Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=[O:26])[CH2:23][CH2:24][CH3:25])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)#[N:2].C[Sn]([N:31]=[N+:32]=[N-:33])(C)C.[N-]=[N+]=[N-].[Na+].C[Sn](Cl)(C)C>C1(C)C=CC=CC=1>[NH:31]1[C:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=[O:26])[CH2:23][CH2:24][CH3:25])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=2)=[N:2][N:33]=[N:32]1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Agent: C[Sn](C)(C)Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCC(=O)C(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)C(=O)OCC
Reaction time: 16 h
Yield: 73.9 %

Procedure:
A mixture of 69.9 g of ethyl 2-[(2'-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate, prepared according to Example 5, 700 ml of anhydrous toluene and 47.5 g of trimethyltin azide, prepared from sodium azide and trimethyltin chloride, is refluxed for 24 h. A further 47.5 g of trimethyltin azide are added and reflux is continued for 16 h. The mixture is concentrated to 50%. The orange solution obtained is purified by chromatography twice in succession (eluent: chloroform 90%/methanol 10%, then chloroform 95%/methanol 5%) to give 58 g of an orange oil, which crystallizes.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1O)(=[O:3])[CH3:2].[CH:18](N(C(C)C)CC)(C)C.CI>CN(C=O)C>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([O:11][CH3:18])=[O:10])=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1c(O)cc(C(=O)O)cc1[N+](=O)[O-]
Reactant: CCN(C(C)C)C(C)C
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(C)=O)c([N+](=O)[O-])c1
Yield: 94.1 %

Procedure:
Compound 107 (1.50 g, 6.69 mmol) was dissolved in DMF (25 mL), and diisopropylethylamine (16.0, 92.7 mmol) and MeI (2.3 mL, 39 mmol) were added. The solid which formed was filtered and the filtrate was concentrated to dryness on a rotary evaporator to provide 15 (1.50 g, 94.3%) as a yellow solid: mp 123°-124° C. (ethanol). The literature (Appleton et al., 1970) reports mp 127° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[CH:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[NH2:34][C:35]([CH3:39])([CH3:38])[CH2:36][OH:37]>C1COCC1.CCOC(C)=O>[OH:37][CH2:36][C:35]([NH:34][S:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:10]2[CH:9]=[C:8]([C:6]3[CH:5]=[C:4]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][CH:25]=4)[CH:3]=[C:2]([CH3:1])[N:7]=3)[CH:13]=[CH:12][N:11]=2)[CH:15]=1)(=[O:21])=[O:22])([CH3:39])[CH3:38]
Reactant: CC(C)(N)CO
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(S(=O)(=O)Cl)c3)c2)n1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(S(=O)(=O)NC(C)(C)CO)c3)c2)n1
Temperature: 25 °C
Yield: 16 %

Procedure:
The title compound was prepared from the solution of 3-[6-methyl-4-(4-trifluoromethylphenyl)-[2,4′]bipyridinyl-2′-yl]-benzenesulfonyl chloride (example 346 step 2) (ca. 0.2 g, 0.41 mmol) by treatment with excess 2-amino-2-methyl-1-propanol in THF (5 mL) at 50° C. for 16 h. Cooled to rt, diluted with EtOAc, washed with 1 N HCl, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with n-heptane/EtOAc followed by trituration with n-heptane/diethyl ether to give the title compound (0.035 g, 16%) as a white solid. MS (ISP) 542.2 [(M+H)+]; mp 92° C.
Reaction SMILES: [NH:1]([C:6]([CH2:11][OH:12])([CH2:9][OH:10])[CH2:7][OH:8])[CH2:2][C:3]([OH:5])=[O:4].S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>>[CH2:18]([O:4][C:3](=[O:5])[CH2:2][NH:1][C:6]([CH2:9][OH:10])([CH2:11][OH:12])[CH2:7][OH:8])[CH3:19]
Reactant: O=C(O)CNC(CO)(CO)CO
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)CNC(CO)(CO)CO

Procedure:
Tricine ethyl ester is prepared by mixing a 500 ml of a suspension of tricine 0.5 g/ml in ethanol with 1 ml of concentrated sulfuric acid. Subsequent distillation of the ethanol water azeotrope forms the ester.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[CH:12]([O:15][CH3:16])[O:13][CH3:14])[N:8]([C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][N:21]=1)=[O:18])[CH2:7][CH2:6][CH2:5]2.[Li]C.[Li]CCCC.CN([CH:38]=[O:39])C.[NH4+].[Cl-].[BH4-].[Na+]>C1COCC1.C(Cl)Cl>[C:26]([C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:17]([N:8]2[C:9]3[C:4](=[CH:3][C:2]([CH2:38][OH:39])=[C:11]([CH:12]([O:15][CH3:16])[O:13][CH3:14])[N:10]=3)[CH2:5][CH2:6][CH2:7]2)=[O:18])=[N:21][CH:22]=1)#[N:27]
Reactant: CN(C)C=O
Reactant: COC(OC)c1nc2c(cc1Br)CCCN2C(=O)Nc1ccc(C#N)cn1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li]C
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(OC)c1nc2c(cc1CO)CCCN2C(=O)Nc1ccc(C#N)cn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 6-bromo-N-(5-cyanopyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 2H, 171 mg, 0.396 mmol) in THF (5 ml) at −78° C., was added MeLi (1.6 M in Et2O, 0.247 ml, 0.396 mmol), the solution was stirred for 5 min. Then, n-BuLi (1.6 M in hexane, 0.272 ml, 0.435 mmol) was added and the solution was stirred for 20 min. Then, DMF (0.184 ml, 2.37 mmol) was added. The reaction mixture was stirred at −78° C. for 1.5 h and then allowed to warm to room temperature. The reaction mixture was poured into sat. aq. NH4Cl and extracted twice with DCM. The organic phase was then dried over Na2SO4, filtered and evaporated. The residue was purified by normal phase chromatography (12 g gold silica gel cartridge, heptanes/EtOAc 100:0 to 0:100). The N-(5-cyanopyridin-2-yl)-7-(dimethoxymethyl)-6-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide containing fraction were concentrated. The residue was dissolved in MeOH (1.5 ml) and DCM (1.5 ml) and treated with NaBH4 (5.32 mg, 0.141 mmol). The reaction mixture was stirred at room temperature for 30 min, then poured into sat. aq. NH4Cl and extracted with DCM (3×). The combined organic phases were then dried over Na2SO4, filtered and evaporated. The crude material was purified by normal phase chromatography (4 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100) followed by a reverse phase chromatography (13 g C18 cartridge, 0.1% TFA in water/acetonitrile 80:20 to 0:100). The product containing fractions were treated with sat. aq. Na2CO3, concentrated until the organic solvent had been removed extracted with DCM (3×). The combined organic layers were dried over Na2SO4, filtered and evaporated to give the title compound as a colorless resin. (UPLC-MS 3) tR 0.92 min; ESI-MS 384.1 [M+H]+.
Reaction SMILES: CCN=C=NC[CH2:7][CH2:8][N:9]([CH3:11])C.Cl.[CH2:13]([C:17]1=[CH:18][N:19]([C:36]([CH3:39])([CH3:38])[CH3:37])[S:20]/[C:21]/1=[N:22]\[C:23]([C@:25]1([CH3:35])[CH2:29][CH2:28][C@H:27]([C:30]([OH:32])=O)[C:26]1([CH3:34])[CH3:33])=[O:24])[CH2:14][CH2:15][CH3:16].OC1C2N=NNC=2C=CC=1.Cl.N1CCC1.C(N(CC)CC)C>C(OCC)(=O)C.O.CN(C)C=O>[N:9]1([C:30]([C@H:27]2[CH2:28][CH2:29][C@@:25]([CH3:35])([C:23](/[N:22]=[C:21]3/[C:17]([CH2:13][CH2:14][CH2:15][CH3:16])=[CH:18][N:19]([C:36]([CH3:38])([CH3:37])[CH3:39])[S:20]/3)=[O:24])[C:26]2([CH3:33])[CH3:34])=[O:32])[CH2:8][CH2:7][CH2:11]1
Reactant: CCN=C=NCCCN(C)C
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@]1(C)CC[C@H](C(=O)O)C1(C)C
Agent: C1CNC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@]1(C)CC[C@H](C(=O)N2CCC2)C1(C)C
Yield: 58.1 %

Procedure:
Solid N-(3-dimethylaminopropyl)-n′-ethylcarbodiimide hydrochloride (EDC) (Aldrich, 216 mg, 1.12 mmol), the product from Example 173 (296 mg, 0.750 mmol), hydroxybenzotriazole (Aldrich, 152 mg, 1.12 mmol), azetidine hydrochloride (Aldrich, 105 mg, 1.12 mmol), triethylamine (Aldrich, 152 mg, 1.50 mmol) and anhydrous N,N-dimethylformamide (4 mL) were mixed together at room temperature. Water was added to quench and the mixture was extracted with dichloromethane. The extracts were dried over sodium sulfate and concentrated by rotary evaporator to give a brown oil. Flash chromatography (silica gel: 20-75% ethyl acetate in hexanes) afforded 189 mg (58%) of the title compound. 1H NMR (DMSO-d6) δ 0.50 (s, 3H), 0.90 (t, J=7.8 Hz, 3H), 1.22 (s, 3H), 1.23 (s, 3H), 1.23-1.35 (m, 4H), 1.37-1.46 (m, 1H), 1.56 (s, 9H), 1.56-1.67 (m, 2H), 1.90-2.03 (m, 1H), 2.08-2.22 (m, 2H), 2.71-2.76 (m, 2H), 2.77-2.83 (m, 1H), 3.73-3.81 (m, 1H), 3.82-3.91 (m, 1H), 4.06-4.14 (m, 1H), 4.18-4.26 (m, 1H), 8.50 (s, 1H). MS (ESI+) m/z 434 (M+H)+. Anal. calcd. for C24H39N3O2S: C, 66.47; H, 9.06; N, 9.69. Found: C, 66.60; H, 9.02; N, 9.47.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10](=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:24]>CO>[CH2:17]([O:16][C:14]([C:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][C:10]=1[NH2:24])=[O:15])[CH3:18]
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1=O
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CO
Product: CCOC(=O)C1=C(N)CN(Cc2ccccc2)CC1

Procedure:
Ethyl 1-benzyl-3-oxopiperidine-4-carboxylate (25 g, 83.96 mM) and ammonium acetate (32.36 g, 419.79 mM) in MeOH (250 mL) were agitated overnight. The mixture was concentrated, the crude product was dissolved in methylene chloride and washed sequentially with aqueous saturated potassium carbonate solution and water. The organic was dried and reduced in vacuo to yield the title compound (24.0 g, 110%, higher yield possibly due to accluded solvents) as an oil which solidified on standing.
Reaction SMILES: C1(OC)C=CC=CC=1.[CH2:9]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[C:10]1[CH:18]=[CH:17][C:16]2[O:15][CH2:14][O:13][C:12]=2[CH:11]=1.[Cl:25][C:26]1[C:31]2[NH:32][C:33]3[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=3[NH:35][C:36](=O)[C:30]=2[CH:29]=[CH:28][CH:27]=1.N>C1(C)C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl.C(O)(C)C>[Cl:25][C:26]1[C:31]2[NH:32][C:33]3[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=3[N:35]=[C:36]([N:22]3[CH2:23][CH2:24][N:19]([CH2:9][C:10]4[CH:18]=[CH:17][C:16]5[O:15][CH2:14][O:13][C:12]=5[CH:11]=4)[CH2:20][CH2:21]3)[C:30]=2[CH:29]=[CH:28][CH:27]=1
Reactant: c1cc2c(cc1CN1CCNCC1)OCO2
Reactant: O=C1Nc2ccccc2Nc2c(Cl)cccc21
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: N
Solvent: COc1ccccc1
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: Clc1cccc2c1Nc1ccccc1N=C2N1CCN(Cc2ccc3c(c2)OCO3)CC1
Temperature: 60 °C
Yield: 70.5 %

Procedure:
To a stirred solution of anisole (0.40 mL, 3.68 mmol) in dry toluene (2.00 mL) was added titanium tetrachloride (0.24 mL, 2.18 mmol) at room temperature under argon. The mixture was then treated with 1-piperonylpiperazine (2.07 g, 9.40 mmol) and 4-chloro-11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepine (0.49 g, 2.00 mmol) (Giani et al, supra) and diluted with toluene (1.00 mL). After more 1-piperonylpiperazine (1.19 g, 5.40 mmol) was added, toluene (8.00 mL) was added and the resulted reaction mixture was heated at reflux for 6 h before it was cooled to 60° C. Isopropanol (0.80 mL), celite (0.40 g) and ammonia (30%, 0.50 mL) were added sequentially and the whole mixture was filtered hot. Upon cooling to room temperature, the filtrate was concentrated in vacuo to dryness and the residue was subjected to column chromatography using ethyl acetate/hexanes (1/2) as the eluent. Thus 0.63 g (70%) of the title compound was afforded as a light yellow solid; m.p. 160-162° C.; MS 447 (M+ +1).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([NH2:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:13]1[CH2:19][S:16](=[O:18])(=[O:17])[O:15][CH2:14]1>C(#N)C>[C:10]([C@@H:2]([NH:1][CH2:14][CH2:13][CH2:19][S:16]([OH:18])(=[O:17])=[O:15])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:11])[NH2:12]
Reactant: NC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=S1(=O)CCCO1
Solvent: CC#N
Product: NC(=O)[C@H](Cc1ccccc1)NCCCS(=O)(=O)O
Temperature: 25 °C
Yield: 83 %

Procedure:
To a solution of L-Phenylalaninamide (3.93 g, 23.9 mmol) in acetonitrile (25 mL) was added 1,3-propane sultone (2.70 g, 21.8 mmol). The solution was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid was filtered and washed with acetonitrile (2×25 mL). The solid product was suspended in EtOH (100 mL). The suspension was stirred at reflux for 1 hour. The solid material was filtered and dried in vacuo, affording the title compound (5.18 g, 83%). 1H NMR (D2O, 500 MHz) δ ppm 7.24 (m, 3H), 7.16 (m, 2H), 4.02 (m, 1H), 3.15 (m, 1H), 3.01 (m, 3H), 2.83 (m, 2H), 2.02 (m, 2H), 1.98 (m, 2H). 13C (D2O, 125 MHz) δ ppm 170.48, 133.72, 129.58, 129.21, 128.11, 61.55, 47.95, 45.52, 36.21, 21.44. [α]D=+23.1° (c=0.0021 in water), ES-MS 285 (M−1).
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:4]([O:6][CH3:7])=[O:5].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.N1C=CC=CC=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22]([O:1][CH2:2][C@H:3]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:4]([O:6][CH3:7])=[O:5])(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)[C@H](CO)NC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)[C@H](COS(=O)(=O)c1ccc(C)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl (3-hydroxy)-2-(S)-(t-butoxycarbonylamino)propionate (58 g, 196 mmol), dry methylene chloride (150 ml), p-toluenesulfonyl chloride (43.35 g, 227.4 mmol), 4-(dimethylamino)pyridine (2.4 g, 19.6 mmol) and pyridine (30 ml, 371 mmol) were combined and stirred at room temperature overnight. The reaction solution was concentrated in vacuo to a pale yellow oil. The oil was stored in vacuo overnight, then the white solid that formed was isolated to give 75.33 g of crude product. The product was triturated in petroleum ether (approximately 200 ml) to yield methyl 3-(p-toluenesulfonyloxy)-2-(S)-(t-butoxycarbonylamino)propionate: n.m.r.: (CDCl3, 90 MHz): δ7.72, 7.31 (2x dd, 4, aromatic protons), 5.26 (m, 1, nitrogen proton), 4.48 (m, 1, C-2 proton), 4.32 (m, 2, C-3 protons), 3.68 (s, 3, methyl protons of methyl ester), 2.44 (s, 3, methyl protons of toluene moiety), 1.40 (s, 9, protons of t-butyl moiety); i.r. (CHCl3): 3435, 3019, 1753, 1711, 1502, 1369, 1351, 1250, 1215, 1190, 1177 cm-1 ; m.s.: 279, 210, 172, 91, 41;
Reaction SMILES: C([O:4][C:5]([C:7](=[C:27]1[S:31][CH2:30][CH2:29][S:28]1)[C:8]([NH:10][C@@H:11]1[C:25](=[O:26])[N:13]2[CH:14]([C:19]([O:21]CC=C)=[O:20])[C:15]([CH3:18])([CH3:17])[S:16][C@H:12]12)=[O:9])=[O:6])C=C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(C(CCCC)C([O-])=O)C.[Na+:61].C(OCC)(=O)C>CN(C)C=O.C(OCC)(=O)C.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>[C:5]([C:7](=[C:27]1[S:28][CH2:29][CH2:30][S:31]1)[C:8]([NH:10][C@@H:11]1[C:25](=[O:26])[N:13]2[CH:14]([C:19]([O-:21])=[O:20])[C:15]([CH3:18])([CH3:17])[S:16][C@H:12]12)=[O:9])([O-:6])=[O:4].[Na+:61].[Na+:61]
Reactant: C=CCOC(=O)C(C(=O)N[C@@H]1C(=O)N2C(C(=O)OCC=C)C(C)(C)S[C@H]12)=C1SCCS1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCCC(CC)C(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)S[C@@H]2[C@H](NC(=O)C(C(=O)[O-])=C3SCCS3)C(=O)N2C1C(=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
Allyl 6β-[(allyloxycarbonyl)(1,3-dithiolan-2-ylidene)acetamido]-2,2-dimethylpenam-3-carboxylate (485 mg, 1 mmol) was dissolved in a mixture of dimethylformamide (2 mL), ethyl acetate (2 mL) and 0.5N sodium 2-ethylhexanoate/ethyl acetate solution (4 mL), and treated with triphenyl-phosphine (30 mg) and tetrakis(triphenylphosphine)palladium(0) (30 mg). The reaction mixture was stirred at room temperature for 1 h under a nitrogen atmosphere. The resulting precipitate was collected by filtration, washed successively with ethyl acetate and diethyl ether, and dried under vacuum to give the title compound (388 mg, 87%) as a light yellow powder: 1H NMR (D2O) δ 1.31 and 1.36 (each 3H, s, C2 -(CH3)2), 3.30-3.50 (4H, m, SCH2CH2S), 3.96 (1H, s, C3 -H), 5.98 (1H, d, J=5Hz, C6 -H).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10](=[O:22])[NH:11][C:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=1)([CH3:14])[CH3:13])[CH2:2]2.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10](=[O:22])[NH:11][C:12]([C:15]1[CH:16]=[C:17]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:18]=[CH:19][CH:20]=1)([CH3:14])[CH3:13])[CH2:2]2
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(NC(=O)OC1CN2CCC1CC2)c1cccc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: CC(C)(NC(=O)OC1CN2CCC1CC2)c1cccc(-c2ccccc2)c1
Yield: 63.8 %

Procedure:
Using general procedure E, 1-azabicyclo[2.2.2]oct-3-yl[2-(3-bromophenyl)propan-2-yl]carbamate (600 mg, 1.63 mmol), phenylboronic acid (398 mg, 3.27 mmol) and palladium (II) acetate gave the title compound as a white solid (379 mg, 64%). 1H NMR (400 MHz, CDCl3) δ 7.61 (s, 1H), 7.56 (d, J=7.4 Hz, 2H), 7.50-7.38 (m, 4H), 7.34 (m, 2H), 5.16 (s, 1H), 4.63 (s, 1H), 3.39-2.09 (m, 6H), 1.72 (s, 6H), 2.02-0.73 (m, 5H) ppm. 13C NMR (100 MHz, CDCl3) δ 154.8, 147.8, 141.6, 129.0, 129.0, 128.6, 127.5, 125.8, 125.0, 124.0, 71.6, 71.3, 55.9, 55.5, 47.6, 46.8, 31.5, 30.2, 30.0, 29.5, 25.6, 24.8, 19.8 ppm. Purity: 99% UPLCMS (210 nm); retention time 0.84 min; (M+1) 365.0. Anal. Calcd. for C23H28N2O2.0.29 (CHC3): C, 70.02; H, 7.14; N, 7.01. Found: C, 70.02; H, 7.37; N, 6.84.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].C=O.[O:14]1CCOC[CH2:15]1>O>[OH:14][CH2:15][N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3]
Reactant: C1COCCO1
Reactant: O=C1Nc2ccccc2C1=O
Agent: C=O
Solvent: O
Product: O=C1C(=O)N(CO)c2ccccc21
Temperature: 100 °C
Yield: 93 %

Procedure:
Isatin (25 g, 0.17 mol) and 30% formalin (30 ml, 0.3 mol) were added to a mixture of dioxane (10 ml) and water (20 ml) and the mixture was heated at 100° C. for 5 hours. The reaction mixture was cooled and crystals formed were filtered off. N-hydroxymethylisatin (28 g, yield 93%) was obtained. The melting point was 138° C. (decomposed).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].CN(C=O)C.C[O:11][C:12]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[CH:17][C:13]=1[C:14]([OH:16])=[O:15].Cl>C1(C)C=CC=CC=1.O>[OH:11][C:12]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[CH:17][C:13]=1[C:14]([OH:16])=[O:15]
Reactant: COc1cc(OC)c(C(=O)O)cc1OC
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(O)c(C(=O)O)cc1OC
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 96.4 %

Procedure:
In 20 g of toluene was suspended 6.28 g of AlCl3 in a stream of argon, to which 20 g of DMF was then added dropwise at 26° C. before adding 10.0 g of compound (1a), followed by heat stirring at 85° C. for 1.5 hours. The reaction mixture was cooled, to which 5.89 g of 35% hydrochloric acid was then added dropwise before adding 17.0 g of water, followed by heat stirring at 75° C. for one hour. The precipitated crystal was collected by filtration and washed with water. The resultant crystal was dried under reduced pressure at 60° C. to provide 9.0 g of compound (2a) at a yield of 96%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[OH:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[CH3:19].C(N(C(C)C)CC)(C)C>CN1CCCC1=O>[CH3:19][C:11]1[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:10]=1[O:9][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[CH:7]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1O
Reactant: Nc1cc(Cl)ccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1cc([N+](=O)[O-])ccc1Oc1ccnc(N)c1
Temperature: 150 °C
Reaction time: 120 h
Yield: 45.7 %

Procedure:
2-Amino-4-chloropyridine (5.0 g), N-methylpyrrolidone (40 ml), 2-hydroxy-5-nitrotoluene (11.9 g) and diisopropylethylamine (20.1 g) were placed in a reaction vessel, followed by stirring under a nitrogen atmosphere at 150° C. for 5 days. The reaction mixture was allowed to cool down to room temperature and concentrated under reduced pressure. To the residue was added a saturated aqueous solution of sodium hydrogencarbonate, followed by stirring overnight at room temperature. Liquid-liquid separation was carried out after addition of tetrahydrofuran (200 ml) to the reaction mixture. The aqueous layer was extracted with diethyl ether (100 ml). The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The precipitated solid was suspended in diethyl ether and collected by filtration. The solid was washed with diethyl ether:ethyl acetate=1:1 and dried under aeration to provide the titled compound as a yellow solid (4.36 g, 45:7%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH:5]=[C:6]([Cl:8])[CH:7]=1.S(=O)(=O)(O)O.[CH3:24]O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[CH2:14][CH2:15][C:16]([O:18][CH3:24])=[O:17])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CO
Reactant: O=C(O)CCc1cnoc1-c1cc(Cl)cc(Cl)c1
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1cnoc1-c1cc(Cl)cc(Cl)c1
Yield: 99 %

Procedure:
A mixture of 3-[5-(3,5-dichlorophenyl)-4-isoxazolyl]propionic acid (3.50 g), conc. sulfuric acid (0.1 ml) and methanol (100 ml) was refluxed for 4 hr. The reaction mixture was concentrated, water was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[5-(3,5-dichlorophenyl)-4-isoxazolyl]propionate (3.49 g, yield 99%) was obtained as a pale yellow oil from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). NMR (CDCl3) δ: 2.62–2.72 (2H, m), 2.92–3.02 (2H, m), 3.70 (3H, s), 7.45 (1H, t, J=1.8 Hz), 7.60 (1H, d, J=1.8 Hz), 8.24 (1H, s).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1I)[C:5]([O:7][CH3:8])=[O:6].[F:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1B(O)O.C(O)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].O>[F:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[OH:1]
Reactant: COc1ccc(F)c(B(O)O)c1
Reactant: COC(=O)c1ccc(I)c(O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(O)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 76.8 %

Procedure:
To a round bottom flask containing 83.26A (1.0938 g, 3.93 mmol) and 2-fluoro-5-methoxyphenylboronic acid (0.7053 g, 4.15 mmol) (commercially available from Aldrich) was added a premixed solution of 1:1 isopropanol (6 mL) and water (6 mL). After stirring at room temperature for 5 minutes, sodium carbonate (0.5526 g, 5.21 mmol) and palladium, 10 wt % on activated carbon (0.0725 g, 0.0681 mmol) were added, and the reaction was then heated to 65° C. After 17 hours, the reaction was cooled to room temperature and then filtered through Celite. The filtrate was concentrated and then saturated aqueous ammonium chloride was added. After extracting three times with EtOAc, the organic solvent was removed under reduced pressure. The residue was purified by silica gel flash chromatography (0-40% EtOAc/hexane) to afford 83.26B (834.3 mg, 77% yield). 1H NMR (500 MHz, CDCl3) δ ppm 7.69 (2H, td, J=7.7, 1.7 Hz), 7.33 (1H, d, J=7.8 Hz), 7.14 (1H, t, J=9.0 Hz), 6.94 (1H, dt, J=9.0, 3.5 Hz), 6.89 (1H, dd, J=5.9, 3.2 Hz), 5.42 (1H, s), 3.94 (3H, s), 3.82 (3H, s).