Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:8]=[N:9][C:10]3[CH:11]=[CH:12][CH:13]=[C:14]([CH:17]=O)[C:15]=3[CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19]/[C:20](/[CH3:24])=[CH:21]\[C:22]#[N:23].[C:25]([O:31][CH:32]([CH3:34])[CH3:33])(=[O:30])[CH2:26][C:27]([CH3:29])=O>C(O)C>[C:22]([C:21]1[CH:17]([C:14]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:15]=2[CH:16]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[N:9]3)[C:26]([C:25]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30])=[C:27]([CH3:29])[NH:19][C:20]=1[CH3:24])#[N:23]
Reactant: C/C(N)=C/C#N
Reactant: CC(=O)CC(=O)OC(C)C
Reactant: O=Cc1cccc2nnc(-c3ccccc3)cc12
Solvent: CCO
Product: CC1=C(C#N)C(c2cccc3nnc(-c4ccccc4)cc23)C(C(=O)OC(C)C)=C(C)N1
Yield: 23.6 %

Procedure:
750 mg (3.2 mmol) of 3-phenyl-5-cinnolinecarboxaldehyde, 263 mg (3.2 mmol) of 3-aminocrotononitrile and 457 mg (3.2 mmol) of isopropyl acetoacetate are boiled under reflux for 2.5 days in 25 ml of ethanol. The mixture is concentrated and separated on a silica gel column using toluene/ethyl acetate mixtures. The desired fractions are collected and concentrated. The evaporation residue obtained is crystallised using ether and filtered off with suction. 320 mg of crystals of melting point 200°-202° C. are obtained.
Reaction SMILES: Cl.[OH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:21]2[CH:20]=[CH:19][C:18]([CH:22]=[O:23])=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2.[Si:24](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25].N1C=CN=C1>ClCCl.ClCCCl>[Si:24]([O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:21]2[CH:20]=[CH:19][C:18]([CH:22]=[O:23])=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: O=Cc1ccc2c(c1)c1ccccc1n2CCCCCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)[Si](C)(C)OCCCCCCn1c2ccccc2c2cc(C=O)ccc21

Procedure:
In Reaction 1, a reactant reacts with 1,2-dichloroethane at 0° C. to thus prepare a precursor 2, which is then further reacted in the presence of 10% HCl, affording a precursor 3. The reaction is progressed through reflux. Then, 9-(6-hydroxyhexyl)-9H-carbazole-3-carbaldehyde, dichloromethane, tert-butyldimethylsilyl chloride, and imidazole are reacted together, thus producing 4 (9-(6-(tert-butyldimethylsilyloxy)hexyl)-9H-carbazole-3-carbaldehyde) as a precursor. Then, the precursor 4 is dissolved in sodium borohydride and methanol to thus allow the obtained solution to react, yielding 5 ((9-(6-(tert-butyldimethylsilyloxy)hexyl)-9H-carbazol-3-yl)methanol as a precursor.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.Cl.[CH2:11]([NH2:13])[CH3:12].CCN(CC)CC>C(O)CCC>[NH2:8][C:6]1[CH:5]=[C:4]([Cl:9])[N:3]=[C:2]([NH:13][CH2:11][CH3:12])[N:7]=1
Reactant: CCN
Reactant: Nc1cc(Cl)nc(Cl)n1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: CCNc1nc(N)cc(Cl)n1
Temperature: 90 °C

Procedure:
A mixture of 2,6-dichloro-4-aminopyrimidine 18-1 (Avocado; 4.8 g, 29.3 mmol), ethylamine hydrochloride (7.0 g, 85.8 mmol), Et3N (20 mL, 144 mmol) and n-butanol (150 mL) was heated to 90° C. for 6 hours. After cooling, the solvent was removed in vacuo and the residue partitioned between saturated Na2CO3 solution and EtOAc. The EtOAc layer was washed with brine, dried (MgSO4) and concentrated to give an orange solid. Purification by column chromatography (EtOAc/hexane 1:1) gave the title compound 18-2 as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][CH2:9][C:8](=[O:12])[N:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.CI.[C:22](=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:22])[CH2:10][CH2:9][C:8](=[O:12])[N:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1CCNc2ccc(Cl)cc2N1c1ccccc1
Agent: [K+]
Solvent: CI
Product: CN1CCC(=O)N(c2ccccc2)c2cc(Cl)ccc21

Procedure:
20.4 g 8-chloro-1-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-one is stirred for 2 hours on a water bath with 12.8 g methyl iodide and 10 g anhydrous potassium carbonate. The inorganic material is removed by filtration under suction and the filtrate is diluted with 200 ml water. The crystalline precipitate is filtered under suction, washed with water, and recrystallized from alcohol. The yield is 20 g of the m.p.=143°-144° C. (93% of the theory).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[O:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([N:14]3[CH2:18][CH2:17][C@@H:16]([NH2:19])[CH2:15]3)[C:8]=2[CH2:7][CH2:6]1.[N:20]1[CH:25]=[CH:24][CH:23]=CC=1.C1(N)CC1>C1COCC1>[O:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([N:14]3[CH2:18][CH2:17][C@@H:16]([NH:19][C:1]([NH:20][CH:25]4[CH2:23][CH2:24]4)=[O:2])[CH2:15]3)[C:8]=2[CH2:7][CH2:6]1
Reactant: O=C(Cl)Cl
Reactant: c1ccncc1
Reactant: N[C@@H]1CCN(c2cccc3c2CCO3)C1
Agent: NC1CC1
Solvent: C1CCOC1
Product: O=C(NC1CC1)N[C@@H]1CCN(c2cccc3c2CCO3)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 77 %

Procedure:
Phosgene (1 mL, 20% in toluene) was added to a solution of (R)-N-(2,3-dihydrobenzofuran-4-yl)-3-(amino)pyrrolidine (102 mg) and pyridine (79 mg) in THF (5.6 mL) at 0° C. After stirring for 20 min, cyclopropylamine (228 mg) was added to the reaction and the reaction mixture was allowed to warm to room temperature. After stirring for 2 h, the reaction was quenched with water and THF was removed. The residue was purified by flash chromatography over silica gel (elution with 5% methanol in ethyl acetate) to give 110 mg (77%) of the desired product as solid.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([OH:9])[CH2:5][CH2:4]1.C[O-].[Na+].[F:13][C:14]([F:21])([F:20])[C:15](OCC)=[O:16]>O1CCOCC1>[F:13][C:14]([F:21])([F:20])[C:15]([NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([OH:9])[CH2:5][CH2:4]1)=[O:16]
Reactant: CCOC(=O)C(F)(F)F
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(N[C@H]1CC[C@H](O)CC1)C(F)(F)F

Procedure:
25 g of trans-4-aminocyclohexanol hydrochloride were suspended in 250 mL of dry dioxane and 30 mL of sodium methylate solution (30% in methanol, 1 equivalent) were added. 39.3 mL of ethyl trifluoroacetate were added and the reaction mixture was allowed to stir until the reaction was complete. The reaction mixture was evaporated, taken up in 50 mL of 0.1 N HCl and extracted several times with dichloromethane:isopropanol 3:1. The combined organic layer was extracted once with 0.1 N HCl and brine, dried over sodium sulfate and evaporated to dryness to yield 29.0 g of 148. Rt=0.69 min (Method C). Detected mass: 212.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][C:5]2[O:6][C:7]3([C:32]4[N:33]([CH:34]=[CH:35][CH:36]=4)[C:4]=2[CH:3]=1)[CH2:12][CH2:11][N:10]([C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C@@H:23]2[CH2:27][O:26]C(C)(C)[O:24]2)=[C:17]([O:30][CH3:31])[CH:16]=1)=[O:14])[CH2:9][CH2:8]3.O.CC1C=CC(S(O)(=O)=O)=CC=1.O>CO>[Cl:1][C:2]1[CH:38]=[CH:37][C:5]2[O:6][C:7]3([C:32]4[N:33]([CH:34]=[CH:35][CH:36]=4)[C:4]=2[CH:3]=1)[CH2:12][CH2:11][N:10]([C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C@@H:23]([OH:24])[CH2:27][OH:26])=[C:17]([O:30][CH3:31])[CH:16]=1)=[O:14])[CH2:9][CH2:8]3
Reactant: COc1cc(C(=O)N2CCC3(CC2)Oc2ccc(Cl)cc2-n2cccc23)ccc1OC[C@@H]1COC(C)(C)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COc1cc(C(=O)N2CCC3(CC2)Oc2ccc(Cl)cc2-n2cccc23)ccc1OC[C@@H](O)CO
Temperature: 80 °C

Procedure:
(R)-(8-Chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-3-methoxyphenyl)methanone (41 mg, 0.076 mmol) and 4-methylbenzenesulfonic acid hydrate (2.9 mg, 0.015 mmol) were dissolved in MeOH (760 μL) and H2O (76 μL) was added. The reaction mixture was heated at 80° C. for 45 min. The mixture was filtered and the residue was purified by reverse phase HPLC using 5 mM HCl/H2O and MeOH to yield (S)-(8-chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(4-(2,3-dihydroxypropoxy)-3-methoxyphenyl)methanone. ESI-MS m/z calc. 498.2. found 499.3 (M+1)+; Retention time: 4.72 minutes (15 min run).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=1.[F:21][C:22]([F:29])([F:28])[C:23](OCC)=[O:24].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[Br:20][C:17]1[CH:16]=[CH:15][C:14]([F:13])=[C:19]([C:23](=[O:24])[C:22]([F:29])([F:28])[F:21])[CH:18]=1
Reactant: Fc1ccc(Br)cc1
Reactant: CCOC(=O)C(F)(F)F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(c1cc(Br)ccc1F)C(F)(F)F
Temperature: -40 °C
Reaction time: 1 h

Procedure:
To a stirring solution of diisopropylamine (56.4 g, 0.55 mol) in THF (500 mL) at −40° C., n-butyl lithium (200 mL, 2.66 M hexane solution) was added dropwise. The mixture was stirred at −40° C. for 1 hour and then cooled to −78° C. Then, a solution of 4-fluorobromobenzene (87.5 g, 0.50 mol) in THF (100 mL) was slowly added dropwise thereto such that the inner temperature of the reaction solution did not exceed −70° C. After the reaction solution was stirred at −78° C. for 1 hour, a solution of ethyl trifluoroacetate (65.4 mL, 0.55 mol) in THF (100 mL) was added thereto at the same temperature. After the temperature of the reaction solution was raised to 0° C. over 1 hour under stirring, a saturated aqueous ammonium chloride solution was added thereto, and the solution was diluted with ethyl acetate. The organic layer was separated and washed with saturated brine and then dried over magnesium sulfate. After the drying agent was removed by filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/4), and the resulting yellow oily substance was purified again by distillation under reduced pressure (1 mmHg, 53° C.), whereby the objective compound (83.8 g, 61.8%) was obtained as a yellow oily substance.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([C:12]2[CH2:13][CH2:14][N:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:16][CH:17]=2)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:30])[N:7]2[C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:29].FC(F)(F)[C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1.C(O)(C(F)(F)[F:47])=O>>[C:18]([N:15]1[CH2:14][CH2:13][CH:12]([C:10]2[CH:9]=[C:8]3[C:3]([CH:4]=[CH:5][C:6](=[O:30])[N:7]3[C:22]3[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:29])=[C:2]([C:38]3[CH:37]=[CH:36][C:35]([F:47])=[CH:34][CH:33]=3)[CH:11]=2)[CH2:17][CH2:16]1)([CH3:19])([CH3:21])[CH3:20]
Reactant: CC(C)(C)N1CC=C(c2cc(Br)c3ccc(=O)n(-c4c(Cl)cccc4Cl)c3c2)CC1
Reactant: O=C(O)C(F)(F)F
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Product: CC(C)(C)N1CCC(c2cc(-c3ccc(F)cc3)c3ccc(=O)n(-c4c(Cl)cccc4Cl)c3c2)CC1

Procedure:
The title compound was prepared from 5-bromo-7-(1-tert-butyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(2,6-dichlorophenyl)quinolin-2(1H)-one (INTERMEDIATE ABA5) and using 3-trifluoromethylphenylboronic acid as described in EXAMPLE ABA11. 1H NMR (CD3OD, 500 MHz) TFA salt: δ 1.358 (s, 9H), 1.780 (q, J=10.5, 12.8 Hz, 2H), 2.062 (d, J=15.6 Hz, 2H), 2.702 (m, 1H), 3.004 (t, J=13.0 Hz, 2H), 3.612 (d, J=13.0 Hz, 2H), 6.460 (s, 1H), 6.682 (d, J=10.2 Hz, 1H), 7.204 (s, 1H), 7.565 (t, J=8.8 Hz, 1H) 7.672-7.742 (m, 5H), 7.778 (m, 1H), 7.844 (d, J=10.2 Hz, 1H). Mass spectrum (ESI): 573.5 (M+1).
Reaction SMILES: O.[C@@H:2]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[CH2:3]1.O.C[Si](C)(C)N[Si](C)(C)C.CO[C:32]1[CH:51]=[CH:50][CH:49]=[CH:48][C:33]=1[C:34](Cl)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.CN1CC[O:56][CH2:55]C1>C(#N)C.N1C=CC=CC=1>[CH3:55][O:56][NH:15][C:14]1[C:13]2[N:12]=[CH:11][N:10]([C:19]=2[N:18]=[CH:17][N:16]=1)[C@:2]1([C:34]([C:33]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:32]=2)([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[CH2:3]1
Reactant: CN1CCOCC1
Reactant: Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1
Reactant: COc1ccccc1C(Cl)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: c1ccncc1
Solvent: CC#N
Solvent: O
Product: CONc1ncnc2c1ncn2[C@@]1(C(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H](O)[C@@H](CO)O1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Deoxyadenosine hydrate dA×H2O (50 g, 186 mmol.) was dried by coevaporation with pyridine and acetonitrile, and suspended in acetonitrile (200 ml). 1,1,1,3,3,3-hexamethyldisilazane (96 ml, 74.9 g, 465 mmol) was added and the resulting suspension was stirred over night at ambient temperature. The reaction mixture was concentrated to dryness by evaporation. The residue was dried by coevaporation with pyridine and dissolved in pyridine (260 ml). The solution was cooled on an ice bath and monomethoxytritylchloride (54.5 g, 177 mmol) was added. The reaction mixture was kept in a refrigerator at appr. 4° C. for 3 days. Additional portions of monomethoxytritylchloride (2 times 13.6 g, 45 mmol) were added successively in 24-hour time intervals while the reaction mixture was stirred at ambient temperature. The reaction mixture was treated with N-methylmorpholine (30 ml), stirred at ambient temperature for 30 minutes and evaporated to dryness. The residue was dissolved in ethylacetate (330 ml) and extracted with water (200 ml), 5% aqueous sodium hydrogencarbonate solution (2 times 200 ml) and brine (200 ml). The organic phase was concentrated to dryness by evaporation. The residue was dissolved in pyridine (100 ml) and water (20 ml), and stirred at 40° C. for 2 days. The solution was concentrated to a foam by evaporation. Purification by column chromatography on silica gel (acetone/dichloromethane, gradient elution) afforded the product in 99.9% purity by RP-HPLC (70 g, 67%). UV λmax 272 nm.
Reaction SMILES: [CH3:1][CH2:2][CH2:3]Br.[OH:5][CH2:6][CH2:7][S:8]([C:11]1[CH:12]=[C:13]([C:26](=[O:43])[CH2:27][CH2:28][C:29]([C:31]2[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[C:33]([O:41][CH3:42])[CH:32]=2)=[O:30])[CH:14]=[C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:16]=1[OH:17])(=[O:10])=[O:9].C(=O)([O-])[O-]>CN(C=O)C>[OH:5][CH2:6][CH2:7][S:8]([C:11]1[CH:12]=[C:13]([C:26](=[O:43])[CH2:27][CH2:28][C:29]([C:31]2[CH:32]=[C:33]([O:41][CH3:42])[C:34]([O:39][CH3:40])=[C:35]([O:37][CH3:38])[CH:36]=2)=[O:30])[CH:14]=[C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:16]=1[O:17][CH2:1][CH2:2][CH3:3])(=[O:10])=[O:9]
Reactant: COc1cc(C(=O)CCC(=O)c2cc(OCc3ccccc3)c(O)c(S(=O)(=O)CCO)c2)cc(OC)c1OC
Reactant: CCCBr
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCCOc1c(OCc2ccccc2)cc(C(=O)CCC(=O)c2cc(OC)c(OC)c(OC)c2)cc1S(=O)(=O)CCO
Temperature: 75 °C
Reaction time: 2 h

Procedure:
n-Propyl bromide (1.63 mL, 17.8 mmol) was added to a solution of 1-[3-(2-hydroxyethylsulfonyl)-4-hydroxy-5-benzyloxyphenyl]-4-(3,4,5-trimethoxyphenyl)butan-1,4-dione (5.53 g, 9.91 mmol) in DMF (10 mL) containing postassium carbonate (2.74 g, 19.9 mmol). The mixture was stirred at 75° C. for 2 h, and partitioned between ethyl ether and water. The aqueous layer was re-extracted with ether (2×) and ethyl acetate. The organic extracts were combined, dried, and evaporated to dryness. The residue was triturated with Et2O to give crystals, which was washed with Et2O containing a small volume of acetone. This material, Rf 0.53 (hexane-ethyl acetate; 1:2, v/v), was used directly in the next experiment without further purification.
Reaction SMILES: [F:1][C:2]1([N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[N+:24]([O-])=O)[C:15]2=[O:27])[CH2:7][CH:6]([O:8][C:9](=[O:11])[CH3:10])[C:5](=[O:12])[NH:4][C:3]1=[O:13]>CO.[Pd]>[NH2:24][C:20]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:21]=1[C:22](=[O:23])[N:14]([C:2]1([F:1])[CH2:7][CH:6]([O:8][C:9](=[O:11])[CH3:10])[C:5](=[O:12])[NH:4][C:3]1=[O:13])[C:15]2=[O:27]
Reactant: CC(=O)OC1CC(F)(N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)C(=O)NC1=O
Agent: [Pd]
Solvent: CO
Product: CC(=O)OC1CC(F)(N2C(=O)c3cccc(N)c3C2=O)C(=O)NC1=O

Procedure:
A solution of 3-fluoro-3-(4-nitro-1,3-dioxoisoindolin-2-yl)-2,6-dioxo-5-acetoxypiperidine (1.0 g, 2.6 mmol) and Pd/C (10%, 0.1 g) in methanol (100 mL) is shaken under hydrogen (50-60 psi) for 3 hours. The suspension is filtered through a pad of Celite and washed with methanol to give 3-(4-amino-1,3-dioxoisoindolin-2-yl)-3-fluoro-2,6-dioxo-5-acetoxypiperidine which is further purified by column chromatography.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](=[O:16])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:9]=1)([O-])=O>C(OCC)(=O)C.C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7](=[O:16])[N:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:9]=1
Reactant: O=c1ccc([N+](=O)[O-])cn1-c1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(=O)n(-c2ccccc2)c1
Reaction time: 3 h

Procedure:
To a suspension of 5-nitro-1-phenyl-1H-pyridin-2-one (60 mg, 0.28 mmol) in ethyl acetate (2 mL) and ethanol (2 mL) was added 5% Pd—C (10 mg), the resulting mixture was stirred under hydrogen atmosphere for 3 h. The catalyst was removed by filtration, and the filtrate was concentrated to give the title compound as a green oil. The product was used to next step without further purification. LC-MS (ES, Pos.): 187 [MH+], and 1H NMR (CDCl3, 400 MHz): δ=3.09 (br s, 2H), 6.60 (d, J=9.6 Hz, 1H), 6.82 (d, J=3.0 Hz, 1H), 7.12 (dd, J=9.6, 3.0 Hz, 1H), 7.37-7.41 (m, 3H), 7.45-7.49 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:4]([CH3:9])([CH3:8])[CH:5]=[CH:6][CH:7]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>CCCCC>[CH3:1][C:2]1[CH:7]=[CH:6][CH2:5][C:4]([CH3:8])([CH3:9])[C:3]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C1C(C)=CC=CC1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCC
Solvent: c1ccccc1
Product: CCOC(=O)C1=C(C)C=CCC1(C)C

Procedure:
A mixture of 2.0 g of 2,6,6-trimethyl-1-ethoxycarbonyl-2,4-cylohexadiene [prepared according to the process indicated in Example 1], 100 mg of p-toluenesulphonic acid and 25 ml of anhydrous benzene were refluxed for 4 hours in a nitrogen atmosphere. The resulting solution was diluted with pentane, washed with a 5 % solution of sodium bicarbonate, then with water, and then dried over Na2SO4 and concentrated.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[C:15]([C:18]([O:20][CH3:21])=[O:19])[CH:16]=[CH:17][C:4]=2[O:3]1.ClC1C=CC=C(C(OO)=[O:31])C=1>ClCCl>[CH3:21][O:20][C:18]([C:15]1[CH:16]=[CH:17][C:4]2[O:3][C:2]([CH3:22])([CH3:1])[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=3[O-:31])[C:5]=2[CH:14]=1)=[O:19]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1ccc2c(c1)C(c1ccccn1)=CC(C)(C)O2
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)C(c1cccc[n+]1[O-])=CC(C)(C)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.3 %

Procedure:
402 mg of methyl 2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran-6-carboxylate were dissolved in 15 ml of dichloromethane at room temperature and 330 mg of m-chloroperbenzoic acid were added. After stirring at room temperature overnight the mixture was washed with sodium bisulphite solution and sodium bicarbonate solution, dried over sodium sulphate and evaporated. The residue was chromatOgraphed on silica gel using 10% (v/v) methanol/ethyl acetate for the elution. The product was recrystallized from t-butyl methyl ether to give 65 mg of 2-[6-(methoxycarbonyl)-2,2-dimethyl-2H-1-benzopyran-4-yl]pyridine N-oxide of melting point 155-157° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[Br:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCOCC>C(#N)C>[BrH:11].[CH3:1][C:2]1[C:10]2[C:5]([N:6]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:7]=[CH:8][CH:9]=2)=[N:4][CH:3]=1
Reactant: BrCCc1ccccc1
Reactant: Cc1c[nH]c2ncccc12
Solvent: CCOCC
Solvent: CC#N
Product: Br
Product: Cc1cnc2n(CCc3ccccc3)cccc1-2
Yield: 27.4 %

Procedure:
A solution of 0.3 g (2.3 mmol) 3-methylpyrrolo[2,3-b]pyridine and 0.5 g (2.7 mmol) (2-bromoethyl)benzene in 10 ml acetonitril was refluxed for 72 h. The solvent was evaporated and the solid that formed was treated with ether. Recrystalization from ethyl acetate gave 0.2 g (27%) of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([CH3:10])[CH:3]=1.[Si]([C:15]([F:18])([F:17])[F:16])(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.Cl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[C:15]([F:18])([F:17])[F:16])=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C=O
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1cc(Br)ccc1C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-2-methylbenzaldehyde (1.5 g, 7.5 mmol) in THF (20 mL) was added TMSCF3 (2.2 g, 15.5 mmol) at 0° C. and then TBAF (1.1 mL, 1.0 M in THF). The mixture was stirred at RT for 1 h, then diluted with HCl (3.0 M, 10 mL), stirred at RT for 1 h and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification by normal phase silica gel column provided 1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethanol as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:16])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1.[Cl:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([I:28])[CH:26]=2)[N:21]=[CH:20][N:19]=1.ClCCCl>CC(O)(C)C>[ClH:17].[I:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][N:19]=[C:18]2[NH:16][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=2)=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1ccc(Oc2ccc(N)cc2C)cn1
Reactant: Clc1ncnc2ccc(I)cc12
Solvent: ClCCCl
Solvent: CC(C)(C)O
Product: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(I)cc34)cc2C)cn1
Product: Cl
Temperature: 0 °C
Yield: 75.8 %

Procedure:
A mixture of 3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamine (4.96 g, 23.18 mmol), 4-Chloro-6-iodo-quinazoline 604 g, 22.06 mmol) in tBuOH (60 mL) and DCE (60 mL) was refluxed for 6 hours. The reaction was cooled to 0° C. and the solid product (8.44 g, 76%) was isolated by filtration and washed with cold CH2Cl2 (50 mL).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:20]3[C:19](=[O:21])[O:18][CH2:17][NH:16][C:15]=3[C:14]([C:22]3[CH:26]=[CH:25][O:24][CH:23]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C-:27]#[N:28].[Na+].C(O)(=O)C>CS(C)=O.O>[C:1]1([S:7]([CH2:10][C:11]2[C:20]([C:19]([OH:18])=[O:21])=[C:15]([NH:16][CH2:17][C:27]#[N:28])[C:14]([C:22]3[CH:26]=[CH:25][O:24][CH:23]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1OCNc2c(-c3ccoc3)ccc(CS(=O)(=O)c3ccccc3)c21
Reactant: [C-]#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CS(C)=O
Product: N#CCNc1c(-c2ccoc2)ccc(CS(=O)(=O)c2ccccc2)c1C(=O)O
Temperature: 60 °C
Yield: 85.9 %

Procedure:
A solution of 5-(benzenesulphonylmethyl)-8-(furan-3-yl)-1,2-dihydro-benzo[d][1,3]oxazin-4-one (Intermediate 210, 0.115 g) and sodium cyanide (0.03 g) in DMSO (4 ml) was stirred and heated at 60° C. for 2 hours. After cooling, the mixture was diluted with water, acidified with acetic acid and extracted with ethyl acetate. The organic layer was dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of DCM:methanol:water:acetic acid (350:20:3:2). The product was crystallized from DCM and cyclohexane to give 6-(benzenesulphonylmethyl)-2-(cyanomethylamino)-3-(furan-3-yl)benzoic acid (0.106 g).