Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[CH2:3][CH2:4][C:5]([OH:7])=O.C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH2:46]([O:48][C:49]([C:51]1([CH2:57][CH2:58][O:59][CH3:60])[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1)=[O:50])[CH3:47]>>[CH2:46]([O:48][C:49]([C:51]1([CH2:57][CH2:58][O:59][CH3:60])[CH2:52][CH2:53][N:54]([C:5](=[O:7])[CH2:4][CH2:3][C:2]([CH3:1])([CH3:9])[CH3:8])[CH2:55][CH2:56]1)=[O:50])[CH3:47]
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: CC(C)(C)CCC(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(CCOC)CCN(C(=O)CCC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 52.8 %

Procedure:
To a solution of 4,4-dimethyl-pentanoic acid (0.351 g) in acetronitril (15 ml) were added under an argon atmosphere N-ethyldiisopropylamin (0.7 g, 0.96 ml) and BOP (1.195 g) and the mixture was stirred for 50 minutes at RT. Then 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (0.581 g) was added and the mixture was stirred for further 12 h at RT. The reaction mixture was then partitioned between ethyl acetate and aqueous 1M HCl, the layers were separated and the aqueous layer washed with 2M aqueous KHCO3 then dried over Na2SO4. The solvent was evaporated off, the residue purified by flash chromatography (methylene chloride/AcOEt, gradient from 0 to 30%) to give 1-(4,4-dimethyl-pentanoyl)-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (0.466 g) as a yellow semi-solid that was used in the next step without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([O:13][C:14]2[C:23]3[C:18](=[C:19]([Cl:26])[C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[N:17]=[C:16]([C:27]3[S:28][CH:29]=[C:30]([CH:32]([CH3:34])[CH3:33])[N:31]=3)[CH:15]=2)[CH2:10][CH:9]1[C:35](=[O:47])[NH:36][C:37]1([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:39][CH:38]1[CH:40]=[CH2:41])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:45]([O:44][C:42]([C:37]1([NH:36][C:35]([CH:9]2[CH2:10][CH:11]([O:13][C:14]3[C:23]4[C:18](=[C:19]([Cl:26])[C:20]([O:24][CH3:25])=[CH:21][CH:22]=4)[N:17]=[C:16]([C:27]4[S:28][CH:29]=[C:30]([CH:32]([CH3:33])[CH3:34])[N:31]=4)[CH:15]=3)[CH2:12][NH:8]2)=[O:47])[CH2:39][CH:38]1[CH:40]=[CH2:41])=[O:43])[CH3:46]
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3nc(C(C)C)cs3)nc3c(Cl)c(OC)ccc23)CN1C(=O)OC(C)(C)C)C(=O)OCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3nc(C(C)C)cs3)nc3c(Cl)c(OC)ccc23)CN1)C(=O)OCC
Reaction time: 2 h
Yield: 97.2 %

Procedure:
To a stirred solution of 4-[8-chloro-2-(4-isopropylthiazol-2-yl)-7-methoxyquinolin-4-yloxy]-2-(1-ethoxycarbonyl-2-vinylcyclopropylcarbamoyl)pyrrolidine-1-carboxylic acid tert-butyl ester (49, 0.7 g, 1.02 mmol) in CH2Cl2 (8 mL) was added trifluoroacetic acid (2.0 mL). After 2 h at room temperature, the reaction mixture was concentrated and the residue was partitioned between a saturated solution of NaHCO3 and DCM. The organic layer was dried (MgSO4) filtered and concentrated to give 580 mg (97%) of the title product (50) as a colorless oil: m/z=585 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])=[C:6]([O:13][CH2:14][O:15][CH3:16])[CH:5]=[C:4]([O:17][CH2:18][O:19][CH3:20])[C:3]=1[C:21](=[O:23])[CH3:22].[H][H]>C(O)C>[OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[C:6]([O:13][CH2:14][O:15][CH3:16])[CH:5]=[C:4]([O:17][CH2:18][O:19][CH3:20])[C:3]=1[C:21](=[O:23])[CH3:22]
Reactant: [H][H]
Reactant: COCOc1cc(OCOC)c(C(C)=O)c(O)c1CC=C(C)C
Solvent: CCO
Product: COCOc1cc(OCOC)c(C(C)=O)c(O)c1CCC(C)C
Temperature: 25 °C
Yield: 82.7 %

Procedure:
A solution of 2.08 g of the 2'-hydroxy-4',6'-bis(methoxymethoxy)-3'-(3-methyl-2-butenyl)acetophenone obtained in Production Example 13 in ethanol (20 ml) was added to a sufficiently hydrogen gas-absorbed suspension of 1.0 g of 5% palladium-carbon in 30 ml of ethanol, and the mixture was stirred at room temperature under atmospheric pressure in a hydrogen atmosphere. After the reaction, the reaction mixture was filtered, and the solvent was removed from the filtrate by distillation. The obtained residue was subjected to the silica gel column chromatography (3.0 cm in diameter, 60 g of silica gel, 0.3 kg/cm2) using a mixed solvent of n-hexane and ethyl acetate (n-hexane/ethyl acetate-3/1). Fractions of 50 ml were recovered, and 1.73 g (yield=82.8%) of 2'-hydroxy-3'-isopentyl-4',6'-bis(methoxymethoxy)acetophenone in the form of a yellow oil was obtained from the third to fifth fractions.
Reaction SMILES: [F:1][C:2]1[C:18]([N+:19]([O-])=O)=[CH:17][CH:16]=[C:15]([F:22])[C:3]=1[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[C:11]([O:13][CH3:14])=[O:12])=[O:5]>[Pd]>[NH2:19][C:18]1[C:2]([F:1])=[C:3]([C:15]([F:22])=[CH:16][CH:17]=1)[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[C:11]([O:13][CH3:14])=[O:12])=[O:5]
Reactant: COC(=O)[C@@H]1CCCN1C(=O)c1c(F)ccc([N+](=O)[O-])c1F
Agent: [Pd]
Product: COC(=O)[C@@H]1CCCN1C(=O)c1c(F)ccc(N)c1F
Reaction time: 2 h

Procedure:
0.71 g (28% by weight) of palladium on carbon at 10% was added to a solution of 2.52 g of methyl (S)-1-(2,6-difluoro-3-nitrobenzoyl)pyrrolidine-2-carboxylate under nitrogen. The reaction medium was stirred under a hydrogen atmosphere for 2 hours. The reaction medium was filtered through celite and concentrated. The residue was used as it is in the next step.
Reaction SMILES: [CH3:1][C:2]([NH2:12])([CH3:11])[CH2:3][CH2:4][NH:5][CH2:6][C:7]([F:10])([F:9])[F:8].[C:13](ON1C(=O)CCC1=O)([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>C1COCC1>[CH3:11][C:2]([NH:12][C:13](=[O:14])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH2:3][CH2:4][NH:5][CH2:6][C:7]([F:8])([F:9])[F:10])[CH3:1]
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CC(C)(N)CCNCC(F)(F)F
Solvent: C1CCOC1
Product: CC(C)(CCNCC(F)(F)F)NC(=O)OCc1ccccc1
Temperature: 0 °C
Yield: 68.4 %

Procedure:
Crude 3-methyl-N1-(2,2,2-trifluoroethyl)butane-1,3-diamine (3.86 g, 21.0 mmol) was dissolved into THF (200 mL) and cooled in an ice bath. A THF (50 mL) solution of CbzOSu (5.22 g, 1 equiv, 21.0 mmol) was added to the reaction dropwise over 5 min. The reaction was left to stand in an ice chest for 16 h. The solvent was removed and the residue was taken up in a mixture of ethyl acetate (150 mL) and water (50 mL). The layers were separated and the organic layer washed with 1 M sodium carbonate (2×50 mL), 1 M HCl (50 mL) and brine (50 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated to a pale yellow oil (6.15 g). The crude oil was purified on an ISCO purification system with gradient elution from 0-6% methanol in DCM. The desired fractions were collected and concentrated to give a pale yellow oil (4.57 g, yield: 68.5%). 1H NMR (CDCl3, 400 MHz): δ 1.33 (s, 6H), 1.75-1.83 (t, J=7.2, 2H), 2.74-2.85 (t, J=7.2, 2H) 3.10-3.18 (q, J=9.4, 2H), 5.04 (s, 2H), 7.27-7.38 (m, 5H). LRMS (ESI+) for C15H21F3N2O2 (318.2); Found: 319 (MH+).
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:5]2[CH:12]=[C:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[S:14][C:4]=2[C:3]=1[CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.[CH:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O)=[O:29].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:22]1([C:3]2[C:4]3[S:14][C:13]([C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])=[CH:12][C:5]=3[N:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:2]=2[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[CH:28]=[O:29])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: COC(=O)Cn1c(Br)c(C2CCCCC2)c2sc(C(=O)OC(C)(C)C)cc21
Reactant: O=Cc1ccccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)Cn1c(-c2ccccc2C=O)c(C2CCCCC2)c2sc(C(=O)OC(C)(C)C)cc21
Temperature: 25 °C
Yield: 68 %

Procedure:
tert-Butyl 5-bromo-6-cyclohexyl-4-(2-methoxy-2-oxoethyl)-4H-thieno[3,2-b]pyrrole-2-carboxylate (1 eq., from Step 3) and 2-formyl-phenylboronic acid (1.5 eq.) were dissolved in dioxane (0.1 M) and treated with 2 M Na2CO3 solution (2 eq.). The solution was degassed by bubbling argon through it and Pd(PPh3)2Cl2 (0.1 eq.) was added. The reaction mixture was heated to reflux for 20 min then allowed to cool down to RT, diluted with EtOAc and washed with 1 N hydrochloric acid and with brine. The organic layer was dried over sodium sulfate, evaporated in vacuo and the residue purified by chromatography (PE:EtOAc, 9:1) to afford the pure title compound (68%) as a solid. 1H-NMR (400 MHz, DMSO-d6, 300 K, δ) 9.70 (s, 1H), 7.96 (dd, J 7.7, 1.3, 1H), 7.91 (s, 1H), 7.84 (dt, J 7.6, 1.5, 1H), 7.80 (t, J 7.7, 1H), 7.47 (d, J 7.6, 1H), 4.93 (d, J 18.2, 1H), 4.76 (d, J 18.2, 1H), 3.48 (s, 3H), 2.15-2.08 (m, 1H), 1.73-1.02 (m, 10H), 1.52 (s, 9H). MS (ES+) m/z: 482 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]([C:12](O)=[O:13])[CH2:3]1.B.CSC.Cl>C1COCC1>[OH:13][CH2:12][CH:4]1[CH2:3][C:2](=[O:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5]1
Reactant: O=C1CC(C(=O)O)Oc2ccccc21
Agent: B
Agent: Cl
Solvent: CSC
Solvent: C1CCOC1
Product: O=C1CC(CO)Oc2ccccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.5 %

Procedure:
The 3 g of 4-oxo-chromane-2-carboxylic acid in THF (65 mL) was stirred was cooled to 0° C. and borane-methyl sulfide complex (2.5 mL of M solution, 25 mmoles) was added dropwise for about 15 minutes. The solution was warmed to room temperature and then heated at reflux for 4 hours. The solution was cooled to room temperature and 10% aqueous hydrochloric acid (20 mL) was added over 15 minutes and the solution was stirred at room temperature for 2 hours. The mixture was concentrated to approximately 25 mL. The solution was poured into ethyl acetate (50 mL) and washed with water (2×30 mL), saturated sodium bicarbonate (2×30 mL) and saturated ammonium chloride (2×30 mL). The organic layer was separated dried over anhydrous MgSO4, and then concentrated in vacuo to yield about 2.6 g of 2-(hydroxymethyl)-chroman-4-one (86.7% yield)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-])=O.[C:14]1([NH:20][C:21](=O)[CH3:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:22][C:21]1[N:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=2[N:11]=1
Reactant: CC(=O)Nc1ccccc1
Reactant: CC(=O)c1ccc(Br)c([N+](=O)[O-])c1
Product: CC(=O)c1ccc2c(c1)nc(C)n2-c1ccccc1
Yield: 62.3 %

Procedure:
The title compound was prepared with the analogous procedure described in example 1 using 1-(4-Bromo-3-nitrophenyl)-ethanone (122 mg, 0.5 mmol) and N-phenylacetamide (81 mg, 0.6 mmol) as starting materials to yield the title compound as a yellow solid (78 mg, 62%). 1H NMR (DMSO) δ 2.54 (s, 3 H), 2.68 (s, 3 H), 7.27 (d, J=8.6 Hz, 1 H), 7.58-7.71 (m, 5 H), 7.92 (d, J=8.86 Hz, 1 H), 8.35 (br s, 1 H); 13C NMR δ 13.8, 27.0, 110.4, 117.9, 123.5, 126.7, 129.7, 130.0, 132.4, 133.9, 137.9, 153.8, 157.2, 197.0.
Reaction SMILES: [CH2:1]([C:12]1[N:16]=[C:15]([C:17]2[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=2)[O:14][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[Cl:25][C:26]1[CH:27]=[C:28]([CH2:33][CH2:34][NH2:35])[CH:29]=[CH:30][C:31]=1[Cl:32]>>[Cl:25][C:26]1[CH:27]=[C:28]([CH2:33][CH2:34][NH:35][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([C:15]3[O:14][N:13]=[C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[N:16]=3)=[CH:18][CH:19]=2)[CH:29]=[CH:30][C:31]=1[Cl:32]
Reactant: CCCCCCCCCCCc1noc(-c2ccc(C=O)cc2)n1
Reactant: NCCc1ccc(Cl)c(Cl)c1
Product: CCCCCCCCCCCc1noc(-c2ccc(CNCCc3ccc(Cl)c(Cl)c3)cc2)n1

Procedure:
The same procedure as employed in the preparation of Example 357 (step a) but using 4-(3-undecyl-1,2,4-oxadiazol-5-yl)benzaldehyde and 2-(3,4-dichlorophenyl)ethylamine gave the title compound as an oil.
Reaction SMILES: [O:1]([C:3]1[CH:23]=[CH:22][C:6]([O:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[N:16]=3)[CH:9]=2)=[CH:5][CH:4]=1)[CH3:2].[C:24](Cl)(=[O:27])[CH:25]=[CH2:26].C([O-])(O)=O.[Na+]>C1COCC1.CN1C(=O)CCC1.C(OCC)(=O)C.CCN(CC)CC>[CH3:2][O:1][C:3]1[CH:23]=[CH:22][C:6]([O:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[N:16]=[C:17]([NH:21][C:24](=[O:27])[CH:25]=[CH2:26])[CH:18]=[CH:19][CH:20]=3)[CH:9]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Oc2cc(Nc3cccc(N)n3)ncn2)cc1
Reactant: C=CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CC(=O)Nc1cccc(Nc2cc(Oc3ccc(OC)cc3)ncn2)n1
Reaction time: 0.5 h

Procedure:
To a stirred solution of N2-(6-(4-methoxylphenoxy)pyrimidin-4-yl)pyridine-2,6-diamine (150 mg, 0.474 mmol) in THF/NMP (1 mL/0.5 mL) was added acryloyl chloride (64 mg, 0.712 mmol) at −10° C. under N2 atmosphere. After stirring at this temperature for 30 min, the reaction was stopped and the reaction mixture was slowly added to NaHCO3 solution (10 mL). A white solid was precipitated which was isolated by filtration and was dissolved in a mixture of ethyl acetate (5 mL) and Et3N (0.5 mL). The solution was washed with water (2 mL) and brine (2 mL). Drying over Na2SO4 followed by filtration and concentration under reduced pressure afforded a yellow solid. It was further purified by column chromatography (SiO2, 60-120, chloroform/methanol, 9/1) to give N-(6-(6-(4-methoxyphenoxy)pyrimidin-4-ylamino)pyridine-2-yl)acrylamide (I-91) as an off white solid. 1H NMR (DMSO-d6) δ ppm: 3.76 (s, 3H), 5.79 (dd, J=1.84 & 10.16 Hz, 1H), 6.30 (dd, J=1.84 & 17 Hz, 1H), 6.65 (dd, J=10.12 & 16.92 Hz, 1H), 6.96-6.99 (m, 2H), 7.02 (d, J=7.88 Hz, 1H), 7.09-7.13 (m, 2H), 7.69 (t, J=7.96 Hz, 1H), 7.76 (d, J=7.44 Hz, 1H), 7.86 (s, 1H), 8.30 (d, J=0.88 Hz, 1H), 10.17 (s, 1H), 10.17 (s, 1H); LCMS: m/e 364 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH:9][C:10]2[S:11][C:12]3[CH2:13][N:14]([CH3:19])[CH2:15][CH2:16][C:17]=3[N:18]=2)=[CH:5][C:4]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([N:26]3[C:38](=[O:39])[C:37]4[S:36][C:35]5[CH2:34][CH2:33][CH2:32][CH2:31][C:30]=5[C:29]=4[CH:28]=[N:27]3)[C:21]=2[CH:40]=[O:41])=[CH:3]1.[BH4-].[Na+]>CO>[OH:41][CH2:40][C:21]1[C:22]([N:26]2[C:38](=[O:39])[C:37]3[S:36][C:35]4[CH2:34][CH2:33][CH2:32][CH2:31][C:30]=4[C:29]=3[CH:28]=[N:27]2)=[N:23][CH:24]=[CH:25][C:20]=1[C:4]1[CH:5]=[C:6]([NH:9][C:10]2[S:11][C:12]3[CH2:13][N:14]([CH3:19])[CH2:15][CH2:16][C:17]=3[N:18]=2)[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1
Reactant: CN1CCc2nc(Nc3cc(-c4ccnc(-n5ncc6c7c(sc6c5=O)CCCC7)c4C=O)cn(C)c3=O)sc2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN1CCc2nc(Nc3cc(-c4ccnc(-n5ncc6c7c(sc6c5=O)CCCC7)c4CO)cn(C)c3=O)sc2C1
Temperature: 30 °C
Reaction time: 1 h
Yield: 45.4 %

Procedure:
To a solution of 216b (100 mg, 0.15 mmol) in methanol (6 mL) was added NaBH4 (18 mg, 0.45 mmol). The reaction mixture was stirred at 30° C. for 1 h and quenched with brine (10 mL). It was then evaporated under reduced pressure. The residue was extracted with dichloromethane (2×20 mL) and the combined organic layer was concentrated under reduced pressure. The resulting residue was purified by reverse-phase prep-HPLC to afford 216 as a white solid (40 mg, 40%). MS-ESI: [M+H]+ 588.3. 1H NMR (500 MHz, CDCl3) δ 8.68 (d, J=5.0 Hz, 1H), 8.43 (d, J=2.0 Hz, 1H), 8.31 (s, 1H), 8.29 (s, 1H), 7.79 (d, J=2.5 Hz, 1H), 7.55 (d, J=5.0 Hz, 1H), 4.43-4.39 (m, 3H), 3.73 (s, 3H), 3.57-3.55 (m, 2H), 3.00-2.98 (m, 2H), 2.88-2.86 (m, 2H), 2.82-2.80 (m, 4H), 2.50 (s, 3H), 2.03-1.95 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([NH2:15])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][CH:3]=1.[C:16]([C:24](O)=[O:25])(=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:24]2=[O:25])=[CH:4][CH:3]=1
Reactant: O=C(O)C(=O)c1ccccc1
Reactant: Nc1ccccc1Nc1ccc(Cl)cc1
Solvent: CCOCC
Product: O=c1c(-c2ccccc2)nc2ccccc2n1-c1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
To a solution of N-(4-chlorophenyl)benzene-1,2-diamine (12.0 g) in a minimum quantity of ether was added benzoylformic acid (7.5 g) dissolved in ether and the mixture was stirred for 8 hours. The resulting precipitate was filtered, dried, and recrystallised from ethanol giving the title compound (11.0 g) mp 214.5°-216.5° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.C(=O)([O-])O.[Na+].C(O)C.[C:19]([NH:27][C:28]1[CH:40]=[C:39](B2OC(C)(C)C(C)(C)O2)[CH:38]=[CH:37][C:29]=1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:19]([NH:27][C:28]1[CH:40]=[C:39]([C:2]2[CH:3]=[CH:4][C:5]3[S:9][CH:8]=[CH:7][C:6]=3[CH:10]=2)[CH:38]=[CH:37][C:29]=1[C:30]([O:32][C:33]([CH3:35])([CH3:36])[CH3:34])=[O:31])(=[O:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1NC(=O)c1ccccc1
Reactant: Brc1ccc2sccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(-c2ccc3sccc3c2)cc1NC(=O)c1ccccc1
Temperature: 25 °C
Yield: 57.9 %

Procedure:
48 mg of 5-bromobenzothiophene, 40 mg of sodium hydrogen carbonate, 0.6 mL of ethanol, 0.3 mL of water and 11 mg of tetrakis(triphenylphosphine)palladium(0) were added to 1.6 mL of toluene solution containing 80 mg of tert-butyl 2-(benzamido)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate at room temperature, and the resulting mixture was heated to reflux under nitrogen atmosphere for 5 hours. Ethyl acetate and water were added after the reaction mixture was cooled to room temperature. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium chloride aqueous solution, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [PSQ100B (spherical) manufactured by Fuji Silysia Chemical Ltd., eluent; hexane; ethyl acetate=20:1] to obtain 47 mg of tert-butyl 2-(benzamido)-4-(benzothiophen-5-yl)benzoate as white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][N:10]=1)=O)C.[NH3:15]>>[C:11]([C:8]1[O:7][C:6]([C:4]([NH2:15])=[O:3])=[N:10][CH:9]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: N
Reactant: CCOC(=O)c1ncc(C(C)(C)C)o1
Product: CC(C)(C)c1cnc(C(N)=O)o1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The mixture of 5-tert-butyl-oxazole-2-carboxylic acid ethyl ester(0.52 g, 2.64 mmol) and NH3 (2.0M solution in MeOH, 6.6 mL, 13.2 mmol) was stirred at RT under N2 for 20 h. The solvents were removed under reduced pressure and the residue was dissolved in EtOAc washed with brine, dried with Na2SO4 and filtered. Removal of the solvents afforded the title compound as a white solid. MS m/z: 169.2 (M+H). Calc'd for C8H12N2O2-168.19
Reaction SMILES: C[N:2]1[CH2:7][CH2:6][C:5]2([C:18]3[C:10](=[CH:11][C:12]4[CH2:13][CH2:14][N:15]([C:19]([C:21]5[CH:26]=[CH:25][C:24]([C:27]6[CH:32]=[CH:31][C:30]([C:33]7[N:37]=[C:36]([CH3:38])[O:35][N:34]=7)=[CH:29][C:28]=6[CH3:39])=[CH:23][CH:22]=5)=[O:20])[C:16]=4[CH:17]=3)[O:9][CH2:8]2)[CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.ClC(OC(Cl)C)=O>ClCCCl>[CH3:39][C:28]1[CH:29]=[C:30]([C:33]2[N:37]=[C:36]([CH3:38])[O:35][N:34]=2)[CH:31]=[CH:32][C:27]=1[C:24]1[CH:23]=[CH:22][C:21]([C:19]([N:15]2[C:16]3[CH:17]=[C:18]4[C:5]5([CH2:8][O:9][C:10]4=[CH:11][C:12]=3[CH2:13][CH2:14]2)[CH2:4][CH2:3][NH:2][CH2:7][CH2:6]5)=[O:20])=[CH:26][CH:25]=1
Reactant: Cc1nc(-c2ccc(-c3ccc(C(=O)N4CCc5cc6c(cc54)C4(CCN(C)CC4)CO6)cc3)c(C)c2)no1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2ccc(-c3ccc(C(=O)N4CCc5cc6c(cc54)C4(CCNCC4)CO6)cc3)c(C)c2)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.2 %

Procedure:
A stirred solution of 1'-methyl-5-(2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-carbonyl)-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (E1, 350 mg, 0.67 mmole) in 1,2-dichloroethane (15 ml) under argon was treated with diisopropylethylamine (0.14 ml, 0.80 mmole) and 1-chloroethyl chloroformate (0.09 ml, 0.80 mmole). The mixture was stirred at room temperature for 2 h followed by 1 h at reflux temperature. Additional diisopropylethylamine (0.10 ml, 0.57 mmole) and 1-chloroethyl chloroformate (0.06 ml, 0.53 mmole) was added and reaction maintained at reflux for a further 1 h. The solution was concentrated in vacuo and the residue treated with methanol (20 ml) and heated under reflux for 1 h. The solution was concentrated in vacuo and the residue treated with conc. K2CO3 solution (25 ml) and chloroform (25 ml), shaken well and the chloroform solution separated, dried (Na2SO4) and concentrated in vacuo to afford the title compound as a beige solid (340 mg, 100%). The hydrochloride salt was prepared from acetone/ether as a white solid mp 203-210° C.
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.Br[C:31]1[CH:32]=[N:33][CH:34]=[C:35]([CH:38]=1)[C:36]#[N:37].[CH2:39]=[CH:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>CN(C)C=O.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].O>[CH:39](/[C:31]1[CH:32]=[N:33][CH:34]=[C:35]([CH:38]=1)[C:36]#[N:37])=[CH:40]\[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: C=Cc1ccccc1
Reactant: N#Cc1cncc(Br)c1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cncc(/C=C/c2ccccc2)c1
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 33.7 %

Procedure:
Add tris(dibenzylideneacetone)dipalladium (125 mg, 0.136 mmol) and tri-o-tolylphosphine (86 mg, 0.273 mmol) to a solution of triethylamine (0.77 mL, 5.46 mmol), 5-bromonicotinonitrile (500 mg, 2.73 mmol) and styrene (0.48 mL, 4.1 mmol) in anhydrous N,N-dimethylformamide (10 mL) under an inert atmosphere, and stir at 100° C. for 3.5 h. Cool to room temperature, add water and extract three times with diethyl ether. Combine the organic layers, dry (sodium sulfate), filter, and concentrate. Purify the residue by silica gel chromatography, eluting with dichloromethane, to give the title compound as a white solid (190 mg, 34%).
Reaction SMILES: [CH2:1]1O[C:4]([N:8]2[CH2:13][CH2:12][CH:11]([CH3:14])[C:10](=[O:15])[CH2:9]2)([O:5]CC)[O:3][CH2:2]1.Cl>O1CCCC1>[CH3:14][CH:11]1[CH2:12][CH2:13][N:8]([C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH2:9][C:10]1=[O:15]
Reactant: CCOC1(N2CCC(C)C(=O)C2)OCCO1
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(C)C(=O)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.5 %

Procedure:
To a solution of ethyl 4-methyl-3-oxopiperidine-1-carboxylate ethylene ketal (94 g, 0.41 mol) in tetrahydrofurane (200 ml) was added concentrated hydrochloric acid (200 ml), and the mixture was stirred for 16 hours at room temperature. Most of the tetrahydrofurane was evaporated in vacuo, and the residue was extracted with dichloromethane (3×200 ml). The organic phase was washed with saturated brine (2×150 ml), dried over magnesium sulphate and evaporated in vacuo to yield oily title product (60.1 g, 0.33 mol, 79%).