Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[Br:10][CH:11]([CH:17]([Br:19])[CH3:18])[C:12]([N:14]=[C:15]=[O:16])=[O:13]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:15]([NH:14][C:12](=[O:13])[CH:11]([Br:10])[CH:17]([Br:19])[CH3:18])=[O:16])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: CC(Br)C(Br)C(=O)N=C=O
Product: CC(Br)C(Br)C(=O)NC(=O)Nc1ccc(Cl)c(Cl)c1

Procedure:
m.p: 196° - 197° C. (from 3,4-dichloroaniline and 2,3-dibromobutyryl isocyanate)
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH2:11])=[CH:6][CH:5]=2.[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][NH:22][C:23]([C:25]2[S:33][C:32]3[C:27](=[N:28][CH:29]=[CH:30][C:31]=3Cl)[CH:26]=2)=[O:24])[CH2:15][CH2:14]1>>[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][NH:22][C:23]([C:25]2[S:33][C:32]3[C:27](=[N:28][CH:29]=[CH:30][C:31]=3[NH:11][C:7]3[CH:8]=[C:9]4[C:4](=[CH:5][CH:6]=3)[NH:3][C:2]([CH3:1])=[CH:10]4)[CH:26]=2)=[O:24])[CH2:15][CH2:14]1
Reactant: CN1CCN(CCCNC(=O)c2cc3nccc(Cl)c3s2)CC1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)NCCCN5CCN(C)CC5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 2-methyl-1H-indol-5-ylamine and 7-chloro-thieno[3,2-b]pyridine-2-carboxylic acid [3-(4-methyl-piperazin-1-yl)-propyl]-amide by a procedure analogous to Example 1C. MS: 463 (MH+), HPLC Rf: 3.41 min.; HPLC purity: 99%.
Reaction SMILES: [BrH:1].S[C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.BrBr>CO>[Br:1][C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Sc1nc2ccccc2[nH]1
Reactant: Br
Agent: BrBr
Solvent: CO
Product: Brc1nc2ccccc2[nH]1
Reaction time: 16 h

Procedure:
To a flask were added 24 ml 48% hydrobromic acid and 120 ml methanol. The mixture was cooled to 5 C and 10 g 2-mercaptobenzimidazole was added. Maintaining a temperature of less than 10 C, 41.5 g of bromine were added in small portions. The mixture was allowed to warm to 22 C, and stirred for 16 hours under nitrogen. After cooling to 5 C, the solid was filtered and then added to 50 ml methanol containing 20 ml aqueous ammounium hydroxide. The pH was adjusted to 6.5 with acetic acid, and the mixture was cooled to 5 C. The product was filtered and washed with water, and dried. A second crop was obtained by cooling the filtrates which was filtered, washed with water and dried. The combined crops resulted in 9.05 g of a solid.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:22]=[CH:21][C:14]([CH2:15][N:16]([OH:20])[C:17]([NH2:19])=[O:18])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4]CC1.[OH-].[NH4+]>Cl>[OH:20][N:16]([CH2:15][C:14]1[CH:13]=[CH:12][C:11]([N:8]2[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]2)=[CH:22][CH:21]=1)[C:17]([NH2:19])=[O:18]
Reactant: NC(=O)N(O)Cc1ccc(N2CCC3(CC2)OCCO3)cc1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: NC(=O)N(O)Cc1ccc(N2CCC(=O)CC2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 98.7 %

Procedure:
A mixture of N-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)benzyl]-N-hydroxyurea (2.2 g, 7.16 mmol) (which was obtained in Example 53) and hydrochloric acid (concentrated, 10 mL) was stirred at room temperature for three days. The mixture was then neutralized with ammonium hydroxide, and extracted with ethyl acetate. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography (ethyl acetate) gave a white solid (1.86 g, 98% yield); mp 138-140° C.; 1H NMR (300 MHz, DMSO-d6) δ 2.41 (m, 4H), 3.60 (m, 4H), 4.43 (s, 2H), 6.37 (brs, 2H), 7.03 (m, 2H), 7.21 (m, 2H), 9.31 (s, 1H); MS (ES) m/z: 264 (MH+);
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].S(Cl)([Cl:14])=O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([Cl:14])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(F)cc1C(=O)O
Product: Cc1ccc(F)cc1C(=O)Cl
Temperature: 25 °C

Procedure:
A solution of 5-fluoro-2-methylbenzoic acid (380 mg, 2.47 mmol) in thionyl chloride (5 mL) was heated to reflux for 3 hours. The solution was cooled to ambient temperature and the volatile components were removed under reduced pressure. The residue was dissolved in fresh toluene (10 mL) and concentrated under reduced pressure twice and then placed under high vacuum to afford the title compound (420 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:16]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:16]=1[O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH:12]=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1cc(OCc2ccccc2)c(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1cc(OCc2ccccc2)c(OCc2ccccc2)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.9 %

Procedure:
To a solution of 3,4,5-tribenzyloxy-benzyl alcohol 11 (8.9 g, 21 mmol) in methylene chloride (200 mL) at 0° C. was added pyridinium chlorochromate (5.43 g, 25 mmol) in small portions with vigorous stirring. The cooling was discontinued and reaction stirred at room temperature for 4 h. The dark brown suspension was filtered over a long pad of silica gel in a sintered glass funnel, and eluted with methylene chloride, until all the pure product eluted out. The organic filtrate was evaporated down to give the pure product 12 as a soft white solid (8.1 g, 91.5% yield). 1H NMR (300 MHz, CDCl3): δ 5.16 (s, 6H, OCH2), 7.18 (s, 2H, 2,6-Ar—H), 7.26–7.41 (m, 15H, Ar—H), 9.80 (s, 1H, CHO).
Reaction SMILES: [CH3:1][O-:2].[Na+].[Cl:4][C:5]1[C:10]([O:11][CH:12]([F:14])[F:13])=[C:9](F)[N:8]=[C:7]([NH:16][CH3:17])[N:6]=1>CO>[Cl:4][C:5]1[C:10]([O:11][CH:12]([F:14])[F:13])=[C:9]([O:2][CH3:1])[N:8]=[C:7]([NH:16][CH3:17])[N:6]=1
Reactant: C[O-]
Reactant: CNc1nc(F)c(OC(F)F)c(Cl)n1
Agent: [Na+]
Solvent: CO
Product: CNc1nc(Cl)c(OC(F)F)c(OC)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
At 0° C. and over a period of 10 minutes, 4.7 g (0.026 mol) of 30% strength sodium methylate was added, while stirring, to 6.0 g (0.0263 mol) of 4-chlorodifluoromethoxy-6-fluoro-2-methylaminopyrimidine in 100 ml of methanol. The mixture was stirred for 1 hour at 0° C. and for 1 hour at 25° C. Conventional working up gave 6.3 g (100% of theory) of the title compound of melting point 49°-53° C.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[OH:8][CH2:9][CH2:10][N:11]([CH2:16][CH2:17][OH:18])[C:12](=[O:15])[CH2:13][OH:14]>>[CH3:1][C:2]([CH3:7])([CH3:6])[C:3]([O:8][CH2:9][CH2:10][N:11]([CH2:16][CH2:17][O:18][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])[C:12](=[O:15])[CH2:13][O:14][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])=[O:4]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=C(CO)N(CCO)CCO
Product: CC(C)(C)C(=O)OCCN(CCOC(=O)C(C)(C)C)C(=O)COC(=O)C(C)(C)C

Procedure:
This compound was prepared from 73 g (0.6 mole) of trimethylacetyl chloride and 32.6 g (0.2 mole) of N,N-bis(hydroxyethyl)hydroxyacetamide by the procedure of Example 1. Its structure was established by infrared and nuclear magnetic resonance spectroscopy. It was a white solid with m.p. 51.4° C.
Reaction SMILES: Br[CH:2]([CH3:24])[CH2:3][CH2:4][C:5](=[O:23])[C:6]([N:9]1[C:14](=[O:15])[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([CH3:22])[O:11][CH2:10]1)([CH3:8])[CH3:7].C([O-])(=[O:27])C.[Na+].O>CN(C)C=O>[CH3:22][C:12]1[O:11][CH2:10][N:9]([C:6]([CH3:8])([C:5](=[O:23])[CH2:4][CH2:3][CH:2]([OH:27])[CH3:24])[CH3:7])[C:14](=[O:15])[C:13]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(=O)[O-]
Reactant: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)CCC(C)Br)CO1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)CCC(C)O)CO1
Temperature: 70 °C
Yield: 25.2 %

Procedure:
A mixture of 6-bromo-2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylheptan-3-one (1.04 g), sodium acetate (0.43 g) and water (0.10 g) in N,N-dimethylformamide was heated at 70° C. for 2 hours. Water was added and the mixture extracted (dichloromethane) and the organic phase dried (magnesium sulphate) and evaporated. The residue was purified by chromatography on silica gel eluting with hexane/ethyl acetate (3:1), to give 2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methyl-3-oxo-heptan-6-ol (Compound 212, 0.22 g) as a brown gum, NMR 1.2(d,3H), 1.4(2s,6H), 1.6(m,1H), 1.9(m,2H), 1.9(s,3H), 2.5(m,1H), 2.8(m,1H), 3.8(m,1H), 5.3(m,2H), 7.3(m,5H).
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[C:5]([C:7]1[CH:11]=[CH:10][O:9][C:8]=1[CH3:12])=O.Cl.[CH3:21][CH:22]1[CH2:27][CH2:26][CH2:25][N:24]([C:28](=[NH:30])[NH2:29])[CH2:23]1.CC(C)([O-])C.[K+]>C(O)C.O>[CH3:12][C:8]1[O:9][CH:10]=[CH:11][C:7]=1[C:5]1[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:3][N:29]=[C:28]([N:24]2[CH2:25][CH2:26][CH2:27][CH:22]([CH3:21])[CH2:23]2)[N:30]=1
Reactant: CC1CCCN(C(=N)N)C1
Reactant: Cc1occc1C(=O)C(=CN(C)C)c1ccccn1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cc1occc1-c1nc(N2CCCC(C)C2)ncc1-c1ccccn1
Temperature: 25 °C
Yield: 66.7 %

Procedure:
A mixture of 3-(dimethylamino)-1-(2-methyl-3-furanyl)-2-(2-pyridinyl)-2-propen-1-one (256 mg, 1 mmol) and 3-methyl-1-piperidinecarboximidamide hydrochloride (267 mg, 1.5 mmol) in ethanol (5 ml) was stirred at room temperature. Potassium tert-butoxide (224 mg, 2 mmol) was added and the mixture was heated at reflux for 45 minutes. After cooling to room temperature the reaction mixture was diluted with water and extracted with ethyl acetate. The organic extracts were combined, washed with water and brine, dried and evaporated. The residue was purified by silica gel chromatography eluting with 25% ethyl acetate and isohexane followed by mass-directed automated HPLC to give 4-(2-methyl-3-furanyl)-2-(3-methyl-1-piperidinyl)-5-(2-pyridinyl)pyrimidine (223 mg, 67%).
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[CH:16]1([CH2:19][O:20][C:21]2[N:26]=[CH:25][C:24]([CH:27]([NH2:29])[CH3:28])=[CH:23][C:22]=2[CH3:30])[CH2:18][CH2:17]1>>[Cl:14][C:13]1[C:3]2[CH2:2][N:29]([CH:27]([C:24]3[CH:25]=[N:26][C:21]([O:20][CH2:19][CH:16]4[CH2:18][CH2:17]4)=[C:22]([CH3:30])[CH:23]=3)[CH3:28])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Reactant: Cc1cc(C(C)N)cnc1OCC1CC1
Agent: Cl
Product: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)cnc1OCC1CC1
Yield: 95 %

Procedure:
The title compound is prepared in 95% yield (1.39 g, colorless oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (1.14 g, 4.09 mmol, Step-1 of Intermediate-1) and 1-(6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)ethanamine hydrochloride (994 mg, 4.09 mmol, Amine-70, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [Br:1][CH:2]1[CH2:8][CH:7]([Br:9])[C:6](=[O:10])[O:5][C:3]1=[O:4].[CH2:11]([OH:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>[Br:9][CH:7]([CH2:8][CH:2]([Br:1])[C:3]([O:5][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:4])[C:6]([O:18][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10]
Reactant: O=C1OC(=O)C(Br)CC1Br
Reactant: OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: O=C(OCc1ccccc1)C(Br)CC(Br)C(=O)OCc1ccccc1
Yield: 100.2 %

Procedure:
2.18 g (8 mmol) of 2,4-dibromoglutaric anhydride, 2.1 ml (20 mmol) of benzyl alcohol, and 2 ml of benzene are stirred for 1.5 hours at room temperature. 76 mg (0.4 mmol) of p-toluenesulfonic acid monohydrate and 8 ml of benzene are added, and the solution is refluxed under a Dean-Stark trap for 2 hours. Filtration over silica gel and evaporation yields 3.77 g (100%) of dibenzyl 2,4-dibromoglutarate as a colourless oil. 1H NMR (CDl3): δ7.37 (br. s., 10H), 5.21 (narrow AB system, 4H, J=12.5); dl isomer: δ4.55 (dd, 2H, J=6.5, 7.5), 2.69 (dd, 2H, J=6.5, 7.5); meso isomer: δ4.42 (t, 2H, J=7.5), 2.90 (dt, 1H, J=7.5 (t), 14.5 (d)), 2.66 (dt, 1H, J=7.5 (t), 14.5 (d)); dl/meso=6:1. IR (neat): 3034, 1740, 1499, 1456, 1385, 1273, 1154, 750, 696 cm-1.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[C:9]([C:19]([OH:21])=O)[CH:10]=[N:11][C:12]=2[O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:22]1([NH2:27])[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH:1]1([C:7]2[CH:8]=[C:9]([C:19]([NH:27][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:21])[CH:10]=[N:11][C:12]=2[O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NN1CCCC1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1
Product: O=C(NN1CCCC1)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-cyclohexyl-6-(2,2,2-trifluoro-ethoxy)-3-pyridinecarboxylic acid (example 12c) and 1-pyrrolidinamine (CAN 16596-41-1) as starting materials; LC-MS (UV peak area/ESI) 100.0%, 372.1899 (M+H)+.
Reaction SMILES: [N:1]([CH:4]1[CH2:23][N:8]2[C:9]3[C:14]([C:15]([CH2:16][C:17]([O:19]CCC)=[O:18])=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N+:2]=[N-:3].[CH:24]#[C:25][CH:26]([C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1>>[F:33][C:30]1[CH:29]=[CH:28][C:27]([CH:26]([C:34]2[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=2)[C:25]2[N:1]([C@H:4]3[CH2:23][N:8]4[C:9]5[C:14]([C:15]([CH2:16][C:17]([OH:19])=[O:18])=[C:7]4[CH2:6][CH2:5]3)=[CH:13][CH:12]=[CH:11][CH:10]=5)[N:2]=[N:3][CH:24]=2)=[CH:32][CH:31]=1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)CC(N=[N+]=[N-])CC2
Reactant: C#CC(c1ccc(F)cc1)c1ccc(F)cc1
Product: O=C(O)Cc1c2n(c3ccccc13)C[C@H](n1nncc1C(c1ccc(F)cc1)c1ccc(F)cc1)CC2

Procedure:
The title compound was prepared using procedures described in EXAMPLE 8 from enantiomerically pure propyl (7-azido-6,7,8,9-tetrahydropyrido[1,2-α]indol-10-yl)acetate and 1,1′-prop-1-yne-3,3-diylbis(4-fluorobenzene) MS (+ESI) m/z: 499.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[CH2:5][N:6]1[C:11](=[O:12])[CH:10]=[CH:9][C:8]([C:13]([OH:15])=O)=[CH:7]1.Cl.Cl.[NH:22]1[C:26]2([CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH2:25][NH:24]/[C:23]/1=[N:32]\[C:33]([C:35]1[C:40]([NH2:41])=[N:39][C:38]([NH2:42])=[C:37]([Cl:43])[N:36]=1)=[O:34].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN1C(=O)CCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[CH2:5][N:6]1[C:11](=[O:12])[CH:10]=[CH:9][C:8]([C:13]([N:29]2[CH2:30][CH2:31][C:26]3([NH:22]/[C:23](=[N:32]/[C:33]([C:35]4[C:40]([NH2:41])=[N:39][C:38]([NH2:42])=[C:37]([Cl:43])[N:36]=4)=[O:34])/[NH:24][CH2:25]3)[CH2:27][CH2:28]2)=[O:15])=[CH:7]1
Reactant: O=C(O)c1ccc(=O)n(Cc2ccc(F)c(F)c2)c1
Reactant: Nc1nc(N)c(C(=O)/N=C2\NCC3(CCNCC3)N2)nc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CN1CCOCC1
Product: Nc1nc(N)c(C(=O)/N=C2\NCC3(CCN(C(=O)c4ccc(=O)n(Cc5ccc(F)c(F)c5)c4)CC3)N2)nc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-(3,4-Difluoro-benzyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid (0.15 mmol) in NMP (0.5 ml) is added to a solution of 3,5-Diamino-6-chloro-pyrazine-2-carboxylic acid [1,3,8-triaza-spiro[4.5]dec-(2E)-ylidene]-amide dihydrochloride (Ex. 38) (0.049 g, 0.15 mmol) and N-methyl morpholine (0.033 ml, 0.30 mmol) in NMP (1 ml), followed by a solution of HATU (0.11 g, 0.3 mmol) in NMP (0.5 ml). The reaction mixture is shaken at room temperature overnight. The reaction mixture is purified by mass-directed preparative HPLC. Fractions containing pure product are eluted through SCX-2 cartridges (Biotage 1 g/6 ml cartridge), and the cartridge is washed with MeOH (4 ml), followed by 3M NH3 in MeOH solution (4 ml) to afford the title compound; [M+H]+ 572.0
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11](=[O:18])[NH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:26]([CH3:28])[CH3:27].O>CN(C=O)C>[CH3:27][CH:26]([N:10]1[CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:17]2[N:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:11]1=[O:18])[CH3:28]
Reactant: O=c1[nH]cc(-c2cccc(Cl)c2)c2ncccc12
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1cc(-c2cccc(Cl)c2)c2ncccc2c1=O
Temperature: 21 °C
Reaction time: 8 h
Yield: 40.2 %

Procedure:
To a suspension of 8-(3-chlorophenyl)-1,6-naphthyridin-5-one (128 mg, 0.5 mmoles) and potassium carbonate (83 mg, 0.6 mmoles) in 10 ml DMF was added dropwise 2-iodopropane (0.075 ml, 0.75 mmoles) under an atmosphere of nitrogen and stirred overnight at 21° C. The reaction mixture was poured into 50 ml water and after stirring for one hour the white precipitate was collected and dried. Crystallization from methanol gave 60 mg (40% yield) of the desired 6-(2-propyl)-8-(3-chlorophenyl)-1,6-naphthyridin-5-one as a white solid. Characteristic analytical data are as follows: mp 163.5°-164.5° C.; TLC 1:4 EtOAc/Hex; 1H NMR (CDCl3, 300 MHz) δ1.454 (d, 6H, J=6.8), 5.3 (m, 1H, J=6.8), 7.36-7.60 (m, 6H), 8.77 (dd, 1H, J=8.3, 1.7), 8.93 (dd, 1H, J=4.4, 1.7); 13C NMR (75 MHz, CDCl3) δ154.20, 151.13, 137.54, 136.85, 134.18, 129.99,129.55, 128.28, 127.69, 121.95, 119.70, 46.57, 21.87; IR (KBr) vmax 1647, 1614, 1591, 1566, 1552, 1487, 1468, 1441, 1419, 1400, 1388, 1273, 1242, 1182, 1170, 796, 783, 711, 700, 605 cm-1 ; mass spectrum (EI), m/e 298. Anal. (C17H15ClN2O) Calcd.: C, 68.34; H, 5.06; N, 9.38. Found: C, 68.25; H, 5.11; N, 9.38.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C:13]([CH:14]=[O:15])=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]1.[CH3:16]I.O>CN(C)C=O>[CH3:16][N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[C:13]([CH:14]=[O:15])[C:4]1=[O:3]
Reactant: CI
Reactant: O=Cc1cc2ccccc2[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)c(C=O)cc2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
Sodium hydride (55% w/w suspension in oil; 0.268 g) was added portionwise to a stirred suspension of 1,2-dihydro-2-oxoquinoline-3-carbaldehyde (1 g) in dimethylformamide (10 ml) which had been cooled in an ice bath. The mixture was allowed to warm to ambient temperature and was then heated to 60° C. for 1 hour. The mixture was recooled in an ice bath and methyl iodide (0.41 ml) was added. Dimethylformamide (50 ml) was added and the mixture was stirred at ambient temperature for 16 hours. The mixture was poured into water (50 ml) and extracted with methylene chloride (3×50 ml). The combined extracts were washed with water (50 ml) and evaporated. The residue was triturated under diethyl ether to give 1,2-dihydro-1-methyl-2-oxoquinoline-3-carbaldehyde as a pale yellow solid (0.81 g, 74%).
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.[CH3:11][C:12]1[CH:26]=[CH:25][C:15]([O:16][C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[CH:20]=O)=[CH:14][CH:13]=1>>[CH3:8][C:6]1([CH3:9])[CH2:7][C:2]2[NH:1][C:2]3[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[C:3]=3[CH:20]([C:19]3[CH:22]=[CH:23][CH:24]=[C:17]([O:16][C:15]4[CH:25]=[CH:26][C:12]([CH3:11])=[CH:13][CH:14]=4)[CH:18]=3)[C:3]=2[C:4](=[O:10])[CH2:5]1
Reactant: Cc1ccc(Oc2cccc(C=O)c2)cc1
Reactant: CC1(C)CC(=O)C=C(N)C1
Product: Cc1ccc(Oc2cccc(C3C4=C(CC(C)(C)CC4=O)NC4=C3C(=O)CC(C)(C)C4)c2)cc1

Procedure:
3-Amino-5,5-dimethyl-2-cyclohexen-1-one was reacted with 3-(4-methylphenoxy)benzaldehyde in an analogous manner to that described in Example 1 to give 3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-9-[3-(4-methylphenoxy)-phenyl]-1,8(2H,5H)-acridinedione. Crystallization from ethanol gave a pale yellow crystalline solid of melting point 202-203° C.
Reaction SMILES: [C:1]([C:3]([C:14](=[O:29])[N:15]([CH:26]([CH3:28])[CH3:27])[C:16]1[CH:25]=[CH:24][C:19]2[N:20]=[C:21]([SH:23])[S:22][C:18]=2[CH:17]=1)=[CH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)#[N:2].[CH2:30]([NH2:34])[CH:31]([CH3:33])[CH3:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C1COCC1>[CH2:30]([NH:34][C:9](=[O:11])[C:8]1[CH:7]=[CH:6][C:5]([CH:4]=[C:3]([C:1]#[N:2])[C:14](=[O:29])[N:15]([CH:26]([CH3:27])[CH3:28])[C:16]2[CH:25]=[CH:24][C:19]3[N:20]=[C:21]([SH:23])[S:22][C:18]=3[CH:17]=2)=[CH:13][CH:12]=1)[CH:31]([CH3:33])[CH3:32]
Reactant: CC(C)CN
Reactant: CC(C)N(C(=O)C(C#N)=Cc1ccc(C(=O)O)cc1)c1ccc2nc(S)sc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CNC(=O)c1ccc(C=C(C#N)C(=O)N(c2ccc3nc(S)sc3c2)C(C)C)cc1
Reaction time: 2 h

Procedure:
Combined 4-{2-Cyano-2-[isopropyl-(2-mercapto-benzothiazol-6-yl)-carbamoyl]-vinyl}benzoic acid (50 mg, 0.118 mmol), isobutylamine (13 μl, 0.130 mmol), HATU (58 mg, 0.153 mmol), and N,N-diisopropylethylamine (27 μl, 0.153 mmol) in anhydrous THF (1.1 ml). The mixture was stirred 2 hours, filtered through celite and concentrated in vacuo. The residue was partitioned between ethyl acetate and 1 M aqueous citric acid. The organic extract was dried over magnesium sulfate and purified by preparative TLC (10% methanol, 90% dichloromethane) to yield 28 mg (50%). 1H NMR(CDCl3) δ0.93 (d, 6H), 1.18 (d, 6H), 1.86 (m, 1H), 3.25 (t, 1H), 4.95 (m, 1H), 6.39 (t, 1H), 7.13 (dd, 1H), 724 (m, 3H), 7.72 (app q, 4H), 7.91 (s, 1H); ESIMS: m/z 477 (M-H).
Reaction SMILES: [NH2:1][C:2]1[C:13]2[C@@:12]3([CH3:16])[C@H:14]([CH3:15])[C@H:8]([N:9]([C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH2:10][CH2:11]3)[CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[OH:23].[C:24](OC)(OC)(OC)[CH3:25]>>[F:20][C:18]([F:21])([F:19])[C:17]([N:9]1[CH2:10][CH2:11][C@:12]2([CH3:16])[C@H:14]([CH3:15])[C@H:8]1[CH2:7][C:6]1[CH:5]=[CH:4][C:3]3[O:23][CH:24]([CH3:25])[NH:1][C:2]=3[C:13]=12)=[O:22]
Reactant: COC(C)(OC)OC
Reactant: C[C@@H]1[C@H]2Cc3ccc(O)c(N)c3[C@]1(C)CCN2C(=O)C(F)(F)F
Product: CC1Nc2c(ccc3c2[C@]2(C)CCN(C(=O)C(F)(F)F)[C@H](C3)[C@H]2C)O1
Temperature: 100 °C

Procedure:
1-[(2R,6R,11S)-7-Amino-8-hydroxy-6,11-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-2,2,2-trifluoro-ethanone (200 mg) taken up in trimethyl orthoacetate (1 mL) is heated at 100° C. for 3 h. After cooling to ambient temperature, the mixture is concentrated and the residue is triturated with little methanol and dried to give the title compound.
Reaction SMILES: CN(C)C=O.[C:6]([N:13]1[CH2:18][CH2:17][CH2:16][CH:15](OS(C)(=O)=O)[CH2:14]1)([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[C:24]([O-:27])(=[S:26])[CH3:25].[K+]>O>[C:6]([N:13]1[CH2:18][CH2:17][CH2:16][CH:15]([S:26][C:24](=[O:27])[CH3:25])[CH2:14]1)([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7]
Reactant: CC([O-])=S
Reactant: CC(C)(C)OC(=O)N1CCCC(OS(C)(=O)=O)C1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)SC1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 95 °C
Reaction time: 1.5 h
Yield: 47.1 %

Procedure:
2.7 l of dimethylformamide are placed in a reactor under inert atmosphere. 251.4 g of N-BOC-3(R,S)-methylsulfonyloxy-piperidine are added with warming. At an internal temperature of 50° C. 256.8 g of potassium thioacetate are added at once. After stirring for 90 min at 95° C. the reaction mixture is transferred into a reactor filled with 4 l of water. 4.2 l of petroleum ether are added. After vigorous stirring for 5 minutes the aqueous phase is removed. After readdition of water the pH is adjusted to >8 with sodium hydroxide. The organic phase is separated, washed with water and treated with active charcoal. The solution is evaporated to dryness. After flash chromatography on silica with petroleum ether, toluene, and ethyl acetate and concentration of the product containing solution crystallization occurs on cooling and 110 g of N-BOC-3(R,S)-acetylthio-piperidine are obtained.