Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][O:6][N:7]=[C:8]([C:16](=[O:18])[CH3:17])[C:9]([O:11]C(C)(C)C)=[O:10])=[O:4].Br.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C.C([O-])(=O)C.C(Cl)Cl.CCCCCC>[CH3:1][O:2][C:3]([CH2:5][O:6][N:7]=[C:8]([C:16](=[O:18])[CH3:17])[C:9]([OH:11])=[O:10])=[O:4]
Reactant: COC(=O)CON=C(C(C)=O)C(=O)OC(C)(C)C
Agent: Br
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)CON=C(C(C)=O)C(=O)O
Yield: 51 %

Procedure:
To a solution of tert-butyl 2-methoxycarbonylmethoxyimino-3-oxobutyrate (syn isomer) (10 g) in glacial acetic acid (5 ml) was added 30% hydrobromic acid in acetate acid (10 ml) at ambient temperature with stirring. The reaction mixture was stirred at 40° C. for 3 hours. The resultant solution was concentrated under reduced pressure and the residual oil was dissolved into ethyl acetate (100 ml). The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride four times and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give a crude oil (8.6 g). The oil was dissolved in methylene chloride (100 ml). To the solution was added potassium carbonate (1.87 g) and the suspension was stirred at ambient temperature for 30 minutes. The solution was diluted with n-hexane (100 ml). The solvent was decanted and the residual glassy mass was dissolved in ethyl acetate and 10% hydrochloric acid. The separated organic layer was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was concentrated under reduced pressure to give 2-methoxycarbonylmethoxyimino-3-oxobutyric acid (syn isomer) (4.0 g) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[C:6]([C:8]([OH:10])=O)[N:5]([CH3:11])[N:4]=1.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:25]=[C:26]([CH:43]=[CH:44][C:45]=1[Cl:46])[O:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([CH:34]=[C:35]([NH:37][C:38]([CH:40]3[CH2:42][CH2:41]3)=[O:39])[N:36]=2)[N:33]=1>CN(C)C(=O)C.O1CCCC1>[Cl:46][C:45]1[CH:44]=[CH:43][C:26]([O:27][C:28]2[CH:29]=[CH:30][C:31]3[N:32]([CH:34]=[C:35]([NH:37][C:38]([CH:40]4[CH2:42][CH2:41]4)=[O:39])[N:36]=3)[N:33]=2)=[CH:25][C:24]=1[NH:23][C:8]([C:6]1[N:5]([CH3:11])[N:4]=[C:3]([O:2][CH3:1])[CH:7]=1)=[O:10]
Reactant: COc1cc(C(=O)O)n(C)n1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Product: COc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2Cl)n(C)n1
Yield: 61.8 %

Procedure:
Using 3-methoxy-1-methyl-1H-pyrazole-5-carboxylic acid (191 mg, 1.22 mmol), tetrahydrofuran (4.5 mL), N,N-dimethylformamide (30 μL, 0.39 mmol), oxalyl chloride (107 μL, 1.22 mmol), N-[6-(3-amino-4-chlorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (300 mg, 0.87 mmol) and N,N-dimethylacetamide (6.0 mL), and in the same manner as in Example 238, the title compound (259 mg, 62%) was obtained as a white powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([NH:26][C@@H:27]1[C:33](=[O:34])[N:32]([CH2:35][C:36]([O:38]C(C)(C)C)=[O:37])[C:31]2[CH:43]=[CH:44][CH:45]=[CH:46][C:30]=2[O:29][CH2:28]1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25])=[O:5])[CH3:2].C(OCC)(=O)C.[ClH:53]>>[ClH:53].[CH2:1]([O:3][C:4]([C@@H:6]([NH:26][C@@H:27]1[C:33](=[O:34])[N:32]([CH2:35][C:36]([OH:38])=[O:37])[C:31]2[CH:43]=[CH:44][CH:45]=[CH:46][C:30]=2[O:29][CH2:28]1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H](CCCCCCCCN1C(=O)c2ccccc2C1=O)N[C@H]1COc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](CCCCCCCCN1C(=O)c2ccccc2C1=O)N[C@H]1COc2ccccc2N(CC(=O)O)C1=O
Reaction time: 3 h

Procedure:
A mixture of tert-butyl 3(S)-[1(S)-ethoxycarbonyl-9-phthalimidononyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.08 g) and 5N hydrogen chloride-ethyl acetate solution (5 ml) is allowed to stand at room temperature for 3 hours. The mixture is diluted with petroleum ether (80 ml) to precipitate colorless powder, which is collected and dried under reduced pressure to yield 3(S)-[1(S)-ethoxycarbonyl-9-phthalimidononyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid hydrochloride (0.066 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([C:12](=[O:37])[N:13]([CH3:36])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[O:28])[CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6].Cl.C(N=C=NCCCN(C)C)C.C1C=C2N=NN(O)C2=CC=1.N.[NH2:61][C:62]1[C:70]2[N:69]=[C:68]([CH2:71][N:72]3[CH2:77][CH2:76][N:75]([CH3:78])[CH2:74][CH2:73]3)[NH:67][C:66]=2[CH:65]=[CH:64][CH:63]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([CH:9]=[CH:8][C:4]=1[C:5](=[O:6])[NH:61][C:62]1[C:70]2[N:69]=[C:68]([CH2:71][N:72]3[CH2:73][CH2:74][N:75]([CH3:78])[CH2:76][CH2:77]3)[NH:67][C:66]=2[CH:65]=[CH:64][CH:63]=1)[C:12]([N:13]([CH3:36])[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]1[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]1)=[O:28])=[O:37]
Reactant: CN1CCN(Cc2nc3c(N)cccc3[nH]2)CC1
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1C(=O)Nc1cccc2[nH]c(CN3CCN(C)CC3)nc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 36 %

Procedure:
To a solution of 2methoxy-4-[N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]-carbamoyl]benzoic acid (200 mg) in N,N-dimethylformamide (3 ml) at 0° C. were added 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (97 mg), N-hydroxybenzotrizole (79 mg) and 4-amino-2-[(4-methylpiperazin-1-yl)methyl]-1H-benzimidazole (105 mg) and the mixture was stirred at ambient temperature for 15 hours. The reaction mixture was poured into saturated sodium bicarbonate aqueous solution and extracted with chloroform. The organic layer was washed with saturated sodium bicarbonate aqueous solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) to give 3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl) carbonylpent-1-yloxy]-phenyl]-4-[2-[(4-methylpiperazin-1-yl)methyl]-1H-benzimidazol-4-yl]carbamoylbenzamide (104 mg).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[C:7]1(B(O)O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.I[C:17]1[CH:39]=[CH:38][C:20]([CH2:21][N:22]([S:34]([CH3:37])(=[O:36])=[O:35])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:19][CH:18]=1>C1(C)C=CC=CC=1.CCO.CCOC(C)=O>[C:17]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:39]=[CH:38][C:20]([CH2:21][N:22]([S:34]([CH3:37])(=[O:36])=[O:35])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:19][CH:18]=1
Reactant: CCOC(=O)CCCCCCN(Cc1ccc(I)cc1)S(C)(=O)=O
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCCCCN(Cc1ccc(-c2ccccc2)cc1)S(C)(=O)=O
Yield: 80.2 %

Procedure:
Tetrakis(trphenylphosphine)palladium(0) (102 mg, 0.09 mmol), aqueous Na2CO3 (0.9 mL, 1 M), and phenyl boronic acid (216 mg, 1.77 mmol) were added to a solution of ethyl 7-{[4-iodobenzyl]-methanesulfonyl-amino}-heptanoate (415 mg, 0.89 mmol) in toluene (37 mL) and EtOH (7 mL). The reaction mixture was heated at reflux for 3 h. The solution was diluted with EtOAc and was washed with water (2×) followed by brine (1×). The organic solution was dried over MgSO4, filtered, and concentrated in vacuo. Purification by radial chromatography (10% EtOAc-hexanes to 30% EtOAC/hexanes) provided the title compound of Step A (298 mg). 1H NMR (400 MHz, CDCl3) δ 7.62-7.30 (m, 4H), 4.41 (s, 2H), 4.12 (q, 2H), 3.20 (t, 2H), 2.82 (s, 3H), 2.23 (t, 3H), 1.58 (m, 4H), 1.35 (m, 7H); MS 418.3 (M+).
Reaction SMILES: C1(P([N:15]=[N+:16]=[N-:17])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCC=C1CCCCN2.[Cl:29][C:30]1[CH:31]=[C:32]([C:37]2([C:51]([F:54])([F:53])[F:52])[O:41][N:40]=[C:39]([C:42]3[S:46][C:45]([CH:47](O)[CH3:48])=[C:44]([CH3:50])[CH:43]=3)[CH2:38]2)[CH:33]=[C:34]([Cl:36])[CH:35]=1>C1(C)C=CC=CC=1>[N:15]([CH:47]([C:45]1[S:46][C:42]([C:39]2[CH2:38][C:37]([C:32]3[CH:31]=[C:30]([Cl:29])[CH:35]=[C:34]([Cl:36])[CH:33]=3)([C:51]([F:54])([F:53])[F:52])[O:41][N:40]=2)=[CH:43][C:44]=1[CH3:50])[CH3:48])=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)sc1C(C)O
Agent: C1=C2CCCCNN2CCC1
Solvent: Cc1ccccc1
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)sc1C(C)N=[N+]=[N-]
Reaction time: 19 h

Procedure:
Diphenylphosphoryl azide (0.53 ml) and diazabicyclo-[5.4.0]-undec-7-ene (DBU, 0.40 ml) is added to a solution of 1-{5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophen-2-yl}-ethanol (0.87 g) in toluene (9 ml). After 19 hours at room temperature, the reaction is quenched with a saturated aqueous solution of NH4Cl in water. The reaction mixture is extracted three times with ethyl acetate. The organic phases are combined, dried over MgSO4 and concentrated in vacuo. The crude product is purified on a semi-preparative HPLC to yield 3-[5-(1-azido-ethyl)-4-methyl-thiophen-2-yl]-5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole (0.64 g) as a yellow oil. MS (HPLC/MS): 449 (MH+). Retention time: 2.45 min.
Reaction SMILES: [O:1]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]2[S:18][C:17]3[N:19]=[CH:20][CH:21]=[N:22][C:16]=3[NH:15][C:14]=2[CH:23]=1)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[C:24](Cl)(=[O:27])[O:25][CH3:26]>>[CH3:26][O:25][C:24]([N:15]1[C:14]2[CH:23]=[C:10]([CH2:9][O:1][Si:2]([C:5]([CH3:6])([CH3:7])[CH3:8])([CH3:4])[CH3:3])[CH:11]=[CH:12][C:13]=2[S:18][C:17]2[N:19]=[CH:20][CH:21]=[N:22][C:16]1=2)=[O:27]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc2c(c1)Nc1nccnc1S2
Reactant: COC(=O)Cl
Product: COC(=O)N1c2cc(CO[Si](C)(C)C(C)(C)C)ccc2Sc2nccnc21

Procedure:
4.0 g of 8-(tert-butyldimethylsiloxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazine was subjected to the procedure described in Example 1570 but using methyl chlorocarbonate instead of acetyl chloride to thereby give 2.5 g of the title compound as a yellow oily substance.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[F:9][C:10]([F:23])([F:22])[O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:14][CH:13]=1.I[CH2:25][CH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>O1CCCC1.CN1CCCN(C)C1=O.CN1CCCN(C)C1=O>[CH:26]1([CH2:25][CH:18]([C:15]2[CH:14]=[CH:13][C:12]([O:11][C:10]([F:22])([F:23])[F:9])=[CH:17][CH:16]=2)[C:19]([OH:21])=[O:20])[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=C(O)Cc1ccc(OC(F)(F)F)cc1
Reactant: ICC1CCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: O=C(O)C(CC1CCCC1)c1ccc(OC(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 30.3 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (23 mL of a 0.31M stock solution, 7.13 mmol) cooled to −78° C. was treated with (4-trifluoromethoxy-phenyl)-acetic acid (0.74 g, 3.39 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (8.5 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. At this time, the reaction was treated with a solution of iodomethylcyclopentane (0.78 g, 3.73 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1 mL). The reaction mixture was stirred at −78° C. for 4 h. The reaction was then warmed to 25° C. and was stirred at 25° C. for 18 h. The reaction mixture was then quenched by the dropwise addition of saturated aqueous ammonium chloride solution (10 mL). The resulting mixture was concentrated in vacuo to remove the excess solvent. The residue was diluted with water (100 mL) and acidified to pH=1 with a 1N aqueous hydrochloric acid solution. This solution was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with a saturated aqueous lithium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-trifluoromethoxy-phenyl)-propionic acid (0.31 g, 30.6%) as a tan solid: mp 62-64° C.; EI-HRMS m/e calcd for C15H17F3O3(M+) 302.1129 found 302.1131.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])([CH3:4])([CH3:3])[CH3:2].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[Cl:28][C:29]1[CH:30]=[C:31]([CH3:37])[C:32]([CH:35]=O)=[N:33][CH:34]=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:35][C:32]1[C:31]([CH3:37])=[CH:30][C:29]([Cl:28])=[CH:34][N:33]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: Cc1cc(Cl)cnc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(Cl)cnc1CNCCCCNC(=O)OC(C)(C)C

Procedure:
Using General Procedure B: Reaction of (4-amino-butyl)-carbamic acid tert-butyl ester in CH2Cl2 and 5-chloro-3-methyl-pyridine-2-carbaldehyde with NaBH(OAc)3 gave {4-[(5-chloro-3-methyl-pyridin-2-ylmethyl)-amino]-butyl}-carbamic acid tert-butyl ester as a colorless oil. 1H NMR (CDCl3) δ 1.41 (s, 9H), 1.54 (m, 4H), 2.13 (s, 1H), 2.28 (s, 3H), 2.68 (t, 2H, J=6.0 Hz), 3.11 (d, 2H, J=6.0 Hz), 3.81 (s, 2H), 4.77 (br s, 1H), 7.41 (s, 1H), 8.31 (s, 1H).
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:31])[C:6]1[CH:11]=[C:10]([NH:12][C:13](=[O:28])[C@:14]([OH:27])([CH3:26])[CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([F:25])[CH:18]=2)[CH:9]=[CH:8][C:7]=1[C:29]#[N:30]>C1COCC1.CO>[C:29]([C:7]1[CH:8]=[CH:9][C:10]([NH:12][C:13](=[O:28])[C@:14]([OH:27])([CH3:26])[CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([F:25])[CH:18]=2)=[CH:11][C:6]=1[C:5]([OH:31])=[O:4])#[N:30]
Reactant: COC(=O)c1cc(NC(=O)[C@@](C)(O)COc2ccc(C#N)c(F)c2)ccc1C#N
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@](O)(COc1ccc(C#N)c(F)c1)C(=O)Nc1ccc(C#N)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
1 M LiOH (34 ml) was added to a solution of 2-cyano-5-[(S)-3-(4-cyano-3-fluorophenoxy)-2-hydroxy-2-methylpropionylamino]benzoic acid methyl ester (4.52 g, 11.4 mmol) in THF (50 ml) and methanol (6 ml) at 16-18° C. The resulting solution was stirred at room temperature for 2.5 h. The solvents were evaporated and pH was adjusted to 2 with HCl solution. The product was extracted into ethyl acetate. The organic phase was washed with water, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (eluent: CH2Cl2/MeOH 98:2). Trituration in hot CH2Cl2, cooling to room temperature and filtration yielded the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=2)[N:10]=[C:9]1[CH:20]=O.[F:22][C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1[NH2:25].C(O)(=O)C.C([BH3-])#N.[Na+]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=2)[N:10]=[C:9]1[CH2:20][NH:25][C:24]1[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=1[F:22]
Reactant: Nc1ccccc1F
Reactant: O=Cc1nc2ccc(F)cc2c(=O)n1-c1ccccc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: O=c1c2cc(F)ccc2nc(CNc2ccccc2F)n1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76.2 %

Procedure:
A mixture of 3-(2-chloro-phenyl)-6-fluoro-3,4-dihydro-quinazolin-4-one-2-carboxaldehyde (0.10 g, 0.33 mmol), 2-fluoroaniline (0.064 mL, 0.66 mmol) and acetic acid (0.038 mL, 0.66 mmol) in methanol (10 mL) was stirred 1.5 hours at ambient temperature. Sodium cyanoborohydride (0.083 g, 1.32 mmol) was added and the reaction was stirred overnight. The reaction was diluted with water and concentrated to remove most of the methanol. The milky white liquid residue was treated with saturated aqueous bicarbonate and extracted with ethyl acetate. The organic layer was washed with aqueous bicarbonate and brine, dried over magnesium sulfate and concentrated. The residue was flash chromatographed on silica gel (20 g) eluting the product with 5% and then 10% ethyl acetate/hexane. In this fashion 0.10 g (76%) of 3-(2-chloro-phenyl)-6-fluoro-2-[(2-fluoro-phenylamino)-methyl]-3H-quinazolin-4-one was isolated as a yellow foam which had: 1H NMR δ 7.95 (dd, J=3, 8.5 Hz, 1H), 7.85 (dd, J=5, 9 Hz, 1H), 7.69 (dd, J=2, 7.5 Hz, 1H), 7.63-7.46 (m, 3H), 7.43-7.37 (m, 1H), 7.05-6.90 (m, 2H), 6.70-6.62 (m, 1H), 6.43 (dt, J=1, 9 Hz, 1H), 5.30 (br s, 1H), 3.91 (ABq, Δv1-3=27.5 Hz, J=17 Hz, 2H). Analysis calculated for C21H14ClF2N3O•0.25 H2O: C, 62.70; H, 3.63; N, 10.44. Found: C, 62.78; H, 3.51; N, 10.29.
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]1=[O:22])=O)(C)(C)C.[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26]>>[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26].[NH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:10]1=[O:22]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(OCc2ccccc2)C1=O
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H]1CCN(OCc2ccccc2)C1=O
Yield: 100 %

Procedure:
(3R)-3-t-Butoxycarbonylamino-1-benzyloxypyrrolidin-2-one (Example 1(c), 19.02 g, 62.2 mmol) was dissolved in trifluoracetic acid (150 ml). After 15 mins the solution was evaporated and the residue was crystallised from diethyl ether to give the title compound (20.31 g, 100%). mp=185° C. [α]D =+41.4° (c=1% MeOH), 1H NMR δ (D2O) 7.52-7.48 (5H, m, phenyl), 5.04 (2H, s, OCH2), 4.13 (1H, t, J=9.26 Hz, αCH--CH2), 3.63-3.59 (2H, m, CH2 --N), 2.61-2.57 (1H, m, --CH--CHA --HB), 2.13-2.02 (1H, m, --CH--CHAHB). m/e (FAB+) 207 (M+1); (FAB-) 205 (M-1).
Reaction SMILES: [S:1]1[C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=[CH:2]1.[C:16](Cl)(=O)[CH2:17][CH2:18][CH3:19].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[CH2:16]([C:2]1[S:1][C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCC(=O)Cl
Reactant: O=C1Nc2ccccc2Oc2sccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCCCc1cc2c(s1)Oc1ccccc1NC2=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 63.6 %

Procedure:
Thieno[2,3-b][1,5]benzoxazepin-4(5H)-one (1.5 g) was suspended in 1,2-dichloroethane (20 ml) and butyryl chloride (880 mg) was added. To this reaction system was added portionwise aluminium chloride (4.6 g) under ice-cooling. The mixture was stirred at room temperature for 45 minutes. Insoluble matter was filtrated and the filtrate was poured into ice water, and chloroform was added. The organic layer was washed with water and dried over sodium sulfate. The solvent was evaporated under reduced pressure and water-ethanol was added. The precipitated crystals were collected by filtration. The obtained crystals were washed with chloroform-diisopropyl ether to give 2-butylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one (1.2 g).
Reaction SMILES: [CH2:1]([C:3]1([C:12]2[CH2:17][CH2:16][CH2:15][C:14](=[O:18])[CH:13]=2)[CH2:9][CH2:8][CH2:7][CH2:6][N:5]([CH3:10])[C:4]1=[O:11])[CH3:2].BrBr.O>C(Cl)Cl>[CH2:1]([C:3]1([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)[CH2:9][CH2:8][CH2:7][CH2:6][N:5]([CH3:10])[C:4]1=[O:11])[CH3:2]
Reactant: CCC1(C2=CC(=O)CCC2)CCCCN(C)C1=O
Agent: BrBr
Solvent: ClCCl
Solvent: O
Product: CCC1(c2cccc(O)c2)CCCCN(C)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
A solution of crude 3-ethyl-hexahydro-1-methyl-3-(3-oxocyclohexen-1-yl)-2H-azepin-2-one (280.5 g) in methylene chloride (1.41) was stirred and treated with bromine (180 g) over 1.5 hours at 20°-25° C. with occasional water cooling. The reaction mixture was stirred at room temperature for two hours but TLC examination showed some starting material still present. Additional bromine (18 g) was added over ten minutes and the solution was stirred for a further one hour. TLC analysis detected no starting material so water (500 ml.) was added with cooling and the methylene chloride layer was washed with water (500 ml). The two water washes were combined, back-extracted woth methylene chloride (200 ml.) and the extract washed with water (100 ml.). The methylene chloride extracts were combined, evaporated to dryness, the fawn-coloured solid was triturated with ethyl acetate (250 ml), filtered, washed with ethyl acetate (50 ml) and dried in an air oven at 60° C. to give 244.7 g of title compound, m.p. 172°-175° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:38])=[C:6]([N:8]2[C:15](=[O:16])[C:14]3[N:13]=[C:12]([C:17]4[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=4)[N:11]([CH:27]([CH3:29])[CH3:28])[C:10]=3[C@H:9]2[C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=2[CH3:37])[CH:7]=1.[CH3:39][Si]([N-][Si](C)(C)C)(C)C.[K+].CI>C1COCC1.CCOC(C)=O>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([C:9]2([CH3:39])[C:10]3[N:11]([CH:27]([CH3:28])[CH3:29])[C:12]([C:17]4[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=4)=[N:13][C:14]=3[C:15](=[O:16])[N:8]2[C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[CH3:38])=[C:31]([CH3:37])[CH:32]=1
Reactant: COc1ncc(-c2nc3c(n2C(C)C)[C@@H](c2ccc(Cl)cc2C)N(c2cc(Cl)ccc2C)C3=O)c(OC)n1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ncc(-c2nc3c(n2C(C)C)C(C)(c2ccc(Cl)cc2C)N(c2cc(Cl)ccc2C)C3=O)c(OC)n1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of the product from example 76 (100 mg, 0.18 mmol) in THF (2 mL) at −78° C. was added KHMDS (217 μL, 0.22 mmol, 1M in THF) and the mixture was stirred at −78° C. for 15 min. Methyl iodide (34 μL, 0.54 mmol) was added and the mixture was allowed to warm to rt and the mixture was stirred at rt for 20 h. The reaction mixture was diluted with EtOAc and extracted with a 5% citric acid solution. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by preparative HPLC, then the residue was lyophilized in dioxane. tR: 1.25 min (LC-MS 2); ESI-MS: 566.3/568.2 [M+H]+ (LC-MS 2).
Reaction SMILES: [C:1]1([CH:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH2:8][C:9](OCC)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[C:1]1([CH:7]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=2)[CH2:8][CH2:9][OH:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CC(Cc1ccc(C(F)(F)F)cc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCC(Cc1ccc(C(F)(F)F)cc1)c1ccccc1
Temperature: 22 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
A solution of 4.4 g (13.1 mmole) of ethyl 3-phenyl-4-(4-trifluoromethylphenyl)butanoate dissolved in 50 ml of tetrahydrofuran was added dropwise over a ten minute period to a 250 ml flask containing a 0° C. mixture of lithium aluminum hydride (745 mg, 19.6 mmole) in 50 ml of tetrahydrofuran. The resulting mixture was warmed to room temperature (22° C.), stirred at that temperature for about 2 hours, cooled to 0° C. again, and quenched by adding approximately 25 ml of water dropwise over a five minute period. The reaction mixture was acidified to a pH of about 1.0 using 6N hydrochloric acid and extracted with ethyl acetate. The organic extracts were combined, washed with water and a saturated brine solution, and finally dried over anhydrous sodium sulfate. The volatiles were removed under reduced pressure to provide 3.66 g of 3-phenyl-4-(4-trifluoromethylphenyl)butanol as a colorless oil. The compound was identified by N.M.R. analysis employing a 300 mHz instrument in CDCl3 ; δ=1.92 (multiplet, 2H); 2.97 (multiplet, 3H); 3.43 and 3.52 (multiplet, 2H); 7.08-7.53 (multiplet, 9H).