Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8](=[S:28])[NH:9][C:10]=2[C:11]2[C:20]([F:21])=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.Cl[C:30]1[S:31][C:32]([CH2:35][S:36]([CH3:39])(=[O:38])=[O:37])=[CH:33][N:34]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>>[F:21][C:20]1[C:11]([C:10]2[N:9]=[C:8]([S:28][C:30]3[S:31][C:32]([CH2:35][S:36]([CH3:39])(=[O:38])=[O:37])=[CH:33][N:34]=3)[N:4]3[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=23)=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]=[C:17]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:16]=[CH:15]2
Reactant: CS(=O)(=O)Cc1cnc(Cl)s1
Reactant: Nc1nccn2c(=S)[nH]c(-c3ccc4ccc(-c5ccccc5)nc4c3F)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)Cc1cnc(Sc2nc(-c3ccc4ccc(-c5ccccc5)nc4c3F)c3c(N)nccn23)s1
Temperature: 100 °C

Procedure:
A 10 mL microwave vessel was charged with a solution of 8-amino-1-(8-fluoro-2-phenyl-quinolin-7-yl)-2H-imidazo[1,5-a]pyrazine-3-thione (24 mg, 0.000062 mol), 2-chloro-5-[(methylsulfonyl)methyl]-1,3-thiazole (0.026 g, 0.00012 mol), potassium carbonate in DMF (1.7 mL, 0.022 mol). The reaction mixture was heated in the microwave at 100° C. for 10 min. The reaction mixture was heated again at 120° C. for 10 min in the microwave to get full consumption of SM. Reaction mixture was purified by Gilson HPLC eluting with 10→65% acetonitrile: H2O to afford the title compound as an off white solid. 1H NMR (400 MHz, CDCl3): δ=2.85 (s, 3H), 4.36 (s, 2H), 7.34 (d, J=4.80 Hz, 1H), 7.48-7.59 (m, 4H), 7.67 (s, 1H), 7.74-7.78 (m, 2H), 8.04 (d, J=8.84 Hz, 1H), 8.24 (dd, J=8.21, 1.39 Hz, 2H), 8.31 (dd, J=8.72, 1.39 Hz, 1H). MS (ES+): m/z 563.18 (100) [MH+]. HPLC: tR=2.89 min (Open Lynx polar—5 min).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:7]=1[Cl:13])[CH3:2].[Br:15][C:16]1[CH:17]=[CH:18][C:19](F)=[C:20]([CH:23]=1)[CH:21]=[O:22].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[C:10]([O:12][C:19]2[CH:18]=[CH:17][C:16]([Br:15])=[CH:23][C:20]=2[CH:21]=[O:22])[CH:9]=[CH:8][C:7]=1[Cl:13])[CH3:2]
Reactant: CCOC(=O)Cc1cc(O)ccc1Cl
Reactant: O=Cc1cc(Br)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)Cc1cc(Oc2ccc(Br)cc2C=O)ccc1Cl
Temperature: 110 °C
Yield: 32.8 %

Procedure:
(2-Chloro-5-hydroxy-phenyl)-acetic acid ethyl ester (0.5 g, 2.3 mmol), 5-bromo-2-fluorobenzaldehyde (0.33 mL, 2.8 mmol), and potassium carbonate (0.5 g, 3.5 mmol) were combined in 1,4-dioxane (30 mL) and heated to 110° C. for 3 days. After work-up, the crude material was purified by silica gel chromatography (0-20% EtOAc in hexanes) to give the desired product (0.3 g).
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1)[CH2:2][CH3:3].Cl.[NH2:17][OH:18]>>[CH2:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][C:12](=[N:17][OH:18])[CH2:11][CH2:10]1)[CH2:2][CH3:3]
Reactant: CCCOCCCCN1CCC(=O)CC1
Reactant: NO
Agent: Cl
Product: CCCOCCCCN1CCC(=NO)CC1

Procedure:
1-(4-Propoxybutyl)-4-piperidone oxime is prepared from 1-(4-propoxybutyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[S:18]([N:28]1[CH2:33][CH2:32][CH2:31][C@@H:30](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:29]1)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>C1(C)C=CC=CC=1>[C:8]([C:7]([C@H:32]1[CH2:31][CH2:30][CH2:29][N:28]([S:18]([C:21]2[CH:22]=[CH:23][C:24]([CH3:25])=[CH:26][CH:27]=2)(=[O:20])=[O:19])[CH2:33]1)([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)#[N:9]
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CCCN(S(=O)(=O)c3ccc(C)cc3)C2)cc1
Reactant: N#CC(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H](C(C#N)(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 25 °C

Procedure:
Diphenylacetonitrile (13.5 g) was added to a stirred suspension of sodium hydride (3.2 g of a 60% suspension in mineral oil) in anhydrous toluene (250 ml) and the mixture was heated under reflux for 2 hours. On cooling to room temperature, 1-tosyl-3-(R)-(+)-tosyloxypiperidine (23 g) was added in portions and the mixture heated under reflux for 4 hours. The mixture was diluted with toluene (200 ml) and washed with 10% sodium hydroxide (2×100 ml) and brine (100 ml) then dried (MgSO4) and concentrated in vacuo to give an oil which was purified by column chromatography on silica eluting with toluene containing ethyl acetate (0% up to 10%). The product-containing fractions were combined and concentrated in vacuo to give an oil which was crystallised from ethanol to give the title compound, yield 16 g, m.p. 148°-150° C., [α]D25 -94.4° (c 1.0, CH2Cl2).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[O:8])[CH:4]=[CH:3]1>CC(=O)OCC.[Pd]>[CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1
Reactant: CC1(C)C=CC(=O)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1(C)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.3 %

Procedure:
To a solution of 4,4-dimethyl-cyclohex-2-enone (50 g, 403 mmol) in EA (230 mL) a suspension of Pd/C (2.5 g, 10% Pd) in EA is added. The suspension is stirred at rt for 2 h under 1 bar H2. The catalyst is filtered off and the solvent of the filtrate is carefully evaporated to give 4,4-dimethyl-cyclohexanone (50 g) as a colourless oil which slowly crystallizes; 1H NMR (CDCl3): δ 2.34 (t, J=6.4 Hz, 4H), 1.66 (t, J=6.4 Hz, 4H), 1.09 (s, 6H).
Reaction SMILES: Cl.[NH2:2]O.[Cl:4][C:5]1[CH:10]=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:8]=[CH:7][C:6]=1[C:16](=[O:27])[C:17](=[CH:23]OCC)[C:18]([CH:20]1[CH2:22][CH2:21]1)=[O:19].C([O-])(=O)C.[Na+].O>C(O)C>[Cl:4][C:5]1[CH:10]=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:8]=[CH:7][C:6]=1[C:16]([C:17]1[CH:23]=[N:2][O:19][C:18]=1[CH:20]1[CH2:22][CH2:21]1)=[O:27]
Reactant: CCOC=C(C(=O)c1ccc(NS(C)(=O)=O)cc1Cl)C(=O)C1CC1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc(C(=O)c2cnoc2C2CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Hydroxylamine hydrochloride (0.53 g) was added to a stirred solution of 1-[2-chloro-4-(methylsulphonylamino)phenyl]-3-cyclopropyl-2-ethoxymethylenepropane-1,3-dione (2.8 g) in ethanol. Sodium acetate (0.63 g) was then added portionwise over a period of ten minutes. The mixture was then stirred at room temperature for 0.5 hours. Further quantities of hydroxylamine hydrochloride (0.2 g) and sodium acetate (0.24 g) were added and stirring was continued for 0.5 hours. Water was added, the mixture was extracted with dichloromethane and the combined organic extracts were washed with water, dried and the solvent evaporated. The crude product was purified by column chromatography to yield 4-[2-chloro-4-(methylsulphonylamino)benzoyl]-5-cyclopropylisoxazole (compound 1) as a white solid, 1.66 g, m.p. 122.8-124.5° C.
Reaction SMILES: C(OC(=O)[NH:10][C@@H:11]1[CH2:25][C:24]2=[CH:26][N:21]([CH:22]=[N:23]2)[CH2:20][CH:19]=[CH:18][CH2:17][O:16][CH2:15][C@H:14]([CH:27]([CH3:29])[CH3:28])[NH:13][C:12]1=[O:30])C1C=CC=CC=1>CO.[Pd]>[NH2:10][C@@H:11]1[CH2:25][C:24]2=[CH:26][N:21]([CH:22]=[N:23]2)[CH2:20][CH2:19][CH2:18][CH2:17][O:16][CH2:15][C@H:14]([CH:27]([CH3:28])[CH3:29])[NH:13][C:12]1=[O:30]
Reactant: CC(C)[C@H]1COCC=CCn2cnc(c2)C[C@@H](NC(=O)OCc2ccccc2)C(=O)N1
Agent: [Pd]
Solvent: CO
Product: CC(C)[C@H]1COCCCCn2cnc(c2)C[C@@H](N)C(=O)N1
Yield: 17.9 %

Procedure:
A solution of 0.49 g (1.14 mmol) of benzyl((8S,11R)-8-isopropyl-10-oxo-6-oxa-1,9,14-triazabicyclo[11.2.1]hexadeca-3,13(16),14-trien-11-yl)carbamate from step C in 80 ml of methanol was hydrogenated over 0.12 g of palladium on carbon (10%) under a hydrogen atmosphere under autogenous pressure at RT. After the starting material had completely reacted, the mixture was filtered and concentrated. The residue was purified by preparative HPLC. 0.06 g of the title compound was obtained.
Reaction SMILES: [CH3:1]I.[Mg].[CH3:4][O:5][C:6]1[CH:16]=[CH:15][C:9]2[C:10](=[O:14])[CH2:11][CH2:12][O:13][C:8]=2[CH:7]=1.[Cl-].[NH4+]>CCOCC>[OH:14][C:10]1([CH3:1])[C:9]2[CH:15]=[CH:16][C:6]([O:5][CH3:4])=[CH:7][C:8]=2[O:13][CH2:12][CH2:11]1
Reactant: COc1ccc2c(c1)OCCC2=O
Reactant: CI
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: COc1ccc2c(c1)OCCC2(C)O

Procedure:
Methyl iodide (145 g; 64.2 ml) in dry ether (50 ml) was added dropwise with stirring to magnesium turnings (22 g) in dry ether (730 ml). After the initial reaction had ceased the reaction mixture was refluxed for 1 hour, cooled and 2,3-dihydro-7-methoxy-4-oxo-4H-1-benzopyran, (77.9 g) in dry ether (440 ml) was added dropwise with stirring. After addition the reaction mixture was refluxed for 1 hour, cooled and the complex was decomposed by the addition of ammonium chloride solution. The ethereal layer was separated, washed with water and dried. Evaporation of the solvent left 76 g of the title compound as an oil (89%). MS and NMR analysis were correct for the required compound.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[NH2:10][CH2:11][C:12]([OH:14])=[O:13].[OH-].[Na+]>O>[N:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:3][N:10]([CH2:11][C:12]([OH:14])=[O:13])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: ClCc1ccccn1
Reactant: NCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CN(Cc1ccccn1)Cc1ccccn1

Procedure:
2-Chloromethylpyridine hydrochloride (9.2 g, 8.53 mmol) and glycin (2 g, 26.6 mmol) were dissolved in water (30 mL) and stirred at room temperature for five days, with addition of 5 mol aqueous NaOH solution at intervals to maintain the pH at 8-10. The resulting dark red solution was extracted with ethyl acetate, neutralized with HCl and concentrated. The residue was dissolved in dichloromethane, and the insoluble sodium chloride was filtered. Pale yellow crystals formed from the filtrate, which were collected and dried under vacuum. Yield (2.87 g) (11.2 mmol, 42%). 1H NMR (CDCl3), 300 MHz): 3.39 (s, 2H), 3.98 (s, 4H), 7.06 (t, 2H), 7.30 (d, 2H), 7.56 (t, 2H), 8.36 (d, 2H). 13C NMR (CD3OD, 300 MHz): 57.36 (C, CH2), 59.77 (2C, PyCH2), 124.77 (2CH, Py), 125.15 (2CH, Py), 139.00 (C, CH2), 149.76 (2CH, Py), 156.10 (2C, Py), 173.05 (C, CO2H).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[C:5](Cl)(=[O:9])[CH:6]([CH3:8])[CH3:7]>C1(C)C=CC=CC=1>[C:5]([NH:1][C:2]([NH2:4])=[S:3])(=[O:9])[CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)C(=O)Cl
Reactant: NC(N)=S
Solvent: Cc1ccccc1
Product: CC(C)C(=O)NC(N)=S
Temperature: 25 °C
Yield: 30.8 %

Procedure:
Thiourea (152 g, 2 mol) was dissolved in toluene (1520 mL). To the solution was added isobutyryl chloride (213 g, 2 mol) under mechanical stirring. The reaction mixture was refluxed for 3 hours. TLC monitored the reaction. After the reaction completed, the reaction mixture was cooled to room temperature and filtered to remove insoluble solids. The filtrate was concentrated to dryness. The yellow solids were collected by filtration, washed with petroleum ether (100 mL×3) to appear white, dried in vacumm to give the desired product 11A (90 g, 30% yield) as a white solid (mp: 114˜116° C.).
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[C:6]2=[CH:16][S:17][C:18]([CH3:19])=[C:5]12)=[O:3].[CH2:20]([N:22]([CH2:32][CH3:33])[CH2:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]1)[CH3:21].C(OC(C)C)(C)C>>[CH2:32]([N:22]([CH2:20][CH3:21])[CH2:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:2]([N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7](=[O:15])[C:6]3=[CH:16][S:17][C:18]([CH3:19])=[C:5]23)=[O:3])[CH2:27]1)[CH3:33]
Reactant: CCN(CC)CCCC1CCCNC1
Reactant: Cc1scc2c1N(C(=O)Cl)c1ccccc1NC2=O
Solvent: CC(C)OC(C)C
Product: CCN(CC)CCCC1CCCN(C(=O)N2c3ccccc3NC(=O)c3csc(C)c32)C1
Yield: 34 %

Procedure:
Prepared analogously to Example 4 from 4-(chlorocarbonyl)-4,9-dihydro-3-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 3-[3-(diethylamino)propyl]piperidine in a yield of 34% of theory. Colourless crystals, m.p. 136.0°-137.5° C. (diisopropylether).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C([Li])CCC.Br[CH2:19][CH2:20][CH2:21][Cl:22]>C1COCC1>[Cl:22][CH2:21][CH2:20][CH2:19][C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)([CH3:12])[C:9]([OH:11])=[O:10]
Reactant: ClCCCBr
Reactant: CC(C(=O)O)c1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(CCCCl)(C(=O)O)c1ccc(Cl)cc1
Temperature: -20 °C
Reaction time: 12 h
Yield: 83.5 %

Procedure:
Under a nitrogen atmosphere, to a mixture of 2-(4-chlorophenyl)propanoic acid (13.3 g) in THF (140 mL) was added n-butyllithium (1.6M hexane solution, 90.3 mL) at −60° C. to −70° C., and the mixture was allowed to warm to −20° C. 1-Bromo-3-chloropropane (11.4 g) was added to the reaction mixture at −20° C. to 10° C., and the mixture was stirred at room temperature for 12 hr. The reaction mixture was extracted with 1N aqueous sodium hydroxide solution (2×100 mL), and the extract was acidified with 3N hydrochloric acid (100 mL). The mixture was extracted with ethyl acetate (3×100 mL), the extract was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (15.7 g).
Reaction SMILES: [CH2:1]([C@H:5]1[CH2:10][C:9](=[O:11])[O:8][C:6]1=O)[CH:2]([CH3:4])[CH3:3].C(O)(=O)C.[CH2:16]([O:18][P:19]([CH2:39][NH2:40])([CH2:21][CH:22]([C:27](=[O:38])[NH:28][C@H:29]([C:34](=[O:37])[NH:35][CH3:36])[CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:20])[CH3:17]>>[CH2:16]([O:18][P:19]([CH2:39][N:40]1[C:9](=[O:11])[CH2:10][C@H:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[C:6]1=[O:8])([CH2:21][CH:22]([C:27](=[O:38])[NH:28][C@H:29]([C:34](=[O:37])[NH:35][CH3:36])[CH2:30][CH:31]([CH3:32])[CH3:33])[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:20])[CH3:17]
Reactant: CC(C)C[C@H]1CC(=O)OC1=O
Reactant: CCOP(=O)(CN)CC(CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NC
Solvent: CC(=O)O
Product: CCOP(=O)(CC(CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NC)CN1C(=O)C[C@H](CC(C)C)C1=O
Yield: 42.5 %

Procedure:
In a manner analogous to that described in Example 24(A), from 0.17 g (1.09 mmol) of 2(S)-isobutylsuccinic anhydride and 0.32 g (0.73 mmol) of (aminomethyl)[(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid ethyl ester acetate, there was obtained 0.16 g of [[(S)-2-isobutylsuccinimido]methyl][(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid ethyl ester.
Reaction SMILES: [CH2:1]([N:8]([CH:35]([CH3:37])[CH3:36])[C:9](=[O:34])[CH2:10][N:11]1[C:20](=[O:21])[CH2:19][C:18]2[N:14]([C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:16][N:17]=2)[C:13]2[CH:28]=[C:29]([F:33])[C:30]([F:32])=[CH:31][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:40]([CH:47]=O)=[CH:39]1>>[CH2:1]([N:8]([CH:35]([CH3:37])[CH3:36])[C:9](=[O:34])[CH2:10][N:11]1[C:20](=[O:21])[C:19](=[CH:47][C:40]2[C:41]3[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=3)[NH:38][CH:39]=2)[C:18]2[N:14]([C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:16][N:17]=2)[C:13]2[CH:28]=[C:29]([F:33])[C:30]([F:32])=[CH:31][C:12]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: CC(C)N(Cc1ccccc1)C(=O)CN1C(=O)Cc2nnc(-c3ccccc3)n2-c2cc(F)c(F)cc21
Product: CC(C)N(Cc1ccccc1)C(=O)CN1C(=O)C(=Cc2c[nH]c3ccccc23)c2nnc(-c3ccccc3)n2-c2cc(F)c(F)cc21
Yield: 75.7 %

Procedure:
Following the procedure described for Example 1(A), Step A, N-benzyl-2-(8,9-difluoro-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-N-isopropyl-acetamide (Preparation 9) (200 mg, 0.399 mmol) was condensed over 24 hours with 1H-indole-3-carbaldehyde (70 mg, 0.479 mmol). Purification by medium pressure chromatography eluting with a solvent gradient (CH2Cl2 to 20% acetone in CH2Cl2) provided 190 mg of N-benzyl-2-[8,9-difluoro-4-(1H-indol-3-ylmethylene)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-acetamide. MS 629.3 (M+1), 627.3 (M−1).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[C:18](B(O)O)[CH:17]=[CH:16][N:15]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([C:18]3[CH:17]=[CH:16][N:15]=[C:14]([O:13][CH3:12])[CH:19]=3)=[CH:3][N:4]=2)[CH:7]=1
Reactant: COc1cc(B(O)O)ccn1
Reactant: Clc1ccc2ncc(Br)n2c1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(-c2cnc3ccc(Cl)cn23)ccn1

Procedure:
To a solution of 3-bromo-6-chloro-imidazo[1,2-a]pyridine (1 eq, 0.72 mmol, 0.2 g), 2-methoxypyrid-4-yl boronic acid (1.0 eq, 0.72 mmol, 0.11 g), Na2CO3 (2 eq, 1.44 mmol, 0.152 g) in dioxane (0.6 ml) and water (0.2 ml), under an inert atmosphere of argon is added bis(triphenylphosphine)palladium II chloride (50 mg). The reaction mixture is heated using microwave radiation at 100° C. for 2 hours. The mixture is diluted with H2O (50 ml) and extracted with EtOAc. The combined organic portions are washed with brine, dried (MgSO4) and concentrated in vacuo. The residue is purified by flash chromatography on silica eluting with 0-25% EtOAc in iso-hexane to afford the title compound; [M+H]+=260 (262).
Reaction SMILES: [Mg].CCO[Si:5]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].II.Br[C:18]1[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=1>C1COCC1>[CH2:13]([O:12][Si:5]([O:6][CH2:7][CH3:8])([O:9][CH2:10][CH3:11])[C:18]1[CH:23]=[CH:22][C:21]([Si:5]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8])=[CH:20][CH:19]=1)[CH3:14]
Reactant: CCO[Si](OCC)(OCC)OCC
Reactant: Brc1ccc(Br)cc1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CCO[Si](OCC)(OCC)c1ccc([Si](OCC)(OCC)OCC)cc1
Reaction time: 0.5 h
Yield: 43 %

Procedure:
A mixture of magnesium turnings (15 g) and TEOS (450 mL, 2 mol) in THF (300 mL) were placed under nitrogen in a 1 L three-neck round bottom flask equipped with magnetic stir bar, condenser, and addition funnel. A small crystal of iodine was added and the mixture was brought to reflux. A solution of 1,4-dibromobenzene (48 g, 204 mmol) in THF (100 mL) was added dropwise over 2 h. Within 30 min of initiating the addition, the reaction became mildly exothermic. The reaction mixture was kept at reflux for 1 h after the completion of the addition of dibromide. The gray-green mixture was allowed to cool to room temperature before the THF was removed in vacuo. Hexane (200 mL) was added to precipitate any remaining magnesium salts in solution and the mixture was quickly filtered under nitrogen to produce a clear, light brown solution. Hexane was removed in vacuo. The product was purified by fractional distillation. The product was recovered as a clear liquid at 130–5° C. (0.2 mmHg) in 43–47% yield. 1H NMR (500 MHz, CDCl3) δ 7.67 (s, 4H, ArH), 3.86 (q, J=7.00 Hz, 12H, OCH2CH3), 1.23 (t, J=7.00 Hz, 18H, ArH); 13C NMR (125 MHz, CDCl3) δ 133.25,57.98, 17.43; 29Si NMR (99 MHz, CDCl3) δ−58.25; MS m/e calc'd for CI (M) C18H34Si2O6: 402.1894, found 402.1886.
Reaction SMILES: [CH:1]1([CH:7]2[CH:16]3[CH2:17][CH2:18][CH2:19][O:20][CH:15]3[C:14]3[CH:13]=[C:12]([O:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH:11]=[CH:10][C:9]=3[NH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH-](OC(C)=O)(OC(C)=O)O[C:29](C)=O.[Na+].C=O>CO>[CH:1]1([CH:7]2[CH:16]3[CH2:17][CH2:18][CH2:19][O:20][CH:15]3[C:14]3[CH:13]=[C:12]([O:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH:11]=[CH:10][C:9]=3[N:8]2[CH3:29])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C)CCOc1ccc2c(c1)C1OCCCC1C(C1CCCCC1)N2
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CC(C)CCOc1ccc2c(c1)C1OCCCC1C(C1CCCCC1)N2C
Temperature: 120 °C
Yield: 15.4 %

Procedure:
To a microwave vial was added sequentially (4aSR*,5RS*,10bSR*)-5-cyclohexyl-9-(isopentyloxy)-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinoline (base of example 27) (200 mg, 0.56 mmol, 1 equiv.), methanol (2.5 mL) and NaBH(OAc)3 (237 mg, 1.12 mmol, 2 equiv.). The microwave vial was capped with a septum and formaldehyde (43 μL, 1.4 mmol, 2.5 equiv.) was added via syringe. The reaction mixture was heated under microwave heating at 120° C. for 10 min. The solvent was evaporated under reduced pressure and the crude taken up in CH2Cl2 and washed with sat. NaHCO3 solution. The combined organic fractions were dried over MgSO4 and the solvent removed under reduced pressure after filtration. The residue was purified by Combiflash column chromatography (SiO2, c-Hexane/AcOEt) to afford (4aSR*,5RS*,10bSR*)-5-cyclohexyl-9-(isopentyloxy)-6-methyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinoline (32 mg, 15%) as white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[BH4-].[Na+]>CO>[CH2:12]([NH:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:10])[CH3:9])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCNCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a solution of tert-butyl 2-aminoethylcarbamate (6.4 g, 40.0 mmol) in methanol (60 mL) was added benzaldehyde (4.7 g, 44.0 mmol) and molecular sieve 3 Å. After stirring at ambient temperature overnight, the mixture was cooled down to ca. −10° C. (ice/salt bath) and treated portion wise with NaBH4 (9.1 g, 240.0 mmol) over 30 min. After complete addition, the bath was removed and the reaction mixture stirred at ambient temperature for 16 h. The solvent was evaporated and the residue taken into EtOAc (150 mL) and poured into water (100 mL). The organic layer was extracted with 0.5 N HCl (3×100 mL). The combined aqueous solution was cooled to 0° C., basified with sat. NaHCO3 and extracted with CHCl3 (3×100 mL). The combined organic layers were washed with brine (200 mL). After drying over MgSO4 and filtering, the solvent was evaporated in vacuo to give compound A (9.2 g, 36.8 mmol, 92%) as a colorless oil. LC-MS [M+H] 251.2 (C14H22N2O2+H, calc: 251.3). TLC Rf (DCM/MeOH 9:1): 0.30. Compound A was used without further purification.
Reaction SMILES: C([O:4][C:5]1[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:7]([OH:9])=O)(=O)C.[Br:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18]>>[Br:14][C:15]1[CH:16]=[C:17]([NH:18][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[OH:4])[CH:19]=[CH:20][CH:21]=1
Reactant: CC(=O)Oc1ccccc1C(=O)O
Reactant: Nc1cccc(Br)c1
Product: O=C(Nc1cccc(Br)c1)c1ccccc1O

Procedure:
This compound was obtained as a white solid starting from acetylsalicyclic acid and 3-bromoaniline using the same procedure described in example 5.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]([OH:10])=O.[CH2:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20](=[O:22])[CH3:21])[CH3:12].[OH-].[Na+]>O>[C:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:13]([CH2:11][CH3:12])[CH:8]=[O:10])(=[O:22])[CH3:21]
Reactant: O=CO
Reactant: CCNc1ccccc1C(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CCN(C=O)c1ccccc1C(C)=O
Reaction time: 4 h

Procedure:
A mixture of acetic anhydride (23 ml) and formic acid (15.5 ml) was stirred at 50° for 4 hours and then cooled to 0° in an ice/salt bath. 2'-(Ethylamino)-acetophenone (20.5 g) was added in small portions over 15 minutes and the mixture allowed to stand at room temperature for 1 hour. The mixture was cooled to 0° and water (100 ml) followed by aqueous sodium hydroxide (specific gravity 1.5, 10 ml) was added dropwise whilst maintaining the temperature below 10°. The resultant mixture was extracted with dichloromethane (4×100 ml) and the combined extracts were dried over magnesium sulphate to give a solution of 2'-acetyl-N-ethylformanilide.