Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([O:14][C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=3[Br:22])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:29][C:30]([OH:34])([C:32]#[CH:33])[CH3:31]>[Cu]I.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.O>[Br:22][C:16]1[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=1[O:14][CH:11]1[CH2:12][CH2:13][N:8]([C:5]2[N:4]=[CH:3][C:2]([C:33]#[C:32][C:30]([CH3:31])([OH:34])[CH3:29])=[CH:7][N:6]=2)[CH2:9][CH2:10]1
Reactant: Fc1ccc(Br)c(OC2CCN(c3ncc(Br)cn3)CC2)c1
Reactant: C#CC(C)(C)O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: O
Product: CC(C)(O)C#Cc1cnc(N2CCC(Oc3cc(F)ccc3Br)CC2)nc1
Temperature: 90 °C

Procedure:
Into a flame-dried 25-mL sealable pressure flask equipped with a magnetic stirbar and under nitrogen was added 5-bromo-2-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]pyrimidine (500 mg, 1.16 mmol), copper(I) iodide (44 mg, 0.23 mmol), Pd(PPh3)4 (100 mg, 0.09 mmol) and potassium carbonate (400 mg, 2.90 mmol). The flask was evacuated under vacuum (1 mm Hg) and backfilled with nitrogen (repeated 3 times). The solids were taken up in dimethoxyethane (4 mL) and water (4 mL) and degassed for 10 min with a stream of nitrogen. The contents of the flask where then heated to 90° C. and 2-methyl-3-butyn-2-ol (0.135 mL, 1.39 mmol) was added and the mixture heated at 90° C. for 1 h. The mixture was cooled, poured into a 250-mL separatory funnel containing water (125 mL) and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and the solvent was evaporated under reduced pressure. Purification by column chromatography through silica gel, eluting with 10% EtOAc in hexanes to 50% EtOAc in hexanes as a gradient gave the desired product as a beige solid.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1.[NH4+:14].[OH-]>CCO>[NH2:14][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1
Reactant: [NH4+]
Reactant: O=[N+]([O-])c1cnc(Cl)c([N+](=O)[O-])c1
Agent: [OH-]
Solvent: CCO
Product: Nc1ncc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 89 %

Procedure:
To a mixture of 2-chloro-3,5-dinitropyridine (2.035 g, 10 mmol) in EtOH (15 mL) was added aq. NH4OH (6 mL) dropwise at room temperature with stirring over 20 min. The resulting mixture was stirred at room temperature for 15 min, then cooled to 0° C. The precipitate was filtered, washed with water (3×5 mL) and dried to give 1.64 g (89%) of 61 as a yellow powder, mp 190°-1° C. (lit. 190°-2° C., Chemical Abstracts 63:14876 (1965)). 1H NMR (DMSO-d6): 8.697 (bs, 1H, D2O exchange), 8.947 (d, 1H, J=2.5), 9.164 (d, 1H, J=2.5), 9.224 (bs, 1H, D2O exchange).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8](=[O:27])[NH:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[CH2:28](O)[CH3:29].CN1CCCN(C)C1=O.ICC>C(=O)([O-])[O-].[Ag+2]>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([O:27][CH2:28][CH3:29])=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: CCO
Reactant: O=c1[nH]c(-c2ccc3ccc(-c4ccccc4)nc3c2)c2c(Cl)nccn12
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CCI
Solvent: CN1CCCN(C)C1=O
Product: CCOc1nc(-c2ccc3ccc(-c4ccccc4)nc3c2)c2c(Cl)nccn12
Temperature: 40 °C

Procedure:
A 80 mL sealed tube is charged with 8-chloro-1-(2-phenyl-quinolin-7-yl)-2H-imidazo[1,5-a]pyrazin-3-one (50.00 mg, 0.1341 mmol), silver carbonate (74 mg, 0.27 mmol), anhydrous ethanol (2.00 mL, 0.034 mol), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (0.002 mL, 0.01 mmol), and iodoethane (0.012 mL, 0.15 mmol). The reaction was sealed under an atmosphere of nitrogen and heated at 40° C. for 24 hours. The reaction was cooled and filtered. Water and EtOAc were added and the organic layer was isolated, dried over sodium sulfate, filtered and concentrated in vacuo to yield a yellow gum. The crude product was purified via silica gel column chromatography, (Jones, 5 gram column eluting with 50% EtOAc: Hex) to yield the title compound as a yellow gum; MS (ES+): m/z 401.03 (100) [MH+], 402.98 (30) [MH+++]; HPLC: tR=4.13 min (OpenLynx, polar—5 min); 1HNMR (400 MHz, CHLOROFORM-d) δ ppm 1.41-1.72 (m, 3H), 4.55-4.86 (m, 2H), 7.18 (d, J=4.80 Hz, 1H), 7.38-7.65 (m, 4H), 7.75-8.00 (m, 3H), 8.09-8.33 (m, 3H), 8.52 (br. s., 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]([CH3:13])([CH3:12])[CH2:5][NH:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.[Cl:15][C:16]1[N:21]=[C:20](Cl)[C:19]([N+:23]([O-:25])=[O:24])=[CH:18][N:17]=1.CCOCC.C(=O)(O)[O-].[K+]>O>[CH3:1][O:2][C:3](=[O:14])[C:4]([CH3:12])([CH3:13])[CH2:5][N:6]([C:18]1[C:19]([N+:23]([O-:25])=[O:24])=[CH:20][N:21]=[C:16]([Cl:15])[N:17]=1)[CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: COC(=O)C(C)(C)CNC1CCCC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: COC(=O)C(C)(C)CN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 96.4 %

Procedure:
To a mixture of 5.02 g (0.025 mole) of 3-cyclopentylamino-2,2-dimethyl-propanoic acid methyl ester, 5.30 g (0.0276 mole) of 2,4-dichloro-5-nitro-pyrimidine and 100 mL of ether was added 20 mL of water and 5.00 g (0.050 mole) of potassium bicarbonate. The mixture was stirred at room temperature for 14 hours. The resulting two-layer mixture was separated and the aqueous layer was extracted twice with 20 mL of ether. The combined ether extracts were washed successively with 20 mL of aqueous sodium carbonate, twice with 20 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 8.60 g of 3-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]-2,2-dimethyl-propanoic acid methyl ester (IV-38) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=3)[N:10]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])O.[Na+].[Br:42]Br>ClCCl>[Br:42][C:15]1[C:14]([NH2:17])=[CH:13][CH:12]=[C:11]2[C:16]=1[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)=[N:9][N:10]2[C:18]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccc2c(c1)c(-c1cccc(F)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Nc1ccc2c(c(-c3cccc(F)c3)nn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1Br

Procedure:
A total of 1.04 g of 3-(3-fluoro-phenyl)-1-trityl-1H-indazol-5-ylamine was dissolved in 22.3 ml of dichloromethane, and 375 mg of sodium hydrogencarbonate was added. Under ice-cooling and stirring, a solution of 0.12 ml of bromine in 50 ml dichloromethane was added dropwise over 50 minutes. After stirring for 2 hours while ice-cooling, saturated aqueous sodium thiosulfate solution and the mixture was extracted with diethyl ether. The resulting organic layer was washed with brine, dried over magnesium sulfate and the solvent was evaporated. The residue was purified and separated by silica gel column chromatography (ethyl acetate:hexane=1:5), to give 1.18 g of the title compound as a white foam.
Reaction SMILES: [OH:1][CH2:2][C:3]([F:9])([F:8])[S:4](Cl)(=[O:6])=[O:5].C(=O)([O-])O.[Na+].[OH:15][N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26].O>C(#N)C>[F:8][C:3]([F:9])([S:4]([O:15][N:16]1[C:20](=[O:21])[C:19]2[C:18](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17]1=[O:26])(=[O:6])=[O:5])[CH2:2][OH:1]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: O=S(=O)(Cl)C(F)(F)CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1OS(=O)(=O)C(F)(F)CO
Temperature: 0 °C
Yield: 54.7 %

Procedure:
In 100 mL of acetonitrile, 25.5 g of a liquid of 2-hydroxy-1,1-difluoroethanesulfonyl chloride (purity: 98%, equivalent to 0.138 mol) was dissolved by stirring. The resulting solution was cooled to 0° C., admixed with 14.0 g (0.166 mol) of sodium hydrogencarbonate and 24.8 g (0.152 mol) of N-hydroxyphthalimide, and then, reacted at 0° C. for 24 hours. To the thus-obtained reaction solution, 125 mL of water was added. The reaction solution was subsequently extracted twice with 100 mL of ethyl acetate. The resulting organic layer was washed twice with 100 mL of water and subjected to concentration. The concentration residue was admixed with 75 mL of ethyl acetate, followed by heating the solution at 60° C. to dissolve the solid substance. Then, 150 mL of heptane was dropped into the solution. The solution was gradually cooled to 0° C. to precipitate a crystalline out of the solution. The crystalline precipitate was filtered out and dried. With this, 23.2 g of the target compound was obtained as a white solid (yield: 53%, purity: 97%, pure content: 22.5 g).
Reaction SMILES: [CH2:1]([OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9].[C:12](OC)(=[O:16])[C:13]([CH3:15])=[CH2:14].C[Sn](Cl)(Cl)C.C[O-].[Na+].COC1C=CC(O)=CC=1.C1(C=CC(O)=CC=1)O>CCCCCCC>[C:12]([O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([CH3:9])[CH3:10])(=[O:16])[C:13]([CH3:15])=[CH2:14]
Reactant: C=C(C)C(=O)OC
Reactant: CC(C)CCCCCCCO
Agent: COc1ccc(O)cc1
Agent: C[O-]
Agent: C[Sn](C)(Cl)Cl
Solvent: CCCCCCC
Product: C=C(C)C(=O)OCCCCCCCC(C)C
Yield: 97.6 %

Procedure:
In a similar manner, 634.3 parts isodecyl alcohol, 603 parts methyl methacrylate, 220.6 parts heptane, 3.1 parts dimethyltin dichloride, 1.4 parts sodium methoxide (molar ratio 1.84:1) 2.21 parts 4-methoxyphenol and 0.73 parts hydroquinone were reacted as in Example 1 to yield 185.9 parts (97.6 percent yield, based on starting alcohol) of isodecyl methacrylate having a purity of 99.0 percent and containing no detectable tin.
Reaction SMILES: FC1C=CC(CN2C(=O)N(C3SC(C(O)=O)=C(C)C=3)C=N2)=CC=1.[CH3:24][C:25]1[CH:29]=[C:28]([N:30]2[C:34](=[O:35])[N:33]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=3)[N:32]=[CH:31]2)[S:27][C:26]=1[C:47]([OH:49])=O.[NH2:50][CH2:51][C:52]1[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=1>>[CH3:24][C:25]1[CH:29]=[C:28]([N:30]2[C:34](=[O:35])[N:33]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=3)[N:32]=[CH:31]2)[S:27][C:26]=1[C:47]([NH:50][CH2:51][C:52]1[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=1)=[O:49]
Reactant: Cc1cc(-n2cnn(Cc3ccc(C(F)(F)F)cc3)c2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: Cc1cc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Product: Cc1cc(-n2cnn(Cc3ccc(C(F)(F)F)cc3)c2=O)sc1C(=O)NCc1cccnc1
Yield: 87 %

Procedure:
Following the procedure as described in Example 31, making variations as required to replace 5-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-3-methylthiophene-2-carboxylic acid with 3-methyl-5-(5-oxo-1-(4-(trifluoromethyl)-benzyl)-1H-1,2,4-triazol-4(5H)-yl)thiophene-2-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a colorless solid in 87% yield: mp 176-178° C.; 1H NMR (300 MHz, CDCl3) δ 8.58 (s, 1H), 8.52 (d, J=3.2 Hz, 1H), 7.74 (s, 1H), 7.69 (d, J=7.9 Hz, 1H), 7.60 (d, J=8.1 Hz, 2H), 7.48 (d, J=8.1 Hz, 2H), 7.27 (dd, J=7.9, 3.2 Hz, 1H), 6.88 (s, 1H), 6.45 (t, J=5.5 Hz, 1H), 5.04 (s, 2H), 4.59 (d, J=5.5 Hz, 2H), 2.49 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 162.5, 150.5, 149.2, 149.0, 140.7, 139.2, 135.6, 134.4, 133.7, 132.6, 130.3, 128.6, 125.8 (q, JC-F=3.8 Hz), 125.5, 123.6, 120.4, 49.1, 41.4, 16.0; MS (ES+) m/z 474.4 (M+1).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([NH:19][C:20](=[O:34])[C:21]([NH:23][C:24]([CH3:33])([CH3:32])[CH2:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:22])[CH:11]=[CH:12][C:13]=1[C:14]1[O:18][CH:17]=[N:16][CH:15]=1.C(N1CCOCC1)C>ClCCl.C(OCC)(=O)C>[CH3:1][S:2]([N:29]1[CH2:30][CH2:31][CH:26]([CH2:25][C:24]([NH:23][C:21](=[O:22])[C:20]([NH:19][C:10]2[CH:11]=[CH:12][C:13]([C:14]3[O:18][CH:17]=[N:16][CH:15]=3)=[C:8]([O:7][CH3:6])[CH:9]=2)=[O:34])([CH3:33])[CH3:32])[CH2:27][CH2:28]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(NC(=O)C(=O)NC(C)(C)CC2CCNCC2)ccc1-c1cnco1
Agent: CCN1CCOCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cc(NC(=O)C(=O)NC(C)(C)CC2CCN(S(C)(=O)=O)CC2)ccc1-c1cnco1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
14 mg (0.12 mmol) of methanesulphonyl chloride were added to a solution of 40 mg (0.1 mmol) of N-[3-methoxy-4-(5-oxazolyl)phenyl-N′-[1,1-dimethyl-2-(4-piperidinyl)ethyl]oxalamide in 1 ml of dichloromethane followed by 17 mg (0.15 mmol) of N-ethylmorpholine and the mixture stirred at room temperature for 4 hours. The resulting solution was diluted with ethyl acetate, washed with 2M hydrochloric acid and saturated sodium bicarbonate solution, dried over magnesium sulphate, evaporated to dryness and the residue triturated with diethyl ether. There was obtained 23 mg of N-[2-[1-(methanesulfonyl)-4-piperidinyl]-1,1-dimethylethyl]-N′-(3-methoxy-4-(5-oxazolyl)phenyl]oxalamide as an off-white solid. MS m/e 479 [M+]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][CH:12]([CH2:14][OH:15])[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25].O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][CH:12]([CH2:14][O:15][S:24]([CH3:23])(=[O:26])=[O:25])[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: OCC1CC(c2ccc(F)c(F)c2)=NO1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CC(c2ccc(F)c(F)c2)=NO1
Reaction time: 0.5 h

Procedure:
(5RS)-3-(3,4-Difluorophenyl)-5-hydroxymethyl-4,5-dihydroisoxazole (3.79 g, 17.8 mM) was dissolved in anhydrous dichloromethane (200 ml) under a nitrogen atmosphere, cooled to 0°, and treated with triethylamine (2.51 g, 24.9 mM). Methanesulfonyl chloride (2.45 g, 21.4 mM) was added dropwise with stirring during a period of 30 minutes, then the mixture allowed to come to ambient temperature over 2 hours. The mixture was treated with water (200 ml), the organic layer separated, and washed with aqueous hydrochloric acid (2N, 100 ml), sodium bicarbonate (100 ml), and brine (200 ml). After drying (magnesium sulfate) and evaporation, the desired product was obtained as a white solid (4.85 g).
Reaction SMILES: C([NH:3][CH2:4][C:5]1[CH:18]=[CH:17][C:8]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:7][CH:6]=1)=O>Cl.C(O)C>[NH2:3][CH2:4][C:5]1[CH:18]=[CH:17][C:8]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:7][CH:6]=1
Reactant: O=CNCc1ccc(C(=O)c2ccccc2)cc1
Agent: Cl
Solvent: CCO
Product: NCc1ccc(C(=O)c2ccccc2)cc1

Procedure:
70 g of 4-(N-formylaminomethyl)benzophenone are stirred in a mixture of 40 g of concentrated hydrochloric acid and 100 g of ethanol for 5 hours at 50° C. The alcohol is then removed by distillation and the pH is adjusted to 10 with sodium hydroxide solution. 4-aminomethylbenzophenone precipitates as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:8][CH:9]=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:2]=1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[NH2:29][C:30]1[CH:31]=[C:32]([C:36]2[CH:37]=[C:38]([N:42]3[C:47](=[O:48])[C:46]([CH2:49][C:50]4[CH:51]=[N:52][CH:53]=[CH:54][CH:55]=4)=[N:45][C:44]4[CH:56]=[CH:57][CH:58]=[N:59][C:43]3=4)[CH:39]=[CH:40][CH:41]=2)[CH:33]=[CH:34][CH:35]=1>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:8][CH:9]=[C:10]([C:12]([NH:29][C:30]3[CH:31]=[C:32]([C:36]4[CH:37]=[C:38]([N:42]5[C:47](=[O:48])[C:46]([CH2:49][C:50]6[CH:51]=[N:52][CH:53]=[CH:54][CH:55]=6)=[N:45][C:44]6[CH:56]=[CH:57][CH:58]=[N:59][C:43]5=6)[CH:39]=[CH:40][CH:41]=4)[CH:33]=[CH:34][CH:35]=3)=[O:14])[N:11]=2)[CH:2]=1
Reactant: Nc1cccc(-c2cccc(-n3c(=O)c(Cc4cccnc4)nc4cccnc43)c2)c1
Reactant: O=C(O)c1csc(-c2cccnc2)n1
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cccc(-c2cccc(-n3c(=O)c(Cc4cccnc4)nc4cccnc43)c2)c1)c1csc(-c2cccnc2)n1
Reaction time: 2 h
Yield: 32.8 %

Procedure:
To a stirred suspension of 2-(3-pyridyl)thiazole-4-carboxylic acid (0.56 g) and triethylamine (0.55 g) in methylene chloride (25 ml) was added pivaloyl chloride (0.33 g) in methylene chloride (5 ml) and the mixture was stirred for 2 hours. After the reaction mixture was cleared, 4-[3-(3-aminophenyl)phenyl]-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (1.0 g) was added thereto and the mixture was stirred under reflux for 2 hours. The reaction mixture was washed with sodium bicarbonate solution and water, dried over magnesium sulfate and concentrated. Crude residue was chromatographed on silica gel (70 g, chloroform-methanol 100:1 as eluent) to give 4-[3-[3-[2-(3-pyridyl)thiazol-4-ylcarbonylamino]phenyl]phenyl]-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine as colorless crystals (0.48 g).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[O:28]=[C:29]1[C@H:35]2[CH2:36][C@H:31]([CH2:32][CH2:33][C@@H:34]2[C:37]([OH:39])=O)[O:30]1.[C:40]1([N:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.CN(C)C=O.C(N(CC)C(C)C)(C)C>>[C:40]1([N:46]2[CH2:51][CH2:50][N:49]([C:37]([C@H:34]3[CH2:33][CH2:32][C@H:31]4[CH2:36][C@@H:35]3[C:29](=[O:28])[O:30]4)=[O:39])[CH2:48][CH2:47]2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: O=C(O)[C@H]1CC[C@H]2C[C@@H]1C(=O)O2
Reactant: c1ccc(N2CCNCC2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1O[C@H]2CC[C@H](C(=O)N3CCN(c4ccccc4)CC3)[C@@H]1C2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (7.0 g, 0.016 mol) was added To a solution of (1S,2S,5S)-7-oxo-6-oxabicyclo[3.2.1]octane-2-carboxylic acid (14.4 mmol, 0.0144 mol) and 1-Phenylpiperazine (2.4 mL, 0.016 mol) in N,N-dimethylformamide (30 mL, 0.4 mol) at 0 Celsius. After 5 minutes, N,N-diisopropylethylamine (7.5 mL, 0.043 mol) was added at 0 Celsius. The mixture was stirred at RT for overnight. The product was purified by flash chromatography on silica gel column (ethyl acetate in hexanes: 60%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([CH2:18][N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:15][CH:16]=3)[C:11](=[O:25])[C:10]([C:26]([O:28]CC)=O)=[CH:9]2)[CH2:4][CH2:3]1.[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH2:37])=[CH:34][CH:33]=1>>[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH:37][C:26]([C:10]2[C:11](=[O:25])[C:12]3[C:17](=[CH:16][CH:15]=[C:14]([CH2:18][N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[CH:13]=3)[N:8]([CH:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[CH:9]=2)=[O:28])=[CH:34][CH:33]=1
Reactant: CCOC(=O)c1cn(C2CCN(C)CC2)c2ccc(CN3CCOCC3)cc2c1=O
Reactant: NCc1ccc(Cl)cc1
Product: CN1CCC(n2cc(C(=O)NCc3ccc(Cl)cc3)c(=O)c3cc(CN4CCOCC4)ccc32)CC1
Temperature: 165 °C

Procedure:
A flask containing crude ethyl 1-(1-methyl-4-piperidinyl)-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylate (0.31 g) is treated with 4-chlorobenzylarnine (2.0 mL). The reaction is tightly capped and heated to 165° C. overnight. The reaction is cooled to room temperature, adsorbed onto silica and chromatographed on silica eluting with 2% to 10% methanol saturated with ammonia in dichloromethane and then by recrystallization from ethyl acetate-hexanes to afford 0.11 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8]2([S:14][CH2:13][CH2:12][CH2:11][S:10]2)[CH2:7][N:6]1[C:15](=[O:29])[CH:16]([NH:21]C(OC(C)(C)C)=O)[C:17]([CH3:20])([CH3:19])[CH3:18])=[O:4].Cl.O1CCOCC1>O1CCOCC1>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8]2([S:10][CH2:11][CH2:12][CH2:13][S:14]2)[CH2:7][N:6]1[C:15](=[O:29])[CH:16]([NH2:21])[C:17]([CH3:18])([CH3:19])[CH3:20])=[O:4]
Reactant: COC(=O)C1CC2(CN1C(=O)C(NC(=O)OC(C)(C)C)C(C)(C)C)SCCCS2
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)C1CC2(CN1C(=O)C(N)C(C)(C)C)SCCCS2
Temperature: 25 °C
Reaction time: 2 h
Yield: 110.3 %

Procedure:
Boc protected amine 28 (243 mg) in dioxane (1 mL) was treated with a 4.ON HCl/dioxane solution (2 mL) and stirred for 2 hours at room temperature. The mixture was concentrated in vacuo, slurried in CH2Cl2 and evaporated in vacuo to give 208 mg (100%) of desired 2-(2-amino-3,3-dimethyl-butyryl)-6,10-dithia-2-aza-spiro[4.5]decane-3-carboxylic acid methyl ester 29 as a white solid and as the HCl salt. Mass Spec. MH+=347.1.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].[CH3:32][O:33][N:34]=[C:35]([C:40]1[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=1)[CH2:36][CH2:37][CH2:38]I.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[F:46][C:43]1[CH:42]=[CH:41][C:40]([C:35](=[N:34][O:33][CH3:32])[CH2:36][CH2:37][CH2:38][N:9]2[CH2:10][CH2:11][C:6]3([N:5]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH2:4][N:3]([CH2:18][C:19]4[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=4)[C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[C:2]3=[O:1])[CH2:7][CH2:8]2)=[CH:45][CH:44]=1
Reactant: CON=C(CCCI)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CON=C(CCCN1CCC2(CC1)C(=O)N(Cc1cccc(C(=O)OC(C)(C)C)c1)CN2c1ccccc1)c1ccc(F)cc1
Yield: 76.8 %

Procedure:
tert-Butyl 3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.25 g, 0.593 mmol), 1-(4-fluorophenyl)-4-iodobutan-1-one O-methyl oxime (0.19 g, 0.593 mmol), and potassium carbonate (0.12 g, 0.890 mmol) in N,N-dimethylformamide (8 mL) were stirred at 65° C. for 2 hours. The reaction was diluted with ethyl acetate, washed with water and brine, dried (MgSO4), and evaporated. The residue was purified by PTLC (5% methanol/dichloromethane) to give product as an oil (0.28 g, 78%); MS for C36H43FN4O4 m/z 615 (M+H)+.