Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([OH:11])([C:7]([F:10])([F:9])[F:8])[C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[F:26][C:27]1[CH:28]=[C:29]([NH2:42])[CH:30]=[CH:31][C:32]=1[S:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(=[O:35])=[O:34]>O1CCCC1>[F:26][C:27]1[CH:28]=[C:29]([NH:42][C:4](=[O:6])[C:3]([OH:11])([C:2]([F:1])([F:13])[F:12])[C:7]([F:10])([F:9])[F:8])[CH:30]=[CH:31][C:32]=1[S:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(=[O:35])=[O:34]
Reactant: O=C(O)C(O)(C(F)(F)F)C(F)(F)F
Reactant: Nc1ccc(S(=O)(=O)c2ccccc2)c(F)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(S(=O)(=O)c2ccccc2)c(F)c1)C(O)(C(F)(F)F)C(F)(F)F
Temperature: 45 °C
Yield: 13.3 %

Procedure:
To a solution of 3,3,3-trifluoro-2-hydroxy-2-trifluoromethylpropanoic acid (1.26 g, 5.9 mmol) in dry tetrahydrofuran (35 mL) was added 1,1'-carbonyldiimidazole (0.89 g, 5.5 mmol). The mixture was heated to 45° C. in an ultrasound bath for 30 minutes, then 3-fluoro-4-phenylsulfonylbenzeneamine (1.35 g, 5.4 mmol) was added in one portion. The reaction mixture was heated at 65° C. in the ultrasound bath for 30 hours. Tetrahydrofuran was removed from the reaction mixture in vacuo, and the residue partitioned between water and ethyl ether. The aqueous layer was extracted with ethyl ether (2×50 mL), and the combined ether portions were dried (MgSO4) and concentrated in vacuo to an off-white solid. The solid was dissolved in ethyl ether, treated with HCl/ethyl ether and filtered to remove unreacted 3-fluoro-4-phenylsulfonylbenzeneamine. The filtrate was concentrated in vacuo, and the resulting solid recrystallized from ethyl ether/hexane to yield the title propanamide as a white solid (0.32 g, 13%); mp 188°-189° C. 1H-NMR (250 MHz, d6-DMSO): 7.62-7.84 (m, 4H, aromatic) 7.91-7.94 (m, 3H, aromatic) 8.03-8.09 (m, 2H, aromatic) 9.60 (s, 1H, NH). MS (CI, CH4): 446 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([CH2:9][C:10]#[N:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]([F:26])([F:25])[C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19].[H-].[Na+].Cl[C:30]([O:32][CH2:33][CH3:34])=[S:31]>CN(C)C=O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9](=[C:18]([O:19][C:30]([O:32][CH2:33][CH3:34])=[S:31])[C:17]2[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=2[C:15]([F:26])([F:25])[F:14])[C:10]#[N:11])=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=S)Cl
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: CC(C)(C)c1ccc(CC#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=S)OC(=C(C#N)c1ccc(C(C)(C)C)cc1)c1ccccc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65.8 %

Procedure:
A mixture comprising 2.0 g of 4-tert-butylbenzyl cyanide, 2.34 g of 2-trifluoromethylbenzoyl chloride and 8 ml of dimethylformamide, was dropwise added to a mixture comprising 0.83 g of 68% sodium hydride and 13 ml of dimethylformamide while maintaining the temperature at a level of from 40 to 500C. After completion of the dropwise addition, the reaction was carried out for 30 minutes at room temperature. The reaction mixture was cooled with ice, and a mixture comprising 2.1 g of ethyl chlorothioformate and 1.2 ml of dimethylformamide, was dropwise added. After completion of the dropwise addition, the reaction was carried out for 30 minutes under cooling with ice. The reaction mixture was poured into ice water and extracted with methylene chloride and then washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate/n-hexane=1/9) to obtain 3.2 g of the desired product (isomer ratio 35:65) having a melting point of 62 to 64° C. The HPLC conditions for the analysis of this product were the same as in Preparation Example 1. Further, the NMR spectrum data of the respective geometrical isomers are as follows.
Reaction SMILES: [C:1]([P:3](=[O:6])([O-:5])[O-:4])#[N:2].[Na+].[Na+].N[CH2:10][C:11]([OH:13])=[O:12].Cl.O1CCOCC1.[H][H]>O.[Pd]>[P:3]([O-:5])([O-:12])([O-:4])=[O:6].[P:3]([CH2:1][NH:2][CH2:10][C:11]([OH:13])=[O:12])([OH:5])([OH:4])=[O:6]
Reactant: NCC(=O)O
Reactant: N#CP(=O)([O-])[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CNCP(=O)(O)O
Product: O=P([O-])([O-])[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 1.2 %

Procedure:
Disodium cyanophosphonate (partially hydrated) (0.170 g, 1.06 mmol) was dissolved in water (5 ml) in a Fisher Porter bottle containing a magnetic stir bar, and glycine (0.0862 g, 1.148 mmol) was added. Three percent palladium on carbon (0.060 g, prepared as per Example 3) was added along with HCl-dioxane (0.25 ml, 4N, 1 mmol). After three pressure-release cycles with hydrogen, the bottle was pressurized to 25 psi with hydrogen and stirred overnight at ambient temperature. The pressure was released, and the reaction mixture was filtered through Celite and washed with D2O. HPLC analysis (system for phosphate analysis) gave a 1.2% yield of N-phosphonomethylglycine.
Reaction SMILES: C(O)C.[C:4]1([NH:10][NH2:11])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(N(CC)CC)C>[C:4]1([NH:10][NH:11][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NNc1ccccc1
Reactant: CCOC(=O)Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)NNc1ccccc1
Temperature: 0 °C
Yield: 86 %

Procedure:
Into 200 ml of ethanol were poured 21.6 g (0.2 mol) of phenylhydrazine and 30 ml of triethylamine, and 21.6 g (0.2 mol) of ethyl chloroformate was slowly added dropwise thereto. After the addition, the mixture was refluxed for 30 minutes and then poured into ice-water. The mixture was extracted with ethyl acetate, and the extract was concentrated and purified by column chromatography to obtain 31 g of N-phenyl-N'-ethoxycarbonylhydrazine as an oily substance.
Reaction SMILES: O.NN.[O:4]([N:11]1C(=O)C2[C:13](=CC=CC=2)[C:12]1=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[N:22]1[C:31]2[C:26](=[CH:27][C:28]([CH2:32][C:33]3[N:37]4[N:38]=[C:39](C(=O)C)[CH:40]=[CH:41][C:36]4=[N:35][N:34]=3)=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1.Cl>CO>[C:5]1([O:4]/[N:11]=[C:12](/[C:39]2[CH:40]=[CH:41][C:36]3[N:37]([C:33]([CH2:32][C:28]4[CH:27]=[C:26]5[C:31](=[CH:30][CH:29]=4)[N:22]=[CH:23][CH:24]=[CH:25]5)=[N:34][N:35]=3)[N:38]=2)\[CH3:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(=O)c1ccc2nnc(Cc3ccc4ncccc4c3)n2n1
Reactant: O=C1c2ccccc2C(=O)N1Oc1ccccc1
Agent: Cl
Agent: NN
Solvent: CO
Solvent: O
Product: C/C(=N\Oc1ccccc1)c1ccc2nnc(Cc3ccc4ncccc4c3)n2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.3 %

Procedure:
Hydrazine monohydrate (5.45 mg, 0.109 mmol) was added to a solution of 2-phenoxyisoindoline-1,3-dione (Organic Lett, 2001, 31, 139) (30.8 mg, 0.129 mmol) in 10 mL of MeOH. The solution was heated at reflux for 2 h and then cooled to rt. White precipitate was filtered off and 1-(3-(quinolin-6-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (41.2) (30 mg, 0.1 mmol) was added. The pH value of solution was adjusted to 5-6 with 1N HCl solution. The reaction solution was then stirred at it overnight. Solvent was evaporated and the crude was purified by HPLC (acidic with 0.05% TFA) to give 23 mg (59%) of the title compound as a white solid (TFA salt). 1H-NMR (400 MHz, CDCl3) δ ppm 9.23 (d, 1H), 8.68 (d, 1H), 8.53 (d, 1H), 8.15 (m, 3H), 8.04 d, 1H), 7.83 (m, 1H), 7.40 (t, 2H), 7.29 (m, 2H), 7.15 (t, 1H), 4.92 (s, 2H), 2.56 (s, 3H). LC-MS (method H): [MH]+=395.2, tR=2.42 min.
Reaction SMILES: [OH:1][C@@H:2]([C:4]1[N:15]([C@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22](=[O:28])[CH2:23][CH2:24][C:25]([NH2:27])=O)[CH2:17]2)[C:7]2=[C:8]3[S:14][CH:13]=[CH:12][C:9]3=[N:10][CH:11]=[C:6]2[N:5]=1)[CH3:3].C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCCC1>[OH:1][C@@H:2]([C:4]1[N:15]([C@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22](=[O:28])[CH2:23][CH2:24][C:25]#[N:27])[CH2:17]2)[C:7]2=[C:8]3[S:14][CH:13]=[CH:12][C:9]3=[N:10][CH:11]=[C:6]2[N:5]=1)[CH3:3]
Reactant: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CCCN(C(=O)CCC(N)=O)C1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CCCN(C(=O)CCC#N)C1
Temperature: 0 °C
Yield: 55.9 %

Procedure:
To a mixture of 4-((3S)-3-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}piperidin-1-yl)-4-oxobutanamide (5.5 mg, 0.014 mmol) and triethylamine (9.6 μL, 0.069 mmol) in tetrahydrofuran (0.2 mL) stirring at about 0° C. was added trifluoroacetic anhydride (4.8 μL, 0.034 mmol). The resulting mixture was kept cold and stirred for 2 h. The mixture was concentrated then purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give 3 mg (57%) of the desired product. LCMS calculated for C19H22N5O2S (M+H)+: m/z=384.1. Found: 384.2.
Reaction SMILES: [C:1]([N:4]1[C:8]([CH3:9])=[C:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6](=[O:17])[NH:5]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[C:25]1(Br)[O:51][C@H:50]([CH2:52][O:53][C:54](=[O:59])[C:55]([CH3:58])([CH3:57])[CH3:56])[C@@H:42]([O:43][C:44](=[O:49])[C:45]([CH3:48])([CH3:47])[CH3:46])[C@H:34]([O:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])[C@H:26]1[O:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30]>C(#N)C.O1CCCC1>[C:1]([N:4]1[C:8]([CH3:9])=[C:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]([O:17][C@@H:25]2[O:51][C@H:50]([CH2:52][O:53][C:54](=[O:59])[C:55]([CH3:58])([CH3:57])[CH3:56])[C@@H:42]([O:43][C:44](=[O:49])[C:45]([CH3:46])([CH3:47])[CH3:48])[C@H:34]([O:35][C:36](=[O:41])[C:37]([CH3:38])([CH3:39])[CH3:40])[C@H:26]2[O:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:30])[CH3:31])=[N:5]1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)C(=O)OC[C@H]1OC(Br)(Br)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Reactant: CC(=O)n1[nH]c(=O)c(Cc2ccccc2)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(=O)n1nc(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)c(Cc2ccccc2)c1C
Temperature: 25 °C
Yield: 79.2 %

Procedure:
To a suspension of 1-acetyl-4-benzyl-1,2-dihydro-5-methyl-3H-pyrazol-3-one (0.75 g) in acetonitrile (5 mL) and tetrahydrofuran (3 mL) was added potassium carbonate (0.675 g) under stirring at room temperature. After the mixture was stirred at 50° C. for 1 hour, 1-bromo-2,3,4,6-tetra-O-pivaloyl-α-D-glucopyranosyl bromide (2.27 g) was added to the mixture. The mixture was stirred at 50° C. for 6 hours. After the reaction completed, the insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane=1/10 to 1/5) to give 1-acetyl-4-benzyl-5-methyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole (1.88 g).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[N+:13]([C:16]1[CH:29]=[CH:28][C:19]([CH2:20][CH:21]2[C:25](=[O:26])[NH:24][C:23](=[O:27])[NH:22]2)=[CH:18][CH:17]=1)([O-:15])=[O:14].O[CH2:31][CH2:32][C:33]1[CH:42]=[CH:41][C:36]([NH:37][C:38](=[O:40])[CH3:39])=[CH:35][CH:34]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>COCCOC>[N+:13]([C:16]1[CH:29]=[CH:28][C:19]([CH2:20][CH:21]2[C:25](=[O:26])[N:24]([CH2:31][CH2:32][C:33]3[CH:42]=[CH:41][C:36]([NH:37][C:38](=[O:40])[CH3:39])=[CH:35][CH:34]=3)[C:23](=[O:27])[NH:22]2)=[CH:18][CH:17]=1)([O-:15])=[O:14]
Reactant: O=C1NC(=O)C(Cc2ccc([N+](=O)[O-])cc2)N1
Reactant: CC(=O)Nc1ccc(CCO)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: CC(=O)Nc1ccc(CCN2C(=O)NC(Cc3ccc([N+](=O)[O-])cc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 71.8 %

Procedure:
A solution of diethylazodicarboxylate (7.8 g) in DME (40 ml) was added dropwise under N2 to a stirred mixture of the product from step (a) (10.5 g), the product from step (c) (8.0 g) and triphenylphosphine (11.7 g) in DME (400 ml). When addition was complete, the mixture was stirred at room temperature for 17 hours, then evaporated in vacuo and the residue crystallised from ethanol/ether (1:4 v/v) to give the desired product as a pale yellow solid (12.7 g), [α]D25 -97.8° (c=0.50, MeOH).
Reaction SMILES: [OH:1][C:2]1([CH3:14])[CH2:11][CH2:10][C:9]2[CH:5]([CH2:6][CH2:7][C:8]=2[CH3:12])[CH:4]([CH3:13])[CH2:3]1.[H-].[Na+].S(OC)(O[CH3:21])(=O)=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1C=CC=CC=1>[CH3:21][O:1][C:2]1([CH3:14])[CH2:11][CH2:10][C:9]2[CH:5]([CH2:6][CH2:7][C:8]=2[CH3:12])[C:4](=[CH2:13])[CH2:3]1
Reactant: CC1=C2CCC(C)(O)CC(C)C2CC1
Reactant: COS(=O)(=O)OC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: C=C1CC(C)(OC)CCC2=C(C)CCC12
Yield: 74 %

Procedure:
9.6 g of 6-hydroxy-1,6-dimethyl-4-methyl-2,3,3a,4,5,6,7,8-octahydroazulene in 300 ml of absolute benzene were heated to reflux for 15 hours with 4.8 g of sodium hydride (50% paraffin-containing paste, purified by washing with benzene). Then 95 ml of freshly distilled dimethyl sulphate were added at 40°. The mixture was stirred at reflux for a further 7 hours, cooled to 5°, treated with 20% citric acid solution and extracted with ether. The ethereal phase was washed with bicarbonate solution and water, dried in a conventional manner and concentrated under reduced pressure. The oily residue so obtained (12.5 g) was loaded onto 125 g of silica gel and by elution with hexane there were obtained 7.65 g (74%) of 6-methoxy-1,6-dimethyl-4-methylen-2,3,3a,4,5,6,7,8-octahydroazulene which was then distilled in high vacuum; b.p.0.02 ca 55°; IR(film):νmax =3090, 1640, 1450/40, 1370, 1252, 1120, 1080, 890, 835, 765/55 cm-1. The compound has a camphorous, woody odour.
Reaction SMILES: [C:1]([C:5]1[CH:26]=[CH:25][C:8]([CH2:9][N:10]([CH2:22][CH2:23][OH:24])[C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:21]=2[NH:20][CH:19]=[CH:18]3)=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]1[CH:33]=[CH:32][C:31](O)=[CH:30][CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C>C1COCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]([CH2:22][CH2:23][O:24][C:31]2[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=2)[C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:21]=2[NH:20][CH:19]=[CH:18]3)=[O:12])=[CH:25][CH:26]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Oc1ccc(F)cc1
Reactant: CC(C)(C)c1ccc(CN(CCO)C(=O)c2cccc3cc[nH]c23)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(CN(CCOc2ccc(F)cc2)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Yield: 45 %

Procedure:
To a solution of 175 mg (0.5 mmol) of 1H-indole-7-carboxylic acid (4-tert-butyl-benzyl)-(2-hydroxy-ethyl)-amide, 62 mg (0.55 mmol) of 4-fluorophenol and 144 mg (0.55 mmol) of triphenyl phosphine in 5 ml THF were added dropwise 88 μl (0.55 mmol) of azodicarboxylic acid diethyl ester at 0° C. The reaction mixture was stirred at rt over night. The solvent was evaporated and the residue was dissolved in diethyl ether. The organic layer was washed twice with 2N aqueous NaOH solution, once with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and the solvent was evaporated. The residue was purified by column chromatography (silica gel; diethyl ether/heptane 1:1) to yield 100 mg (45%) product as a white solid. MS (ISP) 445.4 (M+H)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:9]=[C:10](/[C:15](/[CH3:25])=[CH:16]\[CH:17]=[CH:18]\[C:19](\[CH3:24])=[CH:20]\[C:21]([OH:23])=O)[CH:11]=[C:12]([Br:14])[CH:13]=1.C[Si](C)(C)[O:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][Si](C)(C)C)=[CH:31][CH:30]=1.[F-].[K+]>CN(C=O)C.CCOCC>[OH:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:21](=[O:23])/[CH:20]=[C:19](\[CH3:24])/[CH:18]=[CH:17]/[CH:16]=[C:15](\[C:10]2[CH:11]=[C:12]([Br:14])[CH:13]=[C:8]([Br:7])[CH:9]=2)/[CH3:25])=[CH:31][CH:30]=1
Reactant: C[Si](C)(C)Nc1ccc(O[Si](C)(C)C)cc1
Reactant: C/C(=C/C=C/C(C)=C/C(=O)O)c1cc(Br)cc(Br)c1
Agent: O=C(Cl)C(=O)Cl
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C/C(=C/C=C/C(C)=C/C(=O)Nc1ccc(O)cc1)c1cc(Br)cc(Br)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of dry ether (30 mL) and DMF (0.5 g, 7 mmol) was cooled to 15° C. and then treated with oxalyl chloride (0.2 g, 1.5 mmol) and stirred for 15 min. All solvent was then removed and dimethylchloroformamidinium chloride (Helv. Chim. Acta 42, 1653 (1959)) as a white solid was suspended in DMF (5 mL). To this was added (2E,4E,6Z)-7-(3,5-dibromophenyl)-3,7-dimethyl-2,4,6-heptatrienoic acid (0.30 g, 0.8 mmol) and the mixture was stirred at room temperature for 3-4 h. The reaction was cooled to 0° C. and treated over a 10 min period with a solution of O,N-bis(trimethylsilyl)-4-aminophenol (0.6 g, 2.4 mmol) in DMF (5 mL). Once the addition was complete stirring was continued for 1 h and then it was poured into 5% aqueous KF (10 mL) and stirred a further 1 h. The aqueous mixture was extracted with ether, purified by HPLC using 35% EtOAc/hexanes as eluent to give N-(4-hydroxyphenyl)-(2E,4E,6Z)-7-(3,5-dibromophenyl)-3,7-dimethyl-2,4,6-heptatrienamide.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([Br:22])[CH:16]=2)[CH2:9]1)(OC(C)(C)C)=O.C(N1CCO[C@H:32]([CH2:36][C:37]2C=CC=C(C=CC3C=NC=CC=3)C=2)[CH2:31]1)(OC(C)(C)C)=O.BrCCCC.C(O)(C(F)(F)F)=O>>[Br:22][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[O:21][CH2:31][CH2:32][CH2:36][CH3:37])[CH2:14][C@H:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2ccc(O)c(Br)c2)C1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cccc(C=Cc3cccnc3)c2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCBr
Product: CCCCOc1ccc(C[C@@H]2CNCCO2)cc1Br

Procedure:
Example 61 was prepared using the same procedure as described for example 4, starting from N-BOC-(R)-2-(3-bromo-4-hydroxybenzyl)morpholine, example 4, intermediate (a), and 1-bromobutane. The resulting intermediate was deprotected with TFA as described for example 4 to yield the desired morpholine example 61 as a colorless oil (28 mg, 63% over 2 steps) after purification by HPLC.
Reaction SMILES: [CH2:1]([N:3]([CH2:28][CH3:29])[CH2:4][CH2:5][N:6]([S:24]([CH3:27])(=[O:26])=[O:25])[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:23])[CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:15][CH3:16])=[CH:9][CH:8]=1)[CH3:2].C(OCC)C.[C:35]1([Mg]Br)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[Cl-].[NH4+]>O>[CH2:28]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]([S:24]([CH3:27])(=[O:26])=[O:25])[C:7]1[CH:8]=[CH:9][C:10]([C:13]([OH:23])([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:15][CH3:16])=[CH:11][CH:12]=1)[CH3:29]
Reactant: Br[Mg]c1ccccc1
Reactant: CCC(C(=O)c1ccc(N(CCN(CC)CC)S(C)(=O)=O)cc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Product: CCC(c1ccccc1)C(O)(c1ccccc1)c1ccc(N(CCN(CC)CC)S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
N-(2-Diethylaminoethyl)-4'-(1-oxo-2-phenylbutyl)methanesulfonanilide (24.0 g., 0.0576 mole) is dissolved in 500 ml. ethyl ether and added dropwise during 1/2 hr. to a solution of phenylmagnesium bromide (0.145 mole) in 500 ml. ethyl ether. The mixture is heated at reflux for 16 hrs. After cooling to room temperature, 100 g. of ammonium chloride in 400 ml. water is added and the solution is stirred for 15 min. The ether layer is separated and the aqueous layer is extracted with ethyl ether and the combined ether solutions are washed with water followed by 1N HCl. The acidic aqueous wash is washed with ethyl ether and basified with 50% NaOH to pH 11. The product is extracted with ethyl ether and the ether solution is washed with water and dried (MgSO4). Evaporation of the ethyl ether yields 28 g. of product as an oil (100% yield).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.Cl[C:19]([O:21][CH3:22])=[O:20]>>[CH3:22][O:21][C:19]([NH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:6][CH2:7]1)=[O:20]
Reactant: NC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: COC(=O)Cl
Product: COC(=O)NC1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
The title compound is prepared from benzyl 4-aminopiperidine-1-carboxylate and methyl chloroformate following a procedure analogous to that described for Intermediate 26 Step 1. LC (method 1): tR=0.92 min; Mass spectrum (ESI+): m/z=293 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].O.Cl[CH2:17][C:18](=[O:25])[C:19]([CH3:24])([CH3:23])[CH2:20][CH2:21][Cl:22]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:17][C:18](=[O:25])[C:19]([CH3:24])([CH3:23])[CH2:20][CH2:21][Cl:22])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(C)(CCCl)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(CCCl)C(=O)COc1ccc(Cl)cc1
Temperature: 40 °C
Yield: 82.6 %

Procedure:
92.5 g (0.72 mol) of 4-chlorophenol and 99.4 g (0.72 mol) of potassium carbonate in 500 ml of toluene are heated under reflux for 2 hours, the water of reaction distilling off azeotropically. The mixture is cooled to 40° C., and 110 g (0.6 mol) of 1,5-dichloro-3,3-dimethyl-pentan-2-one in 300 ml of toluene are added. The reaction mixture is heated at 100° C. for 5 hours, and is then cooled and filtered off under suction from the inorganic residue. The filtrate is washed with dilute sodium hydroxide solution and water, dried over sodium sulphate and evaporated down. 136.3 g (82.6% of theory) of crude 1-(4-chlorophenoxy)-5-chloro-3,3-dimethyl-pentan-2-one are obtained, and this product is directly reacted further. ##STR32##
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:8]12[CH2:14][CH:11]([CH2:12][CH2:13]1)[CH2:10][C:9]2=O.N1C2C=CC=CC=2N=N1.[BH4-].[Na+]>CO.O.C1(C)C(C)=CC=CC=1>[C:8]12([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[NH2:1])[CH2:14][CH:11]([CH2:12][CH2:13]1)[CH2:10][CH2:9]2
Reactant: O=C1CC2CCC1C2
Reactant: Nc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Agent: c1ccc2[nH]nnc2c1
Solvent: Cc1ccccc1C
Solvent: O
Solvent: CO
Product: Nc1ccccc1C12CCC(CC1)C2
Reaction time: 16 h
Yield: 106.9 %

Procedure:
In a 250 mL flask equipped with a Dean-Start separator, the following mixture is brought to reflux: 9.3 g of aniline, 12.1 g 2-norbornanone, 13.2 g benzotriazole and 120 mL xylene. After 16 h, the mixture is reduced to dryness, then it is solubilized in 300 mL methanol, and the product is reduced with 6 g NaBH4 at 50° C. for 1 h. The mixture is then poured into 200 mL water and the organic product is extracted with 3×100 mL toluene. The organic phase is recovered, dried over magnesium sulfate, and then reduced to dryness. In this manner, 20 g of the desired amine are produced.
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.[OH:21][CH2:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][NH:26][CH2:27]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[OH:21][CH2:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][N:26]([C:3]1[C:2]([F:1])=[CH:15][C:14]3[C:13](=[O:16])[C:12]([C:17]([OH:19])=[O:18])=[CH:11][N:6]4[CH:7]([CH3:10])[CH2:8][O:9][C:4]=1[C:5]=34)[CH2:27]2
Reactant: CC1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: OCc1cccc2c1CNC2
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC1COc2c(N3Cc4cccc(CO)c4C3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Yield: 29.3 %

Procedure:
281 mg of 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido [1,2,3-de][1,4]-benzoxazine-6-carboxylic acid, 179 mg of 4-hydroxymethylisoindoline, 304 mg of DBU, and 2 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 120 mg of the target compound.