Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][C:4]=1[OH:15].CCCCCC>CC(C)=O.[O-2].[O-2].[Mn+4]>[OH:15][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:3]=1[CH:2]=[O:1])=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2
Reactant: COc1ccc2ncc(O)c(CO)c2c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(C)=O
Solvent: CCCCCC
Product: COc1ccc2ncc(O)c(C=O)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.8 %

Procedure:
Manganese dioxide (650 mg, 7.5 mmol, 10.0 eq) is added at room temperature to a stirred solution of 4-hydroxymethyl-6-methoxy-quinoline-3-ol (220 mg, 0.75 mmol, 1.0 eq) in acetone (30 mL). After 2 hours stirring at room temperature, the reaction mixture is filtered through decalite and the filtrate is concentrated to give a residue that is purified by column chromatography (silica gel, eluent: hexane:acetone, 1:1, v/v) to afford 3-hydroxy-6-methoxy-quinoline-4-carbaldehyde as a yellow solid (85 mg, 34% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:10][C:11]2[N:12]([C:14](=[O:17])[NH:15][N:16]=2)[CH:13]=1.Cl[CH2:26][C:27]1[C:28]([CH3:37])=[N:29][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:32]=1.BrC1C2N(C(=O)N(CC3C(C)=NC(C(F)(F)F)=CC=3)N=2)C(C)=CC=1C1C=CC(Cl)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[CH:10][C:11]2[N:12]([C:14](=[O:17])[N:15]([CH2:26][C:27]3[C:28]([CH3:37])=[N:29][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:31][CH:32]=3)[N:16]=2)[CH:13]=1
Reactant: Cc1nc(C(F)(F)F)ccc1CCl
Reactant: O=c1[nH]nc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)cn12
Agent: Cc1nc(C(F)(F)F)ccc1Cn1nc2c(Br)c(-c3ccc(Cl)cc3)cc(C)n2c1=O
Product: Cc1nc(C(F)(F)F)ccc1Cn1nc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)cn2c1=O
Yield: 47.2 %

Procedure:
The title compound (25 mg, 47% yield) as an off-white solid was prepared from 6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (36 mg, 0.1 mmol) and 3-(chloromethyl)-2-methyl-6-(trifluoromethyl)pyridine (31 mg, 0.15 mmol) in a manner analogous to that in which 8-bromo-7-(4-chlorophenyl)-5-methyl-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one was prepared. HPLC/MS: retention time=4.30 min, [M+H]+=529.1.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.[C:18](=[O:21])([O-])[O-].[K+].[K+]>C(O)(C)C>[C:12]1([C:4]2[N:3]=[C:2]([NH:5][C:6]3[CH:11]=[CH:10][CH:9]=[C:8]([O:21][CH3:18])[CH:7]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Clc1nc(-c2ccccc2)nc2ccccc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: COc1cccc(Nc2nc(-c3ccccc3)nc3ccccc23)c1

Procedure:
4-Chloro-2-phenylquinazoline, 2 equivalents, 3-methoxyanilinyl, 2 equivalents, and potassium carbonate, 2 equivalents, were dissolved in 10 mL isopropanol and refluxed for 2 hours. The precipitated product formed was filtered and washed with water. Recrystallization from methanol provided the product as a white solid that was found to be homogenous by thin layer chromatography (TLC) and confirmed by EIMS.
Reaction SMILES: [CH:1]1([C:4](=[O:15])[CH2:5][O:6][CH2:7][CH:8]2[CH2:12][O:11][C:10]([CH3:14])([CH3:13])[O:9]2)[CH2:3][CH2:2]1.[BH4-].[Na+]>CO>[CH:1]1([CH:4]([OH:15])[CH2:5][O:6][CH2:7][CH:8]2[CH2:12][O:11][C:10]([CH3:13])([CH3:14])[O:9]2)[CH2:3][CH2:2]1
Reactant: CC1(C)OCC(COCC(=O)C2CC2)O1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC1(C)OCC(COCC(O)C2CC2)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
Dissolve 1-cyclopropyl-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)ethanone (1.2 g, 5.6 mmol), MeOH (20 mL) and sodium tetrahydroborate (310 mg, 8.19 mmol). Stir at ambient temperature for 1 hour. Concentrate under reduced pressure. Add water (30 mL) and extract with EtOAc (3×). Combine the extracts; wash with brine; and dry over MgSO4. Filter; collect the filtrate; and remove the solvents under reduced pressure to give the title compound as a colorless oil (1.2 g, 99%). MS (m/z): 199 (M-H2O+1).
Reaction SMILES: C[O:2][C:3](=[O:22])[CH:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH2:17][C:18]([O:20]C)=[O:19])[CH:12]=2)[CH:7]=1)[CH3:5].Cl>[OH-].[Na+]>[C:18]([CH2:17][O:16][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[CH:7]=[C:6]([CH:4]([CH3:5])[C:3]([OH:22])=[O:2])[CH:15]=[CH:14]2)([OH:20])=[O:19]
Reactant: COC(=O)COc1ccc2cc(C(C)C(=O)OC)ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C(=O)O)c1ccc2cc(OCC(=O)O)ccc2c1
Yield: 71.8 %

Procedure:
2-(6-Methoxycarbonylmethoxynaphthalen-2-yl)propionic acid methyl ester 7 (23 g, 76.16 mmol) in 4 N aqueous NaOH (230 ml) was heated on a water bath at 90° C. for 8 hrs. The reaction mass was cooled to room temp. and the pH adjusted to 2 with con. HCl. Crude 96 was filtered, dried and recrystallised from a mixture of ethyl acetate:hexane (1:6) to give pure 96 (15 g, 71.9%) as a white powder. Mp: 185-188° C.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[C:15]([CH3:18])([CH3:17])[CH3:16])[O:11][C:10]([CH3:30])([CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=1)[CH2:9][C:8]2=[O:31])(=[O:3])[CH3:2].[H][H]>C(O)(=O)C.[Pd]>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[C:15]([CH3:18])([CH3:16])[CH3:17])[O:11][C:10]([CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)([CH3:30])[CH2:9][C:8]2=[O:31])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc2c(cc1C(C)(C)C)OC(C)(COc1ccc([N+](=O)[O-])cc1)CC2=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(=O)Oc1cc2c(cc1C(C)(C)C)OC(C)(COc1ccc(N)cc1)CC2=O

Procedure:
In a similar manner to Preparation 44, 0.9 g of 6-acetoxy-7-t-butyl-2-methyl-2-(4-nitrophenoxymethyl)chroman-4-one was dissolved in 20 ml of acetic acid, and catalytic hydrogenation was performed for 5.5 hours with a hydrogen pressure of 45-55 lb/sq. inch (3.1-3.8 bars), using Pearl's apparatus, in the presence of 0.4 g of 10% w/w palladium-on-carbon. The palladium-on-carbon was removed by filtration from the reaction mixture and washed with acetic acid. The filtrate and the washings were combined, and the mixture was poured into ice-water, neutralized with sodium carbonate, and extracted with benzene. The benzene extract was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography, eluted with a 5:1 by volume mixture of benzene and ethyl acetate, to give the desired 6-acetoxy-2-(4-aminophenoxymethyl)-7-t-butyl-2-methylchroman-4-one.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:9].[N-:10]=[N+:11]=[N-:12].[Na+]>C(#N)C>[N:10]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:9])=[N+:11]=[N-:12]
Reactant: Clc1ccccc1CBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC#N
Product: [N-]=[N+]=NCc1ccccc1Cl

Procedure:
A mixture of 1-(bromomethyl)-2-chlorobenzene (5 g, 24.3 mmol) and sodium azide (2.37 g, 36.5 mmol) in acetonitrile (48.7 mL) was refluxed for 3 h under N2 atmosphere. Then, the mixture was filtered and concentrated in vacuo. The residue was diluted in DCM, washed with H2O and brine, dried over Na2SO4 and concentrated in vacuo to afford crude 1-(azidomethyl)-2-chlorobenzene. The residue was used for the next reaction without further purification. A mixture of the above crude residue, 2-cyanoacetamide (1.82 g, 21.7 mmol) and sodium ethanolate (1.47 g, 21.7 mmol) in ethanol (43.3 mL) was refluxed for 3 h under N2 atmosphere. The mixture was concentrated in vacuo, diluted with 4M AcOH aq. and filtered. The residue was washed with H2O and dried in vacuo to afford 5-amino-1-(2-chlorobenzyl)-1H-1,2,3-triazole-4-carboxamide as pale-orange solid (5.10 g, 94% for 2 steps). MS (m/e): 252.1 (MH+).
Reaction SMILES: N(C(OCC)=O)=N[C:3](OCC)=[O:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:32][O:33][C:34](=[O:48])[C@@H:35]1[CH2:39][C@@H:38]([OH:40])[CH2:37][N:36]1[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]>O1CCCC1.C(O)=O>[CH3:32][O:33][C:34](=[O:48])[C@@H:35]1[CH2:39][C@H:38]([O:40][CH:3]=[O:4])[CH2:37][N:36]1[C:41]([O:43][C:44]([CH3:45])([CH3:47])[CH3:46])=[O:42]
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=CO
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@H](OC=O)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1.67 h

Procedure:
Diethyl azodicarboxylate (2.2 mL) was added to a cold (−15° C.) stirred solution of triphenyl phosphine (3.67 g) in tetrahydrofuran (40 mL). After stirring at 0° C. for 100 min, a solution of N-tert-butoxycarbonyl-trans-4-hydroxy-L-proline methyl ester (2.29 g) in tetrahydrofuran (20 mL) and formic acid (2.20 mL) were added. The mixture was stirred at room temperature for 14 hr, the solvent was removed and coevaporated several times with toluene in vacuo. The residue was diluted with toluene and precipitated solids were removed by filtration which was washed with toluene. The combined organic layers were evaporated in vacuo and the residue was purified by silica gel column chromatography (chloroform then chloroform:methanol=15:1, v/v) to give the title compound (4.07 g) as a pale yellow oil: 1H NMR (400 MHz, CDCl3) δ 1.39-1.50 (m, 9H), 2.25-2.34 (m, 1H), 2.43-2.60 (m, 1H), 3.54-3.67 (m, 1H), 3.72-3.83 (m, 1H), 3.75 (s, 3H), 4.37-4.55 (m, 1H), 5.35-4.41 (m, 1H), and 7.97 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]3[O:15][CH2:14][CH:13]([CH2:16][O:17][CH3:18])[O:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[CH3:27])[NH2:23]>>[Cl:19][C:20]1[CH:21]=[C:22]([NH:23][C:2]2[C:11]3[C:6](=[CH:7][C:8]4[O:15][CH2:14][CH:13]([CH2:16][O:17][CH3:18])[O:12][C:9]=4[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:24]=[CH:25][C:26]=1[CH3:27]
Reactant: Cc1ccc(N)cc1Cl
Reactant: COCC1COc2cc3ncnc(Cl)c3cc2O1
Product: COCC1COc2cc3ncnc(Nc4ccc(C)c(Cl)c4)c3cc2O1
Yield: 48.4 %

Procedure:
The titled compound (54 mg, 49%) was prepared in a similar manner as in Example 8, except for employing 4-chloro-7-methoxymethyl-[1,4]dioxano[2,3-g]quinazoline (80 mg, 0.3 mmol) and 3-chloro-4-methylaniline (84 mg, 0.6 mmol).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[CH2:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][C:34]=1[CH3:43].[I-].[K+]>O1CCCC1.C(OCC)(=O)C.O>[C:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH2:32][C:33]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=[CH:35][C:34]=2[CH3:43])[C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[NH:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CNc2ccccc2NC1=O
Reactant: Cc1ccc2ccccc2c1CCl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc2ccccc2c1CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CNc2ccccc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 68.5 %

Procedure:
To a solution of 3.0 g (10.83 mmol) ((S)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-carbamic acid tert-butyl ester (Intermediate 2) in 55 mL of anhydrous tetrahydrofuran at −78° C. was added slowly a solution of 1 M lithium bis(trimethylsilyl)amide in tetrahydrofuran (24 mL, 24 mmol). The solution was stirred at −78° C. for 30 min. A solution of 5.35 g (28.2 mmol) 1-chloromethyl-2-methyl-naphthalene in 15 mL of tetrahydrofuran was slowly added. The reaction mixture was stirred at −78° C. for 10 min, the cooling bath was removed and the mixture stirred overnight. Potassium iodide (1.8 g, 10.83 mmol) was added to the mixture. After 2 h, water and ethyl acetate were added to the mixture, the organic layer was washed with 10% aqueous sodium bisulfate, brine, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated. The residue was purified by silica gel chromatography to afford the title compound (3.2 g) as a light yellow solid. LC-MS: 432 (M+H).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[N:7]1[CH:12]=[CH:11][C:10](B(O)O)=[CH:9][CH:8]=1.[CH2:16]([O:23][C:24]1[CH:39]=[CH:38][C:37](Br)=[CH:36][C:25]=1[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCOCC1.O.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>[C:17]1([CH2:16][O:23][C:24]2[CH:39]=[CH:38][C:37]([C:10]3[CH:11]=[CH:12][N:7]=[CH:8][CH:9]=3)=[CH:36][C:25]=2[C:26]([O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:27])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(OCc1ccccc1)c1cc(Br)ccc1OCc1ccccc1
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(OCc1ccccc1)c1cc(-c2ccncc2)ccc1OCc1ccccc1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
Na2CO3 (0.53 g, 5.00 mmol), followed by pyridin-4-ylboronic acid (0.34 g, 2.75 mmol) and Pd(Ph3P)4 (0.144 g, 0.125 mmol) were added to a mixture of benzyl 2-(benzyloxy)-5-bromobenzoate (may be prepared as described in Description 4; 1.0 g, 2.50 mmol) in 1,4-dioxane (25 ml) and water (5 ml) under nitrogen. After addition, the mixture was stirred at 90° C. for 4 hours. The reaction mixture was evaporated to give brown crude product, which was purified by chromatography (silica gel, 40 g, eluent: ethyl acetate/petroleum ether=1:2, 1.2 L) to yield the title compound as a white solid. 0.81 g.
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[C:8]1([P:14](Cl)[Cl:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CCCCCC>[Cl:15][P:14]([N:4]([CH:5]([CH3:7])[CH3:6])[CH:1]([CH3:3])[CH3:2])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)NC(C)C
Reactant: ClP(Cl)c1ccccc1
Solvent: CCCCCC
Product: CC(C)N(C(C)C)P(Cl)c1ccccc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
A solution of diisopropylamine (8.90 grams, 88.3 mmol) in dry hexane (100 ml) was added dropwise to a stirred solution of phenyldichlorophosphine (7.91 grams, 44.2 mmol) in hexane (100 ml) cooled to 0° C., during 45 minutes. The resulting mixture was allowed to warm to room temperature and was then stirred for additional 18 hours and thereafter filtered. The precipitate was washed with hexane, and the product was further purified by distillation under reduced pressure, to give 8.62 grams (80% yield) of Compound 59 (see, Scheme 34 below) as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C@:9]23[CH2:18][O:17][C@@H:16]([CH3:19])[CH2:15][C@H:14]2[CH2:13][S:12][C:11]([NH:20]C(=O)C2C=CC=CC=2)=[N:10]3)[CH:6]=[CH:7][CH:8]=1)#[N:2].NC1SC[C@@H]2C[C@H](C)OC[C@]2(C2C=C(C=CC=2Cl)C#N)N=1>>[NH2:20][C:11]1[S:12][CH2:13][C@@H:14]2[CH2:15][C@H:16]([CH3:19])[O:17][CH2:18][C@:9]2([C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[C:1]#[N:2])[N:10]=1
Reactant: C[C@H]1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2cccc(C#N)c2)CO1
Agent: C[C@H]1C[C@H]2CSC(N)=N[C@@]2(c2cc(C#N)ccc2Cl)CO1
Product: C[C@H]1C[C@H]2CSC(N)=N[C@@]2(c2cccc(C#N)c2)CO1

Procedure:
N-[(4aR,6S,8aS)-8a-(3-Cyanophenyl)-6-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C24) was converted to the product using the method described for the synthesis of 3-[(4aR,6S,8aS)-2-amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-4-chlorobenzonitrile (6) in Example 6. Purification by reverse phase HPLC (Column: Waters Sunfire C18, 19×100 mm, 5 μm; Mobile phase A: 0.05% trifluoroacetic acid in water (v/v); Mobile phase B: 0.05% trifluoroacetic acid in acetonitrile (v/v); Gradient: 20.0% to 60% B, linear over 8.5 minutes). QC conditions: (Column: Waters Atlantis dC18, 4.6×50 mm, 5 μm; Mobile phase A: 0.05% trifluoroacetic acid in water (v/v); Mobile phase B: 0.05% trifluoroacetic acid in acetonitrile (v/v); Gradient: 5.0% to 95% B, linear over 4.0 minutes; Flow rate: 2 mL/minute). Yield 22.5 mg, 0.08 mmol, 50%. LC/MS m/z 288.2 [M+H+]. Retention time: 1.62 minutes.
Reaction SMILES: ClC1C=C(NC2C=CC(F)=CC=2F)C=CC=1C(C1C=C(C2N=NN(CCO)C=2)C=CC=1C)=O.[Cl:34][C:35]1[CH:40]=[C:39]([NH:41][C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:43]=2[F:49])[CH:38]=[CH:37][C:36]=1[C:50]([C:52]1[CH:57]=[C:56]([C:58]2[N:59]=[N:60][N:61]([CH2:63][CH2:64][CH2:65][O:66]C3CCCCO3)[CH:62]=2)[CH:55]=[CH:54][C:53]=1[CH3:73])=[O:51]>>[Cl:34][C:35]1[CH:40]=[C:39]([NH:41][C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:43]=2[F:49])[CH:38]=[CH:37][C:36]=1[C:50]([C:52]1[CH:57]=[C:56]([C:58]2[N:59]=[N:60][N:61]([CH2:63][CH2:64][CH2:65][OH:66])[CH:62]=2)[CH:55]=[CH:54][C:53]=1[CH3:73])=[O:51]
Reactant: Cc1ccc(-c2cn(CCCOC3CCCCO3)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Agent: Cc1ccc(-c2cn(CCO)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Product: Cc1ccc(-c2cn(CCCO)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 102, using compound 103 (0.2 mmol). The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 50:50 to 100:0 as the eluent to afford the title compound as colourless foam. 13C NMR (CDCl3) δ 196.1, 159.2 (dd), 155.6 (dd), 148.0, 146.9, 139.9, 137.7, 135.3, 133.8, 131.9, 129.1, 128.0, 127.9, 126.4, 124.5 (dd), 124.3 (dd), 120.3, 116.3, 112.8, 111.6 (dd), 104.9 (dd), 58.8, 47.0, 32.6, 20.2
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH2:9][C-:8]=[CH:7][C:6]=1[CH2:10][NH:11]C1C=CN=C2C=1C=CC(Cl)=C2)[CH3:3].[CH2:23]1[C-:27]=[CH:26][CH:25]=[CH:24]1.[Fe+2:28].CN(C[C-]1C=CC=C1C=O)C.[CH-]1C=CC=C1.[Fe+2].CN(C[C-]1C=CC=C1)C.[CH-]1C=CC=C1.[Fe+2]>>[NH2:11][CH2:10][C-:6]1[CH:7]=[CH:8][CH:9]=[C:5]1[CH2:4][N:2]([CH3:3])[CH3:1].[CH-:23]1[CH:27]=[CH:26][CH:25]=[CH:24]1.[Fe+2:28]
Reactant: [C-]1=CC=CC1
Reactant: CN(C)CC1=C(CNc2ccnc3cc(Cl)ccc23)C=[C-]C1
Agent: [Fe+2]
Agent: CN(C)C[c-]1cccc1
Agent: CN(C)C[c-]1cccc1C=O
Product: CN(C)Cc1ccc[c-]1CN
Yield: 85 %

Procedure:
The known method for the manufacture of ferroquine, partially represented in scheme 2 below, consists in synthesizing firstly 1-[(dimethylamino)methyl]-2-formyl-ferrocene from (dimethylamino)methyl-ferrocene with a yield of about 85%, then in preparing the corresponding intermediate oxime, and finally in carrying out reduction of this oxime which leads to obtaining 1-(aminomethyl)-2-[(dimethylamino)methyl]-ferrocene which can be isolated in the form of dihydrochloride. The yield of synthesis of the dihydrochloride 1-(aminomethyl)-2-[(dimethylamino)methyl]-ferrocene relative to 1-[(dimethylamino)methyl]-2-formyl-ferrocene is 55-65%.
Reaction SMILES: C(S)C.[H-].[Na+].[OH:6][C:7]1[C:12]2[C:13]([CH3:25])=[C:14]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][CH:18]=3)[O:15][C:11]=2[CH:10]=[CH:9][C:8]=1[CH2:26][CH2:27][CH3:28].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[OH:6][C:7]1[C:12]2[C:13]([CH3:25])=[C:14]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[O:15][C:11]=2[CH:10]=[CH:9][C:8]=1[CH2:26][CH2:27][CH3:28]
Reactant: CCCc1ccc2oc(Cc3ccc(OC)cc3)c(C)c2c1O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCS
Product: CCCc1ccc2oc(Cc3ccc(O)cc3)c(C)c2c1O
Reaction time: 0.25 h
Yield: 92.8 %

Procedure:
Under nitrogen atmosphere, ethanethiol (4.9 g; 80 mmoles) was added dropwise over 5 minutes to a mixture Of 99% sodium hydride (1.9 g; 80 mmoles) in dimethylformamide (100 ml). After stirring for 15 minutes, a solution of 4-hydroxy-2-(4-methoxybenzyl)-3-methyl-5-propylbenzofuran (2.4 g; 8mmoles) in dimethylformamide (5 ml) was added in one portion. The mixture was refluxed for 2 hours, cooled, acidified with 20% citric acid solution and extracted with ether. The ether solution was washed with water, dried (Na2SO4), filtered, concentrated, and chromatographed to obtain 2.2 g of the title compound as an oil which crystallized from an ether hexane mixture.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[S:32][C:31]([C:33](O)=[O:34])=[CH:30][CH:29]=1>>[CH:18]1([CH2:17][NH:16][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[C:5]([CH3:21])=[CH:4][CH:3]=[C:2]([NH:1][C:33]([C:31]4[S:32][C:28]([C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=5)=[CH:29][CH:30]=4)=[O:34])[CH:7]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20][CH2:19]1
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Reactant: O=C(O)c1ccc(-c2ccccn2)s1
Product: Cc1ccc(NC(=O)c2ccc(-c3ccccn3)s2)cc1-c1ccc(C(=O)NCC2CC2)cc1

Procedure:
N-(4′-{[(Cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-5-(pyrid-2-yl)thiophene-2- carboxamide was prepared from 5′-amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4-carboxamide and 5-(pyrid-2-yl)thiophene-2-carboxylic acid using method D. The product was further purified by preparative HPLC. NMR; δH [2H6]—DMSO 10.29,(1H, s), 8.63,(1H, t), 8.58,(1H, d), 8.02-7.99,(2H, m), 7.94,(2H, d), 7.90-7.86,(2H, m), 7.70,(1H, dd), 7.65,(1H, d), 7.46,(2H, d), 7.35,(1H, m), 7.30,(1H, d), 3.17,(2H, t), 2.21,(3H, s), 1.04,(1H, m), 0.43,(2H, m), 0.24,(2H, m). LCMS: retention time 3.60 min, MH+468.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][C:9]2[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:16])[N:5]=[C:4]([NH:17][C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)[N:3]=1.[NH2:26][CH2:27][CH:28]([OH:31])[CH2:29][OH:30]>O1CCOCC1.CN1CCCC1=O>[Cl:16][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([Cl:15])[C:9]=1[CH2:8][C:6]1[N:7]=[C:2]([NH:26][CH2:27][CH:28]([OH:31])[CH2:29][OH:30])[N:3]=[C:4]([NH:17][C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)[N:5]=1
Reactant: N#Cc1ccc(Nc2nc(Cl)nc(Cc3c(Cl)cccc3Cl)n2)cc1
Reactant: NCC(O)CO
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: N#Cc1ccc(Nc2nc(Cc3c(Cl)cccc3Cl)nc(NCC(O)CO)n2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 98.2 %

Procedure:
A mixture of intermediate (27) (0.00256 mol) and 3-amino-1,2-propanediol (0.00563 mol) in 1,4-dioxane (10 ml) and 1-methyl-pyrrolidinone (2 ml) was stirred at RT for 48 hours under argon. The reaction mixture was concentrated, quenched with DCM/H2O and stirred. The precipitate was filtered off, yielding 1.12 g (86.9%) of (±)-4-[[4-[(2,6-dichlorophenyl)methyl]-6-[(2,3-dihydroxypropyl)amino]-1,3,5-triazin-2-yl]amino]benzonitrile (compound 26).