Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[CH:2].[N+:9]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])([O-])=[O:10].C1N2CCN(CC2)C1>C(O)C>[CH:3]1([C:1]2[O:10][N:9]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:2]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: C#CC1CCCCC1
Reactant: CCOC(=O)C[N+](=O)[O-]
Agent: C1CN2CCN1CC2
Solvent: CCO
Product: CCOC(=O)c1cc(C2CCCCC2)on1
Temperature: 80 °C
Yield: 97.2 %

Procedure:
To a mixture of ethynylcyclohexane (0.600 g; 5.44 mmol) and ethyl 2-nitroacetate (1.23 mL; 10.87 mmol) in ethanol (9 mL) in an Ace pressure tube was added 1,4-diazobicyclo[2.2.2]octane (DABCO, 0.070 g; 0.60 mmol). The tube was heated at 80° C. for 96 h. The mixture was evaporated. The flash chromatography on silica gel (eluent: 20 to 80% dichloromethane in heptane) of the residue provided 1.18 g (97%) of ethyl 5-cyclohexylisoxazole-3-carboxylate as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[C:12](=O)[C:13](=[O:19])[NH:14]3)=[CH:4][CH:3]=1.[CH:21]1[C:26]([NH:27][NH2:28])=[CH:25][CH:24]=[C:23]([S:29]([NH2:32])(=[O:31])=[O:30])[CH:22]=1.Cl>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[C:12](=[N:28][NH:27][C:26]2[CH:25]=[CH:24][C:23]([S:29]([NH2:32])(=[O:30])=[O:31])=[CH:22][CH:21]=2)[C:13](=[O:19])[NH:14]3)=[CH:4][CH:3]=1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: O=C1Nc2cccc(/C=C/c3ccc(O)cc3)c2C1=O
Agent: Cl
Product: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3cccc(C=Cc4ccc(O)cc4)c32)cc1
Yield: 27 %

Procedure:
A mixture of 1.0 g (3.6 mmol) of 4-iodo-1H-indole-2,3-dione (Snow, et al., Journal of the American Chemical Society 1977, 99, 3734–44), 0.42 g (4.2 mmol) of TEA, 0.06 g (0.27 mmol) of palladium(II) acetate, 0.16 g (0.54 mmol) of tri-o-tolylphosphine and 5.0 g (4.2 mmol) of a 10% solution of 4-vinylphenol in propylene glycol was suspended in 15 mL of dry acetonitrile in a pyrex sealed tube and heated to 100° C. for 4 h. The mixture was cooled to rt, quenched with 50 mL of 10% hydrochloric acid and extracted with two 100 mL-portions of EtOAc. The combined extracts were dried over MgSO4 and concentrated to give a brown solid, which was subjected to chromatography on silica gel, eluting with hexane:EtOAc (3:1), to yield 0.125 g (13%) of trans-4-[2-(4-hydroxyphenyl)-vinyl]-1H-indole-2,3-dione as a red solid: 1H NMR (DMSO-d6): δ 6.6–7.6 (m, 8H), 7.77 (d, J=16.4 Hz, 1H), 9.85 (bs, 1H), 11.00 (bs, 1H); APCI-MS m/z 264 (M−1)−. Condensation of trans-4-[2-(4-hydroxyphenyl)-vinyl]-1H-indole-2,3-dione and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G gave the title compound in 27% yield as an orange solid: 1H NMR (DMSO-d6): δ 6.78 (d, J=7.8 Hz, 1H), 6.88 (d, J=8.7 Hz, 2H), 7.26 (t, J=7.8 Hz, 1H), ), 7.29 (s, 2H), 7.36 (d, J=16.5 Hz, 1H), 7.47 (d, J=7.8 Hz, 1H), 7.53 (d, J=8.7 Hz, 2H), 7.57 (d, J=8.7 Hz, 2H), 7.81 (d, J=8.7 Hz, 2H), 8.03 (d, J=16.5 Hz, 1H), 9.78 (s, 1H), 11.17 (s, 1H), 13.02 (s, 1H); APCI-MS m/z 433 (M−1)−.
Reaction SMILES: NC[C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([N:25]5[CH2:33][C:32]6[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=6)[C:26]5=[O:34])[C:20]=4[CH3:35])=[CH:9][CH:10]=[C:11]([C:16]([NH2:18])=[O:17])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1.N(C(C)C)=C=O>C1COCC1>[CH3:35][C:20]1[C:21]([N:25]2[CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]2=[O:34])=[CH:22][CH:23]=[CH:24][C:19]=1[C:8]1[C:7]2[C:6]3[C:14](=[CH:15][CH:3]=[CH:4][CH:5]=3)[NH:13][C:12]=2[C:11]([C:16]([NH2:18])=[O:17])=[CH:10][CH:9]=1
Reactant: Cc1c(-c2ccc(C(N)=O)c3[nH]c4cc(CN)ccc4c23)cccc1N1Cc2ccccc2C1=O
Agent: CC(C)N=C=O
Solvent: C1CCOC1
Product: Cc1c(-c2ccc(C(N)=O)c3[nH]c4ccccc4c23)cccc1N1Cc2ccccc2C1=O
Yield: 20.7 %

Procedure:
A solution of 7-(aminomethyl)-4-(2-methyl-3-(1-oxoisoindolin-2-yl)phenyl)-9H-carbazole-1-carboxamide (Example 33-1, 30 mg, 0.065 mmol) and 2-isocyanatopropane (0.019 mL, 0.195 mmol) in THF (3 mL) was stirred at 40° C. overnight. The mixture was concentrated and purified by preparative HPLC. The appropriate effluent fractions were concentrated and partitioned between EtOAc and NaHCO3 (aq). The organic phase was dried and concentrated to provide 7-(3-isopropylureido)methyl)-4-(2-methyl-3-(1-oxoisoindolin-2-yl)phenyl)-9H-carbazole-1-carboxamide as a white solid (5.8 mg, 14%). 1H NMR (400 MHz, methanol-d4) δ 7.84 (1 H, d, J=7.7 Hz), 7.77 (1 H, d, J=7.5 Hz), 7.53-7.63 (2 H, m), 7.38-7.51 (4 H, m), 7.30 (1 H, dd, J=7.2, 1.7 Hz), 6.93-6.99 (2 H, m), 6.85 (1 H, dd, J=8.3, 1.4 Hz), 4.79-4.91 (2 H, m), 4.33 (2 H, s), 3.69-3.78 (1 H, m), 1.79 (3 H, s), 1.03 (6 H, d, J=6.4 Hz). Mass spectrum m/z 546.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:34][C:35]2[CH:36]=[N:37][CH:38]=[CH:39][C:40]=2[CH3:41])[CH:10]2[CH2:15][CH2:14][N:13]([C@H:16]([CH3:33])[CH2:17][CH2:18][NH:19][C:20](=[O:32])[C:21]3[C:29]([CH3:30])=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][C:22]=3[CH3:31])[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.C[CH2:43][N:44]=[C:45]=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CNC.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]([CH2:34][C:35]2[CH:36]=[N:37][CH:38]=[CH:39][C:40]=2[CH3:41])[CH:10]2[CH2:15][CH2:14][N:13]([C@H:16]([CH3:33])[CH2:17][CH2:18][NH:19][C:20](=[O:32])[C:21]3[C:22]([CH3:31])=[CH:23][C:24]([C:25]([N:44]([CH3:45])[CH3:43])=[O:27])=[CH:28][C:29]=3[CH3:30])[CH2:12][CH2:11]2)=[CH:7][CH:8]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1ccc(N(Cc2cnccc2C)C2CCN([C@H](C)CCNC(=O)c3c(C)cc(C(=O)O)cc3C)CC2)cc1
Agent: CNC
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N(Cc2cnccc2C)C2CCN([C@H](C)CCNC(=O)c3c(C)cc(C(=O)N(C)C)cc3C)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.8 %

Procedure:
N-((R)-3-{4-[(4-Methoxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-3,5-dimethyl-terephthalamic acid (0.070 g, 0.12 mmol), EDCI (0.026 g, 0.13 mmol) and HOBT (0.019 g, 0.13 mmol) were combined in DMF (5 mL) to give a pale yellow solution. To this solution was added dimethylamine (2M in THF) (94 μL, 0.18 mmol) followed by DIPEA (33 μL, 0.18 mmol) and the resulting mixture was stirred at 25° C. for 16 h. Standard workup according to General Procedure C gave the crude product as a tan oil. Purification by column chromatography on silica gel (CH2Cl2:MeOH:NH4OH, 93:5:2, v/v/v) afforded N-((R)-3-{4-[(4-methoxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-2,6, N′,N′-tetramethyl-terephthalamide (0.028 g, 38%) as a white foam. 1H NMR (CDCl3) δ 0.99 (d, 3H, J=6.0 Hz), 1.26 (m, 1H), 1.37 (m, 1H), 1.62 (m, 2H), 1.78-1.85 (m, 3H), 2.14 (br t, 1H), 2.33 (s+m, 8H), 2.47 (br t, 1H), 2.74 (m, 3H), 2.94 (s, 3H), 3.06 (s, 3H), 3.32-3.46 (m, 2H), 3.66 (m, 1H), 3.72 (s, 3H), 4.10 (s, 2H), 6.66 (d, 2H, J=9.0 Hz), 6.73 (d, 2H, J=9.0 Hz), 6.93 (br t, 1H), 7.02 (d, 1H, J=3.0 Hz), 7.05 (s, 2H), 8.29 (s, 1H), 8.31 (d, 1H, J=6.0 Hz). 13C NMR (CDCl3) δ 13.8, 19.2, 19.6, 29.9, 30.7, 32.8, 39.0, 39.9, 44.8, 47.6, 51.8, 56.0, 58.8, 58.9, 114.8, 119.4, 125.3, 126.4, 133.8, 134.8, 143.0, 145.4, 148.3, 149.6. ES-MS m/z 586 (M+H), 608 (M+Na). Anal. Calcd. for C35H47N5O3.0.2 CH2Cl2: C, 70.14; H, 7.93; N, 11.62. Found: C, 70.06; H, 8.03; N, 11.54.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:3]1.P(Cl)(Cl)Cl.[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:25]([S:28](=[O:31])(=[O:30])[NH2:29])=[CH:24][C:20]=1[C:21](O)=[O:22]>N1C=CC=CC=1>[CH:7]1([N:4]2[CH2:5][CH2:6][CH:2]([NH:1][C:21](=[O:22])[C:20]3[CH:24]=[C:25]([S:28](=[O:30])(=[O:31])[NH2:29])[CH:26]=[CH:27][C:19]=3[O:18][CH3:17])[CH2:3]2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: NC1CCN(C2CCCCC2)C1
Reactant: COc1ccc(S(N)(=O)=O)cc1C(=O)O
Solvent: c1ccncc1
Solvent: ClP(Cl)Cl
Product: COc1ccc(S(N)(=O)=O)cc1C(=O)NC1CCN(C2CCCCC2)C1
Reaction time: 1 h

Procedure:
To 3.7 g. (0.022 mole) of 3-amino-1-cyclohexylpyrrolidine in 100 ml. of pyridine was added dropwise with cooling 1.1 g. (0.008 mole) of phosphorous trichloride at 20°C. After stirring one hour, 3 g. (0.013 mole) of 2-methoxy-5-sulfamoylbenzoic acid was added and refluxed 6 hrs. The solution was concentrated and the residue partitioned between dilute hydrochloride acid and isopropyl ether. The acid was made basic with ammonium hydroxide and extracted with chloroform which was dried (sodium sulfate) and concentrated. The residue was crystallized from ethyl acetate and recrystallized from isopropyl alcohol. Yield 1 g. (33%); m.p. 184°-187°C.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2.[NH4+].[OH-:16]>O>[OH:16][CH2:3][C:4]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2
Reactant: Oc1ccc(CCl)c2cccnc12
Reactant: [OH-]
Agent: Cl
Agent: [NH4+]
Solvent: O
Product: OCc1ccc(O)c2ncccc12
Yield: 86.8 %

Procedure:
In a 500 ml Ehrlenmeyer flask with a magnetic stirrer, 23 grams (0.1 moles) of 5-chloromethyl-8-hydroxyquinoline hydrochloride and 200 ml of H2O were stirred, producing a bright yellow solution. NH4OH (7.0 grams; 0.2 moles) in concentrated form was added slowly. The color of the solution changed to amber. As the pH approached neutral, the color disappeared, and a precipitate formed. The precipitate was filtered, washed with water, and oven dried at 105° C. After drying, 15.2 grams (87% yield) of product was left.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH3:13])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Cl[C:15]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])=[O:16]>>[OH:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[C:5]([CH3:13])[C:4]=1[C:15]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[O:16]
Reactant: CCOC(=O)CCCCC(=O)Cl
Reactant: COc1cc(C)cc(OC)c1OC
Product: COc1cc(C)c(C(=O)CCCCC(=O)O)c(O)c1OC

Procedure:
3,4,5-Trimethoxytoluene(formula VII wherein R=H3CO, X=H, Y=H3CO)(2.09 parts) and ethyl 5-chloroformylpentanoate (2.66 parts) were treated in the same manner as Example 4. The procedure provided 5-(2'-hydroxy-3',4'-dimethoxy-6'-methylbenzoyl)pentanoic acid (formula II-1 wherein R=H3CO, X=H, Y=OH, n=4, in the free form)(1.97 part) as pale-brown needles melting at 111°-112° C.
Reaction SMILES: Cl[C:2]1C=CC(N)=NC=1C.[N:10]1([C:15]2[N:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=[O:23])=[CH:17][CH:16]=2)[CH:14]=[N:13][N:12]=[N:11]1>>[CH3:2][C:19]1[C:18]([CH2:21][C:22]([OH:24])=[O:23])=[CH:17][CH:16]=[C:15]([N:10]2[CH:14]=[N:13][N:12]=[N:11]2)[N:20]=1
Reactant: Cc1nc(N)ccc1Cl
Reactant: O=C(O)Cc1ccc(-n2cnnn2)nc1
Product: Cc1nc(-n2cnnn2)ccc1CC(=O)O

Procedure:
The title compound was prepared from 5-chloro-6-methylpyridin-2-amine in six steps in an analogous fashion to that described for the synthesis of [6-(1H-tetrazol-1-yl)pyridin-3-yl]acetic acid (Method 1, Steps A-F): LC-MS (IE, m/z): 192 [M+1-N2]+, 220 [M+1]+; 1H-NMR (400 MHz, CDCl3) δ 9.88 (s, 1H), 7.9 (d, 1H), 7.85 (d, 1H), 3.79 (s, 2H), 2.59 (s, 3H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:32](OC)=[O:33])=[C:13]2[C:17]=1[N:16]=[C:15]1[N:18]([C:22]3[C:23]([CH3:31])=[N:24][C:25]([O:29][CH3:30])=[N:26][C:27]=3[CH3:28])[CH2:19][CH2:20][CH2:21][N:14]21.[OH-].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>O1CCCC1.O>[CH3:7][O:8][C:9]1[C:17]2[N:16]=[C:15]3[N:18]([C:22]4[C:23]([CH3:31])=[N:24][C:25]([O:29][CH3:30])=[N:26][C:27]=4[CH3:28])[CH2:19][CH2:20][CH2:21][N:14]3[C:13]=2[C:12]([CH2:32][OH:33])=[CH:11][CH:10]=1
Reactant: COC(=O)c1ccc(OC)c2nc3n(c12)CCCN3c1c(C)nc(OC)nc1C
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: COc1nc(C)c(N2CCCn3c2nc2c(OC)ccc(CO)c23)c(C)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
To a suspension of lithium aluminum hydride (0.14 g, 3.69 mmol) in tetrahydrofuran (10 mL) was added dropwise a solution of methyl 9-methoxy-1-(2-methoxy-4,6-dimethylpyrimidin-5-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carboxylate (720 mg, 1.81 mmol) in tetrahydrofuran (30 mL) at 0° C. After stirring at 0° C. for 1 hr, water (0.14 mL), 15% aqueous sodium hydroxide (0.14 mL) and water (0.42 mL) were successively added dropwise to the reaction mixture at 0° C. The mixture was stirred at room temperature for 4 hr and anhydrous magnesium sulfate was added to the mixture. The solid was removed by filtration. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel eluting with a 5-25% methanol/ethyl acetate gradient mixture to give the title compound as a colorless solid (478 mg, 1.29 mmol, 71%).
Reaction SMILES: C(OC([NH:11][C@H:12]([C:17]([NH:19][C@@H:20]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C@H:21]([OH:35])[CH2:22][N:23]1[C@H:27]([C:28]([NH:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][S:25][CH2:24]1)=[O:18])[CH2:13][C:14](=[O:16])[NH2:15])=O)C1C=CC=CC=1.Br>C(O)(=O)C.C(OCC)C>[NH2:11][C@H:12]([C:17]([NH:19][C@@H:20]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C@H:21]([OH:35])[CH2:22][N:23]1[C@H:27]([C:28]([NH:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])[CH2:26][S:25][CH2:24]1)=[O:18])[CH2:13][C:14](=[O:16])[NH2:15]
Reactant: CC(C)(C)NC(=O)[C@@H]1CSCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CC(C)(C)NC(=O)[C@@H]1CSCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
A mixture of 170 mg of 3-[3(S)-[[N-(benzyloxycarbonyl)-L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-4(R)-thiazolidinecarboxamide and 0.3 ml of 32% (w/w) hydrogen bromide in glacial acetic acid was stirred at room temperature for 1 hour. The solution was diluted with diethyl ether and the precipitated solid was rapidly filtered off, washed with diethyl ether and dissolved in water. The solution was made alkaline by the addition of potassium carbonate and extracted with three portions of chloroform. The combined chloroform extracts were dried over anhydrous sodium sulphate, filtered and evaporated to give 110 mg of 3-[3(S)-[[L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-4(R)-thiazolidinecarboxamide; MS: m/e 466 [M+H]+.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([C:15]2[CH2:16][CH2:17][C:18](=[O:21])[NH:19][N:20]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH:12]1[O:14][CH2:13]1)[CH:2]=[CH2:3].[CH:22]([NH2:25])([CH3:24])[CH3:23]>CO>[CH2:1]([C:4]1[CH:5]=[C:6]([C:15]2[CH2:16][CH2:17][C:18](=[O:21])[NH:19][N:20]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH:12]([OH:14])[CH2:13][NH:25][CH:22]([CH3:24])[CH3:23])[CH:2]=[CH2:3]
Reactant: C=CCc1cc(C2=NNC(=O)CC2)ccc1OCC1CO1
Reactant: CC(C)N
Solvent: CO
Product: C=CCc1cc(C2=NNC(=O)CC2)ccc1OCC(O)CNC(C)C
Yield: 119.4 %

Procedure:
A stirred mixture of 6-[3-allyl-4-(2,3-epoxypropoxy)-phenyl]-4,5-dihydro-3(2H)-pyridazinone (46g, 0.16 mole), methanol (500 ml) and isopropylamine (85 ml, 1 mole) was heated under reflux for 60 minutes. Evaporation of the solution under reduced pressure gave an oil (66 g) which was purified on a silica column by elution with mixtures of chloroform and methanol to give 6-[3-allyl-4-(2-hydroxy-3-isopropylaminopropoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone (45g, 85%, m.p. 94°-96.5° C). The hemisulphate hemihydrate, crystallised from aqueous ethanol, had m.p. 238°-242° C.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[CH3:19][CH:20]([CH3:30])/[CH:21]=[CH:22]/[CH2:23][CH2:24][CH2:25][CH2:26][C:27](Cl)=[O:28]>C1COCC1>[CH3:19][CH:20]([CH3:30])/[CH:21]=[CH:22]/[CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:9]1[C@H:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:12][O:11][C:10]1=[O:13])=[O:28]
Reactant: CC(C)/C=C/CCCCC(=O)Cl
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)/C=C/CCCCC(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 85.3 %

Procedure:
To a cooled (−78° C.) solution of (R)-4-benzyloxazolidin-2-one (2.817 g, 15.899 mmol) in 40 mL of THF, was added n-BuLi (6.4 mL, 15.899 mmol, 2.5 M in hexane). The resulting mixture was stirred at −78° C. under N2 for 15 min. and then (E)-8-methylnon-6-enoyl chloride (3.000 g, 15.899 mmol) was added. After stirring at −78° C. for 1 h and then being warmed to room temperature under N2 for overnight, the reaction mixture was quenched with 80 mL of NH4Cl solution and extracted with dichloromethane (60 mL×3). The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The product was isolated by Flash column chromatography (silica gel column) eluting with 0-30% ethyl acetate/hexanes to give the title compound as colorless oil (4.468 g, 85% yield). GC-MS: tR=6.2 min; m/z 329 (M+).
Reaction SMILES: [C:1]1([C:7]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH2:10])=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]1(=[O:22])[CH2:21][CH2:20][CH:19]=[CH:18]1>C1(C)C=CC=CC=1>[C:1]1([C:7]2[CH2:8][CH:20]3[CH:21]([CH2:10][C:9]=2[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:17](=[O:22])[CH2:18][CH2:19]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1C=CCC1
Reactant: C=C(C(=C)c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: O=C1CCC2CC(c3ccccc3)=C(c3ccccc3)CC12

Procedure:
A mixture of 2,3-diphenyl-1,3-butadiene (2.772 g, 13.44 mmol) and cyclopent-2-enone (1 eq.) was refluxed in toluene (26 mL) for 48 h. The reaction mixture was then concentrated and purified on SiO2 (20% ethyl acetate/hexane) to yield 5,6-diphenyl-2,3,3a,4,7,7a-hexahydro-inden-1-one.
Reaction SMILES: [CH:1]1([CH:7]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([NH:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[O:34])=[CH:29][CH:28]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[O:10][C:9]=2[CH2:23][S:24][CH3:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:43]OS([O-])=O.[K+]>CO.O>[CH:1]1([CH:7]([NH:26][C:27]2[CH:28]=[CH:29][C:30]([C:33]([NH:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[O:34])=[CH:31][CH:32]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][CH:14]=3)[O:10][C:9]=2[CH2:23][S:24]([CH3:25])=[O:43])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S([O-])OO
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(c2cc(-c3ccc(C(F)(F)F)cc3)oc2CSC)C2CCCCC2)cc1
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCOC(=O)CCNC(=O)c1ccc(NC(c2cc(-c3ccc(C(F)(F)F)cc3)oc2CS(C)=O)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.9 %

Procedure:
Ethyl 3-[({4-[(cyclohexyl{2-[(methylsulfanyl)methyl]-5-[4-(trifluoromethyl)phenyl]furan-3-yl}methyl)amino]phenyl}carbonyl)amino]propanoate (482 mg) was dissolved in methanol (9 mL) and water (1 mL), OXONE (295 mg) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (25% ethyl acetate/hexane to 100% ethyl acetate/hexane) to give the title compound (232 mg, 47%) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[NH:5][CH3:6].Br.Br[CH:13]([C:15]1[CH:16]=[C:17]([C:32]([N:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)=[O:33])[CH:18]=[C:19]2[C:24]=1[O:23][C:22]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[CH:21][C:20]2=[O:31])[CH3:14].[I-].[K+]>C(Cl)(Cl)Cl.CO.C(#N)C.O>[F:1][C:2]1[CH:3]=[C:4]([N:5]([CH3:6])[CH:13]([C:15]2[CH:16]=[C:17]([C:32]([N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)=[O:33])[CH:18]=[C:19]3[C:24]=2[O:23][C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:21][C:20]3=[O:31])[CH3:14])[CH:7]=[C:8]([F:10])[CH:9]=1
Reactant: CNc1cc(F)cc(F)c1
Reactant: CC(Br)c1cc(C(=O)N2CCCC2)cc2c(=O)cc(N3CCOCC3)oc12
Agent: Br
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(c1cc(C(=O)N2CCCC2)cc2c(=O)cc(N3CCOCC3)oc12)N(C)c1cc(F)cc(F)c1
Yield: 59.3 %

Procedure:
3,5-difluoro-N-methylaniline (222 mg, 1.55 mmol), 8-(1-bromoethyl)-2-morpholino-6-(pyrrolidine-1-carbonyl)-4H-chromen-4-one hydrobromide (200 mg, 0.39 mmol) and potassium iodide (64.3 mg, 0.39 mmol) in CHCl3 (0.8 mL) and MeOH (0.2 mL) were stirred at 20° C. for 25 hrs. The reaction mixture was concentrated to dryness, diluted with DCM (30 mL), washed with water, brine, dried over magnesium sulfate and concentrated to afford the crude product. Purification was done by flash chromatography on silica gel eluting with 2 to 4% MeOH in DCM. The solvent was evaporated to dryness to afford a foam which was dissolved in acetonitrile-water and concentrated under vacuum to give 8-(1-((3,5-difluorophenyl)(methyl)amino)ethyl)-2-morpholino-6-(pyrrolidine-1-carbonyl)-4H-chromen-4-one (115 mg, 60%) as a white solid. Mass Spectrum: M+H+ 498. NMR is Spectrum (DMSOd6): 1.56 (d, 3H), 1.78-1.93 (m, 4H), 2.62 (s, 3H), 3.23-3.29 (m, 2H), 3.35-3.56 (m, 10H), 5.55 (s, 1H), 5.59 (q, 1H), 6.40 (t, 1H), 6.53 (d, 2H), 7.79 (d, 1H), 8.01 (d, 1H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[CH:21]=[O:22]>CN(C=O)C.[Cu]>[O:7]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[CH:21]=[O:22])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1cnccc1Cl
Reactant: Oc1ccccc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cnccc1Oc1ccccc1
Reaction time: 2 h
Yield: 92 %

Procedure:
A solution of phenol (1.34 g, 14.3 mmol) in DMF (25 ml) was stirred with anhydrous potassium carbonate (0.99 g, 7.2 mmol) at 70°-80° C. for 40 minutes. 4-Chloro-3-pyridinecarboxaldehyde (2.02 g, 14.3 mmol) and copper bronze powder (0.10 g) were added and the resulting suspension stirred at 100°-110° C. for 2 hours. The reaction mixture was cooled, filtered and the residues washed with ether. The combined ether washings were diluted to 400 ml with more ether, washed with saturated brine (4×) and the solvent removed to give 4-phenoxy-3-pyridinecarboxaldehyde as a pale yellow crystalline solid (2.62 g); melting point 74°-75° C.; infrared max (nujol) 1590, 1695, 2760 cm-1 ; 1H NMR delta (CDCl3) 6.75 (1H broad), 7.15 (2H,d), 7.35 (1H,t), 7.50 (2H,t), 8.5-9.7 (2H,broad), 10.7 (1H,s).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]=[C:4](O)[N:3]=1.O=P(Cl)(Cl)[Cl:13].N(C1C=CC=CC=1)(CC)CC>>[Cl:13][C:4]1[N:3]=[C:2]([CH3:1])[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc(O)nc(C)c1C
Solvent: CCN(CC)c1ccccc1
Product: Cc1nc(Cl)nc(C)c1C
Yield: 101.9 %

Procedure:
To 4,5,6-trimethylpyrimidin-2-ol (3.69 g, 26.7 mmol) was added POCl3 (21.7 mL, 26.7 mmol) followed by Et2NPh (2.17 mL, 13.6 mmol) dropwise. The mixture was heated at reflux for 48 h and then added to ice dropwise. The aqueous layer was extracted with EtOAc (2×). Extraction was difficult due to a large amount of precipitate. The aqueous layer pH was adjusted to pH 4-5 with 28% NH4OH and was filtered through Celite®. The aqueous layer was then extracted with DCM and the combined organic extracts dried over Na2SO4, filtered and concentrated in vacuo to a yellow solid. Chromatography (FCC) (0 to 30% EtOAc/Hex) afforded 2-chloro-4,5,6-trimethylpyrimidine (4.26 g, 100%).