Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[N:7]([CH2:9][C:10]1[C:11]2[C:16]([C:17]([CH:24]=O)=[C:18]3[C:23]=1[CH:22]=[CH:21][CH:20]=[CH:19]3)=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:27][NH2:28].[BH4-].[Na+]>C1COCC1.CO>[C:1]([O:5][C:6](=[O:26])[N:7]([CH3:8])[CH2:9][C:10]1[C:11]2[C:16]([C:17]([CH2:24][NH:28][CH3:27])=[C:18]3[C:23]=1[CH:22]=[CH:21][CH:20]=[CH:19]3)=[CH:15][CH:14]=[CH:13][CH:12]=2)([CH3:2])([CH3:4])[CH3:3]
Reactant: CN
Reactant: CN(Cc1c2ccccc2c(C=O)c2ccccc12)C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CNCc1c2ccccc2c(CN(C)C(=O)OC(C)(C)C)c2ccccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 83 %

Procedure:
Compound 4 (2.29 g, 6.56 mmol) was dissolved in the mixture of THF (50 mL) and MeOH (50 mL). To this solution was added the aqueous solution of methylamine (40%, wt, 20 mL), the reaction mixture was stirred at room temperature under nitrogen for 12 h. Sodium borohydride (1.00 g, 26.3 mmol) was added, and stirred for 30 min. After removal of the solvent in vacuo, the resulting residue was dissolved in ethyl acetate (100 mL), washed with water (3×50 mL), and dried over MgSO4. Solvent evaporation gave a crude product, which was purified on a silica gel column, eluting with MeOH/CH2Cl2 (1/2), giving compound 5 as a yellow solid (2.00 g, 83%). 1H NMR (CDCl3) δ 8.44-8.39 (m, 4H), 7.56-7.53 (m, 4H), 5.51 (s, 2H), 4.71 (s, 2H), 2.69 (s, 3H), 2.46 (s, 3H), 1.55 (s, 9H). 13C NMR (CDCl3) δ 155.6, 132.5, 131.0, 130.0, 125.8, 125.7, 125.4, 125.3, 124.9, 79.7, 47.8, 42.6, 36.9, 31.6, 28.6. IR (cm−1): 1686. HRMS (FAB) calcd for C23H28N2O2 (M+) 364.2151, found 364.2159. Anal. calcd for C23H28N2O2: C, 75.79; H, 7.74; N, 7.69. Found: C, 75.64; H, 7.71; N, 7.53.
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.[NH2:13][CH:14]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:15]1([OH:21])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>C1COCC1.C([O-])(O)=O.[Na+].C(Cl)Cl>[C:22]1([CH:14]2[C:15]3([CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[O:21][C:6](=[O:7])[NH:13]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NC(c1ccccc1)C1(O)CCOCC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C1NC(c2ccccc2)C2(CCOCC2)O1
Reaction time: 5 h

Procedure:
To a mixture of CDI (388 mg, 2.394 mmol) in THF (1.5 mL) was added slowly a solution of 4-(amino(phenyl)methyl)tetrahydro-2H-pyran-4-ol (451 mg, 2.176 mmol) in THF (3 mL). The mixture was stirred under argon for ˜5 hours. The mixture was diluted with saturated aqueous NaHCO3 solution and DCM. The separated aqueous layer was extracted with DCM (2×) and the combined organic layers were washed with 0.5N aqueous HCl solution and brine, dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by column chromatography [SiO2, 12 g, 0-100% heptane/ethyl acetate] providing 4-phenyl-1,8-dioxa-3-azaspiro[4.5]decan-2-one as a white solid. Yield: 330 mg. LCMS m/z 234.1 (M+H)+; Rt 0.52 min.
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]([O:9][CH3:10])=[N:7][C:6]([O:11][CH3:12])=[CH:5][N:4]=1.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[NH:21][CH:22]=[CH:23][N:24]=2)[N:15]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:13][C:14]1[N:15]=[C:16]([C:20]2[N:24]([CH2:2][C:3]3[C:8]([O:9][CH3:10])=[N:7][C:6]([O:11][CH3:12])=[CH:5][N:4]=3)[CH:23]=[CH:22][N:21]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: Fc1cccc(-c2ncc[nH]2)n1
Reactant: COc1cnc(CCl)c(OC)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cnc(Cn2ccnc2-c2cccc(F)n2)c(OC)n1
Temperature: 45 °C
Reaction time: 16 h
Yield: 65 %

Procedure:
A mixture of 2-chloromethyl-3,5-dimethoxy-pyrazine (115 mg, 0.61 mmol), 2-fluoro-6-(1H-imidazol-2-yl)-pyridine (98 mg, 0.60 mmol) and K2CO3 (250 mg, 1.81 mmol) in DMF (7 mL) is stirred at 45° C. for 16 hours. On cooling, the reaction is quenched with saturated NH4Cl (3 mL) and extracted with DCM (3×15 mL). The combined organic layers are dried and solvent removed. PTLC (silica gel) separation (10% MeOH in DCM) gives 123 mg of 2-[2-(6-fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-3,5-dimethoxy-pyrazine as an oil. LRMS calcd 315.30, found 316.20 (MH+). D. 3,5-Dimethoxy-2-(2-thiazol-2-yl-imidazol-1-ylmethyl)-pyrazinel (Compound 5)
Reaction SMILES: [Se].[Br:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([C:16]#[N:17])[C:12]=1[N:13]([CH3:15])[CH3:14])[N:9]=[C:8]([CH3:18])[CH:7]=[CH:6]2.[O:19]1CCOCC1>>[Br:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([C:16]#[N:17])[C:12]=1[N:13]([CH3:14])[CH3:15])[N:9]=[C:8]([CH:18]=[O:19])[CH:7]=[CH:6]2
Reactant: C1COCCO1
Reactant: Cc1ccc2cc(Br)c(N(C)C)c(C#N)c2n1
Agent: [Se]
Product: CN(C)c1c(Br)cc2ccc(C=O)nc2c1C#N
Temperature: 25 °C
Yield: 72 %

Procedure:
Selenium dioxyde (50 mg, 0.45 mmol, 1.3 eq) in suspension in dioxane (1 mL) was heated at 60° C. The 6-bromo-7-dimethylamino-2-methylquinoline-8-carbonitrile (100 mg, 0.34 mmol, 1.0 eq) was then introduced and the mixture was left to react at 80° C. for 3 hours. After cooling to room temperature, the mixture was filtered on celite, eluted with dioxane and concentrated under reduced pressure. The crude product was precipitated from ether to afford 6-bromo-7-dimethylamino-2-formylquinolin-8-carbonitrile as an orange powder (74 mg, 72%).
Reaction SMILES: C(OC([NH:8][C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=O)=O)(C)(C)C.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:46][N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.Cl>C1COCC1.CCOC(C)=O>[NH2:8][C:9]([CH3:13])([CH3:14])[C:10]([N:50]1[CH2:51][CH2:52][N:47]([CH3:46])[CH2:48][CH2:49]1)=[O:12]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: CN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(C(=O)C(C)(C)N)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-((tert-Butoxycarbonyl)amino)-2-methylpropanoic acid (Boc-Aib-OH, 54, 10.0 g, 49.2 mol), EDC.HCl (11.3 g, 59.0 mmol), HOBt (9.97 g, 73.8 mmol) and DIPEA (25.6 mL, 148 mmol) were stirred in 250 mL of THF until all solids dissolved. N-methyl-piperazine was added (10.9 mL, 98.4 mmol) and the reaction was stirred at room temperature for 18 hrs. The mixture was diluted with 300 mL of EtOAc and washed twice with saturated aqueous NaHCO3. The organic layer was then washed with brine, dried over MgSO4, filtered, and the solvent was removed in vacuo. This crude material was dissolved in 300 mL of CH3CN. HCl (4N in dioxane, 49 mL, 196 mmol) was added over 10 minutes. The reaction was stirred for 8 hrs, during which time the product forms a white precipitate. The product was filtered, washed with CH2Cl2, and dried under high vacuum over night to provide the product 55 as the bis-hydrochloride salt (10.4 g, 82% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.30 (br. s., 3 H), 4.35 (d, J=13.6 Hz, 2 H), 3.52 (br. s., 2 H), 3.41 (d, J=11.1 Hz, 2 H), 3.01 (q, J=11.1 Hz, 2 H), 2.77 (d, J=3.5 Hz, 3 H), 1.56 (s, 6 H). MS (ES+) [M+H]+=186.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.[NH:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)N.CCN(CC)CC>C(O)C.O>[N:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[N:25]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: CN(C)C=CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Reactant: NNc1ccccn1
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1-c1ccccn1
Temperature: 100 °C
Reaction time: 5 h
Yield: 50 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (800 mg, 2.4 mmol) in ethanol (20 mL) were added 2-hydrazinopyridine (388 mg, 3.6 mmol) and Et3N (0.66 mL, 4.7 mmol). The mixture was stirred at 100° C. for 5 h. The mixture was diluted with water, extracted with AcOEt, washed with brine, dried over Na2SO4, concentrated in vacuo, purified by HPLC and recrystallized with AcOEt/hexane to yield the title compound as a pale yellow solid (460 mg, 51%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([OH:11])[CH:5]=[C:6]2[CH:10]=[CH:9][S:8][C:7]=12.C([O-])(O)=O.[Na+].[C:17](OC(=O)C)(=[O:19])[CH3:18]>S(=O)(=O)(O)O>[C:17]([O:11][C:4]1[CH:5]=[C:6]2[CH:10]=[CH:9][S:8][C:7]2=[C:2]([CH3:1])[N:3]=1)(=[O:19])[CH3:18]
Reactant: Cc1nc(O)cc2ccsc12
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(=O)Oc1cc2ccsc2c(C)n1
Temperature: 0 °C
Yield: 62 %

Procedure:
A solution of 7-methylthieno[2,3-c]pyridin-5-ol (5.0 g, 30.3 mmol) and concentrated sulfuric acid (3 drops) in acetic anhydride (50 ml) was stirred at room temperature for 16 hours. The mixture was poured into ice water (300 ml), neutralized with NaHCO3, and was extracted with CH2Cl2. The organic layer was washed with a saturated solution of NaHCO3, dried over MgSO4, treated with activated charcoal and evaporated in vacuo to give the product (3.9 g, 62% yield) as an amber oil; IR (neat) 3090, 1770 and 1585 cm-1 ; mass spectrum m/z 207 (M+); 1H NMR (CDCl3) δ2.35 (s, 3H, COCH3), 2.75 (s, 3H, CH3), 7.28 (d superimposed on s, J=5 Hz, 2H, thiophene-H, Ar-H), 7.67 (d, J=5 Hz, 1H, thiophene-H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=[N:2]1.[H-].[Na+].Cl[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[N:22]=1.O>CN(C)C=O>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([CH2:20][O:16][C:13]3[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][CH2:7][CH2:6][N:1]4[CH:5]=[CH:4][N:3]=[N:2]4)=[CH:15][CH:14]=3)[N:22]=2)=[CH:32][CH:31]=1
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Reactant: ClCc1cccc(-c2ccc(Cl)cc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc(-c2cccc(COc3ccc(CCCCn4ccnn4)cc3)n2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45.8 %

Procedure:
A solution of 89 mg (0.42 mmol) 4-(4-[1,2,3]triazol-1-yl-butyl)phenol in 4.0 ml N,N-dimethylformamide was treated at 0° C. with 17 mg (0.42 mmol) of 60% sodium hydride and stirred at 0° C. for 30 min. Then 100 mg (0.42 mmol) 2-Chloromethyl-6-(4-chloro-phenyl)-pyridine [ZA 6706809] were added and stirred continued at r.t. over night. After addition of 8 ml water, the precipitate was isolated, washed thoroughly with water and n-heptane. The residue was dried at 40° C. and purified by LC-MS to give 80.5 mg (47%) of the title compound as white powder.
Reaction SMILES: CC(N=NC(C#N)(C)C)(C#N)C.[CH3:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]#[N:21])=[N:18][CH:19]=1.C1C(=O)N([Br:29])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:29][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]#[N:21])=[N:18][CH:19]=1
Reactant: Cc1ccc(C#N)nc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(CBr)cn1
Temperature: 25 °C
Yield: 43.3 %

Procedure:
Add AIBN (0.25 g, 1.5 mmol) to a slurry of 5-methyl-pyridine-2-carbonitrile (2.5 g, 21.1 mmol) and NBS (3.7 g, 21.1 mmol) in carbon tetrachloride (150 mL) at reflux under a nitrogen atmosphere. Add AIBN (3×0.25 g, 3×1.5 mmol) to the reaction in 0.25 g portions every hour for 3 h. Stir the resulting mixture for one additional hour at reflux. Cool the mixture to room temperature and wash with saturated aqueous NaHCO3 (30 mL). Collect the organic phase, concentrate in vacuo and purify the residue by chromatography on silica gel (330 g) eluting with DCM to obtain the desired intermediate (1.8 g, 44%). MS (ES+) m/z: 199 (M+2)+.
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][OH:8])[CH2:4][O:3]1.C(N(CC)CC)C.[S:17](Cl)([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18]>C(Cl)(Cl)Cl>[S:17]([O:3][CH2:4][C@@H:5]([OH:6])[CH2:7][OH:8])([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1(C)OC[C@@H](CO)O1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)OC[C@@H](O)CO)cc1
Yield: 67.8 %

Procedure:
8.6 g of (R)-glycerol acetonide [bp.: 88°-106° C. (18 mmHg); specific rotation: [α]D25 -12.10° (c 5.64, methanol)] was dissolved in 70 ml of chloroform, and 10.0 g of triethylamine was added. With stirring and ice cooling, a solution of 13.8 g of tosyl chloride in 30 ml of chloroform was added dropwise, and the mixture was stirred overnight. The reaction mixture was washed with an aqueous solution of potassium hydrogen carbonate and water, and the solvent was evaporated. The residue (18.7 g) was dissolved in 75 ml of acetone, and 225 ml of 1N hydrochloric acid was added. The mixture was stirred at 80° C. for 30 minutes. The reaction mixture was concentrated and extracted with 450 ml of ethyl acetate. The extract was washed with water, and the solvent was evaporated. The residue was purified by silica gel column chromatography [solvent: chloroform-methanol (40:1)] to give 10.86 g (yield 67.8%) of (S)-3-tosyloxy-1,2-propanediol as colorless needles having a melting point of 57° to 60° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=C[CH:11]=1)[C:5](OO)=[O:6].[OH:12][C:13]1[CH:14]=[C:15]([S:19]([C:21]2[C:29]3[C:28](=[O:30])[N:27]([CH3:31])[C:26](=[O:32])[N:25]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:24]=3[S:23][C:22]=2[CH2:37][C:38]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH:41]=[CH:40][CH:39]=2)=[O:20])[CH:16]=[CH:17][CH:18]=1.C(OCC)(=O)C>ClCCl>[CH3:11][CH2:2][CH2:3][CH:4]([CH3:9])[CH3:5].[OH:12][C:13]1[CH:14]=[C:15]([S:19]([C:21]2[C:29]3[C:28](=[O:30])[N:27]([CH3:31])[C:26](=[O:32])[N:25]([CH2:33][CH:34]([CH3:35])[CH3:36])[C:24]=3[S:23][C:22]=2[CH2:37][C:38]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH:41]=[CH:40][CH:39]=2)(=[O:6])=[O:20])[CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(S(=O)c3cccc(O)c3)c(Cc3cccc4ccccc34)sc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(S(=O)(=O)c3cccc(O)c3)c(Cc3cccc4ccccc34)sc21
Product: CCCC(C)C
Reaction time: 2 h
Yield: 29.1 %

Procedure:
3-Chloroperoxybenzoic acid (50 mg) was added to a solution of 5-[(3-hydroxyphenyl)sulfinyl]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione (Example 28, 80 mg) in dichloromethane (2 ml). After 2 hours, ethyl acetate (25 ml) was added and the solution was washed with saturated sodium bisulfite solution (10 ml), then with saturated sodium hydrogen carbonate solution (10 ml), then with brine (10 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was recrystallised from ethyl acetate:isohexane to give the title compound (24 mg).
Reaction SMILES: O[O:2][S:3]([O-:5])=O.[K+].[Cl:7][C:8]1[C:13]([C:14]#[N:15])=[C:12]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[CH3:23])[CH:11]=[C:10]([N:24]2[CH2:29][CH2:28]S[CH2:26][CH2:25]2)[N:9]=1.N#N>CN1C(=O)CCC1.O>[Cl:7][C:8]1[C:13]([C:14]#[N:15])=[C:12]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[CH3:23])[CH:11]=[C:10]([N:24]2[CH2:25][CH2:26][S:3](=[O:5])(=[O:2])[CH2:28][CH2:29]2)[N:9]=1
Reactant: O=S([O-])OO
Reactant: Cc1cc(F)ccc1-c1cc(N2CCSCC2)nc(Cl)c1C#N
Agent: N#N
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cc(F)ccc1-c1cc(N2CCS(=O)(=O)CC2)nc(Cl)c1C#N
Temperature: 25 °C
Reaction time: 20 h
Yield: 101.1 %

Procedure:
Oxone® (56.18 g, 91.4 mmol) was added to a solution of 2-chloro-3-cyano-4-(4-fluoro-2-methylphenyl)-6-(thiomorpholino)pyridine (26.54 g, 76.3 mmol) in 200 mL of NMP in a 1000-mL, 3-necked flask (equipped with a teflon paddle stirrer, septum with teflon-coated thermocouple, dry N2 adapter). The mixture was stirred at 25° C. for 20 hours, and diluted with 800 mL of water. The resulting mixture was stirred at 25° C. for 30 minutes. The precipitate was filtered, washed several times with H2O, and dried to afford 29.30 g (101.1%) of 2-chloro-3-cyano-4-(4-fluoro-2-methylphenyl)-6-(1,1-dioxo-thiomorpholin-4-yl)pyridine as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[C:10]([Cl:13])[CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([OH:15])[C:6]([OH:14])=[N:7]2.[CH:16]([CH:18]=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>O>[Cl:13][C:10]1[CH:9]=[C:8]2[N:7]=[C:6]([OH:14])[C:5]([OH:15])=[N:4][C:3]2=[C:2]2[C:11]=1[N:12]=[CH:18][CH:16]=[N:1]2
Reactant: Nc1c(Cl)cc2nc(O)c(O)nc2c1N
Reactant: O=CC=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Oc1nc2cc(Cl)c3nccnc3c2nc1O
Temperature: 50 °C
Reaction time: 3 h
Yield: 100.6 %

Procedure:
A mixture of 0,5 g (2,24 mmol) 5,6-diamino-7-chloro-2,3-dihydroxyquinoxaline in 20 ml water was added 0,5 ml (3,36 mmol) 40% aqueous glyoxal and 0,35 g (3,36 mmol) sodium carbonate. The reaction mixture was stirred at 50° C. for 3 h. After cooling to 25° C., the precipitate was filtered off. The crude product was stirred with water and added 1N hydrochloric acid to pH 2-3 to give 0,56 g (100%) 6-chloro-2,3-dihydroxypyrazino(2,3-f)quinoxaline, m.p. >300° C. NMR (DMSO-d6): 9.0 (2H,s), 7.73 (1H,s).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15]([OH:17])=O)[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].[CH:26]1([NH2:30])[CH2:29][CH2:28][CH2:27]1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:18])([CH3:19])[C:15]([NH:30][CH:26]2[CH2:29][CH2:28][CH2:27]2)=[O:17])[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: NC1CCC1
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)O)c2c1N
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)NC3CCC3)c2c1N

Procedure:
Prepared as in Example 24a from 3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoic acid (Example 47b) and cyclobutanamine as an off-white solid (71%). MS 400 (MH+).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:14]#[N:15])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=1.[CH:16]([C:19]1[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:22]=[C:21]([CH:28]([CH3:30])[CH3:29])[C:20]=1[S:31](Cl)(=[O:33])=[O:32])([CH3:18])[CH3:17].C(N(CC)CC)C>C(#N)C>[CH:16]([C:19]1[CH:24]=[C:23]([CH:25]([CH3:26])[CH3:27])[CH:22]=[C:21]([CH:28]([CH3:30])[CH3:29])[C:20]=1[S:31]([O:1][N:2]=[C:3]([C:14]#[N:15])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=1)(=[O:33])=[O:32])([CH3:17])[CH3:18]
Reactant: COc1ccc(C(C#N)=NO)cc1OC
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)Cl)c(C(C)C)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(C(C#N)=NOS(=O)(=O)c2c(C(C)C)cc(C(C)C)cc2C(C)C)cc1OC

Procedure:
As described under 1.2, 8.25 g (0.04 mol) of α-hydroxyimino-3,4-dimethoxybenzyl cyanide are reacted with 13.3 g (0.044 mol) of 2,4,6-tris(isopropyl)benzenesulfonyl chloride in the presence of triethylamine. After recrystallisation of the crude product from ethyl acetate/-hexane, 14.25 g (75%) of α-(2,4,6-tris(isopropyl)phenylsulfonyl-oxyimino)-3,4-dimethoxy-benzyl cyanide are obtained in the form of beige crystals having a melting point of 90.5-93.5° C. The 1H-NMR spectrum of the compound shows that it is a pure stereoisomer. The UV spectrum (acetonitrile) of the substance shows a broad absorption band with a maximum at 352 nm (ε=11000) that extends to 433 nm. Elemental analysis: C25H32N2O5S (472.6)
Reaction SMILES: [S:1]1[C:5]23[CH:13]=[CH:12][CH:11]=[CH:10][C:6]2=[N:7][CH:8]=[CH:9][C:4]3=[C:3]([C:14]([OH:16])=O)[CH2:2]1.[ClH:17].C(OC([NH:28][CH2:29][CH2:30][NH2:31])=O)C1C=CC=CC=1.C(N(CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C)C=O.C(OCC)(=O)C>[ClH:17].[NH2:28][CH2:29][CH2:30][NH:31][C:14]([C:3]1[CH2:2][S:1][C:5]23[CH:13]=[CH:12][CH:11]=[CH:10][C:6]2=[N:7][CH:8]=[CH:9][C:4]=13)=[O:16]
Reactant: NCCNC(=O)OCc1ccccc1
Reactant: O=C(O)C1=C2C=CN=C3C=CC=CC32SC1
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: NCCNC(=O)C1=C2C=CN=C3C=CC=CC32SC1
Reaction time: 1 h
Yield: 35.3 %

Procedure:
In 10 ml of dimethylformamide (DMF) were suspended 487 mg of benzo[b]thieno[2,3-c]pyridine-3-carboxylic acid synthesized in Example 17 and 508 mg of benzyloxycarbonylethylenediamine hydrochloride ##STR58## and after adding thereto 307 μl of triethylamine, the mixture was cooled to 0° C. Then, 660 mg of diphenylphosphorylazide (DPPA) and 336 μl of triethylamine were added thereto and the mixture was stirred for one hour under ice-cooling and stirred overnight at room temperature. The reaction mixture was diluted with 200 ml of ethyl acetate, washed with an aqueous 5% citric acid solution, an aqueous 5% sodium hydrogencarbonate solution, and then a saturated aqueous sodium chloride solution, and then dried by sodium sulfate. Then, ethyl acetate was distilled off under reduced pressure, the residue was dissolved in 10 ml of acetic acid and after adding thereto 5 ml of an acetic acid solution of 25% hydrogen bromide, the mixture was stirred for 2 hours at 50° C. The reaction mixture was diluted with 200 ml of water and washed twice with ether. After adjusting the pH thereof to 11 with sodium hydroxide, the reaction mixture was extracted thrice with chloroform and the extract was dried by sodium sulfate. Chloroform was distilled off under reduced pressure and the residue was diluted with 100 ml of ethyl acetate. Then, 2 ml of a mixture of 1N hydrochloric acid in ethyl acetate was added dropwise to the residue and crystals thus deposited were collected by filtration to provide 230 mg (yield of 37%) of N-(2-aminoethyl)-benzo[b]thieno[2,3-c]pyridine-3-carboamide.hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][C:14]([CH3:30])([N:17]2[CH2:22][CH2:21][CH:20]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19][CH2:18]2)[CH2:13][CH2:12]1)=[O:10].[CH3:31][O:32][C:33](=[O:42])[C:34]1[CH:39]=[CH:38][C:37]([CH2:40]Br)=[CH:36][CH:35]=1>>[CH3:31][O:32][C:33](=[O:42])[C:34]1[CH:39]=[CH:38][C:37]([CH2:40][N:23]([CH:20]2[CH2:21][CH2:22][N:17]([C:14]3([CH3:30])[CH2:15][CH2:16][N:11]([C:9](=[O:10])[C:3]4[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=4[CH3:1])[CH2:12][CH2:13]3)[CH2:18][CH2:19]2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:36][CH:35]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: Cc1cccc(C)c1C(=O)N1CCC(C)(N2CCC(Nc3ccccc3)CC2)CC1
Product: COC(=O)c1ccc(CN(c2ccccc2)C2CCN(C3(C)CCN(C(=O)c4c(C)cccc4C)CC3)CC2)cc1

Procedure:
It is prepared from (2,6-dimethyl-phenyl)-(4′-methyl-4-phenylamino-[1,4′]-bipiperidinyl-1′-yl)-methanone and 4-bromomethyl-benzoic acid methyl ester using a procedure as described for Example 52 of PCT/EP02/03871. MS/ESI 554 [M+H]+. (2,6-Dimethyl-phenyl)-(4′-methyl-4-phenylamino-[1,4′]bipiperidinyl-1′-yl)-methanone used as starting material may be prepared using a procedure similar to that described in Example 51a-e of PCT/EP02/03871. MS/ESI 406 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]1[CH2:13][CH2:12][CH2:11][NH:10]1.[Br:14][C:15]1[N:19]2[N:20]=[C:21](Cl)[CH:22]=[CH:23][C:18]2=[N:17][CH:16]=1.[F-].[K+].O>CS(C)=O.ClCCl>[Br:14][C:15]1[N:19]2[N:20]=[C:21]([N:10]3[CH2:11][CH2:12][CH2:13][CH:9]3[C:3]3[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=3[F:1])[CH:22]=[CH:23][C:18]2=[N:17][CH:16]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: Fc1ccc(F)c(C2CCCN2)c1
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: O
Product: Fc1ccc(F)c(C2CCCN2c2ccc3ncc(Br)n3n2)c1
Temperature: 130 °C
Reaction time: 0.17 h

Procedure:
In step 6A-4, 2-(2,5-difluorophenyl)pyrrolidine (6-5) (1.7 g, 9.3 mmol) was added to a solution of 3-bromo-6-chloroimidazo[1,2-b]pyridazine (11-1) (1.1 g, 230.92) and potassium fluoride (2.7 g, 46 mmol) in DMSO (10 mL). The resulting solution was heated to 130° C. and stirred over-night. The resulting dark orange slurry was cooled to room temperature, poured into 50 mL of DI water and extracted with ethyl acetate (3×150 mL). The ethyl acetate was dried with sodium sulfate and then removed to yield an orange solid. This solid was reconstituted with minimal amounts of dichloromethane (DCM) and purified using a silica gel column (40 g, ISCO) and a 0-5% gradient of methanol:DCM over a 20 minute period followed by 5% methanol for an additional 10 minutes. The solvent was removed from the desired fractions to yield 3-bromo-6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine (6-6) as a light yellow solid. m/z=379.2 [M+1].