Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][C:18]=3[CH3:24])=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:25][C@@H:26]1[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[NH:27]1>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:27]4[C@H:26]([CH3:25])[CH2:30][CH2:29][S:28]4(=[O:32])=[O:31])=[CH:19][C:18]=3[CH3:24])=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: C[C@@H]1CCS(=O)(=O)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(I)cc3C)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4[C@H](C)CCS4(=O)=O)cc3C)CC2)c(C)c1
Yield: 51.8 %

Procedure:
Using [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl](4-iodo-2-methylphenyl)methanone (562 mg) described in Preparation Example 154 and (R)-3-methylisothiazolidine 1,1-dioxide (175 mg) described in Preparation Example 2 and by the reaction and treatment in the same manner as in Example 1, the title compound (296 mg) was obtained.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:6]=1[CH2:7][NH:8][C:9]1[S:10][CH:11]=[CH:12][N:13]=1.Cl[S:21]([C:24]1[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=1)[C:27]([O:29][CH3:30])=[O:28])(=[O:23])=[O:22].O>C1COCC1>[CH3:3][O:4][C:5]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:6]=1[CH2:7][N:8]([C:9]1[S:10][CH:11]=[CH:12][N:13]=1)[S:21]([C:24]1[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=1)[C:27]([O:29][CH3:30])=[O:28])(=[O:23])=[O:22]
Reactant: COC(=O)c1cccc(S(=O)(=O)Cl)c1
Reactant: COc1ccc(CNc2nccs2)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cccc(S(=O)(=O)N(Cc2ccc(OC)cc2OC)c2nccs2)c1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
Sodium hydride (60% in mineral oil, 239 mg, 5.99 mmol, 1.5 eq) was added portionwise to a solution of N-(2,4-dimethoxybenzyl)-1,3-thiazol-2-amine (Preparation 6, 1 g, 3.995 mmol, 1 eq) in THF (10 ml) at 0° C. The mixture was stirred for 40 minutes before the addition of methyl 3-(chlorosulfonyl)benzoate (937, 3.995 mmol, 1 eq) and the reaction mixture stirred for a further 1 hour at 0° C. and 5 hours at room temperature. Water (2 ml) was added and the THF evaporated in vacuo. The residue was extracted from water (10 ml) into ethyl acetate (3×5 ml), washed with brine, dried over magnesium sulphate, filtered and evaporated in vacuo to yield methyl 3-{[(2,4-dimethoxybenzyl)(1,3-thiazol-2-yl)amino]sulfonyl}benzoate.
Reaction SMILES: [CH:1]([O:4][NH:5][C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH:8]=1)([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:39]>C(#N)C>[CH:1]([O:4][N:5]=[C:6]([Cl:39])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)CCc1cccc(C(=O)NOC(C)C)c1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CC(C)CCc1cccc(C(Cl)=NOC(C)C)c1
Yield: 88 %

Procedure:
To 200 ml of acetonitrile were added 5.4 g (23.5 mmol) of O-isopropyl 3-isopentylbenzohydroxamic acid, 9.9 g (37.8 mmol) of triphenylphosphine, and 11.6 g (75.3 mmol) of carbon tetrachloride. The mixture was refluxed for 1 hour. The refluxed mixture was allowed to sit and cool naturally, and the solvent in the mixture was removed under reduced pressure. The residue was purified by column chromatography, thus obtaining the desired product of 5.1 g (yield: 88%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][NH:7][C:6]=2[CH:11]=1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[CH3:19][S:20]([N:7]1[C:6]2[CH:11]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[O:10][CH2:9][CH2:8]1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc2c(c1)NCCO2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(c1)N(S(C)(=O)=O)CCO2
Temperature: 25 °C
Reaction time: 18 h
Yield: 92 %

Procedure:
6-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine (1.49 g, 10 mmol) was dissolved in dichloromethane (50 mL) and treated with triethylamine (1.14 g, 11 mmol) followed by the dropwise addition of methanesulfonyl chloride (1.26 g, 11 mmol). The mixture was stirred at ambient temperature for 18 h then evaporated to dryness under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous NaHCO3. The phases were separated and the organic phase washed with water, saturated brine, dried (MgSO4) and evaporated to dryness under reduced pressure to give the title compound (2.09 g, 93%) as a brown solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][N:11]1[C:15]([CH3:16])=[CH:14][C:13]([C:17]([O:19]CC)=[O:18])=[N:12]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[K+].[Br-]>>[Si:1]([O:8][CH2:9][CH2:10][N:11]1[C:15]([CH3:16])=[CH:14][C:13]([C:17]([OH:19])=[O:18])=[N:12]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cc(C)n(CCO[Si](C)(C)C(C)(C)C)n1
Agent: [Br-]
Agent: [K+]
Product: Cc1cc(C(=O)O)nn1CCO[Si](C)(C)C(C)(C)C

Procedure:
The title compound was prepared from ethyl 1-(2-t-butyldimethylsilyloxyethyl)-5-methylpyrazole-3-carboxylate (16.08 g, 51.5 mM) as described in Example 4 Preparation 2 as a white solid (10.5 g, 72%); νmax (KBr) 1688, 1648, 1533 and 1505 cm-1 ; δH (CDCl3) -0.10 (6H, s), 0.81 (9H, s), 2.35 (3H, s), 4.00 (2H, t, J5 Hz), 4.24 (2H, t, J5 Hz),6.60 (1H, s); NH3DCI m/e 285 (100%).
Reaction SMILES: C(OC(=O)[NH:7][C:8](=[NH:64])[C:9]1[S:10][C:11]([S:62][CH3:63])=[C:12]([S:14]([C:17]2[CH:18]=[C:19]([C:23]3[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=3[NH:30][C:31]([NH:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]3[N:39]=[N:40][N:41](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:42]=3)=[O:32])[CH:20]=[CH:21][CH:22]=2)(=[O:16])=[O:15])[CH:13]=1)(C)(C)C.[C:66]([OH:72])([C:68]([F:71])([F:70])[F:69])=[O:67].C(Cl)Cl>>[F:69][C:68]([F:71])([F:70])[C:66]([OH:72])=[O:67].[CH3:63][S:62][C:11]1[S:10][C:9]([C:8]([NH2:64])=[NH:7])=[CH:13][C:12]=1[S:14]([C:17]1[CH:18]=[C:19]([C:23]2[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=2[NH:30][C:31]([NH:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]2[N:39]=[N:40][NH:41][N:42]=2)=[O:32])[CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:15]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2NC(=O)NCCCCc2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSc1sc(C(=N)N)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2NC(=O)NCCCCc2nn[nH]n2)c1
Yield: 45 %

Procedure:
A solution of {imino-[5-methylsulfanyl-4-(6′-methyl-2′-{3-[4-(2-trityl-2H-tetrazol-5-yl)-butyl]-ureido}-biphenyl-3-sulfonyl)-thiophen-2-yl]-methyl}-carbamic acid tert-butyl ester (15 mg, 16 μmol) in TFA/DCM (1:1, 2.0 mL) was stirred at ambient temperature for 1 h. The mixture was concentrated, and flash chromatographed on silica gel column, eluting with MeOH/DCM (3 to 7.5% containing 0.1% TFA) to give the title compound (5 mg, 45% yield) as a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl.[Cl:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12](=[O:22])[CH:13]([CH2:18]N(C)C)[CH2:14][S:15]2)=[CH:10][CH:9]=1>O>[Cl:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12](=[O:22])[CH:13]([CH2:18][C:2]3[NH:1][CH:5]=[CH:4][N:3]=3)[CH2:14][S:15]2)=[CH:10][CH:9]=1
Reactant: CN(C)CC1CSc2cc(Cl)ccc2C1=O
Reactant: c1c[nH]cn1
Agent: Cl
Solvent: O
Product: O=C1c2ccc(Cl)cc2SCC1Cc1ncc[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolve imidazole (25.8 gms., 380 mmols) in water (100 ml.) and add 7-chloro-3-(dimethylaminomethyl)thiochroman-4-one hydrochloride (11.1 gms., 38.0 mmols). Stir the reaction mixture overnight at room temperature, then add water (1 liter) and extract with chloroform (500 ml.). Wash the chloroform solution with 2 liter portions of water, dry over anhydrous magnesium sulfate, filter and evaporate in vacuo to a residue. Chromatograph the residue on a silica gel column eluting with chloroform. Combine the like eluates as determined by thin layer chromatography and evaporate in vacuo to a residue comprising 7-chloro-3-(1'-imidazolylmethyl)thiochroman-4-one. Further purify by recrystallization from chloroform/hexane, m.p. 104°-105° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])#[N:2].C([Sn](=O)CCCC)CCC.C[Si]([N:27]=[N+:28]=[N-:29])(C)C>C1(C)C=CC=CC=1>[CH3:9][O:8][C:6]([C:5]1[CH:4]=[C:3]([C:1]2[NH:29][N:28]=[N:27][N:2]=2)[CH:12]=[CH:11][CH:10]=1)=[O:7]
Reactant: COC(=O)c1cccc(C#N)c1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(-c2nnn[nH]2)c1
Yield: 97.9 %

Procedure:
A mixture of methyl 3-cyanobenzoate (320 mg, 1.98 mmol), dibutyltin oxide (49.7 mg, 0.20 mmol) and trimethylsilyl azide (0.54 mL, 3.96 mmol) in toluene (4.0 mL) was heated at reflux for 24 hours. The solvent was removed under reduced pressure and chased with methanol (1-2 mL). The residue obtained was flash chromatographed on silica gel eluting with acetic acid and methanol in methylene chloride to give the title compound (395.7 mg). 1H NMR (DMSO-d6, 300 MHz) δ3.0-4.5 (br, 1H), 3.92 (s, 3H), 7.75 (t, J=8 Hz, 1H), 8.11 (d, J=8 Hz, 1H), 8.32 (d, J=8 Hz, 1H), 8.54 (s, 1H). MS (DCl/NH3) m/e 205 (M+H)+, 222 (M+H+NH3)+.
Reaction SMILES: [CH2:1]([N:8]([CH:18]1[CH2:23][CH2:22][N:21]([CH:24]([CH3:44])[CH2:25][CH2:26][NH:27][C:28](=[O:43])[C:29]2[C:34]([CH3:35])=[CH:33][C:32]([C:36]3[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=3)=[CH:31][C:30]=2[CH3:42])[CH2:20][CH2:19]1)[C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+:46]>>[CH2:1]([N:8]([C:9]1[CH:17]=[CH:16][C:12]([C:13](=[O:14])[NH2:46])=[CH:11][CH:10]=1)[CH:18]1[CH2:23][CH2:22][N:21]([CH:24]([CH3:44])[CH2:25][CH2:26][NH:27][C:28](=[O:43])[C:29]2[C:34]([CH3:35])=[CH:33][C:32]([C:36]3[CH:37]=[CH:38][N:39]=[CH:40][CH:41]=3)=[CH:31][C:30]=2[CH3:42])[CH2:20][CH2:19]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: Cc1cc(-c2ccncc2)cc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2ccccc2)c2ccc(C(=O)O)cc2)CC1
Agent: [Cl-]
Product: Cc1cc(-c2ccncc2)cc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2ccccc2)c2ccc(C(N)=O)cc2)CC1
Yield: 72.9 %

Procedure:
Using general procedure E, 4-(benzyl-{1-[3-(2,6-dimethyl-4-pyridin-4-yl-benzoylamino)-1-methyl-propyl]-piperidin-4-yl}-amino)-benzoic acid (see EXAMPLE 91) (60 mg, 0.10 mmol) and ammonium chloride (22 mg, 0.41 mmol) afforded COMPOUND 92 as a white solid (43 mg, 71%). 1H NMR (CDCl3) δ 1.02 (d, 3H, J=5.7 Hz), 1.06-1.35 (m, 2H), 1.51-1.62 (m, 1H), 1.69-1.86 (m, 3H), 2.13-2.31 (m, 1H), 2.40 (s, 6H), 2.52-2.63 (m, 1H), 2.73-2.94 (m, 3H), 3.20-3.40 (m, 2H), 3.62-3.71 (m, 1H), 3.89 (s, 2H), 5.79 (br s, 2H), 6.49 (d, 2H, J=8.1 Hz), 6.84-6.93 (m, 2H), 7.12-7.22 (m, 3H), 7.25-7.33 (m, 2H), 7.41-7.48 (m, 2H), 7.57 (d, 2H, J=8.1 Hz), 8.20 (br s, 1H), 8.60-8.67 (m, 2H). 13C NMR (CDCl3) δ 13.45, 19.34, 29.05, 30.40, 31.30, 39.60, 43.73, 48.18, 51.98, 55.72, 60.12, 111.66, 120.60, 121.49, 125.76, 126.06, 126.75, 128.51, 129.11, 135.24, 138.06, 139.02, 139.21, 147.61, 150.35, 151.34, 169.08, 169.34. ES-MS m/z 590 (M+H).
Reaction SMILES: Br[CH:2]1[CH2:8][NH:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]2[C:13]([CH3:16])=[N:14][N:15]=[C:3]12.CC1(C)C(C)(C)OB([C:25]2[CH:26]=[CH:27][C:28]([NH2:31])=[N:29][CH:30]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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>[CH3:16][C:13]1[N:4]2[C:5]3[CH:12]=[CH:11][C:10]([C:25]4[CH:26]=[CH:27][C:28]([NH2:31])=[N:29][CH:30]=4)=[CH:9][C:6]=3[NH:7][CH2:8][CH2:2][C:3]2=[N:15][N:14]=1
Reactant: Cc1nnc2n1-c1ccccc1NCC2Br
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nnc2n1-c1ccc(-c3ccc(N)nc3)cc1NCC2
Yield: 65.3 %

Procedure:
A solution of bromo-1-methyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine (30 mg, 0.11 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (48 mg, 0.22 mmol), Tetrakis(triphenylphosphine)palladium(0) (10 mg) and Cs2CO3 (72 mg, 0.22 mmol) in dioxane (5 mL) and water (1 mL) was heated at 120° C. under microwave for 20 min. The reaction mixture was concentrated to give the crude product, which was purified by prep-TLC (DCM:MeOH=10:1) to afford 5-(1-methyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-8-yl)pyridin-2-amine (21 mg, yield 55%).
Reaction SMILES: [O:1]([CH:8]([C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][CH:11]=1)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+].O1CCC[CH2:24]1.Cl>O.CO>[CH3:24][C:19]1[CH:18]=[C:13]([CH:12]=[CH:11][C:10]=1[CH2:8][O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:14]([OH:16])=[O:15]
Reactant: C1CCOC1
Reactant: COC(=O)c1ccc(C(C)Oc2ccccc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(C(=O)O)ccc1COc1ccccc1
Temperature: 20 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
A mixture of methyl 4-(1-phenoxyethyl)benzoate (0.32 g, 1.2 mmol), lithium hydroxide monohydrate (571 mg, 13.6 mmol), tetrahydrofuran (15 mL), methanol (5 mL) and water (5 mL) was stirred at 20° C. for 4 hours. The mixture was neutralized to pH=1 with concentrated hydrochloric acid and then extracted with ethyl acetate (15 mL×3). The combined organic phase was dried by sodium sulfate, and then filtered. The filtrate was concentrated in vacuo to give 3-methyl-4-(phenoxymethyl)benzoic acid (0.21 g, 72%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].Br[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N.C(Cl)Cl>[CH3:19][O:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[CH2:11][CH2:10][N:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]1
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: COc1cccc(CCBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: ClCCl
Product: COc1cccc(CCn2cc([N+](=O)[O-])cn2)c1
Temperature: 80 °C

Procedure:
To a solution of 4-nitro-1H-pyrazole (230 mg, 2.03 mmol) in MeCN (9.5 mL), 1-(2-bromo-ethyl)-3-methoxy-benzene (481 mg, 2.24 mmol) dissolved in MeCN (1.5 mL) and Cs2CO3 (729 mg, 2.24 mmol) was added. The resulting mixture was refluxed (80° C.) for 1.5 h, then the reaction mixture was allowed to reach rt. The mixture was diluted with DCM, filtered, the filter cake was washed with DCM and the filtrate was concentrated in vacuo to obtain 1-(3-methoxyphenethyl)-4-nitro-1H-pyrazole as a beige solid which was used in the next step without further purification. LC-MS conditions A: tR=0.86 min, [M+H]+=no ionization.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([NH:24][CH2:25][C:26]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:27]=1[C:28](O)=[O:29])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.[N:43]1(OC(N(C)C)=[N+](C)C)[C:47]2N=CC=C[C:46]=2[N:45]=N1.C(CN)O>CN(C=O)C>[NH2:43][CH2:47][CH2:46][NH:45][C:28]([C:27]1[CH:31]=[C:32]([F:35])[CH:33]=[CH:34][C:26]=1[CH2:25][NH:24][C:22]([C:10]1[N:11]=[C:12]2[N:17]([C:18](=[O:19])[C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:16][CH2:15][O:14][C:13]2([CH3:21])[CH3:20])=[O:23])=[O:29]
Reactant: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1C(=O)O)c(OCc1ccccc1)c2=O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: NCCO
Solvent: CN(C)C=O
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1C(=O)NCCN)c(OCc1ccccc1)c2=O
Reaction time: 0.33 h
Yield: 87 %

Procedure:
A mixture of intermediate 190, 2-((3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorobenzoic acid, (59 mg, 0.12 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, HATU (76 mg, 0.2 mmol; Aldrich) in DMF (1 mL) was stirred for 20 min. To this mixture was added ethanolamine (20 mg, 0.3 mmol) and the stirring continued overnight. The mixture was concentrated in vacuo, dissolved in CH2Cl2, washed with water then dried (MgSO4), filtered, and concentrated to provide 55 mg (Yield 87%) of the title compound: LC/MS m/z 525 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH2:12]([O:14][C:15](=[O:33])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH:24]C(C2OC(Br)=CC=2)=O)[CH:19]=1)[CH3:13]>>[CH2:12]([O:14][C:15](=[O:33])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[F:11])[CH:19]=1)[CH3:13]
Reactant: CCOC(=O)C=Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Reactant: O=C(O)c1cc(Br)ccc1F
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2cc(Br)ccc2F)c1

Procedure:
5-Bromo-2-fluorobenzoic acid (330 mg, 1.5 mmol) was coupled to aniline (99)(290 mg, 1.5 mmol) using Method C to give the title compound.
Reaction SMILES: Br[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=3)=[O:16])[CH:8]=[C:9]([O:11][CH:12]([CH3:14])[CH3:13])[CH:10]=2)[CH:6]=1.[C:25](B(O)O)([CH3:27])=[CH2:26].C([O-])([O-])=O.[Na+].[Na+]>CC#N.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:12]([O:11][C:9]1[CH:10]=[C:4]2[O:3][C:2]([C:25]([CH3:27])=[CH2:26])=[CH:6][C:5]2=[C:7]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=2)=[O:16])[CH:8]=1)([CH3:14])[CH3:13]
Reactant: Cc1ccc(NC(=O)c2cc(OC(C)C)cc3oc(Br)cc23)nc1
Reactant: C=C(C)B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: C=C(C)c1cc2c(C(=O)Nc3ccc(C)cn3)cc(OC(C)C)cc2o1
Yield: 42.8 %

Procedure:
A solution of 2-bromo-6-isopropoxy-N-(5-methylpyridin-2-yl)benzofuran-4-carboxamide (263 mg, 0.68 mmol), isopropenyl boronic acid (58.4 mg, 0.68 mmol), Pd(PPh3)2Cl2 (23.9 mg, 0.034 mmol) and aqueous Na2CO3 (1.0 M in H2O, 1.36 mL) in 1.4 mL of CH3CN was heated in a microwave reactor at 150° C. for 5 min. The solvent was removed in vacuo. The residue was purified with Biotage column chromatography to give a light yellow solid (102 mg, 43% yield). 1H NMR (400 MHz, CDCl3) δ 9.07 (s, 1 H) 8.30 (d, J=8.56 Hz, 1 H) 7.96 (d, J=2.01 Hz, 1 H) 7.56 (dd, J=8.56, 2.27 Hz, 1 H) 7.26 (d, J=2.27 Hz, 1 H) 7.14 (d, J=1.51 Hz, 1 H) 7.09 (s, 1 H) 5.76 (s, 1 H) 5.17 (s, 1 H) 4.53-4.59 (m, 1 H) 2.27 (s, 3H) 2.11 (s, 3 H) 1.36 (d, J=6.04 Hz, 6 H); LCMS for C21H22N2O3 m/z 351.10 (M+H)+.
Reaction SMILES: O[C:2]1[C:3]2[N:4]([C:12]([C:15]([F:18])([F:17])[F:16])=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.P(Cl)(Cl)([Cl:21])=O.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:21][C:2]1[C:3]2[N:4]([C:12]([C:15]([F:18])([F:17])[F:16])=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Oc1nc2ccccc2n2c(C(F)(F)F)nnc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: FC(F)(F)c1nnc2c(Cl)nc3ccccc3n12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
In a flame-dried reaction flask under a dry nitrogen atmosphere, there were placed 3.0 g. (0.0118 mole) of 4-hydroxy-1-trifluoromethyl-[1,2,4]triazolo[4,3-a]quinoxaline and 30 ml. of phosphorus oxychloride in 2.38 g. (0.0236 mole) of triethylamine (3.3 ml.). The reaction mixture was then heated at 100° C. for a period of approximately 16 hours (i.e., overnight). Upon completion of this step, the spent mixture was cooled to room temperature, concentrated in vacuo and then partitioned between ice, water and ethanol, followed by extraction with ethyl acetate. The latter extract was next washed with saturated brine and dried over anhydrous magnesium sulfate. After removal of the drying agent by means of filtration and the solvent by means of evaporation under reduced pressure, there was obtained a residue which was subsequently dissolved in hot chloroform and filtered. The latter filtrate was then allowed to stand overnight at room temperature and filtered again. The final filtrate was then concentrated in vacuo to ultimately afford 1.4 g. of 4-chloro-1-trifluoromethyl-1,2,4]triazolo[4,3-a]quinoxaline in the form of a brownish-colored solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=O)=[CH:5][N:4]=[CH:3]1.Cl.[NH2:16][OH:17]>N1C=CC=CC=1>[OH:17][N:16]=[C:7]([C:6]1[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cn1cncc1C(=O)c1ccccc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: Cn1cncc1C(=NO)c1ccccc1
Reaction time: 3 h
Yield: 47.2 %

Procedure:
A solution of (1-methyl-1H-imidazol-5-yl)(phenyl)methanone (14.0 g, 75 mmol) and hydroxylamine hydrochloride (13.1 g, 188 mmol) in pyridine (60 mL) was stirred for 72 h at room temperature, and for 3 h at 50° C. After removal of the solvent in vacuo, addition of water (600 mL) and extraction with ethyl acetate (4×150 mL), the combined organic layers were washed with water (150 mL), dried over MgSO4 and concentrated in vacuo. The resulting yellow solid was washed with pentane to afford N-hydroxy-1-(1-methyl-1H-imidazol-5-yl)-1-phenylmethanimine [7.12 g, yield 42%; HPLC/MS: m/z=202 (M+H); log P(HCOOH)=0.41]. Further extraction of the neutralised combined aqueous layers afforded a second crop of N-hydroxy-1-(1-methyl-1H-imidazol-5-yl)-1-phenylmethanimine [5.75 g, yield 34%; HPLC/MS: m/z=202 (M+H); log P(HCOOH)=0.41], combined yield 76%.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[NH:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[O:7][CH2:6]1)=[O:4].[CH2:15]([NH:19][C:20](=[O:56])[C@H:21]([CH3:55])[CH2:22][C@H:23]([OH:54])[C@@H:24]([NH:46]C(OC(C)(C)C)=O)[CH2:25][C:26]([CH3:45])([CH3:44])[CH2:27][C:28](N1C2C(=CC=CC=2)CC(NC(C)=O)C1)=[O:29])[CH2:16][CH2:17][CH3:18]>>[CH2:15]([NH:19][C:20](=[O:56])[C@H:21]([CH3:55])[CH2:22][C@H:23]([OH:54])[C@@H:24]([NH2:46])[CH2:25][C:26]([CH3:44])([CH3:45])[CH2:27][C:28]([N:10]1[C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[O:7][CH2:6][CH:5]1[C:3]([O:2][CH3:1])=[O:4])=[O:29])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](CC(C)(C)CC(=O)N1CC(NC(C)=O)Cc2ccccc21)NC(=O)OC(C)(C)C
Reactant: COC(=O)C1COc2ccccc2N1
Product: CCCCNC(=O)[C@H](C)C[C@H](O)[C@@H](N)CC(C)(C)CC(=O)N1c2ccccc2OCC1C(=O)OC

Procedure:
Starting from 78 mg of 5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(R),7,7-trimethyl-8-3(R,S)-methoxycarbonyl-3,4-dihydro-2H-1,4-benzoxazin-4-ylcarbonyl]-octanoic acid (N-butyl)amide (Example 80)) in a manner analogous to that described in Example 1): Rf (S)=0.37; FAB-MS: (M+H)+ =492.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:8][CH:7]2[CH:5]([O:6]2)[C:4](=[O:9])[CH2:3]1.[OH-].[K+].[CH3:13]O>O>[CH3:13][O:6][C:5]1[C:4](=[O:9])[CH2:3][C:2]([CH3:10])([CH3:1])[CH2:8][CH:7]=1
Reactant: CO
Reactant: CC1(C)CC(=O)C2OC2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COC1=CCC(C)(C)CC1=O
Reaction time: 20 h
Yield: 68 %

Procedure:
A solution of 4,4-dimethyl-7-oxa-bicyclo[4.1.0]heptan-2-one (44.0 g, 0.31 mol) in methanol (150 mL) was added to a solution of 85% potassium hydroxide (20.7 g, 0.31 mol) in methanol (450 mL) at room temperature. The mixture was kept at this temperature for 20 hours and was then heated to reflux for 30 minutes. After cooling, the solution was diluted with water (1.2 L) and extracted with ethyl ether (350 mL×5). The organic extracts were collected, washed with brine, dried on Na2SO4 and evaporated under vacuum to remove most of the solvent. The crude material was purified by distillation to obtain pure the title compound (32.8 g, 68% yield) as an oil.