Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4](=[O:14])[NH:5][C:6]([CH:10]2[CH2:13][CH2:12][CH2:11]2)=[CH:7][C:8]=1[CH3:9].[NH2:15][CH2:16][C:17]1[C:18](=[O:28])[NH:19][C:20]([CH3:27])=[CH:21][C:22]=1[CH:23]1[CH2:26][CH2:25][CH2:24]1.CC([O:33][C:34](OC(OC(C)(C)C)=O)=[O:35])(C)C.C(N(CC)CC)C>C1COCC1.CN(C=O)C>[CH3:26][C:23]([N:1]([CH2:2][C:3]1[C:4](=[O:14])[NH:5][C:6]([CH:10]2[CH2:11][CH2:12][CH2:13]2)=[CH:7][C:8]=1[CH3:9])[C:34](=[O:33])[O-:35])([CH3:22])[CH3:24].[CH3:13][C:10]([N:15]([CH2:16][C:17]1[C:18](=[O:28])[NH:19][C:20]([CH3:27])=[CH:21][C:22]=1[CH:23]1[CH2:26][CH2:25][CH2:24]1)[C:34](=[O:33])[O-:35])([CH3:6])[CH3:11]
Reactant: Cc1cc(C2CCC2)[nH]c(=O)c1CN
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Cc1cc(C2CCC2)c(CN)c(=O)[nH]1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cc(C2CCC2)[nH]c(=O)c1CN(C(=O)[O-])C(C)(C)C
Product: Cc1cc(C2CCC2)c(CN(C(=O)[O-])C(C)(C)C)c(=O)[nH]1
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 20 %
Yield: 9.5 %

Procedure:
To an ice bath cooled solution of 3-(aminomethyl)-6-cyclobutyl-4-methyl-2(1H)-pyridinone and 3-(aminomethyl)-4-cyclobutyl-6-methyl-2(1H)-pyridinone (3.5 g, 18 mmol) in THF (10 mL) and DMF (10 mL) were added Boc2O (4.68 g, 21.8 mmol) and triethylamine (5.4 g, 54 mmol). The contents were then stirred for 30 min at 30° C. The reaction was quenched by addition of ice water, during which time precipitation occurred. The reaction mixture was filtered and dried to give a mixture of the crude products. The crude products were separated by HPLC to give 1,1-dimethylethyl[(6-cyclobutyl-4-methyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]carbamate (2.1 g, 20%) and 1,1-dimethylethyl[(4-cyclobutyl-6-methyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]carbamate (1 g, 9.5%). Data for 1,1-dimethylethyl[(6-cyclobutyl-4-methyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]carbamate: 1H NMR (400 MHz, DMSO-d6) δ 11.28 (br s, 1H), 6.49 (br s, 1H), 5.86 (br s, 1H), 3.85 (br s, 2H), 1.97-2.14 (m, 7H), 1.87-1.94 (m, 1H), 1.72-1.77 (m, 1H), 1.28 (s, 9H).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)[C:14]3=[N:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[Cl:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][NH2:32]>>[Cl:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][NH:32][C:5]1[N:10]=[C:9]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)[C:14]3=[N:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1
Reactant: NCc1cccc(Cl)c1
Reactant: CN1CCN(c2nccn3c(-c4ccnc(S(C)(=O)=O)n4)cnc23)CC1
Product: CN1CCN(c2nccn3c(-c4ccnc(NCc5cccc(Cl)c5)n4)cnc23)CC1
Temperature: 140 °C
Reaction time: 2 h

Procedure:
The mixture of 3-(2-methanesulfonyl-pyrimidin-4-yl)-8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazine (from Example 46 supra) (150 mg, 0.402 mmol) and 3-chlorobenzylamine (228 mg, 1.608 mmol) was heated at 140° C. with stirring for 2 hours. The resulting oil was purified by chromatography (silica gel, 10 g, 200-300 mesh, eluting with dichloromethane:methanol, 30:1 to 10:1) to afford the crude product (120 mg). Then the crude product was purified by prep-HPLC. Several drops concentrated HCl were added to the fractions with product. After sonicating for several minutes, solution was concentrated under reduced pressure to afford (3-chloro-benzyl)-{4-[8-(4-methyl-piperazin-1-yl)-imidazo [1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-amine; hydrochloride. (Yield 45 mg, 25.8%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:18].[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([O:29][CH3:30])=[C:24](B(O)O)[CH:25]=1>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([O:29][CH3:30])=[C:22]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)(=[O:10])=[O:9])=[CH:4][C:3]=2[F:18])[CH:21]=1
Reactant: O=S(=O)(c1ccc(F)cc1)c1ccc(Br)c(F)c1
Reactant: COc1ccc(Cl)cc1B(O)O
Product: COc1ccc(Cl)cc1-c1ccc(S(=O)(=O)c2ccc(F)cc2)cc1F

Procedure:
The subtitle compound was prepared by the method of example 2 step (ii) using the product of step (i) and 5-chloro-2-methoxybenzene boronic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:13]([NH:15][C:16]2[N:17]=[CH:18][C:19]([C:22](O)=[O:23])=[N:20][CH:21]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.Cl.[O:38](ON)[C:39]([CH3:42])([CH3:41])[CH3:40].[N:45]1C=CC=CC=1>C(Cl)Cl.CN(C)C=O.O1CCCC1>[C:39]([O:38][NH:45][C:22]([C:19]1[CH:18]=[N:17][C:16]([NH:15][C:13](=[O:14])[C@@H:12]([C:4]2[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[C:2]([Cl:1])[CH:3]=2)[CH2:25][CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30]2)=[CH:21][N:20]=1)=[O:23])([CH3:42])([CH3:41])[CH3:40]
Reactant: c1ccncc1
Reactant: CC(C)(C)OON
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(C(=O)O)cn2)cc1Cl
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)ONC(=O)c1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 72.9 %

Procedure:
A solution of 5-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazine-2-carboxylic acid (401.6 mg, 0.889 mmol) in methylene chloride (4.4 mL) was cooled to 0° C. The reaction mixture was then treated with oxalyl chloride (310 μL, 3.554 mmol) and N,N-dimethylformamide (2 drops). The reaction mixture was stirred at 0° C. for 45 min and then slowly warmed to 25° C. over 1 h 45 min. The solution was then concentrated in vacuo. The residue was dissolved in methylene chloride (3.4 mL) and cooled to 0° C. The resulting solution was then treated with a mixture of O-(tert-butoxyl)hydroxylamine hydrochloride (133.3 mg, 1.061 mmol) and pyridine (180 μL, 2.226 mmol) in tetrahydrofuran (4.4 mL), followed by a methylene chloride rinse (1 mL). The reaction mixture was stirred at 0° C. for 45 min and then stirred at 25° C. for 2 h 15 min. The reaction was then quenched with water (5 mL) and stirred at 25° C. for 30–45 min. The reaction was partitioned between ethyl acetate (300 mL) and a 1N aqueous citric acid solution (250 mL), and the layers were seperated. The organic layer was washed with a saturated aqueous sodium bicarbonate solution (250 mL), water (250 mL), and a saturated aqueous sodium chloride solution (250 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40L, Silica, 2/3 to 1/1 ethyl acetate/hexanes) afforded 5-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazine-2-carboxylic acid tert-butoxy-amide (338.8 mg, 73%) as an off-white foam: mp 128–131° C. (foam to gel); (ES)+-HRMS m/e calcd for C24H31ClN4O5S (M+H)+ 523.1777, found 523.1782.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[CH2:7][N:8]([CH3:20])[S:9]([NH:12]C(=O)OC(C)(C)C)(=[O:11])=[O:10].[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24]>ClCCl>[F:21][C:22]([F:27])([F:26])[C:23]([O-:25])=[O:24].[O:1]1[CH2:6][CH2:5][O:4][CH2:3][C@H:2]1[CH2:7][N:8]([CH3:20])[S:9]([NH3+:12])(=[O:11])=[O:10]
Reactant: CN(CC1COCCO1)S(=O)(=O)NC(=O)OC(C)(C)C
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C[C@@H]1COCCO1)S([NH3+])(=O)=O
Product: O=C([O-])C(F)(F)F
Reaction time: 2 h

Procedure:
tert-butyl {[(1,4-dioxan-2-ylmethyl)(methyl)amino]sulfonyl}carbamate (1.25 g, 4.03 mmol) was dissolved in 10 mL dichloromethane and 20 mL trifluoroacetic acid and stirred at ambient temperature. After 2 hours, the solution was concentrated and azeotroped twice with heptane to afford the title compound. LRMS (APCI) calc'd for (C6H15N2O4S) [M+H]+, 211.1; found, 211.1.
Reaction SMILES: [OH:1][C:2]1[C:14]2[C:13]3C=[CH:11][C:10]([C:15]([F:18])([F:17])[F:16])=[CH:9][C:8]=3[NH:7][C:6]=2[C:5](C#N)=[CH:4][N:3]=1.[C:21]([O-])([O-])=O.[K+].[K+].CI.[NH4+].[Cl-].[CH3:31][N:32]([CH:34]=O)[CH3:33]>CCOC(C)=O.O>[CH3:21][O:1][C:2]1[C:14]2[C:13]3[CH:8]=[CH:9][C:10]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:33]=3[N:32]([CH3:31])[C:34]=2[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: CN(C)C=O
Reactant: N#Cc1cnc(O)c2c1[nH]c1cc(C(F)(F)F)ccc12
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: O
Product: COc1ncc(C#N)c2c1c1ccc(C(F)(F)F)cc1n2C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 1-hydroxy-7-(trifluoromethyl)-5H-pyrido[4,3-b]indole-4-carbonitrile (Example 5, Step 3) and K2CO3 (2.5 equiv) in DMF (0.09 M) at room temperature was added MeI (1.5 equiv). After stirring at room temperature for 30 min, saturated NH4Cl solution was added along with H2O, and EtOAc (same amount as DMF). The resulting suspension was stirred vigorously for 10 min, and the product was then collected by filtration to give the title compound as a beige solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C@@H:12]([C:24]([OH:26])=O)[NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27]([O:31][C:32](=[O:48])[NH:33][CH2:34][CH2:35][CH2:36][C@H:37]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:38][NH2:39])([CH3:30])([CH3:29])[CH3:28].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[CH2:17]([O:16][C:14](=[O:15])[NH:13][C@H:12]([C:24]([NH:39][CH2:38][C@@H:37]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:36][CH2:35][CH2:34][NH:33][C:32]([O:31][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:48])=[O:26])[CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](CN)NC(=O)OC(C)(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCCC[C@@H](CNC(=O)[C@H](CCCNC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
Preparation takes place in analogy to Example 79A from 120 mg (0.33 mmol) of N5-(tert-butoxycarbonyl)-N2-[(benzyloxy)carbonyl]-L-ornithine and 136 mg (0.43 mmol) of tert-butyl{(4S)-5-amino-4-[(tert-butoxycarbonyl)amino]pentyl}carbamate (Example 86A) in 6 ml of dimethylformamide with the addition of 82 mg (0.43 mmol) of EDC and 13 mg (0.1 mmol) of HOBt. The product is purified by preparative RP-HPLC (mobile phase water/acetonitrile gradient: 90:10→5:95).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[N:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C@@H:15]1[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]1.[Br:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C@@H:29]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30][C:31](O)=[O:32])=[CH:24][CH:23]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C@@H:29]([NH:34][C:35](=[O:36])[O:37][C:38]([CH3:40])([CH3:39])[CH3:41])[CH2:30][C:31]([N:17]2[CH2:18][CH2:19][CH2:20][C@@H:15]([C:7]3[N:6]([CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:10]4[CH:11]=[N:12][CH:13]=[CH:14][C:9]=4[N:8]=3)[CH2:16]2)=[O:32])=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccc(Br)cc1
Reactant: COCCCn1c([C@@H]2CCCNC2)nc2ccncc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COCCCn1c([C@@H]2CCCN(C(=O)C[C@@H](Cc3ccc(Br)cc3)NC(=O)OC(C)(C)C)C2)nc2ccncc21
Yield: 85 %

Procedure:
(R)-3-(3-Methoxypropyl)-2-(piperidin-3-yl)-3H-imidazo[4,5-c]pyridine (35E) (0.279 mmol, crude oil) was added to a 15 mL round-bottomed flask equipped for stirring under nitrogen. DMF (2 mL), (R)-4-(4-bromophenyl)-3-(tert-butoxycarbonylamino)butanoic acid (0.335 mmol, 0.086 g) and N-methylmorpholine (1.95 mmol, 0.214 mL) were then added and the solution was allowed to stir at rt for 5 min. HATU (0.335 mmol, 0.127 g) was added and the resultant solution was stirred at room temperature for 3 hr. The reaction solution was then directly purified by preparative LC/MS (25-85% CH3CN in H2O). The resultant fractions were collected and the solvent was removed in-vacuo affording tert-butyl (R)-1-(4-bromophenyl)-4-((R)-3-(3-(3-methoxypropyl)-3H-imidazo[4,5-c]pyridin-2-yl)piperidin-1-yl)-4-oxobutan-2-ylcarbamate (35F) as a clear oil (0.238 mmol, 0.146 g, 85% yield). ESI-ESI-MS: adz 614.3 (M+H)+.
Reaction SMILES: O.[C:2]1([C:8]([CH:10]=[O:11])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([CH3:20])[C:14]=1[CH3:21]>ClC(Cl)C.[Ti](Cl)(Cl)(Cl)Cl>[CH3:19][C:16]1[C:15]([CH3:20])=[C:14]([CH3:21])[C:13]([CH3:12])=[CH:18][C:17]=1[CH:10]([OH:11])[C:8](=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(C)c(C)c1C
Reactant: O=CC(=O)c1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: CC(Cl)Cl
Product: Cc1cc(C(O)C(=O)c2ccccc2)c(C)c(C)c1C
Yield: 70.7 %

Procedure:
Phenylglyoxal monohydrate (304 mg, 2 mM) and 1,2,3,4-tetramethylbenzene (0.60 ml, 4 mM were dissolved in dichloroethane (5 ml), titanium tetrachloride (0.33 ml, 3 mM) was added, and reacted at room temperature for 10 minutes. Using the same procedure as in Example 1, 2',3',4',5'-tetramethylbenzoin was obtained (378.2 mg, 70.7% yield).
Reaction SMILES: [C:1]([O-:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[Na+].[C:12](O)(=O)[C:13]1C(=CC=C[CH:19]=1)O.[OH-].[Na+]>O>[C:1]([O:10][CH2:19][CH:13]=[CH2:12])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4]
Reactant: O=C(O)c1ccccc1O
Reactant: O=C([O-])c1ccccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CCOC(=O)c1ccccc1O

Procedure:
A sodium salicylate solution, prepared from 69 g of salicylic acid (0.5 mol), 25 ml of water and 50 ml of an aqueous solution of 10N caustic soda, was introduced gradually at 60° C., over 6 hours.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[F:26][C:27]([F:39])([F:38])[O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O>>[CH3:25][N:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[O:28][C:27]([F:26])([F:39])[F:38])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Reactant: OB(O)c1ccccc1OC(F)(F)F
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccccc1OC(F)(F)F

Procedure:
The title compound was prepared in analogy to example 25, from N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) and 2-(trifluormethoxy)phenylboronic acid (CAS RN 175676-65-0). Off-white solid (34%). MS (ESI): m/z=509.4 [M+H]+.
Reaction SMILES: [NH2:1][C@:2]1([CH2:15][OH:16])[CH2:6][CH2:5][C@@H:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[CH2:3]1.[C:17]([O-])([O-])=[O:18].[K+].[K+]>C(=O)(OCC)OCC>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([C@@H:4]2[CH2:5][CH2:6][C@@:2]3([NH:1][C:17](=[O:18])[O:16][CH2:15]3)[CH2:3]2)=[CH:8][CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc([C@@H]2CC[C@](N)(CO)C2)cc1
Agent: [K+]
Solvent: CCOC(=O)OCC
Product: COc1ccc([C@@H]2CC[C@]3(COC(=O)N3)C2)cc1
Yield: 79.9 %

Procedure:
To a suspension of [(1R,3R)-1-amino-3-(4-methoxy-phenyl)-cyclopentyl]-methanol (6.70 g, 30.3 mmol) in diethyl carbonate was added K2CO3 (4.83 g, 35.0 mmol) and the mixture was heated at reflux for about 20 hours. The reaction was concentrated, taken up in EtOAc (150 mL), washed with water (75 mL), dried over Na2SO4, filtered and concentrated. The crude product was further purified via flash chromatography with a gradient of from 40% to 80% EtOAc in heptane. Pure fractions were combined and concentrated to yield 5.99 g (80%) of (5R,7R)-7-(4-methoxy-phenyl)-3-oxa-1-aza-spiro[4.4]nonan-2-one as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:9]=[N:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].CN(CCN(C)C)C.[Li]CCCC.[I:34]I>C(OCC)C.C1COCC1>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:9]=[N:10][C:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:12][C:13]=1[I:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: II
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)nc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cnc(-c2ccccc2)cc1I
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 11 %

Procedure:
A solution of (6-phenylpyridin-3-yl)carbamic acid tert-butyl ester (5.54 g, 20.5 mmol) and TMEDA (6.49 mL, 43.0 mmol) in 100 mL of anhydrous diethyl ether was treated with n-BuLi at −78° C. After 15 minutes at −78° C., the mixture was warmed to −10° C. and stirred for an additional 3 hours. The reaction mixture was then cooled to −78° C. and a solution of iodine in a mixture of 10 mL of THF and 100 mL of diethyl ether was added dropwise. After 2 hours at −78° C., the mixture was allowed to warm to 0° C. and was quenched with 400 mL of saturated aqueous ammonium chloride solution. The organic layer was washed with five 100 mL portions of saturated aqueous sodium thiosulfate. The combined aqueous layers extracted with three 200 mL portions of ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Chromatography on SiO2 (0% to 70% ethyl acetate in hexanes, gradient) afforded 900 mg of the title product as yellow oil that solidified over time (11% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:5]2[CH:6]=[CH:7][C:8]3[C:9]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[CH:10]C(C)=[N:12][C:13]=3[C:14]=2[N:15]=1.[Se](=O)=[O:30].[O:32]1[CH2:37][CH2:36]OCC1>O>[C:17]1([C:9]2[C:8]3[C:13](=[C:14]4[C:5](=[CH:6][CH:7]=3)[C:4]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:3][C:2]([CH:1]=[O:30])=[N:15]4)[N:12]=[C:36]([CH:37]=[O:32])[CH:10]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cc(-c2ccccc2)c2ccc3c(-c4ccccc4)cc(C)nc3c2n1
Reactant: O=[Se]=O
Reactant: C1COCCO1
Solvent: O
Product: O=Cc1cc(-c2ccccc2)c2ccc3c(-c4ccccc4)cc(C=O)nc3c2n1
Reaction time: 2 h
Yield: 88 %

Procedure:
A mixture of bathocuproine (0.8 g, 2.2 mmole), selenium dioxide (1.16 g, 10.4 mmole), dioxane (29.6 ml) and water (1.25 ml) was heated with stirring in an oil bath at 110° for 2 hr. The hot mixture was then filtered through Celite to remove selenium metal. Water was added to the hot filtrate until slight cloudiness appeared. The mixture was then placed in the refrigerator to allow the product to precipitate. The product, which was contaminated by red selenium metal, was collected by vacuum filtration. Yield=88%. Mp=165°-170°. IR 3200-3600, 2800-3050, 1717, 1590, 1550, 1495, 1445, 1400, 1355, 1295, 1255, 1190, 1120, 1080, 875, 780, 705, 620 cm-1. 60 MHz proton NMR in CDCl3 δ7.2 (10 protons), δ7.7, δ7.95 (4 protons), δ10.05 (<2 protons).
Reaction SMILES: [OH:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][S:4][N:3]=1.[S:13](Cl)(=[O:16])(=[O:15])[NH2:14].C(N(C(C)C)CC)(C)C>C(#N)C>[C:7]1([C:6]2[C:2]([O:1][S:13](=[O:16])(=[O:15])[NH2:14])=[N:3][S:4][N:5]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NS(=O)(=O)Cl
Reactant: Oc1nsnc1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: NS(=O)(=O)Oc1nsnc1-c1ccccc1

Procedure:
A slurry of 3-hydroxy-4-phenyl-1,2,5-thiadiazole (15.0 g, 0.084 mole) in acetonitrile (100 ml) was treated by the simultaneous dropwise addition of a sulfamoyl chloride solution in acetonitrile (0.20 mole, 66 ml of 3M) and a diisopropylethylamine solution (0.22 mole in enough 1:1 acetonitrile/methylene chloride to make 66 ml). High Pressure Liquid Chromatography analysis indicated a maximum of 85% conversion of starting material to product. The reaction was worked up by concentration of the reaction mixture and partitioning the residue between ethyl ether and water. Concentration of the ether fraction gave a white paste from which desired product was separated by dissolving in a small amount of acetonitrile. The product was crystallized from the acetonitrile to give 2.8 g (13%) of the title compound as a white powder, mp 128°-130° C.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=2[C:9]=1[C:10](=[O:19])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[OH:18])[CH2:2][CH2:3][CH3:4].[CH2:24]([CH:26]1[O:28][CH2:27]1)Cl.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:1]([C:5]1[O:6][C:7]2[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=2[C:9]=1[C:10](=[O:19])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[O:18][CH2:24][CH:26]1[O:28][CH2:27]1)[CH2:2][CH2:3][CH3:4]
Reactant: ClCC1CO1
Reactant: CCCCc1oc2ccccc2c1C(=O)c1ccc(Cl)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCCCc1oc2ccccc2c1C(=O)c1ccc(Cl)cc1OCC1CO1

Procedure:
A mixture of 2-n-butyl-3-(4'-chloro-2'-hydroxybenzoyl)benzofuran, 30 ml. of epichlorohydrin and 15 g. of potassium carbonate in 200 ml. of ethanol was refluxed for 18 hours. The reaction mixture was concentrated, water was added to the residue and the aqueous solution was extracted with methylene chloride. The extracts were washed with water, dried (MgSO4) and concentrated in vacuo to give 2-n-butyl-3-[4'-chloro-2'-(2,3-epoxy)propoxybenzoyl]benzofuran which was purified by dry column chromatography on alumina with chloroform as eluant.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][CH3:16])[CH2:10][C@H:9]1[C:17]([OH:19])=O)=[O:7])(C)(C)C.[O:20]=[C:21]1[C:26](C(Cl)=O)=[CH:25][CH:24]=[C:23]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[O:22]1.[NH2:35][CH:36]1[CH2:39][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:37]1>>[CH2:15]([O:14][N:13]=[C:11]1[CH2:12][N:8]([C:6]([C:26]2[C:21](=[O:20])[O:22][C:23]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:24][CH:25]=2)=[O:7])[C@H:9]([C:17]([NH:35][CH:36]2[CH2:37][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:39]2)=[O:19])[CH2:10]1)[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Reactant: CCCCCc1ccc(C(=O)Cl)c(=O)o1
Reactant: CCON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CCCCCc1ccc(C(=O)N2CC(=NOCC)C[C@H]2C(=O)NC2CN(C(=O)OC(C)(C)C)C2)c(=O)o1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylic acid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and tert-butyl 3-amino-1-azetidinecarboxylate the title compound was obtained in 100% purity by LC/MS. MS(ESI+): m/z=519.6.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[C:15]([OH:25])(=[O:24])[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH2:17]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:17][CH:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]([OH:25])=[O:24])[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: C=C(C(=O)O)c1ccccc1
Solvent: CCO
Product: COc1ccccc1N1CCN(CC(C(=O)O)c2ccccc2)CC1
Temperature: 25 °C
Yield: 34.4 %

Procedure:
1-(2-Methoxyphenyl)piperazine (22.6 g, 0.118 mol) and atropic acid (174 g, 0.118 mol) in ethanol (300 ml) were heated under reflux for 18 hours, cooled to room temperature, and evaporated in vacuo. The solid was triturated with acetone (3×100 ml) to give a first crop of product (13.8 g) as white crystals. The filtrate was evaporated in vacuo to give an oil which slowly crystallised over 1 month. The solid was triturated with acetone (200 ml) to give a second crop of the hemihydrate of the product (9.01 g) as white crystals, m.p. 160°-163°.