Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:6]2[NH:7][C:8]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:5][CH2:4][CH2:3][CH:2]=1.[C:15](/[CH:17]=[CH:18]\[C:19]([O:21][CH2:22][CH3:23])=[O:20])#[N:16]>CCOCC>[C:15]([CH:17]1[CH:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:1]2[CH2:5][CH2:4][CH2:3][C:2]1=2)#[N:16]
Reactant: C1=C(c2cc3ccccc3[nH]2)CCC1
Reactant: CCOC(=O)/C=C\C#N
Solvent: CCOCC
Product: CCOC(=O)C1c2c([nH]c3ccccc23)C2=C(CCC2)C1C#N
Yield: 8.3 %

Procedure:
2-(Cyclopenten-1-yl)indole (13.6 g, 74 mmol), ethyl cis-3-cyanoacrylate (17.8 g, 142 mmol) and BHT (70 mg) were heated to 180° C. under nitrogen for 30 min. The volatiles were removed by kugelrohr distillation at 110° C. and 0.8 mm to afford 19.7 g of an amber-brown tar. Addition of ether (50 mL) afforded a precipitate of a single isomer of white crystalline ethyl 4-cyano-1,2,3,4,5,10-hexahydrocyclopenta[a]carbazole-5-carboxylate (1.89 g, 8.2% yield); mp 192–195° C. NMR (CDCl3) δ 7.91 (s, 1H), 7.46 (d, 1H), 7.34 (d, 1H), 7.12 (m, 2H), 4.31 (d, 1H0, 4.32 (m, 2H), 4.20 (d, 1H), 3.46 (t, 1H), 3.30 (q, 1H), 2.80 (m, 1H), 2.3–1.4 (m, 6H), 1.34 (t, 3H). Anal. Calcd for C19H20N2O2: C, 74.00; H, 6.54; N, 9.08. Found: C, 73.84; H, 6.53; N, 9.03.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[CH:5]=[C:6]2[C:10]=1[NH:9][CH2:8][CH2:7]2.Cl[C:14]1[C:19]2[N:20]=[N:21][N:22]([CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[C:18]=2[CH:17]=[C:16]([CH3:28])[N:15]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C(OCC)(=O)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[CH:5]=[C:6]2[C:10]=1[N:9]([C:14]1[C:19]3[N:20]=[N:21][N:22]([CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[C:18]=3[CH:17]=[C:16]([CH3:28])[N:15]=1)[CH2:8][CH2:7]2
Reactant: CCC(CC)n1nnc2c(Cl)nc(C)cc21
Reactant: COc1cc(Br)c2c(c1)CCN2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(CC)n1nnc2c(N3CCc4cc(OC)cc(Br)c43)nc(C)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
To 7-bromo-5-methoxyindoline (382 mg) and 4-chloro-1-[1-ethylpropyl]-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridine (400 mg) in THF (2.0 mL) was added sodium bis(trimethylsilyl)amide (1.0 M in THF, 15 mL) at 0° C. The reaction was warmed to ambient temperature and stirred for 1 hour. Ethyl acetate (150 mL) was added and washed with water and brine. The organics were dried over MgSO4 and concentrated. The crude product was chromatographed on silica gel using ethyl acetate/hexane (1:4) as eluent to give 4-(7-bromo-5-methoxy-2,3-dihydro-1H-indol-1-yl)-1-(1-ethylpropyl]-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridine (538 mg).
Reaction SMILES: [NH2:1][C@@:2]1([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[CH2:7][O:6][C@@H:5]([CH:8]2[CH2:10][CH2:9]2)[CH2:4][C@H:3]1[C@@H:11]([OH:15])[CH2:12][O:13][CH3:14].C(OC[C@@H]1OC[C@@](N[C:48]([NH:50][C:51](=[O:58])[C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[S:49])(C2C=CC(F)=CC=2F)[C@H](CO)C1)C1C=CC=CC=1>>[CH:8]1([C@@H:5]2[O:6][CH2:7][C@@:2]([NH:1][C:48]([NH:50][C:51](=[O:58])[C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=3)=[S:49])([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[F:23])[C@H:3]([C@@H:11]([OH:15])[CH2:12][O:13][CH3:14])[CH2:4]2)[CH2:10][CH2:9]1
Reactant: O=C(NC(=S)N[C@@]1(c2ccc(F)cc2F)CO[C@@H](COCc2ccccc2)C[C@H]1CO)c1ccccc1
Reactant: COC[C@H](O)[C@@H]1C[C@H](C2CC2)OC[C@@]1(N)c1ccc(F)cc1F
Product: COC[C@H](O)[C@@H]1C[C@H](C2CC2)OC[C@@]1(NC(=S)NC(=O)c1ccccc1)c1ccc(F)cc1F

Procedure:
Conversion of rel-(1R)-1-[(2R,4R,5S)-5-amino-2-cyclopropyl-5-(2,4-difluorophenyl)tetrahydro-2H-pyran-4-yl]-2-methoxyethanol (C40) to the product was carried out via the method described for synthesis of N-{[(3S,4R,6R)-6-[(benzyloxy)methyl]-3-(2,4-difluorophenyl)-4-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]carbamothioyl}benzamide (C7) in Preparation P1. In this case, purification was effected via silica gel chromatography (Gradient: 0% to 60% ethyl acetate in heptane), affording the product as a solid. Yield: 0.55 g, 1.1 mmol, 43%.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:14][C:15]([N:17]([CH3:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:13])=[O:4].[CH3:25][C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1>>[CH3:13][O:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[N:5]([CH2:14][C:15]([N:17]([CH3:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:16])[C:3](=[O:4])[CH2:2][NH:1][C:33]([NH:32][C:28]1[CH:29]=[CH:30][CH:31]=[C:26]([CH3:25])[CH:27]=1)=[O:34]
Reactant: COc1ccccc1N(CC(=O)N(C)c1ccccc1)C(=O)CN
Reactant: Cc1cccc(N=C=O)c1
Product: COc1ccccc1N(CC(=O)N(C)c1ccccc1)C(=O)CNC(=O)Nc1cccc(C)c1
Yield: 67.8 %

Procedure:
Using a procedure similar to that described in Example 1, but starting with 2-[2-amino-N-(2-methoxyphenyl)acetamido]-N-methyl-N-phenylacetamide (2.0 g) and 3-methylphenyl isocyanate (0.64 g), and after recrystallisation in ethyl acetate, 2-{N-(2-methoxyphenyl)-2-[3-(3-methylphenyl)ureido]acetamido}-N-methyl-N-phenylacetamide (1.5 g), m.p. 212° C., is obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[O:11][CH3:12].C(=O)([O-])[O-].[K+].[K+].I[CH2:21][CH3:22].O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:21][CH3:22])=[CH:6][C:5]=1[O:11][CH3:12]
Reactant: CCI
Reactant: COC(=O)c1ccc(O)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(C(=O)OC)c(OC)c1
Temperature: 50 °C
Yield: 496.4 %

Procedure:
To a solution of 4-hydroxy-2-methoxybenzoic acid methyl ester (4.17 g, 22 mmol) in DMF (50 ml) under argon was added potassium carbonate (6.33 g, 4.6 mmol) followed by iodoethane (7.15 g, 4.6 mmol). The mixture was then heated to 50° C. under argon for 12h. On cooling the mixture was poured into a large excess of water and extracted with ether. The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to afford the title compound as a brown oil (4.8 g).
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]2=[C:3]([C:10](=[S:12])[NH2:11])[CH:2]=1.Br[CH:14]([C:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(O)C>[N:1]1[N:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]2=[C:3]([C:10]2[S:12][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:11]=2)[CH:2]=1
Reactant: NC(=S)c1cnn2ccccc12
Reactant: CCOC(=O)C(Br)C(=O)c1ccccc1
Solvent: CCO
Product: CCOC(=O)c1sc(-c2cnn3ccccc23)nc1-c1ccccc1
Temperature: 25 °C
Yield: 31.2 %

Procedure:
To a suspension of commercially available pyrazolo[1,5-a]pyridine-3-carbothioamide (580 mg, 3.3 mmol) in ethanol (20 mL) was added ethyl 2-bromo-3-oxo-3-phenylpropanoate (1.0 g, 3.7 mmol), and the mixture was heated under reflux for 11 hr. The reaction solution was allowed to cool to room temperature, and the resulting solid was collected by filtration and washed with methanol. The collected filtrate and washing solution was concentrated under reduced pressure, and the obtained residue was suspended in ethyl acetate (100 mL). The obtained suspension was washed with saturated aqueous sodium bicarbonate solution (50 mL×2), and the collected aqueous layer was extracted with ethyl acetate (50 mL). The collected organic layer was dried over anhydrous magnesium sulfate, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=5/95→100/0) to give the title compound (360 mg, 31%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]([Cl:18])[CH:12]=2)[CH:9]=1)[C:5]#[N:6].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]>O1CCOCC1>[Cl:18][C:13]1[CH:14]=[C:15]([CH:16]=[C:11]([O:10][C:8]2[CH:7]=[C:4]([C:5]#[N:6])[CH:3]=[C:2]([Cl:1])[CH:9]=2)[CH:12]=1)[O:17][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: N#Cc1cc(Cl)cc(Oc2cc(O)cc(Cl)c2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)COc1cc(Cl)cc(Oc2cc(Cl)cc(C#N)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a dioxane solution (5 mL) of 240 mg (0.857 mmol) of 3-chloro-5-(3-chloro-5-hydroxyphenoxy)benzonitrile (B-4) was added 363 mg (1.12 mmol) of cesium carbonate. This was stirred for 30 minutes at 25° C. and then 217 mg (1.12 mmol) of t-butyl bromoacetate (5-1) was added and the reaction was stirred until the LC/MS analysis indicated that the reaction was complete. The solids were then removed by filtration and the filtrate was concentrated and purified on a CombiFlash silica column eluted with an ethyl acetate:hexanes gradient to recover desired product 5-2 as an oil. Rf=0.9 (EtOAc:hexanes 1:4). MS: M+1=395. 1H NMR(CDCl3): 1.49 (s, 9H), 4.49 (s, 2H), 6.48 (t, 1H), 6.66 (t, 1H), 6.74 (t, 1H), 7.14 (m, 1H), 7.21 (m, 1H), 7.38 (m, 1H).
Reaction SMILES: COC1C=CC(C[N:8]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[NH:20][CH2:19][CH2:18][O:17][C:16]=3[CH:21]=2)(=[O:11])=[O:10])=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[S:23]1[CH:24]=[CH:25][N:26]=[C:22]1[NH:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]2[NH:20][CH2:19][CH2:18][O:17][C:16]=2[CH:21]=1)(=[O:10])=[O:11]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(Nc1nccs1)c1ccc2c(c1)OCCN2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 99.8 %

Procedure:
N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (Intermediate M; 0.200 g, 0.479 mmol) was dissolved in DCM (1.597 ml) and TFA (0.923 ml, 11.98 mmol) was added. The reaction was stirred at RT for 20 minutes at which time it was concentrated in vacuo. The crude reaction was purified via 2-g SCX column (product eluted with ammonia/methanol wash) to yield N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (0.142 g, 0.478 mmol, 100% yield). m/z (ESI) 298.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]1([OH:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:5].Cl.[NH2:23][OH:24].C([O-])(=O)C.[Na+]>CO.O>[Cl:1][C:2]1[CH:19]=[CH:18][C:17]([CH:20]=[N:23][OH:24])=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]1([OH:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:5]
Reactant: NO
Reactant: O=Cc1ccc(Cl)c(C(=O)NCC2(O)CCCCCC2)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(NCC1(O)CCCCCC1)c1cc(C=NO)ccc1Cl
Yield: 45.9 %

Procedure:
A solution of 2-chloro-5-formyl-N-(1-hydroxy-cycloheptylmethyl)-benzamide (290 mg, 0.94 mmol), hydroxylamine hydrochloride (78 mg, 1.13 mmol) and sodium acetate (223 mg, 2.72 mmol) in methanol (5 mL) and water (5 mL) was stirred at room temperature for 3 h. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water, and brine, dried over sodium sulfate, filtered and adsorbed onto silica gel. The residue was purified by chromatography (1:1 ethyl acetate-hexane) to afford the title compound (140 mg).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH:15]=2)[C:10]([C:28](=[O:34])[C:29]([O:31]CC)=[O:30])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl>C1COCC1.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:25])[F:26])=[CH:19][CH:18]=3)[CH:15]=2)[C:10]([C:28](=[O:34])[C:29]([OH:31])=[O:30])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)c1cn(Cc2ccccc2)c2cc(-c3ccc(OC(F)(F)F)cc3)ccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(=O)c1cn(Cc2ccccc2)c2cc(-c3ccc(OC(F)(F)F)cc3)ccc12
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 82.4 %

Procedure:
A mixture of ethyl 2-[1-benzyl-6-(4-trifluoromethoxyphenyl)-1H-indol-3-yl]-2-oxoacetate (1.27 g, 2.72 mmol), potassium hydroxide (0.539 g, 9.61 mmol) in THF (12 mL) and water (12 mL) was stirred at room temperature for 3.5 hours. The mixture was poured into excess water, acidified with 2N hydrochloric acid, and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated to dryness. The residue was dried under vacuum at 92° C. for 15 hours to yield the title compound (0.985 g, 82%) as a yellow solid. A sample crystallized from isopropanol gave a solid, mp: 202-204° C. (dec.). Mass spectrum (+APCI, [M+H]+) m/z 440; 1HNMR (400 MHz, DMSO-d6): δ 13.8-14.2 (br s, 1H), 8.7 (s, 1H), 8.25 (d, 1H, J=8.3 Hz), 7.95 (t, 1H, J=0.73 Hz), 7.8-7.85 (m, 2H), 7.65 (dd, 1H, J=8.3 Hz and 1.5 Hz), 7.45 (d, 2H, J=8.8 Hz), 7.25-7.4 (m, 5H), and 5.65 ppm (s, 2H). Elemental Analysis for C24H16F3NO4: Calculated: C, 65.61; H, 3.67; N, 3.19. Found: C, 65.59; H, 3.54; N, 3.18.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]([CH3:17])([CH3:16])[CH2:14]O)[CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH:8]=[CH:7]2.C(N(S(F)(F)[F:24])CC)C.O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:13]([CH3:17])([CH3:16])[CH2:14][F:24])[CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH:8]=[CH:7]2
Reactant: CC(C)(CO)c1cc(F)c2c(=O)[nH]ccc2c1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CC(C)(CF)c1cc(F)c2c(=O)[nH]ccc2c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 80 %

Procedure:
8-fluoro-6-(1-hydroxy-2-methylpropan-2-yl)isoquinolin-1(2H)-one (114 mg, 485 μmol) was dissolved in DCM (dry) and cooled to −78° C. under argon. To this solution was added the diethylaminosulfur trifluoride (90 μl, 678 μmol) and the reaction was stirred for about 10 min before removal of the cooling bath. The reaction was warmed to ambient and stirred at this temperature for 2 hrs. To the reaction mixture was added 25 ml water and 20 ml DCM. The mixture was shaken and the organics collected. The organics were washed with 25 ml brine. The aqueous phase was extracted (2×20 ml DCM). The combined organics were dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by preparative tlc (2 plates, eluted with 4.5% MeOH/DCM) to afford 92 mg of the desired product as an off-white powder. (M+H)+=238 m/e.
Reaction SMILES: Br[C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH:5]=[CH:4][N:3]=1.O.[NH2:23][NH2:24]>C1COCC1>[C:8]([C:7]1[C:2]([NH:23][NH2:24])=[N:3][CH:4]=[CH:5][C:6]=1[N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)#[N:9]
Reactant: N#Cc1c(N2CCC(c3ccccc3)CC2)ccnc1Br
Reactant: NN
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1c(N2CCC(c3ccccc3)CC2)ccnc1NN
Temperature: 160 °C
Yield: 88.7 %

Procedure:
To a solution of compound D6 (0.5 mg, 1.461 mmol) in THF (4 ml), was added hydrazine monohydrate (0.366 g, 7.305 mmol). The reaction mixture was heated at 160° C. under microwave irradiation for 15 min. After cooling, the resulting mixture was concentrated in vacuo. The residue thus obtained was purified by column chromatography (silica gel; DCM/7M solution of NH3 in MeOH up to 3% as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D7 (0.380 g, 89%) as a white solid.
Reaction SMILES: [Br-].[CH3:2][Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:12]([O:19][C:20](=[O:37])[CH2:21][CH2:22][C:23](=O)[CH2:24][CH2:25][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1.O>[CH2:12]([O:19][C:20](=[O:37])[CH2:21][CH2:22][C:23](=[CH2:2])[CH2:24][CH2:25][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: O=C(CCC(=O)OCc1ccccc1)CCC(=O)OCc1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=C(CCC(=O)OCc1ccccc1)CCC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.9 %

Procedure:
Methyltriphenylphsphonium bromide (536 mg, 1.5 mmol) was suspended in anhydrous THF (1.0 mL) at −5° C. A THF solution of NaHMDS (1.0 M, 1.5 mL, 1.5 mmol) was added dropwise to keep the temperature below 0° C. The mixture was stirred at 0° C. for 0.5 h before cooled to −78° C. To this ylid solution was added a solution of dibenzyl-4-oxopimelate (354 mg, 1.0 mmol) in THF (1.0 mL) dropwise to keep the temperature below −50° C. The temperature was allowed to rise to room temperature in 1.5 h with stirring after addition. The reaction mixture was then poured in icy water (25 mL) and extracted with Et2O (2×25 mL). The organic layer was washed with brine (20 mL) and dried over Na2SO4. The solvent was removed under vacuum and the residue was subjected to silica chromatography (EtOAc/hexanes, up to 1/10) to give compound B4 (197 mg). The yield was 56%. 1H NMR (200 MHz, CDCl3) δ 7.37 (m, 10H), 5.11 (s, 4H), 4.78 (d, 2H, J=1.1 Hz), 2.53 (m, 4H), 2.39 (m, 4H); 13C NMR (50 MHz, CDCl3) δ 173.3, 146.6, 136.4, 129.0, 128.7, 110.5, 66.9, 33.2, 31.6; MS (MALDI-TOF) calcd (M+Na+) 375.4, found 375.6.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]([NH2:10])[CH:7]=[CH:6][CH:5]=1)[CH3:2].[CH:11](O)(C)C>>[CH:1]([O:3][C:4]1[N:9]=[C:8]([NH2:10])[CH:7]=[CH:6][CH:5]=1)([CH3:11])[CH3:2]
Reactant: CC(C)O
Reactant: CCOc1cccc(N)n1
Product: CC(C)Oc1cccc(N)n1

Procedure:
This intermediate is prepared according to the procedure described for 6-ethoxypyridin-2-ylamine, replacing the ethanol with isopropanol. The expected product is obtained in the form of a colourless oil.
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([C@H:15]3[CH2:19][CH2:18][C:17](=O)[CH2:16]3)=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.[CH2:22]([O:24][C:25]1[CH:26]=[C:27]([C@H:31]([NH2:33])[CH3:32])[CH:28]=[CH:29][CH:30]=1)[CH3:23]>>[CH2:22]([O:24][C:25]1[CH:26]=[C:27]([C@H:31]([NH:33][CH:17]2[CH2:18][CH2:19][C@H:15]([C:12]3[CH:13]=[CH:14][C:9]([C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:8])=[CH:10][CH:11]=3)[CH2:16]2)[CH3:32])[CH:28]=[CH:29][CH:30]=1)[CH3:23]
Reactant: O=C1CC[C@H](c2ccc(C(=O)N3CCOCC3)cc2)C1
Reactant: CCOc1cccc([C@@H](C)N)c1
Agent: Cl
Product: CCOc1cccc([C@@H](C)NC2CC[C@H](c3ccc(C(=O)N4CCOCC4)cc3)C2)c1

Procedure:
General procedure B was followed using (3S)-3-[4-(Morpholine-4-carbonyl)phenyl]-cyclopentanone (preparation 15) as the ketone and (1R)-1-(3-ethoxyphenyl)-ethanamine hydrochloride as the amine. 1H NMR (600 MHz, DMSO) δ 7.33-7.21 (m, 4H), 7.19 (t, J=7.8 Hz, 1H), 6.93-6.86 (m, 2H), 6.74 (dd, J=7.9, 2.3 Hz, 1H), 4.00 (q, J=7.0 Hz, 2H), 3.70 (q, J=6.6 Hz, 1H), 3.57 (br s, 4H), 3.33 (br s, 4H), 3.27-3.20 (m, 1H), 3.03 (t, J=8.3 Hz, 1H), 2.11-2.03 (m, 1H), 1.95-1.88 (m, 1H), 1.78-1.72 (m, 1H), 1.64-1.41 (m, 3H), 1.34-1.28 (m, 3H), 1.23 (d, J=6.6 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].I[CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:13]([O:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)[CH3:14]
Reactant: Cc1ccc(O)cc1[N+](=O)[O-]
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(C)c([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
4-Methyl-3-nitrophenol (10.0 g) was mixed with iodoethane (10.5 mL), potassium carbonate (13.5 g) and DMF (130 mL), and the obtained mixture was stirred at 60° C. overnight. Water was added to the reaction mixture, and the mixture was extracted twice with diethyl ether. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a yellow oil (11.8 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[F:9][C:10]([F:19])([F:18])[C:11]1[CH:12]=[C:13](I)[CH:14]=[CH:15][CH:16]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:10]([F:19])([F:18])[F:9])[CH:16]=2)[CH:7]=1
Reactant: FC(F)(F)c1cccc(I)c1
Reactant: Cc1ccc(=O)[nH]c1
Product: Cc1ccc(=O)n(-c2cccc(C(F)(F)F)c2)c1
Yield: 78 %

Procedure:
The reaction of 5-methyl-2-(1H)-pyridone with -3-trifluoromethyl-iodobenzene by the procedure of Example 1, gives a 78% yield of 5-methyl-1-(3'-trifluoromethylphenyl)-2-(1H)-pyridone.
Reaction SMILES: [C:1]1([CH:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:16](=[O:23])[CH2:17][CH2:18][CH2:19][C:20]=53)=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[Cl-:25]>CN(C=O)C>[Cl:25][CH:17]1[C:16](=[O:23])[C:15]2[C:14]3[C:22]4=[C:10]([O:9][CH2:8][CH:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[N:21]4[C:20]=2[CH2:19][CH2:18]1)[CH:11]=[CH:12][CH:13]=3
Reactant: [Cl-]
Reactant: O=C1CCCc2c1c1cccc3c1n2C(c1ccccc1)CO3
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=C1c2c(n3c4c(cccc24)OCC3c2ccccc2)CCC1Cl
Temperature: 65 °C
Reaction time: 50 h
Yield: 71.3 %

Procedure:
A mixture of 1-phenyl-1,2,9,10-tetrahydro[1,4]oxazino[2,3,4-jk]carbazol-7(8H)-one (0.441 g, 1.45 mmol), anhydrous CuCl12 (0.430 mmol, 3.20 mmol), anhydrous LiCl (0.308 g, 7.27 mmol), and DMF (3 mL) is stirred at 65° C. for 50 h. After cooling, the mixture is stored in the refrigerator overnight and then partitioned between CH2C2 and brine. The organic layers are dried over sodium sulfate and taken to dryness. Chromatography on silica gel gel (60 mL) using ethyl acetate/CH2Cl2/hexane (5:45:50) gave 0.349 g (71%) of 8-chloro-1-phenyl-1,2,9,10-tetrahydro[1,4]oxazino[2,3,4-jk]carbazol-7(8H)-one (mixture of diastereomers).
Reaction SMILES: O[C:2]1[N:3]=[C:4]([S:13][CH3:14])[N:5]=[N:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].S(Cl)([Cl:17])=O>>[Cl:17][C:2]1[N:3]=[C:4]([S:13][CH3:14])[N:5]=[N:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1nnc(SC)nc1O
Reactant: O=S(Cl)Cl
Product: CCOC(=O)c1nnc(SC)nc1Cl
Temperature: 75 °C

Procedure:
To 17.0 g (78.98 mmol) of 5-hydroxy-3-methylsulfanyl-1,2,4-triazine-6-carboxylic acid, ethyl ester was added 86 mL (1184.7 mmol) of thionyl chloride. The reaction mixture was heated to 75° C. for 2 hours, cooled, and concentrated. The residue was twice suspended in toluene and concentrated to give a yellow-orange solid, 5-chloro-3-methylsulfanyl-1,2,4-triazine-6-carboxylic acid, ethyl ester.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15](B3OC(C)(C)C(C)(C)O3)=[CH:14][CH:13]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl[C:28]1[N:29]=[C:30]([N:42]2[CH2:47][CH2:46][O:45][CH2:44][C@@H:43]2[CH3:48])[C:31]2[CH2:36][N:35]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:34][C:32]=2[N:33]=1>>[OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:10])[NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:28]3[N:29]=[C:30]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][C@@H:43]4[CH3:48])[C:31]4[CH2:36][N:35]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:34][C:32]=4[N:33]=3)=[CH:16][CH:17]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OB(c2ccc(NC(=O)Nc3cccc(O)c3)cc2)OC1(C)C
Reactant: CCOC(=O)N1Cc2nc(Cl)nc(N3CCOC[C@@H]3C)c2C1
Product: CCOC(=O)N1Cc2nc(-c3ccc(NC(=O)Nc4cccc(O)c4)cc3)nc(N3CCOC[C@@H]3C)c2C1

Procedure:
Method as intermediate 5 using 1-(3-hydroxyphenyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea and (S)-ethyl 2-chloro-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (intermediate 11) as starting materials. Reaction mixture was concentrated in vacuo and purified by prep. HPLC (low pH) to afford a brown solid, 22 mg (8% over 2 steps).