Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[S:11]([NH2:14])(=[O:13])=[O:12].[Mn]([O-])(=O)(=O)=[O:16].[K+]>O>[N+:8]([C:7]1[C:2]2[C:1](=[O:16])[NH:14][S:11](=[O:13])(=[O:12])[C:3]=2[CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: Cc1c([N+](=O)[O-])cccc1S(N)(=O)=O
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Product: O=C1NS(=O)(=O)c2cccc([N+](=O)[O-])c21

Procedure:
8.0 gm (37 mmols) of 2-methyl-3nitro-benzene sulfonamide were oxidized with potassium permanganate in water analogous to Example 8. After extraction with ether, evaporation and recrystallization from water 3.8 gm (45% of theory) of the nitro compound were obtained.
Reaction SMILES: [OH:1][C:2]1([CH3:20])[CH2:8][CH:7]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([O:18][CH3:19])[CH:12]=2)[O:6][C:4](=[O:5])[CH2:3]1.[C:21](OC(=O)C)(=[O:23])[CH3:22].O>N1C=CC=CC=1>[OH:1][C:2]1([CH3:20])[CH2:8][CH:7]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:21](=[O:23])[CH3:22])=[C:13]([O:18][CH3:19])[CH:12]=2)[O:6][C:4](=[O:5])[CH2:3]1
Reactant: COc1cc(CCC2CC(C)(O)CC(=O)O2)ccc1O
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: COc1cc(CCC2CC(C)(O)CC(=O)O2)ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 100 mg of 3-hydroxy-3-methyl-7-(p-hydroxy-m-methoxyphenyl)-5-heptanolide in 1 ml of pyridine was added 1 ml of acetic anhydride and the mixture was stirred overnight at room temperature. After completion of the reaction, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. Evaporation of the solvent from the extract yielded the desired compound as a colorless oily substance.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([CH3:15])=[CH:9][CH:8]=3.[Br:23]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([CH2:15][Br:23])=[CH:9][CH:8]=3
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2c(c1)c1cc(Br)ccc1n2C(=O)OC(C)(C)C
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)n1c2ccc(Br)cc2c2cc(CBr)ccc21
Yield: 69.6 %

Procedure:
A suspension of 3-bromo-9-tert-butoxycarbonyl-6-methylcarbazole obtained from Example 25 (653 mg, 1.81 mmol) and recrystallised N-bromosuccinimide (355 mg, 2.00 mmol) in carbon tetrachloride was refluxed under nitrogen with irradiation from a 150 W halogen lamp for 2.5 h. The reaction mixture was cooled over an ice bath and filtered, and the filtrate evaporated. The crude product was chromatographed (PS with gradient elution to PS:DCM 1:1) to afford 3-bromo-6-bromomethyl-9-tert-butoxycarbonylcarbazole (551 mg, 1.26 mmol, 69%) as a colourless solid, mp 150° C. (dec).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:15][NH:14][C:13]1=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])(CC)C.Cl[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[P:29](=O)([O-:33])[O:30][CH2:31][CH3:32].[Cl-].[Na+]>O1CCCC1>[CH2:31]([O:30][P:29]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:23]=1)([N:14]1[CH2:15][C@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:13]1=[O:16])=[O:33])[CH3:32]
Reactant: O=C(NC1CNC1=O)OCc1ccccc1
Reactant: CCOP(=O)([O-])c1ccccc1Cl
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOP(=O)(c1ccccc1)N1C[C@H](NC(=O)OCc2ccccc2)C1=O
Reaction time: 0.08 h
Yield: 59.3 %

Procedure:
To a solution of 3-benzyloxycarbonylamino-2-azetidinone (5.0 g) in dry tetrahydrofuran (125 ml), cooled to -78° C., was added sec-butyl lithium (18.5 ml) and the mixture was stirred for 5 minutes. Ethyl chlorophenylphosphonate (4.71 g) was added and the mixture was stirred for 1 hour at -78° C. followed by the addition of 125 ml of saturated sodium chloride solution. The mixture was then extracted twice with 125 ml portions of ethyl acetate and the extracts were combined, dried over anhydrous sodium sulfate and the solvent removed in vacuo yielding the crude product as a foam. The crude product was purified by chromatography on silica gel (750 g), eluting with dichloromethane:ethyl acetate (1:1) followed by ethyl acetate. The ethyl acetate fractions were stripped and the residue triturated with ether to yield 4.94 g of product.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C:14](=[O:16])[N:13]=[C:12]1[NH2:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:18]1([C:21](Cl)=[O:22])[CH2:20][CH2:19]1.CCN(C(C)C)C(C)C>C(#N)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C:14](=[O:16])[N:13]=[C:12]1[NH:17][C:21]([CH:18]1[CH2:20][CH2:19]1)=[O:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1=NC(=O)CN1C(=O)OCc1ccccc1
Reactant: O=C(Cl)C1CC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CN(C(=O)OCc2ccccc2)C(NC(=O)C2CC2)=N1
Temperature: 25 °C
Yield: 87.2 %

Procedure:
A suspension of 2-amino-4-oxo-4,5-dihydro-imidazole-1-carboxylic acid benzyl ester (100.0 mg, 0.43 mmol), cyclopropanecarbonylchloride (45.0 mg, 0.43 mmol) and Hunig's base (83.0 mg, 0.64 mmol) in acetonitrile (4 mL) was heated to reflux under argon for 0.5 hr. Cooled to r.t., the reaction mixture was concentrated and the residue was partitioned between EtOAc and water. The organic layer was dried over Na2SO4 and concentrated and the residue was triturated with AcOEt to give a suspension. The solid was filtered to give 2-(cyclopropanecarbonyl-amino)-4-oxo-4,5-dihydro-imidazole-1-carboxylic acid benzyl ester as an oil (113.0 mg, 87.6%).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][C:12](=O)[C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([NH:27][NH2:28])([NH2:26])=[NH:25].[ClH:29].Cl.O>C(O)C>[ClH:29].[CH2:1]([N:8]1[C:16]2[CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][C:12](=[N:28][NH:27][C:24]([NH2:26])=[NH:25])[C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC(c2ccccc2)Cc2c1ccn2Cc1ccccc1
Reactant: N=C(N)NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: N=C(N)NN=C1CC(c2ccccc2)Cc2c1ccn2Cc1ccccc1
Yield: 64.1 %

Procedure:
A mixture of 1-benzyl-6-phenyl-4,5,6,7-tetrahydroindol-4-one (0.8 g), aminoguanidine hydrochloride (0.32 g), concentrated hydrochloric acid (0.13 ml), water (0.13 ml) and ethanol (50 ml) was refluxed for 30 minutes. Under reduced pressure, the solvent was evaporated, and the residue was washed with water and dissolved in ethanol. To the solution was added a solution of 4N hydrochloric acid-ethyl acetate (1 ml), and the mixture was concentrated. The residue was recrystallized from ethanol to give 1-benzyl-4-guanidinoimino-6-phenyl-4,5,6,7-tetrahydroindole hydrochloride (Compound 10) (0.67 g) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH2:8][CH3:9])[CH:3]=1.[C:10]([N:13]1[CH2:17][C:16](=O)[N:15]=[CH:14]1)(=[O:12])[CH3:11]>>[C:10]([N:13]1[CH2:17][CH2:16][N:15]=[C:14]1[NH:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH2:8][CH3:9])[CH:3]=1)(=[O:12])[CH3:11]
Reactant: CCc1cc(N)n(C)n1
Reactant: CC(=O)N1C=NC(=O)C1
Product: CCc1cc(NC2=NCCN2C(C)=O)n(C)n1

Procedure:
5-Amino-3-ethyl-1-methyl pyrazole (British Pat. No. 863,060) (35.2 g.) and 1-acetyl-2-imidazolinone (43.2 g.) were reacted as described in Example I to give 1-acetyl -2-(3-ethyl-1-methyl-5-pyrazolyl) amino-2-imidazoline which was de-acetylated without purification by the method of Example II giving 39.3 g. product. mp 160°-162°
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15]O)[N:10]=[CH:9]2)C=CC=CC=1.[OH:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[C:36](=[O:40])[CH2:35][CH2:34][CH2:33]2>>[NH:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O:29][C:30]2[CH:31]=[C:32]3[C:37](=[CH:38][CH:39]=2)[C:36](=[O:40])[CH2:35][CH2:34][CH2:33]3)[N:10]=[CH:9]1
Reactant: O=C1CCCc2cc(O)ccc21
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Product: O=C1CCCc2cc(OCCCc3c[nH]cn3)ccc21

Procedure:
5 mmol of 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanol and 6 mmol of 3,4-dihydro-6-hydroxy-2H-naphthalen-1-one are treated as described in Example 56.
Reaction SMILES: [C:1]1([CH2:7][O:8][N:9]2[C:15](=[O:16])[N:14]3[CH2:17][C@H:10]2[CH2:11][CH2:12][C@H:13]3[C:18]([OH:20])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C.[NH2:37][C:38]1[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=1>ClCCl>[CH2:7]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:37][C:38]1[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=1)=[O:20])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccncc1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccncc1)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 50 °C

Procedure:
To a solution of (2S,5R)-6-(phenylmethoxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (51.5 mg, 0.186 mmol) in dry dichloromethane (5 mL) was added triethylamine (0.065 mL, 0.466 mmol), 2-chloro-1-methylpyridinium iodide (63.4 mg, 0.248 mmol), and 4-aminopyridine (19.2 mg, 0.204 mmol) sequentially at room temperature under nitrogen. The reaction was then heated to 50° C. for 1.5 hours. LC/MS showed reaction complete. The reaction mixture was concentrated and purified by HPLC on a 30×100 mm Waters Sunfire column to afford the title compound as an orange solid after lyophilization.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[C:5]([O:12][CH3:13])[CH:4]=1.[CH3:14][P:15]([O:19]CC)[O:16][CH2:17][CH3:18]>>[CH3:13][O:12][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][C:6]=1[N+:9]([O-:11])=[O:10])[CH2:2][CH2:14][PH:15](=[O:19])[O:16][CH2:17][CH3:18]
Reactant: CCOP(C)OCC
Reactant: COc1cc(CCl)ccc1[N+](=O)[O-]
Product: CCO[PH](=O)CCc1ccc([N+](=O)[O-])c(OC)c1
Temperature: 100 °C
Yield: 195.5 %

Procedure:
A mixture of 4-(chloromethyl)-2-methoxy-1-nitrobenzene (1.1 g, 5.46 mmol) and diethyl methylphosphonite (0.89 g, 1.2 mmol) were heated at 100° C. for 16 h in a sealed tube. The reaction mixture was concentrated in vacuo and the residue crude purified using an Isco Combiflash system eluting with 0→5% MeOH in DCM as eluent to afford 0.641 g of ethyl (3-methoxy-4-nitrobenzyl)methylphosphinate (yield: 43% yield). MS (ES+): m/z 273.99 [MH+] (ZQ3, polar 5 min).
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[C:21]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[CH:20]=[CH:19][C:3]=1[C:4]([C:6]1[C:14]([Cl:15])=[C:13]([Cl:16])[C:12]([Cl:17])=[C:11]([Cl:18])[C:7]=1[C:8](O)=[O:9])=[O:5].[CH3:28][N:29]([CH3:39])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]([CH3:38])[CH3:37])[CH:31]=1>>[CH3:37][N:36]([CH3:38])[C:32]1[CH:31]=[C:30]([N:29]([CH3:39])[CH3:28])[CH:35]=[CH:34][C:33]=1[C:4]1([C:3]2[CH:19]=[CH:20][C:21]([N:23]([CH2:24][CH3:25])[CH2:26][CH3:27])=[CH:22][C:2]=2[CH3:1])[C:6]2[C:7](=[C:11]([Cl:18])[C:12]([Cl:17])=[C:13]([Cl:16])[C:14]=2[Cl:15])[C:8](=[O:9])[O:5]1
Reactant: CCN(CC)c1ccc(C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)c(C)c1
Reactant: CN(C)c1cccc(N(C)C)c1
Product: CCN(CC)c1ccc(C2(c3ccc(N(C)C)cc3N(C)C)OC(=O)c3c(Cl)c(Cl)c(Cl)c(Cl)c32)c(C)c1

Procedure:
In a manner similar to that of part B of Example 1 condensation of 2-(2-methyl-4-(diethylamino)benzoyl)-3,4,5,6-tetrachlorobenzoic acid (22.4 g.) and N,N,N',N'-tetramethyl-m-phenylenediamine (8.20 g.) in contact with acetic anhydride (75 g.) and recrystallization of the resulting product from toluene afforded 3-(2,4-bis(dimethylamino)phenyl)-3-(2-methyl-4-(diethylamino)phenyl)-4,5,6,7-tetrachlorophthalide (I: X = (CH3)2N, Y2 = CH3, Y4 = (CH3CH2)2N, Z4 = Z5 = Z6 = Z7 = Cl) (m.p. 236°-238° C.; after slurrying in acetone, 237°-239° C.).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:14])[N:5]=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.N1C=CC=CC=1.Br[CH:22]([CH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)[C:23](Cl)=[O:24].C1(CC(Cl)=O)CCCC1>ClCCl>[CH:26]1([C:22]2[N:3]3[C:4]([CH3:14])=[N:5][N:6]=[C:7]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:2]3=[N:1][C:23]=2[OH:24])[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=C(Cl)C(Br)C1CCCC1
Reactant: Cc1nnc(-c2ccccc2)c(N)n1
Agent: O=C(Cl)CC1CCCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1nnc(-c2ccccc2)c2nc(O)c(C3CCCC3)n12
Temperature: 120 °C

Procedure:
To a solution of 5-amino-3-methyl-6-phenyl-[1,2,4]triazine (0.2 g, 1.07 mmol) in dichloromethane (20 ml) was added pyridine (0.104 ml, 1.28 mmol) followed by dropwise addition of 2-bromo-2-cyclopentylacetyl chloride (0.266 ml, 1.18 mmol; prepared from cyclopentylacetyl chloride by the method of Gleason, Tetrahedron Lett., 1970, 39, 3431). The reaction mixture was stirred for 18 h after which time the dichloromethane was evaporated in vacuo. The residue was dissolved in t-butanol (20 ml) to which was added triethylamine (1 ml) and sodium iodide (0.010 g) and the resultant mixture was heated at 120° C. for 18 h. The n-butanol was evaporated in vacuo and the residue was purified by flash chromatography (SiO2; 60% EtOAc in hexanes) to afford the title compound (0.178 g). δH (400 MHz; d6-DMSO) 1.40-2.20 (8H, m), 2.71 (3H, s), 3.65 (1H, m), 7.49 (3H, m), 8.05 (2H, m). m/z (ES+) 295 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH2:12][CH2:13][CH3:14])[C:6](=[O:15])[CH2:5]2.[C:16]([O:20][C:21](=[O:27])[NH:22][CH2:23][C@H:24]1[CH2:26][O:25]1)([CH3:19])([CH3:18])[CH3:17].FC(F)(F)S([O-])(=O)=O.[Li+]>C(#N)C.C(OCC)(=O)C>[C:16]([O:20][C:21](=[O:27])[NH:22][CH2:23][C@H:24]([OH:25])[CH2:26][NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH2:12][CH2:13][CH3:14])[C:6](=[O:15])[CH2:5]2)([CH3:18])([CH3:17])[CH3:19]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CO1
Reactant: CCCN1C(=O)Cc2cc(N)cc(F)c21
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Li+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCN1C(=O)Cc2cc(NC[C@@H](O)CNC(=O)OC(C)(C)C)cc(F)c21

Procedure:
5-Amino-7-fluoro-1-propyl-1,3-dihydro-indol-2-one (0.500 g, 2.40 mmol), (S)-oxiranylmethyl-carbamic acid tert-butyl ester (0.417 g, 2.40 mmol) and lithium trifluoromethanesulfonate (0.368 g, 2.40 mmol) in acetonitrile (8 ml) are heated at 90° C. for 8 hours. The reaction mixture is diluted with ethyl acetate, washed with water and brine, dried (Na2SO4) and evaporated. Final purification by flash chromatography (70% Ethyl acetate/hexane) gives the title compound as a yellow solid. HPLC r.t. 4.30 min; MS for C19H28FN3O4 m/z 382.3 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=2)=[N:6][CH:7]=1.[F:19][C:20]([F:32])([F:31])[O:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[CH3:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:5]2[N:4]=[CH:3][C:2]([C:25]3[CH:24]=[CH:23][C:22]([O:21][C:20]([F:19])([F:31])[F:32])=[CH:27][CH:26]=3)=[CH:7][N:6]=2)=[CH:10][C:11]=1[N+:16]([O-:18])=[O:17]
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: Cc1ccc(Nc2ncc(Br)cn2)cc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1ccc(Nc2ncc(-c3ccc(OC(F)(F)F)cc3)cn2)cc1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
To a solution of 5-bromo-N-(4-methyl-3-nitrophenyl)pyrimidin-2-amine 27 (9.7 mmol) in 1,4-dioxane (29 mL) is added 4-(trifluoromethoxy)phenylboronic acid (10.7 mmol), Na2CO3 (29.2 mmol of 1.8 M aq. solution) and Pd(PPh3)4 (1.46 mmol). The reaction is evacuated and backfilled with nitrogen twice then heated at 100° C. for 12 h. The reaction mixture is diluted with water (20 mL) and extracted with EtOAc (2×50 mL). The organic layer is separated, dried over Na2SO4 and concentrated. Purification by preparative HPLC (ACN gradient 10-70%) affords N-(4-methyl-3-nitrophenyl)-5-(4-(trifluoromethoxy)phenyl)pyrimidin-2-amine 28b. MS (m/z) (M+1)+: 390.1.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:33])[C:6]2[CH:11]=[C:10]([N:12]3[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C@@H:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C@@H:20]([CH3:23])[CH:21]=O)[C:13]3=[O:30])[C:9]([CH3:31])=[C:8]([F:32])[CH:7]=2)[CH2:3][CH2:2]1.[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH:1]1([NH:4][C:5](=[O:33])[C:6]2[CH:11]=[C:10]([N:12]3[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C@@H:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C@@H:20]([CH3:23])[CH2:21][N:34]4[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)[C:13]3=[O:30])[C:9]([CH3:31])=[C:8]([F:32])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(N[C@@H](c2ccccc2)[C@@H](C)C=O)c1=O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(N[C@@H](c2ccccc2)[C@@H](C)CN2CCCCC2)c1=O

Procedure:
The title compound was prepared from N-cyclopropyl-3-fluoro-4-methyl-5-[3-{[(1R,2R)-2-methyl-3-oxo-1-phenylpropyl]amino}-2-oxopyrazin-1(2H)-yl]benzamide (Example 328e) and piperidine using a similar method to that described for Example 328f.
Reaction SMILES: [F:1][CH2:2][CH:3]([OH:7])[C:4]([O-:6])=[O:5].[C:8]1([CH:14]([NH3+])C)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(Br)C1C=CC=CC=1>CN(C=O)C.CCOC(C)=O>[F:1][CH2:2][CH:3]([OH:7])[C:4]([O:6][CH2:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5]
Reactant: CC([NH3+])c1ccccc1
Reactant: O=C([O-])C(O)CF
Agent: BrCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)C(O)CF
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-phenylethanaminium 3-fluoro-2-hydroxypropanoate (11-1) (0.14 g, 0.61 mmol) in DMF (1 mL) was added benzyl bromide (0.087 mL, 0.73 mmol). The mixture was stirred at room temperature overnight, diluted with EtOAc, washed with water and brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0-50% EtOAc/hexanes) to provide 11-2. HRMS: 198.0688 found, 198.0692 required (M+).
Reaction SMILES: C(O[C:5]1[CH:20]=[C:19]([O:21][C:22](=[O:24])[CH3:23])[C:8]2[C:9]([CH3:18])=[C:10]3[N:15]([C:16](=[O:17])[C:7]=2[CH:6]=1)[CH2:14][CH2:13][CH2:12][CH2:11]3)(=O)C.[C:25]([O:28]C(=O)C)(=[O:27])[CH3:26].N1C=CC=CC=1>C(Cl)(Cl)Cl>[C:25]([O:28][C:20]1[CH:5]=[CH:6][C:7]2[C:16](=[O:17])[N:15]3[CH:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)[C:9](=[CH2:18])[C:8]=2[C:19]=1[O:21][C:22](=[O:24])[CH3:23])(=[O:27])[CH3:26]
Reactant: CC(=O)Oc1cc(OC(C)=O)c2c(C)c3n(c(=O)c2c1)CCCC3
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: C=C1c2c(ccc(OC(C)=O)c2OC(C)=O)C(=O)N2CCCCC12

Procedure:
Reflux crude 8,10-bis(acetyloxy)-1,2,3,4-tetrahydro-11-methyl-6H-benzo[b]quinolizin-6-one (11.8 g), acetic anhydride (20.2 ml), pyridine (20.2 ml), and chloroform (400 ml) for 20 hrs. Concentrate the cooled solution to dryness, and dilute the residue with ethyl acetate. Separate the resulting crystals by filtration, and concentrate the mother liquor. Chromatograph the residue over silica gel, and elute the column with 10% ethyl acetate in dichloromethane. Combine and concentrate fractions, and crystallize to obtain 9,10-bis(acetyloxy)-1,2,3,4,11,11a-hexahydro-11-methylene-6H-benzo[b]quinolizin-6-one, m.p. 129°-132° C. (from CHCl3 -EtOAc).
Reaction SMILES: C(=O)(OCC)O[CH:3]([C:6]1[CH:11]=[C:10](F)[CH:9]=[CH:8][C:7]=1[Br:13])[CH:4]=[CH2:5].[F:18][C:19]([F:39])([F:38])[C:20]1[CH:21]=[C:22]([C@H:30]2[O:34][C:33](=[O:35])[NH:32][C@H:31]2[CH:36]=[CH2:37])[CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1>C1C=C2C=CC3C(C=CC2=CC=1)=CC=CC=3.C(Cl)Cl>[F:39][C:19]([F:18])([F:38])[C:20]1[CH:21]=[C:22]([C@H:30]2[O:34][C:33](=[O:35])[N:32]([C@H:3]([C:6]3[CH:11]=[C:10]([C:19]([F:39])([F:38])[F:18])[CH:9]=[CH:8][C:7]=3[Br:13])[CH:4]=[CH2:5])[C@H:31]2[CH:36]=[CH2:37])[CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:25]=1
Reactant: C=C[C@@H]1NC(=O)O[C@@H]1c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C=CC(OC(=O)OCC)c1cc(F)ccc1Br
Agent: C1=C\c2ccccc2/C=C\c2ccccc2/1
Agent: C1=Cc2ccccc2C=Cc2ccccc21
Solvent: ClCCl
Product: C=C[C@@H](c1cc(C(F)(F)F)ccc1Br)N1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C=C
Temperature: 33 °C
Reaction time: 48 h
Yield: 124.4 %

Procedure:
To a 500 mL RBF was added 1-(2-bromo-5-fluorophenyl)prop-2-en-1-yl ethyl carbonate (10.4 g, 29.5 mmol), (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-ethenyl-1,3-oxazolidin-2-one (4 g, 12.3 mmol), DCM (20 mL), and the Helmchen dibenzo[a,e]cyclooctatetraene (dbcot) iridium phosphoramidite catalyst complex (407 mg, 0.369 mmol) (Helmchen et al, Chem. Eur. J., 2010, 16, 6601-6615). The reaction was stirred at 33° C. for 2 days open to air. The reaction was filtered over Celite and purified by column chromatography to yield (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{(1S)-1-[2-bromo-5-(trifluoromethyl)phenyl]prop-2-en-1-yl}-4-ethenyl-1,3-oxazolidin-2-one (4.5 g, 7.65 mmol). 1H NMR (500 MHz, CDCl3) δ7.86 (m, 2H), 7.68 (s, 2H), 7.64 (s, 1H), 7.54 (d, J=6.5 Hz, 1H), 6.22 (m, 1H), 5.75 (m, 2H), 5.43 (m, 2H), 5.20 (m, 1H), 5.03 (d, J=5.0 Hz, 1H), 4.8 (d, J=8.5 Hz, 1H), 4.1 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:22]4[CH:30]=[C:29](F)[N:28]=[CH:27][C:23]=4[N:24]=[CH:25][N:26]=3)=[CH:16][C:15]=2[CH3:32])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1.C1(C(N2CCC(OC3C=CC(NC4C5C=C(N6CCCC6)N=CC=5N=CN=4)=CC=3C)CC2)=O)CCCC1>>[C:1]([O:5][C:6](=[O:33])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:22]4[CH:30]=[C:29]([N:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)[N:28]=[CH:27][C:23]=4[N:24]=[CH:25][N:26]=3)=[CH:16][C:15]=2[CH3:32])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(Nc2ncnc3cnc(F)cc23)ccc1Oc1cccc(C(=O)OC(C)(C)C)c1
Reactant: C1CCNC1
Agent: Cc1cc(Nc2ncnc3cnc(N4CCCC4)cc23)ccc1OC1CCN(C(=O)C2CCCC2)CC1
Product: Cc1cc(Nc2ncnc3cnc(N4CCCC4)cc23)ccc1Oc1cccc(C(=O)OC(C)(C)C)c1

Procedure:
The Title compound was prepared from 3-[4-(6-Fluoro-pyrido[3,4-d]pyrimidin-4-ylamino)-2-methyl-phenoxy]-benzoic acid tert-butyl ester and pyrrolidine by a procedure analogous to that described for the synthesis of Cyclopentyl-{4-[2-methyl-4-(6-pyrrolidin-1-yl-pyrido[3,4-d]pyrimidin-4-ylamino)-phenoxy]-piperidin-1-yl}-methanone. LRMS: 498.3 (MH+). 1H NMR (DMSO-d6, 400 MHz): δ 9.60 (s, 1H), δ 8.76 (s, 1H), δ 8.31 (s, 1H), δ 7.73-7.76 (m, 2H), δ 7.56-7.58 (m, 1H), δ 7.45 (t, J=7.89, 1H), δ 7.31-7.32 (m, 1H), δ 7.13-7.16 (m, 1H), δ 7.09 (s, 1H), 7.01 (d, J=9.14, 1H), δ 3.45-3.48 (m, 4H), δ 2.15 (s, 3H), δ 1.97-2.01 (m, 4H), δ 1.48 (s, 9H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[C:8]([CH2:10][O:11][CH3:12])[CH:7]=[C:6]([O:13][CH3:14])[C:5]=1[C:15]1[N:16]2[N:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:17]2[S:18][CH:19]=1.[N:25]([O-])=[O:26].[Na+].[OH-].[Na+]>C(OCC)(=O)C.O>[CH3:2][O:3][C:4]1[CH:9]=[C:8]([CH2:10][O:11][CH3:12])[CH:7]=[C:6]([O:13][CH3:14])[C:5]=1[C:15]1[N:16]2[N:22]=[C:21]([O:23][CH3:24])[C:20]([N:25]=[O:26])=[C:17]2[S:18][CH:19]=1
Reactant: COCc1cc(OC)c(-c2csc3cc(OC)nn23)c(OC)c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: COCc1cc(OC)c(-c2csc3c(N=O)c(OC)nn23)c(OC)c1
Reaction time: 1 h
Yield: 99.5 %

Procedure:
A mixture of water and 5N hydrochloric acid (1:4, 70 mL) was added to 3-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-6-methoxypyrazolo[5,1-b][1,3]thiazole (2.17 g, 6.47 mmol), and then sodium nitrite (1.06 g, 15.3 mmol) was added at 0° C. and the mixture was stirred for 1 hour. Aqueous 5N sodium hydroxide and ethyl acetate were added to the mixture at room temperature. After thoroughly shaking the mixture, the organic layer was separated and dried over anhydrous magnesium sulfate. The mixture was then filtered, and the solvent in the filtrate was distilled off under reduced pressure to obtain the title compound (2.34 g, 6.44 mmol).