Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([CH3:9])[N:6]=[C:5]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][S:18]([NH:21][CH3:22])(=[O:20])=[O:19])=[CH:13][CH:12]=2)[CH:4]=1)#[N:2].CCO.CCOC(C)=O.[H][H]>[Pd].C(N(CC)CC)C>[NH2:2][CH2:1][C:3]1[N:8]=[C:7]([CH3:9])[N:6]=[C:5]([O:10][C:11]2[CH:12]=[CH:13][C:14]([CH2:17][S:18]([NH:21][CH3:22])(=[O:20])=[O:19])=[CH:15][CH:16]=2)[CH:4]=1
Reactant: CNS(=O)(=O)Cc1ccc(Oc2cc(C#N)nc(C)n2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNS(=O)(=O)Cc1ccc(Oc2cc(CN)nc(C)n2)cc1
Yield: 60.9 %

Procedure:
In a PARR reactor, combine palladium (3.6 g, 10% on charcoal, 1-[4-(6-cyano-2-methyl-pyrimidin-4-yl)oxyphenyl]-N-methyl-methanesulfonamide (18 g, 56.5 mmol), EtOH (270 mL), EtOAc (270 mL), and triethylamine (31.5 mL). Seal the PARR reactor and charge it with hydrogen (400 psi); then shake the reactor at room temperature overnight. Open the reactor and filter the contents through CELITE®; wash the CELITE® pad with EtOH (1000 mL); collect the filtrate; and evaporate the solvent to provide the title compound as a brown solid (11.1 g, 43%). MS (m/z): 323 (M+1). Alternative Preparation 4
Reaction SMILES: C([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][C:13]([O:19][CH3:20])=[C:14]([S:15]([CH3:18])(=[O:17])=[O:16])[C:7]=2[CH2:6][CH2:5]1)(=O)C.[ClH:21]>>[ClH:21].[CH3:20][O:19][C:13]1[CH:12]=[CH:11][C:8]2[CH2:9][CH2:10][NH:4][CH2:5][CH2:6][C:7]=2[C:14]=1[S:15]([CH3:18])(=[O:17])=[O:16]
Reactant: COc1ccc2c(c1S(C)(=O)=O)CCN(C(C)=O)CC2
Agent: Cl
Product: COc1ccc2c(c1S(C)(=O)=O)CCNCC2

Procedure:
Following the procedure of Example 4, 3-acetyl-7-methoxy-6-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine is treated with hydrochloric acid to give 7-methoxy-6-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride which is treated with 48% hydrobromic acid to give 7-hydroxy-6-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1([F:44])[CH2:31][NH:30][CH2:29][C:28]2([CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]2)[O:27]1.[CH:45]([C:48]1[S:49][CH:50]=[C:51]([C:53](O)=[O:54])[N:52]=1)([CH3:47])[CH3:46].C(N(CC)CC)C>CN(C=O)C>[F:44][C:26]1([F:25])[CH2:31][N:30]([C:53]([C:51]2[N:52]=[C:48]([CH:45]([CH3:47])[CH3:46])[S:49][CH:50]=2)=[O:54])[CH2:29][C:28]2([CH2:32][CH2:33][N:34]([C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])[CH2:35][CH2:36]2)[O:27]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNCC(F)(F)O2
Reactant: CC(C)c1nc(C(=O)O)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)c1nc(C(=O)N2CC(F)(F)OC3(CCN(C(=O)OC(C)(C)C)CC3)C2)cs1

Procedure:
HATU (1.184 g) was added to a solution of tert-butyl 2,2-difluoro-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (example 37, step c) (0.7 g) and 2-isopropylthiazole-4-carboxylic acid (0.41 g) and triethylamine (1 mL) in DMF (12 mL) at 20° C. and the resultant mixture stirred for 1 hour. The mixture was partitioned between ethyl acetate and brine, the organic layer was washed twice with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography using 30% ethyl acetate in isohexane as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.78 g.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([C:11]([OH:13])=O)=[CH:9][N:8]=[CH:7][CH:6]=1)=[O:4].S(Cl)([Cl:16])=O>>[CH3:1][O:2][C:3]([C:5]1[C:10]([C:11]([Cl:16])=[O:13])=[CH:9][N:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccncc1C(=O)O
Reactant: O=S(Cl)Cl
Product: COC(=O)c1ccncc1C(=O)Cl

Procedure:
Following the procedure of Example 30, 4-methoxycarbonylnicotinic acid is reacted with thionyl chloride to give 4-methoxycarbonylnicotinoyl chloride. A slurry of the above chloride (22.7 mmol) in 100 ml of monoglyme (ethylene glycol dimethyl ether) is added to a chilled mixture of the sodium salt of diethyl malonate (2.2 eq.) in monoglyme. The mixture is allowed to warm to RT and is stirred at RT for 4 hours. Aq. sodium bicarbonate is added and the mixture is extracted with ether. It is then acidified to pH 2-3 and again extracted with ether. The combined organic phases of the acid layer are dried, filtered and concentrated to give methyl 3-(diethylmalonyl-carbonyl)-isonicotinate, which is then reacted with lithium hydroxide mono-hydrate and then hydrochloric acid to give 3-acetylisonicotinic acid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:35])[NH:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:25]=[C:24]3[C:20]([CH2:21][N:22]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[C:23]3=[O:26])=[CH:19][CH:18]=2)=[N:15][CH:16]=1.N[C:37]1[CH:38]=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=N[CH:42]=1>>[CH2:42]1[C:6]2[C:5](=[CH:4][C:3]([NH:8][C:9](=[O:35])[NH:10][C:11]3[CH:12]=[CH:13][C:14]([C:17]4[CH:25]=[C:24]5[C:20]([CH2:21][N:22]([C@@H:27]([CH:32]([CH3:33])[CH3:34])[C:28]([O:30][CH3:31])=[O:29])[C:23]5=[O:26])=[CH:19][CH:18]=4)=[N:15][CH:16]=3)=[CH:2][CH:7]=2)[CH2:38][CH2:37]1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccccc4Cl)cn3)cc2C1=O
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cn3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc5c(c4)CCC5)cn3)cc2C1=O

Procedure:
The compound of example 401 was prepared analogous to the compound of example 393 by reaction of the compound of example 392 with 2,3-dihydro-1H-indene-5-isocyanate. The compound of example 401 was used directly for the preparation of compound 402 without purification.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]1[CH:12]=[CH:13][C:14]2[N:15]([C:17]([C:20]([F:23])([F:22])[F:21])=[N:18][N:19]=2)[N:16]=1.[NH:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:51]=[CH:50][C:33]([O:34][CH2:35][CH2:36][N:37]3[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]3)=[CH:32][CH:31]=2)[CH2:26][CH2:25]1>CN(C=O)C>[F:21][C:20]([F:23])([F:22])[C:17]1[N:15]2[N:16]=[C:11]([N:24]3[CH2:29][CH2:28][CH:27]([C:30]4[CH:51]=[CH:50][C:33]([O:34][CH2:35][CH2:36][N:37]5[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:47])([CH3:49])[CH3:48])=[O:44])[CH2:39][CH2:38]5)=[CH:32][CH:31]=4)[CH2:26][CH2:25]3)[CH:12]=[CH:13][C:14]2=[N:19][N:18]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: CC(C)(C)OC(=O)N1CCN(CCOc2ccc(C3CCNCC3)cc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(CCOc2ccc(C3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)cc2)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
DIPEA (2.348 mL, 13.48 mmol) was added to 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (obtained as described in Monatsh. Chem. 1972, 103, 1591) (2 g, 8.99 mmol) and tert-butyl 4-[2-[4-(piperidin-4-yl)phenoxy]ethyl]piperazine-1-carboxylate (3.68 g, 9.44 mmol) in DMF (30 mL). The resulting solution was stirred at 80° C. for 2 hours. The reaction mixture was cooled to room temperature and the solvents evaporated to dryness. The resulting solid was triturated with water then collected by is filtration, washed with ether and dried to afford tert-butyl 4-[2-[4-[1-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenoxy]ethyl]piperazine-1-carboxylate (5.02 g, 97%) as a solid.
Reaction SMILES: [CH2:1]=[C:2]([C:4]1[N:5]=[CH:6][C:7]([O:10][C@H:11]2[CH2:32][N:14]3[CH2:15][CH2:16][N:17]([S:19]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)(=[O:21])=[O:20])[CH2:18][C@@H:13]3[CH2:12]2)=[N:8][CH:9]=1)[CH3:3].[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[CH:2]([C:4]1[N:5]=[CH:6][C:7]([O:10][C@H:11]2[CH2:32][N:14]3[CH2:15][CH2:16][N:17]([S:19]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:24][CH:23]=4)(=[O:20])=[O:21])[CH2:18][C@@H:13]3[CH2:12]2)=[N:8][CH:9]=1)([CH3:3])[CH3:1]
Reactant: [H][H]
Reactant: C=C(C)c1cnc(O[C@@H]2C[C@H]3CN(S(=O)(=O)c4ccc(C(F)(F)F)cc4)CCN3C2)cn1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)c1cnc(O[C@@H]2C[C@H]3CN(S(=O)(=O)c4ccc(C(F)(F)F)cc4)CCN3C2)cn1
Yield: 90.1 %

Procedure:
(7R,8aS)-7-{[5-(Prop-1-en-2-yl)pyrazin-2-yl]oxy}-2-{[4-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine (240 mg, 0.512 mmol, Example 116) in ethanol (10 mL) was added to 20% palladium hydroxide on carbon (15 mg, 0.11 mmol). The mixture was stirred at room temperature for 16 hours under 30 psi of hydrogen. The mixture was filtered through a nylon membrane and concentrated. The residue was purified by chromatography on silica gel (hexane/ethyl acetate=3:2) to give the title compound (217 mg, 90% yield) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.21 (s, 6H), 1.77 (m, 1H), 1.91 (m, 1H), 2.09 (m, 1H), 2.21-2.42 (m, 4H), 3.01 (m, 2H), 3.56 (m, 1H), 3.66 (m, 1H), 3.84 (m, 1H), 5.22 (m, 1H), 8.02 (m, 5H), 8.20 (m, 1H); MS (ESI) m/z 471 (M+H)+.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[NH:10][C:11]1[NH:12][CH2:13][CH2:14][N:15]=1.[N+:16]([O-])([O-:18])=[O:17].[K+]>S(=O)(=O)(O)O>[OH2:17].[OH2:17].[OH2:17].[N+:16]([C:8]1[CH:7]=[CH:6][C:5]2[N:1]=[C:2]([NH:10][C:11]3[NH:12][CH2:13][CH2:14][N:15]=3)[NH:3][C:4]=2[CH:9]=1)([O-:18])=[O:17]
Reactant: c1ccc2[nH]c(NC3=NCCN3)nc2c1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O
Product: O=[N+]([O-])c1ccc2nc(NC3=NCCN3)[nH]c2c1
Temperature: -5 °C
Yield: 387.2 %

Procedure:
2-Benzimidazolylamino-2-imidazoline (10.96g 0.055 mol) was added cautiously to concentrated sulphuric acid (62 ml) cooled to -5°C. Potassium nitrate (5.5 g) in concentrated sulphuric acid (3.4 ml) was added dropwise with stirring maintaining the temperature at 0°C. After addition the reaction mixture was allowed to warm to room temperature overnight then poured onto ice/water (250g) with stirring. The resulting pale yellow crystals were filtered, washed with water and recrystallised from aqueous dimethylforamide to yield 2-(5-nitrobenzimidazolinyl)amino-2-imidazoline trihydrate (15.81g) as yellow microcrystals m.p. 257°-259°C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.O.C(O[CH2:15][CH3:16])(=O)C.[CH:17]([N:20](CC)C(C)C)(C)C>CS(C)=O.C(N)CC>[Cl:1][C:2]1[N:7]=[C:6]([NH:20][CH2:17][CH2:15][CH3:16])[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: CCOC(C)=O
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1cc(Cl)nc(Cl)n1
Solvent: CS(C)=O
Solvent: CCCN
Solvent: O
Product: CCCNc1cc(C)nc(Cl)n1
Reaction time: 2 h

Procedure:
To a solution of 2,4-dichloro-6-methylpyrimidine (1.00 g) in dimethyl sulfoxide (10 mL), N,N-diisopropylethylamine (1.07 mL) and propylamine (0.51 mL) were added at room temperature, and the mixture was stirred at the same temperature for 2 hours. To the reaction mixture, N,N-diisopropylethylamine (1.07 mL) and propylamine (0.51 mL) were added at room temperature, and the mixture was stirred at the same temperature for 2 hours. To the reaction mixture, water and ethyl acetate were added. The organic layer was separated, washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 90 to 70% hexane in ethyl acetate) to obtain 2-chloro-6-methyl-N-propylpyrimidin-4-amine (T1, 776 mg).
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]1[C:8]2([CH2:10][CH2:9]2)[CH2:7][NH:6][CH2:5]1.C(N(CC)CC)C.[F:18][B:19][F:20].[F:21][C:22]1[CH:23]=[C:24]2[C:29](=[C:30]([O:33][CH3:34])[C:31]=1F)[N:28]([C@@H:35]1[CH2:37][C@@H:36]1[F:38])[CH:27]=[C:26]([C:39]([OH:41])=[O:40])[C:25]2=[O:42]>CS(C)=O>[NH2:3][C@H:4]1[C:8]2([CH2:10][CH2:9]2)[CH2:7][N:6]([C:31]2[C:30]([O:33][CH3:34])=[C:29]3[C:24]([C:25](=[O:42])[C:26]([C:39]([OH:41])=[O:40])=[CH:27][N:28]3[C@@H:35]3[CH2:37][C@@H:36]3[F:38])=[CH:23][C:22]=2[F:21])[CH2:5]1.[F:18][B:19][F:20]
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Reactant: N[C@@H]1CNCC12CC2
Agent: Cl
Agent: F[B]F
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1c(N2C[C@@H](N)C3(CC3)C2)c(F)cc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Yield: 91 %

Procedure:
(7S)-7-Amino-5-azaspiro[2.4]heptane dihydrochloride (615 mg; 3.32 mmol) and triethylamine (1.40 ml) in dimethylsulfoxide (5 ml) was stirred for 20 minutes at room temperature. 6,7-Difluoro-1-[(1R, 2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid difluoroboron chelate (1.00 g; 2.77 mmol) was added thereto, and the resultant mixture was stirred for 20 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and purified water (50 ml) was added thereto. The pH of the resultant mixture was adjusted to 7.0 with aqueous 1N NaOH solution, and the aqueous layer of the mixture was taken up with chloroform (100 ml×5). The organic layer was dried over sodium sulfate, and the solvent was evaporated. The residue was purified through recrystallization from ethanol, to thereby yield 1.14 g of the title compound as pale yellow crystals (yield: 91%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][C:6]1([NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7]1)[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:27]([C:24]1[CH:23]=[CH:22][C:21]([S:18]([NH:17][C:6]2([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:32])[CH2:9][NH:8][CH2:7]2)(=[O:20])=[O:19])=[CH:26][CH:25]=1)[CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCc1ccc(S(=O)(=O)NC2(CC(=O)OCC)CN(C(=O)OC(C)(C)C)C2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCc1ccc(S(=O)(=O)NC2(CC(=O)OCC)CNC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.5 %

Procedure:
tert-Butyl 3-(2-ethoxy-2-oxoethyl)-3-(4-pentylphenylsulfonamido)azetidine-1-carboxylate (79 mg, 0.169 mmol) was dissolved into DCM (4 mL). The solution was treated with TFA (0.3 mL). The mixture was stirred at room temperature for 4 h. DCM was removed under vacuum. Ethyl acetate (25 mL) was added and the solution was washed with saturated sodium bicarbonate (2×5 mL), water (10 mL), brine (10 mL), dried over MgSO4 and concentrated to afford the title compound as a white powder (52 mg, 84%). 1H NMR (400 MHz, CDCl3) δ 7.79 (d, 2H, J=8 Hz), 7.31 (d, 2H, J=8 Hz), 4.05 (q, 2H, J=7.2 Hz), 3.94 (d, 2H, J=8.8 Hz), 3.36 (d, 2H, J=8.8 Hz), 3.01 (s, 2H), 2.68 (t, 2H, J=8 Hz), 1.66 (m, 2H), 1.34 (br, 4H), 1.22 (t, 3H, J=7.2 Hz), 0.90 (t, 3H, J=6.8 Hz); MS ESI 369.1 [M+H]+, calcd for [C18H28N2O4S+H]+ 369.18.
Reaction SMILES: CN(C)C=O.[C:6](Cl)(=[O:10])[C:7](Cl)=O.[F:12][C:13]1[C:18]([C:19]2[N:20]([Si](C(C)C)(C(C)C)C(C)C)[CH:21]=C[C:23]=2[F:24])=[CH:17][CH:16]=[CH:15][N:14]=1.[OH-].[Na+]>ClCCl>[F:24][C:23]1[C:7]([CH:6]=[O:10])=[CH:21][NH:20][C:19]=1[C:18]1[C:13]([F:12])=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(F)c1-c1cccnc1F
Reactant: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=Cc1c[nH]c(-c2cccnc2F)c1F
Reaction time: 0.17 h
Yield: 78.2 %

Procedure:
To a solution of N,N-dimethylformamide (717 mg) in dichloromethane (20 mL) was added oxalyl chloride (1.13 g) under ice-cooling under an argon atmosphere, and the mixture was stirred for 10 min. To the obtained suspension was added a solution of 2-fluoro-3-{3-fluoro-1-[tris(1-methylethyl)silyl]-1H-pyrrol-2-yl}pyridine (1.50 g) in dichloromethane (5 mL) and the mixture was stirred under refluxing conditions for 10 hr. The reaction mixture was cooled under ice-cooling, 1 mol/L aqueous sodium hydroxide solution (30 mL) was added and the mixture was stirred for 15 min. The solvent was evaporated to a half volume under reduced pressure and the residue was partitioned by adding ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residual solid was washed with diisopropyl ether (30 mL) and filtered by suction to give the title compound as a colorless solid (yield 726 mg, 78%).
Reaction SMILES: [OH:1][CH:2]([CH2:8]Cl)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].ClCC(O)C(O)=O.[CH:17]([NH2:20])([CH3:19])[CH3:18].COC1C=C(C=CC=1OC)CCN>>[CH:17]([NH:20][CH2:8][CH:2]([OH:1])[CH2:3][CH2:4][C:5]([OH:7])=[O:6])([CH3:19])[CH3:18]
Reactant: O=C(O)CCC(O)CCl
Reactant: CC(C)N
Agent: COc1ccc(CCN)cc1OC
Agent: O=C(O)C(O)CCl
Product: CC(C)NCC(O)CCC(=O)O

Procedure:
The procedure is repeated in all essential details, except 4-hydroxy-5-chloropentanoic acid is substituted for β-chlorolactic acid and isopropylamine is substituted for 3,4-dimethoxyphenethylamine to produce the intermediate 5-isopropylamino-4-hydroxypentanoic acid. The hydroxy and amino groups are protected as described in Example I. The resulting acid is reacted with 1-naphthol instead of phenol and the protecting groups are removed as in Example I. The resulting compound should be a short acting β-blocker.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17](=O)[C:16]3[C:11](=[CH:12][C:13]([OH:20])=[C:14]([Cl:19])[CH:15]=3)[O:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:21][NH:22][NH2:23]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([C:16]3[CH:15]=[C:14]([Cl:19])[C:13]([OH:20])=[CH:12][C:11]=3[OH:10])=[N:23][N:22]([CH3:21])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=c1c(-c2ccc(Br)cc2)coc2cc(O)c(Cl)cc12
Reactant: CNN
Product: Cn1cc(-c2ccc(Br)cc2)c(-c2cc(Cl)c(O)cc2O)n1
Reaction time: 16 h
Yield: 73 %

Procedure:
An ethanolic solution (5 ml) of 3-(4-Bromo-phenyl)-6-chloro-7-hydroxy-chromen-4-one (100 mg, 28 mmol) was heated to boiling, methyl hydrazine (0.30 ml, 20 equiv.) added in one portion, and refluxing continued for 16 hrs. After cooling, the volatiles were evaporated under reduced pressure and water added to the residue causing a precipitate to form. This was filtered off and dried under vacuum in the presence of P2O5 to provide 78 mg (73% yield) as a tan coloured powder. Although pure by LCMS further purification by column chromatography, eluting with first 40% EtOAc in Hexane and increasing to 60%, gave a grey-white powder (6 mg). The exact regioisomer was confirmed by NOESY 1H NMR.
Reaction SMILES: CC(C[AlH]CC(C)C)C.[C:10]([O:14][C:15]([NH:17][C:18]1[CH:23]=[C:22]([CH:24]([CH3:30])[C:25](OCC)=[O:26])[CH:21]=[CH:20][N:19]=1)=[O:16])([CH3:13])([CH3:12])[CH3:11].O.[O-]S([O-])(=O)=O.[Mg+2]>C1COCC1.C(Cl)Cl>[OH:26][CH2:25][CH:24]([C:22]1[CH:21]=[CH:20][N:19]=[C:18]([NH:17][C:15](=[O:16])[O:14][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:23]=1)[CH3:30]
Reactant: CCOC(=O)C(C)c1ccnc(NC(=O)OC(C)(C)C)c1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(CO)c1ccnc(NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Yield: 53.5 %

Procedure:
A solution of DIBAL (1M in DCM, 13.8 mL, 13.8 mmol) was added dropwise over 10 min to a stirred solution of the ester (52) (1.35 g, 4.59 mmol) in THF (25 mL) under nitrogen at −78° C. The reaction mixture was warmed to RT and then re-cooled to −78° C. and a second aliquot of DIBAL (1M in DCM, 4.5 mL, 4.5 mmol) was added. The reaction mixture was allowed to warm to RT, then cooled to 0° C. and water (5 mL) and then MgSO4 were added. The mixture was diluted with DCM and filtered to remove the solids. The filter cake was washed with EtOAc, MeOH and DCM and the combined filtrate and washings were evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 40 g, 25-50% EtOAc in isohexane, gradient elution) to afford the title compound (53) (0.62 g, 50%): m/z 253 (M+H)+ (ES+).
Reaction SMILES: C(O[C:6]([N:8](C)[CH:9]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]([CH3:46])[C@@H:17]2[CH2:24][N:23]3[C:25]4[CH:26]=[C:27]([C:38]([O:40][CH3:41])=[O:39])[CH:28]=[CH:29][C:30]=4[C:31]([CH:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[C:22]3[C:21]3[CH:42]=[CH:43][CH:44]=[CH:45][C:20]=3[O:19][CH2:18]2)[CH2:10]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:32]1([C:31]2[C:30]3[CH:29]=[CH:28][C:27]([C:38]([O:40][CH3:41])=[O:39])=[CH:26][C:25]=3[N:23]3[C:22]=2[C:21]2[CH:42]=[CH:43][CH:44]=[CH:45][C:20]=2[O:19][CH2:18][C@H:17]([N:16]([CH3:46])[CH2:15][CH2:14][N:11]2[CH2:12][CH2:13][CH:9]([NH:8][CH3:6])[CH2:10]2)[CH2:24]3)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N(C)CCN1CCC(N(C)C(=O)OC(C)(C)C)C1)COc1ccccc1-3
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC1CCN(CCN(C)[C@H]2COc3ccccc3-c3c(C4CCCCC4)c4ccc(C(=O)OC)cc4n3C2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl (7R)-7-[(2-{3-[(tert-butoxycarbonyl)(methyl)amino]pyrrolidin-1-yl}ethyl)(methyl)amino]-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate was dissolved in DCM and treated with TFA. The solution was stirred for 2 h at RT. The solvents were removed in vacuo to leave the product as pale yellow foam. (ES+) m/z 545 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[CH:7]=[CH:8][C:9](=O)[CH2:10]C(OCC)=O)([O-:3])=[O:2].O=[C:21]([CH2:28][O:29][C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1)[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].[NH3:36]>C(O)C>[CH2:26]([O:25][C:23]([C:8]1[CH:7]([C:6]2[CH:17]=[CH:18][CH:19]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:21]([CH2:28][O:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[NH:36][C:9]=1[CH2:10][O:29][C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1)=[O:24])[CH3:27]
Reactant: N
Reactant: CCOC(=O)CC(=O)COc1cccnc1
Reactant: CCOC(=O)CC(=O)C=Cc1cccc([N+](=O)[O-])c1
Solvent: CCO
Product: CCOC(=O)C1=C(COc2cccnc2)NC(COc2cccnc2)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1

Procedure:
Ethyl 3-nitrobenzylideneacetoacetate (6.47 g. 0.026 mol), ethyl 3-oxo-4-(3-pyridyloxy)butanoate (5.8 g, 0.026 mol) and 0.88 ammonia (2.5 ml) in ethanol were refluxed for 7 hours. The solvent was removed under reduced pressure and the residue partitioned between 2N hydrochloric acid and diethyl ether. The aqueous acid was extracted with chloroform and this was washed with dilute ammonia solution, dried (MgSO4) and evaporated. The residue was purified by chromatography on silica with first chloroform then ethyl acetate as eluent to obtain the title compound. This was dissolved in ethanol and acidified with ethanolic HCl to give the dihydrochloride salt of the title compound (0.95 g) m.p. 206-208° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].Cl[C:11]([O:13][CH3:14])=[O:12].Cl>ClCCl>[F:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([OH:9])[C:2]=1[NH:1][C:11](=[O:12])[O:13][CH3:14]
Reactant: COC(=O)Cl
Reactant: Nc1c(O)cccc1F
Agent: Cl
Solvent: ClCCl
Product: COC(=O)Nc1c(O)cccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 2-amino-3-fluorophenol (2.07 g) and dichloromethane (100 mL) were added TEA (2.29 mL) and methyl chloroformate (1.27 mL) under ice-cooling, followed by stirring at room temperature for 3 hours. The reaction mixture was ice-cooled, and 0.5 M hydrochloric acid solution was added thereto, followed by stirring for 10 minutes. Then, the organic layer was separated. The organic layer was washed with brine, dried over Na2SO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: Hex/EtOAc=100/0-75/25) to obtain methyl (2-fluoro-6-hydroxyphenyl)carbamate (2.55 g).