Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:5]([CH2:10][SH:11])([CH2:8][SH:9])[CH2:6][SH:7])[CH2:4][CH2:3][CH2:2]1.[CH3:12]OC(OC)OC>C1C=CC=CC=1>[CH:1]1([C:5]23[CH2:6][S:7][CH:12]([S:9][CH2:8]2)[S:11][CH2:10]3)[CH2:2][CH2:3][CH2:4]1
Reactant: COC(OC)OC
Reactant: SCC(CS)(CS)C1CCC1
Solvent: c1ccccc1
Product: C1CC(C23CSC(SC2)SC3)C1
Yield: 41.2 %

Procedure:
A mixture of 2-cyclobutyl-2-mercaptomethylpropane-1,3-dithiol (4 g, 20 mmol), trimethylorthoformate (2.5 g, 24 mmol) and Amberlyst 15 ion-exchange resin (1 g) was heated to reflux with stirring under a nitrogen atmosphere for 1 hour in dry benzene (100 ml). The mixture was filtered and evaporated to leave a residue which was washed with diethyl ether to give 4-cyclobutyl-2,6,7-trithiabicyclo[2.2.2]octane as a white solid (1.8 g, 43%) mp 112°-114° C., [M+1]+ 219.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:12](=[C:14]([C:18](O)=[O:19])[CH:15]=[CH:16][CH:17]=3)[N:13]=2)=[C:5]([CH3:21])[CH:4]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.Cl.[NH2:46][C@H:47]1[CH:52]2[CH2:53][CH2:54][N:49]([CH2:50][CH2:51]2)[CH2:48]1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[N:49]12[CH2:54][CH2:53][CH:52]([CH2:51][CH2:50]1)[C@H:47]([NH:46][C:18]([C:14]1[CH:15]=[CH:16][CH:17]=[C:11]3[O:10][C:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=4[CH3:21])=[N:13][C:12]=13)=[O:19])[CH2:48]2
Reactant: COc1ccc(-c2nc3c(C(=O)O)cccc3o2)c(C)c1
Reactant: N[C@@H]1CN2CCC1CC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-c2nc3c(C(=O)N[C@@H]4CN5CCC4CC5)cccc3o2)c(C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 29.9 %

Procedure:
A mixture of 2-(4-methoxy-2-methylphenyl)benzoxazole-4-carboxylic acid (100 mg, 0.35 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (134 mg, 0.70 mmol), 1-hydroxybenzotriazole (95 mg, 0.70 mmol) and (S)-(−)-3-aminoquinuclidine dihydrochloride (87 mg, 0.44 mmol) in DMF (3 mL) was stirred at room temperature for 10 min, then triethylamine (0.20 mL, 1.4 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with dichloromethane (2×50 mL). The combined organic layers were washed with brine (2×50 mL), dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) to afford (S)—N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-methoxy-2-methylphenyl)benzoxazole-4-carboxamide (41 mg, 30%) as an off-white solid: 1H NMR (500 MHz, CDCl3) δ 9.46 (d, J=7.0 Hz, 1H), 8.20-8.15 (m, 2H), 7.72 (dd, J=7.1, 1.0 Hz, 1H), 7.45 (t, J=7.9 Hz, 1H), 6.95-6.90 (m, 2H), 4.51-4.42 (m, 1H), 3.91 (s, 3H), 3.70-3.63 (m, 1H), 3.22-3.00 (m, 4H), 2.98-2.90 (m, 1H), 2.86 (s, 3H), 2.35-2.30 (m, 1H), 2.20-2.10 (m, 1H), 2.00-1.95 (m, 2H), 1.75-1.70 (m, 1H); MS (ESI+) m/z 392 (M+H); HPLC 96.6% (AUC), tR=13.19 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]([NH2:19])=[NH:18])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:20]([F:23])([F:22])[F:21].[OH:24]/[CH:25]=[C:26](/[CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[N:36][CH:37]=1)\[C:27](OC)=O.[C:38]([O-:41])([O-])=[O:39].[Cs+].[Cs+]>CN1C(=O)CCC1>[F:21][C:20]([F:23])([F:22])[C:38]([OH:41])=[O:39].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]3[NH:19][CH:27]=[C:26]([CH2:31][C:32]4[CH:37]=[N:36][CH:35]=[N:34][CH:33]=4)[C:25](=[O:24])[N:18]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:20]([F:21])([F:22])[F:23]
Reactant: O=C([O-])[O-]
Reactant: N=C(N)NCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: COC(=O)/C(=C\O)Cc1cncnc1
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: O=C(O)C(F)(F)F
Product: O=c1nc(NCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)[nH]cc1Cc1cncnc1
Temperature: 130 °C
Yield: 15.2 %

Procedure:
The mixture of N-[(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl) methyl]guanidine (50 mg, 0.109 mmol), methyl (2Z)-3-hydroxy-2-(5-pyrimidinylmethyl)-2-propenoate (33 mg, 0.170 mmol) and Cs2CO3 (143 mg, 0.438 mmol) in NMP (1 mL) was heated with a microwave reactor at 130° C. for 1 h. Purification via MDAP then afforded the title compound (5 mg, 7.60% yield). LCMS: rt=2.93 min, [M+H+]=488
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].[C:16]([CH2:19][N:20]1[CH2:25][CH2:24][N:23]([C:26]([C@@H:28]2[CH2:32][C@H:31]([S:33]CC3C=CC(OC)=CC=3)[CH2:30][N:29]2[C:43]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][C:50]([N+:53]([O-:55])=[O:54])=[CH:49][CH:48]=2)=[O:44])=[O:27])[CH2:22][CH2:21]1)(=[O:18])[NH2:17]>C1(OC)C=CC=CC=1>[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].[C:16]([CH2:19][N:20]1[CH2:21][CH2:22][N:23]([C:26]([C@@H:28]2[CH2:32][C@H:31]([SH:33])[CH2:30][N:29]2[C:43]([O:45][CH2:46][C:47]2[CH:48]=[CH:49][C:50]([N+:53]([O-:55])=[O:54])=[CH:51][CH:52]=2)=[O:44])=[O:27])[CH2:24][CH2:25]1)(=[O:18])[NH2:17]
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(CC(N)=O)CC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: NC(=O)CN1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.88 ml of trifluoroacetic acid and 94 μl of trifluoromethanesulfonic acid were added to a suspension of 305 mg of (2S,4S)-2-(4-carbamoylmethyl-1-piperazinylcarbonyl)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (prepared as described in Preparation 10) in 577 μl of anisole, whilst ice-cooling, and then the resulting mixture was stirred at room temperature for 1 hour. It was then treated in a similar manner to that described in Example 13(1), to give 316 mg of the title compound as a powder.
Reaction SMILES: [C:1](=O)([O:27]C1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][C@@H:4]([N:8]1[CH:13]=[C:12]([Cl:14])[N:11]=[C:10]([NH:15][C:16]2[C:17]([CH3:25])=[N:18][C:19]([O:23][CH3:24])=[C:20]([CH3:22])[CH:21]=2)[C:9]1=[O:26])[CH:5]1[CH2:7][CH2:6]1.[CH2:38]([O:40][C:41]1[N:46]=[C:45]([CH3:47])[C:44]([NH2:48])=[CH:43][C:42]=1[CH3:49])[CH3:39].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.Cl>C1COCC1>[CH2:38]([O:40][C:41]1[N:46]=[C:45]([CH3:47])[C:44]([NH:48][C:1](=[O:27])[O:2][CH2:3][C@@H:4]([N:8]2[CH:13]=[C:12]([Cl:14])[N:11]=[C:10]([NH:15][C:16]3[C:17]([CH3:25])=[N:18][C:19]([O:23][CH3:24])=[C:20]([CH3:22])[CH:21]=3)[C:9]2=[O:26])[CH:5]2[CH2:7][CH2:6]2)=[CH:43][C:42]=1[CH3:49])[CH3:39]
Reactant: COc1nc(C)c(Nc2nc(Cl)cn([C@H](COC(=O)Oc3ccc([N+](=O)[O-])cc3)C3CC3)c2=O)cc1C
Reactant: CCOc1nc(C)c(N)cc1C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOc1nc(C)c(NC(=O)OC[C@H](C2CC2)n2cc(Cl)nc(Nc3cc(C)c(OC)nc3C)c2=O)cc1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 31.5 %

Procedure:
To a solution of (S)-2-(5-chloro-3-(6-methoxy-2,5-dimethylpyridin-3-ylamino)-2-oxopyrazin-1(2H)-yl)-2-cyclopropylethyl 4-nitrophenyl carbonate (30 mg, 0.057 mmol) from Part A, 6-ethoxy-2,5-dimethylpyridin-3-amine (17 mg, 0.100 mmol), HOBt (9 mg, 0.063 mmol) and 4 Å molecular sieves (60 mg) in THF (1 mL) at room temperature was added triethylamine (23 μL, 0.17 mmol). The reaction mixture was stirred at room temperature for 48 h. The mixture was transferred to a separatory funnel containing 1 N HCl (5 mL) and the aqueous layer was extracted with EtOAc (3×10 ml). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by HPLC (MeCN/H2O with 0.1% TFA, C18 column) to afford (S)-2-(5-chloro-3-(6-methoxy-2,5-dimethylpyridin-3-ylamino)-2-oxopyrazin-1(2H)-yl)-2-cyclopropylethyl 6-ethoxy-2,5-dimethylpyridin-3-ylcarbamate (10 mg, 32% yield) as a yellow amorphous solid: 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.92 (s, 1H), 7.44 (s, 1H), 6.80 (s, 1H), 6.13 (s, 1H), 4.61-4.58 (m, 1H), 4.43 (dd, JAB=11.6, JAX=7.5 Hz, 1H), 4.31 (q, J=6.8 Hz, 2H), 4.26-4.21 (m, 1H), 3.92 (s, 3H), 2.41 (s, 3H), 2.29 (s, 3H), 2.17 (s, 3H), 2.10 (s, 3H), 1.33 (t, J=7.0 Hz, 3H), 1.25-1.19 (m, 1H), 0.88-0.81 (m, 1H), 0.65-0.55 (m, 2H), 0.38-0.34 (m, 1H); HRMS (ESI) m/e 557.2269 [(M+H)+, calcd for C27H34N6O5Cl 557.2279].
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[CH:15]=[N:16][N:17]([CH:19]4[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]4)[CH:18]=3)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[O:32]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33]1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>CCOC(C)=O.O>[O:32]1[CH:36]=[CH:35][C:34]([C:2]2[CH:3]=[C:4]([C:8]3[N:9]=[CH:10][C:11]([C:14]4[CH:15]=[N:16][N:17]([CH:19]5[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[CH2:21][CH2:20]5)[CH:18]=4)=[CH:12][N:13]=3)[CH:5]=[CH:6][CH:7]=2)=[CH:33]1
Reactant: OB(O)c1ccoc1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(-c4cccc(N)c4)nc3)cn2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(-c4cccc(-c5ccoc5)c4)nc3)cn2)CC1
Temperature: 120 °C
Yield: 102.7 %

Procedure:
Tert-butyl 4-4-[2-(3-iodophenyl)pyrimidin-5-yl]-1H-pyrazol-1-ylpiperidine-1-carboxylate (intermediate 5; 100 mg; 0.19 mmol; 1.0 eq.), furan-3-boronic acid (25 mg; 0.23 mmol; 1.2 eq.), Pd(Ph3)4 (11 mg; 0.01 mmol; 0.05 eq.) and potassium carbonate (78 mg; 0.56 mmol; 3.0 eq.) were flushed with nitrogen before the addition of dioxane: water (1.5:0.75 mL). The reaction mixture was heated in MW at 120° C. for 30 min. It was then diluted with EtOAc and water. Aqueous phase was extracted with EtOAc (three times) and combined organic phases were dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography (heptane:EtOAc, gradient from 80:20 to 50:50 afforded the title compound as a white solid (92 mg; 100%). 1H NMR (300 MHz, DMSO-d6) δ 9.17 (s, 2H), 8.57-8.54 (m, 2H), 8.30-8.27 (m, 2H), 8.15 (s, 1H), 7.75 (t, J=1.7 Hz, 1H), 7.78-7.74 (m, 1H), 7.55 (t, J=7.8 Hz, 1H), 7.03 (dd, J=1.7 Hz, 1.0 Hz, 1H), 4.47-4.40 (m, 1H), 4.09-4.05 (m, 2H), 2.94 (m, 2H), 2.09-2.05 (m, 2H), 1.88-1.74 (m, 2H), 1.43 (s, 9H). HPLC (Condition A): Rt 5.13 min (purity 92.1%). MS (ESI+): 472.3.
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li]CCCC.[C:13]([CH:15]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]1)#[N:14].IC>C1COCC1>[C:13]([C:15]1([CH3:1])[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]1)#[N:14]
Reactant: CC(C)NC(C)C
Reactant: CC(C)(C)OC(=O)N1CC(C#N)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: CC1(C#N)CN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Yield: 32.5 %

Procedure:
To an oven-dried 25 mL round bottom flask equipped for stirring was added diisopropylamine (1.318 mL, 9.33 mmol) under nitrogen. THF (10 mL) was added and the colorless solution was cooled to 0° C. n-BuLi in hexanes (1.6N, 5.83 mL, 9.33 mmol) was added dropwise and the solution was stirred at 0° C. for 30 min. The solution was cooled to −78° C. and a solution of tert-butyl 3-cyanoazetidine-1-carboxylate (1 g, 5.49 mmol) in THF (3 mL) was added and the solution was stirred at −78° C. for 30 min. Iodomethane (0.445 mL, 7.13 mmol) was added dropwise at −78° C. The reaction mixture was stirred for 30 min; it was then allowed to slowly warm up to 25° C. and was stirred for 16 h. The reaction mixture was quenched at 0° C. with aqueous ammonium chloride (5 mL) and was extracted with DCM (3 times). The extracts were dried over Na2SO4. Purification by silica column chromatography (MeOH/DCM, 0-5%) afforded the title compound as a yellow oil (0.35 g, 32%). 1H NMR (500 MHz, CDCl3) δ 1.45 (s, 9 H) 1.67 (s, 3 H) 3.80 (d, J=8.30 Hz, 2 H) 4.29 (d, J=8.79 Hz, 2 H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[NH4+:17].[CH3:18][N:19]([CH3:22])C=O>O>[C:7]([CH:4]1[CH2:5][CH2:6][N:1]([C:18]2[CH:2]=[CH:3][C:4]([C:5]#[N:17])=[CH:22][N:19]=2)[CH2:2][CH2:3]1)([OH:9])=[O:8]
Reactant: CN(C)C=O
Reactant: O=C(O)C1CCNCC1
Reactant: [NH4+]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc(N2CCC(C(=O)O)CC2)nc1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
A suspension of 1.8 g of 6-bromonicotinic acid nitrile, 1.3 g of 4-piperidinylcarboxylic acid and 1.06 g of sodium carbonate in 15 ml of dimethylformamide is stirred for 2 hours at 120° C. After cooling, the suspension is diluted with water. 2.0 g of ammonium chloride are added and the aqueous phase is extracted with ethyl acetate. The organic phase is washed with saturated saline solution, dried over sodium sulphate and the solvent is removed under reduced pressure. Yield: 1.2 g (52% of theory), Rf value: 0.29 (silica gel; methylene chloride/methanol/conc. ammonia=4:1:0.25)
Reaction SMILES: [Li]N([Si](C)(C)C)[Si](C)(C)C.[C:11]([CH:15]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][N:30]2[C:34]3=[N:35][C:36]([CH3:40])=[CH:37][C:38]([CH3:39])=[C:33]3[N:32]=[C:31]2[CH2:41][CH3:42])=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([O:13][CH3:14])=[O:12].[CH:43]1([CH2:46]Br)[CH2:45][CH2:44]1>>[C:11]([CH:15]([N:22]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][N:30]2[C:34]3=[N:35][C:36]([CH3:40])=[CH:37][C:38]([CH3:39])=[C:33]3[N:32]=[C:31]2[CH2:41][CH3:42])=[CH:25][CH:24]=1)[CH2:46][CH:43]1[CH2:45][CH2:44]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([O:13][CH3:14])=[O:12]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(NC(C(=O)OC)c2ccccc2)cc1
Reactant: BrCC1CC1
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(N(CC2CC2)C(C(=O)OC)c2ccccc2)cc1

Procedure:
Using the general procedure for the alkylation of secondary amines with LiN(TMS)2 described in Step A of Example 29, 3-[4-(N-(1-carbomethoxy -1-phenylmethyl)amino)phenylmethyl]-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]-pyridine (Step A, Example 28) was alkylated with cyclopropylmethyl bromide. Standard workup and purification by flash chromatography afforded the title compound.
Reaction SMILES: [CH:1]([C@H:14]1[CH2:19][C@H:18]([OH:20])[CH2:17][CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>>[CH:1]([C@H:14]1[CH2:19][C@@H:18]([O:20][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:17][CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@@H]1CCO[C@@H](C(c2ccccc2)c2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)O[C@H]1CCO[C@@H](C(c2ccccc2)c2ccccc2)C1
Yield: 97.9 %

Procedure:
Cis-2-diphenylmethyl-4-hydroxy-pyran 3b (0.3 g, 1.12 mmol) was reacted with methanesulfonyl chloride (0.26 g, 2.24 mmol) (Procedure A) to give compound 4b (0.38 g, 98%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:8]([C:11](=[O:15])[C:12]([OH:14])=O)=[CH:9][NH:10][C:3]=12.Cl.[Br:17][C:18]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[C:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(N(C(C)C)CC)(C)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>C(Cl)(Cl)Cl>[Br:17][C:18]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[C:19]1[CH2:20][CH2:21][N:22]([C:12](=[O:14])[C:11]([C:8]2[C:4]3=[N:5][CH:6]=[CH:7][C:2]([Cl:1])=[C:3]3[NH:10][CH:9]=2)=[O:15])[CH2:23][CH2:24]1
Reactant: O=C(O)C(=O)c1c[nH]c2c(Cl)ccnc12
Reactant: BrC(=C1CCNCC1)c1ccccc1
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: O=C(C(=O)N1CCC(=C(Br)c2ccccc2)CC1)c1c[nH]c2c(Cl)ccnc12
Reaction time: 48 h

Procedure:
To a solution of (7-chloro-1H-pyrrolo[3,2-b]pyridin-3-yl)-oxo-acetic acid (191 mg, 0.87 mmol), 4-(bromophenylmethylene)-piperidine hydrochloride salt (245 mg, 0.85 mmol) and diisopropylethylamine (440 mg, 3.4 mmol) in chloroform (10 mL) was added BOPCl (261 mg, 1.02 mmol). The reaction solution was stirred two days, treated with additional diisopropylethylamine (440 mg, 3.4 mmol) and BOPCl (130 mg, 0.50 mmol) and stirred three days. The reaction mixture was concentrated, dissolved into MeOH and purified by preparative HPLC to yield title compound shown (293 mg, 0.64 mmol, 75%) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([O:16][CH2:17][C@H:18]2[CH2:22][CH2:21][CH2:20][N:19]2C(OC(C)(C)C)=O)[CH:4]=1)#[N:2].[H][H].[ClH:32]>C(O)C.O1CCOCC1.[Pd]>[ClH:32].[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([O:16][CH2:17][C@H:18]2[CH2:22][CH2:21][CH2:20][NH:19]2)[CH:4]=1)#[N:2]
Reactant: [H][H]
Reactant: CCOC(=O)C=Cc1ccc(C#N)cc1OC[C@H]1CCCN1C(=O)OC(C)(C)C
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)CCc1ccc(C#N)cc1OC[C@H]1CCCN1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3.0 g (7.5 mmol) of ethyl 3-[4-cyano-(2R)-2-(1-t-butoxycarbonylpyrrolidine-2-ylmethoxy)phenyl]acrylate was dissolved in 20 ml of ethanol. 600 mg of 10% palladium/carbon (50% aqueous) was added to the obtained solution, and they were stirred in the presence of hydrogen overnight. The reaction solution was filtered through Celite, and the solvent was evaporated. The obtained crude product was dissolved in 10 ml of 4 N solution of hydrogen chloride in dioxane, and the obtained solution was stirred at room temperature for 3 hours. The solvent was evaporated to obtain hydrochloride of the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:15]=[CH:14][C:7]2[O:8][C:9]([CH3:13])([CH3:12])CO[C:6]=2[CH:5]=1)(=[O:3])[CH3:2].C[Si](C)(C)N[Si](C)(C)C.[Na].C[Si](Cl)(C)C.[Br:31]Br.C1[CH2:37][O:36]CC1>>[Br:31][CH2:2][C:1]([C:4]1[CH:15]=[CH:14][C:7]2[O:8][C:9]([CH3:12])([CH3:13])[O:36][CH2:37][C:6]=2[CH:5]=1)=[O:3]
Reactant: BrBr
Reactant: CC(=O)c1ccc2c(c1)OCC(C)(C)O2
Reactant: C1CCOC1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Na]
Product: CC1(C)OCc2cc(C(=O)CBr)ccc2O1
Reaction time: 1 h

Procedure:
To the product of step (b) (23.4 g, 0.113 mol) in 600 mL of THF at −78° C. was added 135 mL of 1.0 M sodium hexamethyldisilazane in THF (Sigma-Aldrich). After 1 hour, trimethylsilyl chloride (15.8 mL, 0.124 mol) was added. After another 30 minutes, bromine (5.82 mL, 0.113 mol) was added. After 10 minutes, the reaction was quenched by diluting the reaction mixture with diethyl ether and pouring it onto 500 mL of 5% aqueous Na2SO3 premixed with 500 mL of 5% aqueous NaHCO3. The phases were separated and the organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound as an oil that solidified upon storage in the freezer.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([N:17]2[CH2:22][CH2:21][C@:20]([CH2:30][CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[O:19][C:18]2=[O:40])[CH3:16])=[CH:11][CH:10]=1.[H-].[Na+].I[CH3:44]>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([N:17]2[CH2:22][CH2:21][C@:20]([CH2:30][CH2:31][N:32]([CH3:44])[C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:38])[CH3:37])([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[O:19][C:18]2=[O:40])[CH3:16])=[CH:11][CH:10]=1
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCNC(=O)OC(C)(C)C)(c2ccc(F)cc2)OC1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCN(C)C(=O)OC(C)(C)C)(c2ccc(F)cc2)OC1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.3 %

Procedure:
To a solution of tert-butyl 2-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethylcarbamate (53 mg, 0.1 mmol) in tetrahydrofuran was added NaH (300 mg, 12.5 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h. Then iodomethane (1.3 g, 9.15 mmol) was added to the above mixture and the mixture was stirred for 2 h. The reaction was quenched with H2O and extracted with EtOAc to give the organic layer which was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated to give tert-butyl 2-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl(methyl)carbamate (36 mg, 66%).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23]Cl)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[SH:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23][S:26][C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Sc1ccncc1
Reactant: O=C(CCCCl)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Product: O=C(CCCSc1ccncc1)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Yield: 33 %

Procedure:
Following a procedure similar to that described in Example 34, but using N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]-4-chlorobutyramide (prepared as described in Preparation 2) and 4-mercaptopyridine as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 33% yield.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:3]=1[C:4](Cl)=[O:5].[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([NH2:33])[N:28]=2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][C:4](=[O:5])[C:3]3[C:2]([F:1])=[CH:10][C:9]([F:11])=[CH:8][C:7]=3[F:12])[N:28]=2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(N)n2)CC1
Reactant: O=C(Cl)c1c(F)cc(F)cc1F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc(NC(=O)c3c(F)cc(F)cc3F)n2)CC1
Temperature: 40 °C
Yield: 78.3 %

Procedure:
Add 2,4,6-trifluorobenzoyl chloride (1.64 g, 8.42 mmol) to a solution of 4-(6-amino-pyridin-2-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (preparation 71, 2.06 g, 7.02 mmol) in triethylamine (1.066 g, 1.5 mL, 10.53 mmol) and THF (70 mL). Heat at 40° C. overnight. Dilute the mixture with ethyl acetate, wash with 0.1 N HCl, saturated NaHCO3 solution and saturated NaCl solution sequentially. Dry over Na2SO4, filter and concentrate to give a residue. Chromatography (silica gel) eluting with 14% ethyl acetate in hexanes provides 2.482 g (78%) of the title compound: mass spectrum (ion spray): m/z=452.1 (M+1); 1H NMR (CDCl3, ppm): 8.01 (s, br, 1H), 7.87 (d, br, 1H), 7.67 (t, 1H), 6.81 (m, 2H), 6.55 (d, 1H), 5.11 (m, 1H), 3.73 (m, 2H), 3.33 (m, 2H), 1.93 (m, 2H), 1.74 (m 2H), 1.49 (s, 9H).
Reaction SMILES: [CH2:1]1[O:9][C@@H:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]=[C:19]=O)=[CH:14][CH:13]=1.CN(C)C=[O:24]>[Cl-].[Li+]>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:19][C@@H:2]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[O:9][C:1]2=[O:24])=[CH:14][CH:13]=1
Reactant: COc1ccc(N=C=O)cc1
Reactant: c1ccc([C@@H]2CO2)cc1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li+]
Product: COc1ccc(N2C[C@@H](c3ccccc3)OC2=O)cc1
Temperature: 0 °C
Yield: 53.8 %

Procedure:
3.50 g (29.1 mM) of (R)-(+)-styrene oxide, 0.035 g of lithium chloride and 14 ml of N,N-dimethylformamide (DMF) were placed in a 50 ml-three necked flask. Under refluxing and stirring in nitrogen atmosphere, a solution of 4.38 g (29.4 mM) of 4-methoxyphenyl isocyanate in 3.5 ml of DMF was added dropwise to the mixture in 40 minutes, followed by refluxing for 40 minutes under stirring. After the reaction, the reaction mixture was poured into ice water to precipitate a crystal. The crystal was recovered by filtration, washed with water and recrystallized from methanol. The resultant crystal was purified by silica gel column chromatography (eluent: toluene/ethyl acetate =100/1) and recrystallized from a toluene/methanol mixture solvent to obtain 4.22 g of (5R)-3-(4-methoxyphenyl)-5-phenyl-2-oxazolidinone (Yield: 53.8%). This compound showed the following phase transition series.