 3(h) starting from 3,3′-bipyridine-6-carboxylic acid (0.861 mmol, 172 mg) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (0.718 mmol, 200 mg) using DMF (2 ml) as the solvent. After the reaction had stopped, DCM was added and the reaction mixture was evaporated. The residue was purified by flash chromatography and trituration from methanol, respectively. 75 mg of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.18 (d, 3H), 4.35-4.59 (m, 3H), 7.02 (d, 1H), 7.55-7.62 (m, 1H), 7.87-7.93 (m, 2H), 7.98 (s, 1H), 8.06-8.10 (m, 1H), 8.19-8.25 (m, 1H), 8.35 (dd, 1H), 8.68 (dd, 1H), 8.99-9.05 (m, 2H), 9.13 (d, 1H).
Reaction SMILES: Cl[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.[SH:16][CH2:17][CH:18]([CH2:20][OH:21])[OH:19].C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[OH:19][CH:18]([CH2:20][OH:21])[CH2:17][S:16][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
Reactant: O=C(c1ccccc1)c1ccc(Cl)cc1
Reactant: OCC(O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C(c1ccccc1)c1ccc(SCC(O)CO)cc1

Procedure:
14.0 g (0.07 mol) of 4-chlorobenzophenone, 10.0 g (0.93 mol) of 1-thioglycerol and 28.5 g (0.21 mol) of potassium carbonate in 60 ml of dimethylacetamide are kept at 110° C. for 6 hours, under N2 gas and with stirring. After cooling, the reaction mixture is poured into 200 ml of water. The crude product, which is obtained in the form of an oil, is taken up in ethyl acetate, the solution is washed with water until neutral, dried over K2CO3 and concentrated, isopropanol is poured over the concentrate and the resulting mixture is stirred. The product, which is obtained in the form of crystals, is filtered off. 9.4 g (47%); melting point 86°-88° C.
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[NH:6][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=O)[CH:14]=2)=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])=[O:3].[CH3:21][S-:22].[Na+]>FC(F)(F)C(O)=O.ClCCl>[NH2:1][C:2]([NH:4][C:5]1[NH:6][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][S:22][CH3:21])[CH:14]=2)=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])=[O:3]
Reactant: NC(=O)Nc1[nH]c(-c2cccc(C=O)c2)cc1C(N)=O
Reactant: C[S-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSCc1cccc(-c2cc(C(N)=O)c(NC(N)=O)[nH]2)c1
Reaction time: 0.17 h
Yield: 40.2 %

Procedure:
Under a solution of 2-aminocarbonylamino-5-(3-formylphenyl)pyrrole-3-carboxamide (Compound No. 14-2, 50 mg, 0.18 mmol) in trifluoroacetic acid (4 mL) was added to a solution of sodium methanethiolate (14 mg, 0.20 mmol) in dichloromethane (2 mL) and the mixture was stirred for 10 minutes. Moreover, borane-pyridine complex (41 μL, 0.41 mmol) was added thereto and the whole was stirred for 10 minutes. The reaction solution was concentrated in vacuo. Saturated aqueous sodium hydrogencarbonate (3 mL) and water (2 mL) were added to the residue, extracted with ethyl acetate (10 mL). After the organic layer was dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the target compound (22 mg) as a colorless solid (Yield 39%).
Reaction SMILES: F[C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:9][C:10]([F:13])([F:12])[F:11])=[O:7])=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].[NH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.CCN(CC)CC>CCO>[N+:21]([C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:2]=1[NH:24][CH2:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)[C:6]([N:8]([CH2:14][C:15]([F:18])([F:16])[F:17])[CH2:9][C:10]([F:12])([F:11])[F:13])=[O:7])([O-:23])=[O:22]
Reactant: O=C(c1ccc(F)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F
Reactant: NCC1CCOCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(c1ccc(NCC2CCOCC2)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F

Procedure:
Following the general procedure for Intermediate 2 using 4-fluoro-3-nitro-N,N-bis(2,2,2-trifluoroethyl)benzamide (75 mg, 0.215 mmol) and 4-aminomethyltetrahydropyran (27 mg, 0.236 mmol) in 3 mL of EtOH containing Et3N (0.045 mL, 0.323 mmol). The product was purified by flash chromatography on silica gel using 2:1/hexanes:EtOAc as eluent. Yield: 87 mg (91%); 1H NMR (CDCl3) 1.47 (m, 2H), 1.75 (m, 2H), 1.98 (m, 1H), 3.27 (t, J=5.47 Hz, 2H), 3.43 (m, 2H), 4.03 (m, 2H), 4.24 (q, J=8.33 Hz, 6H), 6.93 (d, J=8.98 Hz, 1H), 7.54 (d, J=8.98 Hz, 1H), 8.30 (s, 1H), 8.40 (brs, 1H); MS (ESI) 444.31 (MH+).
Reaction SMILES: C[C:2]([CH:15]=C)([CH:5](C(C)=C)[CH2:6][CH:7]=[C:8]([CH3:11])[CH:9]=[CH2:10])[CH:3]=[O:4].C(=O)([O-])[O-].[Na+].[Na+].CO.[C:25]1([CH3:32])[C:26](C)=CC=[CH:29][CH:30]=1>>[CH3:11]/[C:8](/[CH2:7][CH2:6]/[CH:5]=[C:2](/[CH:3]=[O:4])\[CH3:15])=[CH:9]\[CH2:10]/[CH:26]=[C:25](/[CH:30]=[CH2:29])\[CH3:32]
Reactant: Cc1ccccc1C
Reactant: C=CC(C)=CCC(C(=C)C)C(C)(C=C)C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: C=C/C(C)=C/C/C=C(\C)CC/C=C(\C)C=O

Procedure:
Low boiling solvents may equally provide useful media whenever the reaction is effected at a pressure higher than the atmospheric pressure. For economical reasons xylene is preferred. It will be appreciated that the reaction time may vary within a wide range and depends particularly on the temperature chosen for carrying out the rearrangement. In a typical experiment 2,6-dimethyl-2-vinyl-3-isopropenyl-octa-5,7-dienal in xylene was heated at reflux for 40 min. under nitrogen. Sodium carbonate and methanol were added to the reaction mixture and the reaction mixture was further refluxed for 18 h while stirring. After dilution with pentane and drying over anhydrous sodium sulphate, the mixture was distilled to yield α-sinensal.
Reaction SMILES: [CH2:1]=[CH:2][C:3]([Cl:5])=[CH2:4].Br[C:7]1[C:8]([O:10][C:11](=[O:13])[CH:12]=1)=[O:9]>>[Cl:5][C:3]1[CH2:4][C:12]2[C:11](=[O:13])[O:10][C:8](=[O:9])[C:7]=2[CH2:1][CH:2]=1
Reactant: O=C1C=C(Br)C(=O)O1
Reactant: C=CC(=C)Cl
Product: O=C1OC(=O)C2=C1CC=C(Cl)C2
Temperature: 50 °C

Procedure:
Chloroprene (13.6 g) and bromomaleic anhydride 14.6 g) were added together and the solution was heated to 50° C. for 11.5 hours. The reaction mixture was taken up in hot petroleum ether (bp 60° to 80° C.) and filtered. After cooling to room temperature, a solid was collected (6.2 g)- An additional 5 g of material remained in the mother liquors. The material consisted of a mixture of 4-chloro-3,6-dihydrophthalic anhydride, 4-chloro-l-bromo-1,2,3,6-tetrahydrophthalic anhydride and 4-chloro-2-bromo-1,2,3,6-tetrahydrophthalic anhydride.
Reaction SMILES: C[CH:2]1[C:11]2[C:10]3[CH:12]=[CH:13][CH2:14][CH2:15][C:9]=3[CH:8]=[CH:7][C:6]=2[NH:5][CH2:4][CH2:3]1.N.[Li].[CH2:18](O)C>CCOCC.O>[CH3:18][N:5]1[CH:6]2[CH:11]([C:10]3[CH2:12][CH:13]=[CH:14][CH2:15][C:9]=3[CH2:8][CH2:7]2)[CH2:2][CH2:3][CH2:4]1
Reactant: CC1CCNc2ccc3c(c21)C=CCC3
Reactant: CCO
Agent: N
Agent: [Li]
Solvent: CCOCC
Solvent: O
Product: CN1CCCC2C3=C(CC=CC3)CCC21

Procedure:
1-Methyl-1,2,3,4,7,8-hexahydrobenzo[f]-quinoline is dissolved in 200 ml of ether and added to 1.5 l of liquid ammonia. Lithium ribbon (16 g) is added portionwise over a period of 15 minutes. After stirring a few minutes, absolute ethanol is added dropwise until the color is discharged (500 ml added over a period of 2.5 hours). More ether is added and the ammonia is boiled off. While cooling in an ice bath, the mixture is diluted to about 1500 ml with water. The layers are separated and the aqueous layer is reextracted with ether. The combined organic layers are dried over potassium carbonate, filtered and the solvent is removed in vacuo leaving the title compound as a crude product.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C(=O)([O-])[O-].[K+].[K+].C1(C(C2C=CC=CC=2)[N:18]2[CH2:21][CH:20]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[CH2:19]2)C=CC=CC=1>C(Cl)Cl>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[O:22][CH:20]1[CH2:21][N:18]([C:1]([Cl:4])=[O:2])[CH2:19]1
Reactant: Clc1ccccc1OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: O=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(Cl)N1CC(Oc2ccccc2Cl)C1
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
A mixture of 12 g (0.122 mol) of phosgene and 17 g (0.122 mol) of potassium carbonate in 350 ml of methylene chloride was stirred under nitrogen for 30 min then cooled in an ice water bath while 35.6 g (0.102 mol) of 1-(diphenylmethyl)-3-(2-chlorophenoxy)azetidine in 50 ml of methylene chloride was added dropwise. The reaction mixture was removed from the bath and stirred for 3 h; then treated with small pieces of ice to control the decomposition of the excess phosgene. When no further evolution of carbon dioxide was evident, the reaction mixture was treated with 20 ml of water and the methylene chloride solution decanted from the inorganic paste. After concentrating in vacuo, trituration of the residue (51 g) with hexane yielded, upon filtration, 20.7 g (82.5%) of white crystalline product, mp 80°-82° C. A sample was recrystallized from hexane for elemental analysis, mp 80°-82° C.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH2:9]([N:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]1=[O:20])[CH2:10][CH2:11][CH3:12].C1(CN2C=CC(O)=CC2=O)CC1>CN(C=O)C>[CH2:9]([N:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([Cl:1])[C:14]1=[O:20])[CH2:10][CH2:11][CH3:12]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCCn1ccc(O)cc1=O
Agent: O=c1cc(O)ccn1CC1CC1
Solvent: CN(C)C=O
Product: CCCCn1ccc(O)c(Cl)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
N-Chlorosuccinimide (1.6 g, 11.96 mmol) was added to a solution of 1-butyl-4-hydroxy-1H-pyridine-2-one (2.0 g, 11.96 mmol), which was prepared as described for description D2, in DMF (30 ml). The reaction was stirred at room temperature overnight and then it was concentrated in vacuo. The crude product was purified by column chromatography (silica gel; 0-5% methanol/DCM as eluent) to yield intermediate D3 (2.0 g, 83%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[C:5]#[N:6].Cl[CH2:14][C:15]1[C:16]([NH:23][CH:24]([CH3:26])[CH3:25])=[N:17][C:18]([S:21][CH3:22])=[N:19][CH:20]=1.[I-].[Na+].C(N(C(C)C)CC)(C)C>CC#N>[CH:24]([NH:23][C:16]1[C:15]([CH2:14][NH:1][C:2]2[CH:3]=[C:4]([CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=2)[C:5]#[N:6])=[CH:20][N:19]=[C:18]([S:21][CH3:22])[N:17]=1)([CH3:26])[CH3:25]
Reactant: N#Cc1cc(N)cc([N+](=O)[O-])c1
Reactant: CSc1ncc(CCl)c(NC(C)C)n1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CSc1ncc(CNc2cc(C#N)cc([N+](=O)[O-])c2)c(NC(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.9 %

Procedure:
A solution of 3-amino-5-nitrobenzonitrile (3.59 g, 22 mmol) in CH3CN (10 mL) was added dropwise to a mixture of 5-(chloromethyl)-N-isopropyl-2-(methylthio)pyrimidin-4-amine from Example A9 (5 g, 22 mmol), sodium iodide (0.33 g, 2.2 mmol), and diisopropylethylamine (2 mL, 12 mmol) in CH3CN (100 mL) at 0° C. The resultant reaction mixture was stirred at RT overnight. The solvent was evaporated and the residue was diluted with water, and extracted with EtOAc. The combined organics were washed with brine, dried (MgSO4), concentrated and purified by silica gel chromatography to afford 3-((4-(isopropylamino)-2-(methylthio)pyrimidin-5-yl)methylamino)-5-nitrobenzonitrile (2.2 g, 28% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.87 (s, 1 H), 7.74 (s, 1 H), 7.56 (s, 1 H), 7.32 (s, 1H), 7.08 (m, 1 H), 6.63 (d, J=7.6 Hz, 1 H), 4.30 (m, 1 H), 4.15 (s, 2 H), 2.50 (s, 3 H), 1.17-1.15 (d, J=6.4 Hz, 6 H); MS (ESI) m/z: 359.2[M+H]+.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[NH2:48][C@H:49]1[CH2:55][CH2:54][CH2:53][CH2:52][N:51]([C:56]2[CH:57]=[N:58][CH:59]=[CH:60][CH:61]=2)[C:50]1=[O:62]>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9](=[O:10])[NH:48][C@H:49]1[CH2:55][CH2:54][CH2:53][CH2:52][N:51]([C:56]2[CH:57]=[N:58][CH:59]=[CH:60][CH:61]=2)[C:50]1=[O:62])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: N[C@H]1CCCCN(c2cccnc2)C1=O
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CCCCN(c4cccnc4)C3=O)Cc3ccccc3)C(=O)N21

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5R)-2,5-dibenzyl-6-oxo-6-((S)-2-oxo-1-(pyridin-3-yl)azepan-3-ylamino)hexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (34 mg, 0.061 mmol) and Intermediate 67 (24 mg, 0.055 mmol) to give a white solid (17 mg, 35% yield). Anal. Calcd. for C42H51N5O6S m/z 753.7. found: 754.3 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 10.68 (s, 1H), 8.90 (d, J=1.9 Hz, 1H), 8.68 (d, J=5.4 Hz, 1H), 8.20 (d, J=8.5 Hz, 1H), 7.82 (dd, J=8.4, 5.5 Hz, 1H), 7.28-7.08 (m, 9H), 7.02 (d, J=6.9 Hz, 1H), 5.31 (t, J=4.5 Hz, 1H), 5.21-5.04 (m, 1H), 5.03-4.93 (m, 1H), 4.92-4.79 (m, 1H), 4.08 (dd, J=15.6, 11.6 Hz, 1H), 3.83-3.71 (m, 1H), 3.68 (s, 3H), 3.22-3.04 (m, 1H), 2.91-2.68 (m, 5H), 2.55-2.33 (m, 3H), 2.16-1.90 (m, 4H), 1.91-1.43 (m, 13H), 1.41-1.21 (m, 1H).