Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:40][C:41]3[CH:49]=[C:48]([CH3:50])[C:44]4[NH:45][CH:46]=[N:47][C:43]=4[CH:42]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:32][CH2:31][N:30](CC5C=CC=CC=5)[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:51]=[CH:52][CH:53]=[CH:54][C:4]=2[NH:3]1.[H][H]>CO.[Pd]>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:40][C:41]3[CH:49]=[C:48]([CH3:50])[C:44]4[NH:45][CH:46]=[N:47][C:43]=4[CH:42]=3)[C:19](=[O:20])[N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]4)[CH2:23][CH2:22]3)=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:51]=[CH:52][CH:53]=[CH:54][C:4]=2[NH:3]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCN(Cc4ccccc4)CC3)CC2)cc2nc[nH]c12
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCNCC3)CC2)cc2nc[nH]c12
Reaction time: 3 h

Procedure:
67 mg (0.08 mmol) (R)-2-[4-(4-benzyl-piperazin-1-yl)-piperidin-1-yl]-1-(7-methyl-1H-benzimidazol-5-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5,-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate were dissolved in 10 mL MeOH and combined with 30 mg 10% Pd/C. The mixture was hydrogenated for 3 h in a Parr apparatus at 50° C. and 50 psi hydrogen pressure. Then the catalyst was filtered off and the filtrate was evaporated down i.vac. The residue was purified by HPLC, the fractions containing the product were combined and lyophilised.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.Cl.Cl[CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[C:4]([F:9])[CH:3]=1
Reactant: ClCCN1CCOCC1
Reactant: Oc1ccc(Br)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1cc(Br)ccc1OCCN1CCOCC1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
4-Bromo-2-fluorophenol (16.7 g, 87.4 mmol) is dissolved in 100 mL DMF. N-(2-Chloro-ethyl)morpholine hydrochloride (18.5 g, 99.4 mmol), potassium carbonate (28.0 g, 203 mmol) and potassium iodide (100 mg, 0.602 mmol) are added and the reaction mixture is stirred for 3 h at 65° C. The reaction mixture is poured in water and extracted with ethyl acetate. The combined organic phases are washed with water and brine, dried over magnesium sulfate and concentrated in vacuo. Yield: 27.7 g.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([O:14][CH3:15])[CH:6]=1.[CH2:16]([NH:18][CH2:19][CH3:20])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.ClCCl>[CH2:16]([N:18]([CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([O:14][CH3:15])[CH:6]=1)[CH2:19][CH3:20])[CH3:17]
Reactant: COc1cc(OCCCl)ccc1[N+](=O)[O-]
Reactant: CCNCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: CCN(CC)CCOc1ccc([N+](=O)[O-])c(OC)c1
Temperature: 80 °C

Procedure:
4-(2-Chloroethoxy)-2-methoxy-1-nitrobenzene (0.22 g, 0.9 mmol) was dissolved in acetonitrile (1 ml). Diethylamine (0.14 ml, 2.6 mmol) and potassium carbonate (0.31 g, 2.2 mmol) were added and the reaction was heated in a sealed pressure tube to 80° C. for 20 h. The reaction mixture was diluted with dichloromethane, then washed with 1M sodium hydroxide and brine, then dried over sodium sulfate. Evaporation of the solvent under reduced pressure gave the title compound as a brown oil.
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[N:32](COCC[Si](C)(C)C)[C:18]4[CH:19]=[N:20][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22](=[O:23])[C:17]=4[C:16]=3[CH2:41][CH2:42][CH:43]3[CH2:45][CH2:44]3)[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:14])[F:13])[CH2:3][CH2:2]1.C1(OC2C=C(C3N(COCC[Si](C)(C)C)C4C=NN(COCC[Si](C)(C)C)C(=O)C=4C=3C)C=CC=2OC(F)F)CC1>>[CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[NH:32][C:18]4[CH:19]=[N:20][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22](=[O:23])[C:17]=4[C:16]=3[CH2:41][CH2:42][CH:43]3[CH2:45][CH2:44]3)[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:14])[F:13])[CH2:2][CH2:3]1
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(CCC3CC3)c(-c3ccc(OC(F)F)c(OC4CC4)c3)n2COCC[Si](C)(C)C)c1=O
Agent: Cc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)n(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Product: C[Si](C)(C)CCOCn1ncc2[nH]c(-c3ccc(OC(F)F)c(OC4CC4)c3)c(CCC3CC3)c2c1=O
Yield: 82.6 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Example 4-(b) except for using 0.44 g (0.66 mmol) of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-(2-cyclopropylethyl)-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Example 70-(b) in place of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-methyl-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one, whereby 0.29 g of the title compound was obtained as a white foam. (Yield: 83%)
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:13])[CH2:9][C:10]([OH:12])=O)=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl.Cl.[F:52][C:53]1[CH:65]=[CH:64][C:63]([F:66])=[CH:62][C:54]=1[O:55][CH:56]1[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1>CN(C=O)C.O>[C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:2]=[CH:3][C:4]([NH:7][C:8](=[O:13])[CH2:9][C:10]([N:59]2[CH2:58][CH2:57][CH:56]([O:55][C:54]3[CH:62]=[C:63]([F:66])[CH:64]=[CH:65][C:53]=3[F:52])[CH2:61][CH2:60]2)=[O:12])=[CH:5][CH:6]=1
Reactant: Fc1ccc(F)c(OC2CCNCC2)c1
Reactant: O=C(O)CC(=O)Nc1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC(=O)N1CCC(Oc2cc(F)ccc2F)CC1)Nc1ccc(-c2ccccc2)cc1
Temperature: 10 °C
Reaction time: 8 h
Yield: 22.2 %

Procedure:
To a stirred solution of N-biphenyl-4-yl-malonamic acid (0.075 g, 0.0003 mole) in DMF (2 mL) was added, HOBt (0.06 g, 0.00045 mole) and DIPEA (0.135 g, 0.001 mole). The mixture was then cooled to 10° C. and EDCI.HCl (0.086 g, 0.00045 mole) followed by 4-(2,5-difluoro-phenoxy)-piperidine hydrochloride (0.073 g, 0.0003 mole) were added. The resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography using neutral aluminium oxide (5% methanol in chloroform) to afford 0.03 g (22%) of N-biphenyl-4-yl-3-[4-(2,5-difluoro-phenoxy)-piperidin-1-yl]-3-oxo-propionamide. LC-MS purity: 451.18 (M+1)+, 90.58%, 1H NMR (DMSO-d6): δ 10.2 (s, 1H), 7.7 (m, 6H), 7.4 (m, 2H), 7.2 (m, 2H), 6.8 (m, 1H), 4.7 (m, 1H), 3.9 (m, 1H), 3.8 (m, 1H), 3.6 (s, 2H), 3.4 (m, 1H), 2.0 (m, 2H), 1.7 (m, 1H), 1.6 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16])[CH3:2].CO[CH:21]([N:24]([CH3:26])[CH3:25])OC>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([CH:11]=[CH:21][N:24]([CH3:26])[CH3:25])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16])[CH3:2]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)c1cc(C)c([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C=CN(C)C)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 32.3 %

Procedure:
A mixture of 5-methyl-2,4-dinitro-benzoic acid ethyl ester (39 g, 0.15 mol) and dimethoxymethyl-dimethylamine (32 g, 0.27 mol) in DMF (200 mL) was heated at 100° C. for 5 h. The mixture was poured into ice water. The precipitate was collected via filtration and washed with water to afford 5-(2-dimethylamino-vinyl)-2,4-dinitro-benzoic acid ethyl ester (15 g, 28%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[O:12][C:13]=2[C:14]2[CH:19]=[CH:18][CH:17]=[C:16](C#N)[CH:15]=2)[CH:5]=[C:6](F)[CH:7]=1.BrC1C=C(C(OCC)=O)OC=1C1C=CC([F:39])=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[O:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([F:39])=[CH:16][CH:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(Br)c(-c2ccc(F)cc2)o1
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(Cl)c2)c(-c2cccc(C#N)c2)o1
Product: CCOC(=O)c1cc(-c2cccc(Cl)c2)c(-c2ccc(F)cc2)o1

Procedure:
The synthesis of the title compound takes place in analogy to the synthesis of the compound from Example 11A starting with the compound from Example 7A. Extraction is carried out with dichloromethane and purification with the mobile phase cyclohexane/ethyl acetate (30:1). 4.12 g (41% of theory) of the title compound with a purity of 50% are obtained.
Reaction SMILES: [OH-].[Na+].C1(S([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:27][C@H:28]4[CH2:33][CH2:32][C@H:31]([OH:34])[CH2:30][CH2:29]4)[N:22]=3)=[CH:13]2)(=O)=O)C=CC=CC=1>CO>[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([NH:27][C@H:28]3[CH2:29][CH2:30][C@H:31]([OH:34])[CH2:32][CH2:33]3)[N:22]=2)=[CH:13]1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(N[C@H]3CC[C@H](O)CC3)n2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O[C@H]1CC[C@H](Nc2nccc(-c3c[nH]c4ccccc34)n2)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
NaOH (200 mg, 5 mmol) was added to a solution of trans-4-[4-(1-benzenesulfonyl-1H-indol-3-yl)-pyrimidin-2-ylamino]-cyclohexanol (296 mg, 0.66 mmol) in MeOH (15 mL), and the resulting mixture stirred at RT for 6 h. The reaction mixture was concentrated under reduced pressure, the residue neutralized by addition of aqueous HCl (1 M), and then partitioned between water and EtOAc. The organic layer was separated, washed with water, dried over Na2SO4, filtered and evaporated under reduced pressure to give a crude yellow solid. This crude material was purified by flash chromatography (MeOH/DCM, 5:95) to give trans-4-[4-(1H-indol-3-yl)-pyrimidin-2-ylamino]-cyclohexanol (115 mg, 57% yield) as a white powder. MS=309 [M+H]+; MP=258.1-259.9° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.[CH3:12][C:13](=[CH2:15])[CH3:14]>[Hg](Cl)Cl.[Al]>[C:13]([CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:10][CH2:11][CH:2]1[OH:1])([CH3:15])([CH3:14])[CH3:12]
Reactant: OC1CCc2ccccc2C1
Reactant: C=C(C)C
Agent: Cl[Hg]Cl
Agent: [Al]
Product: CC(C)(C)C1c2ccccc2CCC1O
Temperature: 100 °C
Reaction time: 3 h
Yield: 69.3 %

Procedure:
In an autoclave 222 g of 2-hydroxytetraline, 2.5 g of aluminium grit and 0.2 g of mercury(II) chloride are heated at 180° C for 1 h. After cooling 85 g of isobutylene are added and the mixture is stirred at 100° C for 3 h. In order to eliminate the catalyst the reaction product is washed with diluted hydrochloric acid. A subsequent distillation yields 212 g of 1-t-butyl-2-hydroxytetraline. Boiling point (13 mm Hg): 171° C. Melting point: 104° C.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].CO[C:8](=[O:26])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH:16]([CH3:23])[CH2:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[C:11]([O:24][CH3:25])[CH:10]=1>>[CH3:23][CH:16]([O:15][C:12]1[CH:13]=[CH:14][C:9]([C:8]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[O:26])=[CH:10][C:11]=1[O:24][CH3:25])[CH2:17][CH2:18][CH2:19][CH:20]([CH3:21])[CH3:22]
Reactant: COC(=O)c1ccc(OC(C)CCCC(C)C)c(OC)c1
Reactant: CCNCC
Product: CCN(CC)C(=O)c1ccc(OC(C)CCCC(C)C)c(OC)c1

Procedure:
By the procedure described in Example 38, diethylamine is reacted with 4-[(1,5-dimethyl-hexyl)-oxy]-m-methoxy-benzoic acid methyl ester to produce 4-[(1,5-dimethyl-hexyl)-oxy]-m-methoxy-N,N-diethyl-benzamide (boiling point = 180°-182°C/0.1 mmHg).
Reaction SMILES: [OH-:1].[Na+].[CH:3]([C:6]1[C:7]([O:39][CH2:40][O:41][CH3:42])=[CH:8][C:9]([O:35][CH2:36][O:37][CH3:38])=[C:10]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)=[CH:19][CH:18]=3)[C:15](S(C)(=O)=O)=[N:14][N:13]=2)[CH:11]=1)([CH3:5])[CH3:4]>CS(C)=O>[CH:3]([C:6]1[C:7]([O:39][CH2:40][O:41][CH3:42])=[CH:8][C:9]([O:35][CH2:36][O:37][CH3:38])=[C:10]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)=[CH:19][CH:18]=3)[C:15](=[O:1])[NH:14][N:13]=2)[CH:11]=1)([CH3:5])[CH3:4]
Reactant: [OH-]
Reactant: COCOc1cc(OCOC)c(C(C)C)cc1-c1nnc(S(C)(=O)=O)n1-c1ccc(CN2CCN(C)CC2)cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: COCOc1cc(OCOC)c(C(C)C)cc1-c1n[nH]c(=O)n1-c1ccc(CN2CCN(C)CC2)cc1
Yield: 95 %

Procedure:
At room temperature, aqueous sodium hydroxide (1.0 M aqueous solution, 5 mL) was added to a dimethylsulfoxide (5 mL) solution of 3-(5-isopropyl-2,4-bis-methoxymethoxyphenyl)-4-[4-(4-methylpiperazin-1-ylmethyl)phenyl]-5-methanesulfonyl-[1,2,4]triazole (F652-08, 1.07 g, 1.86 mmol), and the mixture was heated for 3 hours under reflux. An additional aqueous sodium hydroxide (1.0 M aqueous solution, 5 mL) was added, and the mixture was heated under flux for further 1 hour. After returned to room temperature, the reaction mixture was extracted with ethyl acetate and chloroform. The combined extracts were washed twice with water and then with saturated sodium chloride solution, and dried over anhydrous sodium sulfate, and sodium sulfate was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (NH silica, chloroform, methanol) to obtain 5-(5-isopropyl-2,4-bis-methoxymethoxyphenyl)-4-[4-(4-methylpiperazin-1-ylmethyl)phenyl]-2,4-dihydro-[1,2,4]triazol-3-one (F652-09, pale yellow foam, 900 mg, 95%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[C:5]([NH:7][C:8]1[CH:9]=[N:10][C:11]([O:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH2:17][CH2:18][C:19]3=[O:24])=[CH:12][CH:13]=1)=[O:6].C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:40](OC(C)=C)(=[O:42])[CH3:41]>>[C:40]([O:24][C:19]1[C:20]2[C:16](=[C:15]([O:14][C:11]3[N:10]=[CH:9][C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:25]=[CH:26][C:27]([Cl:28])=[C:2]([Cl:1])[CH:3]=4)=[CH:13][CH:12]=3)[CH:23]=[CH:22][CH:21]=2)[CH2:17][CH:18]=1)(=[O:42])[CH3:41]
Reactant: O=C(Nc1ccc(Oc2cccc3c2CCC3=O)nc1)c1ccc(Cl)c(Cl)c1
Reactant: C=C(C)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(=O)OC1=CCc2c(Oc3ccc(NC(=O)c4ccc(Cl)c(Cl)c4)cn3)cccc21
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A mixture of 1.00 g of 3,4-dichloro-N1-[6-(1-oxo-2,3-dihydro-1H-inden-4-yl)oxy]-3-pyridinyl]benzamide obtained in Example 1, 50 mg of p-toluenesulfonic acid and 5 ml of isopropenyl acetate was stirred overnight at 70° C. The reaction mixture was concentrated and the resulting residue was extracted with ethyl acetate. This extracted solution was washed in turn with a saturated sodium hydrogencarbonate solution and a saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (2:1)) to obtain the titled compound (230 mg, white powder). Melting point: 161-164° C.
Reaction SMILES: [OH:1][C:2]1[N:3]=[N:4][C:5]([OH:10])=[C:6]([Cl:9])[C:7]=1[Cl:8].[OH-].[Na+].[CH2:13](I)[CH3:14].C(O)C>C1C=CC=CC=1.O>[CH2:13]([N:3]1[C:2](=[O:1])[C:7]([Cl:8])=[C:6]([Cl:9])[C:5]([OH:10])=[N:4]1)[CH3:14]
Reactant: Oc1nnc(O)c(Cl)c1Cl
Reactant: CCI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: c1ccccc1
Product: CCn1nc(O)c(Cl)c(Cl)c1=O
Reaction time: 4 h

Procedure:
A mixture comprising 5.00 g of 3,6-dihydroxy-4,5-dichloropyridazine, 2.21 g of sodium hydroxide, 5.60 g of ethyl iodide, 40 ml of ethanol and water, was stirred at a temperature of from 60° to 70° C. for 4 hours. Most ethanol was distilled off under reduced pressure. Then, dilute hydrochrolic acid and chloroform were added to the residue, and the mixture was vigorously shaked. The chloroform layer was separated and washed with water, followed by drying over sodium sulfate. Then, the solvent was distilled off to obtain a light orange solid substance. The solid substance was treated with benzene to obtain 3.56 g of the above identified compound as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14](OCC)=[O:15])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[NH2:21][NH2:22]>C(O)C>[CH3:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([NH:21][NH2:22])=[O:15])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCOC(=O)CN1CCN(Cc2ccc(C)cc2)CC1
Solvent: CCO
Product: Cc1ccc(CN2CCN(CC(=O)NN)CC2)cc1

Procedure:
Synthesized according to General Procedure C: 6{13} (7.66 g, 27.7 mmol, 1 equiv.), anhydrous hydrazine (2.6 mL, 83.2 mmol, 3 equiv.), ethanol (55.4 mL). Purification by silica gel column chromatography (4:1 EtOAc:MeOH) afforded 1{13} (6.10 g, 84%) as a beige solid. 1H-NMR (500 MHz, CDCl3): δ 8.14 (br s, 1H), 7.18 (d, 2H, J=8.0 Hz), 7.12 (d, 2H, J=8.0 Hz), 3.84 (br s, 2H), 3.46 (s, 2H), 3.06 (s, 2H), 2.52 (br s, 4H), 2.45 (br s, 4H), 2.33 (s, 3H). 13C-NMR (125 MHz, CDCl3): δ 170.5, 136.7, 134.6, 129.1, 128.9, 62.5, 60.5, 53.6, 52.9, 21.1.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH:7]1[CH:11]=[C:10](/[CH:12]=[CH:13]/[C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:15])[CH:9]=[N:8]1.Br[CH2:32][CH2:33][O:34][C:35]1[CH:40]=[C:39]([F:41])[CH:38]=[C:37]([Cl:42])[CH:36]=1>CN(C=O)C.CCOC(C)=O>[Cl:42][C:37]1[CH:36]=[C:35]([CH:40]=[C:39]([F:41])[CH:38]=1)[O:34][CH2:33][CH2:32][N:7]1[CH:11]=[C:10](/[CH:12]=[CH:13]/[C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:15])[CH:9]=[N:8]1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)/C=C/c1cn[nH]c1
Reactant: Fc1cc(Cl)cc(OCCBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)/C=C/c1cnn(CCOc2cc(F)cc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
Cesium carbonate (98 mg, 0.30 mmol) was added to a solution of (E)-tert-butyl (2-(3-(1H-pyrazol-4-yl)acrylamido)phenyl)carbamate (100 mg, 0.30 mmol) in anhydrous DMF (4 mL). A solution of 1-(2-bromoethoxy)-3-chloro-5-fluorobenzene (76 mg, 0.30 mmol) in DMF (1 mL) was then added and the reaction mixture was stirred overnight at room temperature under a nitrogen atmosphere. It was diluted with EtOAc (30 mL) and washed with water (2×40 mL) and brine (10 mL). The organic layer was dried over anhydrous Na2SO4 and filtered. The evaporated crude was purified by silica gel column chromatography using a gradient of 0-100% of EtOAc in hexanes to provide 144 mg of (E)-tert-butyl (2-(3-(1-(2-(3-chloro-5-fluorophenoxy)ethyl)-1H-pyrazol-4-yl)acrylamido)phenyl)carbamate as a white solid. MS: ES+(M+Na)+: 523
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[S:16][CH2:15][C:14]2([CH2:20][CH2:19][CH2:18][CH2:17]2)[NH:13]1.[CH:21]1(Br)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[S:16][CH2:15][C:14]2([CH2:17][CH2:18][CH2:19][CH2:20]2)[N:13]1[CH:21]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C1NC2(CCCC2)CS1
Reactant: BrC1CCCCCC1
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SCC2(CCCC2)N1C1CCCCCC1

Procedure:
1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was sequentially reacted with SOCl2 and 2-methyl-4-nitrophenyl isothiocyanate according to Method C2a to give 2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with cycloheptyl bromide according to Method D2e to give 2-(2-methyl-4-nitrophenylimino)-1-cycloheptyl-3-thia-1-azaspiro [4.4]nonane.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:15]=[CH:14][C:11]([CH2:12][O-:13])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Na+].[C:17]1([CH2:23][CH2:24][CH2:25]Br)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[C:17]1([CH2:23][CH2:24][CH2:25][O:13][CH2:12][C:11]2[CH:10]=[CH:9][C:8]([CH2:7][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[CH:15][CH:14]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCCCc1ccccc1
Reactant: [O-]Cc1ccc(CN2CCCCC2)cc1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: c1ccc(CCCOCc2ccc(CN3CCCCC3)cc2)cc1

Procedure:
4-(Piperidinomethyl)benzoic acid methyl ester (22 mmol) in dry tetrahydrofurane was added dropwise to a suspension of 44 mmol of lithium aluminium hydride in 30 ml of dry tetrahydrofurane at 0° C. After refluxing for 2 hours a saturated solution of ammonium chloride in water was added dropwise. After stirring for 12 hours at ambient temperature the organic layer was isolated and the aqueous layer extracted with methylene chloride. The organic extracts were combined and the solvent was evaporated under reduced pressure. The residue was crystallized with maleic acid from diethyl ether/2-propanol (Yield: 91%). Sodium 4-(piperidinomethyl)benzyl alcoholate (5 mmol) and 6 mmol of 3-phenylpropyl bromide in 10 ml of dry toluene were refluxed for 6 hours. The solvent was evaporated under reduced pressure. The residue was purified by rotatory chromatography on silica gel using methylene chloride/ammonia atmosphere as eluent. The product was crystallized with oxalic acid from diethyl ether/ethanol.
Reaction SMILES: C([Mg]Cl)(C)C.[C:6]([CH2:8][C:9]([OH:11])=O)#[N:7].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19]C(O)=O)=[CH:15][CH:14]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.O>C1COCC1.CC(O)=O>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:9](=[O:11])[CH2:8][C:6]#[N:7])=[CH:15][CH:14]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: N#CCC(=O)O
Agent: CC(C)[Mg]Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: N#CCC(=O)Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
2 M of isopropylmagnesium chloride in THF (300 mL) was added to a −78° C. solution of cyanoacetic acid (28.3 g, 333 mmol) in anhydrous THF (600 mL, 7000 mmol). After 1 h, a solution of 4-chlorophenylacetic acid (20 g, 100 mmol) and N,N-carbonyldiimidazole (21.7 g, 134 mmol) in anhydrous THF (200 mL, 2000 mmol) was added. The reaction mixture was warmed to rt. After 16 h, the reaction mixture was poured into water (1 L, 60000 mmol). The mixture was adjusted to pH 4 with glacial AcOH. Gas evolution was evident during addition of the AcOH. The mixture was concentrated in vacuo to remove the THF (in 1 L portions). The product crystallized from the aqueous portions. The solid was collected by filtration, washing with water. Dried under vacuum to afford the product as a fluffy light orange-yellow solid (15.89 g, 60%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[C:16]([NH2:18])[C:15]([NH2:19])=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:20]=[C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](=[O:30])[N:22]1[CH2:31][C:32]1[CH:46]=[CH:45][C:35]2[NH:36][C:37]([CH2:39][C:40](OCC)=O)=[N:38][C:34]=2[CH:33]=1>C(OCC)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]3[NH:19][C:40]([CH2:39][C:37]4[NH:38][C:34]5[CH:33]=[C:32]([CH2:31][N:22]6[C:23](=[O:30])[C:24]7[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=7)[C:21]6=[O:20])[CH:46]=[CH:45][C:35]=5[N:36]=4)=[N:18][C:16]=3[CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)Cc1nc2cc(CN3C(=O)c4ccccc4C3=O)ccc2[nH]1
Reactant: Nc1ccc(OCCCCc2ccccc2)cc1N
Solvent: CCOCC
Product: O=C1c2ccccc2C(=O)N1Cc1ccc2nc(Cc3nc4cc(OCCCCc5ccccc5)ccc4[nH]3)[nH]c2c1
Temperature: 185 °C
Reaction time: 1 h
Yield: 76.9 %

Procedure:
A mixture of 5-(4-phenylbutoxy)benzene-1,2-diamine (0.06 g, 0.234 mmol) and ethyl 5-(1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl)-1H-benzoimidazol-2-ylacetate (0.1 g, 0.234 mmol) was heated 1 hour at 185° C. under nitrogen. The mixture was suspended in diethyl ether, stirred vigorously for 1 hour. The solids were collected by filtration, washed with diethyl ether and dried to provide 2-{2-[5-(4-phenylbutoxy)-1H-benzoimidazol-2-ylmethyl]-3H-benzoimidazol-5-ylmethyl}isoindole-1,3-dione (0.1 g, 0.18 mmol).