Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH:10]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:3]=12.[Cl:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[ClH:21].[CH2:25]([O:24][C:22]([N:18]1[CH2:19][CH2:20][C:3]2[C:4](=[N:5][C:6]3[CH:7]=[CH:8][C:9]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:11]=3[C:2]=2[CH3:1])[CH2:16][CH2:17]1)=[O:23])[CH3:26]
Reactant: CCOC(=O)Cl
Reactant: Cc1c2c(nc3ccc(C(F)(F)F)cc13)CCNCC2
Product: CCOC(=O)N1CCc2nc3ccc(C(F)(F)F)cc3c(C)c2CC1
Product: Cl
Yield: 90 %

Procedure:
1,2,4,5-Tetrahydro-11-methyl-9-trifluoromethyl-3-azepino[4,5-b]quinoline-carboxylic acid ethyl ester hydrochloride was prepared from 1,2,4,5-tetrahydro-11-methyl-9-trifluoromethyl-3H-azepino[4,5-b]quinoline and ethyl chloroformate analogous to Example 155.
Reaction SMILES: [CH3:1][C:2]([CH3:5])=[C:3]=[O:4].[C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[N:18]=[N:19][NH:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1[C:31]#[N:32])#[N:7]>C(OCC)(=O)C.CCOCC>[C:3]([N:18]([C:9]1[CH:10]=[C:11]([C:14]([F:15])([F:16])[F:17])[CH:12]=[CH:13][C:8]=1[C:6]#[N:7])[N:19]=[N:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1[C:31]#[N:32])(=[O:4])[CH:2]([CH3:5])[CH3:1]
Reactant: N#Cc1ccc(C(F)(F)F)cc1N=NNc1cc(C(F)(F)F)ccc1C#N
Reactant: CC(C)=C=O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)C(=O)N(N=Nc1cc(C(F)(F)F)ccc1C#N)c1cc(C(F)(F)F)ccc1C#N
Reaction time: 12 h

Procedure:
A solution of 3.5 g. (0.05 mol.) of dimethylketene in ethyl acetate is added dropwise under a nitrogen atmosphere to a cooled (0°) solution of 18.6 g. (0.05 mol.) of 1,3-bis(2-cyano-5-trifluoromethylphenyl)triazene in ether. The reaction mixture is stirred for 12 hours then concentrated at reduced pressure. Crystallization of the residue from ether gives 3-isobutyryl-1,3-bis(2-cyano-5-trifluoromethylphenyl)triazene.
Reaction SMILES: [F:1][CH:2]([F:37])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][N:23]([S:26]([CH:29]=[CH2:30])(=[O:28])=[O:27])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1.[CH3:38][NH:39][CH3:40]>C1COCC1>[F:37][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]3[CH2:21][CH2:22][N:23]([S:26]([CH2:29][CH2:30][N:39]([CH3:40])[CH3:38])(=[O:28])=[O:27])[CH2:24][CH2:25]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1
Reactant: C=CS(=O)(=O)N1CCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(OC)cccc43)n2)CC1
Reactant: CNC
Solvent: C1CCOC1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(S(=O)(=O)CCN(C)C)CC2)n1
Reaction time: 0.25 h

Procedure:
A mixture of 2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[4-(vinylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-1H-benzimidazole (Example 3) (0.536 g, 1 mmol) and 40% aqueous dimethylamine (10 mL) in THF (200 mL) was warmed gently until a clear solution was obtained. After 15 min, the THF was removed under vacuum and the residue was diluted with water to give N-[2-({4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinyl}sulfonyl)ethyl]-N,N-dimethylamine: 1H NMR (CDCl3) δ 7.86 (dd, J=8.4, 0.6 Hz, 1H), 7.45 (t, JHF=53.5 Hz, 1H), 7.36 (t, J=8.2 Hz, 1H), 6.82 (d, J=7.8 Hz, 1H), 4.05 (s, 3H), 4.00 (m, 4H), 3.89 (m, 4H), 3.79 (m, 4H), 3.39 (m, 4H), 3.11 (dd, J=8.1, 6.4 Hz, 2H), 2.78 (dd, J=8.1, 6.4 Hz, 2H), 2.26 (s, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]1[CH:10]=[C:9]([S:11](=[O:14])(=[O:13])[NH2:12])[C:8]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:7]([NH:22][CH2:23][CH:24]=[CH2:25])[CH:6]=1)[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:26])[C:5]1[CH:10]=[C:9]([S:11](=[O:14])(=[O:13])[NH2:12])[C:8]([O:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[C:7]([NH:22][CH2:23][CH2:24][CH3:25])[CH:6]=1)[CH3:2]
Reactant: [H][H]
Reactant: C=CCNc1cc(C(=O)OCC)cc(S(N)(=O)=O)c1Oc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCCNc1cc(C(=O)OCC)cc(S(N)(=O)=O)c1Oc1ccccc1

Procedure:
A solution of ethyl-3-allylamino-4-phenoxy-5-sulphamyl-benzoate (1.65 g) in ethanol (150 ml) was hydrogenated at room temperature and 1.1. atmospheres hydrogen pressure after the addition of a palladium-on-carbon catalyst (0.6 g catalyst containing 10% Pd). After the hydrogen uptake had become negligible, the catalyst was removed by filtration, and the filtrate was evaporated in vacuo. The residue was recrystallized twice from aqueous ethanol, resulting in ethyl-4-phenoxy-3-n-propylamino-5-sulphamyl-benzoate with a melting point of 150°-151° C.
Reaction SMILES: [O:1]=[C:2]1[N:11]([CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([C:19](O)=[O:20])[CH2:15][CH2:14]2)[C:10](=[O:22])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:56]1[CH:61]=[CH:60][CH:59]=[N:58][C:57]=1[N:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1>CN(C=O)C.CO>[N:56]1[CH:61]=[CH:60][CH:59]=[N:58][C:57]=1[N:62]1[CH2:67][CH2:66][N:65]([C:19]([C@H:16]2[CH2:15][CH2:14][C@H:13]([CH2:12][N:11]3[C:10](=[O:22])[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[NH:3][C:2]3=[O:1])[CH2:18][CH2:17]2)=[O:20])[CH2:64][CH2:63]1
Reactant: O=c1[nH]c2ccccc2c(=O)n1C[C@H]1CC[C@H](C(=O)O)CC1
Reactant: c1cnc(N2CCNCC2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CO
Product: O=c1[nH]c2ccccc2c(=O)n1C[C@H]1CC[C@H](C(=O)N2CCN(c3ncccn3)CC2)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of trans-4-(2,4-Dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl)-cyclohexanecarboxylic acid (100 mg, 0.33 mmol) in DMF(2 mL), diisopropylethylamine (58 μL, 0.33 mmol) and HATU (126 mg, 0.33 mmol) were added. The mixture was left 6 hours stirring at room temperature and then 1-(2-pyrimidyl)piperazine was added. After 16 hours at room temperature the solvent was removed under reduced pressure; the residue was dissolved in 2 mL of DCM and washed with 2 mL of 0.4N Na2CO3 solution. The organic layer was separated, dried over Na2SO4 and the solvent removed under reduced pressure. The titled compound (58 mg, yield 39%) was purified by precipitation from methanol.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10][C:9](=[O:19])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:21][CH2:22][CH2:23][CH2:24][C:25]([CH3:31])([CH3:30])[C:26]([O:28][CH3:29])=[O:27]>C(=O)([O-])[O-].[Ag+2].C1(C)C=CC=CC=1>[CH3:30][C:25]([CH3:31])([CH2:24][CH2:23][CH2:22][CH2:21][O:19][C:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:12]=[C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:10]=1)[C:26]([O:28][CH3:29])=[O:27]
Reactant: COC(=O)C(C)(C)CCCCBr
Reactant: O=c1cc(-c2ccccc2)cc(-c2ccccc2)[nH]1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)C(C)(C)CCCCOc1cc(-c2ccccc2)cc(-c2ccccc2)n1

Procedure:
The procedure in Example 4 is followed but using 4,6-diphenyl-2-pyridinone (4 g), methyl 6-bromo-2,2-dimethylhexanoate (5.8 g) (prepared according to the method described in Patent EP 108 592), silver carbonate (2.3 g) and toluene (150 cc). The product is purified by chromatography under pressure on silica gel (30-60 mm; eluent: n-hexane-ethyl acetate 95-5, brown oil)
Reaction SMILES: I[C:2]1[N:3]=[N:4][N:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]=1[CH2:7][CH2:8][CH3:9].[C:16](=[O:19])([O-])[O-:17].[K+].[K+].[CH3:22][N:23]([CH3:26])C=O>>[C:10]1([N:5]2[C:6]([CH2:7][CH2:8][CH3:9])=[C:2]([C:6]3[CH2:7][CH:22]([C:16]([O:17][CH:10]([CH3:15])[CH3:11])=[O:19])[NH:23][CH2:26][CH:2]=3)[N:3]=[N:4]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C([O-])[O-]
Reactant: CN(C)C=O
Reactant: CCCc1c(I)nnn1-c1ccccc1
Agent: [K+]
Product: CCCc1c(C2=CCNC(C(=O)OC(C)C)C2)nnn1-c1ccccc1
Temperature: 80 °C

Procedure:
In a nitrogen atmosphere, 30 mg of 4-iodo-1-phenyl-5-propyl-1H-[1,2,3]-triazole prepared in the above 2), 34 mg of isopropyl 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaboran-2-yl)-1,2,3,6-tetrahydropyridine-carboxylate prepared in Example 45-6 and 26 mg of potassium carbonate were dissolved in 3 ml of N,N-dimethylformamide, 7.7 mg of [1,1-bis(diphenylphosphino)-ferrocene]dichloropalladium was added thereto and the mixture was stirred with heating at 80° C. for one night. After the reaction solution was cooled down to room temperature, insoluble matters were removed by filtering through Celite. Water was added to the filtrate, the mixture was extracted with diethyl ether and the diethyl ether layer washed with a saturated saline solution and dried over sodium sulfate. After the solvent was evaporated in vacuo, the residue was separated and purified by a thin-layer chromatography (hexane/ethyl acetate=2/1) to give 9.04 mg of a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])=[C:6]([Cl:15])[N:5]=[C:4]([S:16][CH3:17])[N:3]=1.[CH:18]1([NH2:23])[CH2:22][CH2:21][CH2:20][CH2:19]1.C(OCC)(=O)C>C(Cl)Cl.C(OC(=O)C)C.C(OCC)C>[Cl:15][C:6]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])=[C:2]([NH:23][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:3]=[C:4]([S:16][CH3:17])[N:5]=1
Reactant: NC1CCCC1
Reactant: CSc1nc(Cl)c(-c2ccccc2F)c(Cl)n1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CSc1nc(Cl)c(-c2ccccc2F)c(NC2CCCC2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 25.1 %

Procedure:
To a solution of 4,6-dichloro-5-(2-fluorophenyl)-2-methylthiopyrimidine (0.74 g, 256 mmol) in methylene chloride (1 ml) at room temperature under nitrogen atmosphere was added cyclopentyl-amine (1.01 ml, 10.24 mmol) and the reaction mixture was stirred at room temperature for 15 hours. The reaction mixture was then diluted with 1:1 v/v diethyl ether ethyl acetate (75 ml), washed with 1 M aqueous hydrochloric acid (2×75 ml), saturated aqueous sodium bicarbonate solution (75 ml) and saturated brine (75 ml), dried over magnesium sulfate and concentrated in vacuo to afford a colorless syrup. The crude product was chromatographed on silica gel eluting with 95:5 v/v hexane: ethyl acetate to afford 0.87 g (100% yield) of the title compound as a white crystalline solid (melting point: 81–83° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[H-].[Na+].CC1C=CC(S(O[CH2:35][C@H:36]2[CH2:38][O:37]2)(=O)=O)=CC=1.C(OCC)(=O)C>CN(C)C=O.O>[NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:35][C@H:36]4[CH2:38][O:37]4)=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1cc2c(Oc3ccc(N)cc3)ccnc2cc1O
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc2c(Oc3ccc(N)cc3)ccnc2cc1OC[C@H]1CO1
Temperature: 25 °C
Yield: 97 %

Procedure:
After dissolving 4-(4-aminophenoxy)-6-cyano-7-hydroxyquinoline (277 mg, 1.00 mmol) in dimethylformamide (3.0 ml), sodium hydride (40 mg, 1.00 mmol, 60% in oil) was added at room temperature and the mixture was stirred. There was then added (2R)-oxiran-2-ylmethyl 4-methyl-1-benzenesulfonate (228 mg, 1.00 mmol), and the mixture was heated and stirred at 60° C. for 5 hours. After cooling to room temperature, the reaction solution was distributed between ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain the title compound (322 mg, 0.97 mmol, 97%)-as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[CH:6]3[CH2:13][O:14][CH2:15][CH2:16][N:5]3[C:4]=2[N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:27][S:28]([C:31]1[CH:38]=[CH:37][C:34]([CH2:35]Br)=[CH:33][CH:32]=1)(=[O:30])=[O:29]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:35][C:34]3[CH:33]=[CH:32][C:31]([S:28]([CH3:27])(=[O:30])=[O:29])=[CH:38][CH:37]=3)[C:7](=[O:12])[CH:6]3[CH2:13][O:14][CH2:15][CH2:16][N:5]3[C:4]=2[N:3]=1
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Reactant: O=C1Nc2cnc(Cl)nc2N2CCOCC12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(CN2C(=O)C3COCCN3c3nc(Cl)ncc32)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-Chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (PREPARATION x1, 1.5 g, 6.23 mmol) was dissolved in DMF (25 mL) to give an orange solution. The mixture was cooled to 0° C. and lithium bis(trimethylsilyl)amide (1.04 g, 6.23 mmol), followed by 4-methylsulfonylbenzyl bromide (1.71 g, 6.86 mmol), were added. The reaction mixture was stirred at 0° C. for 1 hour and was subsequently diluted with ethyl acetate and washed with brine (100 mL) to give a suspension. An orange precipitate was collected on a fitted glass funnel and was washed with water (3×20 mL) and dried over night in a stream of nitrogen. The crude solid was triturated with hot ethyl acetate (2×) to give the title compound which was used without further purification (1.78 g, 69.8%). ESI-MS m/z [M+H]+ calc'd for C17H17ClN4O4S, 409.07; found 409.3.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S].S1C2C=CC=CC=2N=C1.[C:18](=[S:20])=[S:19]>>[SH:20][C:18]1[S:19][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: Nc1ccccc1
Reactant: S=C=S
Agent: [S]
Agent: c1ccc2scnc2c1
Product: Sc1nc2ccccc2s1

Procedure:
reacting starting materials comprising (1) aniline, carbon disulphide and sulphur, (2) benzothiazole and sulphur or (3) aniline, carbon disulphide, benzothiazole and sulphur, to form crude 2-mercaptobenzothiazole,
Reaction SMILES: [C:1]1(C)C=CC=CC=1.N1CCCCC1.[CH3:14][C:15]1([C:21]2[CH:22]=[C:23]([C:29]3[CH:30]=[C:31]4[C:36](=[CH:37][CH:38]=3)[CH:35]=[C:34](C=O)[CH:33]=[CH:32]4)[CH:24]=[CH:25][C:26]=2[O:27][CH3:28])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[S:41]1[CH2:45][C:44](=[O:46])[NH:43][C:42]1=[O:47]>C(O)(=O)C>[CH3:14][C:15]1([C:21]2[CH:22]=[C:23]([C:29]3[CH:30]=[C:31]4[C:36](=[CH:37][CH:38]=3)[CH:35]=[C:34]([N:43]3[C:44](=[O:46])[C:45](=[CH2:1])[S:41][C:42]3=[O:47])[CH:33]=[CH:32]4)[CH:24]=[CH:25][C:26]=2[O:27][CH3:28])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: COc1ccc(-c2ccc3cc(C=O)ccc3c2)cc1C1(C)CCCCC1
Reactant: Cc1ccccc1
Reactant: O=C1CSC(=O)N1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: C=C1SC(=O)N(c2ccc3cc(-c4ccc(OC)c(C5(C)CCCCC5)c4)ccc3c2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
A solution of toluene (2.5 mL), piperidine (0.003 mL), acetic acid (0.003 mL), 6-[3-(1-methylcyclohexyl)-4-methoxyphenyl]-2-naphthaldehyde (0.100 g, 0.28 mmol) and 2,4-thiazolidinedione (0.033 mg, 0.28 mmol) was heated at reflux for 15 hours under an argon atmosphere. The resulting suspension was filtered and the solid was stirred at room temperature in EtOH. After 1 hours, the solid was filtered and dried under high vacuum to afford 0.048 g (37%) of 6-[3-(1-methylcyclohexyl)-4-methoxyphenyl]-naphthalen-2-yl-methylene-2,4-thiazolidinedione, mp 268–271° C. 1H NMR (300 MHz, DMSO-d6): δ 1.21–1.61 (m, 9H), 1.69–1.81 (m, 2H), 2.15 (t, J=10.7 Hz, 2H), 3.86 (s, 3H), 7.14 (d, J=8.7 Hz, 1H), 7.65 (s, 1H), 7.69 (brt, J=9.6 Hz, 2H), 7.90 (d, J=9.9 Hz, 1H), 7.94 (s, 1H), 8.10 (d, J=8.7 Hz, 1H), 8.12 (d, J=8.7 Hz, 1H), 8.19 (s, 2H), 12.66 (brs, 1H).
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5]([NH2:6])=[N:4][C:2]1=[O:3].[H-].[Na+].Br[CH2:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].CN(C=[O:27])C>>[N:1]1([CH2:12][C:13]([O:15][C:16](=[O:27])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH:8]=[CH:7][C:5]([NH2:6])=[N:4][C:2]1=[O:3]
Reactant: CN(C)C=O
Reactant: O=C(CBr)OCc1ccccc1
Reactant: Nc1cc[nH]c(=O)n1
Agent: [H-]
Agent: [Na+]
Product: Nc1ccn(CC(=O)OC(=O)c2ccccc2)c(=O)n1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Reference is made to FIG. 1 where to cytosine (20 g, 0.18 mmol) in 400 mL DMF was added 7.2 g (0.18 mmol) of NaH (disp. in oil 60%). The mixture was heated to 50° C. and stirred for 2 h under nitrogen. After cooling to room temperature, 29 mL (1.1 eq.) of benzyl bromoacetate was added over 2 h. After stirring overnight, the dark suspension was filtered and the filtrate washed with cold DMF and 0.2 M sodium bicarbonate. The product (1) was crystallized from ethanol. Yield: 37 g (79%). 1H NMR (d6-DMSO): δ 4.56 (s, 2 CH2O), 5.24 (s, 2 H, CH2CO), 5.77 (d, 1 H, H5), 7.20 (dd, 2 H, NH2), 7.45 (m, 5 H, aromatic), 7.65 (d, 1 H, H6). MS (FAB) m/z 260 (M+H)+ (calcd 260).
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]2[CH2:9][CH2:10][C@:11]([CH2:14][CH2:15]/[CH:16]=[C:17](/[CH2:19][CH2:20]/[CH:21]=[C:22](/[CH2:24][CH2:25][CH:26]=[C:27]([CH3:29])[CH3:28])\[CH3:23])\[CH3:18])([CH3:13])[O:12][C:4]=2[C:3]=1[CH3:30].[C:31]([O:34]C(=O)C)(=[O:33])[CH3:32].C(O)(=O)C>C(OCC)(=O)C.CCCCCCC>[CH3:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]2[CH2:9][CH2:10][C@:11]([CH2:14][CH2:15]/[CH:16]=[C:17](/[CH2:19][CH2:20]/[CH:21]=[C:22](/[CH2:24][CH2:25][CH:26]=[C:27]([CH3:29])[CH3:28])\[CH3:23])\[CH3:18])([CH3:13])[O:12][C:4]=2[C:3]=1[CH3:30].[C:31]([O-:34])(=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Agent: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC[C@]1(C)CCc2cc(O)c(C)c(C)c2O1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)[O-]

Procedure:
γ-Tocotrienol (crude product, prepared in accordance with Example 3, 4.8 g) was heated with 10 ml of acetic anhydride for 3.5 h under reflux and then freed from acetic acid and acetic anhydride under reduced pressure. Flash chromatography of the crude product with ethyl acetate/heptane as eluent on silica gel gave 3.7 g of γ-tocotrienol acetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[C:13](=[O:17])[NH:14][CH2:15][CH2:16][C:11]=3[NH:10][C:9]=2[CH:18]=O)=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH2:24]2>>[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[C:24]2=[CH:18][C:9]1[NH:10][C:11]2[CH2:16][CH2:15][NH:14][C:13](=[O:17])[C:12]=2[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: O=Cc1[nH]c2c(c1-c1ccc(F)cc1)C(=O)NCC2
Product: O=C1Nc2ccc(Cl)cc2C1=Cc1[nH]c2c(c1-c1ccc(F)cc1)C(=O)NCC2
Yield: 34.2 %

Procedure:
The title compound was prepared under the same conditions as described in Example 46 with 3-(4-fluoro-phenyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 5-chloro-1,3-dihydro-indol-2-one as starting materials to give 2-(5-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-(4-fluoro-phenyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (32 mg, 34.2%) as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].Br[CH:19]([CH3:24])[C:20]([O:22][CH3:23])=[O:21]>C(#N)C>[CH3:23][O:22][C:20]([CH:19]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:9])=[O:10])[CH3:24])=[O:21]
Reactant: NS(=O)(=O)c1ccccc1O
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C(C)Oc1ccccc1S(N)(=O)=O
Yield: 80.7 %

Procedure:
34.6 g of 2-hydroxybenzenesulfonamide and 55.3 g of potassium carbonate are added to 800 ml of acetonitrile. With efficient stirring, 33.4 g of methyl 2-bromopropionate are added dropwise over 10 minutes and the suspension is then heated for 5 hours to 45° C. After the reaction mixture has cooled, the precipitated salts are isolated and the filtrate is concentrated in vacuo. The residue is recrystallised from ethanol, affording 41.8 g of 2-(1-methoxycarbonylethoxy)-benzenesulfonamide with a melting point of 140°-142° C.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH2:10]([Li])[CH2:11][CH2:12][CH3:13].Br[CH:16](Br)[CH3:17].O>O1CCCC1>[CH:1]1([CH2:13][CH2:12][CH:11]2[C:10]3[C:1](=[CH:2][CH:3]=[CH:16][CH:17]=3)[CH:9]=[CH:8]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CC(Br)Br
Reactant: C1=Cc2ccccc2C1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: C1=CC(CCC2C=Cc3ccccc32)c2ccccc21
Temperature: -78 °C
Reaction time: 4 h
Yield: 51.6 %

Procedure:
Into a 2 litre two-necked round-bottomed flask, 50 g of indene (437 mmol) were dissolved under inert atmosphere with 500 ml of tetrahydrofuran and were cooled to −78° C. By slow dropping (1 hour) 175 ml of n-butyllithium (2.5 M in hexane, 437.5 mmol) were added. The mixture was allowed to heat up to room temperature and was kept under stirring for 4 hours. It was cooled to −78° C. and 40.42 g of dibromoethane (215 mmol) dissolved in 100 ml of tetrahydrofuran were dropped (within 20 minutes). After the end of the addition, the temperature was raised to 50° C., the whole was kept under stirring for 12 hours, then was cooled down to room temperature and 20 ml of water were added. The organic phase was dried and the residue was extracted with pentane. By evaporation under vacuum 28.65 g of product were obtained (yield=51.6%).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[N:6][NH:5][C:4](=[O:11])[C:3]=1[C:12]([O:14]CC)=O.[H-].[Na+].[Br:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1.[Na+].[NH2:29][CH2:30][C:31]([O-:33])=[O:32].Cl>CN(C)C=O.O>[Br:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][N:5]2[C:4](=[O:11])[C:3]([C:12]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:14])=[C:2]([OH:1])[C:7]([CH:8]([CH3:9])[CH3:10])=[N:6]2)=[CH:22][CH:21]=1
Reactant: NCC(=O)[O-]
Reactant: CCOC(=O)c1c(O)c(C(C)C)n[nH]c1=O
Reactant: BrCc1ccc(Br)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1nn(Cc2ccc(Br)cc2)c(=O)c(C(=O)NCC(=O)O)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.4 %

Procedure:
To a solution of ethyl 5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinecarboxylate (example 46a, 1.32 g, 5.83 mmol) in N,N-Dimethylformamide (DMF) (30 ml) at 0° C. was added sodium hydride (0.5 g, 14.58 mmol) in portions. The reaction mixture was stirred at room temperature for 30 minutes and then cooled back to 0° C. and 4-bromobenzyl bromide (1.46 g, 5.83 mmol) was added. The mixture was stirred at ambient temperature for 2 hours then quenched with 1N HCl (10 ml). The aqueous solution was extracted with ethyl acetate (2×50 ml), the organic layers combined, dried over Magnesium sulfate, filtered and solvents removed with rotary evaporation. The crude residue was dissolved in 2-methoxyethanol (10 ml), place in a 20 ml microwave tube and glycine sodium salt (0.75 g, 7.7 mmol) was added. The mixture was irradiated at 150° C. for 20 minutes, diluted with water (15 ml) and acidified with 1N HCl to cause a precipitate. The precipitate was collected by filtration and dried to give the product as an off white solid (0.750 g, 1.77 mmol, 30.3%) 1H NMR (400 MHz, DMSO-d6) d ppm 15.89 (s, 1H), 12.97 (s, 1H), 10.16 (t, J=5.31 Hz, 1H), 7.55 (d, J=8.34 Hz, 2H), 7.26 (d, J=8.34 Hz, 2 H), 5.22 (s, 2H), 4.10 (d, J=5.81 Hz, 2H), 3.18 (m, 1H), 1.19 (d, J=6.82 Hz, 6H). MS (ES+) m/e 425 [M+H]+.
Reaction SMILES: [OH:1][C@@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@H:4]([CH3:8])[CH2:3]1.CC[N:27](C(C)C)C(C)C.[CH:34]1([CH:37]2[CH2:41][CH2:40][N:39](N)[CH:38]2[CH3:43])[CH2:36][CH2:35]1>>[OH:1][C@@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:39]4[CH2:40][CH2:41][CH:37]([CH:34]5[CH2:36][CH2:35]5)[C:38]4([CH3:43])[NH2:27])=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@H:4]([CH3:8])[CH2:3]1
Reactant: CC1C(C2CC2)CCN1N
Reactant: CCN(C(C)C)C(C)C
Reactant: C[C@H]1CCC[C@@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Product: C[C@H]1CCC[C@@](O)(CNC(=O)c2c(Cl)ccc3nc(N4CCC(C5CC5)C4(C)N)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid ((1S,3S)-1-hydroxy-3methyl-cyclohexylmethyl)-amide, DIPEA and 3-cyclopropyl-methyl-amino-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 4.16 (s, 1H), 4.00 (t, 2H), 3.80 (t, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.22 (s, 3H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27 (t, 1H), 1.07 (t, 1H), 0.83 (d, 4H). m/z: 472 [M+H]