Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([NH:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([O:23][CH3:24])=[O:22])[CH2:16]1)=[O:13].Br[CH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]#[C:38][CH2:39][O:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:31][CH:30]=1>>[CH3:24][O:23][C:21]([CH:17]1[CH2:18][CH2:19][CH2:20][CH:15]([NH:14][C:12]([C:3]2[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=2[O:1][CH2:26][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]#[C:38][CH2:39][O:40][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)=[CH:31][CH:30]=2)[C:6]([O:8][CH3:9])=[O:7])=[O:13])[CH2:16]1)=[O:22]
Reactant: BrCCCc1ccc(OCC#CCOc2ccccc2)cc1
Reactant: COC(=O)c1ccc(O)c(C(=O)NC2CCCC(C(=O)OC)C2)c1
Product: COC(=O)c1ccc(OCCCc2ccc(OCC#CCOc3ccccc3)cc2)c(C(=O)NC2CCCC(C(=O)OC)C2)c1

Procedure:
Preparation takes place in analogy to Example 22 from the (+)-B-enantiomer of methyl 4-hydroxy-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate (see Example IX, method 2) and 1-(3-bromopropyl)-4-[(4-phenoxybut-2-yn-1-yl)oxy]benzene.
Reaction SMILES: [BH4-].[Na+].[C:3](O)(=O)[CH2:4][CH3:5].[CH3:8][NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[OH-].[Na+]>>[CH3:8][N:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:3][CH2:4][CH3:5]
Reactant: CCC(=O)O
Reactant: CCCCCCCCNC
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCN(C)CCC
Reaction time: 3 h
Yield: 63 %

Procedure:
Sodium borohydride (6.62 g) was added in portions to propionic acid (52.5 ml), cooled to 5°, maintaining the temperature below 20°. N-methyloctylamine (5 g) was added dropwise, keeping the temperature at 20°. The reaction was stirred at 80° for 3 hours, cooled and basified with 2N sodium hydroxide. The aqueous solution was extracted with dichloromethane (2×75 ml). The combined extracts were dried with anhydrous magnesium sulphate and evaporated to dryness. The resulting oil was purified by column chromatography to give N-methyl-N-propyloctylamine as a colourless oil (4.09 g, 63%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([C:12]2[CH:17]=[CH:16][C:15]([C@H:18]([NH:20][C:21]([C:23]3([NH2:27])[CH2:26][O:25][CH2:24]3)=[O:22])[CH3:19])=[C:14]([F:28])[CH:13]=2)=[CH:7][CH:8]=[CH:9][C:10]=1[Cl:11])=[O:4].[O:29]1[C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=[N:30]1>>[CH3:1][O:2][C:3]([C:5]1[C:6]([C:12]2[CH:17]=[CH:16][C:15]([C@H:18]([NH:20][C:21]([C:23]3([NH:27][C:34]([C:33]4[O:29][N:30]=[CH:31][CH:32]=4)=[O:35])[CH2:24][O:25][CH2:26]3)=[O:22])[CH3:19])=[C:14]([F:28])[CH:13]=2)=[CH:7][CH:8]=[CH:9][C:10]=1[Cl:11])=[O:4]
Reactant: O=C(O)c1ccno1
Reactant: COC(=O)c1c(Cl)cccc1-c1ccc([C@@H](C)NC(=O)C2(N)COC2)c(F)c1
Product: COC(=O)c1c(Cl)cccc1-c1ccc([C@@H](C)NC(=O)C2(NC(=O)c3ccno3)COC2)c(F)c1

Procedure:
The title compound was prepared in analogy to example 1 using intermediate 4 instead of intermediate 1 and isoxazole-5-carboxylic acid instead of 3-fluoro-5-(trifluoromethyl)benzoic acid and was obtained as white solid. MS: 502.1 [M+H]+.
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[NH:13][C:12]1=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[CH2:24]([O:26][C:27]([CH2:29][NH:30][CH2:31][CH2:32][C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=1)=[O:28])[CH3:25]>CN(C=O)C>[CH2:24]([O:26][C:27]([CH2:29][NH:30][CH2:31][CH2:32][C:33]1[CH:39]=[CH:38][C:36]([NH:37]/[C:4](=[C:11]2\[C:12](=[O:23])[NH:13][C:14]3[C:19]\2=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)/[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[CH:35][CH:34]=1)=[O:28])[CH3:25]
Reactant: CCOC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: CCOC(=O)CNCCc1ccc(N)cc1
Solvent: CN(C)C=O
Product: CCOC(=O)CNCCc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Examples 43 and 89 from 3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-(2-ethoxycarbonylmethylamino-ethyl)-aniline in DMF.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].C(O)(=O)[CH2:12][C:13]([OH:15])=[O:14].Cl>N1C=CC=CC=1.N1CCCCC1>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH:12][C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1)#[N:2]
Reactant: O=C(O)CC(=O)O
Reactant: N#Cc1ccc(C=O)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: N#Cc1ccc(C=CC(=O)O)cc1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
0.2mol of p-cyanobenzaldehyde and 0.3mol of malonic acid were dissolved in 80ml of pyridine at room temperature, and 30 drops of piperidine were added thereto. The mixture was heated and stirred for 4 hours at about 100° C. After the reaction, the solution was poured slowly into dilute hydrochloric acid (250ml hydrochloric acid/250g water). Then, the resulting white precipitate was separated by filtering and washed with dilute hydrochloric acid and water, and was recrystallized by use of glacial acetic acid to obtain p-cyanocinnamic acid. 0.3mol of thionyl chloride was added to 0.1mol of the p-cyanocinnamic acid and the mixture was heated and stirred at about 80° C for 3 hours. An excess thionyl chloride was then removed under reduced pressure to obtain p-cyanocinnamic acid chloride.
Reaction SMILES: Cl[CH:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1.[N-:14]=[N+:15]=[N-:16].[Na+].C1(C)C=CC=CC=1.[Cl-]>CN(C=O)C>[N:14]([CH:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1)=[N+:15]=[N-:16]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc2c(c1)OCCC2Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(c1)OCCC2N=[N+]=[N-]
Temperature: 80 °C

Procedure:
4-Chloro-7-cyanochroman (Step C) (8.1 g, 42 mmol) was dissolved in dry DMF (90 mL) and NaN3 (4.0 g, 62 mmol) was added and the reaction was heated to 80° C. under N2. After 5 h TLC (SiO2, toluene) showed that no starting chloride was present. The reaction was cooled and partitioned between EtOAc (200 mL) and H2O (150 mL). The organic phase was washed with H2O (2×100 mL) and brine (100 mL). The solution was dried over MgSO4, filtered and concentrated in vacuo to provide a residue which was purified by column chromatography (SiO2, 15% EtOAc in hexane) to provide the title compound.
Reaction SMILES: C=O.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([NH:17][C:18]2[N:19]=[C:20]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=3)[C:21]3[CH2:27][NH:26][CH2:25][CH2:24][C:22]=3[N:23]=2)[CH:8]=[CH:9][C:10]=1[N:11]1[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]1.[C:37]([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([NH:17][C:18]2[N:19]=[C:20]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=3)[C:21]3[CH2:27][N:26]([CH3:37])[CH2:25][CH2:24][C:22]=3[N:23]=2)[CH:8]=[CH:9][C:10]=1[N:11]1[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]1
Reactant: [BH3-]C#N
Reactant: COc1cccc(Cc2nc(Nc3ccc(-n4cnc(C)c4)c(OC)c3)nc3c2CNCC3)c1
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1cccc(Cc2nc(Nc3ccc(-n4cnc(C)c4)c(OC)c3)nc3c2CN(C)CC3)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Formaldehyde (3.15 μL, 0.04 mmol) was added to a solution of N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-4-(3-methoxybenzyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (13.70 mg, 0.03 mmol) in methanol (1.5 mL). Sodium cyanoborohydride (0.943 mg, 0.02 mmol) and acetic acid (1.030 μL, 0.02 mmol) was added and the reaction mixture stirred for 2 h at rt and purified by preparative HPLC to afford the titled compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12](=O)[C:13]([O:15]CCCCCC)=O)[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[OH:8].[C:23]1([NH2:30])[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH2:29]>CO>[OH:1][C:2]1[CH:3]=[C:4]([C:12]2[C:13](=[O:15])[NH:29][C:24]3[C:23]([N:30]=2)=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[OH:8]
Reactant: Nc1ccccc1N
Reactant: CCCCCCOC(=O)C(=O)c1cc(O)c(O)c([N+](=O)[O-])c1
Solvent: CO
Product: O=c1[nH]c2ccccc2nc1-c1cc(O)c(O)c([N+](=O)[O-])c1

Procedure:
A mixture of 396.0 mg of n-hexyl 3,4-dihydroxy-5-nitrophenylglyoxylate and 137.6 mg of 1,2-phenylenediamine is heated to 120° for 60 minutes. Thereafter, the mixture is suspended in methanol, filtered under suction and recrystallized from N,N-dimethylformamide/water. There is obtained 3-(3,4-dihydroxy-5-nitrophenyl)-2(1H)-quinoxalinone of m.p. >300 °.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]([O:23]CC)=[O:22])[CH:12]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[OH-].[Na+].Cl>C1COCC1.CCO>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]([OH:23])=[O:22])[CH:12]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)Cn1cc(Cc2cccc([N+](=O)[O-])c2)c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)Cn1cc(Cc2cccc([N+](=O)[O-])c2)c2ccccc21
Temperature: 0 °C
Yield: 70.9 %

Procedure:
3-(3-Nitrophenyl)methyl-indole-N-acetic Acid, ethyl ester (0.175 g, 0.5 mmol) was dissolved in THF:EtOH (1:4, 5 mL) at room temperature with stirring. The mixture was cooled to 0° C. and treated with 1N NaOH (1.55 mL, 1.6 mmol). The mixture was allowed to stir at this temperature for 2 h. 1 N HCl was added and the mixture extracted with EtOAc (2×). The organics were combined and washed with a sat'd brine solution, dried over MgSO4, filtered and concentrated in vacuo. The residue was triturated with heptane and vacuum-filtered with several heptane washings to give 110 mg (69%) the desired compound as an off-white powder. mp 163-165° C.; 1H NMR (DMSO-d6, 300 MHz) δ 8.11 (s, 1 H), 8.03 (d, J=8.1 Hz, 1 H), 7.75 (d, J=8.1 Hz, 1 H), 7.53 (t, J=8.1 Hz, 1 H), 7.45 (d, J=8.1 Hz, 1 H), 7.33 (d, J=8.4 Hz, 1 H), 7.20 (s, 1 H), 7.11 (t, J=7.2 Hz, 1 H), 6.97 (t, J=7.2 Hz, 1 H), 4.96 (s, 2 H), 4.18 (s, 2 H); LRMS calcd for C17H14N2O4S: 310.0; found 311 (M+1)+.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:11][C:12]([CH3:16])([CH3:15])[CH2:13][OH:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:32](Cl)(=[O:34])[CH3:33]>C1COCC1>[C:32]([O:14][CH2:13][C:12]([CH3:16])([CH3:15])[CH2:11][C@H:10]([N:17]([C:18]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:24])[CH3:25])[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3])(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)CC(C)(C)CO
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)OCC(C)(C)C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
To a solution of (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)-5-hydroxy-4,4-dimethylpentan-2-yl(methyl)carbamate (1.23 g, 3.27 mmol) in THF (20 mL) were added pyridine (0.79 mL) and acetyl chloride (0.386 g, 4.91 mmol). The reaction mixture was stirred at RT overnight and filtered. The filtrate was concentrated to give (S)-4-(tert-butoxycarbonyl(methyl)amino)-5-(tert-butyldimethylsilyloxy)-2,2-dimethylpentyl acetate (1.36 g, crude), which was used without further purification. LRMS (M-Boc+H+) m/z 318.2
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]2[N:6]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:7](=[O:10])[N:8]([CH3:9])[C:4]=2[CH:3]=1.C([Li])(C)(C)C.[F:25][C:26]([F:40])([F:39])[C:27]([C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]([CH3:38])[CH:30]=1)=[O:28]>C1COCC1>[F:17][C:14]1[CH:15]=[CH:16][C:11]([N:6]2[C:5]3[CH:18]=[CH:19][C:2]([C:27]([OH:28])([C:29]4[C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[N:31]([CH3:38])[CH:30]=4)[C:26]([F:25])([F:40])[F:39])=[CH:3][C:4]=3[N:8]([CH3:9])[C:7]2=[O:10])=[CH:12][CH:13]=1
Reactant: Cn1c(=O)n(-c2ccc(F)cc2)c2ccc(Br)cc21
Reactant: Cn1cc(C(=O)C(F)(F)F)c2ccccc21
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Cn1cc(C(O)(c2ccc3c(c2)n(C)c(=O)n3-c2ccc(F)cc2)C(F)(F)F)c2ccccc21
Reaction time: 0.02 h
Yield: 12.8 %

Procedure:
To a chilled (−78° C.) solution of 5-bromo-1-(4-fluorophenyl)-3-methyl-1,3-dihydro-benzimidazol-2-one (80 mg, 0.25 mmol) in anhydrous THF (3 mL) was added tert-butyllithium (0.2 mL of 1.7 M solution in heptane, 0.34 mmol). After 1 minute, a chilled (−78° C.) solution of 2,2,2-trifluoro-1-(1-methyl-1H-indol-3-yl)ethanone (57 mg, 0.25 mmol) in anhydrous THF (1 mL) was added. After 10 minutes, the mixture was quenched with ammonium chloride solution and extracted with three 15 mL portions of methylene chloride. The combined organic layers were washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo to afford a brownish oil. The residue was purified by column chromatography over silica gel eluting with 0-10% ethyl acetate in methylene chloride to afford 15 mg of the title compound as a white powder. MS m/z 470 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]([O:21]CC)=O)=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH3:24][NH2:25]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]([NH:25][CH3:24])=[O:21])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: CN
Reactant: CCOC(=O)COC(=O)N1CCC(Oc2ccc(Br)cc2)CC1
Product: CNC(=O)COC(=O)N1CCC(Oc2ccc(Br)cc2)CC1

Procedure:
2.9 g (7.5 mmol) of 2-(ethyloxy)-2-oxoethyl 4-[(4-bromophenyl)oxy]-1-piperidinecarboxylate, prepared in Step 4.3., in solution in 10 ml of a 33% ethanolic solution of methylamine are stirred at ambient temperature for 20 hours. Following evaporation, the product is purified by chromatography on silica gel, eluting with ethyl acetate, to give 0.8 g of product in gum form, which is used as it is in the following step.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[NH:13][C:12]([C:14]([C:46]4[CH:51]=[CH:50][C:49]([OH:52])=[CH:48][CH:47]=4)=[C:15]4[N:45]=[C:18]([C:19]([C:38]5[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=5)=[C:20]5[NH:37][C:23](=[C:24]([C:30]6[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=6)[C:25]6[CH:26]=[CH:27][C:28]=2[N:29]=6)[CH:22]=[CH:21]5)[CH:17]=[CH:16]4)=[CH:11][CH:10]=3)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:59](Br)[CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH3:67]>CN(C=O)C>[OH:52][C:49]1[CH:48]=[CH:47][C:46]([C:14]2[C:12]3[NH:13][C:9]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([O:1][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH3:67])=[CH:3][CH:4]=4)=[C:28]4[N:29]=[C:25]([C:24]([C:30]5[CH:31]=[CH:32][C:33]([OH:36])=[CH:34][CH:35]=5)=[C:23]5[NH:37][C:20](=[C:19]([C:38]6[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=6)[C:18]6[CH:17]=[CH:16][C:15]=2[N:45]=6)[CH:21]=[CH:22]5)[CH:26]=[CH:27]4)=[CH:10][CH:11]=3)=[CH:51][CH:50]=1
Reactant: Oc1ccc(-c2c3nc(c(-c4ccc(O)cc4)c4ccc([nH]4)c(-c4ccc(O)cc4)c4nc(c(-c5ccc(O)cc5)c5ccc2[nH]5)C=C4)C=C3)cc1
Reactant: CCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCOc1ccc(-c2c3nc(c(-c4ccc(O)cc4)c4ccc([nH]4)c(-c4ccc(O)cc4)c4nc(c(-c5ccc(O)cc5)c5ccc2[nH]5)C=C4)C=C3)cc1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
5,10,15,20-tetrakis-(4-Hydroxy-phenyl)-porphyrin (200 mg, 0.294 mmol) is dissolved and potassium carbonate (487 mg, 3.53 mmol, 12 eqv.) is suspended under argon in absolute DMF (50 mL) and the mixture heated to 55° C. A solution of nonyl bromide (49.4 μl, 0.206 mmol, 0.7 eqv.) in absolute DMF (10 mL) is added dropwise during 30 min. The mixture is stirred at 55° C. for 2 h. The solvent is removed in vacuo at 50° C., water (80 mL) is added and the mixture extracted with ethyl acetate (3×40 mL). The combined organic extracts are dried (Na2SO4) and solvent removed under reduced pressure. The product is isolated by chromatography on a column (300 g) of silica. Tetra-alkylated and tri-alkylated compounds are eluted with toluene:ethyl acetate (30:1 by vol.), di-substituted compound (trans-isomer) with toluene:ethyl acetate (15:1 by vol.). di-substituted compound (cis-isomer) with toluene:ethyl acetate (10:1 by vol.) and the desired product (mono-alkylated compound) is eluted with toluene:ethyl acetate (5:1 by vol.). The solvent is removed under reduced pressure and the residue dried at high vacuum to afford the product as a violet solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].CO[CH:12](OC)[N:13]([CH3:15])[CH3:14].C(OCC)C>CCCCCC>[CH3:12][N:13]([CH3:15])[CH:14]=[CH:2][C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: CC(=O)c1cccnc1
Reactant: COC(OC)N(C)C
Solvent: CCOCC
Solvent: CCCCCC
Product: CN(C)C=CC(=O)c1cccnc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 358.4 %

Procedure:
3-Acetylpyridine (100 g, 0.19 mol) was added to dimethylformamide dimethylacetal (156.5 g, 1.27 mol), and the mixture was reacted under reflux for 23 hours. After the reaction mixture was cooled to 0° C., a mixture of diethyl ether and hexane (3:2, v/v) (500 ml) was added and the whole mixture was stirred for 4 hours. The resulting solid was filtered and washed with a mixture of diethyl ether and hexane (500 ml, 3/2, v/v) to give 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one (120 g).
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:1]([S:8][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: SCc1ccccc1
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: N#Cc1ccc(SCc2ccccc2)cc1
Yield: 68.2 %

Procedure:
A mixture of 37.2 g of benzylmercaptan, 36.3 g of 4-fluorobenzonitrile and 42 g of potassium carbonate in 700 ml of 2-butanone is refluxed for 7 hours. The solvent is evaporated off under vacuum and the residue is taken up with water and petroleum ether. The crystals formed are filtered off and washed with water and petroleum ether to give 46 g of 4-benzylthiobenzonitrile in the form of crystals melting at 85° C.
Reaction SMILES: [ClH:1].O1CCOCC1.[CH2:8]([NH:15][C:16]([C:18]1[O:22][C:21]([N:23]2[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH:24]2[CH2:36][O:37][C:38]2[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=2)=[N:20][C:19]=1[CH3:44])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CO>[ClH:1].[ClH:1].[ClH:1].[CH2:8]([NH:15][C:16]([C:18]1[O:22][C:21]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH:24]2[CH2:36][O:37][C:38]2[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=2)=[N:20][C:19]=1[CH3:44])=[O:17])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Cc1nc(N2CCN(C(=O)OC(C)(C)C)CC2COc2cccnc2)oc1C(=O)NCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1nc(N2CCNCC2COc2cccnc2)oc1C(=O)NCc1ccccc1
Reaction time: 1 h
Yield: 3 %

Procedure:
4 M HCl in 1,4-dioxane (4 mL, 16 mmol) was added to a solution of tert-butyl 4-(5-(benzylcarbamoyl)-4-methyloxazol-2-yl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate in MeOH (1 mL). After 1 h, the reaction mixture was concentrated under reduced pressure and purified by HPLC (10 to 90% MeCN/0.1% TFA in H2O/0.1% TFA gradient). The desired chromatography fractions were concentrated under reduced pressure, dissolved in MeOH (1 mL), and treated with 4 M HCl in 1,4-dioxane. This was concentrated under reduced pressure, yielding 3.6 mg (3%) of the title compound as an off-white solid. LC-MS: RT=4.12 min, [M+H]+=408.7.
Reaction SMILES: [CH2:1]([N:3]([CH2:22][CH3:23])[C:4]1[CH:20]=[CH:19][C:7]([C:8]([C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](O)=[O:13])=[O:9])=[C:6]([CH3:21])[CH:5]=1)[CH3:2].[CH3:24][N:25]([C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([N:40]([CH3:42])[CH3:41])=[CH:36][CH:35]=2)=[CH:29][CH:28]=1)[CH3:26]>>[CH2:1]([N:3]([CH2:22][CH3:23])[C:4]1[CH:20]=[CH:19][C:7]([C:8]2([N:33]([C:34]3[CH:35]=[CH:36][C:37]([N:40]([CH3:42])[CH3:41])=[CH:38][CH:39]=3)[C:30]3[CH:29]=[CH:28][C:27]([N:25]([CH3:24])[CH3:26])=[CH:32][CH:31]=3)[C:10]3[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:12](=[O:13])[O:9]2)=[C:6]([CH3:21])[CH:5]=1)[CH3:2]
Reactant: CN(C)c1ccc(Nc2ccc(N(C)C)cc2)cc1
Reactant: CCN(CC)c1ccc(C(=O)c2ccccc2C(=O)O)c(C)c1
Product: CCN(CC)c1ccc(C2(N(c3ccc(N(C)C)cc3)c3ccc(N(C)C)cc3)OC(=O)c3ccccc32)c(C)c1
Yield: 54 %

Procedure:
Following a procedure similar to that described in Example 4 but employing 3.1 g of 2-[4-(diethylamino)-2-methylbenzoyl]benzoic acid and 3.0 g of 4,4'-bis(dimethylamino)diphenylamine there was obtained 2.95 g of 3-[4-(diethylamino)-2-methylphenyl]-3-{bis[4-(dimethylamino)phenyl]amino}phthalide, m.p. 67°-83° C. A toluene solution of the product contacted with acidic clay or phenolic resin developed a black-colored image.
Reaction SMILES: [Na].[CH2:2]([OH:5])[CH:3]=[CH2:4].Br[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[N:10]=[CH:9][CH:8]=1.ClCCl>CO>[CH2:2]([O:5][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[N:10]=[CH:9][CH:8]=1)[CH:3]=[CH2:4]
Reactant: COc1ccc2nccc(Br)c2c1
Reactant: C=CCO
Agent: [Na]
Solvent: ClCCl
Solvent: CO
Product: C=CCOc1ccnc2ccc(OC)cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.7 %

Procedure:
Sodium (1.22 g, 52.9 mmol, 2.1 eq) is added portionwise at 0° C. to a stirred solution of allyl alcohol (117.1 g, 201.6 mmol, 80.0 eq). After 30 minutes stirring at 0° C., 4-bromo-6-methoxy-quinoline (6.0 g, 25.2 mmol, 1.0 eq) is added to the reaction mixture that is heated under reflux for 5 hours. The reaction mixture is then cooled down to room temperature, and filtered. The filtrate is evaporated under reduced pressure to give a residue that is extracted with ethyl acetate (3×100 mL) and water (100 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by column chromatography (silica gel, eluent: dichloromethane:methanol, 60:1, v/v) to afford 4-allyloxy-6-methoxy-quinoline as a white solid (4.0 g, 74% yield).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:16][CH2:17][CH3:18])[C:3]=1[C:19](O)=[O:20].[NH2:22][C:23]1[S:24][CH:25]=[CH:26][N:27]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[S:24]1[CH:25]=[CH:26][N:27]=[C:23]1[NH:22][C:19]([C:3]1[C:4]([CH2:16][CH2:17][CH3:18])=[N:5][C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]([F:15])([F:14])[F:13])=[O:20]
Reactant: Nc1nccs1
Reactant: CCCc1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: CCCc1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1
Yield: 31.3 %

Procedure:
Using the procedure of Step F of Example 6, 6.3 g of the acid of Step E and 2.1 g of 2-amino-thiazole were reacted in the presence of dicyclohexylcarbodiimide in dimethylformamide to obtain 2.5 g of N-(2-thiazolyl)-4-hydroxy-2-n-propyl-8-trifluoromethyl-quinoline-3-carboxamide in the form of colorless crystals melting at 222° C after crystallization from acetic acid.
Reaction SMILES: O[C:2]1[C:7]([CH3:8])=[C:6]([CH2:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[N:5]=[C:4]([CH3:19])[N:3]=1.O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:2]1[C:7]([CH3:8])=[C:6]([CH2:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[N:5]=[C:4]([CH3:19])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(C)c(Cc2nc(C)nc(O)c2C)c(C)c1
Product: Cc1cc(C)c(Cc2nc(C)nc(Cl)c2C)c(C)c1
Yield: 97 %

Procedure:
A mixture of 4-hydroxy-2,5-dimethyl-6-(2,4,6-trimethyl-benzyl)-pyrimidine (1.2 g, 4.68 mmol) and POCl3 (25 ml) was heated at reflux for 1 hour. The mixture was cooled and evaporated to dryness. The residue was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated to dryness to give 1.24 g (97%) of golden crystals, mp 82-84° C.