Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([OH:13])=O)=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.Cl.[CH2:53]([O:55][C:56](=[O:59])[CH2:57][NH2:58])[CH3:54]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([NH:58][CH2:57][C:56]([O:55][CH2:53][CH3:54])=[O:59])=[O:13])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CN
Reactant: CC(C)(CC(=O)O)Nc1ccc(Cl)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)CC(C)(C)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
To a solution of 3-(4-chlorophenylamino)-3-methylbutanoic acid (1 g, 4.7 mmol) in CH2Cl2 (20 mL), was added BOP (2.07 g, 4.7 mmol), DIPEA (1.63 mL, 9.4 mmol) and glycine ethyl ester hydrochloride (0.79 g, 4.7 mmol). The mixture was stirred at rt overnight. The reaction was quenched with aq. NaHCO3, extracted with CH2Cl2, and the combined organic extracts were dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography using 0-30% EtOAc in hexanes as eluent to give ethyl 2-(3-(4-chlorophenylamino)-3-methylbutanamido)acetate (1.34 g, 96% yield) as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH2:16][CH2:17][CH3:18])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C=O)C>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][O:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:10][C:11]=1[CH2:16][CH2:17][CH3:18])[CH3:27]
Reactant: CCCc1cc(OCc2ccccc2)ccc1O
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1cc(OCc2ccccc2)ccc1OCC(=O)OCC
Reaction time: 18 h
Yield: 97.3 %

Procedure:
A solution of 4-benzyloxy-2-propylphenol (0.50 g, 1.94 mmol) in dry DMF (7 mL) was cooled in an ice bath and treated with NaH (0.15 g, 3.8 mmol, 60% oil dispersion). The ice bath was removed, ethyl bromoacetate (0.43 mL, 3.9 mmol) was added, and the mixture was placed in an oil bath (T=85° C.). After 18 h, the reaction mixture was cooled and concentrated in vacuo. The residue was diluted with EtOAc, washed with brine (2×), dried (Na2SO4), and concentrated. The crude product was purified by radial chromatography using 10% ethyl acetate in hexanes to give a tan solid (0.62 g, 97%). 1H NMR (400 MHz, CDCl3) δ 7.44-7.31 (m, 5H), 6.82 (d, J=2.9 Hz, 1H), 6.72 (dd, J=8.8, 2.9 Hz, 1H), 6.66 (d, J=8.8 Hz, 1H), 5.00 (s, 2H), 4.57 (s, 2H), 4.25 (q, J=7.0 Hz, 2H), 2.63 (t, J=7.6 Hz, 2H), 1.64 (q, J=7.5 Hz, 2H), 1.29 (t, J=7.1 Hz, 3H), 0.95 (t, J=7.3 Hz, 3H); MS (FIA) m/e 329 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:24])([C@H:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[C:25](=O)([O-])[O-:26].[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:24])([C@H:16]([N:18]1[CH2:19][CH2:20][N:21]([CH:25]=[O:26])[CH2:22][CH2:23]1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: C[C@@H](N1CCNCC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](N1CCN(C=O)CC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 120 °C
Yield: 36.5 %

Procedure:
A mixture of compound 2 (200 mg, 0.6 mmol) and potassium carbonate (248 mg, 1.8 mmol) in DMF (5 ml) was heated at 120° C. for 24 h. The contents were poured into cold water and extracted with ethyl acetate (3×20 ml). The combined organic extract was washed with water, brine and dried over sodium suphate. The solvent was removed under reduced pressure and the resulting product was purified on a column of silica gel (EtOAc/MeOH; 98:2) to give the title compound as colorless solid (80 mg, 36%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]([CH:9]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10]2)[C:4](=[O:15])[N:3]=1.[N+:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1)([O-:18])=[O:17]>>[NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]([CH:9]2[CH2:13][CH2:12][CH:11]([O:14][C:23](=[O:24])[C:22]3[CH:21]=[CH:20][C:19]([N+:16]([O-:18])=[O:17])=[CH:27][CH:26]=3)[CH2:10]2)[C:4](=[O:15])[N:3]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1nc(=O)n(C2CCC(O)C2)cc1F
Product: Nc1nc(=O)n(C2CCC(OC(=O)c3ccc([N+](=O)[O-])cc3)C2)cc1F

Procedure:
4-Amino-5-fluoro-1-(3-hydroxy-cyclopentyl)-1H-pyrimidin-2-one was inverted via the Mitsunobu reaction (General Method A) with 4-nitrobenzoic acid to provide 4-nitro-benzoic acid 3-(4-amino-5-fluoro-2-oxo-2H-pyrimidin-1-yl)-cyclopentyl ester 28.
Reaction SMILES: Cl.[O:2]=[C:3]([C:23]1([CH2:36][CH2:37][CH3:38])[C:35]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][CH:10]([N:13]2[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]2=[O:22])[CH2:9][CH2:8]1.[BH4-].[Na+]>CO.ClCCl>[OH:2][CH:3]([C:23]1([CH2:36][CH2:37][CH3:38])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=2[C:30]2[C:35]1=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:4][CH2:5][CH2:6][N:7]1[CH2:8][CH2:9][CH:10]([N:13]2[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]2=[O:22])[CH2:11][CH2:12]1
Reactant: CCCC1(C(=O)CCCN2CCC(N3Cc4ccccc4C3=O)CC2)c2ccccc2-c2ccccc21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCCC1(C(O)CCCN2CCC(N3Cc4ccccc4C3=O)CC2)c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A solution of Example 311 Part D free amine (300 mg, 0.61 mmol) in 12 ml of methanol was cooled to 0° C. under an argon atmosphere and 2 equiv. of sodium borohydride (48.5 mg, 1.28 mmol) was added. The reaction mixture was stirred at 0° C. for 45 min. The reaction was quenched with 1 N hydrochloric acid and extracted with ethyl acetate (3×20 ml). The extract was washed with brine and dried over sodium sulfate. Evaporation yielded an oily residue which was dissolved in dichloromethane, dried over sodium sulfate and evaporated to yield 550 mg of a colorless solid. The crude product was purified on a Merck EM silica column eluting with 5% methanol/dichloromethane yielding 290 mg (96%) of title compound as colorless solid.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]([NH2:8])=[O:7])=[N:2]1.[C:9]1([S:15](Cl)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CCOCC>C(N(CC)CC)C>[C:9]1([S:15]([C:5]2[NH:1][N:2]=[C:3]([C:6]([NH2:8])=[O:7])[N:4]=2)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NC(=O)c1nc[nH]n1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: NC(=O)c1n[nH]c(S(=O)(=O)c2ccccc2)n1
Temperature: 25 °C

Procedure:
To a cooled, stirred mixture of 3 g. of 1,2,4-triazole-3-carboxamide and 4.8 g. of benzenesulfonyl chloride in 125 ml. of anhydrous ether is added rapidly 2.75 g. of triethylamine. The cooling bath is removed and the mixture is stirred at room temperature for 17.5 hours. The heterogeneous mixture is filtered and the colorless solid washed successively with ether, cold water and ether again, then air dried for approximately 10 minutes and dried in vacuo for 6 hours. The dried product is extracted with about 50 ml. of hot, dry acetonitrile then concentrated to about 25 ml. by water pump evacuation. The mixture is heated to redissolve the colorless crystalline solids which is again separated on cooling to room temperature. The solid is collected and washed with acetonitrile then dried in vacuo overnight, m.p. 150° -153° C.
Reaction SMILES: B(Br)(Br)Br.C(Cl)Cl.[CH2:8]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([O:23]C)=[CH:20][CH:21]=2)[C:16]([CH2:25][C:26]([NH2:28])=[O:27])=[C:15]1[CH3:29])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>C(Cl)Cl.C(OCC)(=O)C>[CH2:8]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([OH:23])=[CH:20][CH:21]=2)[C:16]([CH2:25][C:26]([NH2:28])=[O:27])=[C:15]1[CH3:29])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCn1c(C)c(CC(N)=O)c2cc(OC)ccc21
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCCCn1c(C)c(CC(N)=O)c2cc(O)ccc21
Reaction time: 16 h
Yield: 101 %

Procedure:
A mixture of 1 mL of 1M BBr3/methylene chloride and 0.24 g (0.79 mmol) of 1-hexyl-5-methoxy-2-methyl-1H-indole-3-acetamide in 20 mL of methylene chloride as stirred for 16 hours, diluted with ethyl acetate and washed twice with water. The solution was dried (Na2SO4) and the solvent removed at reduced pressure to give 0.23 g of crude 1-hexyl-5-hydroxy-2-methyl-1H-indole-3-acetamide.
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH2:12]Cl)[CH2:10]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14]([NH2:16])[CH3:15]>O>[CH2:1]([O:8][CH:9]1[CH2:12][N:16]([CH2:14][CH3:15])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCC(CCl)OCc1ccccc1
Reactant: CCN
Solvent: O
Product: CCN1CC(OCc2ccccc2)C1
Temperature: 90 °C
Yield: 61 %

Procedure:
21.9 parts of 2-benzyloxy-1,3-dichloro-propane, 45.1 parts of monoethylamine and 45.1 parts of water were added to an autoclave and the mixture was heated at 90° C. for 48 hours with agitation. The reaction mixture was cooled and treated in the same manner as in Example 29, followed by distillation under reduced pressure. As a result, 11.6 parts of 3-benzyloxy-1-ethylazetidine boiling at 73°-74° C. under 2 mm Hg were obtained. The yield was 61%. The results of infra-red spectrum analysis and nuclear magnetic resonance analysis of the product are as follows:
Reaction SMILES: [C:1](#[N:4])[CH2:2][CH3:3].[C:5]([C:8]1[CH:22]=[CH:21][CH:20]=[CH:19][C:9]=1[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15](Cl)=[CH:14][CH:13]=1)([OH:7])=[O:6].N>[NH2-].[Na+]>[C:5]([C:8]1[CH:22]=[CH:21][CH:20]=[CH:19][C:9]=1[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH:2]([CH3:3])[C:1]#[N:4])=[CH:14][CH:13]=1)([OH:7])=[O:6]
Reactant: CCC#N
Reactant: O=C(O)c1ccccc1CCc1ccc(Cl)cc1
Agent: N
Agent: [NH2-]
Agent: [Na+]
Product: CC(C#N)c1ccc(CCc2ccccc2C(=O)O)cc1
Yield: 43.9 %

Procedure:
Propionitrile (286.5 g.) is added over the course of 40 minutes and with vigorous stirring to a suspension of sodamide (248 g.) [prepared from sodium (139.5 g.) and liquid ammonia (4 liters)] and then 4-(2-carboxyphenethyl)chlorobenzene (117 g.) is added over the course of 10 minutes. The ammonia is allowed to evaporate during a period of 16 hours. The brown residue is taken up in anaesthetic grade diethyl ether (1 liter) and then in water (2 liters) with care. The alkaline aqueous solution is decanted, extracted with diethyl ether (2 × 400 cc.) and then acidified by adding sulphuric acid (d = 1.36; 350 cc.) whilst cooling. The oil which separates out is extracted with methylene chloride (2 × 500 cc.). The organic extracts are dried over anhydrous sodium sulphate (100 g.) and concentrated to dryness under reduced pressure (20 mm.Hg) at 60°C. The residual oil is dissolved in hot diisopropyl ether (120 cc.); on cooling, a product crystallises and is filtered off. 2-[4-(2-Carboxyphenethyl)phenyl]propionitrile (55 g.), melting at 73°C., is thus obtained; after three recrystallisations from ethyl acetate, the product melts at 129°C.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].Cl.[NH2:25][OH:26]>C(O)C>[CH2:1]([CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[N:25][OH:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2CCC1Cc1ccccc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: ON=C1c2ccccc2CCC1Cc1ccccc1
Temperature: 25 °C
Yield: 97.2 %

Procedure:
To a solution of 2-benzyl-1-tetralone (prepared according to Org. Prep. Proc. Inter., 2, 37 (1970)), (58.95 g, 0.250 mol) and 95% ethanol (500 mL) was added sodium acetate (45.1 g, 0.55 mol) and hydroxylamine hydrochloride (20.8 g, 0.30 mol). The reaction was heated to reflux overnight and then allowed to cool to room temperature and concentrated under vacuum. The residue was partitioned between water (300 mL) and ethryl acetate (500 mL), the organic layer was then sequentially washed with water (300 mL), and brine (500 mL). This was then dried over sodium sulfate and concentrated to give 61.1 g of an orange solid. Recrystalization from ethyl acetate/hexanes gave the title compound as a white solid, m.p. 123-124° C.
Reaction SMILES: [C:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:10](=[O:18])[CH2:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19](I)[CH:20]([CH3:22])[CH3:21]>>[CH2:19]([N:11]1[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][CH2:9][C:10]1=[O:18])[CH:20]([CH3:22])[CH3:21]
Reactant: O=C1CN=C(c2ccccc2)c2ccccc2N1
Reactant: CC(C)CI
Product: CC(C)CN1C(=O)CN=C(c2ccccc2)c2ccccc21

Procedure:
1,3-Dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (prepared according to the procedure of M. G. Bock et al., J. Org. Chem. 1987, 52, 3232-3239, incorporated herein by reference) was alkylated with isobutyl iodide using General Procedure 8-G to afford 1,3-dihydro-1-isobutyl-5-phenyl-2H-1,4-benzodiazepin-2-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20]>C1COCC1.[Ni]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)=[CH:4][C:3]=1[C:19]([F:20])([F:21])[F:22]
Reactant: O=[N+]([O-])c1ccc(/C=C/c2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1ccc(CCc2ccc(Cl)c(C(F)(F)F)c2)cc1
Yield: 96.7 %

Procedure:
The title compound was prepared from trans-1-chloro-2-trifluoromethyl-4-[2-(4-nitrophenyl)ethenyl]benzene (22.53 g, 0.069 mol) and Ra—Ni (22 g) in THF (0.5 L) at 18° C. to 29° C. (ΔP=20.5 psi) under a hydrogen atmosphere using the procedure described in Example 1, Step B. This procedure yielded a white solid, 20.0 g (66.73 mmol, 97%) of the desired product. mp 62-64° C.
Reaction SMILES: [CH2:1]([O:17][C@H:18]([CH2:21][O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:19][OH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].N1C=CC=CC=1.[O:45](S(C(F)(F)F)(=O)=O)[S:46]([C:49]([F:52])([F:51])[F:50])(=O)=[O:47]>C(Cl)Cl>[F:50][C:49]([F:52])([F:51])[S:46]([O:20][CH2:19][C@H:18]([O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:21][O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])(=[O:47])=[O:45]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCCCCCCCCCCCCCCCOC[C@H](CO)OCCCCCCCCCCCCCCCC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCOC[C@H](COS(=O)(=O)C(F)(F)F)OCCCCCCCCCCCCCCCC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-2,3-bis(hexadecyloxy)propan-1-ol (1 eq) and pyridine (4 eq) in DCM (0.1 M) at 0° C., was added Tf2O (2 eq). The reaction was stirred at 0° C. for 1 hour and quenched by H2O. The aqueous phase was extracted with DCM. The combined organic phases were washed with H2O, and the aqueous phase was back extracted with DCM. The combined organic phases were washed with saturated NaHCO3 and brine, dried over anhydrous Na2SO4 and concentrated en vaccuo. The resulting crude was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-10% EtOAc/Hex to give (R)-2,3-bis(hexadecyloxy)propyl trifluoromethanesulfonate as a colorless oil.
Reaction SMILES: [NH:1]([C:5]1[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][C:6]=1[CH2:7][N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])C(C)=O.[OH-].[Na+].C([OH:23])C>O>[NH2:1][C:5]1[CH:16]=[CH:15][C:14]([C:17](=[O:23])[NH2:18])=[CH:13][C:6]=1[CH2:7][N:8]([CH2:11][CH3:12])[CH2:9][CH3:10]
Reactant: CCO
Reactant: CCN(CC)Cc1cc(C#N)ccc1NC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCN(CC)Cc1cc(C(N)=O)ccc1N
Reaction time: 4 h

Procedure:
A mixture of 10 gm of 2-acetamino-5-cyano-N,N-diethyl-benzylamine, 100 ml of 5 N sodium hydroxide and 70 ml of ethanol was boiled for 4 hours. Thereafter, the reaction solution was cooled, diluted with 200 ml of water and extracted three times with 250 ml of chloroform each. The combined chloroform extracts were dried over sodium sulfate and evaporated in vacuo, and the residue was recrystallized from ethanol. The 2-amino-5-carbamoyl-N,N-diethyl-benzylamine of m.p. 129°-131°C was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[O:20][CH:19]([CH2:21][OH:22])[CH2:18][C:4]=2[C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])[C:6]=2[CH:17]=1.O.S(=O)(=O)(O)[OH:25]>CC(C)=O.[O-2].[Cr+6].[O-2].[O-2]>[Cl:1][C:2]1[C:3]2[O:20][CH:19]([C:21]([OH:25])=[O:22])[CH2:18][C:4]=2[C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])[C:6]=2[CH:17]=1
Reactant: OCC1Cc2c(c(Cl)cc3c(-c4ccccc4F)noc23)O1
Reactant: O=S(=O)(O)O
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)C1Cc2c(c(Cl)cc3c(-c4ccccc4F)noc23)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
A portion (6.4 g) of the 5-chloro-7,8-dihydro-3-(2-fluorophenyl)furo[2,3-g]-1,2-benzisoxazole-7-methanol prepared in Example 11 was dissolved in 150 ml of acetone. To the stirred solution, a mixture of chromium (VI) oxide (7.2 g), water (15 ml) and concentrated sulfuric acid (10.2 g) was added dropwise overtime, and the mixture was agitated for 8 hours at room temperature. The insolubles were filtered off by suction. After distilling off the acetone, water was added and the mixture was subjected to extraction with ether. The ether layer was washed with water and dried. After distilling off the solvent, the residue was recrystallized from acetone-water, yielding 6.0 g of 5-chloro-7,8-dihydro-3-(2-fluorophenyl)furo[2,3-g]-1,2-benzisoxazole-7-carboxylic acid. m.p. 199°-200° C. This compound exhibited a mass spectrum having a molecular ion peak at m/e 333.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][C:46](=[O:53])[N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[O:55]1[C:59]([C:60](Cl)=[O:61])=[CH:58][CH:57]=[N:56]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][C:46]([N:47]1[CH2:52][CH2:51][N:50]([C:60]([C:59]2[O:55][N:56]=[CH:57][CH:58]=2)=[O:61])[CH2:49][CH2:48]1)=[O:53]
Reactant: O=C(COc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2)N1CCNCC1
Reactant: O=C(Cl)c1ccno1
Solvent: O=C(O)C(F)(F)F
Product: O=C(COc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2)N1CCN(C(=O)c2ccno2)CC1
Yield: 60 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using 6-chloro-12-(2-oxo-2-piperazin-1-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and isoxazole-5-carbonyl chloride as the starting materials in 60% yield. LCMS for C27H26ClN8O4 (M+H)+: m/z=561.0.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5]=1[C:18]([OH:26])([CH3:25])[CH2:19][N:20]1[CH:24]=[N:23][CH:22]=[N:21]1.[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1.[Cl-].[Na+].O>[CH2:27]([O:26][C:18]([C:5]1[CH:6]=[CH:7][C:8]([O:10][C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)=[CH:9][C:4]=1[Cl:3])([CH3:25])[CH2:19][N:20]1[CH:24]=[N:23][CH:22]=[N:21]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(O)(Cn1cncn1)c1ccc(Oc2ccc(Cl)cc2)cc1Cl
Reactant: BrCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(Cn1cncn1)(OCc1ccccc1)c1ccc(Oc2ccc(Cl)cc2)cc1Cl
Reaction time: 18 h
Yield: 68.9 %

Procedure:
Sodium hydride (0.04 g) was added to a solution of 2-[2-chloro-4-(4-chlorophenoxy)phenyl]-1-(1,2,4-triazol-1-yl)propan-2-ol (0.5 g) in THF (15 mL). After 30 min benzylbromide (0.27 g) was added and the mixture was stirred for 18 h at reflux. Brine was added and the mixture was extracted with dichloro methane (3×). The combined organic phases were dried, filtered through a silica plug and evaporated. The crude product was purified by column chromatography to yield 0.43 g of the desired compound.
Reaction SMILES: [Na].[CH:2]1([C:5](=[O:7])[CH3:6])[CH2:4][CH2:3]1.[C:8](OCC)(=[O:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10].Cl>C(O)C.O>[CH:2]1([C:5](=[O:7])[CH2:6][C:8](=[O:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:4][CH2:3]1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)C1CC1
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(=O)CC(=O)C1CC1
Temperature: 25 °C

Procedure:
Sodium metal (2.411 g, 105 mmol) was dissolved in ethanol (50 mL). The solution was heated to reflux followed by addition of a mixture of 1-cyclopropylethanone (8.4 g, 100 mmol) and diethyl oxalate (14.59 g, 100 mmol) dropwise over 30 minutes. The reaction mixture was heated at reflux for an additional 2 h, and then allowed to cool to room temperature over a 2 d period. The contents were diluted with water (200 mL) and acidified by dropwise addition of 6N HCl. The contents were extracted with EtOAc (3×75 mL), washed with water, brine, dried over MgSO4, filtered, and concentrated in vacuo. The final product was collected as 14.3 g (74%). LCMS E-S (M+H)=184.8 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.03 (d, J=7.83 Hz, 2H) 1.13-1.19 (m, 2H) 1.31 (t, J=7.07 Hz, 3H) 1.81-1.90 (m, 1H) 4.29 (q, J=7.16 Hz, 2H) 6.43 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([C@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.Cl.[Br:17][C:18]1[CH:19]=[C:20]([O:27][CH3:28])[CH:21]=[C:22]2[C:26]=1[NH:25][CH2:24][CH2:23]2>>[Br:17][C:18]1[CH:19]=[C:20]([O:27][CH3:28])[CH:21]=[C:22]2[C:26]=1[N:25]([C:2]1[C:3](=[O:15])[N:4]([C@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1)[CH2:24][CH2:23]2
Reactant: COc1cc(Br)c2c(c1)CCN2
Reactant: CC[C@@H](COC)n1cc(Cl)nc(Cl)c1=O
Agent: Cl
Product: CC[C@@H](COC)n1cc(Cl)nc(N2CCc3cc(OC)cc(Br)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1S)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone and 7-bromo-5-methoxyindoline hydrochloride as the starting materials. mp 100-102° C.; 1H NMR (300 MHz, CDCl3): δ 7.00 (s, 1 H), 6.92 (d, J=2.5 Hz, 1 H), 6.78 (d, J=2.6 Hz, 1 H), 4.99-4.90 (m, 1 H), 4.35 (t, J=7.7 Hz, 2 H), 3.78 (s, 3 H), 3.67 (dd, J=10.6, 5.7 Hz, 1 H), 3.56 (dd, J=10.6, 3.5 Hz, 1 H), 3.35 (s, 3 H), 3.10 (t, J=7.7 Hz, 2 H), 1.92-1.72 (m, 2 H), 0.93 (t, J=7.3 Hz, 3 H); HRMS (ESI) calcd for C18H22N3O3BrCl (M+H)+: 442.0533; found m/z 442.0516.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](O)=[O:9])=[C:6]([O:11][CH3:12])[N:5]=[C:4]([S:13][CH3:14])[N:3]=1.S(Cl)([Cl:17])=O>>[Cl:1][C:2]1[C:7]([C:8]([Cl:17])=[O:9])=[C:6]([O:11][CH3:12])[N:5]=[C:4]([S:13][CH3:14])[N:3]=1
Reactant: O=S(Cl)Cl
Reactant: COc1nc(SC)nc(Cl)c1C(=O)O
Product: COc1nc(SC)nc(Cl)c1C(=O)Cl
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
A mixture of 4-chloro-5-carboxy-6-methoxy-2-methylthiopyrimidine (prepared in the above (3)) 2.00 g and thionyl chloride 5 ml is stirred at 40° C. for 15 minutes. Thionyl chloride, etc. is distilled off and the solvent is removed with azeotrope with methylene chloride to give 4-chloro-5-chloroformyl-6-methoxy-2-methylthiopyrimidine.