Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-:1].[CH2:2]([N+:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH3:14])=[CH:6][CH:5]=1)[CH3:3].[CH3:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][N:22]1[C:34]2[CH:33]=[CH:32][C:31]([CH:35]=O)=[CH:30][C:29]=2[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2.N1CCCCC1>C(O)C>[Br-:1].[CH2:2]([N+:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](/[CH:14]=[CH:35]/[C:31]2[CH:32]=[CH:33][C:34]3[N:22]([CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:16][CH3:15])[C:23]4[C:28]([C:29]=3[CH:30]=2)=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:6][CH:5]=1)[CH3:3]
Reactant: CC[n+]1ccc(C)c2ccccc21
Reactant: COCCOCCn1c2ccccc2c2cc(C=O)ccc21
Agent: [Br-]
Solvent: C1CCNCC1
Solvent: CCO
Product: CC[n+]1ccc(/C=C/c2ccc3c(c2)c2ccccc2n3CCOCCOC)c2ccccc21
Temperature: 25 °C
Yield: 53 %

Procedure:
A solution mixture of 6 (0.20 g, 0.8 mmol), 3a (0.33 g, 1.1 mmol) and piperidine (0.1 mL) in ethanol (40 mL) was heated to reflux overnight. After cooling down to room temperature, the organic solvent was removed. The residue was purified by precipitation from methanol and ethyl acetate to afford SLE (0.22 g) in 53% yield. 1H NMR (400 MHz, DMSO-d6) δ 9.34 (d, J=8.4 Hz, 1H), 9.15 (d, J=8.4 Hz, 1H), 8.86 (s, 1H), 8.54-8.51 (m, 2H), 8.44 (d, J=16 Hz, 1H), 8.36 (d, J=16 Hz, 1H), 8.28-8.23 (m, 2H), 8.12 (d, J=8.0 Hz, 1H), 8.05 (t, J=7.6 Hz, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.52 (t, J=7.6 Hz, 1H), 7.31 (t, J=7.6 Hz, 1H), 4.99 (tr, J=6.8 Hz, 2H), 4.63 (t, J=4.8 Hz, 2H), 3.84 (t, J=4.8 Hz, 2H), 3.48 (t, J=4.8 Hz, 2H), 3.31 (t, J=4.8 Hz, 2H), 3.11 (s, 3H), 1.59 (t, J=6.8 Hz, 3H). 13C NMR (400 MHz, DMSO-d6) δ 153.2, 146.7, 145.1, 142.2, 140.9, 137.7, 135.0, 128.9, 127.4, 126.8, 126.7, 126.5, 126.4, 122.8, 122.2, 121.8, 120.4, 119.9, 119.0, 116.2, 115.5, 110.4, 110.3, 71.3, 69.8, 68.9, 58.1, 51.9, 15.1. HRMS (MALDI-TOF) m/z Calcd for C30H31N2O2 451.2380. Found 451.2362 [M]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[NH:7][CH:8]=1.Br[CH2:11][C:12]([C:14]1[CH:23]=[C:18]([C:19]([O:21][CH3:22])=[O:20])[C:17]([OH:24])=[CH:16][CH:15]=1)=[O:13]>C(N(CC)CC)C.C(O)C>[Cl:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[N:7]([CH2:11][C:12]([C:14]2[CH:23]=[C:18]([C:19]([O:21][CH3:22])=[O:20])[C:17]([OH:24])=[CH:16][CH:15]=2)=[O:13])[CH:8]=1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: COC(=O)c1cc(C(=O)CBr)ccc1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COC(=O)c1cc(C(=O)Cn2cc(Cl)cnc2=O)ccc1O

Procedure:
A solution of 5-chloropyrimidin-2-one hydrochloride (508 mg) and methyl 5-bromoacetylsalicylate (827 mg) in triethylamine (1 ml) and ethanol (20 ml) was stirred at ambient temperature for 13/4 hours, by which time a precipitate had formed. This suspension was chilled in ice, and the collected solid was crystallised from chloroform-ethanol to give the title pyrimidinone: yield 442 mg: m.p. 203°-204° dec: λmaxEtOH 228.5 nm (ε 40720), 269.5 nm (ε 16930), 312.5 nm (ε 6320).
Reaction SMILES: [CH3:1][CH:2]([C:11](=[O:21])[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[Cl:22][C:23]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][C:24]=1[NH2:25].C1(C)C=CC(S(O)(=O)=O)=CC=1>ClC1C=CC=CC=1>[Cl:22][C:23]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][C:24]=1[N:25]1[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:12][C:11](=[O:21])[C:2]([CH3:1])=[C:3]1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(C(=O)CC(=O)c1ccccc1)C(=O)c1ccccc1
Reactant: Nc1cc([N+](=O)[O-])ccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Clc1ccccc1
Product: Cc1c(-c2ccccc2)n(-c2cc([N+](=O)[O-])ccc2Cl)c(-c2ccccc2)cc1=O

Procedure:
To 170 ml of chlorobenzene were added 3.4 g (0.012 mole) of 2-methyl-1,5-diphenyl-1,3,5-pentanetrione, 10.4 g (0.060 mole) of 2-chloro-5-nitroaniline, 4.1 g (0.022 mole) of para-toluenesulfonic acid and 35.0 g of Molecular Sieves 5A, followed by refluxing for 2 hours. After cooling the reaction mixture, solid matter was removed from the reaction mixture, followed by addition of 200 ml of chloroform. The resultant mixture was washed first with 100 ml of 10% hydrochloric acid and then with 100 ml of a 10% aqueous solution of sodium hydroxide. The mixture was washed further with water and was then dried over anhydrous sodium sulfate. Subsequent to removal of the sodium sulfate, the solvent was distilled off and the residue was purified by chromatography on a silica gel column (eluent: ethyl acetate). Upon recrystallization of the resultant crystals from a 2:1 mixed solvent of acetone and hexane, 1.9 g of 1-(2-chloro-5-nitrophenyl)-3-methyl- 2,6-diphenyl-4(1H)-pyridinone having a melting point of 277°-279° C. was obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:20]=[CH:19][C:14]4[NH:15][C:16](=O)N[C:13]=4[CH:12]=3)[O:10][C:3]=12.[O:21]1[CH2:26][CH2:25][CH:24]([O:27][C:28]2[CH:35]=[CH:34][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][C:29]=2[C:30]#[N:31])[CH2:23][CH2:22]1>>[N:15]1([C:14]2[CH:19]=[CH:20][C:11]([C:9]3[O:10][C:3]4[C:4](=[N:5][CH:6]=[CH:7][C:2]=4[C:33]4[CH:34]=[CH:35][C:28]([O:27][CH:24]5[CH2:23][CH2:22][O:21][CH2:26][CH2:25]5)=[C:29]([CH:32]=4)[C:30]#[N:31])[CH:8]=3)=[CH:12][CH:13]=2)[CH2:8][CH2:9][O:10][CH2:3][CH2:16]1
Reactant: CC1(C)OB(c2ccc(OC3CCOCC3)c(C#N)c2)OC1(C)C
Reactant: O=c1[nH]c2ccc(-c3cc4nccc(Cl)c4o3)cc2[nH]1
Product: N#Cc1cc(-c2ccnc3cc(-c4ccc(N5CCOCC5)cc4)oc23)ccc1OC1CCOCC1

Procedure:
from 5-(7-chloro-furo[3,2-b]pyridin-2-yl)-1,3-dihydro-benzoimidazol-2-one and 2-(tetrahydro-pyran-4-yloxy)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitrile; HPLC/MS: 1.811 min, [M+H]=453;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([C:17]([OH:19])=O)=[C:10]2[O:13][CH:14]([CH3:16])[CH3:15])=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.CN(C=O)C.[CH:31]([NH2:34])([CH3:33])[CH3:32]>C1COCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([C:17]([NH:34][CH:31]([CH3:33])[CH3:32])=[O:19])=[C:10]2[O:13][CH:14]([CH3:15])[CH3:16])=[CH:5][CH:4]=1
Reactant: COc1ccc2ccc(C(=O)O)c(OC(C)C)c2c1
Reactant: CC(C)N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc2ccc(C(=O)NC(C)C)c(OC(C)C)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
To a room temperature solution of 7-methoxy-1-(1-methylethoxy)-2-naphthalenecarboxylic acid (200 0.77 mmol) in 5 mL of THF is added oxalyl chloride (0.08 mL, 0.92 mmol) followed by DMF (0.015 mL). The solution is stirred at room temperature for 2 hours. Isopropylamine (0.39 mL) is added and the reaction mixture is stirred at room temperature overnight. The reaction mixture is diluted with ethyl acetate and washed with 1N HCI, saturated NaHCO3, and brine. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo. The crude product is chromatographed on silica gel eluting with hexane:ethyl acetate (2:1) to provide 7-methoxy-1-(1-methylethoxy)-N-(1-methylethyl)-2-naphthalenecarboxamide in 72% yield; mp 62°-64° C.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(ON1C(=O)N(OC(=O)C)C(=O)N(OC(=O)C)C1=O)(=[O:16])C.O=O>C([O-])(=O)C.[Co+2].C([O-])(=O)C.C([O-])(=O)C.[Mn+2].C([O-])(=O)C.C(O)(=O)C>[C:1]1(=[O:16])[C:13]2[C:5]([C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:4][CH:3]=[CH:2]1.[CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)On1c(=O)n(OC(C)=O)c(=O)n(OC(C)=O)c1=O
Agent: [Co+2]
Agent: [Mn+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: O=C1C=CC=C2C1=Cc1ccccc12

Procedure:
A mixture of 1.00 g of fluorene, 0.055 g of 1,3,5-triacetoxy-hexahydro-1,3,5-triazine-2,4,6-trione (3% by mole relative to fluorene), 9.0 g of acetic acid, 0.008 g of cobalt(II) acetate.4H2O and 0.007 g of manganese(II) acetate.4H2O was stirred at 120° C. in an atmosphere of oxygene gas (1 atm=0.1 MPa) for 6 hours. The resulting product in the reaction mixture was analyzed by gas chromatography and was found to yield fluorenon in 93% yield at 99% conversion of fluorene.
Reaction SMILES: [CH2:1]([C@H:8]([NH:24][C:25](=[O:41])[C:26]1[CH:31]=[C:30]([N:32]2[CH2:36][CH2:35][CH2:34][C:33]2=[O:37])[CH:29]=[C:28]([N+:38]([O-])=O)[CH:27]=1)[C@H:9]([OH:23])[CH2:10][NH:11][C@H:12]([C:14](=[O:22])[NH:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCO>[Pd].O>[NH2:38][C:28]1[CH:27]=[C:26]([CH:31]=[C:30]([N:32]2[CH2:36][CH2:35][CH2:34][C:33]2=[O:37])[CH:29]=1)[C:25]([NH:24][C@@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@H:9]([OH:23])[CH2:10][NH:11][C@H:12]([C:14](=[O:22])[NH:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH3:13])=[O:41]
Reactant: C[C@H](NC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(N2CCCC2=O)cc([N+](=O)[O-])c1)C(=O)NC1CCCCC1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: C[C@H](NC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(N)cc(N2CCCC2=O)c1)C(=O)NC1CCCCC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
A mixture of N-[(1S,2R)-1-benzyl-3-((S)-1-cyclohexylcarbamoyl-ethylamino)-2-hydroxy-propyl]-3-nitro-5-(2-oxo-pyrrolidin-1-yl)-benzamide (E62) (40 mg, 0.07 mmol, 1 equiv), 10% Pd on charcoal (50% wet, 10 mg, 12.5% w/w), NH4COOH (55 mg, 0.90 mmol, 13 equiv), EtOH (5 ml) and H2O (2.5 ml) was stirred at 50° C. for 2 h, cooled to room temperature and the catalyst was filtered off through a pad of celite. Most of the EtOH was removed in vacuo and the residue was partitioned between AcOEt and saturated aqueous NaHCO3 solution. The aqueous phase was extracted with AcOEt. The combined organic phases were dried over MgSO4 and concentrated in vacuo. The residue was triturated with Et2O to give 3-amino-N-[(1S,2R)-1-benzyl-3-((S)-1-cyclohexylcarbamoyl-ethylamino)-2-hydroxypropyl]-5-(2-oxo-pyrrolidin-1-yl)-benzamide (E63) (15 mg, 38%) as a pale yellow solid. [M+H]+=536.1 RT-=2.27 min
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[NH:14][C:15](=[O:29])[CH:16]([NH2:28])[CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].[CH3:31]C(C)([O-])C.[Na+].O>C1COCC1>[CH2:11]([O:10][C:8]([C:7]1[CH:12]=[CH:13][C:4]2[C:3](=[O:2])[NH:28][CH:16]([CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[C:15](=[O:29])[NH:14][C:5]=2[CH:6]=1)=[O:9])[CH3:31]
Reactant: COC(=O)c1ccc(C(=O)OC)c(NC(=O)C(N)CCCNC(=O)OC(C)(C)C)c1
Reactant: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1ccc2c(c1)NC(=O)C(CCCNC(=O)OC(C)(C)C)NC2=O
Temperature: 60 °C
Reaction time: 15 h

Procedure:
The compound (303.8 mg) obtained in Example 14-2 and sodium t-butoxide (manufactured by Wako Pure Chemical Industries, Ltd.) (138.4 mg) were dissolved in anhydrous THF (6.0 ml) and the whole was stirred at 60° C. for 15 hours. After completion of the reaction, water was added thereto and the whole was subjected to extraction with chloroform.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[Si](C)(C)C.[C:30]([CH2:32][C:33](Cl)=[O:34])#[N:31]>ClCCl>[C:30]([CH2:32][C:33]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:6][CH:7]=1)=[O:34])#[N:31]
Reactant: N#CCC(=O)Cl
Reactant: Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#CCC(=O)Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Yield: 98.9 %

Procedure:
Using the method for the preparation of the side chain acid in Example 3, 11.5 g (50 mmol) of 6-(4-aminophenyl)-1,2-dihydro-2-oxonicotinic acid, 500 ml of dichloromethane, 21.0 ml (150 mmol) of triethylamine, 20 ml (158 mmol) of chlorotrimethylsilane, and 5.67 g (55 mmol) of cyanoacetyl chloride [Org. Syn. Col. Vol. V p. 171] gives 14.7 g of 6-[4-(cyanoacetylamino)phenyl]-1,2-dihydro-2-oxonicotinic acid; mp>280°.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:20][CH:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH3:22])=[N:6][C:7]([C:10]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][CH:14]=[N:15]3)=[CH:8][CH:9]=1)([O-])=O.ClC1N=C(NC(C2C=CC=CC=2)C)C([N+]([O-])=O)=CC=1.N1C2C(=C(B(O)O)C=CC=2)C=CC=1.[C:61](=O)([O-])[O-:62].[K+].[K+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:23]1([CH:21]([N:20]2[C:5]3=[N:6][C:7]([C:10]4[CH:19]=[CH:18][CH:17]=[C:16]5[C:11]=4[CH:12]=[CH:13][CH:14]=[N:15]5)=[CH:8][CH:9]=[C:4]3[NH:1][C:61]2=[O:62])[CH3:22])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C([O-])[O-]
Reactant: CC(Nc1nc(-c2cccc3ncccc23)ccc1[N+](=O)[O-])c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(Nc1nc(Cl)ccc1[N+](=O)[O-])c1ccccc1
Agent: OB(O)c1cccc2ncccc12
Solvent: O
Solvent: CN(C)C=O
Product: CC(c1ccccc1)n1c(=O)[nH]c2ccc(-c3cccc4ncccc34)nc21
Temperature: 85 °C
Yield: 79 %

Procedure:
3-Nitro-N-(1-phenylethyl)-6-(quinolin-5-yl)pyridin-2-amine. To a solution of 6-chloro-3-nitro-N-(1-phenylethyl)pyridin-2-amine (2.24 g, 8.07 mmol) and quinolin-5-ylboronic acid (1.81 g, 10.5 mmol) in DMF (150 mL) was added potassium carbonate (4.46 g, 32.3 mmol) in water (25 mL). The reaction solution was purged with a stream of nitrogen followed by the addition of tetrakis(triphenylphosphine)palladium(0) (932 mg, 0.81 mmol). After heating at 85° C. for 2 h, the solvent was removed under reduced pressure. The crude product was purified by silica gel chromatography to afford the title compound (2.36 g, 79% yield). MS (ESI) m/z 371.3 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:5].C[O-].[Na+].[ClH:17]>CO>[ClH:17].[CH3:1][O:2][C:3](=[O:13])[CH:4]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:5]
Reactant: COC(=O)[C@H](N)Cc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(N)Cc1ccccc1

Procedure:
5.0 Parts of D-phenylalanine methyl ester, dissolved in 80 parts of methanol, is treated, at room temperature, with 0.90 part of sodium methoxide. The mixture is heated rapidly to reflux and maintained at reflux for about 21/21/2 hours. Then the reaction mixture is cooled, acidified to pH 2 with concentrated hydrochloric acid and evaporated to dryness. The remaining crystalline residue is taken up in water, and sodium carbonate is added. 1,2-Dichloroethane is added to form two phases and the mixture is shaken and filtered. The organic layer is separated, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. The filtrate is acidified with hydrochloric acid, cooled and stripped of solvent. Trituration with ether of the material which remains after solvent removal and subsequent filtration yields DL-phenylalanine methyl ester hydrochloride, melting at about 162°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.[NH2:14][C@@H:15]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C@H:16]1[NH:24][S:25]([CH3:28])(=[O:27])=[O:26].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:14][C@@H:15]1[CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C@H:16]1[NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[O:13])=[CH:5]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: CS(=O)(=O)N[C@@H]1c2ccccc2C[C@H]1N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 79.2 %

Procedure:
5-Chloro-1H-indol-2-carboxylic acid (196 mg, 1.0 mmol), N-[(1R,2R)-2-amino-2,3-dihydro-1H-inden-1-yl]methanesulfonamide (Method 2; 226 mg, 1.0 mmol), DIPEA (0.17 ml, 1.0 mmol), and HOBT (130 mg, 1.0 mmol) was stirred in DCM (10 ml) for one minute. EDCI (240 mg, 1.25 mmol) was added and the mixture stirred at room temperature for 20 hours. The mixture was diluted with EtOAc, washed with water (2×25 ml), dried over magnesium sulphate and evaporated to give the title compound (320 mg, 79%) as a foam.
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13](Cl)[N:14]3[C:19]([CH:20]=2)=[C:18]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:28])[C:17](=[O:29])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].Cl>COCCOC.C(OCC)(=O)C>[ClH:27].[C:1]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[Cl:31])[N:14]3[C:19]([CH:20]=2)=[C:18]([C:21]2[C:22]([Cl:28])=[CH:23][CH:24]=[CH:25][C:26]=2[Cl:27])[C:17](=[O:29])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)N1CC=C(c2cc(Cl)n3ccc(=O)c(-c4c(Cl)cccc4Cl)c3c2)CC1
Reactant: OB(O)c1ccccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(C)(C)N1CC=C(c2cc(-c3ccccc3Cl)n3ccc(=O)c(-c4c(Cl)cccc4Cl)c3c2)CC1
Temperature: 80 °C
Yield: 73.4 %

Procedure:
To a solution of 8-(1-tert-butyl-1,2,3,6-tetrahydropyridin-4-yl)-6-chloro-1-(2,6-dichlorophenyl)-2H-quinolizin-2-one (57 mg) in DME was added 2-chlorophenylboronic acid (38 mg), palladium tetrakis triphenylphosphine (14 mg) and 2N sodium carbonate (0.36 mL). The mixture was heated to 80° C. for a couple of hours, then cooled to room temperature, and diluted with ethyl acetate/saturated aqueous sodium bicarbonate. The organic layers were dried over magnesium sulfate and concentrated. The residue was purified by silica gel (100% acetone). The free base was dissolved in methylene chloride and 3 eq. of HCl (1N in ethyl ether) was added to give the HCl salt (26 mg).
Reaction SMILES: [Na+].[SH2:2].Br[CH2:4][CH2:5][O:6][CH3:7]>>[CH3:7][O:6][CH2:5][CH2:4][S:2][S:2][CH2:4][CH2:5][O:6][CH3:7]
Reactant: COCCBr
Reactant: S
Agent: [Na+]
Product: COCCSSCCOC
Temperature: 23.5 °C

Procedure:
To 8 mL of the sodium polysulfide solution of Example 1 was added 1-bromo-2-methoxy ethane (3.7 g) with stirring at 22-25° C. Extraction of the reaction mixture with ether, washing of the ethereal solution with water, and concentration gave an oil. Distillation of the oil yielded 1.0 g of bis(methoxyethyl)disulfide. Analysis of the oil gave the following results: C, 38.27%; H, 7.82%; S, 36.18%. Calculated for C6H14O2S2: C, 39.56%; H, 7.69%; S, 35.16%.
Reaction SMILES: [NH:1]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C@@H:2]([C:19]([NH:21][CH2:22][C:23]([NH:25][C@H](C(NNC(CC)=O)=O)CC1C=CC=CC=1)=[O:24])=[O:20])[CH2:3][C:4]1[N:8]=[CH:7][N:6](S(C2C=CC(C)=CC=2)(=O)=O)[CH:5]=1.[OH-:49].[Na+]>CO>[NH:1]([C:42]([O:44][C:45]([CH3:46])([CH3:47])[CH3:48])=[O:43])[C@@H:2]([C:19]([NH:21][CH2:22][C:23]([NH:25][NH:1][C:2]([CH2:3][CH3:4])=[O:49])=[O:24])=[O:20])[CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1
Reactant: CCC(=O)NNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@@H](Cc1cn(S(=O)(=O)c2ccc(C)cc2)cn1)NC(=O)OC(C)(C)C
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: CCC(=O)NNC(=O)CNC(=O)[C@@H](Cc1c[nH]cn1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
BOC-(D)-His(Tos)-Gly-Phe-NHNH-COCH2CH3 (0.55 g) is suspended in MeOH (15 ml) and to this is added 1 N-sodium hydroxide solution (1 ml) at 0° C. The mixture is stirred for 60 min. at room temperature and evaporated. The residue is treated with acetonitrile to give a powder, which is washed with water and dried; yield 0.29 g. m.p. 261°-263° C., [α]D23 +9.5°(c=0.40, DMF), Rf2 =0.38
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]1[N:6]=[C:7]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][N:8]2[C:9](=[O:12])[C:10]=1[CH3:11].[CH3:18][C:19]([C:21]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=1)=O>CO>[CH3:11][C:10]1[C:9](=[O:12])[N:8]2[CH:13]=[CH:14][CH:15]=[C:16]([CH3:17])[C:7]2=[N:6][C:5]=1[CH:4]=[C:19]([CH3:18])[C:21]1[CH:22]=[C:23]([O:31][CH3:32])[C:24]([O:29][CH3:30])=[C:25]([O:27][CH3:28])[CH:26]=1
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Reactant: Cc1nc2c(C)cccn2c(=O)c1C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(C(C)=Cc2nc3c(C)cccn3c(=O)c2C)cc(OC)c1OC

Procedure:
To a solution of 1.3g of sodium methoxide in 75 ml of absolute methanol is added 2.0g of 2,3,9-trimethyl-4H-pyrido[1,2-a]pyrimidin-4-one, followed by 4.2g of 3,4,5-trimethoxyacetophenone. The mixture is stirred and heated under reflux for 97 hours to yield the title compound.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@H:6]1[O:15][C@H:16]1[C@@H:31]([OH:32])[C@@H:30]([CH2:33][O:34][C@@H:35]2[O:42][C@H:41]([CH2:43][OH:44])[C@@H:39]([OH:40])[C@H:37]([OH:38])[C@H:36]2[NH:45][C:46](=[O:48])[CH3:47])[O:29][C@@H:18]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[C@@H:17]1[OH:49])(=[O:3])[CH3:2].C1C(=O)NC(=O)NC=1[C@@H]1O[C@H](COP(OP(O[C@H:73]2[O:78][C@H:77]([CH2:79][OH:80])[C@H:76]([OH:81])[C@H:75]([OH:82])[C@H:74]2[OH:83])(O)=O)(O)=O)[C@@H](O)[C@H]1O>[As](C)(C)(=O)[O-].[Na+].[Cl-].[Mn+2].[Cl-]>[C@@H:18]1([O:12][C@@H:9]2[C@@H:8]([CH2:13][OH:14])[O:7][C@@H:6]([O:15][C@H:16]3[C@@H:31]([OH:32])[C@@H:30]([CH2:33][O:34][C@@H:35]4[O:42][C@H:41]([CH2:43][OH:44])[C@@H:39]([O:40][C@@H:73]5[O:78][C@H:77]([CH2:79][OH:80])[C@H:76]([OH:81])[C@H:75]([OH:82])[C@H:74]5[OH:83])[C@H:37]([OH:38])[C@H:36]4[NH:45][C:46](=[O:48])[CH3:47])[O:29][C@@H:18]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[C@@H:17]3[OH:49])[C@H:5]([NH:4][C:1](=[O:3])[CH3:2])[C@H:10]2[OH:11])[O:29][C@H:30]([CH2:33][OH:34])[C@H:31]([OH:32])[C@H:16]([OH:15])[C@H:17]1[OH:49]
Reactant: COC(=O)CCCCCO[C@@H]1O[C@H](CO[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2NC(C)=O)[C@H](O)[C@H](O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2NC(C)=O)[C@H]1O
Reactant: O=c1cc([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)O[C@H]3O[C@H](CO)[C@H](O)[C@H](O)[C@H]3O)[C@@H](O)[C@H]2O)[nH]c(=O)[nH]1
Agent: [Mn+2]
Agent: C[As](C)(=O)[O-]
Agent: [Cl-]
Product: COC(=O)CCCCCO[C@@H]1O[C@H](CO[C@@H]2O[C@H](CO)[C@@H](O[C@@H]3O[C@H](CO)[C@H](O)[C@H](O)[C@H]3O)[C@H](O)[C@H]2NC(C)=O)[C@H](O)[C@H](O[C@@H]2O[C@H](CO)[C@@H](O[C@@H]3O[C@H](CO)[C@H](O)[C@H](O)[C@H]3O)[C@H](O)[C@H]2NC(C)=O)[C@H]1O
Reaction time: 22 h

Procedure:
A solution of compound 19 of Example 19 (85 mg), UDP-galactose, (190 mg), bovine galactosyltransferase (6.25 U) and bovine serum albumin (3 mg) in 30 mM sodium cacodylate buffer (7 mL, pH 7.0) containing manganese chloride (40 umol) was incubated at 37° C. for 22 h. The reaction mixture was diluted to 20 mL and purified as described in Example 21. Yield of the product was 114 mg. The structural identity of titled compound 25 was unambiguously assigned by 1H-- and 13C-n.m.r (see Tables 4 and 5, respectively).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:18][N:19](C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.CN>O1CCCC1.ClCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:19][CH3:18])=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)C1CCN(Cc2ccccc2)CC1
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CNC(=O)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-Benzyl 4-piperidinecarboxylic acid (5.00 g, 22.8 mmol), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (5.25 g, 27.4 mmol) and 1-hydroxybenzotriazole hydrate (3.84 g, 25.1 mmol) were added to a solution of methylamine (11.4 ml of a 2.0M solution in tetrahydrofuran, 22.8 mmol) in dichloromethane (100 ml). The mixture was stirred for 1 hour at room temperature, then partitioned between dichloromethane and water. The organic layer was separated and washed with brine, dried (MgSO4), filtered and evaporated under reduced pressure to furnish a pale yellow solid, 3.50 g.