Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][S:24](=[O:27])[CH2:23][CH2:22]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:6]=2[N:7]=1.[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[O:27]=[S:24]1[CH2:25][CH2:26][N:21]([C:4]2[C:5]3[N:11]=[CH:10][N:9]=[C:8]([S:12][CH2:13][CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:6]=3[N:7]=[C:2]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[N:3]=2)[CH2:22][CH2:23]1
Reactant: C1CNCCN1
Reactant: O=S1CCN(c2nc(Cl)nc3c(SCCc4ccccc4)ncnc23)CC1
Product: O=S1CCN(c2nc(N3CCNCC3)nc3c(SCCc4ccccc4)ncnc23)CC1

Procedure:
This compound was prepared analogous to Example 1 from 2-chloro-4-(1-oxido-thiomorpholino)-8-phenethylthio-pyrimido-[5,4-d]-pyrimidine (m.p.: 232°-234° C.) and piperazine.
Reaction SMILES: BrC(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([CH:29]([O:54][SiH](C)C)[C:30]1[N:31]=[C:32]2[CH2:38][N:37]=[C:36]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[F:45])[C:35]3[CH:46]=[C:47]([Cl:50])[CH:48]=[CH:49][C:34]=3[N:33]2[C:51]=1[CH2:52]O)(C)(C)C.[CH2:58]([NH2:61])[CH:59]=[CH2:60]>O1CCCC1>[CH2:58]([NH:61][CH2:52][C:51]1[N:33]2[C:34]3[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][C:35]=3[C:36]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[F:45])=[N:37][CH2:38][C:32]2=[N:31][C:30]=1[CH2:29][OH:54])[CH:59]=[CH2:60]
Reactant: C[SiH](C)OC(c1nc2n(c1CO)-c1ccc(Cl)cc1C(c1ccccc1F)=NC2)C(C)(C)C
Reactant: C=CCN
Agent: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CCNCc1c(CO)nc2n1-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.3 %

Procedure:
3.07 g of tetrabromomethane and 2.43 g (9.3 mmol) of triphenylphosphine were added in succession and portionwise to a solution of 3.0 g of [2-(tert.-butyl-dimethylsilanyloxymethyl)-8-chloro-6-(2-fluoro-phenyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-1-yl]methanol in 10 ml of tetrahydrofuran. After stirring at room temperature for 3 h. the mixture was filtered and the residue was rinsed with a small amount of tetrahydrofuran. 25 ml (333 mmol) of allylamine were added to the filtrate and this reaction mixture was stirred at 50° C. for 2 h. Then, all volatiles were removed at 40° C. in an oil pump vacuum, the residue was taken up with 30 ml of tetrahydrofuran and 30 ml of 1N hydrochloric acid and stirred at room temperature for 3 h. After the addition of 100 ml of ethyl acetate the separated organic phase was again extracted with 30 ml of 1N hydrochloric acid. The combined aqueous phases were treated with 30 ml of 2N sodium hydroxide solution and extracted three times with 100 ml of ethyl acetate each time. Drying of the organic phase over magnesium sulphate and removal of the solvent in a vacuum yielded 2.6 g of crude product which was purified by chromatography on 300 g of silica gel with a mixture of dichloromethane/methanol/ammonium hydroxide 200:10:1. 1.96 g (77%) of 1-allylaminomethyl-8-chloro-6-(2-fluorophenyl)-4H-imidazo [1,2-a][1,4]benzodiazepine-2-methanol were thus isolated as a crystalline foam. After recrystallization from dichloromethane/diethyl ether the melting point lay at 173° C. For the preparation of the hydrochloride, 776 mg of this product were dissolved in 30 ml of dioxan and 18.9 ml of 0.1N hydrochloric acid were added dropwise. The mixture was lyophilized, taken up with 10 ml of water, filtered, again lyophilized and there was thus obtained 1-allylaminomethyl-8-chloro-6-(2-fluorophenyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol hydrochloride (1:1) of m.p. 140° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[C:7]([C:17]([F:20])([F:19])[F:18])=[CH:6][C:5]=1[NH2:21].[C:23](Cl)(Cl)=[O:24]>>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[C:7]([C:17]([F:19])([F:20])[F:18])=[CH:6][C:5]=1[N:21]=[C:23]=[O:24]
Reactant: O=C(Cl)Cl
Reactant: COC(=O)c1cc(Oc2cccnc2)c(C(F)(F)F)cc1N
Product: COC(=O)c1cc(Oc2cccnc2)c(C(F)(F)F)cc1N=C=O

Procedure:
300 mg of 2-amino-5-(pyridin-3-yloxy)-4-trifluoromethyl-benzoic acid methyl ester are treated with phosgene according to the procedure described in example 74, yielding 291 mg of 2-isocyanato-5-(pyridin-3-yloxy)-4-trifluoromethyl-benzoic acid methyl ester as a brownish oil. 1H-NMR (CDCl3): 8.50 br s, 1H; 8.40 s, 1H; 7.60 s, 1H; 7.50 s, 3H; 3.95 s, 3H.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:22])=[O:13])=O)(C)(C)C.[ClH:23]>C(Cl)Cl>[ClH:23].[NH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:22])=[O:13]
Reactant: Cc1cccc(C)c1OC(=O)CCCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1cccc(C)c1OC(=O)CCCN
Temperature: 0 °C
Yield: 86 %

Procedure:
2,6-Dimethylphenyl 4-[(tert-butoxycarbonyl)amino]butanoate (0.49 g, 1.594 mmol) was dissolved in DCM (20 ml) and HCl (4M in dioxane, 1.2 ml) was added dropwise at 0° C. The mixture was stirred for 30 minutes at 0-2° C. before the ice bath was removed and stirring was continued at rt. The mixture was evaporated in vacuum to give the title compound (0.371 g, 86%) as a white solid. It was used without further purification. 1H NMR (400 MHz, DMSO-d6): δ 1.88-1.96 (m, 2H), 2.07 (s, 6H), 2.80 (t, 2H), 2.85 (bs, 2H), 7.02-7.11 (m, 3H), 8.10 (bs, 3H).
Reaction SMILES: N#N.[N+:3]([C:6]1[CH:10]=[N:9][N:8]([CH2:11][C:12]2[O:16][C:15]([CH:17]=[O:18])=[CH:14][CH:13]=2)[N:7]=1)([O-:5])=[O:4].[CH3:19][Al](C)C.[NH4+].[Cl-].Cl>C(Cl)Cl.CCCCCCC>[N+:3]([C:6]1[CH:10]=[N:9][N:8]([CH2:11][C:12]2[O:16][C:15]([CH:17]([OH:18])[CH3:19])=[CH:14][CH:13]=2)[N:7]=1)([O-:5])=[O:4]
Reactant: C[Al](C)C
Reactant: O=Cc1ccc(Cn2ncc([N+](=O)[O-])n2)o1
Agent: Cl
Agent: N#N
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCCCCCC
Product: CC(O)c1ccc(Cn2ncc([N+](=O)[O-])n2)o1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-(4-nitro-[1,2,3]triazol-2-ylmethyl)-furan-2-carbaldehyde (180 mg, 0.81 mmol) in CH2Cl2 (8.0 mL) was treated at −10° C. with trimethylaluminum (0.32 mL of a 2M solution in heptane, 0.64 mmol). The reaction mixture was stirred at 0° C. for 2 h then poured on sat. aq. NH4Cl (5 mL), diluted with CH2Cl2 (10.0 mL) followed by 1N HCl (10 mL). The mixture was extracted with CH2Cl2 (2×20 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (50:50 hept-EA) gave the title compound as a yellow oil: TLC:rf (50:50 hept-EA)=0.31. LC-MS-conditions 02: tR=0.82 min.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH2:16][C:17]([F:20])([F:19])[F:18])[CH:10]=1)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[OH:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH2:16][C:17]([F:20])([F:18])[F:19])[CH:10]=1
Reactant: O=c1ccn(CC(F)(F)F)cc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=c1ccn(CC(F)(F)F)cc1O
Yield: 96.2 %

Procedure:
5-(Benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid (10.5 g, 42.7 mmol) was dissolved in sodium hydroxide solution (1.71 g, 42.7 mmol in 77 mL de-ionized water). 2,2,2-Trifluoroethylamine hydrochloride (23.1 g, 171 mmol) was added and the resulting suspension was stirred at 70° C. (oil-bath temperature) in the sealed flask for 17 hours. The reaction mixture was then filtered and the off-white solid was washed with de-ionized water (20 mL×5) to give 5-(benzyloxy)-4-oxo-1-(2,2,2-trifluoroethyl)-1,4-dihydropyridine-2-carboxylic acid (6.00 g). Yield=43%; 1H NMR (MeOD-D4, 90 MHz) δ 7.30 (s, 1H), 6.76-7.09 (m, 5H), 6.71 (s, 1H), 4.93 (d, J=8.4 Hz, 2H) and 4.65 (s, 2H); MS m/z 328 [M+1]+. (b) 5-(Benzyloxy)-4-oxo-1-(2,2,2-trifluoroethyl)-1,4-dihydropyridine-2-carboxylic acid (4.70 g, 14.4 mmol) was mixed with DMF (25 mL) and heated to 130° C. (bath temperature) for 3 hours. The mixture was concentrated under reduced pressure using a rotary evaporator and the residue was mixed with ethyl acetate (50 mL). It was then stirred for 2 hours at room temperature and filtered. The filtrate was concentrated to give 3-(benzyloxy)-1-(2,2,2-trifluoroethyl)pyridin-4(1H)-one (3.58 g). Yield=69%; 1H NMR (DMSO-D6, 400 MHz) δ (ppm) 7.57-7.84 (m, 2H), 7.22-7.57 (m, 5H), 6.25 (br. s, 1H) and 4.69-5.28 (m, 4H); MS m/z 284 [M+1]+. (c) 3-(Benzyloxy)-1-(2,2,2-trifluoroethyl)pyridin-4(1H)-one (1.2 g, 4.2 mmol) was mixed with 10% Palladium on charcoal (wet, 0.12 g) in ethanol (70 mL). The resulting mixture was hydrogenated at 15 psi of hydrogen pressure for 1.5 hours. Palladium was removed by filtration through a layer of Celite™ and the Celite™ cake was washed with methanol (5 mL×3). The filtrate was evaporated to give 3-hydroxy-1-(2,2,2-trifluoroethyl)pyridin-4(1H)-one (0.78 g) as white solid. Yield=95%; 1H NMR (DMSO-D6, 400 MHz) δ (ppm) 7.60 (d, J=7.1 Hz, 1H), 7.46 (s, 1H), 6.23 (d, J=7.1 Hz, 1H) and 4.80-5.00 (m, 2H); MS m/z 194 [M+1]+.
Reaction SMILES: [CH2:1]([OH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[CH2:9](Br)[CH2:10][CH:11]([CH3:13])[CH3:12]>>[CH2:9]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:8])[CH2:10][CH:11]([CH3:13])[CH3:12]
Reactant: OCCCCCCO
Reactant: CC(C)CCBr
Product: CC(C)CCOCCCCCCO

Procedure:
Using 1,6-hexandiol and isopentylbromide, the above compound is produced. B.P.: 164°-170°/12 mm Hg.
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]1[CH2:8][C@@H:7]([OH:9])[CH2:6][N:5]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].S(C)C.CO.C(Cl)(Cl)Cl>C1COCC1>[C:13]([O:12][C:10]([N:5]1[CH2:6][CH:7]([OH:9])[CH2:8][CH:4]1[CH2:3][OH:2])=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(O)CC1CO
Reaction time: 4 h
Yield: 89.8 %

Procedure:
To a stirred solution of N-Boc-hydroxyproline-methyl ester (343) (15 g, 65 mmol) in THF (70 mL) was added BH3.SMe2 (55 mL, 2.0 M in Et2O, 110 mmol). The solution was heated to reflux with stirring for four hours and reaction progress was monitored by TLC (5% MeOH/CHCl3, product had lower Rf than starting material, stained with K2MnO4). The heat was removed and the reaction was quenched by the slow addition of MeOH (40 mL). The resulting solution was heated to reflux again for 45 minutes, allowed to cool and concentrated to yield an oil that was purified by flash chromatography (1–15% MeOH in CHCl3) to give 12.68 g (˜90% yield) of the desired product (344).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([N+:26]([O-:28])=[O:27])[CH:20]=1.O>C1(C)C=CC=CC=1.C(O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([N+:26]([O-:28])=[O:27])[CH:20]=2)=[CH:5][CH:4]=1
Reactant: Cc1ccc(Br)cc1[N+](=O)[O-]
Reactant: COc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2ccc(C)c([N+](=O)[O-])c2)cc1
Temperature: 100 °C
Reaction time: 7 h
Yield: 78.7 %

Procedure:
To a solution of 4-methoxyphenyl-boronic acid (500 mg, 3.29 mmol) in toluene (5.2 mL) and ethanol (1.3 mL), potassium carbonate (910 mg, 6.58 mmol), tetrakis(triphenylphosphine)-palladium (228.1 mg, 0.099 mmol) and 4-bromo-1-methyl-2-nitrobenzene (711 mg, 3.29 mmol) are added and stirred at 100° C. for 7 hours. The mixture is poured into water and extracted with ethyl acetate two times. The organic layer is washed with water and then brine, dried over magnesium sulfate, and evaporated in vacuo. The residue is purified with silica gel column chromatography (n-hexane:ethyl acetate=5:1) to afford the 4′-methoxy-4-methyl-3-nitrobiphenyl (630 mg, 79%) as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:12]=[N:13][CH:14]=[N:15][CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=1>>[C:25]([C:22]1[CH:23]=[CH:24][C:19]([CH2:18][N:10]([C:11]2[CH:16]=[N:15][CH:14]=[N:13][CH:12]=2)[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[CH:20][CH:21]=1)#[N:26]
Reactant: O=[N+]([O-])c1ccc(Nc2cncnc2)cc1
Reactant: N#Cc1ccc(CBr)cc1
Product: N#Cc1ccc(CN(c2ccc([N+](=O)[O-])cc2)c2cncnc2)cc1

Procedure:
Starting compounds: 5-[(4-nitrophenyl) amino]pyrimidine and α-bromo-p-tolunitrile
Reaction SMILES: [C:1]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]2=O)=[CH:7][C:6]=1[O:19][CH3:20])([CH3:4])([CH3:3])[CH3:2].C([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1OC)(C)(C)C.C(C(=C)C(O)=O)C(C)C.C1(=O)C2C(=CC=CC=2)CC1>>[C:1]([C:5]1[CH:13]=[C:12]2[C:8](=[C:7]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:6]=1[O:19][CH3:20])[CH2:9][C:10]([CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:11]2)([CH3:3])([CH3:2])[CH3:4]
Reactant: COc1cc2c(cc1C(C)(C)C)C(=O)C(CC(C)C)C2
Reactant: COc1ccccc1C(C)(C)C
Agent: C=C(CC(C)C)C(=O)O
Agent: O=C1CCc2ccccc21
Product: COc1c(C(C)(C)C)cc2c(c1-c1ccccc1)CC(CC(C)C)=C2

Procedure:
The bis-indenyl ligand of formula (VIII) can be prepared following a synthetic strategy as outlined in Scheme 1. The key intermediate, the 6-tert-butyl-2-isobutyl-5-methoxyindan-1-one, was prepared by acylation of 2-tert-butylanisol with 2-isobutylacrylic acid followed by Nazarov cyclisation. Subsequent bromination, cross-coupling reaction with sodium tetraphenyl borate and reduction/dehydration of the obtained indanone gave the 5-tert-butyl-2-isobutyl-6-methoxy-7-phenyl-1H-indene. Reaction of its lithium salt with dichlorodimethylsilane produced the actual ligand bis(6-tert-butyl-2-isobutyl-5-methoxy-4-phenyl-1H-inden-1-yl)(dimethyl)silane in almost quantitative yield.
Reaction SMILES: Br[CH2:2][C:3]1[O:19][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH:4]=1)[NH:11][C:10](=[O:16])[C:9]([CH2:17][CH3:18])=[CH:8]3.[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C)C=O>[N:20]([CH2:2][C:3]1[O:19][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH:4]=1)[NH:11][C:10](=[O:16])[C:9]([CH2:17][CH3:18])=[CH:8]3)=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=[N-]
Reactant: CCc1cc2c([nH]c1=O)c(C)cc1cc(CBr)oc12
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1cc2c([nH]c1=O)c(C)cc1cc(CN=[N+]=[N-])oc12
Temperature: 120 °C
Reaction time: 1.67 h
Yield: 85.5 %

Procedure:
To a solution of the compound obtained in Example 308 (3.04 g, 9.45 mmol) in dimethylformamide (150 ml), sodium azide (1.54 g, 26.6 mmol) was added, and the solution was stirred at 120° C. for 100 minutes. The reaction liquid was condensed under reduced pressure, and the residue was extracted from a solvent mixture of chloroform-methanol (4:1). The organic phase was washed with saturated aqueous NaCl solution, dried over sodium sulfate, and condensed under reduced pressure. The resultant residue was recrystallized from chloroform-methanol-hexane. 2.28 g of the title compound was obtained as colorless needles (84.6%).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C:7]2[CH:8]=[CH:9][C:10]([C:13]([CH2:15][CH2:16][C:17]([OH:19])=O)=[O:14])=[CH:11][CH:12]=2)=[CH:5][CH:6]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[N:53]([CH2:56][CH2:57][CH2:58][CH2:59][NH2:60])=[N+:54]=[N-:55]>CC(C)=O.CCCCCC.CN(C=O)C>[N:53]([CH2:56][CH2:57][CH2:58][CH2:59][NH:60][C:17](=[O:19])[CH2:16][CH2:15][C:13]([C:10]1[CH:11]=[CH:12][C:7]([C:4]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)=[CH:8][CH:9]=1)=[O:14])=[N+:54]=[N-:55]
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccccc2)cc1
Reactant: [N-]=[N+]=NCCCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCCC
Product: [N-]=[N+]=NCCCCNC(=O)CCC(=O)c1ccc(-c2ccccc2)cc1
Reaction time: 1 h
Yield: 77 %

Procedure:
A solution of fenbufen (214 mg, 0.8 mmol), HBTU (302 mg, 0.8 mmol), DIEA (1 mL, 0.8 mmol) and DMF (15 mL) was stirred. 4-azido-1-butanamine was added. TLC (acetone/n-hexane= 3/7) indicated the consumption of starting material (Rf=0.39) and the formation of the product (Rf=0.78). After stirring for 1 hr, the mixture was concentrated under high vacuum at 60° C. The residue was purified by flash chromatography using acetone: n-hexane=3:7 as eluents to provide a snow-white solid in 77% yield (269 mg).
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][C:5]1[C:9]2[C:10]([Cl:27])=[CH:11][C:12]([O:15][CH2:16][C:17]3[N:21]([CH3:22])[N:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)=[C:13]([F:14])[C:8]=2[S:7][CH:6]=1.C1COCC1.[OH-].[Na+].Cl>CO>[Cl:27][C:10]1[C:9]2[C:5]([CH2:4][C:3]([OH:28])=[O:2])=[CH:6][S:7][C:8]=2[C:13]([F:14])=[C:12]([O:15][CH2:16][C:17]2[N:21]([CH3:22])[N:20]=[C:19]([C:23]([F:25])([F:26])[F:24])[CH:18]=2)[CH:11]=1
Reactant: COC(=O)Cc1csc2c(F)c(OCc3cc(C(F)(F)F)nn3C)cc(Cl)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1nc(C(F)(F)F)cc1COc1cc(Cl)c2c(CC(=O)O)csc2c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
To a mixture of methyl(4-chloro-7-fluoro-6-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methoxy)-1-benzothiophen-3-yl)acetate (133 mg), THF (dry) (2.0 mL) and MeOH (2.0 mL) was added 1N NaOH (0.913 mL) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was neutralized with 1N HCl. The resulting precipitate was collected by filtration to give a solid. The solid was crystallized from EtOAc-hexane to give the title compound (114 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[CH2:11]OC2C=CC=CC=2)=[CH:5][CH:4]=1.[C:19]1([CH3:28])[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6](/[CH:9]=[CH:10]/[CH2:11][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH3:28])=[CH:7][CH:8]=1
Reactant: COc1ccc(/C=C/COc2ccccc2)cc1
Reactant: Cc1ccccc1B(O)O
Product: COc1ccc(/C=C/Cc2ccccc2C)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 85.6 %

Procedure:
Following the general procedure using (E)-1-methoxy-4-(3-phenoxyprop-1-enyl)benzene (60 mg, 0.25 mmol), o-tolylboronic acid (51 mg, 0.38 mmol) and PdCl2(DPEphos) (0.015 mmol, 11 mg), the reaction was stirred for 6 h at rt. Column chromatography on silica gel (eluting with 3% EtOAc/hexanes) afforded the product as a colorless liquid (51 mg, 84%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH2:9]([O:11][C:12]1[C:13](=O)[C:14](=[O:19])[C:15]=1[O:16]CC)[CH3:10]>C(O)C>[CH2:9]([O:11][C:12]1[C:15](=[O:16])[C:14](=[O:19])[C:13]=1[NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([F:1])[CH:3]=1)[CH3:10]
Reactant: Nc1cccc(F)c1
Reactant: CCOc1c(OCC)c(=O)c1=O
Solvent: CCO
Product: CCOc1c(Nc2cccc(F)c2)c(=O)c1=O

Procedure:
A solution of 3-fluoroaniline and 3,4-diethoxy-3-cyclobutene-1,2-dione in ethanol was processed as described in Example IA to provide the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:14]([C:15]([OH:17])=O)[CH2:13][C:10]2([CH2:12][CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:18]>>[C:15]([CH:14]1[CH2:13][C:10]2([CH2:12][CH2:11]2)[CH2:9][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])(=[O:17])[NH2:18]
Reactant: N
Reactant: CC(C)(C)OC(=O)N1CC2(CC2)CC1C(=O)O
Product: CC(C)(C)OC(=O)N1CC2(CC2)CC1C(N)=O
Yield: 78 %

Procedure:
In analogy to the procedure described in Example 127 c), 5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid (CAN 1454843-77-6, 112 mg, 464 μmol) was condensed with ammonia to give the title compound (87 mg, 78%) as colorless liquid, MS (EI): m/e=240.0 [M+].
Reaction SMILES: CC([O-])(C)C.[Na+].[C:7]1(Cl)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[C:7]1([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Clc1ccccc1
Reactant: C1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: c1ccc(N2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.9 %

Procedure:
In a drybox, 14.4 mg (0.087 mmol) of (Me3C)2PH(O) from Experiment 2, 20.0 mg (0.0218 mmol) of Pd2(dba)3 (dba=bis(dibenzylideneacetone)) and 4.0 mL of toluene were loaded into a reactor (20 mL) equipped with a magnetic stir bar. The resulting mixture was stirred at room temperature overnight. Next, 144 mg (1.5 mmol) of NaOtBu was added into the mixture above, followed by syringing 122 μl (1.2 mmol) of PhCl, and 100 μl (1.0 mmol) of piperidine into the reactor. The resulting mixture was refluxed for 5 h. The reaction mixture was then cooled to room temperature, chromatographed on silicon gel using ethyl acetate/hexane (5% volume ratio) as eluant. The eluate was concentrated by rotary evaporation followed by high vacuum to yield 82 mg (51% yield) of N-phenylpiperidine. It was >95% pure by 1H NMR and GC/MS. 1H NMR (500 MHz, CDCl3): δ 7.15 (m, 2H), 6.84 (m, 2H), 6.72 (m, 1H), 3.06 (t, J=5.48 Hz, 4H), 1.61 (m, 4H), 1.48 (m, 2H) ppm. 13C NMR (125 MHz, CDCl3): d 152.3, 129.0, 119.2, 116.5, 50.7, 25.9, 24.4 3 ppm. MS: Calculated for C11H15N(M+): 161.3. Found: 162.3 (M++H).
Reaction SMILES: [CH2:1]([NH:9][C:10]([C@@H:12]1[CH2:16][CH2:15][CH:14]([OH:17])[N:13]1[CH3:18])=[O:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:19]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CO>[CH2:1]([NH:9][C:10]([C@@H:12]1[CH2:16][CH2:15][CH:14]([O:17][CH3:19])[N:13]1[CH3:18])=[O:11])[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Reactant: CN1C(O)CC[C@H]1C(=O)NCCc1ccccc1
Solvent: CO
Product: COC1CC[C@@H](C(=O)NCCc2ccccc2)N1C
Reaction time: 1 h

Procedure:
Product 11B is dissolved hemi-aminal in 10 mL anhydrous methanol and 100 mg 10-camphorsulfonic acid is added. Methanolysis is complete in 1 hour. The resulting material is filtered and concentrated, then reconstituted with ethyl acetate and washed with saturated bicarb followed by drying over anhydrous sodium sulfate, filtered and concentrated. LCMS characterization ES+383.1 (m+1).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([OH:15])=[O:14])=[CH:12][C:7]=2[S:6][CH2:5][CH2:4][CH2:3]1.O1CCOC[CH2:17]1.Cl.C(=O)([O-])O.[Na+]>CO>[CH3:17][O:14][C:13]([C:11]1[CH:10]=[CH:9][C:8]2[C:2](=[O:1])[CH2:3][CH2:4][CH2:5][S:6][C:7]=2[CH:12]=1)=[O:15]
Reactant: O=C(O)c1ccc2c(c1)SCCCC2=O
Reactant: C1COCCO1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc2c(c1)SCCCC2=O
Temperature: 25 °C

Procedure:
This 5-oxo-2,3,4,5-tetrahydro-1-benzothiepine-8-carboxylic acid (3.42 g) was dissolved in methanol (100 ml) and 4N hydrochloric acid dioxane solution (15 ml) was added. The mixture was stirred under reflux for 3 hr. The reaction mixture was cooled to room temperature and saturated aqueous sodium hydrogencarbonate solution (250 ml) was added. The mixture was extracted with ethyl acetate. The obtained organic layer was washed with water, saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure to give the objective 5-oxo-2,3,4,5-tetrahydro-1-benzothiepine-8-carboxylic acid methyl ester (3.35 g) as colorless crystals.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1.[H-].[Na+].Br[CH2:17][CH2:18][CH3:19]>CN(C=O)C>[CH2:17]([N:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1)[CH2:18][CH3:19]
Reactant: CCCBr
Reactant: N#Cc1ccnc(-c2c[nH]cn2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1cnc(-c2cc(C#N)ccn2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71.1 %

Procedure:
A solution of 2-(1H-imidazol-4-yl)pyridine-4-carbonitrile (90 mg, 0.53 mmol) in anhydrous DMF (2 mL) was cooled in an ice-water bath. Sodium hydride (60%, 32 mg, 0.8 mmol) was added carefully at 0° C. The reaction mixture was stirred for 10 minutes, after which 1-bromopropane (73 μL, 0.8 mmol) was added. The reaction mixture was warmed up to r.t. and stirred for 1 hr and it was then purified by ISCO flash column (MeOH/DCM=0-5%). 80 mg title compound was obtained as white solid (71%). [M+H] Calc'd for C12H12N4, 213. Found, 213.