Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[C:10](\[CH3:13])/[CH2:11][OH:12])=[CH:5][CH:4]=1)[CH3:2].[C:14](OC(=O)C)(=[O:16])[CH3:15].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.ClCCl>[C:14]([O:12][CH2:11]/[C:10](/[CH3:13])=[CH:9]/[C:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=1)(=[O:16])[CH3:15]
Reactant: CCc1ccc(/C=C(\C)CO)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCc1ccc(/C=C(\C)COC(C)=O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 1790 %

Procedure:
(E)-3-(4-Ethylphenyl)-2-methyl-2-propen-1-ol (4.6 g, 26 1 mmol, obtained by LiAlH4 reduction of (E)-3-(4-ethylphenyl)-2-methyl-2-propenal as described for (E)-2-Ethyl-3-(4-methylphenyl)-2-propen-1-ol) was added to a mixture of acetic anhydride (4.0 g, 39 mmol), pyridine (3.5 g, 44 mmol) and DMAP (0.46 g, 3.7 mmol) in 50 ml of dichloromethane. The mixture was stirred for 20 hours at room temperature. The dichloromethane was removed on a rotary evaporator, and the residue dissolved in EtOAc. This solution was washed with aqueous 10% HCl, aqueous 10% NaOH, and saturated aqueous NaCl. The organic phase was dried (MgSO4), filtered and concentrated. The product was purified by silica gel flash chromatography (hexane/EtOAc=80:20) followed by Kugelrohr distillation (140-160° C., 0.05 mbar) yielding 3.9 g (17.9 mmol, 69% yield) of the product as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH3:14])[NH:11][C@H:10]([CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:17][C:18]1[S:26][C:25]2[C:24]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[N:23][C:22]([Cl:33])=[N:21][C:20]=2[CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CC#N.C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([CH3:14])[N:11]([CH2:17][C:18]2[S:26][C:25]3[C:24]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[N:23][C:22]([Cl:33])=[N:21][C:20]=3[CH:19]=2)[C@@H:10]([CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1

Procedure:
A mixture of (3R,5S)-3,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (0.92 g), 6-bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (1 g) and potassium carbonate (1.59 g) in MeCN (10 ml) was heated to reflux for 5 days. The reaction mixture was subsequently cooled, diluted with chloroform, washed with brine and dried (MgSO4), and the solvent was removed in vacuo. The residue was purified by flash column chromatography to yield (3S,5R)-4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-3,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester, 170 (1.2 g). Treatment of this compound with HCl in DCM/MeOH produced 2-chloro-6-(2S,6R)-2,6-dimethyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, 171, which was then methylated using 37% formaldehyde solution and sodium borohydride in MeOH, furnishing 172.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([NH:23][C@H:24]1[C@@H:28]([NH:29]C(OCC[Si](C)(C)C)=O)[CH2:27][N:26]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:25]1)[N:17]=[CH:16]2.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CO.ClCCl>[NH2:29][C@@H:28]1[C@H:24]([NH:23][C:18]2[N:17]=[CH:16][C:15]3[C:20](=[CH:21][CH:22]=[C:13]([C:3]4[C:2]([Cl:1])=[C:7]([O:8][CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=4[Cl:12])[CH:14]=3)[N:19]=2)[CH2:25][N:26]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:27]1
Reactant: COc1cc(OC)c(Cl)c(-c2ccc3nc(N[C@@H]4CN(C(=O)OC(C)(C)C)C[C@@H]4NC(=O)OCC[Si](C)(C)C)ncc3c2)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(OC)c(Cl)c(-c2ccc3nc(N[C@@H]4CN(C(=O)OC(C)(C)C)C[C@@H]4N)ncc3c2)c1Cl
Yield: 95.8 %

Procedure:
A mixture of tert-butyl (3R,4S)-3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)-4-(((2-(trimethylsilyl)ethoxy)carbonyl)amino)pyrrolidine-1-carboxylate (2.77 g, 4.1 mmol) and 1M TBAF in THF (6.1 mL, 6.1 mmol) was stirred in THF (27 mL) at 50° C. for 4 h and then 16 h at room temperature. The reaction mixture was diluted with 10% methanol in dichloromethane (100 mL) and washed with water (50 mL). The aqueous layer was then extracted with fresh dichloromethane (3×20 mL). The combined organic layers were washed with saturated brine solution, dried over sodium sulfate, filtered, concentrated down, and dried to yield tert-butyl (3S,4R)-3-amino-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)pyrrolidine-1-carboxylate as a yellow solid (2.1 g, 94%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:16]=[CH:15][C:14]([C:17](N)=[O:18])=[C:13]3[C:8]=2[CH:9]=[CH:10][CH:11]=[N:12]3)[CH2:3][CH2:2]1.S(=O)(=O)(O)[OH:21].[CH2:25](O)[CH3:26]>>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:16]=[CH:15][C:14]([C:17]([O:18][CH2:25][CH3:26])=[O:21])=[C:13]3[C:8]=2[CH:9]=[CH:10][CH:11]=[N:12]3)[CH2:3][CH2:2]1
Reactant: CCO
Reactant: NC(=O)c1ccc(N2CCOCC2)c2cccnc12
Reactant: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(N2CCOCC2)c2cccnc12
Yield: 85 %

Procedure:
To 0.17 g of 5-morpholino-8-quinolinecarboxamide (Compound No. 22) 10 ml of anhydrous ethanol and 2 ml of concentrated sulfuric acid were added, and the mixture was heated under reflux. The solvent was evaporated and the residue was neutralized with saturated aqueous solution of sodium bicarbonate. After extraction with ethyl acetate, the extract was washed with saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. Ethyl acetate was evaporated, and the residue was refined by column chromatography on silica gel using chloroform-n-hexane (3:2) as an eluent. The crystals thus obtained were recrystallized from chloroform-ether to yield 0.16 g (yield: 85%) of ethyl 5-morpholino-8-quinolincarboxylate (Compound No. 23).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH:14][C:15]2[CH:27]=[CH:26][C:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:17][CH:16]=2)[N:3]=1.[NH2:28][C:29]1([C:32]2[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=2)[CH2:31][CH2:30]1.CCN(C(C)C)C(C)C>C1COCC1.C(Cl)Cl>[OH:38][C:35]1[CH:34]=[CH:33][C:32]([C:29]2([NH:28][C:2]3[N:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH:14][C:15]4[CH:27]=[CH:26][C:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:17][CH:16]=4)[N:3]=3)[CH2:30][CH2:31]2)=[CH:37][CH:36]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Nc2nc(Cl)nc(OCC(F)(F)F)n2)cc1
Reactant: NC1(c2ccc(O)cc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(Nc2nc(NC3(c4ccc(O)cc4)CC3)nc(OCC(F)(F)F)n2)cc1
Temperature: 65 °C
Reaction time: 16 h
Yield: 78.2 %

Procedure:
To a solution of tert-butyl 4-(4-chloro-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (2 g, 4.94 mmol) in THF (30 mL) was added 4-(1-aminocyclopropyl)phenol (0.811 g, 5.44 mmol) and Hunig's Base (3.45 mL, 19.76 mmol). The resulting mixture was stirred for 16 h. The reaction was then warmed to 65° C. for 2 h at which point the reaction became a homogeneous solution. The reaction was cooled and diluted with DCM and washed with water and brine. The organic layer was collected, dried over sodium sulfate, and concentrated under vacuum to give an oily residue. The residue was purified by silica gel chromatography using 20-40% EtOAc/Hexanes to give tert-butyl 4-(4-(1-(4-hydroxyphenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (2 g). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.30-1.37 (m, 4H), 1.60 (s, 9H), 4.67-4.77 (m, 2H), 4.85 (br. s., 1H), 6.04 (br. s., 1H), 6.70-6.81 (m, 2H), 7.11-7.22 (m, 2H), 7.47-7.66 (m, 2H), 7.79-8.01 (m, 2H); LC-MS (Condition A), MS m/z (M++H) 518.0.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.CN(C)C=O.[H-].[Na+].Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>CO.ClCCl>[CH2:36]([O:35][C:33]([CH2:32][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)=[O:34])[CH3:37]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc3ccccc3[nH]2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: CCOC(=O)Cn1c(NC2CCN(C(=O)OC(C)(C)C)CC2)nc2ccccc21
Reaction time: 0.5 h

Procedure:
Combine (1H-benzimidazol-2-yl)(1-(t-butoxycarbonyl)piperidin-4-yl)amine (0.5 g, 1.58 mmol) and dimethylformamide (10 mL). Add portionwise, sodium hydride (0.08 g, 60% in oil, 1.66 mmol). After 30 minutes, add ethyl bromoacetate (0.277 g, 1.66 mmol). After 12 hours, quench by the addition of water and extract the quenched reaction mixture with dichloromethane. Separate the layers and extract the organic layer with five times with water. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 5% methanol/dichloromethane to give (1-(ethoxycarbonylmethyl)-1H-benzimidazol-2-yl)(1-(t-butoxycarbonyl)piperidin-4-yl)amine.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[C:27]1([CH2:33][O:34][CH2:35][CH2:36][Br:37])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CC#N>[Br-:37].[OH:10][C:9]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1)([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)[C:4]12[CH2:5][CH2:6][N+:1]([CH2:36][CH2:35][O:34][CH2:33][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([CH2:2][CH2:3]1)[CH2:8][CH2:7]2
Reactant: BrCCOCc1ccccc1
Reactant: COc1cccc(C(O)(c2cccc(OC)c2)C23CCN(CC2)CC3)c1
Solvent: CC#N
Product: COc1cccc(C(O)(c2cccc(OC)c2)C23CC[N+](CCOCc4ccccc4)(CC2)CC3)c1
Product: [Br-]
Yield: 33.8 %

Procedure:
Following the general procedure outlined in Example 3, 1-azabicyclo[2.2.2]oct-4-yl{bis[3-(methyloxy)phenyl]}methanol (0.0538 g, 0.152 mmol) and 2-bromoethyl phenylmethyl ether (0.0361 mL, 0.228 mmol) in 2 CH3CN/3 CHCl3 (4.0 mL) were reacted to give the desired product (0.0292 g, 33.8%). EI-MS m/z 488 (M+) Rt (2.03 min).
Reaction SMILES: O1CCCC1.[F:6][C:7]1[CH:23]=[CH:22][C:10]([O:11][C:12]2[S:16][C:15]([CH2:17][C:18](Cl)=[N:19][OH:20])=[CH:14][CH:13]=2)=[CH:9][CH:8]=1.[C:24]([C:26]1[C:27]([NH2:32])=[N:28][CH:29]=[CH:30][CH:31]=1)#[CH:25].C(N(CC)CC)C>O>[F:6][C:7]1[CH:23]=[CH:22][C:10]([O:11][C:12]2[S:16][C:15]([CH2:17][C:18]3[CH:25]=[C:24]([C:26]4[C:27]([NH2:32])=[N:28][CH:29]=[CH:30][CH:31]=4)[O:20][N:19]=3)=[CH:14][CH:13]=2)=[CH:9][CH:8]=1
Reactant: ON=C(Cl)Cc1ccc(Oc2ccc(F)cc2)s1
Reactant: C#Cc1cccnc1N
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ncccc1-c1cc(Cc2ccc(Oc3ccc(F)cc3)s2)no1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 7.2 %

Procedure:
To a tetrahydrofuran (5.00 mL) solution of (5-(4-fluoro-phenoxy)-thiophen-2-yl)-acetohydroximoyl chloride (250 mg, 0.875 mmol) described in Manufacturing Example 91-1-4 and 3-ethynyl-pyridin-2-ylamine (50.0 mg, 0.423 mmol) described in Manufacturing Example 1-2-3 was added triethylamine (177 μL, 1.27 mmol) at room temperature, which was stirred for 30 minutes at 60° C. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:2→1:1) to obtain the title compound (11.2 mg, 7.21%).
Reaction SMILES: [CH3:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([F:23])[C:3]=1[C:4]([C:6](=[CH:12]OCC)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH2:24]([NH2:26])[CH3:25]>>[CH3:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([F:23])[C:3]=1[C:4]([C:6](=[CH:12][NH:26][CH2:24][CH3:25])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCN
Reactant: CCOC=C(C(=O)OCC)C(=O)c1c(C)c(F)c(F)c(F)c1F
Product: CCNC=C(C(=O)OCC)C(=O)c1c(C)c(F)c(F)c(F)c1F

Procedure:
Employing ethyl 2-(2-methyl-3,4,5,6-tetrafluorobenzoyl)-3-ethoxyacrylate (10.0 g) and ethylamine gas, the procedure of Reference Example 21 is repeated to give ethyl 2-(2-methyl-3,4,5,6-tetrafluorobenzoyl)-3-ethylaminoacrylate (9.0 g, white crystals), which is then treated with 60% sodium hydride (1.30 g) as in Reference Example 22 to give ethyl 1-ethyl-5-methyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (6.76 g), as pale yellow needles (recrystallized from dichloromethane - n-hexane), m.p. 197°-198° C.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:38])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:37])[CH2:33][CH2:34]SC)[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:39]2[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].O[O:47][S:48]([O-:50])=O.[K+].[CH3:52]N(C=O)C>O.CO.CC(O)=O>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:38])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:37])[CH2:33][CH2:34][S:48]([CH3:52])(=[O:50])=[O:47])[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:39]2[CH:40]=[CH:41][C:42]([CH3:45])=[CH:43][CH:44]=2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=S([O-])OO
Reactant: CN(C)C=O
Reactant: CSCCC(=O)Nc1cc(COc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc(C)cc3)c3ccccc23)ccn1
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCc3ccnc(NC(=O)CCS(C)(=O)=O)c3)c3ccccc23)cc1
Reaction time: 1 h
Yield: 38 %

Procedure:
To a stirred solution of the sulfide (12) (47 mg, 0.075 mmol) in DMF (0.5 mL) was added a solution of Oxone (93 mg, 0.151 mmol) in water (1 mL). After 10 min a precipitate had formed and MeOH (2 mL) was added and stirring continued for 1 hr. The mixture was diluted with a further aliquot of MeOH (2 mL) and glacial AcOH (0.5 mL) was added. The suspension was subjected to SCX capture and release and then purified by flash column chromatography (SiO2, 12 g, 2-8% MeOH in DCM, gradient elution) to afford the title compound (Example 17) (20 mg, 38%): m/z 655 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.27 (9H, s), 2.39 (3H, s), 2.90 (2H, t), 3.01 (3H, s), 3.43 (2H, t), 5.38 (2H, s), 6.35 (1H, s), 7.00 (1H, d), 7.27 (1H, dd), 7.36 (2H, m), 7.44 (2H, m), 7.56-7.65 (3H, overlapping m), 7.93 (1H, m), 8.29-8.33 (2H, overlapping m), 8.34 (1H, d), 8.58 (1H, br s), 8.79 (1H, br s), 10.72 (1H, br s).
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:12][C:11]2[N:10]=[CH:9][C:8](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:7][C:6]=2[CH2:5][CH2:4]1.Cl.[CH3:19][C:20]1[O:24][N:23]=[C:22]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][NH:26]2)[N:21]=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CC(C)=O.CN(C=O)C>[CH3:19][C:20]1[O:24][N:23]=[C:22]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][N:26]2[C:15](=[O:17])/[CH:14]=[CH:13]/[C:8]2[CH:7]=[C:6]3[C:11](=[N:10][CH:9]=2)[NH:12][C:3](=[O:2])[CH2:4][CH2:5]3)[N:21]=1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: Cc1nc(C2CCCCN2)no1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(C2CCCCN2C(=O)/C=C/c2cnc3c(c2)CCC(=O)N3)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
A 16 mL vial flask was successively charged with (2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride (30 mg, 0.12 mmol), DMF (3 mL), 2-(5-methyl-1,2,4-oxadiazol-3-yl)piperidine hydrochloride (29 mg, 0.14 mmol; which may be prepared as described in Step 3), DIPEA (48 μL, 0.28 mmol) and EDAC (27 mg, 0.14 mmol). The reaction mixture was stirred at room temperature overnight and concentrated to dryness. The residue was purified on preparative TLC (eluent: dichloromethane/NH3 7N in MeOH, 2.5%) to give an oil. This oil was taken up in acetone, diethyl ether and concentrated. The resulting wax was finally dissolved in dichloromethane, concentrated and dried to give the title compound (15 mg, 34%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[C:21]([F:22])=[CH:20][C:19]([O:23][CH3:24])=[CH:18][C:17]=2[F:25])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:28])=O>>[Cl:28][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[C:21]([F:22])=[CH:20][C:19]([O:23][CH3:24])=[CH:18][C:17]=1[F:25]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc(F)c(-c2c(-c3ccc(Cl)cc3)c(C)n[nH]c2=O)c(F)c1
Product: COc1cc(F)c(-c2c(Cl)nnc(C)c2-c2ccc(Cl)cc2)c(F)c1
Temperature: 110 °C
Reaction time: 1 h
Yield: 82.8 %

Procedure:
185 mg of 5-(4-chlorophenyl)-4-(2,6-difluoro-4-methoxyphenyl)-6-methyl-2H-pyridazin-3-one and 5 g of phosphorus oxychloride were mixed and stirred at 110° C. for 1 hour. The reaction mixture was allowed to cool down to room temperature and concentrated under reduced pressure. To the residue was added ethyl acetate and ice water, and separated to two layer. The organic layer was washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate, then, concentrated under reduced pressure. The residue was subjected to preparative thin layer chromatography (stationary phase: silica gel, developing solvent: hexane/ethyl acetate=3/1), to obtain 161 mg of 3-chloro-5-(4-chlorophenyl)-4-(2,6-difluoro-4-methoxyphenyl)-6-methylpyridazine (hereinafter, referred to as compound (v) of the present invention).
Reaction SMILES: [I:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>N1C=CC=CC=1>[C:10]([N:4]1[C:3](=[O:9])[C:2]([I:1])=[CH:7][NH:6][C:5]1=[O:8])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=c1[nH]cc(I)c(=O)[nH]1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: O=C(c1ccccc1)n1c(=O)[nH]cc(I)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.5 %

Procedure:
A solution of 5-iodouracil (2 g, 8.4 mmol) in dry pyridine (20 ml) was added dropwise to a solution of benzoyl chloride (3.5 g, 25.3 mmol) in pyridine (10 ml). The mixture was stirred at room temperature for 3 hours. Water (70 ml) was added and extracted with ethyl acetate. The organic phase washed with a saturated solution of NH4Cl and then with 2% HCl (40 ml×4). The solvent was removed under vacuum and the residue was triturated with i-Pr2O to give the title compound as a white solid (2.6 g, 90% yield).
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[CH:29]=[C:28]([Cl:30])[S:27][C:17]=2[N:18]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[N:20]=1>>[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:19]1[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:13][CH2:1][O:2][C:3]=3[CH:4]=2)[C:16]2[CH:29]=[C:28]([Cl:30])[S:27][C:17]=2[N:18]=1
Reactant: Clc1cc2c(Cl)nc(-c3ccccn3)nc2s1
Reactant: NCCc1ccc2c(c1)OCCO2
Product: Clc1cc2c(NCCc3ccc4c(c3)OCCO4)nc(-c3ccccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(pyridin-2-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(3,4-ethylenedioxyphenethylamino)-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[S:10]([N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[C:26]([F:29])([F:28])[F:27])[CH2:15][C@H:14]1[CH3:30])(=[O:12])=[O:11])[C:5]#[N:6].[OH:31]S(O)(=O)=O>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[S:10]([N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[C:26]([F:28])([F:27])[F:29])[CH2:15][C@H:14]1[CH3:30])(=[O:11])=[O:12])[C:5]([NH2:6])=[O:31]
Reactant: O=S(=O)(O)O
Reactant: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1ccc(C#N)cc1Cl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1ccc(C(N)=O)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
A mixture of (R)-3-chloro-4-(4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin-1-ylsulfonyl)benzonitrile (290 mg, 0.626 mmol) in H2SO4 (3 mL) and TFA (6 mL) was stirred at rt overnight. To this was added ice-water. The precipitate was collected by filtration and washed with water to give the desired product as a white solid (267.5 mg, 89%). HRMS: calcd for C19H18ClF4N3O3S+H+, 480.07663. found (ESI-FTMS, [M+H]1+), 480.07642.
Reaction SMILES: C(C1C(=O)O[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH:8]=2)(=O)C.[CH3:20][C:21]([C:23]1[C:32](=[O:33])[O:31][C:30]2[C:25](=[CH:26][C:27]3[CH2:40][CH2:39][CH2:38][N:37]4[C:28]=3[C:29]=2[CH2:34][CH2:35][CH2:36]4)[CH:24]=1)=[O:22]>C(O)C>[CH2:17]([N:14]([CH2:15][CH2:16][N:37]1[CH2:28][CH2:29][CH2:34][CH2:35][CH2:36]1)[C:9]1[CH:8]=[CH:7][C:12]([CH:13]=[CH:20][C:21]([C:23]2[C:32](=[O:33])[O:31][C:30]3[C:25](=[CH:26][C:27]4[CH2:40][CH2:39][CH2:38][N:37]5[C:28]=4[C:29]=3[CH2:34][CH2:35][CH2:36]5)[CH:24]=2)=[O:22])=[CH:11][CH:10]=1)[CH3:18]
Reactant: CC(=O)c1cc2cc3c4c(c2oc1=O)CCCN4CCC3
Reactant: CCN(CC)c1ccc2cc(C(C)=O)c(=O)oc2c1
Solvent: CCO
Product: CCN(CCN1CCCCC1)c1ccc(C=CC(=O)c2cc3cc4c5c(c3oc2=O)CCCN5CCC4)cc1

Procedure:
10-(3-(N-ethyl-N-(2-piperidinoethyl)-4-aminophenyl)propenoyl)-1H,2H,3H,5H,6H,7H,11H-[1]benzopyrano[6,7,8-ij]quinolizin-11-one (7) was prepared according to the procedure of Example 3 wherein 3-acetyl-7-diethylaminocoumarin was replaced by Coumarin 334; (Eastman Kodak, Rochester, N.Y.) λmax (ethanol)=503 nm ##STR14##
Reaction SMILES: Cl.Cl[C:3]([C:5]1[CH:6]=[CH:7][N:8]2[C:12]=1[CH2:11][S:10][CH:9]2[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:4].[NH2:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][N:21]=1.C(N(CC)CC)C.C>O1CCOCC1.C(#N)C>[CH3:26][C:24]1[CH:23]=[CH:22][N:21]=[C:20]([NH:19][C:3]([C:5]2[CH:6]=[CH:7][N:8]3[C:12]=2[CH2:11][S:10][CH:9]3[C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:4])[CH:25]=1
Reactant: O=C(Cl)c1ccn2c1CSC2c1cccnc1
Reactant: Cc1ccnc(N)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccnc(NC(=O)c2ccn3c2CSC3c2cccnc2)c1
Temperature: 65 °C
Reaction time: 0.75 h
Yield: 22.4 %

Procedure:
7-Chloroformyl-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole hydrochloride (6 g) is added, at a temperature between 65° and 72° C., to a solution of 2-amino-4-methylpyridine (2.15 g) and triethylamine (4.05 g) in dioxane (100 cc) which is heated to a temperature in the vicinity of 65° C., in the course of 20 minutes. The suspension obtained is heated, with stirring, at a temperature in the vicinity of 100° C. for 5 hours and 45 minutes and then stirred at a temperature in the vicinity of 20° C. for 16 hours. The solvent is evaporated off under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 60° C. The residue is dissolved in methylene chloride (250 cc). The solution obtained is washed with distilled water (100 cc) and then with an aqueous 4N sodium hydroxide solution (100 cc) and 3 times with distilled water (450 cc in total) and then dried over anhydrous magnesium sulphate, treated with decolorizing charcoal (0.5 g), filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 50° C. A crude product (4.8 g) is thereby obtained, which is dissolved in boiling acetonitrile (50 cc). Decolorizing charcoal (0.5 g) is added to the solution obtained and the suspension is filtered in the heated state. The filtrate is cooled at a temperature in the vicinity of 4° C. for 1 hour. The crystals formed are separated by filtration, washed twice with acetonitrile cooled to a temperature in the vicinity of 4° C. (10 cc in total) and then dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 20° C. in the presence of potassium hydroxide pellets. N-(4-methyl-2-pyridyl)-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole-7-carboxamide (1.5 g) in the form of cream-coloured crystals, m.p. 163° C., is thereby obtained.