Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:5]=1[NH2:13].[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17]([C:25](O)=[O:26])[N:16]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[NH2:13].[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:25]([C:17]2[N:16]=[CH:15][C:24]3[C:19]([CH:18]=2)=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:26])[C:5]=1[NH2:13]
Reactant: O=C(O)c1cc2ccccc2cn1
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COC(=O)c1cccc(N)c1N
Product: COC(=O)c1cccc(NC(=O)c2cc3ccccc3cn2)c1N

Procedure:
The 2,3-diamino-benzoic acid methyl ester was synthesized from 2-amino-3-nitro-benzoic acid methyl ester (2.0 g, 10.2 mmol) as described in general procedure C. 1.7 g (10.2 mmol) of the above synthesized diamine was reacted with 1.7 g (10.0 mmol) of isoquinoline-3-carboxylic acid and 4.6 g (12.0 mmol) of HBTU as described in general procedure A to provide 2-amino-3-[(isoquinoline-3-carbonyl)-amino]-benzoic acid methyl ester. LCMS: 322 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:34](=[O:40])OC(Cl)(Cl)Cl)Cl.[N:42]1([CH2:48][CH2:49][NH2:50])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:34]([NH:50][CH2:49][CH2:48][N:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)=[O:40])=[CH:18][CH:17]=1
Reactant: NCCN1CCCCC1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Oc3ccc(NC(=O)NCCN4CCCCC4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml) to prepare a solution. A solution of triphosgene (151 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, 2-piperidino-1-ethanamine (65 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (84 mg, yield 55%).
Reaction SMILES: [CH2:1]([OH:13])[C@H:2]([OH:12])[C@@H:3](O)[C@H:4]([OH:10])[C:5]([C:7]([OH:9])=[O:8])=[O:6].Cl.O>[Cl-].C[N+](C)(C)CCCCCCCCCCCCCCCC.C(OCCCC)CCC>[O:8]=[C:7]1[O:9][C@H:3]([C@H:2]([CH2:1][OH:13])[OH:12])[C:4]([OH:10])=[C:5]1[OH:6]
Reactant: O=C(O)C(=O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CCCCOCCCC
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of 2-keto-L-gulonic acid (125 g, 0.584 mol, content: 90.7%, water: 8.5%) and trimethylcetylammonium chloride (0.084 g) was stirred in dibutyl ether (500 ml), and 36% conc. hydrochloric acid (18.0 g) was added. At this time, the amount of water in the reaction system was calculated as 2.1 mol per mol of 2-keto-L-gulonic acid. This mixture was stirred at 60° C. for 1 hour, a solution of hydrogen chloride gas (17.2 g) in dibutyl ether (91 g) was added, and the mixture was stirred at the same temperature for 5 hours. Then, about 900 g of the solvent was distilled away under reduced pressure while continuously introducing toluene (1000 ml). The residue was filtered to give crude crystals of L-ascorbic acid. The crude crystals were dissolved in water. Quantitative analysis of the solution by HPLC showed that the solution contained L-ascorbic acid (92.4 g, yield: 90.0%) and no residual starting compound, i.e. 2-keto-L-gulonic acid.
Reaction SMILES: [C:1]([CH:4]([C:12](=O)[CH3:13])[CH:5]([C:9](=O)[CH3:10])[C:6](=O)[CH3:7])(=O)[CH3:2].[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:24][CH2:25][CH3:26])=[C:20]([CH2:22][OH:23])[CH:21]=1.[NH2:27][NH2:28]>>[CH2:25]([O:24][C:19]1[CH:18]=[CH:17][C:16]([N:15]2[C:1]([CH3:2])=[C:4]3[C:5]([C:9]([CH3:10])=[N:27][N:28]=[C:12]3[CH3:13])=[C:6]2[CH3:7])=[CH:21][C:20]=1[CH2:22][OH:23])[CH3:26]
Reactant: CC(=O)C(C(C)=O)C(C(C)=O)C(C)=O
Reactant: CCOc1ccc(N)cc1CO
Reactant: NN
Product: CCOc1ccc(-n2c(C)c3c(C)nnc(C)c3c2C)cc1CO

Procedure:
Utilizing the general procedure outlined in Example 48, 1,1,2,2-tetraacetylethane (308 mg, 1.56 mol), (5-amino-2-ethoxy-phenyl)-methanol (250 mg, 1.0 mmol) and hydrazine (100 μL) reacted to give [2-ethoxy-5-(1,4,5,7-tetramethyl-pyrrolo[3,4-d]pyridazin-6-yl)-phenyl]-methanol as yellow solid: 1H NMR (CDCl3, 500 MHz) δ 7.24 (s, 1H), 7.08-7.01 (m, 2H), 4.81 (s, 2H), 4.18 (q, 2H), 2.77 (s, 6H), 2.43 (s, 6H), 1.51 (t, 3H); MS (ESI) 326 (M+H)+.
Reaction SMILES: [CH2:1]([O:19][CH2:20][CH:21]([OH:32])[CH2:22][O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C([Zn][CH2:36][CH3:37])C.ICI.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl.CCCCCC>[CH2:24]([O:23][CH2:22][CH:21]([OH:32])[CH2:20][O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]1[CH2:10][CH:11]1[CH2:12][CH:13]1[CH2:14][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:36][CH3:37])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCOCC(O)COCCCCCCCC
Reactant: CC[Zn]CC
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ICI
Solvent: ClCCl
Solvent: CCCCCC
Product: CCCCCCCCOCC(O)COCCCCCCCCC1CC1CC1CC1CCCCC
Reaction time: 8 h
Yield: 97 %

Procedure:
A solution of 1-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]-3-(octyloxy)propan-2-ol in DCM (166 ml) in a 1 L flask under nitrogen was cooled in an ice/IPA bath (−15° C.) and then 1 M diethylzinc in hexane (199 ml, 199 mmol) added, followed by diiodomethane (24.05 ml, 298 mmol). The mixture was allowed to stir in the cooling bath overnight to gradually come up to room temperature. Reaction was quenched by addition of excess saturated ammonium chloride. Washed reaction into 2 L separatory funnel with hexane and water and added excess hexane, shook vigorously. Discarded lower aqueous layer, dried organic layer with sodium sulfate and evaporated to 1-(octyloxy)-3-[(8-{2-[(2-pentylcyclopropyl)methyl]cyclopropyl}octyl)oxy]propan-2-ol (15.5 g, 32.2 mmol, 97% yield) as a yellow oil. Material was used with no further purification. MS (ESI): 481 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:3]=1[C:4]#[N:5].Br[CH2:12][CH2:13][CH2:14][N:15]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[O:25].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[O:25]=[C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:23](=[O:24])[N:15]1[CH2:14][CH2:13][CH2:12][O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[C:3]=1[C:4]#[N:5]
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: N#Cc1c(O)cccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1c(F)cccc1OCCCN1C(=O)c2ccccc2C1=O
Yield: 94.8 %

Procedure:
2-fluoro-6-hydroxybenzonitrile (411 mg, 3 mmol), 2-(3-bromopropyl)isoindoline-1,3-dione (885 mg, 3.3 mmol), and potassium carbonate (1.24 g, 9 mmol) were heated overnight at 70° C. in N,N-dimethylformamide (6 mL). The mixture was cooled, diluted with water, and the precipitate filtered and dried to give 922 mg of the title compound as a white solid. 1H NMR (DMSO-d6) δ 7.79-7.87 (m, 4H), 7.69 (td, J=8.6, 6.9 Hz, 1H), 7.01-7.07 (m, 2H), 4.22 (t, J=5.8 Hz, 2H), 3.79 (t, J=6.6 Hz, 2H), 2.11 (quin, J=6.1 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].[F:17][C:18]([F:28])([F:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][NH2:26].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.CN(C=O)C>[F:17][C:18]([F:27])([F:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][NH:26][C:14]([CH:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]1)=[O:16]
Reactant: NCc1ccccc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NCc2ccccc2C(F)(F)F)CC1
Reaction time: 8 h
Yield: 86.5 %

Procedure:
To a suspension of 1-{[(1,1-dimethylethyl)oxy]carbonyl}-4-piperidinecarboxylic acid (8.00 g, 34.9 mmol, 1.00 equiv) in CH2Cl2/DMF (7/1, 350 ml) at room temperature, 1-[2-(trifluoromethyl)phenyl]methanamine (4.90 mL, 34.9 mmol, 1.00 equiv), EDCI (8.03 g, 41.9 mmol, 1.20 equiv), HOBT (5.66 g, 41.9 mmol, 1.20 equiv), and diisopropylethylamine (DIEA, 18.3 ml, 105 mmol, 3.00 equiv) were added. Stirring was continued overnight at room temperature. The reaction mixture was partitioned between water and ethyl acetate (1:1, 600 ml). The product was extracted three times with ethyl acetate (100 ml). The organic extracts were combined and washed successively with saturated ammonium chloride (200 ml), water (200 ml), and saturated sodium chloride (200 ml). The ethyl acetate solution was dried with Na2SO4, filtered, and concentrated under reduced pressure to afford 11.67 g (87%) of the title compound. MS (ES+): m/e 408.9 [M+Na]+.
Reaction SMILES: [C:1]([N:5]([CH3:32])[C:6]([C:8]1[N:12]2[CH2:13][CH2:14][C:15]3[C:20]([C:11]2=[C:10]([C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)[N:9]=1)=[CH:19][C:18]([O:21][CH2:22][CH2:23][NH2:24])=[C:17]([O:25][CH3:26])[CH:16]=3)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:34]([O:36][CH3:37])=[O:35]>>[CH3:37][O:36][C:34](=[O:35])[NH:24][CH2:23][CH2:22][O:21][C:18]1[CH:19]=[C:20]2[C:15]([CH2:14][CH2:13][N:12]3[C:8]([C:6](=[O:7])[N:5]([C:1]([CH3:3])([CH3:4])[CH3:2])[CH3:32])=[N:9][C:10]([C:27]4[S:28][CH:29]=[CH:30][CH:31]=4)=[C:11]32)=[CH:16][C:17]=1[O:25][CH3:26]
Reactant: COC(=O)Cl
Reactant: COc1cc2c(cc1OCCN)-c1c(-c3cccs3)nc(C(=O)N(C)C(C)(C)C)n1CC2
Product: COC(=O)NCCOc1cc2c(cc1OC)CCn1c(C(=O)N(C)C(C)(C)C)nc(-c3cccs3)c1-2

Procedure:
Coupling of the product of example 31 (50 mg) with methyl chloroformate (11 μl) was performed according to the method described in example 32.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][N:8]2[CH2:12][CH:11]([CH2:13][CH2:14][CH3:15])[CH2:10][C:9]2=[O:16])=[C:5]([C:17]#[N:18])[N:4]=[CH:3]1.C[OH:20]>O.[OH-].[Na+]>[CH3:1][N:2]1[C:6]([CH2:7][N:8]2[CH2:12][CH:11]([CH2:13][CH2:14][CH3:15])[CH2:10][C:9]2=[O:16])=[C:5]([C:17]([NH2:18])=[O:20])[N:4]=[CH:3]1
Reactant: CCCC1CC(=O)N(Cc2c(C#N)ncn2C)C1
Reactant: CO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCC1CC(=O)N(Cc2c(C(N)=O)ncn2C)C1
Temperature: 25 °C
Yield: 43 %

Procedure:
In a 25 ml, three-necked flask fitted with a magnetic stirrer, a reflux condenser and a dropping funnel under inert atmosphere, 150 mg (0.61 mmol) of 1-methyl-5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazole-4-carbonitrile 122 is dissolved in MeOH (9 ml) with water (3 ml) and aqueous NaOH (35% w/w, 30 μl). The reaction mixture is refluxed 72 h, cooled down to room temperature and the solvent is evaporated to dryness. The crude reaction mixture is purified by preparative chromatography on silicagel (CH2Cl2/MeOH/NH4OH: 96/3.6/0.4 (v/v/v/v)) and recristallized in CH2Cl2/hexane to afford 1-methyl-5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazole-4-carboxamide 123 (0.07 g).
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH2:10][CH2:11][OH:12].[H][H].[N+:15]([C:18]1[CH:23]=[CH:22][C:21](F)=[CH:20][CH:19]=1)([O-:17])=[O:16]>CN(C=O)C>[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([O:12][CH2:11][CH2:10][O:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=2)=[CH:20][CH:19]=1)([O-:17])=[O:16]
Reactant: OCCOc1ccccn1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCCOc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of sodium hydride (21.6 mg, 0.90 mmol) in anhydrous DMF (0.5 mL), 2-(pyridin-2-yloxy)-ethanol (100 mg, 0.72 mmol) in DMF (1.5 mL) was added drop-wise under a N2 atmosphere. Once hydrogen gas evolution ceased, 4-nitrofluorobenzene (102 mg, 0.72 mmol, 76 μL) was added drop-wise to the yellow suspension. The resultant red-orange solution was allowed to stir at rt for 18 h. Upon completion, distilled water (2 mL) was added and the bright yellow solid precipitate was filtered, washed with distilled water, and dried in vacuo to give 2-[2-(4-nitrophenoxy)ethoxy]pyridine as a pale yellow solid. 1H NMR (d6-DMSO, 400 MHz): δ 8.21 (ddd, J=5.6, 3.6, 3.6 Hz, 2H), 7.72 (ddd, J=9.2, 7.2, 2.0 Hz, 1H), 7.21 (ddd, J=5.6, 3.6, 3.6 Hz, 1H), 7.01 (ddd, J=7.0, 4.8, 0.8 Hz, 1H), 6.86 (ddd, J=8.4, 0.8, 0.8 Hz, 1H), 4.62 (m, 2H), 4.49 (m, 2H). MS(ES+): m/z 261 [MH+].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]=[C:21]([Cl:23])[N:20]=[C:19]3[C:15]=2[N:16]=[C:17](Cl)[N:18]3[CH3:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(=[O:28])C.[Na+].C(=O)(O)[O-].[Na+].Cl>CS(C)=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]=[C:21]([Cl:23])[N:20]=[C:19]3[C:15]=2[NH:16][C:17](=[O:28])[N:18]3[CH3:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: Cn1c(Cl)nc2c(N3CCN(C(=O)OC(C)(C)C)CC3)nc(Cl)nc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cn1c(=O)[nH]c2c(N3CCN(C(=O)OC(C)(C)C)CC3)nc(Cl)nc21
Temperature: 120 °C
Reaction time: 22 h
Yield: 21 %

Procedure:
4-(2,8-Dichloro-9-methyl-9H-purin-6-yl)piperazine-1-carboxylic acid t-butyl ester (1.0 g) was dissolved in dimethylsulfoxide (10 mL), and then sodium acetate (425 mg) and sodium bicarbonate (326 mg) were added to this solution. After stirring the reaction solution at 120° C. for 22 hours, 1 N aqueous hydrochloric acid (5.0 mL) and water (80 mL) were added to the reaction solution, and this was extracted with ethyl acetate. The obtained organic layer was washed sequentially with water and saturated brine, and dried over anhydrous magnesium sulfate. The organic layer was then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (200 mg).
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1OC)[C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)=[O:7].[C:23]1(OC)[C:24](=[CH:27][CH:28]=[CH:29][CH:30]=1)OC.[Cl-].[Al+3].[Cl-].[Cl-].C1(C2C=CC=CC=2)C=CC(C(Cl)=O)=CC=1>>[CH3:17][O:16][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][C:11]=1[O:14][CH3:15])[C:6]([C:5]1[CH:4]=[CH:3][C:20]([C:23]2[CH:24]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:19][CH:18]=1)=[O:7]
Reactant: COc1ccc(C(=O)c2ccc(OC)c(OC)c2)cc1OC
Reactant: COc1ccccc1OC
Agent: O=C(Cl)c1ccc(-c2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)c2ccc(-c3ccccc3)cc2)cc1OC

Procedure:
3,4-Dimethoxy-4′-phenylbenzophenone was prepared analogously to 3,4,3′,4′-tetra-methoxybenzophenone using veratrole (2.4 g, 17 mmol), aluminum chloride (2.5 g, 19 mmol) and 4-biphenylcarbonyl chloride (4 g, 18 mmol) with a reaction time of 24 hours at room temperature. The crude product was purified by flash column chromatography (silica gel, 2% ethyl acetate/methylene chloride) to afford 3.86 g (70%) of the product as a white solid: mp 103-104° C.; 1H NMR (CDCl3) δ7.88-7.84 (m, 2 H), 7.73-7.64 (m, 4 H), 7.52-7.40 (m, 5 H), 6.93-6.90 (m, 1 H), 3.97 (s, 3 H), 3.96 (s, 3 H); 13C NMR (CDCl3) δ194.9, 152.9, 148.9, 144.5, 139.8, 136.8, 130.2, 130.2, 128.8, 127.9, 127.1, 126.7, 125.2, 112.0, 109.7, 55.9, 55.9; Anal. Calcd for C21H18O3. Theoretical: C, 79.23; H, 5.70. Found: C, 78.91; H, 5.87.
Reaction SMILES: C([Li])CCC.[S:6]1[C:10]([C:11]2[N:12]3[CH2:18][CH2:17][N:16]=[C:13]3[S:14][CH:15]=2)=[CH:9][C:8]2[CH:19]=[CH:20][CH:21]=[CH:22][C:7]1=2.[CH3:23][S:24]SC.[Cl-].[NH4+]>O1CCCC1>[S:6]1[C:10]([C:11]2[N:12]3[CH2:18][CH2:17][N:16]=[C:13]3[S:14][C:15]=2[S:24][CH3:23])=[CH:9][C:8]2[CH:19]=[CH:20][CH:21]=[CH:22][C:7]1=2
Reactant: C1=C(c2cc3ccccc3s2)N2CCN=C2S1
Reactant: CSSC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CSC1=C(c2cc3ccccc3s2)N2CCN=C2S1
Temperature: -70 °C
Reaction time: 0.42 h

Procedure:
n-Butyllithium (2.5 M solution in hexanes; 4.0 ml) was added dropwise under nitrogen at −70° C. to a stirred solution of 3-(benzo[b]thiophen-2-yl)-5,6-dihydroimidazo[2,1-b]thiazole (2.58 g; prepared in a manner similar to that described in Example 15) in tetrahydrofuran (40 ml), then the mixture was stirred at −70° C. for 25 minutes. Dimethyl disulphide (0.9 ml) was added, the mixture was stirred at ambient temperature for 2 hours, then it was poured into saturated aqueous ammonium chloride solution (200 ml). The product was extracted into ethyl acetate (300 ml), then the extract was washed with water (200 ml) and saturated aqueous sodium chloride solution (2×100 ml), dried (Na2SO4), and the solvents were removed in vacuo. The residue was purified by flash chromatography over silica using a 19:1 mixture of ethyl acetate and methanol as eluant. Appropriate fractions were combined and the solvents removed in vacuo to give 3-(benzo[b]thiophen-2-yl)-2-(methylthio)-5,6-dihydroimidazo[2,1-b]thiazole (0.79 g) as a yellow solid, m.p. 95-97° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([OH:18])[CH2:9][NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.Cl[CH2:20][C:21](Cl)=[O:22].C(N(CC)CC)C.NC(O)C.C[O-].[Na+]>C1(C)C=CC=CC=1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:9][N:10]([CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:21](=[O:22])[CH2:20][O:18]2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCl
Reactant: O[C@H](CNCc1ccccc1)c1ccc(F)cc1
Agent: CC(N)O
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C1CO[C@@H](c2ccc(F)cc2)CN1Cc1ccccc1
Temperature: 2 °C
Reaction time: 2 h
Yield: 108.6 %

Procedure:
To a suspension of (1S)-1-(4-fluorophenyl)-2-(benzylamino)ethanol (22.0 g, 89.69 mmol) in toluene (100 mL) was added dropwise over 1 hr a solution of chloroacetyl chloride (9.3 mL, 116.6 mmol) in toluene (30 mL) at 5-15° C. After stirring for 2 hrs, a solution of triethylamine (17.4 mL, 123.7 mmol) in toluene (20 mL) was added dropwise over 15 min to the mixture at 10-15° C. The mixture was stirred for 17 hrs at room temperature. After HPLC analysis to confirm a disappearance of the aminoethanol, the mixture was cooled to 2° C., and sodium methoxide (52 g, 269.07 mmol, 28% methanol solution) was added dropwise over 15 min. The mixture was stirred at 2-5° C. for 9 hrs, and water (60 mL) was added. The organic layer was separated and washed successively with 0.5N hydrochloric acid and saturated aqueous sodium hydrogencarbonate solution. The solvent was evaporated under reduced pressure to give (6S)-6-(4-fluorophenyl)-4-(benzyl)morpholin-3-one (27.78 g) as a yellow oil.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][N:15]([C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=4)[CH2:14][CH2:13]3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1.C(N1CCN([C:45]2[CH:46]=C[C:48]3[N:49]([C:51]([C:54](F)(F)[CH:55](F)F)=NN=3)[N:50]=2)CC1)(C1C=CC=CC=1)C1C=CC=CC=1>>[F:25][CH:2]([F:1])[C:3]1[N:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][N:15]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:55][CH2:54][C:51]5[N:49]([CH3:48])[N:50]=[CH:45][CH:46]=5)=[CH:20][CH:19]=4)[CH2:14][CH2:13]3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1
Reactant: FC(F)C(F)(F)c1nnc2ccc(N3CCN(C(c4ccccc4)c4ccccc4)CC3)nn12
Reactant: Oc1ccc(N2CCN(c3ccc4nnc(C(F)F)n4n3)CC2)cc1
Product: Cn1nccc1CCOc1ccc(N2CCN(c3ccc4nnc(C(F)F)n4n3)CC2)cc1

Procedure:
The 4-[4-[3-(difluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]phenol used as starting material was prepared in 95% yield by an analogous method to Example 514, preparation of starting materials, starting from 3-(difluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (obtained as described in General Synthetic Method 1, preparation of starting materials).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([N:10]([CH2:14][CH2:15]Cl)[CH2:11][CH2:12]Cl)[CH:6]=[CH:7][C:8]=1[Cl:9].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[CH2:24][NH2:25]>[OH-].[Na+]>[ClH:9].[CH3:32][O:31][C:27]1[CH:26]=[C:23]([CH:22]=[C:21]([O:20][CH3:19])[C:28]=1[O:29][CH3:30])[CH2:24][N:25]1[CH2:15][CH2:14][N:10]([C:5]2[CH:6]=[CH:7][C:8]([Cl:9])=[C:3]([C:2]([F:18])([F:17])[F:1])[CH:4]=2)[CH2:11][CH2:12]1
Reactant: FC(F)(F)c1cc(N(CCCl)CCCl)ccc1Cl
Reactant: COc1cc(CN)cc(OC)c1OC
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(CN2CCN(c3ccc(Cl)c(C(F)(F)F)c3)CC2)cc(OC)c1OC
Product: Cl
Yield: 148.5 %

Procedure:
3.23 g of N-(3-trifluoromethyl-4-chlorophenyl)-N,N-bis-(2-chloroethyl)-amine and 7 g of 3,4,5-trimethoxybenzyl amine are heated to 120° C. under N2 atmosphere for 8 hours. After cooling of the reaction mixture 50 ml of 1 N NaOH is added, excess 3,4,5-trimethoxybenzyl amine being removed by distillation by steam. After evaporation of the residue to dryness it is mixed with methanol, and hydrochloric acid gas is introduced in the solution. After sucking off and drying the resulting precipitate, 3.6 g of N-(3,4,5-trimethoxy-benzyl)-N'-(3-trifluoromethyl-4-chlorophenyl)-piperazine hydrochloride is obtained.
Reaction SMILES: ClN1C(=O)CCC1=O.[Br:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][C@H:13]([CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[NH:14][CH2:15]2.CO.O>O1CCCC1.[OH-].[K+]>[Br:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][C@H:13]([CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:24])[N:14]=[CH:15]2
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1Cc2c(Br)cccc2CN1
Agent: O=C1CCC(=O)N1Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1Cc2c(Br)cccc2C=N1
Reaction time: 0.5 h
Yield: 96.2 %

Procedure:
Add N-chlorosuccinimide (106.7 g, 0.79 mol) to a solution of (3R)-5-bromo-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1,2,3,4-tetrahydroisoquinoline (220 g, 0.52 mol) in tetrahydrofuran (3.85 L) at 20° C. in an appropriate vessel and stir. After 30 minutes concentrate the mixture under reduced pressure and dissolve the residues in 5% w/w potassium hydroxide in methanol (2.2 L, 1.69 moles) and stir at 20° C. After 30 minutes, add the mixture to water (3 L) and extract three times with dichloromethane (3×1 L). Dry the combined organic extracts over anhydrous magnesium sulfate and concentrate under reduced pressure to give the title compound (210 g, 0.50 mol). MS (m/z): 354(M+1 (79Br)), 356(M+1 (81Br)).
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[CH:10]=[C:9]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[N:8]=[CH:7][N:6]=1>C(O)C>[NH:2]([C:5]1[CH:10]=[C:9]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[N:8]=[CH:7][N:6]=1)[NH2:3]
Reactant: Clc1cc(N2CCCCC2)ncn1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNc1cc(N2CCCCC2)ncn1

Procedure:
17.7 ml (18.2 g, 364.2 mmol) hydrazine hydrate are added dropwise to a solution of 6.0 g (30.4 mmol) 4-chloro-6-piperidin-1-ylpyrimidine in 50 ml ethanol at RT, while stirring. The reaction solution is subsequently stirred at 80° C. for 16 h. For working up, the mixture is concentrated in vacuo, the residue is stirred in water, the solid which has precipitated out is filtered off, the residue on the filter is washed twice with 150 ml water each time and twice with 100 ml diethyl ether each time and the product is dried in vacuo.