Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:27]=[CH:26][C:11]([CH2:12][O:13][C:14]([C:22]([F:25])([F:24])[F:23])([C:18]([F:21])([F:20])[F:19])[C:15](Cl)=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH:28][CH2:29][CH2:30][CH2:31][C:32]([N:34]([CH3:36])[CH3:35])=[O:33].C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:12][O:13][C:14]([C:18]([F:19])([F:20])[F:21])([C:22]([F:23])([F:24])[F:25])[C:15]([O:28][CH2:29][CH2:30][CH2:31][C:32](=[O:33])[N:34]([CH3:36])[CH3:35])=[O:16])=[CH:26][CH:27]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(OCc1ccc(-c2ccc(Cl)cc2)cc1)(C(F)(F)F)C(F)(F)F
Reactant: CN(C)C(=O)CCCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)C(=O)CCCOC(=O)C(OCc1ccc(-c2ccc(Cl)cc2)cc1)(C(F)(F)F)C(F)(F)F
Reaction time: 4 h
Yield: 59.2 %

Procedure:
A solution of 2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-trifluoromethylpropionyl chloride (3.10 g.) in tetrahydrofuran (10 ml.) is added dropwise at 0° C. to a stirred mixture of 4-hydroxy-N,N-dimethylbutyramide (885 mg.), triethylamine (773 mg.) and tetrahydrofuran (15 ml.). The mixture is kept at room temperature for 4 hours with stirring, and for 2 days without stirring, then filtered. The filtrate is evaporated, and the residue dissolved in ether. The solution is washed with water, 0.4 N-aqueous sodium hydroxide, N-hydrochloric acid and water again, dried and evaporated to a syrup (3.3 g.). The syrup is dissolved in toluene (10 ml.) and applied to a column of silica gel (90 g.). The column is washed with toluene (700 ml.), and then eluted with ether (900 ml.). The ether is evaporated, and the residue is recrystallised from ether-light petroleum (b.p. 40°-60° C.) to give 3-dimethylcarbamoylpropyl 2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-trifluoromethyl-propionate (2.1 g.), m.p. 54°-55° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[Cl:34][C:35]1[C:36]([N:44]2[CH2:49][CH2:48][CH:47]([N:50]3[CH2:55][CH2:54][N:53]([CH2:56][CH2:57][F:58])[CH2:52][CH2:51]3)[CH2:46][CH2:45]2)=[CH:37][C:38]([O:42][CH3:43])=[C:39]([CH:41]=1)[NH2:40].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.N>CC(O)C.CO>[Cl:34][C:35]1[C:36]([N:44]2[CH2:49][CH2:48][CH:47]([N:50]3[CH2:51][CH2:52][N:53]([CH2:56][CH2:57][F:58])[CH2:54][CH2:55]3)[CH2:46][CH2:45]2)=[CH:37][C:38]([O:42][CH3:43])=[C:39]([NH:40][C:2]2[N:7]=[C:6]([C:8]3[N:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]4=[N:10][C:9]=3[C:17]3[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=3)[C:20]([NH:22][C:23]3[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=3[F:30])=[O:21])[CH:5]=[CH:4][N:3]=2)[CH:41]=1
Reactant: COc1cc(N2CCC(N3CCN(CCF)CC3)CC2)c(Cl)cc1N
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: N
Agent: c1cc[nH+]cc1
Solvent: CC(C)O
Solvent: CO
Product: COc1cc(N2CCC(N3CCN(CCF)CC3)CC2)c(Cl)cc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 80 °C
Yield: 11.6 %

Procedure:
In a 10 mL vial with septum cap, 3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (0.200 g, 0.433 mmol), 5-chloro-4-{4-[4-(2-fluoroethyl)-1-piperazinyl]-1-piperidinyl}-2-(methyloxy)aniline (0.192 g, 0.520 mmol) were taken up in iPrOH (3 mL) and pyridinium p-toluenesulfonate (0.203 g, 1.04 mmol) was added. The vial was sealed and heated to 80° C. overnight. When reaction was complete by MS, it was cooled rt, neutralized with 7N ammonia in MeOH, adsorbed onto silica gel and flash chromatographed. Fractions containing the desired product were concentrated and the resulting solid was triturated with diethyl ether, filtered and air dried to give the title compound (0.040 g, 12%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.23 (s, 1H), 9.44 (br. s., 1H), 8.58 (s, 1H), 8.33 (s, 1H), 8.28 (d, J=5.3 Hz, 1H), 8.05 (d, J=8.1 Hz, 1H), 7.78-7.95 (m, 2H), 7.75 (d, J=9.0 Hz, 1H), 7.60 (t, J=7.8 Hz, 1H), 7.45-7.55 (m, 1H), 7.33-7.45 (m, 1H), 7.11-7.28 (m, 2H), 7.03 (t, J=7.0 Hz, 1H), 6.83 (s, 1H), 6.55 (d, J=5.3 Hz, 1H), 4.57 (t, J=4.9 Hz, 1H), 4.45 (t, J=4.9 Hz, 1H), 3.84 (s, 3H), 3.08-3.51 (m, 2H), 2.09-2.92 (m, 13H), 1.72-2.00 (m, 2H), 1.41-1.72 (m, 2H). MS (M+H, ES+) 796.
Reaction SMILES: [C:1]([O:9]C(=O)C1C=CC=CC=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>ClCCl.N1C=CC=CC=1>[C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(O)c1ccccc1

Procedure:
A solution of 2 (100 mg, 0.36 mmol) and benzoic anhydride (226 mg, 1 mmol) in dichioromethane (10 mL) and pyridine (2 mL) was stirred at rt overnight. The mixture was diluted with dichioromethane (50 mL) and washed with 2 N aq. HCl solution (15 mL, 2×), 10% aq. NaHCO3 solution (20 mL, 2×); dried (MgSO4), filtered and concentrated. The residue was chromatographed on a silica gel column and eluted with 30% Et()Ac in hexanes followed by 50%o EtOAc in hexanes to obtain the title compound contaminated with benzoic acid. The solid was dissolved in EtOAc (40 mL) and washed with satd. KHCO3 solution (15 mL, 4×), dried (MgSO4), filtered and concentrated to obtain the title compound (110 mg, 80%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH:18]([CH3:22])[C:19]([OH:21])=[O:20])=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].O1CCCC1>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH:18]([CH3:22])[C:19]([OH:21])=[O:20])=[CH:23][CH:24]=1
Reactant: [H][H]
Reactant: CC(C(=O)O)c1ccccc1OCCOc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C(=O)O)c1ccccc1OCCOc1ccc(N)cc1

Procedure:
8.4 g (0.025 M) of 2-[2-(4-nitrophenoxy)ethoxy]phenylpropanoic acid and 0.9 g of wet 10% palladium-on-charcoal are added to 60 ml of tetrahydrofuran in a 500 ml reactor. The reaction medium is then stirred vigorously for 3 hours under ambient pressure of hydrogen: exothermicity is observed and the temperature of the reaction medium rises to 40° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6].[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[C:17]([O:16][C:14]([NH:13][C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([N:25]2[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]2)[C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6])=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CN1CCNCC1
Reactant: COC(=O)c1cc(Br)c(Cl)c(NC(=O)OC(C)(C)C)c1
Product: COC(=O)c1cc(NC(=O)OC(C)(C)C)c(Cl)c(N2CCN(C)CC2)c1

Procedure:
Methyl 3-((tert-butoxycarbonyl)amino)-4-chloro-5-(4-methylpiperazin-1-yl)benzoate was prepared starting from methyl 3-bromo-5-((tert-butoxycarbonyl)amino)-4-chlorobenzoate (Intermediate 3) and 1-methylpiperazine according to procedure for example 1A
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[N:14]=[C:15]([N:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[C:4]=2[CH:3]=1.C(N(CC)CC)C.Cl[C:31]([O:33][CH:34]([Cl:36])[CH3:35])=[O:32]>ClCCl>[CH3:1][C:2]1[S:6][C:5]2=[N:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[N:14]([C:31]([O:33][CH:34]([Cl:36])[CH3:35])=[O:32])[C:15]([N:16]3[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]3)=[C:4]2[CH:3]=1
Reactant: CC(Cl)OC(=O)Cl
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc2c(s1)=Nc1ccccc1N(C(=O)OC(C)Cl)C=2N1CCN(C)CC1
Reaction time: 3 h
Yield: 58.4 %

Procedure:
To a solution of olanzapine (1.70 g, 5.44 mmol) in dichloromethane (50 mL) at 0° C. was added triethylamine (1.14 mL, 8.16 mmol) followed by 1-chloroethyl chloroformate (0.70 mL, 6.53 mmol) dropwise. TLC after 3 hours indicated starting material still remaining therefore more 1-chloroethyl chloroformate (0.2 mL) was added and stirred for a further 2 hours. The reaction was diluted with dichloromethane (20 mL) and washed with aq satd NaHCO3 (50 mL), dried (MgSO4) and concentrated. The crude product was purified by column chromatography on silica eluting with 2-5% MeOH/dichloromethane to give 1-chloroethyl 2-methyl-4-(4-methylpiperazin-1-yl)-5H-benzo[b]thieno[2,3-e][1,4]diazepine-5-carboxylate (1.33 g, 58% yield) as an orange foam.
Reaction SMILES: [Na].[N+:2]([CH2:5][C:6]([NH2:8])=[O:7])([O-:4])=[O:3].[F:9][C:10]([C:13]([CH:15]=[CH:16]OCC)=O)([F:12])[F:11].Cl>C(O)C>[N+:2]([C:5]1[C:6](=[O:7])[NH:8][C:13]([C:10]([F:12])([F:11])[F:9])=[CH:15][CH:16]=1)([O-:4])=[O:3]
Reactant: NC(=O)C[N+](=O)[O-]
Reactant: CCOC=CC(=O)C(F)(F)F
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: O=c1[nH]c(C(F)(F)F)ccc1[N+](=O)[O-]
Yield: 57.1 %

Procedure:
To ethanol (1 L) was slowly added sodium metal (4.83 g, 0.21 mol). Once the metal had dissolved, nitroacetamide (21.8 g, 0.21 mol) and (2-ethyloxyvinyl) trifluoromethyl ketone (35 g, 0.21 mol) were added, and the suspension formed was heated at reflux for 16 hrs. The resulting mixture was acidified with aqueous hydrochloric acid (1 M) and concentrated in vacuo. The residue was taken up in ethyl acetate (1 L) and the solid formed removed by filtration. The filtrate was then concentrated and the residue purified by silica chromatography to give the product as an orange solid (25.9 g, 0.12 mol, 59% yield).
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[CH2:13]([O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(N(CC)CC)C>C(Cl)Cl>[CH2:13]([O:27][C:28]1[CH:34]=[CH:33][C:31]([N:32]=[C:2]=[O:4])=[CH:30][CH:29]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCCCCCCCCCCCCCOc1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCOc1ccc(N=C=O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 8.74 g of triphosgene in 125 ml of methylene chloride cooled to 0° C. is added dropwise a solution of p-(tetradecyloxy)aniline, 7.95 g of triethylamine and 239.93 mg of dimethylaminopyrydine in 125 ml of methylene chloride over 30 minutes. Stirring at ambient temperature is continued for 4 hours. The solvent is evaporated and the residue stirred with ether and filtered. The cake is washed with additional ether and the combined flitrates evaporated to give the desired product as an oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:18][OH:19])[CH2:17][CH:6]2[CH2:7][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:9][CH:5]2[CH2:4]1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>[CH3:30][C:20]1[CH:25]=[CH:24][C:23]([S:26]([O:1][CH2:2][C:3]2([CH2:18][O:19][S:26]([C:23]3[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=3)(=[O:28])=[O:27])[CH2:17][CH:6]3[CH2:7][N:8]([C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[CH2:9][CH:5]3[CH2:4]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CC2CC(CO)(CO)CC2C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2(COS(=O)(=O)c3ccc(C)cc3)CC3CN(C(=O)OC(C)(C)C)CC3C2)cc1
Temperature: 25 °C
Yield: 93 %

Procedure:
The diol compound prepared in Example K is dissolved in pyridine and treated with p-toluenesulfonyl chloride at -10° C., warmed to room temperature over two hours, diluted with aqueous sodium bicarbonate and extracted into chloroform to afford the title compound in 93% yield. This material is used without further purification. 1HNMR (400 MHz, CDCl3): β=1.26 ppm (m, 2H); 1.45 (s, 9H); 1.80 (m, 2H); 2.47 (s, 6H); 2.59 (m, 2H); 3.10 (d, 2H); 3.39 (dd, 2H); 3.78 (s, 2H); 3.85 (s, 2H); 7.36 (m, 4H); 7.72 (m, 4H).
Reaction SMILES: [CH2:1](OC1C=CC=CC=1)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:17]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:25]([N:24]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:1]/[CH:2]=[CH:3]/[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: C(=Cc1ccccc1)COc1ccccc1
Reactant: c1ccc(CNCc2ccccc2)cc1
Product: C(=C/c1ccccc1)\CN(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.5 %

Procedure:
Following the general procedure using cinnamyloxybenzene (105 mg, 0.50 mmol) and dibenzylamine (148 mg, 0.75 mmol), the reaction was stirred for 0.5 h at rt. Column chromatography on silica gel (eluting with 8% EtOAc/hexanes) afforded the product as a pale yellow liquid (145 mg, 93%).
Reaction SMILES: [S-2:1].[K+].[K+].CN(C=O)C.Cl[C:10]1[CH:29]=[CH:28][C:13]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)=[O:15])=[CH:12][CH:11]=1.Cl>CC1C=CC=CC=1>[C:22]1([C:19]2[CH:20]=[CH:21][C:16]([C:14](=[O:15])[C:13]3[CH:28]=[CH:29][C:10]([SH:1])=[CH:11][CH:12]=3)=[CH:17][CH:18]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: [S-2]
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(c1ccc(S)cc1)c1ccc(-c2ccccc2)cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
15 g anhydrous potassium sulfide and 100 ml DMF are added into a 250 ml three-neck flask. The solution is heated to 50° C. under stirring, and then 8 g 4-chloro-4′-phenyl benzophenone is added into the solution; the solution is heated to reflux (about 110° C.), and is cooled after 7 h; adding 100 ml methylbenzene, regulating the pH value to 5-6 with diluted hydrochloric acid, and separating the solution; the organic phase is extracted twice with 50 ml NaOH solution having a content of 5%, and the aqueous phases are mixed; the obtained aqueous phase is put into a 250 ml three-neck flask, and nitrogen is supplied to blow for 30 min, then 15% hydrochloric acid is dropped into the aqueous solution while agitating to regulate the pH value to 5-6, and light yellow solid precipitate; filtering to obtain a light yellow solid, and the weight after drying at a reduced pressure is 5.0 g, the purity is 99.11%, the yield is 63%, the melting point is 173˜176.7° C., and 1H-NMR data (solvent CDCl3): δ3.654 ppm, s, 1H, δ7.432, 7.370 ppm, d, 2H, δ7.413, 7.436 ppm, d, 1H, δ7.466, 7.491, 7.515 ppm, t, 2H, δ7.641, 7.665 ppm, d, 2H, δ7.695, 7.719 ppm, 7.743, t, 4H, δ7.850, 7.874 ppm, d, 2H.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46]>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH:28]=1)[C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: CCOC(=O)CCCCCCBr
Agent: Cl
Product: CCOC(=O)CCCCCCn1cc(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(C(C)C)nc2)cn1

Procedure:
By the reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (3.26 g) and ethyl 7-bromoheptanoate (2.0 mL) as starting materials, ethyl 7-(4-{[N-(5-benzyloxy-1,2,3,4-tetrahydronaphthalen-1-ylcarbonyl)-N-(6-isopropylpyridin-3-yl)amino]methyl}pyrazol-1-yl)heptanoate (4.25 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=2[C:13]([NH:15][NH2:16])=[O:14].N1C=CC=CC=1.[C:23](Cl)(Cl)=[O:24]>C(COC)OC>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=2[C:13]1[O:14][C:23](=[O:24])[NH:16][N:15]=1
Reactant: NNC(=O)c1c(Cl)ccc2cc(Cl)cnc12
Reactant: O=C(Cl)Cl
Solvent: c1ccncc1
Solvent: COCCOC
Product: O=c1[nH]nc(-c2c(Cl)ccc3cc(Cl)cnc23)o1
Yield: 62 %

Procedure:
12.8 g (50 millimoles) of 3,7-dichloroquinoline- 8-carboxylic hydrazide (compound No. 1) were suspended in 100 ml of dimethoxyethane, 7.9 g (100 millimoles) of pyridine were added and phosgene was then passed in over a period of 4 hours at 25° C. Excess phosgene and the solvent were removed, the residue was stirred into water and the mixture was filtered under suction to give 8.7 g (62%) of a product of melting point of 87° C. (compound No. 33).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([CH3:14])[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.NC(N)=[S:17]>>[CH3:13][N:12]([CH3:14])[C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2](=[S:17])[N:11]=1
Reactant: CN(C)c1nc(Cl)nc2ccccc12
Reactant: NC(N)=S
Product: CN(C)c1nc(=S)[nH]c2ccccc12

Procedure:
Prepared as in Example 46 from 2-chloro-N,N-dimethylquinazolin-4-amine (Example 40) and thiourea. 1H NMR (400 MHz, DMSO-d6) δ 3.31 (s, 6H), 7.24-7.19 (m, 1H), 7.40-7.38 (m, 1H), 7.65-7.61 (m, 1H), 8.00 (d, J=8.0 Hz, 1H), 12.35(s, 1H). MS 206 (MH+).
Reaction SMILES: [OH:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H-].[Na+].Cl[CH2:21][CH2:22][N:23]([CH2:26][CH3:27])[CH2:24][CH3:25]>>[CH2:22]([N:23]([CH2:26][CH3:27])[CH2:24][CH2:25][O:11][CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:21]
Reactant: O=C1c2ccccc2C(O)N1c1ccccc1
Reactant: CCN(CC)CCCl
Agent: [H-]
Agent: [Na+]
Product: CCN(CC)CCOC1c2ccccc2C(=O)N1c1ccccc1
Yield: 105.3 %

Procedure:
Following the procedure of Example 6 but starting with 3-hydroxy-2-phenyl-isoindolin-1-one (22.5 g.), sodium hydride (50% dispersion in mineral oil) (5.3 g.) and 1-chloro-2-diethylaminoethane (13.5 g.), 3-(2-diethylaminoethoxy)-2-phenyl-isoindolin-1-one (34 g.) is obtained in the form of an 85% pure oil. On treating this oil (28 g.) with fumaric acid (8.5 g.) in ethanol, 3-(2-diethylaminoethoxy)-2-phenyl-isoindolin-1-one hydrogen fumarate (27.6 g.), which melts at 146°-147°C., is obtained.
Reaction SMILES: [NH2:1][C:2](=O)[CH2:3][N:4]1[CH:9]([NH:10]S(C2C=CC(C)=CC=2)(=O)=O)[CH:8]=[CH:7][C:6]([O:21][C:22]2[CH:23]=[CH:24][C:25]([Cl:38])=[C:26]([NH:28][C:29]([C:31]3[N:35]([CH3:36])[N:34]=[C:33]([CH3:37])[CH:32]=3)=[O:30])[CH:27]=2)=[CH:5]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[NH2:1][C:2]1[N:10]=[C:9]2[CH:8]=[CH:7][C:6]([O:21][C:22]3[CH:23]=[CH:24][C:25]([Cl:38])=[C:26]([NH:28][C:29]([C:31]4[N:35]([CH3:36])[N:34]=[C:33]([CH3:37])[CH:32]=4)=[O:30])[CH:27]=3)=[CH:5][N:4]2[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)NC2C=CC(Oc3ccc(Cl)c(NC(=O)c4cc(C)nn4C)c3)=CN2CC(N)=O)cc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)cn4c3)ccc2Cl)n(C)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 64.1 %

Procedure:
A mixture of N-{5-[(1-(2-amino-2-oxoethyl)-6-{[(4-methylphenyl)sulfonyl]amino}-1,6-dihydropyridin-3-yl)oxy]-2-chlorophenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (300 mg, 0.527 mmol), trifluoroacetic anhydride (2 mL) and dichloromethane (2.5 mL) was stirred at room temperature for 5 hr. The reaction solution was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate (×3). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, 1N aqueous sodium hydroxide solution (10 mL) and ethanol (10 mL) were added to the residue, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (NH silica gel, ethyl acetate) and recrystallized from ethyl acetate-hexane to give N-{5-[(2-aminoimidazo[1,2-a]pyridin-6-yl)oxy]-2-chlorophenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (134 mg, 64%) as a white solid. To a solution of N-{5-[(2-aminoimidazo[1,2-a]pyridin-6-yl)oxy]-2-chlorophenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (130 mg, 0.328 mmol) thus-obtained and triethylamine (136 μL, 0.984 mmol) in tetrahydrofuran (4 mL) was added with stirring under ice-cooling cyclopropanecarbonyl chloride (38.7 μL, 0.426 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate=50/50→0/100) and recrystallized from ethyl acetate-tetrahydrofuran to give the title compound (83.0 mg, 54%) as a white solid.
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[NH:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]1[C:17]([NH2:28])=[N:18][CH:19]=[C:20]([C:22]2[CH2:23][CH2:24][NH:25][CH2:26][CH:27]=2)[N:21]=1.CCN(C(C)C)C(C)C>CN(C)C=O>[NH:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]1[C:17]([NH2:28])=[N:18][CH:19]=[C:20]([C:22]2[CH2:23][CH2:24][N:25]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH2:26][CH:27]=2)[N:21]=1
Reactant: Nc1ncc(C2=CCNCC2)nc1-c1nc2ccccc2[nH]1
Reactant: CCS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCS(=O)(=O)N1CC=C(c2cnc(N)c(-c3nc4ccccc4[nH]3)n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
Ethanesulfonyl chloride (16.30 mg, 12.01 μL, 0.1268 mmol) was added to a solution of 3-(1H-benzimidazol-2-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrazin-2-amine (60 mg, 0.1153 mmol) and DIPEA (44.71 mg, 60.26 μL, 0.3459 mmol) in N,N-dimethylformamide (1 mL) and the resulting solution stirred at ambient temperature. Analysis after 30 minutes showed SM still remaining therefore the reaction was treated with further ethanesulfonyl chloride (4 μL, 0.04222 mmol). The mixture was allowed to stir for a further 10 minutes and then partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (2×), DCM (2×), dried (MgSO4), filtered and concentrated. The mixture was triturated with DCM and the resultant yellow solid dried under vacuum at 50° C. (44.33 mg, 57% Yield).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH2:13])=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].Br[CH:15]([CH3:19])[C:16](=O)[CH3:17]>COCCOC>[NH2:1][C:2]1[C:3]2[N:4]([C:15]([CH3:19])=[C:16]([CH3:17])[N:13]=2)[CH:5]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:12]=1
Reactant: CC(=O)C(C)Br
Reactant: CCOC(=O)c1cnc(N)c(N)c1
Solvent: COCCOC
Product: CCOC(=O)c1cc(N)c2nc(C)c(C)n2c1
Yield: 17.9 %

Procedure:
Ethyl 5,6-diaminonicotinate (1.4 g, 7.7 mmol) and 3-bromo-2-butanon (1.16 g, 7.2 mmol) were added to 1,2-dimethoxyethan (50 ml) and refluxed for 20 h. The solvent was evaporated under reduced pressure and the residue was dissolved in methylene chloride. The methylene chloride solution was washed with saturated sodium bicarbonate and dried (Na2SO4). The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using methylene chloride:methanol (10:1) as eluent to give 0.3 g (17%) of the title compound.