Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(CN[NH:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)C1C=CC=CC=1.[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[N:30]1C=CC=C[CH:31]=1>>[CH3:31][NH:30][C:15]1[CH:16]=[C:11]([NH:10][S:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:28])=[O:27])[CH:12]=[CH:13][C:14]=1[N+:17]([O-:19])=[O:18]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(NNCCc2ccccc2)cc1
Reactant: c1ccncc1
Product: CNc1cc(NS(=O)(=O)c2ccccc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 98 %

Procedure:
2.5 g (9.7 mmol) of 3-(N-benzylmethylamino-4-nitroaniline in 15 ml dry pyridine was treated with 1.5 ml of benzenesulphonyl chloride at 0° C. and the mixture was then allowed to warm slowly to room temperature. After 3 h the pyridine was removed under vacuum and the residue was dissolved in 100 ml of 2N HCl in 65% aqueous ethanol. The mixture was then heated under reflux until only one compound was seen by TLC (CHCl3 --MeOH, 9:1). Concentration of the solution then gave crystals of N-(3-methylamino-4-nitrophenyl)benzenesulphonamide 2.93 g, 98%, m.p. 172°-173.5° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=[N:47][C:42]2[CH:43]=C[CH:45]=[N:46][C:41]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CC[N:58](C(C)C)C(C)C>C(Cl)Cl>[NH:46]1[CH:41]=[C:42]([CH2:43][NH:58][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]2)=[O:30])[N:47]=[CH:45]1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)NCc2c[nH]cn2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (200 mg, 0.43 mmol), 1H-(imidazoyl-4-yl)methylamine (62 mg, 0.64 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 243.3 mg, 0.64 mmol) and iPr2NEt (0.22 mL, 1.2 mmol) in CH2Cl2 (10 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, dried over Na2SO4 and filtered. The mixture was then concentrated and purified by reverse phase chromatography (15-95% of ACN/water) to rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (1H-imidazol-4-ylmethyl)-amide (6.2 mg, 2.6%) as an off-white powder. HRMS (ES+) m/z Calcd for C27H26Cl2F2N5O+H [(M+H)+]: 546.1634. found: 546.1632.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1CCN2C(=NCCC2)CC1.[CH3:19][N:20]([CH3:49])[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[N:35]=[C:34]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][C@@H:37]3[CH3:42])[CH:33]=[C:32]([CH2:43]OS(C)(=O)=O)[N:31]=2)=[CH:26][CH:25]=1)=[O:22]>C(#N)C>[CH3:19][N:20]([CH3:49])[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[N:35]=[C:34]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][C@@H:37]3[CH3:42])[CH:33]=[C:32]([CH2:43][S:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:31]=2)=[CH:26][CH:25]=1)=[O:22]
Reactant: C[C@H]1COCCN1c1cc(COS(C)(=O)=O)nc(-c2ccc(NC(=O)N(C)C)cc2)n1
Reactant: Sc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C[C@H]1COCCN1c1cc(CSc2ccccc2)nc(-c2ccc(NC(=O)N(C)C)cc2)n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Thiophenol (0.062 mL) was dissolved in acetonitrile (5 mL). DBU (0.141 mL) was then added to the solution and was allowed to stir at RT for 5 minutes. 1,1-Dimethyl-3-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(methylsulfonyloxymethyl)pyrimidin-2-yl]phenyl]urea (154 mg) was suspended in acetonitrile (5 mL) and added to the thiol. The reaction was left to stir at RT of 1 hour then concentrated in vacuo to give the desired material which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)[CH3:2].[CH:12]1([NH:17][OH:18])[CH2:16][CH2:15][CH2:14][CH2:13]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[N+:17]([CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[O-:18])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(C=O)cc1
Reactant: ONC1CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOc1ccc(C=[N+]([O-])C2CCCC2)cc1
Yield: 65.1 %

Procedure:
4-Ethoxybenzaldehyde (22.0 g, 0.1467 mol) and N-cyclopentylhydroxylamine (14.1 g, 0.1398 mol) were mixed into toluene (200 mL) with p-toluenesulfonic acid monohydrate (1.0 g, 5.26 mmol). The mixture was refluxed for 3 hrs under argon atmosphere with a Dean-Stark trap to remove generated water. The solution was rotary evaporated to give a residue which was purified by flash chromatography over silica gel with EtOAc as an eluant and then recrystallization from a mixed solvent of hexanes and EtOAc. The title compound was obtained as a solid (21.24 g 65.1% yield), m.p. 95.1° C. (Rf =0.18 on a silica gel plate using hexanes:EtOAc, 2:1, v/v, as an eluant).
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:15][CH2:14][CH:13]([NH2:16])[CH2:12][CH2:11]2)=[N:3][CH:2]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23](O)=[O:24])[CH:18]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:1]1[C:6]2=[N:7][CH:8]=[CH:9][C:5]2=[C:4]([N:10]2[CH2:11][CH2:12][CH:13]([NH:16][C:23]([C:19]3[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=3)=[O:24])[CH2:14][CH2:15]2)[N:3]=[CH:2]1
Reactant: O=C(O)c1cccnc1
Reactant: NC1CCN(c2ncnc3[nH]ccc23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC1CCN(c2nc[nH]c3nccc2-3)CC1)c1cccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinamine D2 (100 mg), 3-pyridinecarboxylic acid (56.7 mg, 0.460 mmol), HATU (210 mg, 0.552 mmol) and HOAt (37.60 mg, 0.276 mmol) in DMF (2.3 mL) was added DIPEA (386 μL, 2.209 mmol). The reaction mixture was stirred at room temperature for 2 hours then the solvent was removed in vacuo. The crude mixture was purified by MDAP using a high pH method to afford E10 (113 mg), 1H NMR (d6-DMSO) δ 11.70 (1H, brs), 9.0 (1H, s), 8.70 (1H, d), 8.50 (1H, d), 8.17 (2H, m), 7.50 (1H, m), 7.17 (1H, d), 6.62 (1H, d), 4.70 (2H, dt), 4.17 (1H, m), 3.22 (2H, dt), 1.95 (2H, m), 1.55 (2H, m), MS(ES+) 323 [M+H]+.
Reaction SMILES: N[C:2]1[C:3]([O:12][CH:13]([CH3:15])[CH3:14])=[N:4][CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[N:16]1C=CC=CC=1.Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24]>C(Cl)Cl>[CH3:11][CH:9]([O:8][C:7]1[C:2]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:3]([O:12][CH:13]([CH3:14])[CH3:15])[N:4]=[C:5]([NH2:16])[N:6]=1)[CH3:10]
Reactant: CC(C)Oc1ncnc(OC(C)C)c1N
Reactant: c1ccncc1
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Product: CCOC(=O)c1c(OC(C)C)nc(N)nc1OC(C)C
Yield: 51.5 %

Procedure:
To a mixture of 0.42 g of 5-amino-4, 6-di (1-methylethoxy) pyrimidine, 0.30 g of pyridine and 8 ml of methylene chloride was dropwise added 0.26 g of ethyl chloroformate at room temperature with stirring, and the resultant mixture was stirred for 5 hours. The reaction mixture was washed with water and saturated saline in order, dried over anhydrous sodium sulfate and the solvent evaporated. The residue was chromatographed on a silica gel column, eluting with ethyl acetate-n-hexane (1:5) to give 0.29 g of 4, 6-di (1-methylethoxy)-5-ethoxycarbonyl-aminopyrimidine.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=3)[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[F:19][C:20]1[CH:28]=[CH:27][C:23]([CH2:24][CH2:25]Br)=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:28]=[CH:27][C:23]([CH2:24][CH2:25][N:1]2[CH2:6][CH2:5][CH:4]([N:7]3[C:15]4[C:10](=[CH:11][CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=4)[CH2:9][CH2:8]3)[CH2:3][CH2:2]2)=[CH:22][CH:21]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)N(C1CCNCC1)CC2
Reactant: Fc1ccc(CCBr)cc1
Product: O=[N+]([O-])c1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Yield: 97.5 %

Procedure:
1-(Piperidin-4-yl)-6-nitroindoline (3.5 g) and 4-fluorophenethyl bromide (4.1 g) were treated as in Example 2 to give the title compound (5.1 g) as apaleyellowpowder (yield: 81%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([CH:18]3[CH2:20][CH2:19]3)=O)=[CH:12][CH:11]=2)[N:3]=[CH:2]1.C1(C)C=CC(S(O)(=O)=[O:28])=CC=1.[CH2:32]([OH:35])[CH2:33][OH:34]>>[CH2:32]1[O:35][C:18]([CH2:20][CH2:19][OH:28])([CH2:16][C:13]2[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][CH2:6][C:4]3[N:3]=[CH:2][NH:1][CH:5]=3)=[CH:15][CH:14]=2)[O:34][CH2:33]1
Reactant: O=C(c1ccc(OCCCc2c[nH]cn2)cc1)C1CC1
Reactant: OCCO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Product: OCCC1(Cc2ccc(OCCCc3c[nH]cn3)cc2)OCCO1

Procedure:
1.3 mmol of cyclopropyl 4-(3-(1H-imidazol-4-yl)propyloxy)phenyl ketone (Example 61) and a catalytic amount of 4-toluenesulphonic acid in 15 ml of ethylene glycol are brought to reflux for 5 hours. The solvent is evaporated off under reduced pressure, and the residue is dissolved in 10 ml of H2O and alkalized with ammonia. The crude product is extracted with dichloromethane and purified by rotatory chromatography (eluent: dichloromethane/methanol (99:1-90:10), ammoniacal atmosphere). The product is crystallized in the form of hydrogen maleate from diethyl ether and ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[CH2:16][C@H:15]1[NH:25][C:26]([C:28]1[N:29]=[CH:30][C:31]3[CH2:36][N:35]([C:37](OC(C)(C)C)=O)[CH2:34][C:32]=3[N:33]=1)=[O:27])=[O:12])=[CH:5]2.FC(F)(F)C(O)=O>C(Cl)Cl>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[CH2:16][C@H:15]1[NH:25][C:26]([C:28]1[N:29]=[CH:30][C:31]3[CH2:36][N:35]([CH3:37])[CH2:34][C:32]=3[N:33]=1)=[O:27])=[O:12])=[CH:5]2
Reactant: CN(C)C(=O)[C@H]1CC[C@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)[C@H](NC(=O)c2ncc3c(n2)CN(C(=O)OC(C)(C)C)C3)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1Cc2cnc(C(=O)N[C@@H]3C[C@@H](C(=O)N(C)C)CC[C@@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)nc2C1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound (367 mg) obtained in Example 237 was dissolved in methylene chloride (10 ml), and trifluoroacetic acid (10 ml) was added to stir the mixture at room temperature for 2 hours. The reaction mixture was dried to solid under reduced pressure. The title compound was obtained from the thus-obtained crude product and formalin in a similar manner to the process described in Example 18.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][S:12]([CH3:14])=[O:13])=[C:6]([CH:9]=1)[CH:7]=O.[Cl:15][C:16]1[CH:24]=[C:23]2[C:19]([CH2:20][C:21](=[O:25])[NH:22]2)=[CH:18][CH:17]=1.N1CCCC1.C[OH:32]>>[Cl:15][C:16]1[CH:24]=[C:23]2[C:19](/[C:20](=[CH:7]/[C:6]3[CH:9]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:10][CH2:11][S:12]([CH3:14])(=[O:32])=[O:13])/[C:21](=[O:25])[NH:22]2)=[CH:18][CH:17]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: CO
Reactant: CS(=O)COc1ccc(Cl)cc1C=O
Solvent: C1CCNC1
Product: CS(=O)(=O)COc1ccc(Cl)cc1/C=C1\C(=O)Nc2cc(Cl)ccc21

Procedure:
In a manner similar to the method described in Example 9b, 5-chloro-2-methanesulfinylmethoxy-benzaldehyde (1.25 g, 5 mmol) was reacted with 6-chlorooxindole (0.9 g, 5.4 mmol) and pyrrolidine (0.5 mL, 6.1 mmol) in methanol (50 mL) to give the title compound as a yellow solid (1.8 g).
Reaction SMILES: [CH2:1]([N:8]1[CH:17]=[C:16](Br)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][C:21]1[C:25](B2OC(C)(C)C(C)(C)O2)=[C:24]([CH3:35])[O:23][N:22]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:8]1[CH:17]=[C:16]([C:25]2[C:21]([CH3:20])=[N:22][O:23][C:24]=2[CH3:35])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1noc(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: O=c1c2ccccc2c(Br)cn1Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Cc1noc(C)c1-c1cn(Cc2ccccc2)c(=O)c2ccccc12
Temperature: 100 °C
Reaction time: 17 h
Yield: 41.5 %

Procedure:
A mixture of 2-benzyl-4-bromoisoquinolin-1(2H)-one (0.320 g, 1.02 mmol), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (0.341 g, 1.53 mmol) and Na2CO3 (0.324 g, 3.06 mmol) in toluene (20 mL), ethanol (10 mL) and water (3 mL) was degassed under nitrogen. Pd(PPh3)4 (0.118 g, 0.10 mmol) was then added and the reaction was stirred at 100° C. for 17 h under nitrogen. After that time, the mixture was cooled to rt and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL) and washed with water, brine, dried over Na2SO4 and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 90:10 hexanes/ethyl acetate to 75:25 hexanes/ethyl acetate) to give 2-benzyl-4-(3,5-dimethylisoxazol-4-yl)isoquinolin-1(2H)-one (0.140 g, 42%) as an off white solid: mp 139-141° C.; 1H NMR (400 MHz, CDCl3) δ 8.56 (d, J=7.8 Hz, 1H), 7.60-7.68 (m, 1H), 7.51-7.60 (m, 1H), 7.29-7.39 (m, 5H), 7.19 (d, J=7.8 Hz, 1H), 6.97 (s, 1H), 5.18-5.33 (m, 2H), 2.23 (s, 3H), 2.06 (s, 3H); ESI MS m/z 331 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:35])=[C:4]([CH:32]=[CH:33][CH:34]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:30][CH3:31])=[C:13]([O:16][CH:17]3[CH2:22][CH2:21][N:20]([S:23]([CH2:26][CH2:27][CH2:28]Cl)(=[O:25])=[O:24])[CH2:19][CH2:18]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1.[I-].[Na+].[CH3:38][NH:39][CH3:40]>>[Cl:1][C:2]1[C:3]([F:35])=[C:4]([CH:32]=[CH:33][CH:34]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:30][CH3:31])=[C:13]([O:16][CH:17]3[CH2:22][CH2:21][N:20]([S:23]([CH2:26][CH2:27][CH2:28][N:39]([CH3:40])[CH3:38])(=[O:24])=[O:25])[CH2:19][CH2:18]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: CNC
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(S(=O)(=O)CCCCl)CC1
Agent: [I-]
Agent: [Na+]
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(S(=O)(=O)CCCN(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 4-(3-chloro-2-fluoroanilino)-6-{1-[3-chloropropylsulfonyl]piperidin-4-yloxy}-7-methoxyquinazoline (0.15 g) and sodium iodide (0.03 g) in an ethanolic solution of dimethylamine (33%) (15 ml) was stirred at ambient temperature for 16 hours. The reaction mixture was adsorbed onto silica and purified by column chromatography on silica eluting with increasingly polar mixtures of methylene chloride/methanol (saturated with ammonia) (100/0 to 88/12). The fractions containing the title product were combined and evaporated under vacuum to give the title product (0.105 g); 1H NMR Spectrum: (DMSO d6) 1.75-1.87 (m, 4H), 2.0-2.11 (m, 2H), 2.12 (s, 6H), 2.30 (t, 2H), 3.05-3.14 (m, 2H), 3.17-3.29 (m, 2H), 3.40-3.50 (m, 2H), 3.93 (s, 3H), 4.69 (m, 1H), 7.22 (s, 1H), 7.28 (t, 1H), 7.44-7.55 (m, 2H), 7.86 (s, 1H), 8.37 (s, 1H), 9.53 (s, 1H); Mass Spectrum: (M+H)+ 552
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].Cl.[CH3:23][N:24]([CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:28]3[CH2:27][CH2:26][CH:25]([N:24]([CH3:23])[CH2:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:30][CH2:29]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: CN(CCc1ccccc1)C1CCNCC1
Agent: Cl
Product: CN(CCc1ccccc1)C1CCN(C(=O)Oc2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)CC1

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and methyl-phenethyl-piperidin-4-yl-amine, hydrochloride, preparative HPLC (Method C) (37%, colourless oil). HPLC-MS m/z=500.1 (M+1), Rt: 3.26 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11](=[O:14])[NH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:15]=O.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>CO>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11](=[O:14])[N:12]([CH2:15][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: O=c1ccc(-c2cccc(Br)c2)n[nH]1
Reactant: C=O
Solvent: CO
Product: O=c1ccc(-c2cccc(Br)c2)nn1CN1CCOCC1
Yield: 54.5 %

Procedure:
To 20 ml of methanol were added 1 g of 6-(3-bromophenyl)-3(2H)-pyridazinone, 0.13 g of paraformaldehyde and 0.35 g of morpholine, and the resulting mixture was heated under reflux for 2 hours. The reaction mixture was then left to cool, after which the methanol was distilled off under reduced pressure. The residue was recrystallised from a 1:1 by volume mixture of ethyl acetate and hexane, to afford 0.76 g (yield 54%) of the desired Compound No. 26, melting at 110°-111° C.
Reaction SMILES: CC1(C)[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@@H:12]([OH:41])[CH2:13][N:14]([C@@H](C3C=CC=CC=3)CO)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:11][C:5]=2[CH2:4][O:3]1.O>C(O)C.[OH-].[OH-].[Pd+2]>[OH:3][CH2:4][C:5]1[CH:11]=[C:10]([C@@H:12]([OH:41])[CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:9]=[CH:8][C:6]=1[OH:7]
Reactant: CC1(C)OCc2cc([C@@H](O)CN(CCCCCCOCCCCc3ccccc3)[C@H](CO)c3ccccc3)ccc2O1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: OCc1cc([C@@H](O)CNCCCCCCOCCCCc2ccccc2)ccc1O
Yield: 86.9 %

Procedure:
A solution of (1R)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-{[(1S)-2-hydroxy-1-phenylethyl][6-(4-phenylbutoxy)hexyl]amino}ethanol (110 mg), in ethanol (75 ml), was hydrogenated over Pearlman's catalyst [Pd(OH)2, 60% H2O, 55 mg) for 18 h. The catalyst was removed by filtration and the residue washed with methanol. The combined filtrate and washings were concentrated and then applied to a 10 g SCX ion exchange cartridge. The cartridge was eluted with methanol (4 column volumes) and then with 10% aqueous 880 NH3 in methanol (3 column volumes). The ammoniacal eluent was concentrated under reduced pressure to give the title compound (69 mg) as a colourless oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][OH:8])=[CH:5][N:4]=[C:3]1[SH:9].[CH3:10][C:11](C)([O-])C.[K+].C(I)C>O1CCCC1>[CH2:10]([S:9][C:3]1[N:2]([CH3:1])[C:6]([CH2:7][OH:8])=[CH:5][N:4]=1)[CH3:11]
Reactant: CC(C)(C)[O-]
Reactant: Cn1c(CO)cnc1S
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCI
Product: CCSc1ncc(CO)n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
4.33 g of (1-methyl-2-mercaptoimidazol-5-yl)methanol was added to 90 ml of tetrahydrofuran. Thereto 3.70 g of potassium t-butoxide and 5.15 g of ethyl iodide were then added under ice-cooling. The mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 4.82 g of (2-ethylthio-1-methylimidazol-5-yl)methanol.
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[O:16])[N:14]=2)[CH2:7]1)(=O)=O.[C:24]([O-:27])(=[S:26])[CH3:25].[K+]>CN(C)C=O>[C:24]([S:26][CH:6]1[CH2:7][N:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]([N:17]3[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]3)=[O:16])[N:14]=2)[CH2:9]1)(=[O:27])[CH3:25]
Reactant: CN1CCN(C(=O)c2csc(N3CC(OS(C)(=O)=O)C3)n2)CC1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(C(=O)N3CCN(C)CC3)cs2)C1
Temperature: 90 °C
Reaction time: 4 h
Yield: 51.4 %

Procedure:
To a solution of 3-methanesulfonyloxy-1-[4-(4-methylpiperazine-1-carbonyl)-1,3-thiazol-2-yl]azetidine (537 mg, 1.49 mmol) (obtained as described in Reference Example 20(3)) in dimethylformamide (16 ml) was added potassium thioacetate (1.02 g, 8.94 mmol) at room temperature. The mixture was stirred in an oil bath (90° C.) for 4 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate:methanol (10:1) as the eluant to afford 3-acetylthio-1-[4-(4-methylpiperazine-1-carbonyl)-1,3-thiazol-2-yl]azetidine (261 mg, yield 51%) as a pale brown solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][C:6]=1[CH3:18])=O.[NH2:19][C:20]([NH2:22])=[S:21]>CCO>[CH3:18][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]=[C:10]([CH3:11])[C:5]=1[C:3]1[N:19]=[C:20]([NH2:22])[S:21][CH:2]=1
Reactant: Cc1cc(-c2ccccc2)cc(C)c1C(=O)CBr
Reactant: NC(N)=S
Solvent: CCO
Product: Cc1cc(-c2ccccc2)cc(C)c1-c1csc(N)n1
Yield: 27.9 %

Procedure:
A mixture of 2-bromo-1-(3,5-dimethyl-[1,1′-biphenyl]-4-yl)ethanone (2.56 g, 8.44 mmol) and thiourea (0.64 g, 8.44 mmol) in 95% EtOH (12.1 mL) was heated at reflux for 60 min. The solution was concentrated and added with water (50 mL) and saturated aqueous Na2CO3 (1.0 mL). The resultant precipitate was filtered and recrystallized in toluene (10 mL). The solids were filtered and dried under vacuum to give 4-(3,5-dimethyl-[1,1′-biphenyl]-4-yl)thiazol-2-amine (0.66 g) as yellow solids in 28% yield: 1H NMR (500 MHz, CDCl3) δ 7.60 (d, J=1 Hz, 2 H), 7.43 (t, J=7.5 Hz, 1 H), 7.32 (m, 1 H), 7.25 (s, 2 H), 6.34 (s, 1 H), 5.03 (bs, 2 H), 2.24 (s, 6 H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.[NH2:52][C:53]1[CH:58]=[C:57]([C:59]2[S:60][CH:61]=[CH:62][CH:63]=2)[CH:56]=[CH:55][C:54]=1[NH:64][C:65](=[O:71])[O:66][C:67]([CH3:70])([CH3:69])[CH3:68]>CN(C=O)C.CN(C)C1C=CN=CC=1>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[N:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]([NH:52][C:53]3[CH:58]=[C:57]([C:59]4[S:60][CH:61]=[CH:62][CH:63]=4)[CH:56]=[CH:55][C:54]=3[NH:64][C:65](=[O:71])[O:66][C:67]([CH3:69])([CH3:68])[CH3:70])=[O:17])=[CH:9][CH:8]=2)[CH2:5][CH2:6]1
Reactant: O=C(O)/C=C/c1ccc(N2CCOCC2)nc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1N
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)/C=C/c1ccc(N2CCOCC2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
To a solution of 164 (0.275 g, 1.17 mmol) in DMF (10 mL) was added triethylamine (0.168 mL, 1.21 mmol) and BOP reagent (0.563 g, 1.27 mmol) and the mixture was stirred at room temperature for 30 min. Then amine 4 (0.309 g, 1.06 mmol) and excess triethylamine (0.443 mL, 3.18 mmol) were added and the reaction mixture was allowed to stir for 18 h at room temperature. Then 4-(dimethylamino)pyridine (catalytic amount) was added and the reaction mixture was heated to 50-60° C. for 24 h. The solution was concentrated, diluted with AcOEt, washed with saturated NaHCO3, H2O, brine, dried over MgSO4, filtered and concentrated. The resulting yellow solid was triturated from ethyl ether to give compound 165 (0.435 g, 81% yield).