Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@H:1]1([NH:14]C(=O)OCC2C=CC=CC=2)[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1>CCO.[Pd]>[NH2:14][C@H:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:11])([CH3:10])[CH3:12])[CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](NC(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)C1
Reaction time: 1 h
Yield: 113.3 %

Procedure:
A mixture of benzyl tert-butyl (1S,3S)-cyclopentane-1,3-diylbiscarbamate (2.02 g, 6.04 mmol) and 10% Pd/C (142 mg) in EtOH (200 mL) was shaken on a Parr apparatus under hydrogen (36 psi) for 1 hr. The reaction mixture was filtered through celite and concentrated to give the title compound (1.37 g) as an opaque paste.
Reaction SMILES: ClCCCCC1C2C(=CC=CC=2)NC=1.BrCCCCC1C2C(=CC=CC=2)NC=1.[S:29]1[CH:33]=[CH:32][CH:31]=[C:30]1C1CCNCC=1.Cl.[O:41]=[C:42]1[CH2:47][CH2:46][N:45]([C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:44][CH2:43]1>>[OH:41][C:42]1([C:30]2[S:29][CH:33]=[CH:32][CH:31]=2)[CH2:43][CH2:44][N:45]([C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:46][CH2:47]1
Reactant: C1=C(c2cccs2)CCNC1
Reactant: CCOC(=O)N1CCC(=O)CC1
Agent: BrCCCCc1c[nH]c2ccccc12
Agent: Cl
Agent: ClCCCCc1c[nH]c2ccccc12
Product: CCOC(=O)N1CCC(O)(c2cccs2)CC1

Procedure:
A solution of 2.08 g of 3-(4-chlorobutyl)indole [or 2.52 g of 3-(4-bromobutyl)indole] and 1.65 g of 4-(2-thienyl)-1,2,3,6-tetrahydropyridine [hydrochloride, m.p. 242°; obtainable by reaction of 2-thienyl-Li with ethyl 4-oxo-1-piperidinecarboxylate to give ethyl 4-hydroxy-4-(2-thienyl)-1-piperidinecarboxylate, alkaline elimination of the protective group and dehydration with hydrochloric acid] in 10 ml of acetonitrile is stirred at 20° for 12 hours, worked up as usual and 3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)butyl]indole is obtained; hydrochloride ("T"), Rf 0.52.
Reaction SMILES: [ClH:1].C(OC([NH:12][CH:13]([CH2:23][CH2:24][C:25]([NH:27][CH3:28])=[O:26])[C:14]([N:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])=[O:15])=O)C1C=CC=CC=1>C(O)(C)C.[C].[Pd]>[ClH:1].[NH2:12][CH:13]([CH2:23][CH2:24][C:25]([NH:27][CH3:28])=[O:26])[C:14]([N:16]([CH2:17][CH2:18][CH3:19])[CH2:20][CH2:21][CH3:22])=[O:15]
Reactant: CCCN(CCC)C(=O)C(CCC(=O)NC)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Product: CCCN(CCC)C(=O)C(N)CCC(=O)NC
Yield: 97 %

Procedure:
In 50 ml of isopropanol was dissolved 9.3 g of DL-2-benzyloxycarbonylamino-N5 -methyl-N1,N1 -di(n-propyl)pentane-1,5-diamide, after which 2.2 ml of conc. hydrochloric acid and 0.5 g of 10% palladium-carbon were added and catalytic reduction was carried out at room temperature under atmospheric pressure. After completion of the reaction, the palladium-carbon was removed by filtration and the solvent was removed by distillation under reduced pressure to obtain 6.7 g (yield 97%) of DL-2-amino-N5 -methyl-N1,N1 -di(n-propyl)-pentane-1,5-diamide hydrochloride having a melting point of 125°-127° C.
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:20]1(=[O:26])[O:25][C:23](=[O:24])[CH2:22][CH2:21]1.[OH-].[Ca+2:28].[OH-]>>[C:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:26])[CH2:21][CH2:22][C:23]([O-:25])=[O:24].[Ca+2:28].[CH2:1]([O:19][C:20](=[O:26])[CH2:21][CH2:22][C:23]([O-:25])=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: O=C1CCC(=O)O1
Agent: [Ca+2]
Agent: [OH-]
Product: CCCCCCCCCCCCCCCCCCOC(=O)CCC(=O)[O-]
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
696.4 g of a commercially available technical stearyl alcohol were introduced into a reaction vessel and heated to 80° C. 256.6 g succinic anhydride were then added; the reaction mixture was heated to 130° C. The reaction was mildly exothermic; the temperature rose to 140° C. The reaction mixture was then stirred for 30 minutes at 130 to 140° C.; the acid value of the reaction mixture was 151 to 152. 94.3 g plus 2.8 g (3% excess) calcium hydroxide Were then introduced in portions over a period of 30 minutes at temperatures of 145° to 150° C. The reaction mixture was kept at that temperature for 4 hours, a light vacuum being applied at the beginning of the reaction. The vacuum was increased to 500 hPa after 30 minutes, to 32 hPa after 1 h and 39 hPa after 2 h and was left at that value until the end of the 4-hour reaction time.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][CH2:17][CH:18]1[CH2:22][CH2:21][CH2:20][N:19]1[CH3:23])=[CH:10][CH:9]=2)=[O:5])C.C(OC(C1NC2C(C=1)=CC(O)=CC=2)=O)C.CN1CCCC1CCO>>[CH3:23][N:19]1[CH2:20][CH2:21][CH2:22][CH:18]1[CH2:17][CH2:16][O:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:14]2
Reactant: CCOC(=O)c1cc2cc(OCCC3CCCN3C)ccc2[nH]1
Agent: CCOC(=O)c1cc2cc(O)ccc2[nH]1
Agent: CN1CCCC1CCO
Product: CN1CCCC1CCOc1ccc2[nH]c(C(=O)O)cc2c1

Procedure:
According to the procedure described for the synthesis of Example 5/step 1 5-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-1H-indole-2-carboxylic acid ethyl ester was synthesized from 5-hydroxy-1H-indole-2-carboxylic acid ethyl ester (commercially available) and 2-(1-methyl-pyrrolidin-2-yl)-ethanol (commercially available). The title compound was yielded in 38% as light brown foam. MS (m/e): 317.1 (MH+, 100%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[CH2:13][CH2:12]3)O1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH2:36][CH:37]2[CH2:39][CH2:38]2)[C:28]=1[O:40][CH3:41]>O1CCOCC1.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>[CH:37]1([CH2:36][O:35][C:29]2[C:28]([O:40][CH3:41])=[C:27]([C:9]3[CH:10]=[C:11]4[C:15](=[CH:16][CH:17]=3)[C:14](=[O:18])[CH2:13][CH2:12]4)[CH:32]=[CH:31][C:30]=2[O:33][CH3:34])[CH2:38][CH2:39]1
Reactant: COc1ccc(Br)c(OC)c1OCC1CC1
Reactant: CC1(C)OB(c2ccc3c(c2)CCC3=O)OC1(C)C
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: [Cs+]
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc3c(c2)CCC3=O)c(OC)c1OCC1CC1
Temperature: 85 °C
Yield: 42.8 %

Procedure:
A solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-one (180 mg, 0.69 mmol) in dioxane (25 mL) was purged with argon for 1 h, to this was added cesium carbonate (672 mg, 2.07 mmol), Pd(PPh3)4 (40 mg, 0.034 mmol) and 1-bromo-3-(cyclopropylmethoxy)-2,4-dimethoxybenzene (200 mg, 0.69 mmol) and the resultant reaction mixture was heated to 80-90° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was diluted with water and extracted with ethyl acetate (3×). The combined ethyl acetate layers were washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, 0-10% ethyl acetate in pet ether) afforded the title compound as a solid (100 mg and 42.3%).
Reaction SMILES: [CH2:1]([Li])CCC.C(NC(C)C)(C)C.[CH3:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[C:17]([CH3:24])[CH:16]=1.C=O>CCCCCC.C1COCC1.O>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:18](=[CH:22][CH:23]=1)[C:19](=[O:21])[O:20][CH2:1][CH2:24]2
Reactant: [Li]CCCC
Reactant: COc1ccc(C(=O)O)c(C)c1
Agent: C=O
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCOC2=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A 1.6M solution of n-butyllithium in hexane (145.9 mL) was added dropwise to a solution of diisopropylamine (33.5 mL) in dry THF (190 mL) at −78° C. The reaction mixture was then warmed to room temperature for 5 min and again cooled to −78° C., and a solution of 4-methoxy-2-methylbenzoic acid in dry THF (210 mL) was added dropwise. After stirring at this temperature for 10 min, paraformaldehyde (7 g) was added. The reaction mixture was then allowed to reach room temperature and was stirred at this temperature for 4 h. Water was added to the reaction mixture, and then the THF was removed in vacuo and the aqueous phase was extracted with diethyl ether. The aqueous phase was acidified with conc. HCl, and the resulting precipitate was filtered off and washed with water several times. The product with the molecular weight of 178.06 (C10H10O3) was obtained in this way; MS (ESI): 179 (M+H+).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[CH:7]([N:10]([CH:15]([CH3:17])[CH3:16])[C:11](=[O:14])[CH:12]=[CH2:13])([CH3:9])[CH3:8].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CCCC)CCCC)CCC>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(OCC)C.CN(C=O)C>[CH:15]([N:10]([CH:7]([CH3:9])[CH3:8])[C:11](=[O:14])[CH:12]=[CH:13][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1)([CH3:17])[CH3:16]
Reactant: C=CC(=O)N(C(C)C)C(C)C
Reactant: Brc1cccs1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: CC(C)N(C(=O)C=Cc1cccs1)C(C)C
Temperature: 130 °C

Procedure:
2-Bromothiophene (2.28 g, 14.0 mmol), N,N-diisopropylacrylamide (1.55 g, 10.0 mmol), palladium(II)acetate (34 mg, 0.15 mmol), tri-o-tolylphosphine (183 mg, 0.6 mmol), tri-n-butyl amine (2.04 g, 11.0 mmol) and dry DMF (5 mL) were mixed under a N2-atmosphere. The mixture was heated to 130° C. for 9 hours. Diethyl ether and H2O was added to the somewhat cooled mixture. The aqueous phase was extracted twice with diethyl ether. The combined organic phases were washed twice with 2 M HCl, once with water, once with brine, and dried (MgSO4), and the solvent was then evaporated. The crude product was chromatographed on silica (petroleum ether-ethyl acetate 4:1), affording a yellow oil, 1.58 g (66%): 1H NMR (CDCl3) 67 1.35 (br, 12H), 3.9 (br, 1H), 4.1 (br 1H), 6.65 (d, 1H), 7.00-7.30 (m, 3H), 7.72 (d, 1H).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[C:30]([C:34]1[CH:39]=[CH:38][C:37]([N:40]2[CH2:44][CH2:43][C:42]3([CH2:49][CH2:48][C:47](=O)[CH2:46][CH2:45]3)[C:41]2=[O:51])=[CH:36][CH:35]=1)([CH3:33])([CH3:32])[CH3:31]>C1COCC1>[C:30]([C:34]1[CH:35]=[CH:36][C:37]([N:40]2[CH2:44][CH2:43][C:42]3([CH2:49][CH2:48][C:47](=[CH:2][O:3][CH3:4])[CH2:46][CH2:45]3)[C:41]2=[O:51])=[CH:38][CH:39]=1)([CH3:32])([CH3:31])[CH3:33]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)c1ccc(N2CCC3(CCC(=O)CC3)C2=O)cc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC=C1CCC2(CC1)CCN(c1ccc(C(C)(C)C)cc1)C2=O
Temperature: 25 °C
Yield: 81.5 %

Procedure:
(Methoxymethyl)triphenyl phosphonium chloride (3.05 g, 8.9 mmol) in THF was cooled to −78° C. under argon and a solution of potassium tert-butoxide (832 mg, 7.41 mmol) in THF was added at −78° C. To the resulting red solution was added a solution of 2-(4-tert-butyl-phenyl)-2-aza-spiro[4.5]decane-1,8-dione (described in example 343 step 2, 888 mg, 2.97 mmol) in THF was added dropwise at −78° C. The reaction was allowed to warm to room temperature and the reaction was monitored by TLC. After disappearance of starting material, the reaction was quenched with sat NaHCO3 (aq), and extracted with EtOAc. The organic layers were combined washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to give a crude residue which was purified by flash column chromatography (0% to 50% EtOAc in heptane) to yield the title compound as a white solid (793 mg, 82%). MS (m/e): 328.3 (MH+).
Reaction SMILES: [CH:1](=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.Br[CH:12]([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C1C=CC=CC=1.CCOCC.[Zn]>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:1]([OH:10])[CH:12]([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:3][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CCOC(=O)C(C)Br
Agent: [Zn]
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCOC(=O)C(C)C(O)c1ccc(OC)cc1

Procedure:
To 36.2 g. (0.55 mole) of purified zinc dust is added portionwise a solution of 80 g p-anisaldehyde (0.58 mole) in 80 ml of anhydrous benzene, 20 ml anhydrous ether and 98 g (0.54 mole) of ethyl 2-bromopropionate from a separatory funnel. About 15 ml of this solution is added to the zinc and the flask is warmed until the reaction starts and then heating is removed and allowed to continue exothermally. The addition takes about an hour. The reaction mixture is refluxed for 40 minutes and then cooled in an ice bath and hydrolyzed by the addition of 250 ml of cold 10% sulfuric acid with vigorous stirring. The acid layer is drawn off and the benzene solution is extracted twice with 63 ml of 5% sulfuric acid followed by 30 ml of 10% sodium carbonate solution, then with 3 × 30 ml of 5% sulfuric acid, and finally with 2 × 30 ml of water. The combined acid solution is extracted with 2 × 100 ml of ether and the combined ether and benzene solution is washed with 2 × 50 ml of saturated sodium chloride, then it is dried over sodium sulfate for 11/2 hours and filtered. Most of the solvent is removed on an evaporator. The rest is distilled under vacuum to obtain ethyl β-(p-methoxyphenyl)-β-hydroxy-α-methylpropionate.
Reaction SMILES: [CH3:1][O:2][CH:3]([CH:6]=[CH2:7])[CH2:4][OH:5].[C:8](OC(C)(C)C)(=[O:13])[CH2:9][C:10]([CH3:12])=[O:11]>>[C:8]([O:5][CH2:4][CH:3]([O:2][CH3:1])[CH:6]=[CH2:7])(=[O:13])[CH2:9][C:10]([CH3:12])=[O:11]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: C=CC(CO)OC
Product: C=CC(COC(=O)CC(C)=O)OC
Temperature: 134 °C
Reaction time: 7 h

Procedure:
In a 500 mL 3-neck round bottom flask was placed 2-methoxy-3-butene-1-ol (164.46 g, 1.61 mol) and t-butyl acetoacetate (430.20 g, 2.50 mol). Reaction flask was equipped with magnetic stir bar, thermocouple, vigreaux column, and a still head with thermometer. Reaction was heated to 134° C. with stirring for 7 hours, then cooled to room temperature. Product was purified using a short-path distillation apparatus. Distillate was collected until the head temperature exceeded 67° C. NMR of the remaining material indicated the desired product. 1H NMR (CDCl3): d 5.63-5.75 (m, 1H), 5.32-5.40 (m, 2H), 5.06 (s, 1H), 4.10-4.25 (m, 2H), 3.82-3.90 (m, 1H), 3.5 (s, 1H), 3.34 (s, 3H), 2.28 (s, 3H), 1.96 (s, 3H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][C:9]([CH2:15]Br)=[CH:10][CH:11]=2)[N:6]=1)(=[O:3])[CH3:2].[C-:17]#[N:18].[Na+]>CN(C=O)C>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][C:9]([CH2:15][C:17]#[N:18])=[CH:10][CH:11]=2)[N:6]=1)(=[O:3])[CH3:2]
Reactant: [C-]#N
Reactant: CC(=O)Nc1ccc2ccc(CBr)cc2n1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc2ccc(CC#N)cc2n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 62.6 %

Procedure:
Compound 21 (0.216 g, 0.773 mmol) was diluted with anhydrous DMF (10 mL), and NaCN (0.190 g, 3.87 mmol) was added. The orange mixture was stirred at room temperature for 17 h. The mixture was concentrated and partitioned between EtOAc and H2O (50 mL each), and the layers were separated. The aqueous phase was extracted with EtOAc (2×50 mL), the combined organic layers were washed with H2O (2×80 mL) and sat aq. NaCl (50 mL) and dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography (SiO2), eluting with a gradient of 15% EtOAc in CH2Cl2 to 25% EtOAc in CH2Cl2 to yield the title compound as a white solid (0.109 g, 63%): mp 180-182° C. 1H-NMR (500 MHz; CDCl3): δ 8.44 (dd, J=8.3, 0.4 Hz, 1 H), 8.27-8.22 (m, 1 H), 8.18 (d, J=9.0 Hz, 1 H), 7.81 (d, J=8.4 Hz, 1 H), 7.79 (s, 1 H), 7.40 (dd, J=8.3, 1.7 Hz, 1 H), 3.94 (s, 2 H), 2.28 (s, 3 H); 13C-NMR (126 MHz; CDCl3): δ 169.2 (1 C), 151.5 (1 C), 138.8 (1 C), 132.1 (1 C), 128.7 (1 C), 126.2 (1 C), 125.6 (1 C), 124.9 (1 C), 117.3 (1 C), 114.7 (1 C), 25.1 (1 C), 24.0 (1 C); ESIMS m/z (rel. intensity) 473 (2M+Na+, 100).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].O(C(C)(C)C)[K]>C(COC)OC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH:25][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: Clc1ccc2ccccc2n1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)O[K]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc3ccccc3n2)CC1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To a degassed solution of 2-chloro-quinoline (1.00 g, 6.11 mmol, 1.0 equiv; commercially available) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (1.47 g, 7.33 mmol, 1.2 equiv; commercially available) in dimethoxyethane (15 mL) was added KOtert-Bu (0.96 g, 8.56 mmol, 1.4 equiv), (R)-(−)-1-[(S)-2-(dicyclohexyl-phosphino)-ferrocenyl]ethyl-di-tert-butylphosphine (3.39 mg, 0.0061 mmol, 0.1 mol %; Josiphos ligand [CAS RN 158923-11-6]; commercially available from Strem Chemicals, USA) and palladium(II) acetate (1.37 mg, 0.0061 mmol, 0.1 mol %). The reaction mixture was stirred at 90° C. for 4 h, concentrated by evaporation under reduced pressure and the residue purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane (+1% triethylamine)/ethyl acetate providing 1.0 g (50%) of the title compound. 1H NMR (300 MHz, DMSO): δ 1.28-1.41 (m, 2H), 1.42 (s, 9H), 1.93-1.94 (m, 2H), 2.95-3.02 (m, 2H), 3.87-3.92 (m, 2H), 4.11-4.19 (m, 1H), 6.74 (d, J=8.9 Hz, 1H), 6.94 (d, J=7.6 Hz, 1H), 7.10-7.16 (m, 1H), 7.42-7.51 (m, 2H), 7.59 (d, J=7.6 Hz, 1H), 7.83 (d, J=8.9 Hz, 1H). 13C NMR (75 MHz, DMSO): δ 28.07, 31.49, 42.41, 46.52, 78.52, 113.21, 121.03, 122.80, 125.52, 127.42, 128.89, 136.18, 147.82, 153.92, 156.13. MS (ISP): 328.5 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:18][CH:19]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:20][C:21]#[N:22])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][CH:9]=2)=[N:6][CH:7]=1.[N:27]([Sn](CCCC)(CCCC)CCCC)=[N+:28]=[N-:29]>O1CCOCC1>[CH3:24][C:23]([CH3:26])([CH3:25])[CH:19]([NH:18][C:3]1[C:2]([F:1])=[CH:7][N:6]=[C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][CH:9]=2)[N:4]=1)[CH2:20][C:21]1[N:27]=[N:28][NH:29][N:22]=1
Reactant: CC(C)(C)C(CC#N)Nc1nc(-c2c[nH]c3ncc(F)cc23)ncc1F
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: C1COCCO1
Product: CC(C)(C)C(Cc1nn[nH]n1)Nc1nc(-c2c[nH]c3ncc(F)cc23)ncc1F
Temperature: 130 °C

Procedure:
To a solution of racemic 3-(5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-4,4-dimethylpentanenitrile, 165a, (0.150 g, 0.420 mmol) in 10 mL of dioxane was added azido-tributylstannane (0.221 g, 0.668 mmol). The reaction vessel was sealed and warmed to 130° C. for 12 hours. Upon cooling, the reaction was concentrated to dryness and the resulting residue was purified by silica gel chromatography to afford 48 mg of desired product: 1H NMR (300.0 MHz, d6-DMSO) δ 12.23 (s, H), 8.49 (d, J=9.6 Hz, H), 8.26-8.05 (m, H), 4.03 (d, J=7.1 Hz, H), 3.48-3.35 (m, H), 3.17 (s, H), 2.50 (s, H), 1.99 (s, H), 1.13 (dt, J=25.1, 8.0 Hz, H), 1.01 (s, H), 0.96 (s, H) and 0.87 (d, J=6.6 Hz, H) ppm; LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=1.94 minutes (M+H) 400.46.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH:11][C:12]([CH:14]2[CH2:19][CH2:18][N:17]([C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[CH2:16][CH2:15]2)=O)[CH:6]=[CH:7][CH:8]=1>O=P(Cl)(Cl)Cl>[F:22][C:21]([F:24])([F:23])[C:20]([N:17]1[CH2:18][CH2:19][CH:14]([C:12]2[C:6]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH2:9][CH2:10][N:11]=2)[CH2:15][CH2:16]1)=[O:25]
Reactant: COc1cccc(CCNC(=O)C2CCN(C(=O)C(F)(F)F)CC2)c1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(c1)CCN=C2C1CCN(C(=O)C(F)(F)F)CC1
Temperature: 25 °C
Yield: 88.3 %

Procedure:
A stirred solution of 1-trifluoroacetyl-piperidine-4-carboxylic acid [2-(3-methoxy-phenyl)-ethyl]-amide (1.04 g, 2.9 mmol) in POCl3 under an atmosphere of N2 was heated at reflux for 2.5 hours. The reaction was allowed to cool to RT and the POCl3 was removed in vacuo. The residual oil was suspended in toluene (20 ml) and concentrated in vacuo (this process was repeated twice more), leaving the desired product as a tan colored solid (0.872 g, 2.56 mmol, 88% yield). MS 341 (M+1)
Reaction SMILES: C(OC1C=CC2C(=CC=CC=2)C=1C=NO)C1OC1.[CH2:19]([O:21][C:22]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]=1[CH:40]=[N:41][OH:42])=[O:23])[CH3:20].ClN1C(=O)CCC1=O.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:19]([O:21][C:22]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]=1[C:40]#[N+:41][O-:42])=[O:23])[CH3:20]
Reactant: CCOC(=O)CCCCCOc1ccc2ccccc2c1C=NO
Agent: O=C1CCC(=O)N1Cl
Agent: ON=Cc1c(OCC2CO2)ccc2ccccc12
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CCCCCOc1ccc2ccccc2c1C#[N+][O-]
Yield: 93.3 %

Procedure:
As shown in Chemical Formula 4, 88.2 mg (0.268 mmol) of 2-[5-(ethoxycarbonyl)pentyloxy]-1-naphthoaldehyde oxime (7) was dissolved in 30 mL of chloroform and thereto, 38.2 mg (0.325 mmol) of N-chlorosuccinimide (NCS) and 48.3 mL (0.348 mmol) of triethylamine were added in an ice bath, followed by stirring the resultant reaction mixture for 10 minutes to effect the reaction. Then, the reaction solution was washed with 10 mL of pure water, and the organic phase was dried over MgSO4, followed by concentrating the solvent under reduced pressure to obtain 81.9 mg of 2-[5-(ethoxycarbonyl)pentyloxy]-1-naphthonitrile oxide C as a satisfactorily applicable crude product.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:21]=[CH:22][C:23]=2[O:24][CH3:25])[CH2:10][C:11]2[O:12][C:13]3[C:19]([NH2:20])=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]=O)[CH:27]=1.C([BH3-])#N.[Na+].[OH-].[Na+]>CO.Cl>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:21]=[CH:22][C:23]=2[O:24][CH3:25])[CH2:10][C:11]2[O:12][C:13]3[C:19]([NH:20][CH2:32][C:28]4[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=4)=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1cccnc1
Reactant: COc1ccc(Cc2nc3cccc(N)c3o2)cc1OC1CCCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1ccc(Cc2nc3cccc(NCc4cccnc4)c3o2)cc1OC1CCCC1
Reaction time: 3 h
Yield: 87.5 %

Procedure:
To a stirred suspension of 2-(3-cyclopentyloxy-4-methoxybenzyl)-7-aminobenzoxazole (0.98 g, 0.0029 mol) in 15 ml of methanol, 2.5 ml of 1 N HCl in methanol, was added. Pyridine-3-carboxaldehyde (0.37 g, 3.5 mmol) was added to this suspension followed by sodium cyanoborohydride (0.29 g, 0.0046 mol) and the pH was adjusted to 6 using 1 N HCl in methanol. After 3 hours, 1 N sodium hydroxide was added to bring the pH to 10 and the reaction mixture was extracted with CH2Cl2. The CH2Cl2 layer was separated and the aqueous layer was extracted with 2×50 ml of CH2Cl2. The combined CH2Cl2 layers were washed with water, dried and evaporated to give 1.09 g of yellow oil which crystallized on trituration with ether. After filtration, 0.5 g of white crystalline title compound was separated and the filtrate was concentrated. Flash chromatography of the filtrate on silica gel gave 0.2 g of recovered starting material on elution with CH2Cl2, followed by a further 0.32 g of crystalline title compound when the eluting solvent was 1% methanol in CH2Cl2. This material could be recrystallized from an ether-hexane blend to give the title compound as off-white crystals, mp 90-92° C.