Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][N:3]=1.Br[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.C([O-])([O-])=O.[Cs+].[Cs+].O1CCOCC1>CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([NH:1][C:2]2[N:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:7]=2)[CH:14]=1
Reactant: COC(=O)c1cnc(N)nc1
Reactant: Brc1cccnc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc(Nc2cccnc2)nc1
Temperature: 25 °C
Yield: 141.9 %

Procedure:
Two 20 mL microwave vials were each charged with methyl 2-aminopyrimidine-5-carboxylate (460.0 mg, 3.0 mmol), 3-bromopyridine (711.0 mg, 4.5 mmol), Pd2(dba)3 (110.0 mg, 0.12 mmol), XantPhos (208.3 mg, 0.36 mmol), Cs2CO3 (1.95 g, 6.0 mmol) and anhydrous dioxane (20 mL). The mixture was purged with argon gas for 15 min, then sealed and irradiated in a microwave (Initiator, Biotage) at 180° C. for 60 min. After cooling to room temperature, the cap was removed and the reaction mixtures were combined and diluted with ca. 100 mL of EtOAc. The resulting solution was concentrated in vacuo with ca. 15 g of silica gel. The loaded silica gel was taken to the ISCO system for further purification (80 g column, solid method, 0% to 20% MeOH gradient in DCM, 40 min method). Fractions, containing the product, were combined and concentrated in vacuo to give a reddish solid. The solid was washed with EtOAc (1×10 mL), Et2O (3×40 mL) and dried in vacuo to give the title compound as a fine beige powder (0.98 g, 47% yield).
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][C:6]([C:7]([NH:9][CH2:10][CH:11]([CH3:21])[CH2:12][NH:13]C(=O)OC(C)(C)C)=[O:8])=[CH:5][CH:4]=1)#[N:2].C(O)(C(F)(F)F)=O>>[NH2:13][CH2:12][CH:11]([CH3:21])[CH2:10][NH:9][C:7](=[O:8])[C:6]1[CH:22]=[CH:23][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: CC(CNC(=O)OC(C)(C)C)CNC(=O)c1ccc(C#N)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(CN)CNC(=O)c1ccc(C#N)cc1
Yield: 93 %

Procedure:
A solution of the compound obtained in Step 1 (311 mg, 0.98 mmol) in TFA (1 mL, 12.98 mmol) was stirred at room temperature for 15 min, and concentrated under reduced pressure. To the residue were added ethyl acetate and 1N aqueous sodium hydroxide solution, and the organic layer was separated. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure to give N-(3-amino-2-methylpropyl)-4-cyanobenzamide (198 mg, 0.911 mmol, 93%) as a white powder.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([CH3:48])[S:14]([NH:17][C:18]([C:20]1[CH:28]=[C:27]2[C:23]([C:24]([CH:42]3[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]3)=[C:25]([C:30]3[CH:41]=[CH:40][CH:39]=[CH:38][C:31]=3[O:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[N:26]2[CH3:29])=[CH:22][CH:21]=1)=[O:19])(=[O:16])=[O:15])=O)(C)(C)C.ClCCl>>[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([CH3:48])[S:14]([NH:17][C:18]([C:20]1[CH:28]=[C:27]2[C:23]([C:24]([CH:42]3[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]3)=[C:25]([C:30]3[CH:41]=[CH:40][CH:39]=[CH:38][C:31]=3[O:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[N:26]2[CH3:29])=[CH:22][CH:21]=1)=[O:19])(=[O:16])=[O:15]
Reactant: COC(=O)COc1ccccc1-c1c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)N(C)CCCCNC(=O)OC(C)(C)C)cc2n1C
Solvent: ClCCl
Product: COC(=O)COc1ccccc1-c1c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)N(C)CCCCN)cc2n1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.1 %

Procedure:
To a solution of intermediate 29 (0.675 g, 1 mmol), in dichloromethane 50 mL tri-fluoro-acetic acid (2.86 g, 20 mmol) was added. The resulting mixture was stirred at room temperature for 12 hours. The solvent was removed then the residue was purified by column chromatography using dichloromethane/methanol to yield 0.55 g (95%) of methyl [2-(6-{[(4-aminobutyl)(methyl)sulfamoyl]carbamoyl}-3-cyclohexyl-1-methyl-1H-indol-2-yl)phenoxy]acetate 30: m/z=585 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3(O)[CH2:19][CH2:18][C:13]4([O:17][CH2:16][CH2:15][O:14]4)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1>C1(C)C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH2:19][CH2:18][C:13]4([O:14][CH2:15][CH2:16][O:17]4)[CH2:12][CH:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: OC1(c2ccc3c(c2)OCO3)CCC2(CC1)OCCO2
Solvent: Cc1ccccc1
Product: C1=C(c2ccc3c(c2)OCO3)CCC2(C1)OCCO2
Yield: 73 %

Procedure:
A solution of 8-(1,3-benzodioxol-5-yl)-1,4-dioxaspiro[4.5]decan-8-ol in toluene was reacted as described in example 2 to give the product (73%, mp: 75°-76° C). Calc'd for C15H16O4 : C, 69.22%; H, 6.20%. Found: C, 69.19%; H, 6.14%.
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH2:5][C@@:6]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:11][C:10](=[O:12])[N:9]([C@H:13]([C:15]2[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[CH:17][CH:16]=2)[CH3:14])[CH2:8][CH2:7]1)[C:3]#[N:4].Cl[C:38]1[N:39]=[N:40][C:41]([CH3:44])=[CH:42][CH:43]=1>>[CH3:36][C:2]([CH3:1])([CH2:5][C@@:6]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:11][C:10](=[O:12])[N:9]([C@H:13]([C:15]2[CH:20]=[CH:19][C:18]([C:38]3[N:39]=[N:40][C:41]([CH3:44])=[CH:42][CH:43]=3)=[CH:17][CH:16]=2)[CH3:14])[CH2:8][CH2:7]1)[C:3]#[N:4]
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccccc2)OC1=O
Reactant: Cc1ccc(Cl)nn1
Product: Cc1ccc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)C#N)(c4ccccc4)OC3=O)cc2)nn1

Procedure:
The title compound was prepared from 2,2-dimethyl-3-((R)-2-oxo-6-phenyl-3-((S)-1-(4-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propanenitrile and 3-chloro-6-methylpyridazine following a procedure analogous to that described in Example 459 Step 4. LC-MS Method 1 tR=1.41 min, m/z=455; 1H NMR (CDCl3) 8.20 (d, 1H), 7.92 (d, 1H), 7.74 (d, 2H), 7.37 (dt, 6H), 7.05 (d, 2H), 5.66 (q, 1H), 3.00 (dm, 1H), 2.93 (s, 3H), 2.49 (m, 2H), 2.34 (m, 1H), 2.17 (d, 2H), 1.58 (d, 3H), 1.39 (s, 3H), 1.33 (s, 3H).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[CH3:5][O:6][C:7](=[O:13])[CH:8](Cl)[C:9](=O)[CH3:10]>CCO>[CH3:5][O:6][C:7]([C:8]1[S:3][C:2]([NH2:4])=[N:1][C:9]=1[CH3:10])=[O:13]
Reactant: NC(N)=S
Reactant: COC(=O)C(Cl)C(C)=O
Solvent: CCO
Product: COC(=O)c1sc(N)nc1C

Procedure:
A mixture of thiourea (59.8 mmol) and 2-chloro-3-oxo-butyric acid methyl ester (59.8 mmol) in EtOH (140 mL) is heated at reflux for 14 h and concentrated in vacuo. Water and aq. NaHCO3 are added and the mixture is extracted several times with EtOAc. The combined organic layers are dried and concentrated in vacuo to give the desired amino-thiazole derivative. LC-MS: tR=0.51 min; [M+H]+=173.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:12][NH:11][C:10]3[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:18]=1.N1C=CC=CC=1.[N:25]1([S:31](Cl)(=[O:33])=[O:32])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>ClC(Cl)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:12][N:11]([S:31]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)(=[O:33])=[O:32])[C:10]3[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:18]=1
Reactant: Clc1ccc2c(c1)C=Cc1cc(Br)ccc1CN2
Reactant: O=S(=O)(Cl)N1CCOCC1
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: O=S(=O)(N1CCOCC1)N1Cc2ccc(Br)cc2C=Cc2cc(Cl)ccc21
Temperature: 100 °C
Reaction time: 4 h
Yield: 75.7 %

Procedure:
A solution of 9-Bromo-2-chloro-5,6-dihydro-dibenzo[b,f]azocine (30 mg, 0.09 mmol) (prepared in a manner analogous to that described for Example 1F) in dichloroethane was treated with pyridine (0.02 mL, 0.27 mmol) and morpholine-4-sulfonyl chloride (22 mg, 0.12 mmol). The reaction mixture was stirred at 100° C. for four hours then concentrated, diluted with MeOH and filtered. The crude product was purified by preparative reversed-phase HPLC to afford Example 338A (32 mg). HPLC Rt=3.89 min. m/z=469 (M+H+)
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:31][C:32]2[N:37]=[CH:36][CH:35]=[CH:34][N:33]=2)(=[O:30])=[O:29])=[CH:24][CH:23]=1>ClCCl.N1C=CC=CC=1>[N:37]1[CH:36]=[CH:35][CH:34]=[N:33][C:32]=1[NH:31][S:28]([C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([NH:31][C:32]3[N:33]=[CH:34][CH:35]=[CH:36][N:37]=3)(=[O:30])=[O:29])=[CH:24][CH:23]=2)=[O:13])=[CH:23][CH:24]=1)(=[O:30])=[O:29]
Reactant: Nc1ccc(S(=O)(=O)Nc2ncccn2)cc1
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(S(=O)(=O)Nc2ncccn2)cc1)c1ccccc1SSc1ccccc1C(=O)Nc1ccc(S(=O)(=O)Nc2ncccn2)cc1
Yield: 58.2 %

Procedure:
This compound was prepared according to the general methods described in Example 1 using 2,2'-dithiobisbenzoyl chloride (3.0 g, 8.7 mmol) in 30 mL dichloromethane and 4-amino-N-(2-pyrimidinyl) benzenesulfonamide (5.3 g, 21.7 mmol) in 100 mL pyridine. The crude product was recrystallized from a mixture of dimethylformamide, ethanol, and water to yield 3.9 g of the title compound, mp 280° C.
Reaction SMILES: CON=C(C1N=C(NC=O)SC=1)C(N[CH:8]1[C:41](=[O:42])[N:10]2[C:11]([C:25]([O:27]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:26])=[C:12]([CH2:15][S:16][C:17]3[N:21]([CH2:22][C:23]#[CH:24])[N:20]=[N:19][N:18]=3)[CH2:13][S:14][C@H:9]12)=O.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:22]([N:21]1[C:17]([S:16][CH2:15][C:12]2[CH2:13][S:14][C@@H:9]3[CH2:8][C:41](=[O:42])[N:10]3[C:11]=2[C:25]([OH:27])=[O:26])=[N:18][N:19]=[N:20]1)[C:23]#[CH:24]
Reactant: C#CCn1nnnc1SCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC)c3csc(NC=O)n3)[C@H]2SC1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Product: C#CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C[C@H]2SC1
Yield: 114.3 %

Procedure:
To a mixture of benzhydryl 7-[2-methoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-[1-(2-propynyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylate (syn isomer) (2.8 g) in methylene chloride (24 ml) were added anisole (2.8 g) and trifluoroacetic acid (7.5 g) with stirring under ice-cooling and then the resulting mixture was stirred for one hour and 15 minutes at room temperature. After the evaporation of the reaction mixture, to the residue were added water and ethyl acetate. The mixture was adjusted to pH 7.0 with a saturated aqueous solution of sodium carbonate. The aqueous layer was separated and washed with ethyl acetate (x2) and thereto were added ethyl acetate and tetrahydrofuran. The mixture was adjusted to pH 2.0 with 10% hydrochloric acid. The organic layer was separated, washed with water, dried over magnesium sulfate, treated with activated charcoal and evaporated. The residue was pulverized in isopropyl ether, collected by filtration, washed with isopropyl ether and dried to give 7-[2-methoxyimino-2-(2-formamidothiazol-4 -yl)acetamido[-3-[1-(2-propynyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.48 g).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>C(O)C.O1CCCC1.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2cccc(OCc3ccccc3)c2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1ccc(-c2cccc(O)c2)cc1
Temperature: 30 °C
Reaction time: 5 h
Yield: 82 %

Procedure:
To a solution of tert-butyl N-(3′-bezyloxy-biphenyl-4-ylmethyl)carbamate (1.16 g) in ethanol/tetrahydrofuran (4/1, 30 mL) was added 10% palladium-on carbon (55.4 wt % H2O, 0.520 g), and the resulting mixture was stirred at 30° C. for 5 hours under a hydrogen atmosphere. The insoluble material was filtered out and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=5/2) to give the title compound (0.731 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1B(O)O.[F-].[K+]>O1CCOCC1.O.CCOC(C)=O.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>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1
Reactant: OB(O)c1c(F)cccc1Cl
Reactant: O=[N+]([O-])c1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cccc(-c2c(F)cccc2Cl)c1
Temperature: 120 °C

Procedure:
To a solution of 1-bromo-3-nitrobenzene [585-79-5] (400 mg, 1.98 mmol) and 2-chloro-6-fluorophenylboronic acid [313545-32-3] (414 mg, 2.37 mmol) in dioxane (12 mL) and water (3 mL) was added potassium fluoride (460 mg, 7.92 mmol) and Pd(PPh3)4 (229 mg, 0.20 mmol). The solution was heated for 60 min at 120° C. under microwave irradiation. More 2-chloro-6-fluorophenylboronic acid (414 mg, 2.37 mmol) was added to the mixture followed by heating at 120° C. for 45 min under microwave irradiation. The reaction mixture was then diluted with EtOAc and the resulting solution was washed successively with saturated aqueous NaHCO3 solution and brine, the organics were then dried (Phase separator) and concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30×100 mm, flow: 50 mL/min, eluent: 20-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA) to give the title compound. tR (HPLC conditions c): 5.42 min.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].[C:7](O)(=[O:35])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].[Sn]>>[C:7]([O:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:6])(=[O:35])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCCCCCCCCCCCCCCCCCCCCC(=O)O
Reactant: OCCCCO
Agent: [Sn]
Product: CCCCCCCCCCCCCCCCCCCCCCCCCCCC(=O)OCCCCO
Temperature: 100 °C

Procedure:
57.2 g 1,4-butanediol (0.636 mole), 254.2 g montanic acid and 0.4 g tin powder were heated to 210° C. as in Example 1 with application of a gentle vacuum. The vacuum was increased to 152 mbar over a period of 3 hours. The mixture had an acid value of 1.5. A brownish-yellow wax having a dropping point of 77° C. was obtained after cooling to 100° C., bleaching and filtering.
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]([CH3:27])[N:5]([P:13]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:29][O:30][K].Cl>>[OH:30][NH:29][C:3](=[O:2])[C@H:4]([N:5]([P:13]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:27]
Reactant: NO[K]
Reactant: COC(=O)[C@@H](C)N(Cc1ccccc1)P(=O)(c1ccccc1)c1ccccc1
Agent: Cl
Product: C[C@H](C(=O)NO)N(Cc1ccccc1)P(=O)(c1ccccc1)c1ccccc1
Reaction time: 16 h

Procedure:
To N-(diphenylphosphinyl)-N-benzyl-D-alanine methyl ester (100 mg, 0.25 mmol) is added a solution of NH2OK (0.88 mL, 1.76M in methanol) prepared as described in Fieser and Fieser, Vol. 1, p. 478. The reaction is stirred for 16 hours at which time TLC indicates completion. The reaction mixture is neutralized with 1M aqueous HCl and the volatiles are removed. The product is purified by silica gel flash chromatography (100% ethyl acetate) to give N-hydroxy-2(R)-[[diphenylphosphinyl]benzylamino]-propionamide as an oil: MS-IS m/z 395 [M+H]+, 417 [M+Na]+. (R1 =benzyl, R2 =methyl, R3 =phenyl, R4 =phenyl).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)[CH2:5][C:6]#[N:7].[BH4-].[Na+].[OH-].[NH4+]>C1COCC1.O.O.O.O.O.O.O.[Co](Cl)Cl>[C:28]([Si:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[O:14][CH:11]1[CH2:10][CH2:9][N:8]([CH:4]2[CH2:5][CH2:6][NH:7][C:3]2=[O:2])[CH2:13][CH2:12]1)([CH3:30])([CH3:31])[CH3:29]
Reactant: COC(=O)C(CC#N)N1CCC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OC1CCN(C2CCNC2=O)CC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 53.7 %

Procedure:
Treat a 0° C. mixture of 2-[4-(tert-butyl-diphenyl-silanyloxy)-piperidin-1-yl]-3-cyano-propionic acid methyl ester (3.32 g, 7.40 mmol) and cobalt (II) chloride hexahydrate (0.87 g, 3.65 mmol) in THF (60 mL) and water (30 mL) portion-wise with sodium borohydride (1.39 g, 36.7 mmol), warm to room temperature, and stir for 2 days under N2. Treat the reaction with 28% ammonium hydroxide (1 mL) and filter through hyflo. Remove the solvent from the filtrate in vacuo, dilute the residue with minimal water and brine, and extract three times with 3:1 chloroform:isopropanol. Dry the organic layer (Na2SO4), remove the solvent in vacuo to afford crude product, and purify with a 0 to 10% methanol in CH2Cl2 gradient to afford 1.68 g (54%) of the titled product. Rf=0.39 (9/1 CH2Cl2/methanol). ES MS (m/z): 423 (M+).
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([O:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][C:3]1([CH3:20])[CH3:19].[CH3:21][CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:24]1([CH:23]=[CH:22][CH2:21][O:1][N:2]2[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([O:10][C:11](=[O:18])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:4][C:3]2([CH3:20])[CH3:19])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC=Cc1ccccc1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Product: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1OCC=Cc1ccccc1
Temperature: 120 °C

Procedure:
A mixture of 1.0 g (3.6 mmol) of 1-oxyl-4-benzoyloxy-2,2,6,6-tetramethylpiperidine and 10 g (85 mmol) of β-methylstyrene under a nitrogen atmosphere is heated at 120° C. for 36 hours. The reaction mixture is concentrated in vacuo and the title compound is isolated after column chromatograph as a white solid, melting at 115-116° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19][NH:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)=[CH:15][C:14]([C:31](=O)[CH3:32])=[CH:13][CH:12]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=1.C([O-])(=O)C.[Na+].Cl.[O:40]([NH2:42])[CH3:41]>>[CH3:41][O:40][N:42]=[C:31]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[CH:5]=1)=[C:17]2[CH2:18][CH2:19][NH:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1)[CH3:32]
Reactant: CC(=O)c1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCNCCCCc3ccncc3)c2c1
Reactant: CON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: CON=C(C)c1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCNCCCCc3ccncc3)c2c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 98.1 %

Procedure:
To a solution of 1-{2-(3,5-dimethylphenyl)-3-[2-(4-pyridin-4-yl-butylamino)ethyl]-1H-indol-5-yl}ethanone (22 mg in 0.50 mL methanol) was added 102 mg sodium acetate (trihydrate) followed by 63 mg methoxylamine hydrochloride and the mixture stirred at room temperature. After 20 hours, the mixture was concentrated in vacuo and the residue suspended in ethyl acetate, and washed successively with saturated aqueous sodium bicarbonate and brine. The organic portion was dried over sodium sulfate and the concentrate purified by preparative TLC on silica gel (methylene chloride:methanol:ammonium hydroxide, 90:10:0.25) to give the title compound (23 mg). m/e=469 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.C(N(C(C)C)CC)(C)C.CC1(C)N([O])C(C)(C)CCC1>ClCCCl>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(CO)cc1
Agent: CC1(C)CCCC(C)(C)N1[O]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C=O)cc1
Yield: 5 %

Procedure:
The effect of the additive was then examined for the oxidation of 4-methoxybenzylalcohol using 8 (2 mol %) in 1,2-dichloroethane (Table 2). Triethylamine, diisopropylethylamine, and TEMPO were all effective promoters of the vanadium complex, affording high yields of 4-methoxybenzaldehyde after 24 h at 60° C. (Entries 2 to 5). In contrast, less than 5% yield was observed with the vanadium complex alone (no additive, Entry 1), suggesting a key role for the nitrogen base.
Reaction SMILES: [Cl-:1].[NH2:2][C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N+:4]=1[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14](Cl)=[CH:13][C:12]=1Br.C(=O)([O-])[O-].[K+].[K+]>[Cu].C(O)CC>[Cl:1][C:7]1[CH:6]=[CH:5][N:4]2[CH2:9][O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:2]=[C:3]2[N:8]=1
Reactant: [Cl-]
Reactant: Nc1nccc[n+]1COc1ccc(Cl)cc1Br
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCO
Product: ClC1=NC2=Nc3ccccc3OCN2C=C1
Yield: 73 %

Procedure:
A mixture of 14.0 g of 2-amino-1-[(2-bromo-4-chlorophenoxy)methyl]pyrimidinium chloride, 11.1 g of micronized, anhydrous potassium carbonate, 0.4 g of copper bronze, and 350 ml of anhydrous n-propanol is stirred and heated under reflux for about eight hours, filtered hot, and the deep yellow filtrate is concentrated to dryness in vacuo. Workup gives about 6.8 g of 2-chloro-6H-pyrimido[1,2-c] [1,3,5]-benzoxadiazepine.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([Br:22])=[CH:20][N:19]=[C:18]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][C:32]([F:35])([F:34])[F:33])[N:17]=2)[CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([CH2:14][NH:15][C:16]2[C:21]([Br:22])=[CH:20][N:19]=[C:18]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][C:32]([F:33])([F:34])[F:35])[N:17]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)NC1CCC(CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2Br)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CC[C@H](CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2Br)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
(4-{[5-Bromo-2-(2-trifluoromethoxy-benzylamino)-pyrimidin-4-ylamino]-methyl}-cyclohexyl)-carbamic acid tert-butyl ester (75 mg, 0.13 mmol) was dissolved in CH2Cl2 (2 mL). To this solution was added TFA (2 mL) and the reaction was stirred at 25° C. for 1 h. The volatiles were removed in vacuo. The crude was redissolved in CH2Cl2 and poured into 10% aqueous NaHCO3. The aqueous phase was separated and extracted two more times with CH2Cl2. The organic layers were combined, dried (Na2SO4), decanted and concentrated. The crude was purified via flash chromatography (SiO2, 2-10% (NH4OH:CH3OH:CH2Cl2—CH2Cl2)) to afford 45 mg (73%) of the target compound, m/z 474.38 [M+1]+.