Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C@@H:11]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@H:12]([OH:25])[CH2:13][O:14][S:15]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[CH:6]=[C:5]2[CH3:32].[CH3:33]OS(C(F)(F)F)(=O)=O.C(C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C@@H:11]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@H:12]([O:25][CH3:33])[CH2:13][O:14][S:15]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[CH:6]=[C:5]2[CH3:32]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](O)[C@H](c2ccccc2)n2cc(C)c3cc(Cl)ccc32)cc1
Reactant: COS(=O)(=O)C(F)(F)F
Agent: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Solvent: ClCCl
Product: CO[C@H](COS(=O)(=O)c1ccc(C)cc1)[C@H](c1ccccc1)n1cc(C)c2cc(Cl)ccc21

Procedure:
A mixture of (2S,3S)-toluene-4-sulfonic acid 3-(5-chloro-3-methyl-indol-1-yl)-2-hydroxy-3-phenyl-propyl ester (Intermediate in EXAMPLE 119, step 6, 0.52 g, 1.1 mmol), trifluoro-methanesulfonic acid methyl ester (0.6 mL, 5.5 mmol), and 2,6-di-tert-butyl-4-methyl-pyridine (1.1 g, 5.5 mmol) was heated at reflux in dichloromethane (20 mL) for 2 hours. The reaction was partitioned between ethyl acetate (25 mL) and a 1N aqueous solution of hydrochloric acid (25 mL). The organics were separated and washed with a saturated aqueous solution of sodium bicarbonate (25 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified via flash column chromatography (silica, 20% ethyl acetate in hexane) to give (2S,3S)-toluene-4-sulfonic acid 3-(5-chloro-3-methyl-indol-1-yl)-2-methoxy-3-phenyl-propyl ester. To a solution of toluene-4-sulfonic acid 3-(5-chloro-3-methyl-indol-1-yl)-2-methoxy-3-phenyl-propyl ester (0.13 g, 0.27 mmol) in methanol (10 mL) was added a 2N solution of methylamine in methanol (1.4 mL, 2.7 mmol) and the reaction heated in a sealed tube for 12 hours. Upon completion, the reaction was partitioned between a saturated aqueous solution sodium bicarbonate (25 mL) and dichloromethane (25 mL). The organics were separated and removed in vacuo. The residue was taken up in diethyl ether (25 mL) and washed with a 1 N aqueous solution of hydrochloric acid (25 mL). The aqueous layer was basified to pH 8 with a saturated aqueous solution of sodium bicarbonate (50 mL). The product was extracted with diethyl ether (25 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The free base was dissolved in a minimum amount of ethanol and treated with a 4N solution of hydrochloric acid in dioxane and stirred for 1 hour s. The ethanol was removed in vacuo to give [(2R,3S)-3-(5-chloro-3-methyl-1H-indol-1-yl)-2-methoxy-3-phenylpropyl]methylamine as a yellow oil. MS (ESI) m/z 343
Reaction SMILES: C(OC([NH:8][C:9]([CH3:24])([CH3:23])[CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[CH:16][C:17]([CH:21]=[O:22])=[CH:18][CH:19]=2)[CH:14]=[CH:13]1)=O)(C)(C)C>O>[NH2:8][C:9]([CH3:24])([CH3:23])[CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[CH:16][C:17]([CH:21]=[O:22])=[CH:18][CH:19]=2)[CH:14]=[CH:13]1
Reactant: CC(C)(CCn1ccc2cc(C=O)ccc21)NC(=O)OC(C)(C)C
Solvent: O
Product: CC(C)(N)CCn1ccc2cc(C=O)ccc21
Temperature: 150 °C

Procedure:
A suspension of 1-(3-tert-butoxycarbonylamino-3-methyl-butyl)-1H-indole-5-carbaldehyde (3.5 g; 10.6 mmol) in 18 ml of water is heated for 19 hours at 150° C. in the microwave. Then the reaction mixture is extracted with DCM, dried on magnesium sulphate and freed from the solvent in vacuo. The residue is chromatographed on silica gel (DCM/methanol=1:1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CO.C([O:12][C:13]1[CH:37]=[CH:36][C:16]([C:17]([NH:19][C:20]2[CH:28]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=3)[CH:26]=[CH:25][C:21]=2[C:22]([OH:24])=[O:23])=[O:18])=[CH:15][CH:14]=1)(=O)C>O1CCCC1>[Cl:35][C:31]1[CH:30]=[C:29]([C:27]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[C:20]([NH:19][C:17](=[O:18])[C:16]3[CH:36]=[CH:37][C:13]([OH:12])=[CH:14][CH:15]=3)[CH:28]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: CC(=O)Oc1ccc(C(=O)Nc2cc(-c3cccc(Cl)c3)ccc2C(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1cc(-c2cccc(Cl)c2)ccc1C(=O)O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7.6 mg of potassium carbonate was added to a mixed solution of 0.5 mL of methanol and 0.5 mL of tetrahydrofuran containing 15 mg of 2-(4-acetoxybenzamido)-4-(3-chlorophenyl)benzoic acid and stirred at room temperature for 2 hours. After insoluble were removed by filtration, 10% citric acid aqueous solution was added and a solid substance was separated by filtration to obtain 10 mg of 4-(3-chlorophenyl)-2-(4-hydroxybenzamido)benzoic acid as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:27])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH2:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=3[C:15]([C:23](OC)=[O:24])=[CH:14][C:12]=2[N:13]=1.[CH:28]1([C:31]2[CH:32]=[CH:33][C:34]([F:38])=[C:35]([CH:37]=2)[NH2:36])[CH2:30][CH2:29]1.C[Al](C)C>C1(C)C=CC=CC=1>[CH:28]1([C:31]2[CH:32]=[CH:33][C:34]([F:38])=[C:35]([NH:36][C:23]([C:15]3[C:16]4[O:20][C:19]([CH3:22])([CH3:21])[CH2:18][C:17]=4[C:11]4[NH:10][C:9]([NH:8][C:7]5[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=5[Cl:27])=[N:13][C:12]=4[CH:14]=3)=[O:24])[CH:37]=2)[CH2:30][CH2:29]1
Reactant: COC(=O)c1cc2nc(Nc3c(Cl)cncc3Cl)[nH]c2c2c1OC(C)(C)C2
Reactant: Nc1cc(C2CC2)ccc1F
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC1(C)Cc2c(c(C(=O)Nc3cc(C4CC4)ccc3F)cc3nc(Nc4c(Cl)cncc4Cl)[nH]c23)O1
Yield: 58.2 %

Procedure:
The title compound was prepared following the procedure described for Example-137 by using methyl 2-[(3,5-dichloropyridin-4-yl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylate (Step-1 of Intermediate-3, 0.100 g, 0.245 mmol), 5-cyclopropyl-2-fluoroaniline (0.053 g, 0.357 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL), dry toluene (5.0 mL) at room temperature to afford 0.075 g of the desired product. 1HNMR (DMSO-d6): δ 0.62 (d, J=6.3 Hz, 2H), 0.95 (d, J=8.4 Hz, 2H), 1.55 (s, 6H), 1.91 (m, 1H), 3.09 (s, 2H), 6.82 (m, 1H), 7.17 (t, J=10.5 Hz, 1H), 7.30 (s, 1H), 8.19 (d, J=5.7 Hz, 1H), 8.45 (s, 2H), 9.95 (s, 1H), 10.99 (s, 1H), 11.56 (br s, 1H); MS [M+H]+: 526.12.
Reaction SMILES: [Br:1]Br.[OH:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][C:7]2=[O:14]>C(Cl)(Cl)Cl>[Br:1][CH:8]1[C:7](=[O:14])[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([OH:3])[CH:5]=2)[C:9]1=[O:13]
Reactant: O=C1CC(=O)c2cc(O)ccc21
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: O=C1c2ccc(O)cc2C(=O)C1Br
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
0.02 mol bromine was added dropwise to a solution of 0.02 mol of 5-hydroxyindan-1,3-dione in 60 ml chloroform. The reaction mixture was agitated at 50° C. for 30 minutes and the precipitate obtained after evaporation of the solvent was recrystallised.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+]([O-])=O)[CH:5]=[C:4]([Br:11])[N:3]=1.[K].[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1)([O-:15])=[O:14]>CN(C)C=O>[Br:11][C:4]1[CH:5]=[C:6]([S:22][C:19]2[CH:20]=[CH:21][C:16]([N+:13]([O-:15])=[O:14])=[CH:17][CH:18]=2)[CH:7]=[C:2]([Br:1])[N:3]=1
Reactant: O=[N+]([O-])c1cc(Br)nc(Br)c1
Reactant: O=[N+]([O-])c1ccc(S)cc1
Agent: [K]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Sc2cc(Br)nc(Br)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.9 %

Procedure:
0.48 g (0.0025 mol) of 2,6-dibromo-4-nitropyridine and 0.70 g (0.0024 mol) of 4-nitrothiophenol potassium salt were dissolved in 12.5 ml of dimethylformamide and stirred at room temperature for 3 hrs. The solvent was removed and the residue was partitioned in water and ethyl acetate. The combined organic phases were washed with sat. sodium chloride solution and dried over MgSO4. After filtration and removal of the solvent the residue was chromatographed on silica gel with ethyl acetate/hexane 1:19 and subsequently dried in a high vacuum. There was obtained 0.785 g (81%) of 2,6-dibromo-4-(4-nitrophenylsulphanyl)-pyridine as yellow crystals; m.p. 166-168° C.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]3[C:23]([CH:24]=[O:25])=[CH:22][CH:21]=[C:7]3[C:8]3([CH2:14][CH2:13][N:12](C(=O)C(F)(F)F)[CH2:11][CH2:10]3)[O:9][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].O>CO>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]3[C:23]([CH:24]=[O:25])=[CH:22][CH:21]=[C:7]3[C:8]3([CH2:10][CH2:11][NH:12][CH2:13][CH2:14]3)[O:9][C:4]=2[CH:3]=1
Reactant: O=Cc1ccc2n1-c1ccc(Cl)cc1OC21CCN(C(=O)C(F)(F)F)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=Cc1ccc2n1-c1ccc(Cl)cc1OC21CCNCC1

Procedure:
To 7′-chloro-1-(2,2,2-trifluoroacetyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1′-carbaldehyde (510 mg, 1.28 mmol) dissolved in MeOH (5.1 mL) was added K2CO3 (371 mg, 2.69 mmol) in one portion at room temperature. Water was added (2 mL), and organic solvent was removed under vacuum. The mixture was extracted with DCM (3×10 mL). The organics were combined, dried, filtered, and concentrated to give 7-chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbaldehyde as a yellow oil, which was used as is for the following step. ESI-MS m/z calc. 302.1, found 303.3 (M+1)+; Retention time: 1.07 minutes (3 min run).
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][C@H:12]3[NH:15][CH2:16][CH2:17][C@:6]4([C@H:11]3[CH2:10][CH2:9][CH2:8][CH2:7]4)[C:5]=2[CH:4]=[C:3]([C:18](=[O:20])[CH3:19])[CH:2]=1.C(N(CC)CC)C.[C:28](#[N:31])[CH:29]=[CH2:30]>C(O)C>[C:18]([C:3]1[CH:2]=[CH:1][C:14]2[CH2:13][C@H:12]3[N:15]([CH2:30][CH2:29][C:28]#[N:31])[CH2:16][CH2:17][C@@:6]4([C:5]=2[CH:4]=1)[C@H:11]3[CH2:10][CH2:9][CH2:8][CH2:7]4)(=[O:20])[CH3:19]
Reactant: CC(=O)c1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)NCC3
Reactant: C=CC#N
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)N(CCC#N)CC3
Yield: 94.7 %

Procedure:
To a mixture of 1.5 g of (-)-1-(morphinan-3-yl)ethanone, 2.3 g of triethylamine and 35 ml of absolute ethanol, was added 0.35 g of acrylonitrile. After the mixture had been heated at reflux for 16 hours the solvent and excess of reagents were removed under reduced pressure to give 1.7 g (94%) of crude (-)-3-acetyl-17-morphinanpropanenitrile. For analysis, a sample of this compound was distilled, bp 220°-230° (0.05 mm), [α]25D-65.5° (c 1.03, MeOH).
Reaction SMILES: [CH3:1][N:2]([CH3:57])[C:3]1[N:4]=[C:5]([O:15][C@H:16]2[CH2:56][N:19]3[C:20](=[O:55])[C@@H:21]([NH:47]C(=O)OC(C)(C)C)[C@H:22]([CH3:46])[CH2:23][CH:24]([CH3:45])[CH2:25][CH2:26][CH:27]=[CH:28][C@@H:29]4[CH2:34][C@@:30]4([C:35](=[O:44])[NH:36][S:37]([C:40]4([CH3:43])[CH2:42][CH2:41]4)(=[O:39])=[O:38])[NH:31][C:32](=[O:33])[C@@H:18]3[CH2:17]2)[C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2.[F:58][C:59]([F:64])([F:63])[C:60]([OH:62])=[O:61]>C(Cl)Cl>[OH:62][C:60]([C:59]([F:64])([F:63])[F:58])=[O:61].[NH2:47][C@@H:21]1[C:20](=[O:55])[N:19]2[CH2:56][C@H:16]([O:15][C:5]3[C:6]4[C:11](=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=4)[CH:12]=[C:3]([N:2]([CH3:1])[CH3:57])[N:4]=3)[CH2:17][C@H:18]2[C:32](=[O:33])[NH:31][C@:30]2([C:35]([NH:36][S:37]([C:40]3([CH3:43])[CH2:41][CH2:42]3)(=[O:38])=[O:39])=[O:44])[CH2:34][C@H:29]2[CH:28]=[CH:27][CH2:26][CH2:25][CH:24]([CH3:45])[CH2:23][C@H:22]1[CH3:46]
Reactant: COc1ccc2c(O[C@@H]3C[C@H]4C(=O)N[C@]5(C(=O)NS(=O)(=O)C6(C)CC6)C[C@H]5C=CCCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N4C3)nc(N(C)C)cc2c1
Agent: COc1ccc2c(O[C@@H]3C[C@H]4C(=O)N[C@]5(C(=O)NS(=O)(=O)C6(C)CC6)C[C@H]5/C=C\CCC(C)C[C@@H](C)[C@H](N)C(=O)N4C3)nc(N(C)C)cc2c1
Agent: COc1ccc2c(O[C@@H]3C[C@H]4C(=O)N[C@]5(C(=O)NS(=O)(=O)C6(C)CC6)C[C@H]5/C=C\CCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N4C3)nc(N(C)C)cc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(O[C@@H]3C[C@H]4C(=O)N[C@]5(C(=O)NS(=O)(=O)C6(C)CC6)C[C@H]5C=CCCC(C)C[C@@H](C)[C@H](N)C(=O)N4C3)nc(N(C)C)cc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-butyl ((2R,6S,7R,13aS,14aR,16aS,Z)-2-((3-(dimethylamino)-6-methoxyisoquinolin-1-yl)oxy)-7,9-dimethyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate (50 mg, 0.062 mmol) was dissolved in DCM (4 mL) and trifluoroacetic acid (TFA, 1 ml, 12.98 mmol) was added. The reaction was stirred for 1 h at room temperature. The volatiles were removed under vacuum to give (2R,6S,7R,13aS,14aR,16aS,Z)-6-amino-2-((3-(dimethylamino)-6-methoxyisoquinolin-1-yl)oxy)-7,9-dimethyl-N-((1-methylcyclopropyl)sulfonyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide TFA (51 mg) which was used in the next step as is. MS: MS m/z 711.1 (M++1).
Reaction SMILES: C(N(CC)CC)C.Cl.Cl.[NH2:10][C@H:11]1[CH:16]2[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]2)[CH2:12]1.[CH3:19][O:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](O)=[O:24].[I-].ClC1C=CC=C[N+]=1C>O.C(#N)C>[CH3:19][O:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([NH:10][C@H:11]1[CH:16]2[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]2)[CH2:12]1)=[O:24]
Reactant: COc1ccccc1C(=O)O
Reactant: N[C@@H]1CN2CCC1CC2
Agent: C[n+]1ccccc1Cl
Agent: Cl
Agent: [I-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccccc1C(=O)N[C@@H]1CN2CCC1CC2
Reaction time: 8 h
Yield: 84.9 %

Procedure:
1.5 ml of Acetonitrile and Triethylamine (700 uL, 5.0 mmol) was added to a flask charged with (S)-(−)-3-Aminoquinuclidine dihydrochloride (199 mg, 1.0 mmol) and o-Methoxybenzoic acid (167 mg, 1.1 mmol), followed by addition of 2-Chloro-1-methyl pyridinium iodide (383 mg, 1.5 mmol) at room temperature. After stirring overnight, about 2 ml of water was added to reaction mixture to resolve a clear solution that was subsequently injected into a Preparative HPLC instrument for purification. Desired fractions were combined and concentrated under vacuum. (S)-2-methoxy-N-(quinuclidin-3-yl)benzamide (221 mg, 85% yield) was isolated as an oil. 1H NMR (400 MHz, Methanol-D4) δ (ppm): 7.79 (dd, J=7.7 1.6 Hz, 1H), 7.51 (td, J=8.0, 1.6 Hz, 1H), 7.15 (d, J=8.5 Hz, 1H), 7.06 (t, J=7.4 Hz, 1H), 4.45 (m, 4H), 3.97 (s, 3H), 3.82 (ddd, J=11.7, 9.9, 2.0 Hz 1H), 3.37 (m, 4H), 2.37 (q, J=3.2 Hz, 1H), 2.20 (m, 1H), 2.09 (m, 2H), 1.99 (m, 1H). LCMS (ESI): m/z 261.1 (M+H [C15H20N2O]=261.15).
Reaction SMILES: [CH:1]1([N:4]2[C:10]3[N:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[NH:7][C:6]3[C:16]([CH3:20])=[CH:17][CH:18]=[N:19][C:5]2=3)[CH2:3][CH2:2]1.[H-].[Na+].[O:23]1CCCC1>>[CH:1]1([N:4]2[C:10]3[N:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[N:7]([OH:23])[C:6]3[C:16]([CH3:20])=[CH:17][CH:18]=[N:19][C:5]2=3)[CH2:3][CH2:2]1
Reactant: C1CCOC1
Reactant: Cc1ccnc2c1NC(=O)c1cccnc1N2C1CC1
Agent: [H-]
Agent: [Na+]
Product: Cc1ccnc2c1N(O)C(=O)c1cccnc1N2C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 9.5 %

Procedure:
To a mixture of 0.5 g of 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (Example 12) in 25 ml of tetrahydrofuran was added 0.12 g of 50% sodium hydride in mineral oil. The reaction mixture was stirred at room temperature for one hour and then cooled to 0° C., at which time 0.9 g of oxodiperoxymolybdenum(pyridine)hexamethylphosphoramide (MoOPH) was added in one portion. The reaction mixture was then allowed to warm to room temperature and was allowed to stir overnight. The mixture was quenched with water and the solvents removed in vacuo. The residue was extracted with warm ethyl acetate, concentrated in vacuo and purified on a silica gel column (eluent: ethyl acetate) to give 0.05 g of pure 11-cyclopropyl-5,11-dihydro-5-hydroxy-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one, m.p. 239°-241° C. The yield was 9.5% of theory.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([C:21](OC)=[O:22])[C:12]3[C@@H:25]([C:33]4[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=4)[O:26][C:27]4([CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[C:11]=3[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>O1CCCC1.C(OCC)C>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH2:21][OH:22])[C:12]3[C@@H:25]([C:33]4[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:40])[F:41])=[CH:35][CH:34]=4)[O:26][C:27]4([CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[C:11]=3[C:10]1=2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: COC(=O)c1nc2c(c3c1[C@@H](c1ccc(C(F)(F)F)cc1)OC31CCOCC1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(C)Cc2nc(CO)c3c(c2[C@@H](O[Si](C)(C)C(C)(C)C)C1)C1(CCOCC1)O[C@@H]3c1ccc(C(F)(F)F)cc1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
1.28 g (3R,9S)-methyl 9-(tert-butyldimethylsilyloxy)-7,7-dimethyl-3-(4-(trifluoromethyl)phenyl)-2′,3′,5′,6,6′,7,8,9-octahydro-3H-spiro[furo[3,4-c]quinoline-1,4′-pyran]-4-carboxylate are dissolved in 10 ml tetrahydrofurane cooled to −10° C. and treated dropwise with 1.2 ml of a 1 M solution of lithiumaluminium hydride in tetrahydrofurane. The mixture is warmed to room temperature and stirred for 1 hour. Then it is diluted with diethylether and treated under vigorous stirring with 1 M hydrochloric acid. The organic phase is separated, dried with magnesium sulphate and evaporated in vacuo. The residue is chromatographed on silica gel (petrole ether/ethylacetate 70:30 to 40:60).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:7]1[CH:12]=[N:11][CH:10]=[CH:9][N:8]=1)[C:5]#[N:6].[OH-:13].[K+]>CO.O>[CH3:1][O:2][N:3]=[C:4]([C:7]1[CH:12]=[N:11][CH:10]=[CH:9][N:8]=1)[C:5]([NH2:6])=[O:13]
Reactant: CON=C(C#N)c1cnccn1
Reactant: [OH-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CON=C(C(N)=O)c1cnccn1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
α-Methoxyiminopyrazineacetonitrile Z-isomer (6.0 g) was dissolved in 35 ml of methanol. A solution of potassium hydroxide (4 g) in 10 ml of water was added and the dark reaction mixture was stirred for 1 hour at a temperature of 40° C. The greater part of the methanol was evaporated under reduced pressure.
Reaction SMILES: Br.[NH2:2][C:3]1[N:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Cl[CH2:11][C:12]([CH3:15])([OH:14])[CH3:13].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[NH2:2][C:3]1[N:8]=[CH:7][C:6]([O:9][CH2:11][C:12]([CH3:15])([OH:14])[CH3:13])=[CH:5][CH:4]=1
Reactant: CC(C)(O)CCl
Reactant: Nc1ccc(O)cn1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(O)COc1ccc(N)nc1
Temperature: 140 °C

Procedure:
To a microwave flask containing 6-aminopyridin-3-ol hydrobromide (700 mg, 3.66 mmol) and 1-chloro-2-methyl-2-propanol (597 mg, 5.5 mmol) in anhydrous dimethylformamide (17 ml) was added cesium carbonate (3.7 g, 11.4 mmol) and the material was heated in a microwave oven at 140° C. for 3 hours. The vial was cooled to ambient and the solvent was concentrated in vacuo (rotary evaporator/mechanical pump). The residue was taken up in methylene chloride and filtered to remove insolubles, rinsing well with methylene chloride. The crude material was purified by HPLC on silica gel, eluting with a gradient of 2% to 10% methanol/methylene chloride to provide the desired product as a orange-brown viscous oil which solidified on standing (449 mg). MS (H+)=183 m/e.
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23]([N:30]1[CH:34]=[C:33]([CH2:35]Br)[C:32]([N+:37]([O-:39])=[O:38])=[N:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C=CCO[C@H](C1C2C(=CC=CC=2)N=CC=1)[C@H]1[N+]2(CC3C4C(=CC=CC=4)C=C4C=3C=CC=C4)C[C@H](C=C)[C@@H](CC2)C1.[Br-].O.[OH-].[Cs+]>ClCCl>[CH2:23]([N:30]1[CH:34]=[C:33]([CH2:35][C@@H:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[N:8]=[C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:32]([N+:37]([O-:39])=[O:38])=[N:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=[N+]([O-])c1nn(Cc2ccccc2)cc1CBr
Reactant: CC(C)(C)OC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: C=CCO[C@H](c1ccnc2ccccc12)[C@@H]1C[C@@H]2CC[N+]1(Cc1c3ccccc3cc3ccccc13)C[C@@H]2C=C
Agent: [Br-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)[C@H](Cc1cn(Cc2ccccc2)nc1[N+](=O)[O-])N=C(c1ccccc1)c1ccccc1
Temperature: -30 °C
Reaction time: 18 h

Procedure:
To a −30° C. solution of tert-butyl N-(diphenylmethylene)glycinate (98% 1.16 g, 3.85 mmol), C4 (951 mg, 3.21 mmol) and O-allyl-N-(9-anthracenylmethyl)cinchonidinium bromide (95%, 0.205 g, 0.322 mmol) in dichloromethane (25 mL) was added cesium hydroxide monohydrate (0.647 g, 3.85 mmol). (See E. J. Corey et al., J. Am. Chem. Soc. 1997, 119, 12414-12415.) The reaction was stirred at −30° C. for 18 hours, then washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (Eluants: dichloromethane, then EtOAc) to give C5 as a gum. Yield: 1.63 g, 3.19 mmol, 99%. LCMS m/z 511.3 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.39 (s, 9H), 3.24 (dd, half of ABX pattern, J=14.3, 8.2 Hz, 1H), 3.38 (br dd, half of ABX pattern, J=14.3, 4.6 Hz, 1H), 4.22 (dd, J=8.3, 4.6 Hz, 1H), 5.25 (AB quartet, JAB=14.6 Hz, ΔνAB=18.3 Hz, 2H), 6.72 (br d, J=7 Hz, 2H), 7.16-7.22 (m, 4H), 7.25-7.44 (m, 8H), 7.50-7.54 (m, 2H).
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C@H:17]3[CH2:22][CH2:21][N:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:19][C@H:18]3[CH2:29][C:30]([O:32]CC)=[O:31])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=[NH:4].[ClH:35]>>[ClH:35].[ClH:35].[ClH:35].[OH:1][NH:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:12][CH2:13][N:14]([C@H:17]3[CH2:22][CH2:21][N:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:19][C@H:18]3[CH2:29][C:30]([OH:32])=[O:31])[CH2:15][CH2:16]2)=[CH:7][CH:6]=1)=[NH:4]
Reactant: CCOC(=O)C[C@@H]1CN(CC(=O)OCC)CC[C@@H]1N1CCN(c2ccc(C(=N)NO)cc2)CC1
Agent: Cl
Product: CCOC(=O)CN1CC[C@H](N2CCN(c3ccc(C(=N)NO)cc3)CC2)[C@H](CC(=O)O)C1

Procedure:
(±)-cis-Diethyl 4-[4-(4-hydroxyamidinophenyl)-1-piperazinyl]-1,3-piperidinediacetate (1.5 g) was dissolved in 50 ml of 1N hydrochloric acid and the solution was refluxed overnight. The reaction liquid was concentrated and the concentrate was purified by ODS column chromatography (eluent: water to water:methanol=1:1) to give 100 mg of (±)-cis-4-[4-(4-hydroxyamidinophenyl)-1-piperazinyl]-1-[(ethoxycarbonyl)methyl]piperidine-3-acetic acid trihydrochloride.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[C:23]([C:27]1[S:28][CH:29]=[C:30]([C:32]([N:34]2[CH2:39][C:38]3([CH2:44][CH2:43][N:42]([CH2:45][C:46]4[S:47][CH:48]=[C:49]([CH2:51][CH2:52][OH:53])[CH:50]=4)[CH2:41][CH2:40]3)[O:37][CH2:36][CH2:35]2)=[O:33])[N:31]=1)([CH3:26])([CH3:25])[CH3:24].C(O)(C(F)(F)F)=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[C:23]([C:27]1[S:28][CH:29]=[C:30]([C:32]([N:34]2[CH2:39][C:38]3([CH2:40][CH2:41][N:42]([CH2:45][C:46]4[S:47][CH:48]=[C:49]([CH2:51][CH:52]=[O:53])[CH:50]=4)[CH2:43][CH2:44]3)[O:37][CH2:36][CH2:35]2)=[O:33])[N:31]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cc(CCO)cs4)CC3)C2)cs1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cc(CC=O)cs4)CC3)C2)cs1

Procedure:
Dess-Martin periodinane (0.316 g) was added to stirred solution of (2-tert-butylthiazol-4-yl)(9-((4-(2-hydroxyethyl)thiophen-2-yl)methyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone (example 43, step d) (0.23 g) and TFA (0.05 mL) in DCM (5 mL). After 40 min the reaction mixture was treated with aqueous saturated sodium thiosulphate solution (5 mL), saturated sodium bicarbonate solution (5 mL) and ethyl acetate (30 mL). The mixture was extracted twice with ethyl acetate, the combined organics were washed with saturated sodium bicarbonate solution, acetic acid (0.08 mL) was added, then the solution was dried over sodium sulphate, filtered, and then evaporated in vacuo to afford the subtitled compound. Yield 0.23 g. Used directly.