Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][OH:10])([CH2:7][OH:8])[CH2:6][CH2:5]C1.[C:11]([Si:15](Cl)([CH3:17])[CH3:16])([CH3:14])([CH3:13])[CH3:12]>C1COCC1>[Si:15]([O:10][CH2:9][C:3]1([CH2:7][OH:8])[CH2:6][CH2:5]1)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCC1(CO)CCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC1(CO)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.3 %

Procedure:
To a round bottom flask was added NaH (1.08 g, 27.0 mmol) and THF (35 mL). The reaction mixture was cooled to about 0° C. and a solution of cyclobutane-1,1-diyldimethanol (3.14 g, 27.0 mmol, prepared according to DE 19735574, Beispiel 8d) in THF (100 mL) was added dropwise. The reaction mixture was stirred for about 30 min and then a solution of tert-butylchlorodimethylsilane (4.07 g, 27.0 mmol) in THF (50 mL) was added dropwise. The reaction mixture was warmed to ambient temperature and the reaction mixture was stirred for about 1 h. The reaction mixture was quenched with the addition of saturated aqueous NaHCO3 (200 mL) and the mixture was extracted with EtOAc (3×200 mL). The organics were combined and washed with brine (500 mL), dried with Na2SO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel 120 g RediSep® column; heptane/EtOAc gradient from 1:0 to 0:1) to give the title compound (3.23 g, 52%). 1H NMR (CDCl3) δ 3.72 (s, 2H), 3.70 (s, 2H), 1.97-1.68 (m, 6H), 0.91 (s, 9H), 0.91 (s, 3H), 0.09 (s, 3H).
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.[CH3:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]=O>>[CH3:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5]1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: Cc1ccccc1C=O
Product: Cc1ccccc1CN1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 2-methylbenzaldehyde 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-[(2-methylphenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C@:9]12[C:15]([CH3:17])([CH3:16])[C@H:12]([CH2:13][CH2:14]1)[CH:11]([C:18](Cl)=[O:19])[C:10]2=O.C(O[C:27]([NH:29][N:30]([C:32]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=1[Cl:39])C)=O)(C)(C)C.Cl.O1CCOCC1>ClCCCl.ClCCl>[Cl:39][C:33]1[CH:34]=[CH:35][C:36]([Cl:38])=[CH:37][C:32]=1[N:30]1[C:18](=[O:19])[C:11]2[C@@H:12]3[C:15]([CH3:17])([CH3:16])[C@@:9]([CH3:8])([CH2:14][CH2:13]3)[C:10]=2[N:29]1[CH3:27]
Reactant: CN(NC(=O)OC(C)(C)C)c1cc(Cl)ccc1Cl
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)C(=O)C2C(=O)Cl
Agent: Cl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cn1c2c(c(=O)n1-c1cc(Cl)ccc1Cl)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 44.1 %

Procedure:
Triethylamine (1.2 mL, 8.6 mmol) was added dropwise to a cooled (0° C.) solution of (1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 20; 880 mg, 4.1 mmol) in 1,2-dichloroethane (8 mL) over 1 min. The reaction mixture was stirred for 5 min and then a solution of N′-(2,5-dichloro-phenyl)-N′-methyl-hydrazinecarboxylic acid tert-butyl ester (751 mg, 2.58 mmol) in 1,2-dichloroethane (14 mL) was added over 2 min. The reaction mixture was stirred at 0° C. for 15 min, at room temperature for 30 min, and then in an oil bath at 50° C. for 30 min. A solution of HCl in dioxane (4 M; 8 mL, 32 mmol) was added and the mixture was heated at reflux for 1 h and then allowed to cool to room temperature. Dichloromethane (150 mL) was added and the mixture was washed with 1:1 water/brine (30 mL), dried (magnesium sulfate), filtered, evaporated, and purified using an ISCO 120 g column, eluting with 20-100% ethyl acetate/hexanes. Fractions homogeneous for the product were evaporated, and co-evaporated successively with methanol and diethyl ether. The residue was dried overnight under high vacuum at 70° C. to give (4S,7R)-2-(2,5-dichloro-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (400 mg, 44%) as a white solid. ES(+)-MS (M+H) 351.
Reaction SMILES: [CH2:1]([C:5]1[CH:20]=[CH:19][C:8]([O:9][C:10]2[O:14][C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)[C:2]([CH3:4])=O.[OH:21][CH:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=1)[CH2:23][NH2:24].O.Cl>C1C=CC=CC=1>[ClH:31].[Cl:31][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[CH:22]([OH:21])[CH2:23][NH:24][CH:2]([CH3:4])[CH2:1][C:5]1[CH:20]=[CH:19][C:8]([O:9][C:10]2[O:14][C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1
Reactant: NCC(O)c1cccc(Cl)c1
Reactant: COC(=O)c1ccc(Oc2ccc(CC(C)=O)cc2)o1
Agent: Cl
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)c1ccc(Oc2ccc(CC(C)NCC(O)c3cccc(Cl)c3)cc2)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of methyl 5-[4-acetonylphenoxy]furan-2-carboxylate (1.04 g) and 2-hydroxy-2-(3-chlorophenyl)ethanamine (0.65 ) in dry benzene (100 ml) was heated under reflux, with azeotropic removal of water, for 1 hr. the solvent was evaporated and the residue dissolved in methanol (100 ml), cooled, and treated with sodium borohydride (0.4 g), in portions. The reaction mixture was stirred at ambient temperature for 2 hr. The solvent was evaporated and the residue partitioned between water and chloroform. The organic layer was dried (MgSO4) and evaporated to an oil which was purified by column chromatography on silica gel. Elution with 4% methanol:chloroform gave a colourless oil. An ethereal solution of the free base was treated with hydrogen chloride gas to give methyl 5-[4-[2-[(3-chloro-β-hydroxyphenethyl)amino]propyl]phenoxy]furan-2-carboxylate, hydrochloride as a 65:35 mixture of diastereoisomers, m.p. 148°-150° C. (ethylacetate-ether).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]=[C:11]=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][NH:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:23][CH:22]=2)[CH:18]=[CH:19][CH:20]=1>ClCCl.C(N(CC)CC)C>[CH3:13][N:14]([C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:23][CH:22]=2)[CH:18]=[CH:19][CH:20]=1)[C:11]([NH:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:12]
Reactant: O=C=NCCCc1ccccc1
Reactant: CCOC(=O)CCc1ccc(-c2cccc(NC)c2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CCc1ccc(-c2cccc(N(C)C(=O)NCCCc3ccccc3)c2)cc1
Temperature: 40 °C
Reaction time: 12 h
Yield: 96.6 %

Procedure:
188 μL (1.2 mmol, 1.5 eq) 3-phenylpropyl isocyanate are added to a solution of 230 mg (0.81 mmol, 1 eq) of ethyl 3-(3′-methylaminobiphenyl-4-yl)propanoate (prepared in Example 7c) in 10 mL of an 8/2 dichloromethane/triethylamine mixture. The reaction medium is stirred at 40° C. for 12 hours and then hydrolyzed with water and extracted with ethyl acetate. The organic phases are combined, washed with sodium chloride solution and dried over sodium sulfate. The solvents are evaporated off and the residual oil is chromatographed on silica (7/3 heptane/ethyl acetate). 348 mg of ethyl 3-{3′-[1-methyl-3-(3-phenylpropyl)ureido]biphenyl-4-yl}propanoate are obtained in solid form. Yield=96%
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]#[N:34])=[CH:23][CH:22]=2)[C:7]2[N:8]([C:10]([CH3:19])=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:12]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4].C[Sn]([N:39]=[N+:40]=[N-:41])(C)C.C1(C)C=CC=CC=1>C(Cl)Cl>[CH2:1]([C:5]1[N:6]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[NH:41][N:40]=[N:39][N:34]=3)=[CH:25][CH:26]=2)[C:7]2[N:8]([C:10]([CH3:19])=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:12]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn2c(C)c(-c3ccccc3)nc2n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCCc1nn2c(C)c(-c3ccccc3)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 38.8 %

Procedure:
A mixture of 95.0 mg (0.213 mmol) of 2-butyl-3-[(2'-cyanobiphenyl-4-yl)methyl]-6-methyl-5-phenyl-3H-imidazo[1,2-b][1,2,4]triazole (from Step F), 158 mg (0.769 mmol) of trimethyltin azide, and 2.0 ml of toluene was stirred at reflux under N2 for 24 hours. The mixture was concentrated in vacuo, and the residue was treated with 3 ml of dry MeOH and 1.0 g of silica gel. The resulting mixture was stirred at room temperature in a stoppered flask overnight. The solvent was removed by rotary evaporation in vacuo to give a dry powder, which was added as a slurry in CH2Cl2 to the top of a column of silica gel (26×2.5 cm) packed in CH2Cl2. Gradient elution of the column with 1.5% MeOH in CH2Cl2 and concentration of the product fractions yielded 40.4 mg (37%) of the title compound as a yellow gum, which, upon trituration with ether, was transformed to a tan solid (28 mg, 25%), mp 207°-208° C.; homogeneous by TLC in 90:10:0.1 CH2Cl2 -MeOH-AcOH.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][CH2:11][CH:10]([O:14][C:15]3[CH:20]=[C:19]([F:21])[C:18]([F:22])=[C:17]([F:23])[CH:16]=3)[C:9]2=[O:24])=[CH:5][CH:4]=1.[CH3:27][Si](C)(C)[N-][Si](C)(C)C.[Li+].CI>C1COCC1.[Cl-].[NH4+]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][CH2:11][C:10]([CH3:27])([O:14][C:15]3[CH:16]=[C:17]([F:23])[C:18]([F:22])=[C:19]([F:21])[CH:20]=3)[C:9]2=[O:24])=[CH:25][CH:26]=1
Reactant: COc1ccc(CN2CCCC(Oc3cc(F)c(F)c(F)c3)C2=O)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: COc1ccc(CN2CCCC(C)(Oc3cc(F)c(F)c(F)c3)C2=O)cc1
Reaction time: 0.5 h

Procedure:
To a mixture of 1-(4-methoxybenzyl)-3-(3,4,5-trifluorophenoxy)piperidin-2-one (250 mg) in THF (5 mL) was added lithiumhexamethyl disilazide (1M THF solution, 0.821 mL) at −78° C. under a nitrogen atmosphere, and the mixture was stirred for 30 min. To the reaction mixture was added a mixture of methyl iodide in THF (1 mL), and the mixture was stirred at −78° C. for 30 min under a nitrogen atmosphere, and at room temperature for 2 hr. The reaction mixture was diluted with saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (89 mg).
Reaction SMILES: C[O:2][C:3](=[O:40])[C@@H:4]([NH:30][S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=[O:33])=[O:32])[CH2:5][NH:6][C:7](=[O:29])[CH2:8][CH2:9][NH:10][C:11](=[O:28])[C:12]1[CH:17]=[CH:16][C:15]([C:18](=[NH:27])[NH:19]C(OC(C)(C)C)=O)=[CH:14][CH:13]=1.[C:41]([OH:47])([C:43]([F:46])([F:45])[F:44])=[O:42]>>[OH:47][C:41]([C:43]([F:46])([F:45])[F:44])=[O:42].[C:18]([C:15]1[CH:16]=[CH:17][C:12]([C:11]([NH:10][CH2:9][CH2:8][C:7]([NH:6][CH2:5][C@H:4]([NH:30][S:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)(=[O:33])=[O:32])[C:3]([OH:40])=[O:2])=[O:29])=[O:28])=[CH:13][CH:14]=1)(=[NH:19])[NH2:27]
Reactant: COC(=O)[C@H](CNC(=O)CCNC(=O)c1ccc(C(=N)NC(=O)OC(C)(C)C)cc1)NS(=O)(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)c1ccc(C(=O)NCCC(=O)NC[C@H](NS(=O)(=O)c2ccccc2)C(=O)O)cc1
Reaction time: 0.5 h

Procedure:
The product (0.385 g) obtained in the above (8) is dissolved in TFA (5 ml) under ice-cooling, and the mixture is stirred for 30 minutes, and then stirred at room temperature for one hour. The TFA is distilled off, and a mixture of acetic acid (2 ml) and water (8 ml) is added to the residue, and the mixture is refluxed for 11 hours. The reaction mixture is concentrated under reduced pressure, and the residue is purified by HPLC to give the desired compound (97 mg) as a white powder.
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[Cl-:10].[Na+].N([O-])=O.[Na+].C(=O)(O)[O-]>Cl.O>[Cl:10][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1cc(C)nc(N)c1
Reactant: [Cl-]
Agent: Cl
Agent: O=C([O-])O
Agent: O=N[O-]
Solvent: O
Product: Cc1cc(C)nc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.4 %

Procedure:
A mixture of 2-amino-4,6-dimethylpyridine (90 g, 0.736 mol) and sodium chloride (216 g, 3.69 mol) in concentrated hydrochloric acid (720 mL) was cooled to between −15 and −20° C. A solution of sodium nitrite (71.2 g, 1.03 mol) in water (135 mL) was added over 30 min. More sodium chloride (216 g, 3.69 mol) was added and the reaction mixture was allowed to warm to ambient temperature and stirred for 1 h. The reaction mixture was basified with solid bicarbonate (700 g) and extracted with dichloromethane (1 L), filtered and the two phases separated. The organic layer was concentrated in vacuo and the crude purified by flash column chromatography over silica gel (100-200 mesh) with 20% dichloromethane in petroleum ether as eluent to afford 2-chloro-4,6-dimethylpyridine (40 g, 38%) as a solid.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:13]C1N=CC=CC=1C#N.C(O)(=O)C(C)(C)C>[N+]([O-])([O-])=O.[Ag+].OS(O)(=O)=O>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([Cl:13])[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1cccnc1Cl
Reactant: CC(C)(C)c1ccc(C#N)cn1
Agent: [Ag+]
Agent: CC(C)(C)C(=O)O
Agent: O=S(=O)(O)O
Product: CC(C)(C)c1ccc(C#N)c(Cl)n1
Yield: 42 %

Procedure:
The title compound was synthesized according to the procedure described for the synthesis of 6-tert-butylnicotinonitrile starting from 2-chloronicotinonitrile (3.91 g, 28 mmol), pivalic acid (14.4 g, 141 mmol), AgNO3 (0.622 g, 3.66 mmol), (NH4)2S2O8 (8.36 g, 36.6 mmol) and 50 ml 10% H2SO4. Purified by normal phase chromatography using 100 heptane to 95/5 heptane/ethyl acetate. (Yield: 42%, 2.3 g). 1H NMR (400 MHz, CDCl3) δ ppm 1.34 (s, 9 H), 7.36 (d, J=8.20 Hz, 1 H), 7.88 (d, J=8.20 Hz, 1 H).
Reaction SMILES: [N:1]1([CH2:10][C:11]2[CH:20]=[CH:19][C:14]3[N:15]=[C:16](Br)[S:17][C:13]=3[CH:12]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.CCN(C(C)C)C(C)C.[NH2:30][C@@H:31]1[CH2:36][CH2:35][CH2:34][CH2:33][C@H:32]1[OH:37]>CC(N(C)C)=O>[N:1]1([CH2:10][C:11]2[CH:20]=[CH:19][C:14]3[N:15]=[C:16]([NH:30][C@@H:31]4[CH2:36][CH2:35][CH2:34][CH2:33][C@H:32]4[OH:37])[S:17][C:13]=3[CH:12]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Brc1nc2ccc(Cn3cnc4ccccc43)cc2s1
Reactant: N[C@@H]1CCCC[C@H]1O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4ccccc43)cc2s1
Temperature: 120 °C
Reaction time: 8 h
Yield: 58.1 %

Procedure:
To a suspension of 6-((1H-benzo[d]imidazol-1-yl)methyl)-2-bromobenzo[d]thiazole from Step 1 of Example 1 (34.4 mg, 0.1 mmol) in DMA (3 mL) were added DIEA (15 mg, 0.12 mmol) and (1R,2R)-2-aminocyclohexanol (13.8 mg, 0.12 mmol) at rt. The reaction mixture was stirred in a sealed tube at 120° C. overnight. After cooling to rt, the mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC using a mixture of water (containing 5% CH3CN, 0.05% HCOOH) and CH3CN (containing 0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C-18 column as the stationary phase to afford (1R,2R)-2-((6-((1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (22 mg, 58%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.40 (s, 1H), 7.99 (d, J=7.3 Hz, 1H), 7.60-7.72 (m, 2H), 7.55 (dd, J=2.6, 6.0 Hz, 1H), 7.26-7.34 (m, 1H), 7.12-7.25 (m, 3H), 5.47 (s, 2H), 4.76 (br s, 1H), 3.26-3.39 (m, 2H), 2.03 (d, J=10.0 Hz, 1H), 1.87 (d, J=9.4 Hz, 1H), 1.62 (d, J=4.7 Hz, 2H), 1.03-1.39 (m, 4H). LCMS (ESI) m/z 379 (M+H)+.
Reaction SMILES: Cl[C:2]([C:28](=[O:37])[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)([Cl:27])[C:3]([N:5]([C:12]([O:14][CH:15]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:16][CH2:17][CH2:18][CH3:19])=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[C:38]([C:41]1[CH:42]=[C:43]([N:47]2[C:51]([SH:52])=[N:50][N:49]=[N:48]2)[CH:44]=[CH:45][CH:46]=1)([OH:40])=[O:39].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:36][O:35][C:32]1[CH:33]=[CH:34][C:29]([C:28]([C:2]([S:52][C:51]2[N:47]([C:43]3[CH:44]=[CH:45][CH:46]=[C:41]([C:38]([OH:40])=[O:39])[CH:42]=3)[N:48]=[N:49][N:50]=2)([Cl:27])[C:3]([N:5]([C:12]([O:14][CH:15]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:16][CH2:17][CH2:18][CH3:19])=[O:13])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:4])=[O:37])=[CH:30][CH:31]=1
Reactant: CCCCCCCC(CCCC)OC(=O)N(C(=O)C(Cl)(Cl)C(=O)c1ccc(OC)cc1)c1ccccc1
Reactant: O=C(O)c1cccc(-n2nnnc2S)c1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCC(CCCC)OC(=O)N(C(=O)C(Cl)(Sc1nnnn1-c1cccc(C(=O)O)c1)C(=O)c1ccc(OC)cc1)c1ccccc1
Yield: 84.7 %

Procedure:
33 g of α-chloro-α-(4-methoxybenzoyl)-2-chloro-5-dodecyloxycarbonylacetanilide and 16 g of 1-(3-carboxyphenyl)-5-mercaptotetrazole were dispersed in 200 ml of chloroform and to which was added dropwise 10 ml of triethylamine at room temperature over a period of about 30 minutes. After stirring for 3 hours the chloroform solution washed with water and concentrated under reduced pressure. The residue was crystallized from methanol to obtain 37.4 g of α-(4-methoxybenzoyl)-α-[1-(3-carboxyphenyl)-5-tetrazolylthio]-2-chloro-5-dodecyloxycarbonylacetanilide. Yield: 85%. Melting Point: 155° to 162° C.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH2:6][C:5]2[CH:9]=[CH:10][S:11][C:4]=2[S:3]1(=[O:13])=[O:12].[CH2:14]([N:21]=[C:22]=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.Cl>CS(C)=O>[OH:8][C:7]1[N:2]([CH3:1])[S:3](=[O:13])(=[O:12])[C:4]2[S:11][CH:10]=[CH:9][C:5]=2[C:6]=1[C:22](=[O:23])[NH:21][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CN1C(=O)Cc2ccsc2S1(=O)=O
Reactant: O=C=NCc1ccccc1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN1C(O)=C(C(=O)NCc2ccccc2)c2ccsc2S1(=O)=O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
1 g (4.6 mmol) of 3,4-dihydro-2-methyl-3-oxo-2H-thieno[3,2-e]-1,2-thiazine 1,1-dioxide are stirred at room temperature for 3 hours under nitrogen with 0.61 g (4.6 mmol) of benzylisocyanate and 0.47 g (4.6 mmol) of triethylamine in 10 ml of absolute dimethylsulfoxide. Thereafter, the mixture is poured into 40 ml of 2-N hydrochloric acid and 25 g of ice and stirred for 20 minutes. The separated precipitate is filtered off under suction and washed neutral with water. The precipitate is dissolved in 200 ml of methylene chloride, the turbid solution is dried over sodium sulfate, stirred with 0.3 g of active carbon and filtered. The filtrate is extracted with five 100 ml portions of saturated sodium carbonate solution, each of the aqueous phases being re-extracted with a small amount of methylene chloride. The combined aqueous phases are acidified to pH 1 with concentrated hydrochloric acid. The separated product is extracted with two 150 ml of methylene chloride. The combined organic phases are dried over sodium sulfate, whereupon the solvent is distilled off. For purification, the product is recrystallized from ca 40 ml of methanol. There is obtained 3-hydroxy-2-methyl-4-benzylcarbamoyl-2H-thieno[3,2-e]-1,2-thiazine 1,1-dioxide of melting point 176°-177° C.
Reaction SMILES: [H-].[Na+].[N:3]1[N:4]=[CH:5][N:6]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH:7]=1.[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31]Br)=[CH:27][C:26]=1[Cl:33])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(OCC)(=O)C>CN(C=O)C>[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][N:8]([N:6]2[CH:5]=[N:4][N:3]=[CH:7]2)[C:9]2[CH:10]=[CH:11][C:12]([C:13]#[N:14])=[CH:15][CH:16]=2)=[CH:27][C:26]=1[Cl:33])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Clc1cc(CBr)ccc1OCc1ccccc1
Reactant: N#Cc1ccc(Nn2cnnc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N(Cc2ccc(OCc3ccccc3)c(Cl)c2)n2cnnc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydride (60%, 200 mg, 5.0 mmol) was added to a solution of 4-([1,2,4]triazol-4-ylamino)-benzonitrile (926 mg, 5.0 mmol) in DMF (20 mL) at r.t. The mixture was stirred for 1 hour at this temperature and 1-benzyloxy-4-bromomethyl-2-chloro-benzene (CAB02128, 1.56 g, 5.0 mmol) was added. The reaction mixture was stirred overnight and ethyl acetate (75 mL) was added. The mixture was transferred into a separation funnel and washed with water (two times 100 mL) and brine (20 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was suspended in 2-propanol (20 mL) and heated to reflux for 5 minutes. The white solid was filtered off after cooling to room temperature and dried under high vacuum. Yield: 1.38 g (66%). 1H-NMR (400 MHz, d6-DMSO) δ=4.99 (s, 2H), 5.17 (s, 2H), 6.76 (d, J=9.0 Hz, 2H), 7.16 (d, J−8.6 Hz, 1H), 7.20 (dd, J=8.6, 2.2 Hz, 1H), 7.32-7.47 (m, 6H), 7.76 (d, J=9.0 Hz, 2H), 8.81 (s, 2H). LRMS (FAB+): 416.1 (100, [M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH2:7].Cl[C:14]1[C:23]2[C:18](=[C:19]([C:25]3[CH:26]=[C:27]4[C:32](=[CH:33][CH:34]=3)[N:31]=[C:30]([NH:35][CH3:36])[N:29]=[CH:28]4)[C:20]([CH3:24])=[CH:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1.O>CN1C(=O)CCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH:7][C:14]1[C:23]2[C:18](=[C:19]([C:25]3[CH:26]=[C:27]4[C:32](=[CH:33][CH:34]=3)[N:31]=[C:30]([NH:35][CH3:36])[N:29]=[CH:28]4)[C:20]([CH3:24])=[CH:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1
Reactant: COc1ccc(CN)cc1OC
Reactant: CNc1ncc2cc(-c3c(C)ccc4c(Cl)nccc34)ccc2n1
Solvent: O
Solvent: CN1CCCC1=O
Product: CNc1ncc2cc(-c3c(C)ccc4c(NCc5ccc(OC)c(OC)c5)nccc34)ccc2n1

Procedure:
Dissolved 3,4-dimethoxybenzylamine (3.04 ml, 20.2 mmol) in NMP (15.0 mL) and added 6-(1-chloro-6-methylisoquinolin-5-yl)-N-methylquinazolin-2-amine (2.25 g, 6.72 mmol) as a solid in a sealed vessel and heated the reaction to 220° C. in the microwave 20 minutes. Dripped the reaction mixture into water and isolated the resulting precipitate. Air-dried the solid and redissolved in 2M NH3/MeOH. Concentrated in vacuo, redissolved wet slurry in EtOAc and dried the slurry over Na2SO4. Concentrated and loaded the crude material on a column, and purified the crude eluting with 20-100% EtOAc/hexanes. The pure fractions were combined and concentrated to afford 6-(1-(3,4-dimethoxybenzylamino)-6-methylisoquinolin-5-yl)-N-methylquinazolin-2-amine. MS (M+H)+ 466.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[H-].[Na+].Br[CH2:10][CH2:11][OH:12]>CN(C=O)C>[I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:10][CH2:11][OH:12])[CH:6]=1
Reactant: OCCBr
Reactant: Ic1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OCCn1cc(I)cn1
Temperature: 25 °C
Yield: 64.3 %

Procedure:
A solution of 4-iodo-1H-pyrazole (4.50 g, 23.20 mmol) in DMF (45 mL) was treated with sodium hydride (60% w/w, 1.42 g, 35.5 mmol) at 0° C. and stirred at room temperature. After 1 hour the resulting mixture was treated with 2-bromoethanol (2.5 mL, 35.2 mmol) at 0° C. The resulting mixture was heated to 65° C. for 3 days. The reaction quenched with brine/EtOAc and the aqueous layer extracted with EtOAc. The combined organic layers were washed with water, brine, dried and concentrated. The residue was purified by silica gel column chromatography eluting with 0 to 50% EtOAc in cyclohexane to give the title compound (3.55 g, 64%).