Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:18]3[C:17]4[CH:16]=[CH:15][N:14]=[CH:13][C:12]=4[C:11](=[O:19])[C:10]=3[C:9](=O)[NH:8][C:7]=2[CH:21]=1.[CH3:22][N:23]([CH2:27][CH2:28][NH2:29])[CH2:24][CH2:25][NH2:26].[C:30](=[O:33])([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:18]3[C:17]4[CH:16]=[CH:15][N:14]=[CH:13][C:12]=4[C:11](=[O:19])[C:10]=3[C:9]([NH:26][CH2:25][CH2:24][N:23]([CH3:22])[CH2:27][CH2:28][NH:29][C:9]3[C:10]4[C:11](=[O:19])[C:12]5[CH:13]=[N:14][CH:15]=[CH:16][C:17]=5[C:18]=4[C:6]4[CH:5]=[CH:4][C:3]([O:33][CH3:30])=[CH:21][C:7]=4[N:8]=3)=[N:8][C:7]=2[CH:21]=1
Reactant: O=C([O-])[O-]
Reactant: CN(CCN)CCN
Reactant: COc1ccc2c3c(c(=O)[nH]c2c1)C(=O)c1cnccc1-3
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2c3c(c(NCCN(C)CCNc4nc5cc(OC)ccc5c5c4C(=O)c4cnccc4-5)nc2c1)C(=O)c1cnccc1-3
Temperature: 90 °C

Procedure:
A mixture of 6-chloro-3-methoxy-5,9-diaza-benzo[c]fluoren-7-one (Reference Example 1c-2) (21 mg) and N-methyl-2,2′-diaminodiethylamine (WAKO PURE CHEMICAL: 3.3 mg) and potassium carbonate (10 mg) was suspended in N,N-dimethylformamide (0.5 ml) and stirred at 90° C. for thirteen hours under nitrogen gas. The mixture was evaporated to dryness. The residue was purified by silica gel column chromatography developed by dichloromethane-methanol=30:1 and dichloromethane-methanol-ammonia water (25%)=30:1:0.4. The desired product was obtained as a reddish powder.
Reaction SMILES: [CH:1]1(Br)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[OH:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[N+:23]([O-:25])=[O:24])[C:17]([OH:19])=[O:18]>CN1CCN(C)C1=O>[CH:1]1([O:13][C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=2[N+:23]([O-:25])=[O:24])[C:17]([O:19][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:18])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(O)c1
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCN(C)C1=O
Product: O=C(OC1CCCC1)c1ccc([N+](=O)[O-])c(OC2CCCC2)c1
Reaction time: 14 h
Yield: 63.9 %

Procedure:
Cyclopentyl bromide (20 g, 134 mmol) is added slowly (over 30 minutes) to a stirred suspension of potassium carbonate (27.6 g, 200 mmol) in N,N′-dimethylimidazolidinone (75 mL) containing 3-hydroxy-4-nitrobenzoic acid (9.15 g, 50 mmol) at 85° C. and then stirring is continued for 14 hours. The mixture is allowed to cool and then filtered. The filtrate is diluted with water (100 mL) then extracted with toluene (2×100 mL). The combined organic extract is dried over magnesium sulfate and then the solvent is removed under reduced pressure to give a brown mobile oil. This oil is subjected by flash chromatography on silica gel (dichloromethane as eluent) and the eluent evaporated under reduced pressure to give cyclopentyl 3-cyclopentyloxy-4-nitrobenzoate (10.2 g, 81.6%) as a yellow solid m.p. 45.5-46.5° C. [Elemental analysis: C,63.7; H,6.66; N,4.37%; calculated: C,63.93; H,6.63; N, 4.39%].
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.O1CCCC1.[S:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[N:7]1([CH2:6][C:5]2[CH:13]=[CH:14][C:2]([NH:1][CH:23]3[CH2:24][CH2:25][S:20][CH2:21][CH2:22]3)=[CH:3][CH:4]=2)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1
Reactant: O=C1CCSCC1
Reactant: Nc1ccc(CN2CCOCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: c1cc(NC2CCSCC2)ccc1CN1CCOCC1
Reaction time: 8 h

Procedure:
A flask containing 4-(4-aminobenzyl)morpholine from Preparation No. 22 (0.48 g) is treated with tetrahydrofuran (10 mL) and terahydrothiopyran-4-one (0.35 gm) under an argon atmosphere. The solution is treated with acetic acid (0.20 mL) followed by sodium triacetoxyborohydride (0.80 g). After stirring overnight, the mixture is concentrated under reduced pressure. The residue is partitioned between dichloromethane and dilute aqueous sodium hydroxide. The aqueous is back-extracted with dichloromethane. The combined organic layers are washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue is purified by flash column chromatography on silica eluting with 2% to 6% methanol in dichloromethane and then by recrystallization from cyclohexane to afford 0.53 g of N-[4-(4-morpholinylmethyl)phenyl]tetrahydro-2H-thiopyran-4-amine as a tan solid.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH:12]([F:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])(=O)=O)=CC=1.[CH2:20]([C:28]1[CH:29]=[N:30][C:31]([C:34]2[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=2)=[N:32][CH:33]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[OH-].[Na+].O>C(O)CCC>[CH2:20]([C:28]1[CH:33]=[N:32][C:31]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH2:11][CH:12]([F:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:36][CH:35]=2)=[N:30][CH:29]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCC(F)COS(=O)(=O)c1ccc(C)cc1
Reactant: CCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Solvent: O
Product: CCCCCCCCc1cnc(-c2ccc(OCC(F)CCCCC)cc2)nc1
Reaction time: 5.5 h

Procedure:
0.43 g (1.5 mmol) of the thus obtained (+)-2-fluoroheptyl p-toluenesulfonate and 0.28 g (1.0 mmol) of 5-octyl-2-(4-hydroxyphenyl)pyrimidine were mixed with 0.2 ml of 1-butanol, followed by sufficient stirring. To the solution was quickly added a previously obtained alkaline solution of 0.048 g (1.2 mmol) of sodium hydroxide in 1.0 ml of 1-butanol, followed by 5.5 hours of heat-refluxing. After the reaction, 10 ml of distilled water was added, and the mixture was extracted respectively once with 10 ml of benzene and 5 ml of benzene, followed by drying with an appropriate amount of anhydrous sodium sulfate, distilling-off of the solvent and purification by silica gel column chromatography (chloroform) to obtain 0.17 g (0.43 mmol) of objective (+)-5-octyl-2-[4-(2-fluoroheptyloxy)phenyl]pyrimidine.
Reaction SMILES: C([O:5][C:6](=[O:30])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[C:10]([CH:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[S:20](=[O:28])(=[O:27])[NH:19]2)=[C:9]1[CH3:29])(C)(C)C.[CH2:31](Br)[CH:32]=[CH2:33]>>[CH2:33]([N:19]1[CH:18]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=3)[N:8]([CH2:7][C:6]([OH:5])=[O:30])[C:9]=2[CH3:29])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[S:20]1(=[O:28])=[O:27])[CH:32]=[CH2:31]
Reactant: C=CCBr
Reactant: Cc1c(C2NS(=O)(=O)c3ccccc32)c2cc(Cl)ccc2n1CC(=O)OC(C)(C)C
Product: C=CCN1C(c2c(C)n(CC(=O)O)c3ccc(Cl)cc23)c2ccccc2S1(=O)=O

Procedure:
The title compound was prepared by the method described for example 14 using the product from example 6, step c) and allyl bromide. 1H NMR (DMSO-d6) 13.14 (bs, 1H), 8.00 (d, J=8.7 Hz, 1H), 7.67-7.59 (m, 2H), 7.45 (d, J=8.7 Hz, 1H), 7.06 (d, J=6.3 Hz, 1H), 7.02 (dd, J=1.8, 8.7 Hz, 1H), 6.83 (s, 1H), 5.96 (s, 1H), 5.82-5.69 (m, 1H), 5.14 (d, J=7.5 Hz, 1H), 5.10 (s, 1H), 5.03 (s, 2H), 3.90 (dd, J=4.8, 15.9 Hz, 1H), 3.45-3.36 (m, 1H), 2.37 (s, 3H); MS: ESI (negative): 429, 431 (M−H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]23[O:16][CH2:15][C:12]([CH2:17][CH2:18][CH3:19])([CH2:13][O:14]2)[CH2:11][O:10]3)=[CH:5][CH:4]=1)#[CH:2].[CH3:20][N:21]([CH3:25])[C:22](Cl)=[O:23].[CH3:26][N:27]([CH3:31])[C:28](Cl)=[S:29]>>[CH3:20][N:21]([CH3:25])[C:22](=[O:23])[C:2]#[C:1][C:3]1[CH:4]=[CH:5][C:6]([C:9]23[O:10][CH2:11][C:12]([CH2:17][CH2:18][CH3:19])([CH2:13][O:14]2)[CH2:15][O:16]3)=[CH:7][CH:8]=1.[CH3:26][N:27]([CH3:31])[C:28](=[S:29])[C:2]#[C:1][C:3]1[CH:4]=[CH:5][C:6]([C:9]23[O:10][CH2:11][C:12]([CH2:17][CH2:18][CH3:19])([CH2:13][O:14]2)[CH2:15][O:16]3)=[CH:7][CH:8]=1
Reactant: CN(C)C(=S)Cl
Reactant: C#Cc1ccc(C23OCC(CCC)(CO2)CO3)cc1
Reactant: CN(C)C(=O)Cl
Product: CCCC12COC(c3ccc(C#CC(=O)N(C)C)cc3)(OC1)OC2
Product: CCCC12COC(c3ccc(C#CC(=S)N(C)C)cc3)(OC1)OC2

Procedure:
N,N-Dimethyl-3-[4-(4-n-propyl-2,6,7-trioxabicyclo[2,2,2]oct-1-yl)phenyl]-prop-2-ynamide and N,N-dimethyl-3-[4-(4-n-propyl-2,6,7-trioxabicyclo[2,2,2]oct-1-yl)phenyl]-prop-2-ynthioamide were prepared using similar methodology from 1-(4-ethynylphenyl)-4-n-propyl-2,6,7-trioxabicyclo[2,2,2]octane and dimethylcarbamoyl chloride and dimethylthiocarbamoyl chloride respectively.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:10][CH:9]=[CH:8][C:7]([C:11]([OH:13])=O)=[CH:6]1)(=[O:3])[CH3:2].C(N(CC)CC)C.COC(Cl)=O.[CH2:26]([NH2:29])[CH2:27][CH3:28]>ClCCl>[CH2:26]([NH:29][C:11]([C:7]1[CH:8]=[CH:9][CH2:10][CH:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:6]=1)=[O:13])[CH2:27][CH3:28]
Reactant: CCCN
Reactant: CC(=O)NC1C=C(C(=O)O)C=CC1
Agent: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCNC(=O)C1=CC(NC(C)=O)CC=C1

Procedure:
A solution of 180 mg (1 m mole) of 3-acetamido-1,5-cyclohexadiene carboxylic acid in 5 ml of dichloromethane is treated with 202 mg (2 m mole) of triethylamine and 94 mg (1 m mole) of methylchloroformate. After 30 minutes at 25° C. the solution is treated with 60 mg (1 m mole) of n-propylamine for 1 hour at 25° C. after which the solution is diluted with dichloromethane and, washed with water, dried and evaporated to give N-propyl-3-acetamido-1,5-cyclohexadienecarboxamide.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:11]([O:13][C:14](=[O:23])[C:15]1[C:20](F)=[CH:19][N:18]=[C:17]([Br:22])[CH:16]=1)[CH3:12].O>O1CCCC1>[CH2:11]([O:13][C:14](=[O:23])[C:15]1[C:20]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:19][N:18]=[C:17]([Br:22])[CH:16]=1)[CH3:12]
Reactant: CCOC(=O)c1cc(Br)ncc1F
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(Br)ncc1OCc1ccccc1
Reaction time: 0.08 h
Yield: 61.1 %

Procedure:
To a solution of benzylalcohol (1.5 g) in tetrahydrofuran (30 mL) was added sodium hydride (55%, 0.3 g) under ice cooling, and this mixture was stirred at same temperature for 5 minutes. To this reaction mixture was added a solution of 2-bromo-5-fluoroisonicotinic acid ethyl ester (2.9 g) in tetrahydrofuran (30 mL), and this mixture was stirred at room temperature for 2 hours. This reaction mixture was poured into water, and this mixture was extracted with ethyl acetate. This organic layer was washed with water and brine, dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane) to give the title compound (2.4 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[C:16]([OH:19])[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[C:4]([F:22])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:30][CH2:31][CH2:32][Cl:33].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[C:16]([O:19][CH2:30][CH2:31][CH2:32][Cl:33])[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[C:4]([F:22])[CH:3]=1
Reactant: ClCCCBr
Reactant: COc1cc2ncnc(Nc3ccc(Br)cc3F)c2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2ncnc(Nc3ccc(Br)cc3F)c2cc1OCCCCl
Temperature: 40 °C
Reaction time: 8 h
Yield: 82.89 %

Procedure:
To a suspension of 4-((4-bromo-2-fluorophenyl)amino)-7-methoxyquinazolin-6-ol (2.17 g), K2CO3 (0.99 g) in DMF (20 mL) was added 1-bromo-3-chloropropane (0.71 mL) at rt, the mixture was stirred at 40° C. overnight. The reaction mixture was poured into water and filtered. The filter residue was purified by a silica gel column chromatography (eluting agent: 3:1 (v/v) PE/EA) to give the title compound as a white solid (2.18 g, 82.89%).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([Cl:12])[CH:6]=1.[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.[K].C(Cl)(Cl)Cl>CN(C=O)C>[Cl:12][C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([Cl:11])[CH:8]=1)[O:4][CH2:3][CH2:2][N:17]1[C:13](=[O:23])[C:14]2[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:16]1=[O:18]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Clc1cc(Cl)cc(OCCBr)c1
Agent: [K]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCOc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Yield: 73.6 %

Procedure:
A solution of 1-(2-bromo-ethoxy)-3,5-dichloro-benzene (2.41 g, 8.93 mmol) and potassium phthalimide (2.00 g, 10.64 mmol) in DMF (7.6 mL) was heated at 85° C. for 1 h. The reaction was cooled to room temperature and chloroform was added. The organic solution was washed with 0.2 N aqueous NaOH followed by water. The organic solution was dried (Na2SO4), filtered, and concentrated. The residue was suspended in Et2O and the solid was collected by filtration to provide the title compound (2.21 g). 1HNMR (400 MHz, CDCl3) δ 7.82 (m, 2H), 7.77 (m, 2H), 6.89 (m, 1H), 6.88 (m, 2H), 4.16 (t, 2H), 4.05 (t, 2H); MS 336 (M+).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][CH:9]=[N:8][C:7]=1[CH:11]([CH3:13])[CH3:12])=O)C.CC(C[AlH]CC(C)C)C.O>C1(C)C=CC=CC=1>[OH:3][CH2:4][C:6]1[S:10][CH:9]=[N:8][C:7]=1[CH:11]([CH3:13])[CH3:12]
Reactant: CCOC(=O)c1scnc1C(C)C
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)c1ncsc1CO
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 5.9 g (30 mmol) of 4-isopropyl-thiazole-5-carboxylic acid ethyl ester (J. Chem. Soc. Perkin Trans 1, 1982:159-164) in toluene (100 mL) was cooled in an ice bath under nitrogen and treated dropwise with DIBAL (150 mL of 1.0 M; 150 mmol). The mixture was stirred at low temperature for 45 minutes and then allowed to warm to room temperature overnight. H2O was added cautiously, and the mixture was extracted with EtOAc (3×200 mL). The combined extracts were washed with brine, dried (MgSO4), and concentrated. The crude 5-(hydroxymethyl)-4-isopropyl-thiazole thus obtained was used as is in the next step.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](OC(F)(F)F)[CH:10]=2)[N:5]=[C:4]([N:17]2[CH2:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[S:20](=[O:29])(=[O:28])[CH2:19][CH2:18]2)[CH:3]=1.C[O:31][C:32]([CH:34]1[CH2:38][CH2:37][NH:36][CH2:35]1)=[O:33].[CH:39](N(CC)C(C)C)(C)C>>[O:29]=[S:20]1(=[O:28])[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[CH2:23][N:17]([C:4]2[CH:3]=[C:2]([N:36]3[CH2:37][CH2:38][CH:34]([C:32]([OH:33])=[O:31])[CH2:35]3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:39])[CH:10]=3)[N:5]=2)[CH2:18][CH2:19]1
Reactant: O=S1(=O)CCN(c2cc(Cl)c3cc(OC(F)(F)F)ccc3n2)Cc2ccccc21
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)C1CCNC1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N3CCC(C(=O)O)C3)c2c1
Temperature: 140 °C
Reaction time: 1.5 h
Yield: 19.8 %

Procedure:
A mixture of 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (500 mg, 1.34 mmol, prepared in analogy to 4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 17-1) and methylpyrrolidine-3-carboxylate (173 mg, 1.34 mmol) and N,N-diisopropylethylamine (346 mg, 2.68 mmol) was heated with stirring in a sealed 10 mL of microwave process vial for 1.5 hours at 140° C. under microwave irradiation. The resulting mixture was purified by preparative HPLC to afford 120 mg of the pure product (yield was 19.8%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:46]=[CH:47][CH:48]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([O:33][CH3:34])=[C:25]([NH:27][S:28]([CH2:31][CH3:32])(=[O:30])=[O:29])[CH:26]=4)[CH:19]=3)[N:14](S(C3C=CC(C)=CC=3)(=O)=O)[CH:13]=2)[C:8]([CH3:45])=[N:7]1.[OH-].[Li+]>C1COCC1.CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:46]=[CH:47][CH:48]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([O:33][CH3:34])=[C:25]([NH:27][S:28]([CH2:31][CH3:32])(=[O:30])=[O:29])[CH:26]=4)[CH:19]=3)[NH:14][CH:13]=2)[C:8]([CH3:45])=[N:7]1
Reactant: CCS(=O)(=O)Nc1cc(-c2cnc3c(c2)c(-c2c(C)nn(Cc4cccc(F)c4)c2C)cn3S(=O)(=O)c2ccc(C)cc2)ccc1OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCS(=O)(=O)Nc1cc(-c2cnc3[nH]cc(-c4c(C)nn(Cc5cccc(F)c5)c4C)c3c2)ccc1OC
Yield: 16.5 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, N-(5-(3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-methoxy phenyl)ethane sulfonamide (200 mg, 0.291 mmol) was hydrolyzed by lithium hydroxide (36 mg, 0.87 mmol) in THF/Methanol/Water (10/3/2 ml) to give 25 mg (16.5% yield) after purification by flash chromatography. 1H NMR (DMSO-d6, 300 MHz): δ 11.9 (s, 1H), 9.02 (s, 1H), 8.45 (s, 1H), 7.79 (s, 1H), 7.54-7.49 (m, 3H), 7.19-7.0 (m, 4H), 5.33 (s, 2H), 3.86 (s, 3H), 3.06-3.04 (m, 2H0, 2.17-2.13 (d, 6H), 1.27-1.23 (t, 3H). MS: m/z=534.8 (M+1), HPLC: 90.27% (Method-B).
Reaction SMILES: [C:1]([C:3]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)([CH3:8])[CH2:4][CH:5]1[CH2:7][CH2:6]1)#[N:2].C(Cl)(=O)C(Cl)=O.O1CCCC1.[NH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:52][CH3:53])=[C:34]([CH:51]=1)[O:35][C:36]1[CH:37]=[CH:38][C:39]2[N:40]([CH:42]=[C:43]([NH:45][C:46]([CH:48]3[CH2:50][CH2:49]3)=[O:47])[N:44]=2)[N:41]=1>CN(C)C=O.CN1CCCC1=O>[C:1]([C:3]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH:29][C:30]1[CH:31]=[CH:32][C:33]([O:52][CH3:53])=[C:34]([O:35][C:36]2[CH:37]=[CH:38][C:39]3[N:40]([CH:42]=[C:43]([NH:45][C:46]([CH:48]4[CH2:50][CH2:49]4)=[O:47])[N:44]=3)[N:41]=2)[CH:51]=1)=[O:14])([CH3:8])[CH2:4][CH:5]1[CH2:6][CH2:7]1)#[N:2]
Reactant: CC(C#N)(CC1CC1)c1cccc(C(=O)O)c1
Reactant: COc1ccc(N)cc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)c2cccc(C(C)(C#N)CC3CC3)c2)cc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Yield: 48.7 %

Procedure:
Using 3-(1-cyano-2-cyclopropyl-1-methylethyl)benzoic acid (70 mg, 0.31 mmol), oxalyl chloride (33 μL, 0.38 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (2.0 mL), N-[6-(5-amino-2-methoxyphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (86 mg, 0.25 mmol) and N-methylpyrrolidone (2.0 mL) as starting materials and in the same manner as in Example 335, the title compound (67 mg, 48%) was obtained as a white powder.
Reaction SMILES: [CH2:1]([NH:8][NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.Br[CH2:23][C:24]([O:26]CC)=[O:25]>CCCC[N+](CCCC)(CCCC)CCCC.[I-].CCN(CC)CC>[NH2:8][CH2:23][C:24]([OH:26])=[O:25].[CH2:1]([NH:8][NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: c1ccc(CNNCc2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NCC(=O)O
Temperature: 60 °C
Reaction time: 7 h

Procedure:
To a solution of dibenzylhydrazine (5.30 g, 25.0 mmol) and THF (50 mL) and TBAI (0.46 g, 1.25 mmol) was added BrCH2CO2Et (2.64 mL, 23.8 mmol) and Et3N (3.32 mL, 23.8 mmol). The reaction mixture was stirred at 60° C. for 7 hours, an additional 0.3 eq. of base and electrophile were added (BrCH2CO2Et, 0.83 mL, 7.5 mmol and Et3N, 1.0 mL, 7.5 mmol). The reaction mixture was held overnight at R/T, an additional 0.3 eq. of each reagent was added and the reaction mixture was stirred at 60° C. for 4 more hours. The reaction mixture was partitioned with CH2Cl2, and the isolated organic fraction was washed with brine three (3 times), dried over Na2SO4, and concentrated in vacuo to afford 7.21 g, 24.2 mmol, (97%) of a crude oil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([O:11][Si:12]([CH3:15])([CH3:14])[CH3:13])([CH:9]=[CH2:10])[CH2:6][C:7]#[CH:8].[CH2:16]([SnH:20]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19]>>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([O:11][Si:12]([CH3:14])([CH3:13])[CH3:15])([CH:9]=[CH2:10])[CH2:6]/[CH:7]=[CH:8]/[Sn:20]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: C#CCC(C=C)(CCCCl)O[Si](C)(C)C
Reactant: CCCC[SnH](CCCC)CCCC
Product: C=CC(C/C=C/[Sn](CCCC)(CCCC)CCCC)(CCCCl)O[Si](C)(C)C
Temperature: 140 °C
Reaction time: 0.05 h
Yield: 80 %

Procedure:
A mixture of 7-chloro-4-trimethylsilyloxy-4-vinyl-1-heptyne (17 g, 0.07 mol) and 20.7 g (0.71 mol) of tri-n-butylstannane and 150 mg of azobisisobutrylnitrile (AIBN) is stirred under argon in a 140° oil bath behind a safety shield. After 3 minutes an exotherm occurs and the mixture is maintained at 140° C. for 1.5 hr. After cooling, air is admitted and the unreacted tri-n-butylstannane is removed by distillation via Kuglerohr (140°, 0.5-0.3 mm) to give a very light yellow oil (30 g). This oil consists of a mixture of the E and Z isomers.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:41])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([S:30]([N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)(=[O:32])=[O:31])=[CH:26][C:25]=3[O:38][CH2:39][CH3:40])=[N:9]2)=[CH:4][CH:3]=1.[N:42]1([CH2:48][C:49]([N:51]2[CH2:55][CH2:54][CH2:53][CH2:52]2)=[O:50])[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([CH3:41])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21]([N:45]3[CH2:44][CH2:43][N:42]([CH2:48][C:49]([N:51]4[CH2:52][CH2:53][CH2:54][CH2:55]4)=[O:50])[CH2:47][CH2:46]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([S:30]([N:33]4[CH2:34][CH2:35][CH2:36][CH2:37]4)(=[O:31])=[O:32])=[CH:26][C:25]=3[O:38][CH2:39][CH3:40])=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(CN1CCNCC1)N1CCCC1
Reactant: CCOc1cc(S(=O)(=O)N2CCCC2)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(S(=O)(=O)N2CCCC2)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCCC2)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(pyrrolidine-1-sulfonyl)-phenyl]-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 2-piperazin-1-yl-1-pyrrolidin-1-yl-ethanone (Aldrich) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 30% of 1:1 ethanol/acetonitrile in carbon dioxide). HR-MS (ES, m/z) calculated for C40H48N6O5SCl2 [(M+H)+] 795.2857, observed 795.2851.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[S:20]1[CH:24]=[C:23]([CH:25]=O)[N:22]=[CH:21]1>>[S:20]1[CH:24]=[C:23]([CH2:25][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)[N:22]=[CH:21]1
Reactant: O=Cc1cscn1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4cscn4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 1,3-thiazole-4-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(1,3-thiazol-4-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].OCC[O:11][CH2:12][CH2:13][N:14]1[CH2:19][CH:18]2[CH2:20][CH:15]1[CH2:16][CH2:17]2>CCOCC>[C:5]([O:4][CH2:1][CH2:2][O:11][CH2:12][CH2:13][N:14]1[CH2:19][CH:18]2[CH2:20][CH:15]1[CH2:16][CH2:17]2)(=[O:7])[CH3:6]
Reactant: OCCOCCN1CC2CCC1C2
Reactant: CC(=O)OC(C)=O
Solvent: CCOCC
Product: CC(=O)OCCOCCN1CC2CCC1C2
Reaction time: 3 h
Yield: 52 %

Procedure:
198 g (1.94 moles) of acetic anhydride are added to 286 g (1.55 moles) of N-(2-hydroxyethoxyethyl-)2-azabicyclo[2.2.1]heptane (XV) in the absence of moisture such that the temperature is maintained between 50° and 60° C. The mixture is kept boiling for three hours. After cooling 200 ml of ether are added. The product is neutralized with soda solution, is washed until it is neutral, and--after the ether is withdrawn--it is distilled under high vacuum. The main fraction weighs 185 g and contains 99% (XXI). This corresponds to a yield of 52% of theoretical.