Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH:14](O)[CH3:15])[CH2:10][CH2:11][O:12][CH3:13])=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:18][CH2:15][CH2:14][N:9]([CH2:8][C:5]1[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:10][CH2:11][O:12][CH3:13]
Reactant: BrC(Br)(Br)Br
Reactant: COCCN(Cc1ccc(Cl)nc1)C(C)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COCCN(CCBr)Cc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a cold (0° C.) solution of 1.25 grams (0.0051 mole) of 2-{[(6-chloro(3-pyridyl)methyl](2-methoxyethyl)amino}ethan-1-ol and 1.9 grams (0.0057 mole) of carbon tetrabromide in 70 mL of methylene chloride was added 1.66 grams (0.0064 mole) of triphenylphosphine. The reaction mixture was allowed to warm to ambient temperature where it stirred for 1.5 hours. After this time silica gel was added and the mixture concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel eluting with a 50/50 mixture of diethyl ether and hexanes. The appropriate fractions were combined and concentrated under reduced pressure, yielding 1.17 grams of (2-bromoethyl)[(6-chloro(3-pyridyl))methyl](2-methoxyethyl)amine as an oil. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[C:9]([OH:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH2:14][CH2:15][CH2:16][O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:18]([O:17][CH2:16][CH2:15][CH2:14][O:10][C:9]1[C:2]([Br:1])=[C:3]([CH:6]=[CH:7][C:8]=1[O:11][CH3:12])[CH:4]=[O:5])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCCCOCc1ccccc1
Reactant: COc1ccc(C=O)c(Br)c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(C=O)c(Br)c1OCCCOCc1ccccc1

Procedure:
Synthesized according to the methods of general procedure 4 in U.S. Pat. Pub. No. 20090227541 (U.S. patent application Ser. No. 12/142,692) using the following reactants and amounts: 2-bromo-3-hydroxy-4-methoxy-benzaldehyde (1.0 g, 4.32 mmol), (3-bromo-propoxymethyl)-benzene (0.76 mL, 4.32 mmol), cesium carbonate (2.11 g, 6.5 mmol), DMF (30 mL). Purification: flash chromatography (10% EtOAc/hexanes): yield 1.54 g (95%). 1H NMR (400 MHz, CDCl3) δ (ppm): 10.26 (s, 1H), 7.73 (d, J=8.6 Hz, 1H), 7.46-7.18 (m, 5H), 6.95 (d, J=8.6 Hz, 1H), 4.56 (s, 2H), 4.14 (t, J=6.1 Hz, 2H), 3.92 (s, 3H), 3.77 (t, J=6.2 Hz, 2H), 2.15 (quin, J=6.5 Hz, 2H); MS (ESI): m/z=381 (M+1, positive).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[C:3]([S:7](Cl)(=[O:9])=[O:8])[CH:2]=1.[C:12]1([NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18]>>[C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([NH:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH2:19])(=[O:9])=[O:8])[CH:2]=1
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Reactant: Nc1ccccc1N
Product: Cc1cccc(S(=O)(=O)Nc2ccccc2N)c1

Procedure:
The sulfonamide was synthesized from 3-tolyl sulfonyl chloride(0.01 mol) and o-phenylene diamine(0.01 mol) by general Method C. It was purified by recrystallization from EtOH(0.73 g, 28%).EI-MS m/z 263 (M+H)+.
Reaction SMILES: O.[OH-].[Li+].[O:4]=[C:5]1[C:14]2[NH:15][CH:16]=[CH:17][C:13]=2[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:6]1.C([C:20]([O-:22])=[O:21])C>C(O)C.O>[O:4]=[C:5]1[C:14]2[NH:15][CH:16]=[C:17]([C:20]([OH:22])=[O:21])[C:13]=2[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:6]1
Reactant: CCC(=O)[O-]
Reactant: O=c1[nH]c2ccccc2c2cc[nH]c12
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1c[nH]c2c(=O)[nH]c3ccccc3c12
Yield: 101.1 %

Procedure:
1.64 g (39 mmol) of lithium hydroxide monohydrate is added to 1 g (3.9 mmol) of 4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate (synthesis 1) suspended in 45 mL of ethanol and 45 mL of water, and the solution is stirred for 17 h at 70° C. then 5 h at 100° C. The ethanol is evaporated under vacuum and distilled water is added. The aqueous solution is washed with ethyl acetate then acidified with acetic acid to pH 4-5. The precipitate that forms is filtered then dried under vacuum at 55° C. to give 0.9 g (100%) of 4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid in the form of a beige solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[C:11]([CH2:20][CH2:21][CH:22]=O)[CH:10]=2)=[CH:5][CH:4]=1.[C:24]1([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:12]=[C:11]([CH2:20][CH2:21][CH2:22][N:33]3[CH2:34][CH2:35][N:30]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:31][CH2:32]3)[CH:10]=2)=[CH:5][CH:4]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: COc1ccc(-c2cc(CCC=O)nn2-c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cc(CCCN3CCN(c4ccccc4)CC3)nn2-c2ccccc2)cc1

Procedure:
88 mg (69%) of target compound was obtained by using a method same as in Example 1 by using 3-(5-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-3-yl)propanal (80 mg, 0.261 mmol), 1-phenylpiperazine (0.039 mL, 0.261 mmol), DIPEA (0.068 mL, 0.392 mmol) and NaBH(OAc)3 (166 mg, 0.783 mmol).
Reaction SMILES: Cl.Cl.[C:3]1([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][CH:19]3[O:24][CH2:23][CH2:22][NH:21][CH2:20]3)=[O:16])[CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C=O.O.[C:28](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[C:3]1([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][CH:19]3[O:24][CH2:23][CH2:22][N:21]([CH3:28])[CH2:20]3)=[O:16])[CH2:11][CH2:10]2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(OCC1CNCCO1)N1CCN(c2ccccc2)CC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN1CCOC(COC(=O)N2CCN(c3ccccc3)CC2)C1
Reaction time: 2 h
Yield: 89 %

Procedure:
Morpholin-2-ylmethyl 4-phenylpiperazine-1-carboxylate (non-HCl salt of Example 10; 1.00 g, 3.27 mmol) and 37% formaldehyde in water (1.97 g, 1.82 mL, 65.5 mmol) were dissolved in MeOH (20 mL) at room temperature followed by addition of sodium triacetoxyborohydride (2.78 g, 13.1 mmol) portionwise over 5 minutes. The reaction mixture was stirred for 2 h. The reaction mixture was quenched by the addition of saturated aq Na2CO3 solution. The solvents were removed in vacuo and the residual aqueous phase was loaded onto an Isolute HM-N 20 mL cartridge. The desired product was eluted with DCM (200 mL) and the solvent removed in vacuo to give (4-methylmorpholin-2-yl)methyl 4-phenylpiperazine-1-carboxylate (0.93 g, 88.9%) as a colourless gum.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1(=[O:15])[O:10][C:8](=[O:9])[C:7]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:6]12.[C:16]1([CH3:24])[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[CH:17]=1.Cl>ClCCCl>[CH3:24][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[C:17]=1[C:8]([C:7]1[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=1[C:5]([OH:10])=[O:15])=[O:9]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Cc1cc(C)cc(C)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cc1cc(C)c(C(=O)c2ccccc2C(=O)O)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Aluminum chloride (60 g, 0.45 mol) was added in portions to a solution of phthalic anhydride (30 g, 0.20 mol) and mesitylene (40 mL) in 150 mL of 1,2-dichloroethane at 0 ° 5C. the reaction mixture was stirred at room temperature for 2 hours, then poured into ice-water. The mixture was acidified with 37% hydrochloric acid and extracted with ether. The ether extract was washed with 1 N hydrochloric acid, water, dried and concentrated to give 59 g of the title compound as white solids which was used in the next reaction without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]=[C:10]=[O:11].Cl.[F:13][C:14]1[N:38]=[CH:37][C:17]2[N:18]=[CH:19][N:20]=[C:21]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)=[C:25]([CH3:36])[CH:24]=3)[C:16]=2[CH:15]=1.CCN(CC)CC>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]([N:33]1[CH2:32][CH2:31][CH:30]([O:29][C:26]2[CH:27]=[CH:28][C:23]([NH:22][C:21]3[C:16]4[CH:15]=[C:14]([F:13])[N:38]=[CH:37][C:17]=4[N:18]=[CH:19][N:20]=3)=[CH:24][C:25]=2[CH3:36])[CH2:35][CH2:34]1)=[O:11]
Reactant: O=C=Nc1c(F)cccc1F
Reactant: Cc1cc(Nc2ncnc3cnc(F)cc23)ccc1OC1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(Nc2ncnc3cnc(F)cc23)ccc1OC1CCN(C(=O)Nc2c(F)cccc2F)CC1
Yield: 76.8 %

Procedure:
2,6-difluorophenyl Isocyanate (0.199 g, 1.28 mmol) was added to a solution of (6-Fluoro-pyrido[3,4-d]pyrimidin-4-yl)-[3-methyl-4-(piperidin-4-yloxy)-phenyl]-amine hydrochloride (T) (500 mg, 1.28 mmol) and NEt3 (0.388 g, 3.84 mmol) in CH2Cl2 (20 mL). After 1 h the reaction was quenched with water, the layers were separated and the organic layer was washed with 1N NaOH and water, dried over Na2SO4, and concentrated. Purification by flash column chromatography (CH2Cl2/MeOH 97:3) afforded the title compound as a yellow solid (0.50 g, 77%). LRMS: 509.2 (MH+); 1H NMR (DMSO-d6, 400 MHz): δ 9.90 (s, 1H), δ 8.86 (s, 1H), δ 8.58 (s, 1H), δ 8.28 (s, 1H), δ 8.19 (s, 1H), δ 7.55-7.58 (m, 2H), δ 7.20-7.27 (m, 1H), δ 7.04-7.10 (m, 3H), δ 4.58-4.61 (m, 1H), δ 3.69-3.73 (m, 2H), δ 3.33-3.98 (m, 2H), δ 2.19 (s, 3H), δ 1.91-1.96 (m, 2H), δ 1.60-1.66 (m, 2H).
Reaction SMILES: [N:1]1([CH2:7][C:8]#[CH:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:10][C:11]1[C:12](I)=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])/[C:14]/2=[CH:21]\[C:22]1[NH:26][CH:25]=[N:24][C:23]=1[CH3:27]>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[F:10][C:11]1[C:12]([C:9]#[C:8][CH2:7][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])/[C:14]/2=[CH:21]\[C:22]1[NH:26][CH:25]=[N:24][C:23]=1[CH3:27]
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#CCN1CCOCC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#CCN3CCOCC3)c21

Procedure:
Using Method C above, 3-(4-morpholinyl)-1-propyne (63.6 mg, 0.51 mmol) (prepared according to H. Kano et al., J. Med. Chem. 10:411-418 (1967)) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (75 mg, 0.203 mmol) (Starting Material 3 supra) using (Ph3P)4Pd (23.5 mg) and CuI (4 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 18 h to give (Z)-1,3-dihydro-5-fluoro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-4-[3-(4-morpholinyl)-1-propynyl]-2H-indol-2-one. (Yield 40 mg, 54%).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]3[NH:17][C@H:16]([C:18]([F:21])([F:20])[F:19])[CH2:15][CH2:14][N:10]3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[F:37]>CN(C)C=O>[F:37][C:31]1[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:30]=1[CH2:29][N:17]1[C:9]2=[N:8][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:12][C:11](=[O:13])[N:10]2[CH2:14][CH2:15][C@H:16]1[C:18]([F:20])([F:21])[F:19]
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2Cc1ccc(F)cc1F

Procedure:
The product is prepared according to the procedure described in Example 22, using 100 mg of (8S)-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (Example 1e), 214 mg of caesium carbonate and 75 mg of 1-(bromomethyl)-2,4-difluorobenzene in 2 ml of dimethylformamide. After purification by preparative HPLC/MS (Method C), 86 mg of (8S)-9-(2,4-difluorobenzyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are obtained in the form of an oil, the characteristics of which are the following:
Reaction SMILES: [CH2:1]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[CH2:5][CH2:4][N:3]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:2]1.[H-].[Na+].Cl[CH2:25][C:26]([N:28]([CH3:30])[CH3:29])=[O:27].CCOC(C)=O>CN(C=O)C>[CH3:29][N:28]([CH3:30])[C:26](=[O:27])[CH2:25][N:7]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=2[C:14]2[CH2:1][CH2:2][N:3]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:4][CH2:5][C:6]1=2
Reactant: CN(C)C(=O)CCl
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3ccccc3c2CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)C(=O)Cn1c2c(c3ccccc31)CCN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
tert-Butyl 1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.100 g, 0.349 mmol) was dissolved in DMF (1.0 mL) under N2 at rt. NaH (0.0450 g, 1.13 mmol, 3.22 equiv., 60% dispersion) was added and the mixture was stirred at rt for 30 min. 2-Chloro-N,N-dimethylacetamide (86 μL, 0.102 g, 0.838 mmol, 2.4 equiv.) was added, and the reaction mixture was stirred at rt for 24 h. The reaction mixture was poured over ice, thenextracted with EtOAc (2×). The organic extracts was washed first with water, then with brine and dried over MgSO4. The organic extracts was filtered and concentrated to yield a crude product (0.148 g). The crude product was chromatographed (SiO2 18 g, eluted with 3:1 toluene:acetone) to give tert-butyl 6-[2-(dimethylamino)-2-oxoethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.116 g) in 90% yield. 1H NMR (300 MHz, CDCl3) δ 1.50, 2.87-2.95, 3.01, 3.00-3.07, 3.13, 3.68-3.80, 4.85, 7.07-7.19, 7.47-7.51; MS (ESI+) for C21H29N3O3 m/z 372.2 (M+H)+.
Reaction SMILES: N#N.[CH3:3][N:4]([NH:6][C:7]1[C:12]([N+:13]([O-])=O)=[C:11]([Cl:16])[C:10]([C:17]([F:20])([F:19])[F:18])=[CH:9][C:8]=1[NH2:21])[CH3:5].[N+]([C:25]1C=C(C(F)(F)F)C=C([N+]([O-])=O)[C:30]=1NN)([O-])=O>[Pd].C(O)C>[NH2:13][C:12]1[C:7]2[N:6]([N:4]([CH3:5])[CH3:3])[C:25]([CH3:30])=[N:21][C:8]=2[CH:9]=[C:10]([C:17]([F:20])([F:19])[F:18])[C:11]=1[Cl:16]
Reactant: CN(C)Nc1c(N)cc(C(F)(F)F)c(Cl)c1[N+](=O)[O-]
Reactant: NNc1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: N#N
Solvent: CCO
Product: Cc1nc2cc(C(F)(F)F)c(Cl)c(N)c2n1N(C)C

Procedure:
A solution of 5.2g. of N2 -(dimethylamino)-4-chloro-3-nitro-5-trifluoromethyl-1,2-phenylenediamine (prepared by hydrogenation of the corresponding 3,5-dinitro-4-hydrazinobenzotrifluoride in the presence of palladium catalyst) and 7.5g. of ethyl methylcarboximidate hydrochloride in 60 ml. of ethanol was refluxed for 26 hours. The resultant 7-nitrobenzimidazole was separated by fractionation on a silica gel column and then hydrogenated in the presence of platinum oxide catalyst in dimethoxyethane-methanol to give the desired product (2.8g.) m.p. 173°-174°C.
Reaction SMILES: [CH3:1][C:2](=[O:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[Br:13]Br.O.C([O-])(O)=O.[Na+]>C(Cl)(Cl)(Cl)Cl>[Br:13][CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:2](=[O:12])[CH3:1]
Reactant: CCCCCCCCCC(C)=O
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCCCCC(Br)C(C)=O
Reaction time: 2 h

Procedure:
A solution of undecan-2-one (170 g, 1.0M) in CCl4 (500 ml) was stirred at 20°-25° C. and bromine (160 g) was added over 15 minutes. The solution decolourised rapidly and stirring was continued for 2 hours at 20°-25° C. when water (100 ml) was added. NaHCO3 (92 g) was added portion-wise and the mixture filtered. The filtrate was dried over anhydrous MgSO4 and distilled. The fraction which boiled at 142°-146° C./20 mmHg (116 g) was collected. NMR(CDCl3)=0.7-1.6 (m, 17, C8H17), 2.3 (s, 3, CH3), 4.0-4.4 (t, 1, CH).
Reaction SMILES: [CH2:1]([CH:15]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:16](O)=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].S(Cl)([Cl:35])=O>C1C=CC=CC=1>[CH2:1]([CH:15]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:16]([Cl:35])=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCCCCCCC(CCCCCCCCCCCCCC)C(=O)O
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCC(CCCCCCCCCCCCCC)C(=O)Cl
Yield: 72.1 %

Procedure:
A solution of 1.0 g of 2-tetradecylhexadecanoic acid and 0.79 g of thionyl chloride in 5 ml of benzene was refluxed for 7 hours. After removal of benzene and thionyl chloride, anhydrous benzene was added to the residue and then benzene was removed by distillation. This procedure was repeated 3 times to remove thionyl chloride completely. The residue was recrystallized from anhydrous hexane to obtain 0.75 g of 2-tetradecylhexadecanoyl chloride having a melting point of 51°-53° C. To the solution of 0.85 g of 1-α-O-benzyl-N-acetylmuramyl-L-alanyl-D-isoglutamine benzyl ester in 35 ml of anhydrous pyridine, was added 4.9 g of 2-tetradecylhexadecanoyl chloride dissolved in 35 ml of anhydrous tetrahydrofuran at 17°-18° C. After 45 minutes, 20 ml of water was added and the solution was stirred for 35 minutes at room temperature. The solution was adjusted to pH 3 with 1 M hydrochloric acid and extracted with chloroform. The chloroform solution was washed with saturated brine, and dried. After removal of solvent, the residue was subjected to silica gel column chromatography. Eluate with a mixture of chloroform and methanol (20:1) was concentrated and the residue was recrystallized from methanol to obtain 0.75 g of 6-O-(2-tetradecylhexadecanoyl)-1-α-O-benzyl-N-acetylmuramyl-L-alanyl-D-isoglutamine benzyl ester having a melting point of 173°-174° C.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li]CCCC.[CH3:29][C:30]1([CH3:37])[CH2:35][CH2:34][C:33](=O)[CH2:32][CH2:31]1>C1COCC1.[Cl-].[NH4+].C(OCC)(=O)C>[CH3:29][C:30]1([CH3:37])[CH2:35][CH2:34][C:33](=[CH:2][O:3][CH3:4])[CH2:32][CH2:31]1
Reactant: CC1(C)CCC(=O)CC1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC=C1CCC(C)(C)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture of methoxymethyl triphenylphosphonium chloride (35.5 g, 0.104 mol) in THF (400 mL) at 0° C. was added n-BuLi (33.1 mL of a 2.8M solution in hexanes; 0.095 mol). The mixture was stirred at 0° C. for 30 min., cooled to −78° C. and a solution of 4,4-dimethyl cyclohexanone (10.0 g, 0.079 mol) in THF (100 mL) was added, dropwise. After 1 hr at −78° C. the mixture was slowly warmed to 0° C., diluted with satd ammonium chloride (400 mL) and ethyl acetate (100 mL) and stirred at room temperature for 48 hr. Layers were separated and the aqueous phase was extracted with ethyl acetate. Combined organics were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was triturated with hexanes, solids were removed by filtration and the filtrated was concentrated in vacuo. The residue was dissolved in dichloromethane (40 mL), PS-TsNHNH2 (8 g; ca. 3.7 mmol/g) and acetic acid (2 drops) were added and the mixture was stirred at room temperature for 24 hr. Resin was removed by filtration and washed (CH2Cl2, MeOH, CH2Cl2). Combined filtrate/washings were concentrated in vacuo, affording (4,4-dimethyl cyclohexylidene)methyl methyl ether as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 0.91 (s, 6H); 1.27 (m, 5H); 1.95 (m, 2H); 2.18 (m, 2H); 3.52 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[C:5]2[C:15](=[O:31])[N:16]([CH2:19][CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)[C:17](=O)[C:4]2=[CH:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:41])=CC=1>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:7](=[O:8])[C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[C:5]2[C:15](=[O:31])[N:16]([CH2:19][CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)[C:17](=[S:41])[C:4]2=[CH:3]1
Reactant: Cn1cc2c(c(N3CCOCC3)c1=O)C(=O)N(CCc1ccc3ccccc3n1)C2=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Cn1cc2c(c(N3CCOCC3)c1=O)C(=O)N(CCc1ccc3ccccc3n1)C2=S
Temperature: 120 °C
Yield: 178.9 %

Procedure:
5-Methyl-7-morpholin-4-yl-2-(2-quinolin-2-yl-ethyl)-5H-pyrrolo[3,4-c]pyridine-1,3,6-trione (0.7 g, 1.67 mmol, see Example 1) was dissolved in toluene (20 ml), stirred and heated to 120° C. and Lawesson's reagent (0.338 g, 0.836 mmol) was added. The reaction was stirred at 120° C. for 16 h. The reaction mixture was cooled to r.t., filtered though a pad of silica gel and concentrated to afford the crude title compound (0.65 g, 77% yield), which was used in the next steps without further purification.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]([CH2:6][C:7]([O:9][CH3:10])=[O:8])=[O:5].[C:11]1([CH2:17][C:18](Cl)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O>[CH3:10][O:9][C:7](=[O:8])[CH:6]([C:4](=[O:5])[CH3:3])[C:18](=[O:19])[CH2:17][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)CC(C)=O
Reactant: O=C(Cl)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)C(C(C)=O)C(=O)Cc1ccccc1
Reaction time: 14 h

Procedure:
NaOH (10 N, 4.4 mL, 44 mmol) in H2O is added to a solution of MeCOCH2COOMe (5 g, 43.1 mmol) in THE at RT. PhCH2COCl is added dropwise to the mixture and the mixture is stirred for 14 h. The mixture is extracted with EtOAc (2×30 mL). The organic phase is dried. The product is purified by silica gel column chromatography using 3-5% EtOAc in hexane to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][CH:7]([C:10]#[N:11])[C:8]#[N:9])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:17][CH2:18][F:19]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]([CH2:17][CH2:18][F:19])([C:8]#[N:9])[C:10]#[N:11])=[CH:12][CH:13]=1
Reactant: FCCBr
Reactant: N#CC(C#N)Cc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCF)Cc1ccc(Cl)cc1
Yield: 24.2 %

Procedure:
Using 1.00 g of (4-chlorobenzyl)malononitrile, 10 ml of N,N-di-methylformamide, 0.21 g of sodium hydride (60% in oil), and 0.67 g of 1-bromo-2-fluoroethane, and according to the process described in the Production Example 1, there was obtained 0.30 g of 2-(4-chlorobenzyl)-2-(2-fluoroethyl)malononitrile (the present compound (24)).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH:15][CH3:16])=[O:14])[CH:8]=2)=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][C:21]=1[C:29]([F:32])([F:31])[F:30]>C(OCC)(=O)C>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:1][C:2]2[CH:18]=[CH:17][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH:15][CH3:16])=[O:14])[CH:8]=3)=[CH:4][CH:3]=2)=[O:28])=[CH:22][C:21]=1[C:29]([F:30])([F:31])[F:32]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CNC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Solvent: CCOC(C)=O
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)ccn1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
4-(4-Aminophenoxy)-N-methyl-2-pyridinecarboxamide (52.3 kg, 215 mol) is suspended in ethyl acetate (146 kg) and the suspension is heated to approx. 40° C. 4-Chloro-3-trifluoromethylphenyl isocyanate (50 kg, 226 mol), dissolved in ethyl acetate (58 kg), is then added to such a degree that the temperature is kept below 60° C. After cooling to 20° C. within 1 h, the mixture is stirred for a further 30 min and the product is filtered off. After washing with ethyl acetate (30 kg), the product is dried under reduced pressure (50° C., 80 mbar). 93 kg (93% of theory) of the title compound are obtained as colorless to slightly brownish crystals.