Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:5]1[O:11][CH:10]2[C:7]([C:33](=[O:41])[CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:8](=[O:32])[N:9]2[C:12](=[C:29]([CH3:31])[CH3:30])[C:13]([O:15][CH:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[NH:6]1)([O:3]C)=[O:2].[OH-].[Na+].Cl>CC(C)=O.O>[C:1]([CH:5]1[O:11][CH:10]2[C:7]([C:33](=[O:41])[CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:8](=[O:32])[N:9]2[C:12](=[C:29]([CH3:30])[CH3:31])[C:13]([O:15][CH:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:14])[NH:6]1)([OH:3])=[O:2]
Reactant: COC(=O)C1NC2(C(=O)Cc3ccccc3)C(=O)N(C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C)C)C2O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)=C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C2(C(=O)Cc3ccccc3)NC(C(=O)O)OC12
Reaction time: 1 h
Yield: 113.9 %

Procedure:
To a solution of 11.3 g of diphenylmethyl α-(3ξ-carbomethoxy-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate in 230 ml of acetone is added a solution of 900 mg of sodium hydroxide in 36 ml of water under ice-cooling, and the mixture stirred for 1 hour, then diluted with water, acidified with hydrochloric acid, and then extracted with methylene chloride. The extract is washed with water, dried on magnesium sulfate and concentrated under reduced pressure to yield 12.54 g of diphenylmethyl α-(3ξ-carboxy-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]-heptan-6-yl)-α-isopropylideneacetate as crude product.
Reaction SMILES: C(O[C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=[O:5])C.[I:20][C:21]1[CH:36]=[CH:35][C:24]2[NH:25][C:26]([CH2:31][C:32](O)=[O:33])=[N:27][S:28](=[O:30])(=[O:29])[C:23]=2[CH:22]=1.C1(N=C=NC2CCCCC2)CCCCC1.ClCCl>CN(C)C=O.C(OCC)(=O)C>[F:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][N:11]2[C@@H:7]3[C@@H:6]([CH2:10][CH2:9][CH2:8]3)[C:4]([OH:5])=[C:31]([C:26]3[NH:25][C:24]4[CH:35]=[CH:36][C:21]([I:20])=[CH:22][C:23]=4[S:28](=[O:29])(=[O:30])[N:27]=3)[C:32]2=[O:33])=[CH:18][CH:17]=1
Reactant: CCOC(=O)[C@@H]1CCC[C@@H]1NCc1ccc(F)cc1
Reactant: O=C(O)CC1=NS(=O)(=O)c2cc(I)ccc2N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1C(C2=NS(=O)(=O)c3cc(I)ccc3N2)=C(O)[C@@H]2CCC[C@@H]2N1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of cis-2-(4-fluoro-benzylamino)-cyclopentanecarboxylic acid ethyl ester (prepared as described in Example 11, 1.33 g, 5 mmol) and (7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (2.20 g, 6.0 mmol) in anhydrous N,N-dimethylformamide (15 mL) under a nitrogen atmosphere, a 1.0 M solution of N,N′-dicyclohexylcarbodiimide solution in dichloromethane (6.5 mL, 6.5 mmol) was slowly added. After stirring for 1.5 h at 25° C., the mixture was diluted with ethyl acetate, washed with water and saturated aqueous brine solution, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to afford the amide intermediate, which was used directly in the next step without further purification.
Reaction SMILES: C([Li])(C)(C)C.[C:6]([O:10][C:11]([N:13]1[CH:22]2[CH2:23][CH2:24][CH:14]1[C:15]1[CH:16]=[C:17]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:18]=[CH:19][C:20]=1[CH2:21]2)=[O:12])([CH3:9])([CH3:8])[CH3:7].B(OC)(OC)[O:34]C.OO.Cl>C1COCC1.CO>[C:6]([O:10][C:11]([N:13]1[CH:22]2[CH2:23][CH2:24][CH:14]1[C:15]1[C:16]([OH:34])=[C:17]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:18]=[CH:19][C:20]=1[CH2:21]2)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: COB(OC)OC
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)C1CCC(C2)N1C(=O)OC(C)(C)C
Agent: Cl
Agent: OO
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc2c(c1O)C1CCC(C2)N1C(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 1 h
Yield: 55.5 %

Procedure:
12-Aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-trien-4-ylamine (572 mg, 3.3 mmol), di-tert-butyl dicarbonate (1.6 g, 7.2 mmol), triethylamine (1.0 mL, 7.2 mmol) were stirred at room temperature in tetrahydrofuran (20 mL) for 18 h. The reaction was then concentrated and purified with silica gel chromatography (0-30% EtOAc in hexanes) to obtain 4-tert-Butoxycarbonylamino-12-aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-triene-12-carboxylic acid tert-butyl ester as a white solid (1.1 g, 90%). MS (m/e) 375 (M+1). 92b) Tert-butyllithium (1.7M, 2.3 mL, 4.0 mmol) was added dropwise to a solution of 4-tert-butoxycarbonylamino-12-aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-triene-12-carboxylic acid tert-butyl ester (450 mg, 1.2 mmol) in THF (5 mL) at −78° C. The solution was then allowed to warm slowly to −20° C. and stir at that temperature for 1 h before cooling again to −78° C. and adding trimethyl borate (0.37 mL, 3.2 mmol) via syringe. The reaction was allowed to warm to room temperature slowly and stir overnight. The reaction was quenched with methanol (1 mL) and hydrogen peroxide (30% solution, 0.37 mL, 3.6 mmol) was added to the reaction and allowed to stir at room temperature for 2 h. The mixture was then adjusted to neutral pH with 1 N HCl, extracted with CH2Cl2 (3×10 mL), dried over MgSO4, filtered and concentrated. The resulting residue was purified with silica gel chromatography (0-50% EtOAc in hexanes) to obtain 4-tert-Butoxycarbonylamino-3-hydroxy-12-aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-triene-12-carboxylic acid tert-butyl ester as a brown foam (260 mg, 55%). 1HNMR (400 MHz, CDCl3) δ 7.7 (m, 1H), 7.5 (s, 1H), 7.1 (d, 1H, J=8.1 Hz), 6.9 (m, 1H), 4.5 (d, 1H, J=7.8 Hz), 4.1 (m, 1H), 3.1 (dd, 1H, J=14.4, 4.9 Hz), 2.9 (dd, 1H, J=14.4, 4.9 Hz), 2.7 (dd, 1H, J=18.2, 8.1 Hz), 2.6 (dd, 1H, J=18.2, 10.6 Hz), 2.2-2.1 (m, 1H), 1.5-1.3 (m, 19H); 1H-1H COSY interactions between peak at 7.7 and 7.1 ppm; MS (m/e) 391 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10](F)[CH:9]=2)[CH:5]=[C:4]([N:17]2[CH2:22][CH2:21]O[CH:19]([C:23]3[NH:27][C:26]4[CH:28]=[CH:29][C:30]([Cl:32])=[CH:31][C:25]=4[N:24]=3)[CH2:18]2)[N:3]=1.[OH2:33].[NH2:34][NH2:35]>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:11]([C:12]([NH2:13])=[N:34][NH:35]3)=[CH:14][CH:15]=2)[CH:5]=[C:4]([N:17]2[CH2:22][CH2:21][O:33][CH:19]([C:23]3[NH:27][C:26]4[CH:28]=[CH:29][C:30]([Cl:32])=[CH:31][C:25]=4[N:24]=3)[CH2:18]2)[N:3]=1
Reactant: N#Cc1ccc(-c2cc(N3CCOC(c4nc5cc(Cl)ccc5[nH]4)C3)nc(N)n2)cc1F
Reactant: NN
Reactant: O
Solvent: CCO
Product: Nc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2CCOC(c3nc4cc(Cl)ccc4[nH]3)C2)n1
Temperature: 85 °C
Reaction time: 8 h
Yield: 28.5 %

Procedure:
To a solution of 4-{2-amino-6-[2-(5-chloro-1H-benzimidazol-2-yl)-4-morpholinyl]-4-pyrimidinyl}-2-fluorobenzonitrile (140 mg, 0.311 mmol) in ethanol (5 mL) stirred at room temperature was added hydrazine hydrate (156 mg, 3.11 mmol), and the reaction mixture was stirred overnight at 85° C. The solvent was evaporated in vacuo to give the crude product. The crude product was added to a silica gel column and was eluted with CH2Cl2/MeOH to afford the title compound (41 mg) as a yellow solid. LC-MS (ES) m/z=462 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 3.13-3.17 (m, 2H), 3.81 (t, J=13.2 Hz, 1H), 4.12 (d, J=9.6 Hz, 1H), 4.35 (d, J=9.6 Hz, 1H), 4.84-4.89 (m, 2H), 5.40 (s, 2H), 6.30 (s, 2H), 6.72 (s, 1H), 7.22 (t, J=9.6 Hz, 1H), 7.48-7.50 (m, 1H), 7.60-7.73 (m, 3H), 7.97 (s, 1H), 11.55 (s, 1H), 12.80 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[CH2:14][CH3:15].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.[F:35][C:36]([F:46])([F:45])[C:37]1[CH:44]=[CH:43][C:40]([CH2:41]Br)=[CH:39][CH:38]=1.O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:41][C:40]2[CH:39]=[CH:38][C:37]([C:36]([F:35])([F:45])[F:46])=[CH:44][CH:43]=2)[C:6]=1[CH2:14][CH3:15]
Reactant: CCc1[nH]c2ncccc2c1CC(=O)OC
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: O
Solvent: CN(C)C=O
Product: CCc1c(CC(=O)OC)c2cccnc2n1Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To an ice-cooled stirring solution of (2-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester (80 mg, 0.37 mmol) in DMF (1 ml) is added BEMP (171 μl, 0.59 mmol). The solution is stirred at room temperature for 40 minutes and then re-cooled. 4-(Trifluoromethyl)benzyl bromide ((91 μl, 0.59 mmol) is added and stirring continues while the reaction mixture gradually warmed up to room temperature overnight. The resulting mixture is poured into water (30 ml) and extracted with 1:1 EtOAc/ether. The organic layer is washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue is loaded on a pre-packed Isolute™ silica column and eluted with DCM to yield the titled compound as a pale yellow oil. (MH+ 377)
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5](I)=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[F:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19](B(O)O)[CH:20]=1.[NH2:24][C:25]1[N:26]=[C:27]([CH3:30])[S:28][CH:29]=1>>[F:14][C:15]1[CH:20]=[C:19]([C:5]2[CH:4]=[N:3][C:2]([NH:24][C:25]3[N:26]=[C:27]([CH3:30])[S:28][CH:29]=3)=[C:11]3[C:6]=2[CH:7]=[CH:8][C:9]([CH3:12])=[N:10]3)[CH:18]=[N:17][CH:16]=1
Reactant: Cc1nc(N)cs1
Reactant: Cc1ccc2c(I)cnc(Cl)c2n1
Reactant: OB(O)c1cncc(F)c1
Product: Cc1ccc2c(-c3cncc(F)c3)cnc(Nc3csc(C)n3)c2n1

Procedure:
The title compound, MS: m/e=352.2 (M+H+), was prepared in accordance with the general method of example 15 step 1 and step 3 from 8-chloro-5-iodo-2-methyl-[1,7]naphthyridine (Example I), 3-fluoropyridine-5-boronic acid and 4-amino-2-methylthiazole (Example F).
Reaction SMILES: [F:1][C:2]([F:11])([CH:8]([F:10])[F:9])/[CH:3]=[CH:4]/[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.Cl.[CH3:19][NH:20][C:21]([C:23]1[CH:28]=[C:27]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:26]=[CH:25][N:24]=1)=[O:22].C(N(C(C)C)CC)(C)C>C(Cl)Cl.CN(C=O)C>[CH3:19][NH:20][C:21]([C:23]1[CH:28]=[C:27]([N:29]2[CH2:34][CH2:33][N:32]([C:5](=[O:7])/[CH:4]=[CH:3]/[C:2]([F:1])([F:11])[CH:8]([F:10])[F:9])[CH2:31][CH2:30]2)[CH:26]=[CH:25][N:24]=1)=[O:22]
Reactant: O=C(O)/C=C/C(F)(F)C(F)F
Reactant: CNC(=O)c1cc(N2CCNCC2)ccn1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CNC(=O)c1cc(N2CCN(C(=O)/C=C/C(F)(F)C(F)F)CC2)ccn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
(E)-4,4,5,5-tetrafluoropent-2-enoic acid (19 mg, 0.11 mmol) was dissolved in DCM (1 ml), oxalyl chloride was added (9 μl, 0.11 mmol) followed by a drop of DMF. The mixture was stirred for 10 minutes at room temperature. N-methyl-4-piperazin-1-yl-pyridine-2-carboxamide hydrochloride (25.6 mg, 0.1 mmol) was dissolved in DMF (0.5 ml), the mixtures were combined, diisopropylethylamine (75 μl, 0.4 mmol) was added and the resulting mixture was stirred at room temperature for 1 hour. The mixture was evaporated to dryness under reduced pressure, the residue was purified by preparative HPLC (gradient of water containing 0.1% NH3 and acetonitrile) to yield 20.2 mg (0.054 mmol, 54%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]([C:13]2[C:21]([CH:22]=[CH:23][C:24]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]3[CH2:32][CH3:33])=[O:25])=[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][N:15]3[N:14]=2)[CH:10]=[CH:11][CH:12]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([NH:6][C:7]1[CH:8]=[C:9]([C:13]2[C:21]([CH:22]=[CH:23][C:24]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]3[CH2:32][CH3:33])=[O:25])=[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][N:15]3[N:14]=2)[CH:10]=[CH:11][CH:12]=1)(=[O:4])=[O:3]
Reactant: CCC1CCCCN1C(=O)C=Cc1c(-c2cccc(N)c2)nn2ccccc12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC1CCCCN1C(=O)C=Cc1c(-c2cccc(NS(C)(=O)=O)c2)nn2ccccc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 24.8 %

Procedure:
Methanesulfonyl chloride (0.59 g) was added dropwise to a stirred solution of 1-[3-{2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]- 2-ethylpiperidine (trans isomer) (1.20 g) and triethylamine (0.52 g) in methylene chloride (7.2 ml) with ice-cooling. After being stirred at room temperature for 6 hours, the reaction mixture was washed twice with water and once with saturated sodium chloride aqueous solution, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (22 g) with chloroform as an eluent. The fractions containing the objective compound were combined and evaporated in vacuo to give crystals of 1-[3-{2-(3-methanesulfonamidophenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine (trans isomer) (0.36 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(O)cc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(O)cc(OCc2ccccc2)c1
Temperature: 25 °C
Yield: 21 %

Procedure:
To a stirred solution of methyl 3,5-dihydroxybenzoate (5.95 mol) in DMF (6 L) was added potassium carbonate (9 mol), and the suspension stirred at ambient temperature under argon. To this was added benzyl bromide (8.42 mol) slowly over 1 hour, with a slight exotherm, and the reaction mixture stirred overnight at ambient temperature. The reaction was quenched cautiously with ammonium chloride solution (5 L) followed by water (35 L). The aqueous suspension was extracted with DCM (1×3 L and 2×5 L). The combined extracts were washed with water (10 L) and dried overnight (MgSO4). The solution was evaporated in vacuo, and the crude product chromatographed in 3 batches (flash column, 3×2 kg silica, eluting with a gradient consisting of hexane containing 10% DCM, to neat DCM, to DCM containing 50% ethyl acetate) to eliminate starting material. The crude eluant was further chromatographed in 175 g batches (Amicon HPLC, 5 kg normal-phase silica, eluting with isohexane containing 20% v/v of ethyl acetate) to give the desired compound (21% yield). 1H NMR δ (d6-DMSO): 3.8 (s, 3H), 5.1 (s, 2H), 6.65 (m, 1H), 7.0 (m, 1H), 7.05 (m, 1H), 7.3-7.5 (m, 5H), 9.85 (br s, 1H).
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH2:19])=[NH:18])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CN(C)/[CH:22]=[CH:23]/[C:24]([C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=1)=O.C(=O)([O-])[O-].[K+].[K+]>CN1CCCN(C)C1=O.O>[N:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17]3[N:19]=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:28][CH:27]=4)[CH:23]=[CH:22][N:18]=3)=[CH:14][CH:15]=2)(=[O:8])=[O:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CN(C)/C=C/C(=O)c1ccc(C(F)(F)F)cc1
Reactant: N=C(N)Nc1ccc(S(=O)(=O)N2CCOCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCN(C)C1=O
Product: O=S(=O)(c1ccc(Nc2nccc(-c3ccc(C(F)(F)F)cc3)n2)cc1)N1CCOCC1
Temperature: 107.5 °C
Reaction time: 18 h
Yield: 75.4 %

Procedure:
A mixture of N-[4-(morpholin-4-ylsulfonyl)phenyl]guanidine (85 mg, 0.3 mmol), (2E)-3-(dimethylamino)-1-[4-(trifluoromethyl)phenyl]prop-2-en-1-one (43 mg, 0.18 mmol), and potassium carbonate (83 mg, 0.6 mmol) in 1 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) is stirred at 105 to 110° C. for 18 hrs. It is then cooled to room temperature, and diluted with water (15 ml). The resulting suspension is filtered, and the precipitate is washed with dilute citric acid and water, and then dissolved in ethyl acetate. The organic solution is passed through a pad of silica gel, and the filtrate is evaporated. The residue is triturated with a mixture of methylene chloride and hexanes to give 63 mg of a yellow solid; mp 240-241° C.; MS (ESI) m/z 465.2 (M+H); HRMS: calcd for C21H19F3N4O3S, 464.1130; found (ESI_FT), 465.11835.
Reaction SMILES: [O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@@H:9]3[CH2:10][CH2:11][C@H:12]2OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([O:31][CH3:32])[CH:4]=[CH:5]2.[C:33]1(=[O:43])[NH:37][C:36](=[O:38])[C:35]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:34]12.[K].O>CN(C=O)C>[O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@@H:9]3[CH2:10][CH2:11][C@H:12]2[N:37]2[C:33](=[O:43])[C:34]3=[CH:42][CH:41]=[CH:40][CH:39]=[C:35]3[C:36]2=[O:38])[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([O:31][CH3:32])[CH:4]=[CH:5]2
Reactant: COc1ccc2c3c1O[C@H]1[C@H](OS(=O)(=O)c4ccc(C)cc4)CC[C@H]4[C@@H](C2)N(C)CC[C@@]341
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c3c1O[C@H]1[C@H](N4C(=O)c5ccccc5C4=O)CC[C@H]4[C@@H](C2)N(C)CC[C@@]341
Temperature: 80 °C
Reaction time: 15 h
Yield: 38.5 %

Procedure:
In 15 mL of DMF, 321 mg (0.70 mmol) of toluene-4-sulfonic acid-(4,5α-epoxy-3-methoxy-17-methyl-morphinan-6β-yl)-ester was dissolved, and 196 mg of potassium phthalimide was added thereto, followed by stirring the mixture at 80° C. for 15 hours and then at 140° C. for 20 hours. After allowing the reaction solution to cool to room temperature, water was added to the reaction mixture and the resulting mixture was extracted with chloroform. Organic layers were combined, washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated to obtain a crude product. The thus obtained crude product was purified by silica gel column chromatography to obtain 116 mg (yield: 38%) of the captioned compound.
Reaction SMILES: O=[C:2]1[C:11]([C:12]#[N:13])=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[NH:3]1.P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:2]1[C:11]([C:12]#[N:13])=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: N#Cc1cc2c([nH]c1=O)CCCC2
Reactant: O=P(Cl)(Cl)Cl
Product: N#Cc1cc2c(nc1Cl)CCCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
To 2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carbonitrile (6.0 g, 34.4 mmol) was added phosphorus oxychloride (20 mL), this mixture was stirred at RT for 1 h,and then refluxed for 12 h. The excess phosphorous oxychloride was distilled off, and the residue was poured into ice-water. The aqueous solution was basified with saturated sodium bicarbonate solution, and the precipitate that formed was filtered off. The precipitate was purified by column chromatography eluting with 2% ethyl acetate and petroleum ether to afford 2-chloro-5,6,7,8-tetrahydro-quinoline-3-carbonitrile (5.00 g, yield: 75%).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[NH:3]1.C(C1C=CC=CC=1C(O)=O)#[N:14].C[Li]>O1CCCC1>[NH2:14][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([CH3:12])([CH3:1])[NH:3][C:4]2=[O:11])=[CH:9][CH:8]=1
Reactant: CC1(C)NC(=O)c2ccccc21
Reactant: N#Cc1ccccc1C(=O)O
Agent: [Li]C
Solvent: C1CCOC1
Product: CC1(C)NC(=O)c2cc(N)ccc21
Temperature: -78 °C

Procedure:
3,3-Dimethylisoindolin-1-one. 2-Cyanobenzoic acid (3 g, 20.39 mmol) was dissolved in tetrahydrofuran (300 mL) and then cooled to −78° C. Methyllithium (127 mL, 204 mmol) was added dropwise and the reaction was slowly warmed to room temperature over 2 hours. The reaction was quenched with brine then extracted twice with ethyl acetate. The combined organics were washed with 1 N HCl, saturated sodium bicarbonate and water, dried over magnesium sulfate and concentrated. The residue was purified by column chromatography to give the desired product. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.58-8.69 (m, 1H), 7.53-7.66 (m, 3H), 7.45 (dd, J=1.56, 7.42 Hz, 1H), 1.44 (s, 6H). MS (ESI) m/z 162.2 [M+1]+.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1)=[O:5].[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]1[C:30](O)=[O:31]>>[F:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][C@@H:3]([NH:2][C:30]([C:22]2[NH:21][C:29]3[C:24]([CH:23]=2)=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:31])[C:4]([N:6]2[CH2:7][CH2:8][CH:9]([OH:12])[CH2:10][CH2:11]2)=[O:5])=[CH:19][CH:18]=1
Reactant: N[C@H](Cc1ccc(F)cc1)C(=O)N1CCC(O)CC1
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: Cl
Product: O=C(N[C@H](Cc1ccc(F)cc1)C(=O)N1CCC(O)CC1)c1cc2ccccc2[nH]1

Procedure:
(R)-2-Amino-3-(4-fluoro-phenyl)-1-(4-hydroxy-piperidin-1-yl)-propan-1-one hydrochloride (0.5 mmol) and 1H-indole-2-carboxylic acid (0.5 mmol) were coupled according to Procedure A (0-25° C. reaction temperature) and the product purified by chromatography on silica gel eluted with 25, 30, 50, 75 and 80% ethyl acetate in hexanes. Yield 150 mg, 60%; HPLC (60/40) 3.66 minutes (97%); mp 204-207° C.; PBMS 410 (MH+, 100%);
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[NH:8][O:9][C:10](=[O:12])[CH:11]=2)[CH:2]=1.[N:13]([O-])=[O:14].[Na+]>O.C(O)(=O)C>[N:13](=[C:11]1[C:10](=[O:12])[O:9][N:8]=[C:7]1[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[OH:14]
Reactant: O=c1cc(-c2cccnc2)[nH]o1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C1ON=C(c2cccnc2)C1=NO
Reaction time: 4 h

Procedure:
A suspension of 57 g of 3-(pyrid-3-yl)isoxazol-5-one in 50 ml of water and 350 ml of glacial acetic acid is treated dropwise at 15° C. with a solution of 27 g of sodium nitrite in 60 ml of water. After 4 hours, the precipitate is filtered off with suction, washed with water and dried.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)=[O:3].[Na+].[Cl-].[C:14]1(C(O)(CCCC)CC)C=CC=C[CH:15]=1.CC1C=CC=CC=1C(O)(CC)C>C(Cl)(Cl)Cl>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]([OH:3])([CH2:14][CH3:15])[CH3:1])=[CH:5][CH:6]=1
Reactant: CCCCC(O)(CC)c1ccccc1
Reactant: COc1ccc(C(C)=O)cc1
Agent: CCC(C)(O)c1ccccc1C
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCC(C)(O)c1ccc(OC)cc1
Yield: 85.2 %

Procedure:
The general procedure A was applied to 4-methoxyacetophenone on a 112 mg (0.73 mmol) scale, using 10 mol % of Compound B (40 mg). The crude product was purified by column chromatography on silica gel (hexanes/EtOAc: 8/2) to give 3 (112 mg, 85.2% yield, 94.0% ee) as an oil: [α]D 20=−13.32 (c 1.8, CHCl3); 1H NMR (CDCl3, 500 MHz) δ 0.77 (dd, J=7.4, 7.4 Hz, 3H), 1.50 (s, 3H), 1.76-1.82 (m, 2H), 3.78 (s, 3H), 6.83-6.86 (m, 2H), 7.31-7.34 (m, 2H) ppm; 13C{1H} NMR (CDCl3, 125 MHz) δ 8.8, 29.9, 37.1, 55.6, 75.0, 113.7, 126.5, 140.3, 158.5 ppm; IR (NaCl) 3444, 2967, 1610, 1300, 1179 cm−1; MS (m/z relative intensity) 180 (M)+ (7), 165 (MCH3)+ (5), 163 (—OH)+ (49), 162 (M-H2O) (15); HMRS calcd for C11H15(—OH)+: 163.1122, found 163.1129.
Reaction SMILES: Cl[C:2]1[CH:14]=[CH:13][C:5]2=[N:6][C:7]3[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=3[N:4]2[N:3]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[N:15]1([C:2]2[CH:14]=[CH:13][C:5]3=[N:6][C:7]4[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=4[N:4]3[N:3]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: C1COCCN1
Reactant: Clc1ccc2nc3c(n2n1)CCCC3
Product: c1cc2nc3c(n2nc1N1CCOCC1)CCCC3
Temperature: 0 °C

Procedure:
A mixture was prepared by adding 5.0 g of 2-chloro-6,7,8,9-tetrahydropyridazino[1,6-a]benzimidazole to 30 ml of morpholine and this was stirred and heated at reflux for 24 hours. It was then poured into 200 ml of ice water. A tan solid formed and this was separated by filtration to give 2-(4-morpholinyl)-6,7,8,9-tetrahydropyridazino[1,6-a]benzimidazole melting at 187.5°-188.5° C.