Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[S:2].[CH2:13]([NH:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=[CH:23][C:22]=1[NH2:31])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N1C=CC=CC=1.C1COCC1>[CH2:13]([N:20]1[C:21]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N:24]=[CH:23][C:22]=2[N:31]=[C:1]1[SH:2])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Nc1cnc2ccccc2c1NCc1ccccc1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Sc1nc2cnc3ccccc3c2n1Cc1ccccc1
Temperature: 25 °C

Procedure:
1,1′-Thiocarbonyldiimidazole (5.74 g, 32.2 mmol) was added to a solution of N4-benzylquinoline-3,4-diamine, see U.S. Pat. No. 4,689,338 (Gerster), Example 124, Parts A and B, (6.69 g, 26.8 mmol) in pyridine (50 mL) and THF (50 mL), and the reaction was heated at 80° C. for two hours and cooled to room temperature. A precipitate was present and was isolated by filtration and washed with diethyl ether to provide 4.17 g of 1-benzyl-1H-imidazo[4,5-c]quinoline-2-thiol as a white solid. The filtrate was treated with diethyl ether, and additional precipitate formed. The precipitate was isolated by filtration and washed with diethyl ether to provide an additional 1.90 g of product as a pale yellow solid.
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[CH:14]=[C:13]([O:15][CH:16]([CH3:18])[CH3:17])[N:12]=[C:11](O)[N:10]=1)[CH2:2]2.O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:11]1[N:10]=[C:9]([N:3]2[CH2:4][CH:5]3[O:8][CH:1]([CH2:7][CH2:6]3)[CH2:2]2)[CH:14]=[C:13]([O:15][CH:16]([CH3:18])[CH3:17])[N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)Oc1cc(N2CC3CCC(C2)O3)nc(O)n1
Product: CC(C)Oc1cc(N2CC3CCC(C2)O3)nc(Cl)n1
Temperature: 100 °C
Reaction time: 16 h
Yield: 46 %

Procedure:
In a 25 mL round-bottomed flask was placed 4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-isopropoxypyrimidin-2-ol (31, 215 mg, 0.810 mmol) in POCl3 (20 ml) to give a fine off-white suspension. The mixture was stirred at 100° C. for 16 h. The mixture was cooled to room temperature, concentrated, diluted with dichloromethane, and washed with saturated NaHCO3. The aqueous phase was made basic with NaOH (5N) to pH 10 and extracted with dichloromethane. The combined organic phases were dried over MgSO4, filtered and concentrated to give the title compound (106 mg, 46%). Aryl chloride 32 could be transformed into aniline 19 as described in scheme 2 for the conversion of 5 into 6. Aniline 19 could be transformed into urea or carbamate compounds as described in scheme 2 (and illustrated in the experimental section for scheme 8).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([Cl:21])=[CH:4][N:3]=1.[CH3:22][P:23]([C:26]1[N:31]=[C:30]([O:32][CH3:33])[C:29]([NH2:34])=[CH:28][CH:27]=1)([CH3:25])=[O:24].Cl.[OH-].[Na+]>COCCO.C(O)C>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])=[N:7][C:2]([NH:34][C:29]2[C:30]([O:32][CH3:33])=[N:31][C:26]([P:23]([CH3:22])([CH3:25])=[O:24])=[CH:27][CH:28]=2)=[N:3][CH:4]=1
Reactant: COc1nc(P(C)(C)=O)ccc1N
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Solvent: CCO
Product: COc1nc(P(C)(C)=O)ccc1Nc1ncc(Cl)c(Nc2ccccc2S(=O)(=O)C(C)C)n1
Temperature: 90 °C
Yield: 13.1 %

Procedure:
To a solution of 2,5-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine (86.0 mg, 0.250 mmol) in 1 mL of 2-methoxyethanol was added 6-(dimethylphosphoryl)-2-methoxypyridin-3-ylamine (50.0 mg, 0.250 mmol) and 0.15 mL of 2.5 M HCl in ethanol. The mixture was heated in a sealed tube at 90° C. for 16 h. The mixture was basified with 1N NaOH solution, and extracted with ethyl acetate. The organic layers were combined, washed with saturated sodium chloride solution, dried with sodium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography (0-10% 7N ammonia in methanol:dichloromethane) to afford the desired product (16.7 mg, 22% yield). MS/ES+: m/z=510.
Reaction SMILES: C[O-].[Na+].[C:4]([OH:8])(=[O:7])[CH2:5][SH:6].Cl[CH2:10][C:11]#[C:12][CH2:13][C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].O>CO>[C:4]([OH:8])(=[O:7])[CH2:5][S:6][CH2:10][C:11]#[C:12][CH2:13][C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCC#CCC#CCCl
Reactant: O=C(O)CS
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCCCCCC#CCC#CCSCC(=O)O
Reaction time: 0.5 h
Yield: 49.4 %

Procedure:
2.02 ml of a 30% solution of sodium methoxide in methanol were added dropwise to a solution of 372 μl of thioglycolic acid in 5 ml of methanol, under an inert atmosphere. The mixture was maintained under stirring for 30 min and then a solution of 1.2 g of 1-chloro-2,5-tetradecadiyne in 6 ml of methanol was added under an inert atmosphere. The mixture was maintained under stirring for 20 hours at room temperature and then the reaction medium was poured over 100 ml of acid water (98 ml of water+2 ml concentrated H2SO4) and then extracted 3 times with ethyl ether. The combined organic phases were washed 3 times with water and then with a saturated aqueous solution of NaCl before being dried (Na2SO4) filtered and concentrated under vacuum in a rotary evaporator. The oily residue obtained crystallized on cooling. 3-Thia-5,8-heptadecadiynoic acid was recrystallized from heptane and then from hexane and finally from diisopropyl ether. The acid was thus isolated in the form of beige crystals with a yield of 49.4%.
Reaction SMILES: [N:1]1[CH2:2][C:3](=[N:7][CH2:8][CH3:9])[CH:4]=[CH:5][CH:6]=1.C(N)[C:11]1[CH:16]=[CH:15]C=[CH:13][CH:12]=1>>[N:1]1[CH2:2][C:3](=[N:7][CH2:8][C:9]2[CH:15]=[CH:16][CH:11]=[CH:12][CH:13]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: CCN=C1C=CC=NC1
Reactant: NCc1ccccc1
Product: C1=CC(=NCc2ccccc2)CN=C1
Yield: 98 %

Procedure:
The procedure described for the preparation of compound (XVII) was used, replacing p-methoxybenzylamine with benzylamine, to obtain 3.26 g (98%) of N-(3-pyridylidene)-benzylamine (XXIII).
Reaction SMILES: [Br:1]Br.[OH:3][CH:4]1[C:9]([CH3:11])([CH3:10])[O:8][C:7]2[CH:12]=[CH:13][S:14][C:6]=2[CH:5]1[N:15]1[CH2:19][CH2:18][CH2:17][C:16]1=[O:20]>ClCCl>[Br:1][C:13]1[S:14][C:6]2[CH:5]([N:15]3[CH2:19][CH2:18][CH2:17][C:16]3=[O:20])[CH:4]([OH:3])[C:9]([CH3:10])([CH3:11])[O:8][C:7]=2[CH:12]=1
Reactant: BrBr
Reactant: CC1(C)Oc2ccsc2C(N2CCCC2=O)C1O
Solvent: ClCCl
Product: CC1(C)Oc2cc(Br)sc2C(N2CCCC2=O)C1O

Procedure:
A solution of bromine (0.20 mL, 3.92 mmol) in dichloromethane (5 mL) was slowly added to a solution of 5,6-dihydro-6-hydroxy-5,5-dimethyl-7-(2-oxopyrrolidin-1-yl)-7H-thieno[3,2-b]pyran (1.0 g, 3.74 mmol) at -5° C. The resultant mixture was stirred at rt for 2 h. The resulting precipitate was collected by filtration and purified by medium pressure chromatography using 5% methanol in dichloromethane as the eluant to give the product as a colorless solid, 0.28 g (22%): mp 162°-165° C.; IR(KBr): 3287, 1666 and 1570 cm-1 ; MS: m/z 346 (MH+); 1H NMR (CDCl3): δ1.30 (s, 3H), 1.47 (s, 3H), 2.06 (m, 2H), 7.50 (m, 2H), 3.23 (bs, 1H, exchanges with D2O), 3.34 (m, 2H), 3.76 (d, J=9.1 Hz, 1H) 5.16 (d, J=9.1 Hz, 1H) and 6.56 (s, 1H). Anal. Calcd. for C13H16BrNO3S: C, 45.10; H, 4.66; N, 4.05.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].Cl[C:8]1[C:21]2[C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[S:13][C:12]=2[C:11]([N+:23]([O-:25])=[O:24])=[CH:10][CH:9]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C(C)=CC=CC=1>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH:5][C:8]1[C:21]2[C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[S:13][C:12]=2[C:11]([N+:23]([O-:25])=[O:24])=[CH:10][CH:9]=1
Reactant: CN(C)CCN
Reactant: O=c1c2ccccc2sc2c([N+](=O)[O-])ccc(Cl)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: CN(C)CCNc1ccc([N+](=O)[O-])c2sc3ccccc3c(=O)c12
Yield: 85.6 %

Procedure:
A solution of 9.3 g (0.105 mole) of N,N-dimethylethylenediamine in 35 ml of xylene was added dropwise over ten minutes to a stirred mixture of 1-chloro-4-nitrothioxanthone (24.5 g, 0.084 mole) and K2CO3 (12.2 g, 0.088 mole) in 350 ml of xylene. The mixture was heated for one hour at 70°, an additional 1.8 g (0.088 mole) of N,N-dimethylethylendiamine was added, and heating was continued for an additional hour. The mixture was cooled and the solid was collected, washed with cold xylene, petroleum ether, dried, triturated with water, and dried in vacuo at 70° to give the product (24.7 g) as a yellow solid, mp 177°-179°.
Reaction SMILES: CN1CCN(C2C=CC(NC3C4N(N=CN=4)C(C4C=C(C(N)=O)SC=4)=CN=3)=CC=2)CC1.[Br:32][C:33]1[N:38]2[N:39]=[CH:40][N:41]=[C:37]2[C:36](Br)=[N:35][CH:34]=1.[N:43]1([CH2:49][CH2:50][O:51][C:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[CH:54][CH:53]=2)[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1.C(N(CC)C(C)C)(C)C>CC(O)C>[Br:32][C:33]1[N:38]2[N:39]=[CH:40][N:41]=[C:37]2[C:36]([NH:58][C:55]2[CH:56]=[CH:57][C:52]([O:51][CH2:50][CH2:49][N:43]3[CH2:44][CH2:45][O:46][CH2:47][CH2:48]3)=[CH:53][CH:54]=2)=[N:35][CH:34]=1
Reactant: Nc1ccc(OCCN2CCOCC2)cc1
Reactant: Brc1ncc(Br)n2ncnc12
Agent: CN1CCN(c2ccc(Nc3ncc(-c4csc(C(N)=O)c4)n4ncnc34)cc2)CC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Brc1cnc(Nc2ccc(OCCN3CCOCC3)cc2)c2ncnn12
Temperature: 95 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
According to the procedure described for Compound 6, step 1, 5,8-dibromo-[1,2,4]triazolo[1,5-a]pyrazine (0.5 g, 1.799 mmol), 4-(2-morpholin-4-yl-ethoxy)-phenylamine (0.6 g, 4.5 mmol) and N,N-diisopropylethylamine (0.47 mL, 2.7 mmol) in 2-propanol (6 mL) are stirred at 95° C. overnight. After evaporation of the solvent the residue is dissolved in DCM and washed with water (2×) and brine. The organic layer is dried over MgSO4, filtered and concentrated in vacuo to afford an oil purified by silica gel column chromatography. Elution with a 97:3 mixture DCM:MeOH gives the title compound (650 mg 86%) as a light yellow solid. LCMS: Rt 2.06 nm in (97.7%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[F:10][C:11]([F:32])([F:31])[CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:21]1)[OH:13].[H-].[Na+]>C1COCC1>[Cl:8][C:6]1[CH:5]=[C:4]([O:13][CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:20]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:21]2)[C:11]([F:10])([F:32])[F:31])[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: OC(c1ccccc1-n1ccc(-c2ccccc2)n1)C(F)(F)F
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1nc(Cl)cc(OC(c2ccccc2-n2ccc(-c3ccccc3)n2)C(F)(F)F)n1
Temperature: 42.5 °C
Reaction time: 6 h
Yield: 112.2 %

Procedure:
2-Amino-4,6-dichloro pyrimidine (0.041 g, 0.25 mmol), 2,2,2-trifluoro-1-[2-(3-phenyl-pyrazol-1-yl)-phenyl]-ethanol (0.070 g, 0.22 mmol), and NaH (0.012 g, 0.31 mmol) were added to anhydrous THF (7 ml) under nitrogen atmosphere. The reaction was stirred at 40-45° C. for 6 h, and then cooled to room temperature, and quenched with water (0.04 ml). The reaction mixture was concentrated to give crude 4-chloro-6-{2,2,2-trifluoro-1-[2-(3-phenyl-pyrazol-1-yl)-phenyl]-ethoxy]-pyrimidin-2-ylamine (0.110 g, >90% pure by LCMS), which was directly used in the following step.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7](C)=[N:6][C:5]=1[N:11]1[CH2:14][CH:13]([C:15]2[NH:19][C:18]3[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:17]=3[N:16]=2)[CH2:12]1.O.[Li+].[OH-].Cl>CO>[Cl:24][C:22]1[CH:21]=[CH:20][C:18]2[NH:19][C:15]([CH:13]3[CH2:12][N:11]([C:5]4[N:6]=[CH:7][CH:8]=[CH:9][C:4]=4[C:3]([OH:25])=[O:2])[CH2:14]3)=[N:16][C:17]=2[CH:23]=1
Reactant: COC(=O)c1ccc(C)nc1N1CC(c2nc3cc(Cl)ccc3[nH]2)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cccnc1N1CC(c2nc3cc(Cl)ccc3[nH]2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.7 %

Procedure:
A solution of methyl 2-[3-(5-chloro-1H-benzoimidazol-2-yl)-azetidin-1-yl]-nicotinic acid methyl ester (1.6 g, 4.6 mmol) and water (10 mL) in MeOH (10 mL) at RT was treated with LiOH (414 mg, 9.87 mmol). The mixture was stirred at RT overnight, and made acidic with a 10% HCl solution. The resulting solution was extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was triturated with hexanes and washed several times with hexanes to give the desired carboxylic acid as a white crystalline solid (1.1 g, yield 71%).
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([O:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][C:3]1([CH3:20])[CH3:19].[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:11]([O:10][CH:5]1[CH2:6][C:7]([CH3:9])([CH3:8])[N:2]([O:1][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:3]([CH3:20])([CH3:19])[CH2:4]1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Product: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1OC(=O)c1ccccc1
Yield: 83 %

Procedure:
Using 1-hydroxy-4-benzoyloxy-2,2,6,6-tetramethylpiperidine, prepared as described by: Kurumada T. et al., loc. cit., and benzoyl chloride in a procedure otherwise similar to that for preparing the compound 101 gives an 83% yield of the compound 111 which is obtained in the form of colourless crystals; melting point. 138–140° C. (toluene/hexane).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[N:16]=[N:17][C:18]([CH2:40][CH2:41][CH2:42][CH3:43])=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[C:23]([C:34]4[N:35]=[N:36][N:37]([CH3:39])[N:38]=4)[CH:22]=3)[CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:44]>C(Cl)Cl.O1CCOCC1>[ClH:44].[ClH:44].[CH2:40]([C:18]1[N:17]=[N:16][C:15]([O:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:20][C:19]=1[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]2)=[C:23]([C:34]2[N:35]=[N:36][N:37]([CH3:39])[N:38]=2)[CH:22]=1)[CH2:41][CH2:42][CH3:43]
Reactant: CCCCc1nnc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)c(-c2nnn(C)n2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCCCc1nnc(OC2CCNCC2)cc1-c1ccc(OC2CCCCC2)c(-c2nnn(C)n2)c1
Reaction time: 1 h

Procedure:
To a solution of 4-{6-butyl-5-[4-cyclohexyloxy-3-(2-methyl-2H-tetrazol-5-yl)-phenyl]-pyridazin-3-yloxy}-piperidine-1-carboxylic acid tert-butyl ester (Example 70, 0.156 mmol, 92.1 mg) in DCM (1.5 mL) was added 4 N HCl in dioxane (0.5 mL) and the reaction mixture was stirred for 1 h. The organic solvents were removed in vacuo and the residue was triturated with anhydrous diethyl ether and hexanes. The yellow solid was dried overnight under high vacuum to give 3-butyl-4-[4-cyclohexyloxy-3-(2-methyl-2H-tetrazol-5-yl)-phenyl]-6-(piperidin-4-yloxy)-pyridazine dihydrochloride (65.8 mg).
Reaction SMILES: O.[C:2]([C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:9]=[CH:8][C:7]=1[OH:16])([CH3:5])([CH3:4])[CH3:3].[C:17](O)(=[O:20])[CH:18]=[O:19].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:12]([C:10]1[CH:11]=[C:6]([C:2]([CH3:5])([CH3:4])[CH3:3])[C:7]2[O:16][C:18](=[O:19])[CH:17]([OH:20])[C:8]=2[CH:9]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: O=CC(=O)O
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OC(=O)C2O

Procedure:
A 15 l multi-necked vessel with stirrer, dropping funnel, water separator, condenser and thermometer is charged with stirring and in succession with 300 ml of toluene, 212 g of 97% 2,4-di-tert-butylphenol (Aldrich 99%), 121.9 ml of 50% strength aqueous glyoxylic acid and 0.5 g of p-toluenesulfonic acid monohydrate. The reaction mixture is subsequently refluxed vigorously with thorough stirring. This is accompanied by the separation of the water present in the glyoxylic acid, and the water of reaction from the first stage. After a reflux time of about 3 h, the separation of water ends, to leave a homogeneous, pale yellow solution of 5,7-di-t-butyl-3-hydroxybenzofuran-2-one. Thereafter, the toluene is distilled off under atmospheric pressure and with a heating-bath temperature of up to 142° C. The crystalline solid is subsequently dried at 80° C./50 mbar.
Reaction SMILES: [NH:1]([C:3](=[NH:29])[C:4]1[N:5]=[C:6]([NH:16][C@H:17]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18]2)[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[O:14][CH3:15])[NH2:2].C1N=CN([C:35](N2C=NC=C2)=[O:36])C=1>O1CCOCC1>[CH3:15][O:14][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[C:6]([NH:16][C@H:17]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:18]1)=[N:5][C:4]([C:3]1[NH:29][C:35](=[O:36])[NH:2][N:1]=1)=[CH:13]2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1cccc2cc(C(=N)NN)nc(N[C@H]3CCN(C(=O)OC(C)(C)C)C3)c12
Solvent: C1COCCO1
Product: COc1cccc2cc(-c3n[nH]c(=O)[nH]3)nc(N[C@H]3CCN(C(=O)OC(C)(C)C)C3)c12
Yield: 18.8 %

Procedure:
To a mixture of (S)-tert-butyl 3-((3-(hydrazinyl(imino)methyl)-8-methoxyisoquinolin-1-yl)amino)pyrrolidine-1-carboxylate (400 mg, 1.0 mmol) in dioxane (10 mL) was added CDI (245 mg, 1.5 mmol). The resulting mixture was heated to reflux for 2 hours and then concentrated in vacuo. The crude product was purified by preparative HPLC to give the title compound (80 mg, 18% over 2 steps). ESI-MS m/z [M+H]+ 427.
Reaction SMILES: C([Li])CCC.[C:6](#[N:8])[CH3:7].[CH2:9]([O:16][C:17]1[C:26]([O:27][CH3:28])=[CH:25][C:20]([C:21]([O:23]C)=O)=[C:19]([N:29]=[CH:30]N(C)C)[CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O)(=O)C>C1COCC1>[CH2:9]([O:16][C:17]1[CH:18]=[C:19]2[C:20]([C:21]([OH:23])=[C:7]([C:6]#[N:8])[CH:30]=[N:29]2)=[CH:25][C:26]=1[O:27][CH3:28])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC#N
Reactant: COC(=O)c1cc(OC)c(OCc2ccccc2)cc1N=CN(C)C
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1cc2c(O)c(C#N)cnc2cc1OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 26.9 ml of n-butyllithium (2.5 M in hexane) in 50 ml of THF at −78° C. was added a 3.51 ml of acetonitrile in 20 ml of THF during 10 min. After stirring at −78° C. for 30 min, the mixture was treated with 10 g of methyl 4-benzyloxy-2-(dimethylaminomethyleneamino)-5-methoxybenzoate in 20 ml of THF during 5 min. After 15 min at −78° C. the stirred mixture was warmed to 0° C. for a further 30 min. It was then treated with 5 ml of acetic acid, warmed to 25° C. and stirred for 30 min. The mixture was evaporated to dryness, and diluted with aqueous sodium bicarbonate. The resulting off-white solid was filtered, washed with water, ethyl acetate and ether. After drying, 4.5 g of 7-benzyloxy-4-hydroxy-6-methoxy-quinoline-3-carbonitrile was obtained as an off-white solid, dec>255° C.; mass spectrum (electrospray, m/e) M+H 307.
Reaction SMILES: [CH:1]([PH:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].CN([CH2:11][C-:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH2:17]N(C)C)C.[CH-:21]1[CH:25]=[CH:24][CH:23]=[CH:22]1.[Fe+2:26]>C(O)(=O)C>[CH:1]([P:4]([CH2:11][C-:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH2:17][P:4]([CH:25]([CH3:24])[CH3:21])[CH:1]([CH3:3])[CH3:2])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[CH-:21]1[CH:25]=[CH:24][CH:23]=[CH:22]1.[Fe+2:26]
Reactant: CC(C)PC(C)C
Reactant: CN(C)Cc1ccc[c-]1CN(C)C
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: CC(=O)O
Product: CC(C)P(Cc1ccc[c-]1CP(C(C)C)C(C)C)C(C)C

Procedure:
The title compound was prepared in accordance with the procedure of Example 2 employing di-iso-propylphosphine (Digital Speciality Chemicals 392 mg, 3.33 mmol), 1,2-bis(dimethylaminomethyl)ferrocene (0.5 g, 1.66 mmol) and anhydrous acetic acid (100 ml). Yield 0.262 g.
Reaction SMILES: [F:1][C:2]1[C:12]([NH:13][CH2:14][C:15]2[CH:20]=[C:19]([O:21]C)[CH:18]=[C:17]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[C:16]=2[F:30])=[C:11]([F:31])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([O-:8])=[O:7].[Al+3].[Cl-].[Cl-].[Cl-].[CH2:36](S)[CH3:37].O>C(Cl)Cl>[F:1][C:2]1[C:12]([NH:13][CH2:14][C:15]2[CH:20]=[C:19]([OH:21])[CH:18]=[C:17]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[C:16]=2[F:30])=[C:11]([F:31])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:36][CH3:37])=[O:7]
Reactant: COc1cc(CNc2c(F)ccc(OCC(=O)[O-])c2F)c(F)c(-c2cccc(F)c2)c1
Reactant: CCS
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)COc1ccc(F)c(NCc2cc(O)cc(-c3cccc(F)c3)c2F)c1F
Temperature: 0 °C
Reaction time: 3 h
Yield: 83.4 %

Procedure:
To a solution of 2-[2,4-difluoro-3-[[2-fluoro-3-(3-fluorophenyl)-5-methoxy-phenyl]methylamino]phenoxy]acetate (150 mg, 0.32 mmol, 1.0 eq) and AlCl3 (259 mg, 1.94 mmol, 6.0 eq) in CH2Cl2 (5 mL) at 0° C. was added ethanethiol (120 mg, 1.94 mmol, 6.0 eq). The reaction mixture was stirred at 0° C. for 3 h. The resulting mixture was poured into water and extracted with CH2Cl2. The organic extract was dried (Na2SO4), filtered and evaporated in vacuo and the residue purified by column chromatography (EtOAc:petroleum ether, 0:1 to 1:2) to give the title as a yellow oil (120 mg, 82%).
Reaction SMILES: FC1C=CC=CC=1C=O.[Br:10][C:11]1[CH:12]=[C:13]([CH:25]=[C:26]([Cl:28])[CH:27]=1)[O:14][C:15]1[C:22]([Cl:23])=[CH:21][CH:20]=[C:19](F)[C:16]=1[CH:17]=O.O.[NH2:30][NH2:31]>CS(C)=O>[Br:10][C:11]1[CH:12]=[C:13]([CH:25]=[C:26]([Cl:28])[CH:27]=1)[O:14][C:15]1[C:22]([Cl:23])=[CH:21][CH:20]=[C:19]2[C:16]=1[CH:17]=[N:30][NH:31]2
Reactant: NN
Reactant: O=Cc1c(F)ccc(Cl)c1Oc1cc(Cl)cc(Br)c1
Agent: O=Cc1ccccc1F
Solvent: O
Solvent: CS(C)=O
Product: Clc1cc(Br)cc(Oc2c(Cl)ccc3[nH]ncc23)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A suspension of 2-(3-bromo-5-chlorophenoxy)-3-chloro-6-fluorobenzaldehyde fluorobenzaldehyde (4.5 kg; 12.36 moles; 1.0 eq.) in DMSO (18 L) was degassed, after which hydrazine monohydrate (6.192 kg; 123.7 moles; 10.0 eqs.) was added over 20 minutes at room temperature. The reaction solution was degassed again, stirred at room temperature for 15 minutes, heated to 73° C., and then aged for 16 hours. After the mixture was cooled to room temperature, isopropanol (15 L) and then water (40 L) were added, and the resulting mixture cooled to room temperature, filtered under pressure, and washed with isopropanol:water (1:2; 10 L), water (12 L), and heptane (12 L). The title product as a solid was obtained after drying at 30° C.-35° C. under vacuum for four days.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:12]#[N:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH2:14].O.O.[C:17](O)(=[O:21])[C:18](O)=[O:19]>Cl>[OH:19][C:18]1[C:17]([OH:21])=[N:14][C:3]2[CH:4]=[CH:5][C:6]3[C:7]([C:12]#[N:13])=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[N:1]=1
Reactant: N#Cc1cccc2c(N)c(N)ccc12
Reactant: O=C(O)C(=O)O
Agent: Cl
Solvent: O
Product: N#Cc1cccc2c1ccc1nc(O)c(O)nc12
Temperature: 25 °C
Yield: 44.7 %

Procedure:
A mixture of 0,6 g (3,3 mmol) 1,2-diamino-5-cyanonaphthalene and 1,4 g oxalic acid dihydrate in 35 ml 0,5N hydrochloric acid was refluxed for 3 h. After cooling to 25° C., the precipitate was filtered off and washed with water. The crude product was recrystallized (dimethylsulfoxide-methanol) to give 0,35 g (45%) 2,3-dihydroxy-7-cyano-benzo[f]quinoxaline, m.p. >300° C. IR (KBr): 2190 cm-1 (nitrile function).