Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[C:15][C:16]2[CH:21]=[C:20]([Br:22])[CH:19]=[CH:18][C:17]=2[NH2:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl.CN(C)C=O>[Br:22][C:20]1[CH:21]=[C:16]2[C:17](=[CH:18][CH:19]=1)[NH:23][C:14]([CH:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12]1)=[CH:15]2
Reactant: CC(C)(C)OC(=O)N1CCC(C#Cc2cc(Br)ccc2N)CC1
Agent: Cl[Pd]Cl
Solvent: CN(C)C=O
Solvent: N#Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(c2cc3cc(Br)ccc3[nH]2)CC1
Temperature: 80 °C

Procedure:
A 250 mL round bottom flask was charged with 4-(2-amino-5-bromo-phenylethynyl)-piperidine-1-carboxylic acid tert-butyl ester (5.90 g, 15.6 mmol), dichlorobis(benzonitrile)palladium (II) (1.20 g, 3.13 mmol), and dimethylformamide (175 mL) and the resulting mixture heated to 80° C. for 24 h. The resulting mixture was then concentrated in-vacuo and the residue purified via flash silica gel chromatography (Analogix IF-280, SF25-40 g column, gradient 90:10-80:20 Heptane:EtOAc) to yield tert-butyl 4-(5-bromo-1H-indol-2-yl)piperidine-1-carboxylate. 1H NMR (300 MHz, CDCl3) δ 7.66 (s, 1H), 7.16-7.23 (m, 2H), 6.20 (s, 1H), 2.84-3.02 (m, 5H), 1.97-2.04 (m, 2H), 1.61-1.74 (m, 2H), and 1.48 (s, 9H); MS (ES+) 380 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C@H:4](OS(C(F)(F)F)(=O)=O)[CH3:5].Cl.Cl.[NH2:17][C@@H:18]([C@H:21]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[C@@H:22]([N:32]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=1)CO.C(N(CC)CC)C>ClCCl>[CH2:48]([O:47][C@@H:21]([C@@H:18]1[NH:17][C@@H:4]([CH3:5])[C:3](=[O:14])[O:2][CH2:1]1)[C@@H:22]([N:32]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: N[C@H](CO)[C@H](OCc1ccccc1)[C@H](Cc1cc(F)cc(F)c1)N(Cc1ccccc1)Cc1ccccc1
Reactant: COC(=O)[C@@H](C)OS(=O)(=O)C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1N[C@@H]([C@H](OCc2ccccc2)[C@H](Cc2cc(F)cc(F)c2)N(Cc2ccccc2)Cc2ccccc2)COC1=O
Temperature: 25 °C
Yield: 64.7 %

Procedure:
Add 2(R)-trifluoromethanesulfonyloxypropionic acid methyl ester (6 g, 25.42 mmol) to a solution of (2R,3S,4S)-2-amino-3-benzyloxy-4-dibenzylamino-5-(3,5-difluorophenyl)-pentan-1-ol bishydrochloride (4.7 g, 7.94 mmol) and triethylamine (5 mL, 35.87 mmol) in dichloromethane (150 mL). Stir the reaction mixture at room temperature for 68-hours. Dilute with dichloromethane and wash with 5% aqueous citric acid, saturated aqueous sodium chloride, dry (magnesium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 10:90 to 20:80 ethyl acetate:hexanes) to give the desired compound (2.93 g, 65%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[CH2:26][O:27][C:28]([CH3:51])([CH3:50])[C:29]([F:49])([F:48])[C@:30]([C:33]3[CH:38]=[C:37](B4OCC(C)(C)CO4)[CH:36]=[CH:35][C:34]=3[F:47])([CH3:32])[N:31]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.Br[C:53]1[N:54]=[CH:55][N:56]([C:58]2[CH:63]=[CH:62][C:61]([C:64]([F:67])([F:66])[F:65])=[CH:60][N:59]=2)[CH:57]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[CH2:26][O:27][C:28]([CH3:51])([CH3:50])[C:29]([F:48])([F:49])[C@:30]([C:33]3[CH:38]=[C:37]([C:53]4[N:54]=[CH:55][N:56]([C:58]5[CH:63]=[CH:62][C:61]([C:64]([F:67])([F:66])[F:65])=[CH:60][N:59]=5)[CH:57]=4)[CH:36]=[CH:35][C:34]=3[F:47])([CH3:32])[N:31]=2)([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:4]=1
Reactant: FC(F)(F)c1ccc(-n2cnc(Br)c2)nc1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(B4OCC(C)(C)CO4)ccc3F)C(F)(F)C(C)(C)OC2)(c2ccccc2)c2ccc(OC)cc2)cc1
Product: COc1ccc(C(NC2=N[C@](C)(c3cc(-c4cn(-c5ccc(C(F)(F)F)cn5)cn4)ccc3F)C(F)(F)C(C)(C)OC2)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 25.3 %

Procedure:
Reaction of [bis-(4-methoxy-phenyl)-phenyl-methyl]-{(R)-5-[5-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-2-fluoro-phenyl]-6,6-difluoro-5,7,7-trimethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-yl}-amine (intermediate B10.1) (300 mg, 380 μmol) with 2-(4-bromo-1H-imidazol-1-yl)-5-(trifluoromethyl)pyridine (111 mg, 380 μmol) yielded the [bis-(4-methoxy-phenyl)-phenyl-methyl]-((R)-6,6-difluoro-5-{2-fluoro-5-[1-(5-trifluoromethyl-pyridin-2-yl)-1H-imidazol-4-yl]-phenyl}-5,7,7-trimethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-yl)-amine (77 mg, 25% yield) as a yellow foam. MS (ISP): m/z=800.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](CC#N)[CH:5]=[C:6]([CH3:9])[C:7]=1[OH:8].CO[CH2:15][CH2:16][O:17]C.[OH-:19].[K+]>O>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:15][C:16]([OH:17])=[O:19])[CH:5]=[C:6]([CH3:9])[C:7]=1[OH:8]
Reactant: COCCOC
Reactant: [OH-]
Reactant: Cc1cc(CC#N)cc(C)c1O
Agent: [K+]
Solvent: O
Product: Cc1cc(CC(=O)O)cc(C)c1O
Yield: 5.5 %

Procedure:
A suspension of (3,5-dimethyl-4-hydroxy-phenyl)-acetonitrile (4a) (550 mg, 0.003 mol) in water (0.98 mL) was treated with ethylene glycol dimethyl ether (6.6 mL, 0.063 mol) followed by potassium hydroxide (1.34 g, 0.024 mol). The reaction mixture was heated to reflux for 2 d. The reaction mixture was concentrated under vacuum. The resulting solid was diluted with water (100 mL) and extracted with ethyl acetate (2×75 mL). The organic layers were discarded. The aqueous layer was acidified to pH=2 by the addition of a 1N aqueous hydrochloric acid solution and was extracted with ethyl acetate (2×100 mL). The organic layers were combined, washed with a saturated aqueous sodium chloride solution (2×50 mL), dried with magnesium sulfate, filtered and concentrated under vacuum. The solid was purified by column chromatography using silica gel eluted with 15-25% ethyl acetate in petroleum ether to afford (3,5-dimethyl-4-hydroxy-phenyl)-acetic acid (5a) (30 mg, 5%) as a yellow solid; EI(+)-HRMS m/z calcd for C10H12O3 (M+) 180.0786, found 180.0782. Molecular Weight=180.2053; Exact Mass=180.0786
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][Si:5]([O:10][CH3:11])([O:8][CH3:9])[O:6][CH3:7].[C:12]([C:15]1[O:16][CH2:17][CH2:18][N:19]=1)([CH3:14])=[CH2:13]>C(N(CC)CC)C>[SiH4:5].[O:16]1[CH2:17][CH2:18][N:19]=[C:15]1[CH:12]([CH3:14])[CH2:13][S:1][CH2:2][CH2:3][CH2:4][Si:5]([O:10][CH3:11])([O:6][CH3:7])[O:8][CH3:9]
Reactant: C=C(C)C1=NCCO1
Reactant: CO[Si](CCCS)(OC)OC
Solvent: CCN(CC)CC
Product: CO[Si](CCCSCC(C)C1=NCCO1)(OC)OC
Product: [SiH4]
Temperature: 80 °C

Procedure:
A mixture of 3-mercaptopropyltrimethoxysilane (19.6 g, 0.1 mol), 2-isopropenyloxazoline (11.1 g, 0.1 mol) and 20 drops of triethylamine was heated under a nitrogen atmosphere at 80° C. overnight. A 3.2 g sample of the resulting mixture was vacuum fractionated (150° C., 0.06 torr) using a Kugelrohr apparatus to give 2.43 g of a clear, colorless distillate of a silane coupling agent (6-(2-oxazolinyl)-4-thiaheptyltrimethoxysilane) having the formula (CH3O)3SiCH2CH2CH2SCH2C (Me) C3 H4NO, where --C3H4NO represents an oxazolinyl group.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:8]=[N:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)(=O)=O.[C-:15]#[N:16].[Na+]>C(#N)C>[CH3:14][O:13][CH:10]1[NH:9][CH:8]=[C:7]([CH2:6][C:15]#[N:16])[CH:12]=[CH:11]1
Reactant: COc1ccc(COS(C)(=O)=O)cn1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CC#N
Product: COC1C=CC(CC#N)=CN1
Yield: 86.8 %

Procedure:
A solution of (6-methoxypyridin-3-yl)methyl methanesulfonate (1.4 g, 6.14 mmol) in acetonitrile (13 mL) was treated with sodium cyanide (0.752 g, 15.3 mmol) dropwise and the reaction mixture was heated at reflux for 48 h. After this time, the reaction was cooled and concentrated. The residue was purified by column chromatography (silica, hexanes/ethyl acetate) to afford the title compound (0.800 g, 57%) as a white solid. MW=150.18. 1H NMR (CD3OD, 300 MHz) δ 8.12-8.09 (m, 1H), 7.68 (dd, J1=10.9 Hz, h=2.4 Hz, 1H), 6.82 (d, J=8.6 Hz, 1H), 4.86 (s, 1H), 3.90 (s, 3H), 3.85 (s, 2H); APCI MS m/z 151 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:18][O:19][NH:20][CH3:21].O.N1(O)C2C=CC=CC=2N=N1>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:16])[N:20]([O:19][CH3:18])[CH3:21])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CNOC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (1.0 eq, 21.8 mmol) was dissolved under inert conditions in 35 ml dry N,N-dimethylformamide. O,N-dimethyl-hydroxylamine hydrochloride (1.03 eq, 22.5 mmol), benzotriazol-1-ol monohydrate (1.03 eq, 22.5 mmol) and triethylanine (1.5 eq, 32.7 mmol) were added. The reaction mixture was cooled to 0° C., N-(3-Dimethylaminopropyl)-N-ethylcarbodiimid hydrochloride (1.0 eq, 21.8 mmol) was added over a period of 1.0 minutes and the mixture was stirred vigorously at 0° C. for 1 h and at r.t. for 18 h.
Reaction SMILES: [N:1]1([C:6]2[CH:15]=[CH:14][C:13]3[CH:12]([C:16]([O:18]C)=[O:17])[CH2:11][CH2:10][CH2:9][C:8]=3[N:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.[OH-].[Li+].O.Cl>O1CCCC1>[N:1]1([C:6]2[CH:15]=[CH:14][C:13]3[CH:12]([C:16]([OH:18])=[O:17])[CH2:11][CH2:10][CH2:9][C:8]=3[N:7]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: COC(=O)C1CCCc2nc(-n3cnnn3)ccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1CCCc2nc(-n3cnnn3)ccc21
Reaction time: 1 h

Procedure:
Methyl 2-(1H-tetrazol-1-yl)-5,6,7,8-tetrahydroquinoline-5-carboxylate (1.04 g, 4.01 mmol) and lithium hydroxide (0.202 g, 4.81 mmol) were stirred in a mixture of tetrahydrofuran (10 mL)/water (10.00 mL) for 75 mins. The TLC showed some 20% starting material so more LiOH (50 mg, 1.19 mmol) was added and stirred for another 1 hr. The reaction was adjusted with 2N HCl (3 mL, 6 mmol) to pH 4-5 then extracted with ethyl acetate 2×. The ethyl acetate layers were combined and dried over Na2SO4, filtered and evaporated to dryness to yield the title compound: LC-MS: (M+1)-28=218.
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(=[O:4])=[O:3].Cl.[H][H]>C(O)C.[Pt]=O>[CH3:1][S:2]([NH:5][CH2:6][CH2:7][CH:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)NCCc1ccncc1
Reactant: [H][H]
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Product: CS(=O)(=O)NCCC1CCNCC1
Reaction time: 8 h

Procedure:
4-(2-Methanesulphonamidoethyl)pyridine (8.4 g.) in ethanol (85 ml.) was acidified to pH 2 with 2 N HCl and hydrogenated at room temperature and a pressure of 50 p.s.i. over a platinum oxide catalyst until hydrogen uptake ceased. The catalyst was then removed by filtration and the filtrate was taken to dryness in vacuo to give a white solid which was dissolved in the minimum volume of hot ethanol, filtered quickly, and left at room temperature overnight. The resultant white crystals were collected by filtration and dried to yield 4-(2-methanesulphonamidoethyl)piperidine:hydrochloride (8.3 g.), m.p. 165°-167° C.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[S:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[CH:16]=3)=[CH:11][N:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[N:25]1([CH2:30][CH2:31][O:32][C:33]2[CH:41]=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[CH:35][CH:34]=2)[CH2:29][CH2:28][CH2:27][CH2:26]1.[CH3:42][OH:43]>C(Cl)(Cl)Cl>[C:37]([OH:39])(=[O:38])[C:42]([OH:8])=[O:43].[C:37]([OH:39])(=[O:38])[C:42]([OH:8])=[O:43].[N:1]1([CH2:6][CH2:7][O:8][C:9]2[N:10]=[CH:11][C:12]([C:15]3[S:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[C:16]=3[C:37]([C:36]3[CH:35]=[CH:34][C:33]([O:32][CH2:31][CH2:30][N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[CH:41][CH:40]=3)=[O:38])=[CH:13][CH:14]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: c1ccc2sc(-c3ccc(OCCN4CCCC4)nc3)cc2c1
Reactant: O=C(O)c1ccc(OCCN2CCCC2)cc1
Reactant: CO
Agent: Cl
Solvent: ClC(Cl)Cl
Product: O=C(O)C(=O)O
Product: O=C(c1ccc(OCCN2CCCC2)cc1)c1c(-c2ccc(OCCN3CCCC3)nc2)sc2ccccc12
Yield: 30 %

Procedure:
By essentially following the procedure detailed in Example 1, Part C, the title compound was prepared from 5-(benzo[b]thiophen-2-yl)pyrid-2-yl 2-(1-pyrrolidinyl)ethyl ether (Part B) and 4-[2-(1-pyrrolidinyl)-ethoxy]benzoic acid hydrochloride in 30% yield as a solid following flash chromatography (SiO2; 5% MeOH in CHCl3). The free base was converted to the dioxalate salt according to the conditions outlined in Example 1, Part C.
Reaction SMILES: [NH3:1].S(O)(O)(=O)=O.N[OH:8].S(=O)(=O)(O)O.S([O-])([O-])(=O)=O.[NH4+].[NH4+].[C:21]1(=O)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C1(C)C=CC=CC=1>[C:21]1(=[N:1][OH:8])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C1CCCCCCCCCCC1
Reactant: NO
Reactant: N
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: ON=C1CCCCCCCCCCC1
Temperature: 85 °C

Procedure:
A 25% by weight aqueous ammonia (Wako Pure Chemical Industries, Ltd.) was added to an aqueous solution having a composition of 14.8% by weight of hydroxylamine sulfate, 9.5% by weight of sulfuric acid and 27.1% by weight of ammonium sulfate to adjust pH to 4 (neutralized amine). To the aqueous neutralized amine solution was added a 42.4% by weight aqueous solution of ammonium sulfate such that a concentration of hydroxylamine sulfate was 7.69% by weight. Then, 25383.3 g of the hydroxylamine sulfate solution thus prepared was added to a pillow type oxime reactor having a liquid-phase volume 40 L equipped with a mixing blade, and the mixture was heated to 85° C. and then 7241 g of cyclododecanone and 3113.7 g of toluene were added. A 25% by weight aqueous ammonia was continuously added such that pH became 5.8 at a temperature of 85° C. to promote the reaction. Once a hydroxylamine concentration in the aqueous layer became 1000 ppm or less, stirring and feeding of the aqueous ammonia were stopped and the mixture was allowed to stand, and the aqueous layer was drained. To the remaining oil layer were added 4127.3 g of toluene and 25022.6 g of neutralized amine and feeding of a 25% by weight aqueous ammonia was initiated to adjust pH to 5.8 at a temperature of 85° C. Once a cyclododecanone concentration became 1000 ppm or less, stirring was stopped and after standing, an aqueous layer was drained and the reaction was quenched. The obtained oil layer (cyclododecanone oxime-toluene solution) was analyzed by a Karl Fischer type moisture tester (Hiranuma Sangyo Co., Ltd., type AQ-2100 micro moisture tester) and a water content was 2000 ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](O)([C:14]2[S:15][CH:16]=[CH:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(S(F)(F)[F:26])CC>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([F:26])([C:14]2[S:15][CH:16]=[CH:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2nccs2)CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(F)(c2nccs2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
4-Hydroxy-4-thiazol-2-yl-piperidine-1-carboxylic acid tert-butyl ester 61 (500 mg, 1.76 mmol) was dissolved in CH2Cl2 (20 mL) and cooled to 0° C. DAST (0.46 mL, 3.52 mmol) was then added. The mixture was stirred at 0° C. for 1 hr and then quenched with sat. NaHCO3. The separated organic layer was dried and concentrated in vacuo. The crude was purified with silica gel column (eluting with 12.5% ethyl acetate in hexanes) to yield an off-white solid (443 mg) as the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)[CH3:2].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[C:25]([C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[C:29]([CH3:36])[CH:28]=1)#[N:26]>O1CCCC1>[C:25]([C:27]1[CH:35]=[CH:34][C:30]([C:31](=[O:32])[CH:5]([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=2)[C:4]([O:3][CH2:1][CH3:2])=[O:14])=[C:29]([CH3:36])[CH:28]=1)#[N:26]
Reactant: Cc1cc(C#N)ccc1C(=O)Cl
Reactant: CCOC(=O)Cc1ccc(OC)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)c1ccc(C#N)cc1C)c1ccc(OC)cc1
Reaction time: 0.25 h
Yield: 88.7 %

Procedure:
To a solution of (4-methoxy-phenyl)-acetic acid ethyl ester (25.96 g, 133.7 mmol) in anhydrous tetrahydrofuran (200 mL) was added lithium hexamethyldisilazide (200 mL, 1 M) at −78° C. under nitrogen. After being stirred for 15 min., a solution of A-5 (4-cyano-2-methylbenzoyl chloride) (24 g, 133.6 mmol) in anhydrous tetrahydrofuran (150 mL) was added dropwise, and the resulting mixture was stirred at room temperature overnight for 16 h. The reaction mixture was quenched by the addition of saturated aqueous ammonium chloride solution (200 mL), and the resultant mixture was extracted with ethyl acetate (100 mL×3). The combined organic layers were dried over anhydrous sodium sulfate (20 g), filtered, and evaporated. The residue was purified on silica gel column (petroleum ether/ethyl acetate=25:1) to give A-6 (ethyl 3-(4-cyano-2-methylphenyl)-2-(4-methoxyphenyl)-3-oxopropanoate) (40 g, yield 88.7%).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[C:15]([C:16](=O)/[CH:17]=[CH:18]/N(C)C)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH:32]1([NH:37][C:38]([NH2:40])=[NH:39])[CH2:36][CH2:35][CH2:34][CH2:33]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[C:15]([C:16]4[CH:17]=[CH:18][N:40]=[C:38]([NH:37][CH:32]5[CH2:36][CH2:35][CH2:34][CH2:33]5)[N:39]=4)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(-c2nn3c(NC4CCCC4)cccc3c2C(=O)/C=C/N(C)C)cc1
Reactant: N=C(N)NC1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Temperature: 25 °C
Yield: 73 %

Procedure:
To a solution of (2E)-1-[7-(cyclopentylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one (5.97 g, 14.7 mmol) in dimethylformamide (80 mL) was added N-cyclopentyl guanidine hydrochloride (4.33 g, 26.5 mmol; Prepared by modification of a procedure from Bannard, R. A. B. et al., Can. J. Chem. 1958, 36, 1541–1549), followed by potassium carbonate (2.03 g, 14.7 mmol). The resulting solution was heated at reflux for 6 hours. Upon cooling to room temperature, water was added. The mixture was extracted with ethyl acetate. The ethyl acetate phase was washed with brine, dried (magnesium sulfate), filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (4:6 ethyl acetate:hexane) to give N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-methoxyphenyl)-pyrazolo[1,5-a]pyridin-7-amine (5.02 g, 73%) as a yellow solid. 1H NMR (CDCl3): δ 7.95 (d, 1H), 7.72 (d, 1H), 7.54 (dd, 2H), 7.25 (t, 1H), 6.94 (dd, 2H), 6.28 (d, 1H), 6.00–5.97 (m, 2H), 5.03 (d, 1H), 4.33–4.31 (m, 1H), 3.96 (m, 1H), 3.83 (s, 3H), 2.10–2.01 (m, 4H), 1.77–1.50 (m, 12H); MS m/z 469 (M+1); Anal. Calcd for C28H32N6O: C, 71.77; H, 6.88; N17.93. Found: C, 71.41; H, 7.02; N, 17.89.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]([OH:19])=O.[CH3:20][C:21]1([CH3:35])[C:25]([CH3:27])([CH3:26])[O:24][B:23]([C:28]2[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=2)[O:22]1.C(N(C(C)C)CC)(C)C>CN(C)C=O.ClCCl>[CH3:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]([NH:32][C:31]1[CH:30]=[CH:29][C:28]([B:23]2[O:24][C:25]([CH3:27])([CH3:26])[C:21]([CH3:35])([CH3:20])[O:22]2)=[CH:34][CH:33]=1)=[O:19]
Reactant: Cn1c(C(=O)O)cc2ccccc21
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(C(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc2ccccc21
Yield: 70.2 %

Procedure:
A mixture of oxalyl chloride (0.35 mL) and dimethylformamide (1 drop) was added to a solution of 1-methyl-1H-2-indolecarboxylic acid (440 mg, 2.51 mmol) in dichloromethane (10 mL). After one hour the mixture was evaporated, dissolved in dichloromethane (10 mL), and added to a mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (500 mg, 2.28 mmol) and diisopropylethylamine (0.35 mL) in dichloromethane (10 mL). After 16 hours the mixture was washed with water (10 mL), dried (MgSO4), filtered, concentrated, and purified by flash column chromatography to provide the desired product (600 mg, 1.60 mmol) after lyophilization: MS m/e 377.4 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:27])([CH3:26])[C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[C@@H:11]([CH2:28][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH:30]2[CH2:35][C:36]([OH:38])=O)[CH2:10]1)(=[O:8])=[O:7].[CH3:39][NH:40][CH3:41].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:39][N:40]([CH3:41])[C:36](=[O:38])[CH2:35][CH:30]1[CH2:31][O:32][CH2:33][CH2:34][N:29]1[CH2:28][C@H:11]1[CH2:10][N:9]([S:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)(=[O:7])=[O:8])[CH2:14][CH2:13][N:12]1[C:15]1[CH:20]=[CH:19][C:18]([C:21]([OH:27])([CH3:26])[C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=1
Reactant: CNC
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN2CCOCC2CC(=O)O)cc1)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)CC1COCCN1C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.3 %

Procedure:
A 25-mL round-bottomed flask was charged with (4-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-morpholinyl)acetic acid (65 mg, 0.113 mmol), dimethylamine (2.0 M in MeOH, 1.69 mL, 3.38 mmol, Sigma-Aldrich, St. Louis, Mo.), Hünig's base (0.039 mL, 0.225 mmol), HATU (471 mg, 1.24 mmol) and DMF (3 mL). After stirring at room temperature for 1 h, the reaction was concentrated onto silica gel and purified via column chromatography (12 g silica gel, 0 to 100% hexanes in EtOAc) to give N,N-dimethyl-2-(4-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-morpholinyl)acetamide (20 mg) as a mixture of four isomers.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[NH:8][C:7]=2[CH:13]=1.Cl[CH2:15][CH2:16][CH2:17][O:18][CH3:19].[F-].[K+].[I-].[K+]>C(#N)C>[OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[N:8]([CH2:15][CH2:16][CH2:17][O:18][CH3:19])[C:7]=2[CH:13]=1
Reactant: O=C1COc2ccc(CO)cc2N1
Reactant: COCCCCl
Agent: [F-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COCCCN1C(=O)COc2ccc(CO)cc21
Temperature: 25 °C

Procedure:
A stirred suspension of 1.79 g of 6-hydroxymethyl-4H-benzo[1,4]oxazin-3-one, 2.20 ml of 1-chlor-3-methoxypropane, 10 g of potassium fluoride on aluminium oxide and 0.033 g potassium iodide in 150 ml of acetonitrile is heated to reflux for 72 hours. The reaction mixture is allowed to cool to room temperature, filtered and concentrated under reduced pressure. The residue is purified by flash chromatography (SiO2 60 F) to afford the title compound. Rf=0.60 (dichlormethane-methanol 9:1); Rt=2.74.