Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][C:3]=1[C:15]([O:17]C)=O.C(N(CC)CC)C.[CH2:26]([N:33]=[C:34]=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.ClCCl>C1(C)C=CC=CC=1>[CH2:26]([N:33]1[C:15](=[O:17])[C:3]2[CH2:4][N:5]([CH2:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:6][CH2:7][C:2]=2[NH:1][C:34]1=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C=NCc1ccccc1
Reactant: COC(=O)C1=C(N)CCN(Cc2ccccc2)C1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=c1[nH]c2c(c(=O)n1Cc1ccccc1)CN(Cc1ccccc1)CC2
Temperature: 80 °C
Yield: 34.8 %

Procedure:
A mixture of 165 g of methyl 4-amino-1-benzyl-1,2,5,6-tetrahydropyridine-3-carboxylate, 68 g of triethylamine and 100 g of benzyl isocyanate in 700 ml of toluene was heated at the reflux temperature for 8 h, with stirring. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in 300 ml of ethanol, 58 g of sodium ethylate in 400 ml of ethanol were added and the mixture was heated at 80° C. for 1.5 h, with stirring. After this mixture had been concentrated under reduced pressure, the residue was worked up by extraction with dichloromethane and water and the combined and dried dichloromethane extracts were concentrated under reduced pressure. The combined aqueous phases were adjusted to pH 7 with conc. hydrochloric acid. After drying, the precipitate formed was combined with the concentrated dichloromethane extracts and the mixture was purified by recrystallization from ethanol to give 81 g of 3,6-dibenzyl-5,6,7,8-tetrahydro-1H-pyrido[4,3-d]pyrimidine-2,4-dione. 10 g of this base were dissolved in dichloromethane and the hydrochloride was precipitated by the addition of a solution of hydrochloric acid in ether. Recrystallization from ethanol/water (volume ratio 1:1) gave 10.1 g of 3,6-dibenzyl-5,6,7,8-tetrahydro-1H-pyrido[4,3-d]pyrimidine-2,4-dione hydrochloride.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].C(C1C=CC(C2C=CC(C(C)(C)C)=CN=2)=NC=1)(C)(C)C.[CH3:35][C:36]1([CH3:43])[C:40]([CH3:42])([CH3:41])[O:39][BH:38][O:37]1>>[CH2:13]([O:12][C:10]([C:2]1[NH:1][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][C:8]=2[B:38]1[O:39][C:40]([CH3:42])([CH3:41])[C:36]([CH3:43])([CH3:35])[O:37]1)=[O:11])[CH3:14]
Reactant: CC1(C)OBOC1(C)C
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Agent: CC(C)(C)c1ccc(-c2ccc(C(C)(C)C)cn2)nc1
Product: CCOC(=O)c1cc2cccc(B3OC(C)(C)C(C)(C)O3)c2[nH]1
Temperature: 62 °C

Procedure:
A mixture of ethyl 1H-indole-2-carboxylate (1.89 g), 5,5′-di-tert-butyl-2,2′-bipyridine (0.081 g), and (Ir(OMe)(COD))2 (0.152 g) in hexanes (30 mL) was treated with 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.66 g) via a syringe. The reaction mixture was degassed via vacuum/nitrogen cycle three times. The reaction mixture was heated at 62° C. for 12 hours. After this time, the solvent was removed and the residue was purified by flash chromatography on silica gel eluting with 1:9 ethyl acetate/hexane to give the title compound. 1H NMR (500 MHz, DMSO-d6): 9.75 (s, 1H), 7.87 (d, J=7.93 Hz, 1H), 7.64-7.65 (m, 1H), 7.24 (s, 1H), 7.16-7.17 (m, 1H), 4.36 (q, J=7.02 Hz, 2H), 1.38 (s, 12H), 1.35 (q, J=7.02 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.O(CC)CC.C([Li])CCC.[CH2:17]([N:21]1[C:25]2[CH:26]=[CH:27][C:28]([CH:30]=[O:31])=[CH:29][C:24]=2[N:23]=[N:22]1)[CH2:18][CH2:19][CH3:20]>CCCCCC>[CH2:17]([N:21]1[C:25]2[CH:26]=[CH:27][C:28]([CH:30]([C:2]3[CH:6]=[CH:5][S:4][CH:3]=3)[OH:31])=[CH:29][C:24]=2[N:23]=[N:22]1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCn1nnc2cc(C=O)ccc21
Reactant: Brc1ccsc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CCCCn1nnc2cc(C(O)c3ccsc3)ccc21
Temperature: 0 °C
Yield: 58.9 %

Procedure:
To a stirred and cooled (-78° C.) solution of 7.2 parts of 3-bromothiophene in 70 parts of 1,1'-oxybisethane were added 30 parts of a 1-butyllithium solution 1.6M in hexane. After stirring for 20 minutes at this low temperature, a solution of 6 parts of butyl-1H-benzotriazole-5-carboxaldehyde was added to the previous mixture. The reaction mixture was stirred for 2 hours at -78~-40° C. The whole was poured into 200 parts of ice water and the product was extracted three times with 56 parts of 1,1'-oxybisethane. The combined extracts were dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (98.2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 5 parts (58.9%) of 1-butyl-α-(3-thienyl)-1H-benzotriazole-5-methanol; mp. 80° C. (int. 58).
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[C:2]1[CH:10]=[C:8]([OH:9])[C:6]([OH:7])=[C:4]([OH:5])[CH:3]=1.[C:14](=O)([O-])[O-].[K+].[K+].ICI.Cl>O.CS(C)=O>[OH:9][C:8]1[CH:10]=[C:2]([CH:3]=[C:4]2[O:5][CH2:14][O:7][C:6]=12)[C:1]([O:12][CH3:13])=[O:11]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(O)c(O)c(O)c1
Agent: Cl
Agent: [K+]
Solvent: ICI
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1cc(O)c2c(c1)OCO2
Temperature: 40 °C
Reaction time: 24 h
Yield: 40.4 %

Procedure:
A mixture comprising 34.4 g of commercially available methyl gallate, 25.8 g of anhydrous potassium carbonate, 400 ml of DMSO and 50.0 g of diiodomethane was stirred at 40° C. for 24 hours in a nitrogen current After the reaction, the liquid mixture was poured into water and made acidic by 2N hydrochloric acid, the mixture was extracted with ethyl acetate, and the extract was washed with water. The solvent was removed from the extract and the residue was subjected to flash column chromatography [466 g of 230-400 mesh silica gel, solvent: n-hexane/acetone (3/1), pressure: 0.4 kg/cm2, 5th to 9th fractions when fractions of 100 ml were collected] to effect purification and obtain 14.8 g of methyl 3-hydroxy-4,5-(methylenedioxy)benzoate (the yield was 40.4%).
Reaction SMILES: [C:1](=[O:24])([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[O:2][C:3]1[C:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[C:7]([CH3:16])[N:6]=[C:5]([CH3:17])[C:4]=1I.[Cl-].[Li+].[CH2:27]([Sn](CCCC)(CCCC)C=C)[CH2:28]CC>O1CCOCC1.C(Cl)(Cl)Cl.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:1](=[O:24])([O:2][C:3]1[C:4]([CH:27]=[CH2:28])=[C:5]([CH3:17])[N:6]=[C:7]([CH3:16])[C:8]=1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CCCCCCCc1c(C)nc(C)c(I)c1OC(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: C=Cc1c(C)nc(C)c(CCCCCCC)c1OC(=O)OC(C)(C)C
Yield: 10 %

Procedure:
To a solution of 7 (60 mg, 0.864 mmol) in 1,4-dioxane (4 ml) were added lithium chloride (73.2 mg, 1.73 mmol), tetrakis(triphenylphosphine)palladium (99.8 mg, 10 mol %) and tributyl(vinyl)tin (0.327 ml, 1.12 mmol). The mixture was heated at reflux for 3 h then cooled and diluted with CHCl3. The mixture was washed with brine, dried over Na2SO4, filtered, and concentrated in under diminished pressure. The residue was purified by column chromatography on silica gel [AcOEt/MeOH (20:1)] to afford tert-butyl 3-heptyl-2,6-dimethyl-5-vinylpyridin-4-yl carbonate (9) (30 mg, 64%). 1H NMR (CDCl3) δ 0.85-0.88 (m, 3H), 1.27-1.32 (m, 10H), 1.47 (s, 9H), 2.40 (s, 3H), 2.43 (s, 3H), 2.47-2.50 (m, 2H), 5.50 (dd, 2H, J=18 Hz, 11.2 Hz) and 6.45 (dd, 1H, J=11.6 Hz, 11.6 Hz).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:5]([N:7]1[CH2:14][CH2:13][CH2:12][C@H:8]1[C:9]([OH:11])=[O:10])=[O:6])[CH3:4].[C:15]([CH:23]=[CH:24][C:25]([OH:27])=[O:26])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)(O)[O-].[Na+].CCOC(C)=O>CO.O.CC(O)=O.C(O)CCC>[C:25]([CH:24]([NH:2][C@H:3]([C:5]([N:7]1[CH2:14][CH2:13][CH2:12][C@H:8]1[C:9]([OH:11])=[O:10])=[O:6])[CH3:4])[CH2:23][C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([OH:27])=[O:26]
Reactant: O=C(O)C=CC(=O)c1ccccc1
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Solvent: O
Solvent: CC(=O)O
Product: C[C@H](NC(CC(=O)c1ccccc1)C(=O)O)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 48 h

Procedure:
To a solution of L-alanyl-L-proline hydrochloride (2.26 g; 10.2 mmol) and 3-benzoylacrylic acid (1.97 g; 11.2 mmol) in methanol (50 ml) there was added sodium bicarbonate (1.71 g; 20.3 mmol) and the mixture was stirred for 48 hours. After filtration and evaporation, the residue was purified on DOWEX 50W-XY using 10:1 H2O:CH3OH and then 50:1 H2 :pyr as eluants. Freeze drying of the H2 :pyr fractions gave the product as a mixture (1:1) of diastereomers (2.68 g; 7.40 mmol; 73%). MS: m/e 461 (bis trimethylsilyl M⊕ -CO2TMS). TLC (silica gel; 3:1:1:1 EtOAc, BuOH, HOAc, H2O) Rf=0.35. NMR (D2O): 1.08 (minor), 1.18 (minor), 1.26, 1.34 (3H, 4×d, J=7) (2 rotomers); 1.5-2.2 (4H, m); 2.1-3.8 (4H, m); 3.9-4.3 (3H, m); 7.307.8 (5H,m).
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]2[NH:6][C:7]([CH2:9][CH2:10][N:11]3[CH2:15][CH2:14][CH2:13][CH:12]3[CH3:16])=[N:8][C:4]=2[CH:3]=1.[C:19]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)#[N:20].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:16][C@@H:12]1[CH2:13][CH2:14][CH2:15][N:11]1[CH2:10][CH2:9][C:7]1[NH:6][C:5]2[CH:17]=[CH:18][C:2]([C:24]3[CH:25]=[CH:26][C:21]([C:19]#[N:20])=[CH:22][CH:23]=3)=[CH:3][C:4]=2[N:8]=1
Reactant: CC1CCCN1CCc1nc2cc(Br)ccc2[nH]1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Solvent: ClCCl
Product: C[C@@H]1CCCN1CCc1nc2cc(-c3ccc(C#N)cc3)ccc2[nH]1
Temperature: 80 °C
Reaction time: 24 h
Yield: 40.4 %

Procedure:
Nitrogen (N2) gas was bubbled through a solution of 5-bromo-2-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-1H-benzoimidazole (0.19 g, 0.6 mmol) and 4-cyanophenylboronic acid (0.13 g, 0.9 mmol) in 1,2-dimethoxyethane (4 mL) and H2O (2 mL). To the mixture was added 2M Na2CO3 (1.2 mL, 2.4 mmol) and Pd(dppf)2Cl2:CH2Cl2 (1:1), and this mixture heated to 80° C. After approximately 24 h, the reaction mixture was cooled and extracted with ethyl acetate. The organic layer was then washed with H2O and distilled to dryness. The crude product was purified by column chromatography to afford the title compound (0.08 g). 1H NMR (400 MHz, CDCl3) δ 1.18 (d, 3H), 1.52-1.62 (m, 1H), 1.77-1.95 (m, 2H), 2.03-2.12 (m, 1H), 2.30 (q, 1H), 2.47-2.56 (m, 1H), 2.57-2.62 (m, 1H), 3.15-3.20 (m, 2H), 3.21-3.35 (m, 2H), 7.43 (dd, J=1.7 & 8.3, 1H), 7.62 (d, 1H), 7.68-7.73 (m, 4H), 7.76 (s, 1H); 13C NMR (400 MHz, CDCl3) δ 19.5, 22.2, 27.4, 33.2, 51.5, 53.3, 60.5, 109.9, 118.9, 121.2, 127.5, 132.2, 133.0, 146.1, 156.1 (2 peaks overlapping and some 13C peaks were not readily identified due to exchange broadening). APPI-MS: (M+1)+ at 331 m/z.
Reaction SMILES: Cl.C(OC(=O)[CH2:6][CH:7]([C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=1)[CH2:8][CH2:9][CH2:10][NH2:11])C.C(=O)([O-])[O-:21].[K+].[K+]>C(O)C>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([CH:7]2[CH2:8][CH2:9][CH2:10][NH:11][C:6]2=[O:21])=[CH:13][CH:14]=1
Reactant: CCOC(=O)CC(CCCN)c1ccc(Br)cc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: O=C1NCCCC1c1ccc(Br)cc1
Yield: 86 %

Procedure:
A solution of 6-amino-3-(4-bromo-phenyl)-hexanoic acid ethyl ester hydrochloride, potassium carbonate (1039 mg, 7.52 mmol) in ethanol (50 ml) was refluxed for 20 hr. Solvent was removed in vacuo after addition of dilute hydrochloric acid and water was added to the residue. Filtration, wash with water and dryness afforded 3-(4-Bromo-phenyl)-piperidin-2-one (1387 mg, 86%, 2 steps).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1.CN(C)[C:16](=[O:18])[CH3:17]>CCCCCC.C(OCC)C>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:16](=[O:18])[CH3:17])=[N:8][CH:9]=1
Reactant: Clc1ccc(Br)nc1
Reactant: CC(=O)N(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(=O)c1ccc(Cl)cn1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Under cooling at −78° C., 1.56M n-butyllithium in hexane (27 mL) was added dropwise to 2-bromo-5-chloropyridine (6.8 g) in diethyl ether (45 mL), and then N,N-dimethylacetamide (5 mL) was added dropwise thereto, followed by stirring for 30 minutes. The reaction mixture was partitioned by use of saturated aqueous ammonium chloride and ethyl acetate. The organic layer was dried over sodium sulfate anhydrate, followed by filtration. The solvent was removed under reduced pressure, and the residue was purified through silica gel column chromatography (hexane-ethyl acetate), to thereby give 1-(5-chloro-2-pyridyl)ethanone as a solid (3.26 g, 59%).
Reaction SMILES: [CH3:1][CH:2]([N:4]([CH:23]([CH3:25])[CH3:24])[CH2:5][CH2:6][C:7]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][NH:12]1)[C:8]([NH2:10])=[O:9])[CH3:3].[C:26](OC(=O)C)(=[O:28])[CH3:27]>>[C:26]([N:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]1[C:7]([CH2:6][CH2:5][N:4]([CH:2]([CH3:1])[CH3:3])[CH:23]([CH3:25])[CH3:24])([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:8]([NH2:10])=[O:9])(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)N(CCC(C(N)=O)(c1ccccc1)C1CCCCN1)C(C)C
Product: CC(=O)N1CCCCC1C(CCN(C(C)C)C(C)C)(C(N)=O)c1ccccc1

Procedure:
acylating α-[2-[bis(1-methylethyl)amino]ethyl]-α-phenyl-2-piperidineacetamide with acetic anhydride to form 1-acetyl-α-[2-[bis(1-methylethyl)amino]ethyl]-α-phenyl-2-piperidineacetamide;
Reaction SMILES: FC1C=C2C(C(C3CCN(CCN)CC3)=[N:7]N2)=CC=1.F[C:21]1[CH:22]=[C:23]2[C:28](=O)[O:27][C:25](=[O:26])[C:24]2=[CH:30][CH:31]=1.C(Cl)Cl.CO>CN(C=O)C>[C:25]1(=[O:26])[NH:7][C:28](=[O:27])[C:23]2=[CH:22][CH:21]=[CH:31][CH:30]=[C:24]12
Reactant: O=C1OC(=O)c2cc(F)ccc21
Reactant: NCCN1CCC(c2n[nH]c3cc(F)ccc23)CC1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: O=C1NC(=O)c2ccccc21
Temperature: 80 °C

Procedure:
To a solution consisting of 2-[4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl]ethylamine (6.1 g, 23.2 mmol) in DMF (230 ml) was added 4-fluorophthalic anhydride (4.2 g, 25.5 mmol) at room temperature, under nitrogen. The reaction mixture was warmed at 80° C. for 2.5 hours at which time it was allowed to cool to room temperature. The DMF was removed under reduced pressure (<0.5 mmHg, 55° C.) to give a brown oil which was dissolved into DCM/MeOH. Purification via flash column chromatography (silica gel, 2% MeOH/DCM) afforded 3.6 g of 4-fluoro-N-[2-[4-(6-fluoro-1H-indazol-3-yl)-1yl)-1-piperidinyl]ethyl]phthalimide. To a solution of the latter compound (3.6 g 8.8 mmol) in anhydrous THF (100 ml) was added LAH (18.4 ml of a 1.0M solution in THF, 18.4 mmol) at room temperature, under nitrogen. The reaction mixture was warmed to reflux for 4 hours. Upon cooling to room temperature, the reaction was quenched with water (1.5 ml, dropwise). The precipitated salts were removed via filtration and washed with DCM. The combined filtrates were concentrated to give a solid which was purified via flash column chromatography (silica gel, 0-8% MeOH/DCM). The product containing fractions were concentrated to give 2.4 g product as an off-white solid. The dimaleate salt was prepared in methanol using 2.4 eq. of maleic acid. The white precipitate was collected via filtration and washed with methanol, m.p. 186-188° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@H:4]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]([NH2:16])=[O:15])=[CH:13][C:8]=2[CH2:7][CH2:6][O:5]1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>O1CCCC1.CN(C)C=O>[CH3:24][S:25]([O:1][CH2:2][CH2:3][C@H:4]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]([NH2:16])=[O:15])=[CH:13][C:8]=2[CH2:7][CH2:6][O:5]1)(=[O:27])=[O:26]
Reactant: NC(=O)c1ccc2c(c1)CCO[C@H]2CCO
Reactant: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OCC[C@@H]1OCCc2cc(C(N)=O)ccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(1S)-1-(2-Hydroxyethyl)-3,4-dihydro-1H-2-benzopyran-6-carboxamide (5 g, 22.6 mmol) was dissolved in a mixture of dry tetrahydrofuran (375 mL) and dry dimethylformamide (15 mL) with the aid of gentle heating. Triethylamine (4.6 g, 45.5 mmol) was added, followed by methanesulfonyl chloride (2.72 g, 23.8 mmol). The mixture was stirred under nitrogen at room temperature for 1 day. The reaction mixture was quenched with water (1000 mL) and the product extracted into ethyl acetate (2×500 mL). The combined organic extracts were washed with brine (2×500 mL), dried (MgSO4), and evaporated in vacuo to give the crude product as a white solid (6.5 g, 97%). The solid was triturated with ether (300 mL) to give 2-[(1S)-6-(aminocarbonyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl methanesulfonate as a white solid.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[S:11])=[CH:8][N:7]=1.[ClH:15]>>[CH3:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([Cl:15])=[S:11])=[CH:8][N:7]=1
Reactant: Cl
Reactant: Cc1ccc(C(O)=S)cn1
Solvent: O=S(Cl)Cl
Product: Cc1ccc(C(=S)Cl)cn1

Procedure:
Thionylchloride (23.8 g) was added to 6-methylthionicotinic acid (15.3 g) (from the above referential example 1a). The reaction mixture was gradually heated with stirring and refluxed until the generation of hydrogen chloride ceased. 6-methylthionicotinoylchloride was stoichiometricly obtained by distilling off excess thionylchloride under reduced pressure. 6-methylthionicotinoylchloride dissolved in ether was added dropwise to 20% aqueous solution of sodium borohydride (6.5 g) at 0°~10° C. After adding, the mixture was stirred for one hour and the ether layer was separated and dried. The ether layer was evaporated under reduced pressure to give 2-methylthiopyridine-5-methanol (9.6 g). nD22 1.6084
Reaction SMILES: CC(C1C=C(SC(SC2C=C(C(C)(C)C)C([O:31][C:32](=[O:37])[CH2:33][CH2:34][CH2:35]Br)=C(C(C)(C)C)C=2)(C)C)C=C(C(C)(C)C)C=1O)(C)C.[N+:42]([O-:45])([O-:44])=[O:43].[Ag+]>C(#N)C.C1COCC1>[N+:42]([O:45][CH2:35][CH2:34][CH2:33][C:32]([OH:31])=[O:37])([O-:44])=[O:43]
Reactant: CC(C)(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)Sc1cc(C(C)(C)C)c(OC(=O)CCCBr)c(C(C)(C)C)c1
Reactant: O=[N+]([O-])[O-]
Agent: [Ag+]
Solvent: CC#N
Solvent: C1CCOC1
Product: O=C(O)CCCO[N+](=O)[O-]
Temperature: 60 °C

Procedure:
To a solution of 4-bromobutanoic acid [4-[[1-[[3, 5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenyl]ester (150 mg, 0.22 mmol) in acetonitrile/THF (15 ml 2/1 v/v), AgNO3 was added (80 mg, 0.47 mmol) and the solution was heated in the dark at 60° C. for 6 hours. The silver salt was then filtered off (AgBr) and the solvent was evaporated at reduced pressure. The product thus obtained was purified by chromatography on silica gel with a mixture of ethyl acetate/hexane as eluent (4/6 v/v) to give 4-nitrooxybutanoic acid, [4-[[1-[[3,5-bis(1,1-dimethyletihyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis (1,1-dimethylethyl)-phenyl] ester (100 mg).
Reaction SMILES: [C:1]([C:4]1[CH:5]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:6]([C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][Cl:17])=[C:7]([CH3:11])[NH:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].[I-].[Na+].Cl.[C:31]1([C:37]2([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O1CCOCC1.C(O)(C)C.C(OCC)C>[ClH:17].[C:1]([C:4]1[CH:5]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:6]([C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][N:40]2[CH2:41][CH2:42][C:37]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH2:38][CH2:39]2)=[C:7]([CH3:11])[NH:8][C:9]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)C1=C(C)NC(C)=C(C(=O)CCCCCl)C1c1cccc([N+](=O)[O-])c1
Reactant: c1ccc(C2(c3ccccc3)CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Solvent: CCOCC
Solvent: CC(C)O
Product: CC(=O)C1=C(C)NC(C)=C(C(=O)CCCCN2CCC(c3ccccc3)(c3ccccc3)CC2)C1c1cccc([N+](=O)[O-])c1

Procedure:
5.5 g (14 mmol) 5-acetyl-1,4-dihydro-2,6-dimethyl-3-(5-chloropentanoyl)-4-(3-nitrophenyl)-pyridine and 4.2 g (28 mmol) sodium iodide are boiled under reflux in 200 ml anhydrous acetone for 24 h. The mixture is filtered and concentrated. The residue is boiled under reflux together with 8 g (28 mmol) 4,4-diphenylpiperidine hydrochloride and 8 g (58 mmol) potassium carbonate in 100 ml dioxane for 24 h. The mixture is filtered and concentrated, and the residue is chromatographed over silica gel with toluene/acetone=2/8. The product thus obtained is taken up in 120 ml isopropanol and the mixture is diluted with 150 ml diethyl ether. The title compound is precipitated by addition of ethereal hydrochloric acid . Yield: 4.75 g (54%). M.p.: 164°-167° C. (acetonitrile).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[C:17]3[C:12](=[C:13]([F:18])[CH:14]=[CH:15][CH:16]=3)[C:11]([NH2:19])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[N:30]1[CH:35]=[C:34](B(O)O)[CH:33]=[N:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[C:11]([NH2:19])=[N:10][C:9]2([C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:34]2[CH:35]=[N:30][CH:31]=[N:32][CH:33]=2)[CH:3]=1)[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([C:26]([F:29])([F:27])[F:28])[CH:21]=1
Reactant: OB(O)c1cncnc1
Reactant: NC1=NC(c2ccnc(C(F)(F)F)c2)(c2ccc(F)c(Br)c2)c2cccc(F)c21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: NC1=NC(c2ccnc(C(F)(F)F)c2)(c2ccc(F)c(-c3cncnc3)c2)c2cccc(F)c21
Temperature: 90 °C
Reaction time: 1 h
Yield: 52.8 %

Procedure:
1-(3-Bromo-4-fluorophenyl)-4-fluoro-1-(2-(trifluoromethyl)pyridin-4-yl)-1H-isoindol-3-amine (0.30 g, 0.64 mmol) and 5-pyrimidinylboronic acid (0.104 g, 0.84 mmol) in DMF (5.00 mL) was heated to 90° C. under argon atmosphere. Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (0.039 g, 0.05 mmol) and aqueous potassium carbonate (2.00 M) (0.961 mL, 1.92 mmol) were added and the resulting mixture was stirred at 90° C. for 1 h. The reaction mixture was cooled to room temperature, and then filtered through a syringe filter and purified by preparative HPLC to give the title compound (0.158 g, 51% yield).