Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Sn](CCCC)(CCCC)CCCC)[CH:13]=2)[CH:8]=[N:7]1)[CH3:3].Cl.Br[C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1>C1(C)C=CC=CC=1>[CH3:3][N:2]([CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:30]3[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=3)[CH:13]=2)[CH:8]=[N:7]1)[CH3:1]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc2cnn(CCN(C)C)c2c1
Reactant: Brc1ccncc1
Agent: Cl
Solvent: Cc1ccccc1
Product: CN(C)CCn1ncc2ccc(-c3ccncc3)cc21
Temperature: 25 °C
Yield: 22.9 %

Procedure:
A solution of 1-(2-(N,N-dimethylamino)ethyl)-6-tributylstannyl-1H-indazole (49.1 mg, 0.10 mmol), 4-bromopyridine hydrochloride (21.6 mg, 0.11 mmol), tetrakistriphenylphosphine palladium(0) (10-20 mg, catalytic) in toluene (0.5 mL) was heated at reflux under an inert atmosphere for 18 h. After cooling to room temperature the reaction was quenched by the addition of aqueous sodium hydroxide (1 M, 2 mL) and water (10 mL), and the product extracted into ethyl acetate (50 mL). The organic layer was washed sequentially with water and brine, dried over sodium sulfate and the solvent removed in vacuo. Filtration through an SPE cartridge (Supelco, 6 mL, silica gel, 1000 mg, gradient from 0-10% 2M methanolic ammonia in dichloromethane) gave a crude product which was further purified by flash chromatography (silica gel, 4-10% 2M methanolic ammonia in dichloromethane) to give the title product (6.1 mg, 11%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1.I[CH:15]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[C:22]([O:21][C:19]([N:17]1[CH2:18][CH:15]([N:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH:7]=[CH:8][C:9]2=[O:13])[CH2:16]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Reactant: COc1ccc2ccc(=O)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2ccc(=O)n(C3CN(C(=O)OC(C)(C)C)C3)c2c1
Temperature: 80 °C
Yield: 59.4 %

Procedure:
A mixture of 7-methoxy-2(1H)-quinolinone (commercial; 290 mg; 1.65 mmol) and tert-butyl 3-iodo-1-azetidinecarboxylate (commercial; 391 mg; 1.38 mmol) and Cs2CO3 (613 mg; 1.88 mmol) in DMF (2 mL) was heated at 80° C. for 4 h. The reaction mixture was diluted with water and extracted with EA. The combined org. layers were washed with water and brine, dried over MgSO4, concentrated under reduced pressure and purified by CC (Hept/EA 1:1), affording a pale yellow oil (271 mg, 65% yield).
Reaction SMILES: Cl.C([Cl:5])(=O)C.[CH2:6]([O:13][C:14]([N:16]([CH:20]1[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]1)[CH2:17][CH2:18][CH3:19])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(OCC)(=O)C>CO>[ClH:5].[CH2:6]([O:13][C:14]([N:16]([CH:20]1[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]1)[CH2:17][CH2:18][CH3:19])=[O:15])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(=O)Cl
Reactant: CCCN(C(=O)OCc1ccccc1)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCN(C(=O)OCc1ccccc1)C1CCNCC1
Reaction time: 0.17 h

Procedure:
To a solution of 2.4 mmol of HCl in 2 mL of methanol (prepared by the addition of 0.17 mL of acetyl chloride at 0° C. and stirring for 10 min) was added 90 mg of 4-(N-(benzyloxycarbonyl)-N-(prop-1-yl)amino)-1-t-butoxycarbonylpiperidine. The mixture was stirred at rt for 16 h at which time the reaction was complete by TLC (20% ethyl acetate in hexanes) and was evaporated to dryness in vacuo to afford 75 mg of the title compound as the hydrochloride salt.
Reaction SMILES: [N:1]1([C:8]([NH:10][C@@H:11]([CH:15]([CH3:18])[CH2:16][CH3:17])[C:12]([OH:14])=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:52][C:53]1[CH:58]=[CH:57][C:56]([CH:59]([C:66]2[CH:71]=[CH:70][C:69]([F:72])=[CH:68][CH:67]=2)[N:60]2[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]2)=[CH:55][CH:54]=1>CN(C=O)C.C(OCC)C>[F:72][C:69]1[CH:68]=[CH:67][C:66]([CH:59]([C:56]2[CH:57]=[CH:58][C:53]([F:52])=[CH:54][CH:55]=2)[N:60]2[CH2:61][CH2:62][N:63]([C:12]([C@@H:11]([NH:10][C:8]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]3)=[O:9])[CH:15]([CH3:18])[CH2:16][CH3:17])=[O:14])[CH2:64][CH2:65]2)=[CH:71][CH:70]=1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: CCC(C)[C@H](NC(=O)N1CCCCCC1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C)[C@H](NC(=O)N1CCCCCC1)C(=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 0.58 h
Yield: 87 %

Procedure:
(S)-2-[(Azepane-1-carbonyl)-amino]-3-methyl-pentanoic acid (0.300 g, 1.17 mmol, Example 16, Step B) was dissolved in dry DMF (4 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N,N,-diisopropylethylamine (0.408 mL, 2.34 mmol) and solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.444 g, 1.17 mmol). The resulting reaction mixture was stirred at that temperature for 35 minutes; solid 1-bis(4-fluorophenyl)methyl piperazine (0.337 g, 1.17 mmol) was then added. After stirring for, sequentially, 10 minutes at 0° C. and 30 minutes at ambient temperature, reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×60 mL), brine (2×60 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was further purified by flash chromatography (40% EtOAc in hexane, then 60% EtOAc in hexane) to provide 0.536 g (87%) of the pure titled compound as a white foam: mp 64-77° C. APCI-MS m/z 527.4 (MH+).
Reaction SMILES: C(OC([NH:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[CH:14]=[CH:15][CH:16]=[C:17]2[S:22]([NH:25][C:26]1[C:31]([O:32][CH3:33])=[N:30][C:29]([Br:34])=[CH:28][N:27]=1)(=[O:24])=[O:23])=O)C1C=CC=CC=1.C(OCC)C>Br.C(O)(=O)C>[NH2:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[CH:14]=[CH:15][CH:16]=[C:17]2[S:22]([NH:25][C:26]1[C:31]([O:32][CH3:33])=[N:30][C:29]([Br:34])=[CH:28][N:27]=1)(=[O:23])=[O:24]
Reactant: COc1nc(Br)cnc1NS(=O)(=O)c1cccc2c(NC(=O)OCc3ccccc3)cccc12
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: COc1nc(Br)cnc1NS(=O)(=O)c1cccc2c(N)cccc12
Reaction time: 1 h
Yield: 13.3 %

Procedure:
5-(N-Benzyloxycarbonylamino)-N-(5-bromo-3-methoxy-2-pyrazinyl)-1-naphthalenesulphonamide (0.7 g) was dissolved in 33% hydrobromic acid in acetic acid (14 ml) and the resulting solution was stirred for 1 hour. Diethyl ether (60 ml) was added and after 10 minutes further stirring, the mixture was filtered. The solid was dissolved in water (5 ml), basified to pH 8 by the addition of 1N aqueous sodium hydroxide and extracted with ethyl acetate (3×25 ml). The combined organic extracts were evaporated and the residue was purified by flash chromatography on silica gel (10 g), eluting with a gradient of 20-50% ethyl acetate in hexane to give 5-amino-N-(5-bromo-3-methoxy-2-pyrazinyl)-1-naphthalenesulphonamide (0.07 g); 1H NMR (d6 -DSO): 3.82 (s,3H), 6.78 (d,,H), 7.35 (t,(H), 7.50 (t,(H), 7.78 (s,1H), 7.91 (d,2H), 8.25 (d,2H), 8.40 (d,1H); mass spectrum (+ve FAB, methanol/NBA): 409 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[CH2:11][C@@H:10]2[CH2:12][O:13][C:14]2[C:19]([C:20]3[CH:21]=[N:22][NH:23][CH:24]=3)=[CH:18][N:17]=[C:16]([CH3:25])[N:15]=2)=[N:7][CH:8]=1.Cl[C@@H:27]([CH3:30])[CH2:28][OH:29].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[CH2:11][C@@H:10]2[CH2:12][O:13][C:14]2[C:19]([C:20]3[CH:24]=[N:23][N:22]([C@@H:27]([CH3:30])[CH2:28][OH:29])[CH:21]=3)=[CH:18][N:17]=[C:16]([CH3:25])[N:15]=2)=[N:7][CH:8]=1
Reactant: COc1ccc([C@H]2C[C@@H]2COc2nc(C)ncc2-c2cn[nH]c2)nc1
Reactant: C[C@H](Cl)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc([C@H]2C[C@@H]2COc2nc(C)ncc2-c2cnn([C@@H](C)CO)c2)nc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 4-{[(1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl]methoxy}-2-methyl-5-(1H-pyrazol-4-yl)pyrimidine (NN1) (15 mg, 0.04 mmol) in DMF (0.4 mL) was added and (2S)-2-chloropropan-1-ol (9.0 mg, 0.09 mmol) and potassium carbonate (18.4 mg, 0.13 mmol). The reaction mixture was stirred at ambient temperature for 14 hours. The mixture was filtered and purified by reverse phase chromatography (Waters Sunfire Prep C18 OBD, 5-45% acetonitrile in water with 0.1% TFA modifier) to afford the title compound as a white solid. 1H NMR (500 MHz, DMSO): δ 8.74 (s, 1 H), 8.13 (d, J=11.7 Hz, 2 H), 8.00 (s, 1 H), 7.27 (d, J=7.1 Hz, 2 H), 4.55-4.50 (m, 1 H), 4.37-4.30 (m, 1 H), 3.96 (s, 3 H), 3.78 (s, 3 H), 2.50 (s, 3 H), 2.22 (d, J=7.1 Hz, 1 H), 1.80 (s, 1 H), 1.25-1.16 (m, 2 H), 1.07 (m, 1 H), 1.01 (d, J=5.3 Hz, 3 H); HRMS m/z (M+H) 396.2019 found, 396.2030 required.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([CH3:14])[C@H:10](O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([CH3:14])[C@@H:10]([N:20]2[C:16](=[O:26])[C:17]3[C:18](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:19]2=[O:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1O
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: C1CCOC1
Product: C[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@@H]1N1C(=O)c2ccccc2C1=O
Temperature: 23 °C
Reaction time: 48 h
Yield: 47 %

Procedure:
To a solution of trans-3-Hydroxy-4-methyl-piperidine-1-carboxylic acid tert-butyl ester (1.78 g, 8.28 mmol) (WO 01/87838), phthalimide (1.46 g, 9.94 mmol) and TPP-resin (4.14 g) in anhydrous THF (30 ml) at 23° C. was added DIAD (2.4 ml, 12.4 mmol). The reaction mixture was stirred at 23° C. for 48 h. then the resin was filtered off and the filtrate was concentrated under reduced pressure to give an oil. The crude oil was purified by flash chromatography using silica gel (0-50% EtOAc-Heptane) which gave the title compound VIIa (1.6 g, 47% yield).
Reaction SMILES: CC(C)([O-])C.[Na+].[C:7]1([S:13]([N:16]2[C:21]3[CH:22]=[C:23]([Cl:27])[CH:24]=[C:25](Br)[C:20]=3[O:19][CH2:18][CH2:17]2)(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([C:25]2[C:20]3[O:19][CH2:18][CH2:17][N:16]([S:13]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)(=[O:15])=[O:14])[C:21]=3[CH:22]=[C:23]([Cl:27])[CH:24]=2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: O=S(=O)(c1ccccc1)N1CCOc2c(Br)cc(Cl)cc21
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2cc(Cl)cc3c2OCCN3S(=O)(=O)c2ccccc2)CC1
Temperature: 95 °C
Reaction time: 12 h
Yield: 74.6 %

Procedure:
A three neck flask was charged with tris(dibenzylideneacetone)dipalladium(0) (6.4 mg, 0.007 mmol, 2 mol % Pd), racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (10.8 mg, 0.017 mmol, 5 mol %), and sodium tert-butoxide (47 mg, 0.48 mmol) and flushed with nitrogen. A solution of 4-benzenesulfonyl-8-bromo-6-chloro-3,4-dihydro-2H-benzo[1,4]oxazine (165 mg, 0.35 mmol) and piperazine-1-carboxylic acid tert-butyl ester (71.1 mg, 0.38 mmol) in toluene (2 mL) was added. The mixture was heated to 95° C. and stirred for 12 hours. The mixture was cooled to room temperature, taken up in ethyl acetate, filtered and concentrated. The crude material was purified by flash chromatography on silica gel (eluting with hexane-ethyl acetate; 7:3, v/v) to give 4-(4-Benzenesulfonyl-6-chloro-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-piperazine-1-carboxylic acid tert-butyl ester as an oil (129 mg, 75%). MS: MH+=494. The crude material was dissolved in ethanol (1 mL) and was treated with a solution of 10% hydrogen chloride in ethanol (1 mL). The mixture was heated on a steam bath for 15 minutes. White crystals precipitated upon cooling to room temperature. The solid was collected, washed with cold ethanol. Drying under vacuum gave 4-benzenesulfonyl-6-chloro-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine, hydrochloride salt as a white powder (90 mg, 73%). MS: MH+=394. M.p. 202-205° C.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]4[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=4)[C:19]([OH:21])=O)=[N:11][N:10]3[CH:25]=2)=[O:5])[CH2:3][CH2:2]1.[NH2:26][C:27]1[CH:28]=[C:29]([C:33]([CH3:37])([CH3:36])[C:34]#[N:35])[CH:30]=[CH:31][CH:32]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:34]([C:33]([C:29]1[CH:28]=[C:27]([NH:26][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][CH:24]=[C:16]([O:15][C:12]3[CH:13]=[CH:14][C:9]4[N:10]([CH:25]=[C:7]([NH:6][C:4]([CH:1]5[CH2:2][CH2:3]5)=[O:5])[N:8]=4)[N:11]=3)[CH:17]=2)[CH:32]=[CH:31][CH:30]=1)([CH3:37])[CH3:36])#[N:35]
Reactant: CC(C)(C#N)c1cccc(N)c1
Reactant: O=C(O)c1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C#N)c1cccc(NC(=O)c2cccc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)c1
Yield: 44.4 %

Procedure:
Using 3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)benzoic acid (100 mg, 0.30 mmol), 2-(3-aminophenyl)-2-methylpropanenitrile (57 mg, 0.36 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (68 mg, 0.36 mmol), 4-(dimethylamino)pyridine (43 mg, 0.36 mmol) and pyridine (5.0 mL) as starting materials and in the same manner as in Example 318, the title compound (64 mg, 45%) was obtained as a white powder.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[C:5]([CH2:8][N:9]1[C:13](=[O:14])[C:12](=[CH:15]OCC)[S:11][C:10]1=[S:19])([OH:7])=[O:6]>C(O)C>[C:5]([CH2:8][N:9]1[C:13](=[O:14])[C:12](=[CH:15][NH:4][CH2:1][CH:2]=[CH2:3])[S:11][C:10]1=[S:19])([OH:7])=[O:6]
Reactant: CCOC=C1SC(=S)N(CC(=O)O)C1=O
Reactant: C=CCN
Solvent: CCO
Product: C=CCNC=C1SC(=S)N(CC(=O)O)C1=O
Yield: 52.6 %

Procedure:
0.3 Gram (0.005 mole) of allylamine was added to a mixture of 1.2 g (0.005 mole) of 3-carboxymethyl-5-ethoxymethylidenerhodanine and 10 ml of ethanol, and the resulting mixture was subjected to reaction at a temperature of 50° to 60° C. for 1 hour. The reaction mixture was cooled and the formed precipitate was separated by filtration and recrystalized from a mixture of methanol and ether (7/3 by volume) to give 0.68 g of 3-carboxymethyl-5-allylaminomethylidenerhodanine in the form of yellow crystal (yield: 52.6%).
Reaction SMILES: C[Si](C=[N+]=[N-])(C)C.[Br:8][C:9]1[CH:10]=[C:11]([CH2:17][C:18]([OH:20])=[O:19])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16].[C:21](O)(=O)C>CO.C1(C)C=CC=CC=1>[CH3:21][O:19][C:18](=[O:20])[CH2:17][C:11]1[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:9]([Br:8])[CH:10]=1
Reactant: COc1ccc(CC(=O)O)cc1Br
Reactant: CC(=O)O
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)Cc1ccc(OC)c(Br)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95 %

Procedure:
Trimethylsilyldiazomethane (2 M solution in diethyl ether, 0.306 mL, 0.612 mmol) was added to a solution of (3-bromo-4-methoxy-phenyl)-acetic acid (100 mg, 0.408 mmol) in methanol (1 mL) and toluene (4 mL), and the mixture was stirred at room temperature for 10 minutes. Acetic acid was added to the reaction mixture to terminate the reaction, and then the mixture was concentrated under reduced pressure to give the target compound as a colorless oil (100 mg, 95%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]2[CH:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]3[O:21][C:4]=2[CH:3]=1.[CH3:22]OC1C=CC2C3(C)CCN=CC3OC=2C=1>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([CH3:22])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:10][CH:9]3[O:21][C:4]=2[CH:3]=1
Reactant: COc1ccc2c(c1)OC1C=NCCC21C
Reactant: CC(C)(C)OC(=O)N1CCC2c3ccc(O)cc3OC2C1
Product: CC(C)(C)OC(=O)N1CCC2(C)c3ccc(O)cc3OC2C1

Procedure:
Synthesized as described for tert-butyl 7-hydroxy-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate starting from 7-Methoxy-4a-methyl-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2Br)[O:24][CH2:23][C:22]2[N:17]3[C@H:18]([CH3:30])[C:19](=[O:29])[NH:20][N:21]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:37]([O:39]/[CH:40]=[CH:41]/B1OC(C)(C)C(C)(C)O1)[CH3:38]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2/[CH:38]=[CH:37]/[O:39][CH2:40][CH3:41])[O:24][CH2:23][C:22]2[N:17]3[C@H:18]([CH3:30])[C:19](=[O:29])[NH:20][N:21]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1C(=O)NN=C2COc3cc(Br)c(N[C@H]4CCN(C(=O)OC(C)(C)C)C4)cc3N21
Reactant: CCO/C=C/B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCO/C=C/c1cc2c(cc1N[C@H]1CCN(C(=O)OC(C)(C)C)C1)N1C(=NNC(=O)[C@H]1C)CO2
Temperature: 100 °C
Reaction time: 3 h
Yield: 102.6 %

Procedure:
To a mixture of (S)-3-((R)-7-bromo-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.6 g, 1.249 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.051 g, 0.060 mmol) and K2CO3 (0.259 g, 1.87 mmol) in dioxane (24 mL) and water (4 mL) was added (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.124 g, 0.62 mmol) and the reaction mixture was stirred at 100° C. for 3 h. The reaction mixture was cooled to ambient temperature and concentrated in vacuo to give the crude product, which was purified by column chromatography on silica gel (eluting with 50% EtOAc in petroleum ether) to give (S)-3-[(R)-7-((E)-2-ethoxy-vinyl)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.3 g, 50%) as a light yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.16 (s, 1H), 6.73 (s, 1H), 6.61 (d, J=12.4 Hz, 1H), 6.07 (s, 1H), 5.56 (d, J=12.4 Hz, 1H), 5.23 (s, 1H), 4.65 (m, 1H), 4.37-4.52 (m, 2H), 3.77-3.96 (m, 3H), 3.64 (m, 1H), 3.35 (m, 2H), 3.08-3.31 (m, 1H), 2.06-2.22 (m, 1H), 1.82 (m, 1H), 1.42 (m, 12H), 1.28 (t, J=7.2 Hz, 3H). LC/MS (Table 1, Method 2) Rt=1.097 min.; MS m/z: 472 [M+H]+. SFC (Table 1, Method 37) Rt=1.919 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13](=[O:15])[CH3:14])=[C:11]([CH3:16])[N:10]=[N:9]1.CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.[Br:41]Br>C(Cl)(Cl)Cl>[Br:41][CH2:14][C:13]([C:12]1[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[N:9]=[N:10][C:11]=1[CH3:16])=[O:15]
Reactant: CC(=O)c1c(C)nnn1-c1ccccc1F
Reactant: BrBr
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Solvent: ClC(Cl)Cl
Product: Cc1nnn(-c2ccccc2F)c1C(=O)CBr
Temperature: 25 °C
Yield: 68.2 %

Procedure:
A solution of 1-(1-(2-fluorophenyl)-4-methyl-1H-1,2,3-triazol-5-yl)ethanone (1.66 g, 7.57 mmol) was dissolved in chloroform (12 mL) and acetic (0.24 mL) was heated to reflux and then a solution of bromine (0.41 mL, 7.95 mmol) in chloroform (5 mL) and heated under reflux for 2 h and then bromine (0.12 mL, 2.27 mmol) in chloroforom (2 mL) was added and heated under reflux for a further 30 min. After cooling to room temperature the mixture was poured onto ice-water and the mixture extracted with dichloromethane. The combined organic extracts were washed with water, brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 10 to 60% ethyl acetate in heptane) afforded the title compound (1.54 g, 64%) as an off white solid. MS: m/e=298.1/300.0 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][NH:25][CH3:26])[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>N1C=CC=CC=1>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][N:25]([CH3:26])[S:28]([CH3:27])(=[O:30])=[O:29])[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CNCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CN(Cc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1)S(C)(=O)=O
Reaction time: 0.33 h
Yield: 75.1 %

Procedure:
A solution of tert-butyl (3R)-6-cyclohexyl-3-{3-[(methylamino)methyl]-1,2,4-oxadiazol-5-yl}hexanoate (preparation 5) (300 mg, 0.82 mmol) in pyridine (2 ml) in a water bath was treated with methanesulphonylchloride (64 μl, 0.82 mmol) and stirred under a nitrogen atmosphere for 20 minutes. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc and washed with 2M HCl followed by brine. The organic extract was dried over MgSO4, filtered and the solvent removed under reduced pressure. The residue was purified on a silica column eluting with a solvent gradient of EtOAc:pentane (5:95) gradually changing to (30:70) to afford the title compound as a colourless oil (273 mg, 75%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:18])[C:5]2[CH:11]=[C:10](Br)[C:9](=[O:13])[N:8]([CH:14]3[CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:7]=1.[C:19]([Cu])#[N:20]>CN1C(=O)CCC1.[Cl-].[Na+].O>[NH2:1][C:2]1[N:3]=[C:4]([CH3:18])[C:5]2[CH:11]=[C:10]([C:19]#[N:20])[C:9](=[O:13])[N:8]([CH:14]3[CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:7]=1
Reactant: Cc1nc(N)nc2c1cc(Br)c(=O)n2C1CCC1
Reactant: N#C[Cu]
Agent: [Cl-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1nc(N)nc2c1cc(C#N)c(=O)n2C1CCC1
Temperature: 220 °C
Yield: 78.3 %

Procedure:
To a solution of 2-amino-6-bromo-8-cyclobutyl-4-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (371 mg, 1.20 mmol) in NMP (4 mL) was added CuCN (480 mg, 5.36 mmol). The mixture was sealed and heated at 220° C. for 30 min using microwave irradiation. The mixture was poured into brine and filtered to give a solid. The aqueous phase was extracted with t-butyl methyl ether (3 times), dried and evaporated. The combined solid was purification by flash chromatography, using 0 to 3% MeOH/CHCl3, to give the title compound (240 mg, 78%).
Reaction SMILES: [NH2:1]/[C:2](/[C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)=[CH:3]\[C:4]#[N:5].[C:19]1([CH:25]([C:31](OCC)=[O:32])[C:26](OCC)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[OH:32][C:31]1[C:3]([C:4]#[N:5])=[C:2]([C:6]2[CH:11]=[CH:10][C:9]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:8][CH:7]=2)[NH:1][C:26](=[O:27])[C:25]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Reactant: N#C/C=C(\N)c1ccc(Oc2ccccc2)cc1
Product: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)[nH]c(=O)c(-c2ccccc2)c1O
Temperature: 25 °C
Yield: 61.9 %

Procedure:
A mixture of (Z)-3-amino-3-(4-phenoxyphenyl)acrylonitrile (717 mg, 3.03 mmol) in diethyl 2-phenylmalonate (8 mL, 37.1 mmol) was microwaved at 250° C. for 15 min. After cooling to room temperature, the resulting suspension was filtered. The solid was washed with 20% isopropyl alcohol in heptanes and dried under vacuum to give 4-hydroxy-6-oxo-2-(4-phenoxyphenyl)-5-phenyl-1,6-dihydropyridine-3-carbonitrile (714 mg, 62% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 12.23 (1H, br. s), 10.76 (1H, br. s), 7.72 (2H, δ, J=8.80 Hz), 7.46-7.51 (2H, m), 7.39-7.44 (2H, m), 7.30-7.36 (3H, m), 7.26 (1H, t, J=7.42 Hz), 7.15 (2H, δ, J=7.70 Hz), 7.10 (2H, δ, J=8.80 Hz); MS (ES+) m/z: 381 (M+H); LC retention time: 3.820 min (analytical HPLC Method A).