Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[Br:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][N:12]=[C:11]2[C:18]([NH:20][NH2:21])=O.C(=O)(O)[O-].[Na+].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>O.C(OCC)(=O)C.ClCCl.N1C=CC=CC=1.O1CCCC1>[Br:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][N:12]=[C:11]2[C:18]1[O:5][C:4]([CH:1]2[CH2:3][CH2:2]2)=[N:21][N:20]=1
Reactant: NNC(=O)c1ncnc2ccc(Br)cc12
Reactant: O=C(Cl)C1CC1
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: Brc1ccc2ncnc(-c3nnc(C4CC4)o3)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.4 mL cyclopropane carbonyl chloride was added to a mixture of 796 mg of 6-bromoquinazoline-4-carboxylic acid hydrazide (compound in Production Example 414), 380 mg sodium bicarbonate, 15 mL tetrahydrofuran and 15 mL water, and the mixture was stirred at room temperature for 1 hour. 130 mg sodium bicarbonate and 0.13 mL cyclopropane carbonyl chloride were further added thereto, and the mixture was stirred overnight. An aqueous saturated sodium bicarbonate solution, common salt and tetrahydrofuran were added to the reaction solution, and the organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was evaporated. Diisopropyl ether was added to the resulting residues, and the crystals were collected by filtration and dried under reduced pressure with a vacuum pump. 996 mg crude product of cyclopropane carboxylic acid N′-(6-bromoquinazoline-4-carbonyl) hydrazide was obtained as pale brown crystals. A mixture of 450 mg of this carboxylic acid hydrazide derivative, 0.24 mL pyridine and 20 mL anhydrous dichloromethane was cooled to −10° C. or less with ice/ethanol/dry ice in a stream of nitrogen, and 0.48 mL trifluoromethanesulfonic anhydride was added little by little to the reaction solution. The reaction solution was stirred at the same temperature for 30 minutes, then stirred at about 0° C. under ice-coolingd water for 40 minutes and then at room temperature for 1 hour. An aqueous saturated sodium bicarbonate solution, ethyl acetate and water were added to the reaction solution, and the organic layer was separated, washed with an aqueous saturated ammonium chloride solution and brine, and then dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give 282 mg of the title compound as a yellowish brown solid.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]([O:20][CH2:21][C@@H:22]1[C@@H:27]([CH2:28][O:29][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:26][CH:25]=[CH:24][CH2:23]1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.S([O-])(O)=O.[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl.CCCCCC>[C:30]([O:29][CH2:28][C@@H:27]1[C@@H:22]([CH2:21][O:20][C:12](=[O:19])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:23][CH:24]2[CH:25]([O:9]2)[CH2:26]1)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(OC[C@H]1CC=CC[C@@H]1COC(=O)c1ccccc1)c1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: ClCCl
Product: O=C(OC[C@H]1CC2OC2C[C@@H]1COC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
m-Chloroperbenzoic acid (777 mg, 4.5 mmoles) was added to a solution of (4S,5S)-4,5-bis(benzoyloxymethyl)-1-cyclohexene (1.05 g, 3.0 mmoles) in methylene chloride (6 ml) under cooling with ice. After stirring the mixture at room temperature for 2 hours, a saturated aqueous solution of sodium hydrogen sulfite was added to the reaction mixture and the excessive peracid was decomposed, after which a saturated aqueous solution of sodium hydrogen carbonate was added and the whole mixture was subjected to extraction with ethyl ether. The ether extract solution was washed with water and then with saturated aqueous solution of sodium hydrogen carbonate, and dried on anhydrous sodium sulfate. After distilling off the solvent therefrom under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:3, v/v) to obtain (3S,4S)-3,4-bis(benzoyloxymethyl)-7-oxabicyclo[4.1.0]heptane (1.025 g, Yield 93%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[N:4]=[C:3]1[CH2:8][S:9][CH2:10][CH2:11][NH2:12].[CH3:13][N:14]=[C:15]=[S:16].C(OCC)(=O)C.C(O)C>C(O)C>[CH3:13][NH:14][C:15]([NH:12][CH2:11][CH2:10][S:9][CH2:8][C:3]1[N:2]([CH3:1])[CH:6]=[C:5]([CH3:7])[N:4]=1)=[S:16]
Reactant: CN=C=S
Reactant: Cc1cn(C)c(CSCCN)n1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNC(=S)NCCSCc1nc(C)cn1C

Procedure:
The reaction of 1,4-dimethyl-2-[(2-aminoethyl)thiomethyl]imidazole (derived from the 6.2 g. dihydrobromide) with methyl isothiocyanate (1.34 g.) in ethanol (50 ml.) followed by chromatography on a column of silica gel with ethyl acetate-ethanol (9:1) an eluant gave N-methyl-N'-[2-((1,4-dimethyl-2-imidazolyl)methylthio)ethyl]thiourea (2.1 g.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([N+:9]([O-])=O)[CH:3]=1.CO.[BH4-].[Na+].C(=O)([O-])O.[Na+]>[Ni](Br)Br.O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([CH:3]=1)[NH2:9]
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Agent: Br[Ni]Br
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cc(Br)ccc1F
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
To a mixture of 1-bromo-4-fluoro-3-nitrobenzene (1.56 g), nickel(II) bromide (78 mg), methanol (28 mL) and tetrahydrofuran (28 mL) was added sodium borohydride (805 mg) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. The mixture was stirred at room temperature for 30 minutes, and the reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution. The resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 5-bromo-2-fluoroaniline (1.3 g). This material was dissolved in tetrahydrofuran (30 mL). To the solution were added 4-dimethylaminopyridine(0.26 g)and di(tert-butyl)dicarbonate (3.1 g), and the mixture was heated for reflux for 1.5 hours. The reaction mixture was poured into 0.5 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. To the residue were added methanol (21 mL) and potassium carbonate (2.94 g), and the mixture was heated for reflux for 2 hours. To the reaction mixture was added water, and the mixture was poured into brine. The resulting mixture was extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=95/5) to give the title compound (1.72 g).
Reaction SMILES: [SH:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.Cl.Cl[CH2:14][CH2:15][NH2:16].[H-].[Na+]>O1CCCC1.CN(C)C=O>[S:1]1[C:2]2[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=2[C:4](=[O:6])[NH:16][CH2:15][CH2:14]1
Reactant: COC(=O)c1ccccc1S
Reactant: NCCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C1NCCSc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.9 %

Procedure:
To a cooled solution of methyl 2-sulfanylbenzoate (200 g, 1.19 mol) in tetrahydrofuran and N,N-dimethylformamide (2 L, V/V=1/1) was added 2-chloroethanamine hydrochloride (138 g, 1.19 mol) at 0° C. followed by sodium hydride (143 g, 3.57 mol, 60% in mineral oil) in portions. After being stirred at room temperature overnight, the reaction mixture was poured into ice-water and extracted with ethyl acetate (900 mL×4). The organic layers were combined, washed with brine (900 mL×3), dried over sodium sulfate and concentrated in vacuo. The residue was stirred in a mixture solution of ethyl acetate and petroleum ether (300 mL, V/V=1/1) for 1 hour. The solid was collected by filtration and dried in vacuo to afford 100 g of 3,4-dihydro-1,4-benzothiazepin-5(2H)-one (yield was 47%).
Reaction SMILES: [Cl:1][C:2]1[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:3]=1[CH2:4][NH:5][C:6](=[O:29])[N:7]([CH:9]([CH2:25][CH2:26][CH:27]=O)[CH2:10][O:11][C:12](=[O:24])[NH:13][C:14]1[N:15]=[CH:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:8].[C:35]([O:39][C:40](=[O:45])[NH:41][CH2:42][CH2:43][NH2:44])([CH3:38])([CH3:37])[CH3:36].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CC(O)=O>[C:35]([O:39][C:40]([NH:41][CH2:42][CH2:43][NH:44][CH2:27][CH2:26][CH2:25][CH:9]([N:7]([CH3:8])[C:6]([NH:5][CH2:4][C:3]1[CH:30]=[CH:31][CH:32]=[C:33]([F:34])[C:2]=1[Cl:1])=[O:29])[CH2:10][O:11][C:12](=[O:24])[NH:13][C:14]1[N:15]=[CH:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:45])([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)C(CCC=O)COC(=O)Nc1cc2ccccc2cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN(C(=O)NCc1cccc(F)c1Cl)C(CCCNCCNC(=O)OC(C)(C)C)COC(=O)Nc1cc2ccccc2cn1
Temperature: 24 °C
Reaction time: 10 h
Yield: 25 %

Procedure:
To a solution of isoquinolin-3-yl-carbamic acid 2-[3-(2-chloro-3-fluoro-benzyl)-1-methyl-ureido]-5-oxo-pentyl ester (0.8 g crude mixture, 1.64 mmol) in anhydrous DCE (3 mL) and AcOH (0.1 mL) was added (2-Amino-ethyl)-carbamic acid tert-butyl ester at 24° C. After 10 h of stirring at 24° C., sodium triacetoxyborohydride (1.05 g, 4.92 mmol) was added in one portion. The slurry was stirred for 2 h at 24° C., quenched with methanol and concentrated. The resulting residue was purified on RP-HPLC using a mixture of acetonitrile and H2O to give isoquinolin-3-yl-carbamic acid 5-(2-tert-butoxycarbonylamino-ethylamino)-2-[3-(2-chloro-3-fluoro-benzyl)-1-methyl-ureido]-pentyl ester (0.25 g, 25%) LRMS (M+H+) m/z 631.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])[CH2:11][CH2:10]1.BrCCCCN1[C:29](=[O:30])[C:28]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]2[C:26]1=[O:35].COC1C=CC=CC=1N1CCNCC1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[C:29](=[O:30])[C:28]3=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]3[C:26]2=[O:35])[CH2:13][CH2:14]1
Reactant: COc1ccccc1N1CCN(CCCCN)CC1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: COc1ccccc1N1CCNCC1
Product: COc1ccccc1N1CCN(CCCCN2C(=O)c3ccccc3C2=O)CC1
Yield: 84.3 %

Procedure:
4-[4-(2-methyloxyphenyl)piperazinyl]butylamine: according to the method of claim 1, N-(4-bromobutyl)phthalimide and 2-methyloxyphenyl-piperazine was used in reaction to produce N-{4-[4-(2-methyloxyphenyl)piperazinyl]butyl}phthalimide, which was then reacted with hydrazine hydrate. The yield was: 84.3%. Hydrochloride salt had a mp: 173-175° C.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[C:6]([N+:9]([O-])=O)[CH:5]=[C:4]([F:12])[C:3]=1[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1.[Cl-].[NH4+].CCN(C(C)C)C(C)C.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>CO.[Zn]>[NH2:8][C:7]1[C:2]([F:1])=[C:3]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:4]([F:12])=[CH:5][C:6]=1[NH:9][C:34](=[O:35])[O:36][CH2:37][CH3:38]
Reactant: CCOC(=O)Cl
Reactant: Nc1c([N+](=O)[O-])cc(F)c(NCc2ccc(F)cc2)c1F
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CCOC(=O)Nc1cc(F)c(NCc2ccc(F)cc2)c(F)c1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 23.9 %

Procedure:
To a stirred solution of compound 3 (0.062 g, 0.21 mmol, 1.0 equiv) in methanol (0.560 mL) was added zinc powder (0.068 g, 1.04 mmol, 5.00 equiv) followed by ammonium chloride solution (55.3 mg, 1.04 mmol, 5.00 equiv) drop wise. After being stirred for 4 h at RT, DIPEA (48.0 μL, 0.260 mmol, 1.25 equiv) and ethyl chloroformate (20.0 μL, 0.210 mmol, 1.00 equiv) were added to reaction mixture at 10° C. and the stirring was continued for another 2 h at RT. After consumption of the starting material (by TLC), the reaction mixture was diluted with water (25 mL) and extracted with EtOAc (2×75 mL). The separated organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give crude; which was purified by neutral alumina column chromatography (EtOAc/Hexane 18:82) to afford to compound 4A (0.017 g, 21%) as an off-white solid. TLC: 50% EtOAc/Hexane (Rf: 0.50); 1H NMR (500 MHz, CDCl3): δ 7.30-7.27 (m, 2H), 7.00 (t, J=8.5 Hz, 2H), 6.88 (d, J=11.5 Hz, 1H), 6.26 (br s, 1H, Exc), 4.40 (d, J=6.0 Hz, 2H), 4.21 (q, J=7.0 Hz, 2H), 3.75 (br s, 1H, Exc), 3.50 (s, 2H, Exc), 1.30 (t, J=7.0 Hz, 3H); LC-MS: m/z=340 (M++1) at RT 3.46 (94.3% purity); UPLC purity: 95.2%
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:20][CH3:21])[C:9]([C:11]([N:13]([CH:17]3[CH2:19][CH2:18]3)[CH:14]3[CH2:16][CH2:15]3)=[O:12])=[CH:10][C:5]2=[C:4]2[N:22]([CH3:25])[CH:23]=[N:24][C:3]=12.Br[C:27]1[S:28][CH:29]=[CH:30][N:31]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH:14]1([N:13]([CH:17]2[CH2:19][CH2:18]2)[C:11]([C:9]2[N:8]([CH2:20][CH3:21])[C:6]3=[N:7][C:2]([NH:1][C:27]4[S:28][CH:29]=[CH:30][N:31]=4)=[C:3]4[N:24]=[CH:23][N:22]([CH3:25])[C:4]4=[C:5]3[CH:10]=2)=[O:12])[CH2:16][CH2:15]1
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(N)nc21
Reactant: Brc1nccs1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3nccs3)nc21
Temperature: 85 °C
Yield: 10.7 %

Procedure:
To a mixture of 4-amino-N,N-dicyclopropyl-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 1J, 30 mg, 0.089 mmol), 2-bromothiazole (11.98 μL, 0.133 mmol), Pd2(dba)3 (12.18 mg, 0.013 mmol), BINAP (24.84 mg, 0.040 mmol) and sodium tert-butoxide (13.63 mg, 0.142 mmol) was added PhMe (887 μL). The mixture was sparged with argon gas for 5 min and heated to 85° C. for 5.5 h. The reaction mixture was filtered through a plug of Celite and concentrated. The crude residue was purified by preparative HPLC to provide N,N-dicyclopropyl-6-ethyl-1-methyl-4-(thiazol-2-ylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (4 mg, 10.49% yield) along with some recovered starting material.
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].[F:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[F:14])[C:9]#[N:10].C[Li].[Br-].[Li+].[OH-].[NH4+].Cl>C(OCC)C.C1COCC1>[F:5][C:6]1[CH:7]=[C:8]([CH2:9][NH2:10])[CH:11]=[CH:12][C:13]=1[F:14]
Reactant: N#Cc1ccc(F)c(F)c1
Agent: Cl
Agent: [Br-]
Agent: [Ce+3]
Solvent: CCOCC
Solvent: C1CCOC1
Product: NCc1ccc(F)c(F)c1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
To THF (18 ml) was added cerium(III) chloride (2.84 g, 11.50 mmol) and the solution was purged, backfilled with nitrogen and warmed to 45° C. for 3 h. The reaction was cooled to rt and 3,4-difluorobenzonitrile (0.8 g, 5.75 mmol) was added. The solution was cooled further to −25° C. and methyl lithium/lithium bromide (1.5 M in diethyl ether, 9.59 ml, 14.38 mmol) was added slowly. The reaction was stirred at this temperature for 1 h and ammonium hydroxide solution (28% in water, 4.00 ml, 28.8 mmol) was added and the mixture was allowed to sit overnight at rt. The cerium salts were filtered off and washed with THF. The obtained THF solution was dried with MgSO4, filtered and concentrated. The product was diluted with ethyl ether and THF and HCl (4M in dioxane, 1.438 mL, 5.75 mmol) were added. The residue was concentrated, diluted with hexane and filtered affording the title compound.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[NH:8][CH2:7][CH:6]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:5]2[CH:17]=1.[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].ClCCl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1.O>[Cl:18][C:19]1[CH:24]=[C:23]([C:2]2[CH:3]=[C:4]3[C:9](=[O:10])[NH:8][CH2:7][CH:6]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:5]3[CH:17]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CCOC(=O)CC1CNC(=O)c2cc(I)cn21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(=O)CC1CNC(=O)c2cc(-c3cccc(Cl)c3)cn21
Reaction time: 2 h
Yield: 60 %

Procedure:
To a solution of ethyl (7-iodo-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl)acetate (1.00 g, 2.87 mmol) in a degassed (with Ar stream) mixture of 1,4-dioxane/H2O (25/5 mL) 3-chloro-phenylboronic acid (898 mg, 5.74 mmol), cesium carbonate (2.807 g, 8.61 mmol), and at the end 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride, complex with dichloromethane (1:1) (234 mg 0.287 mmol) were added. The reaction mixture was capped under argon atmosphere and stirred at 80° for 2 h. The solvent was evaporated under vacuum and the residue partitioned between ethyl acetate and water. The organic phase was dried on Na2SO4 and concentrated to dryness. The crude was purified by chromatography on a silica gel column (eluent: DCM/EtOAc/EtOH: 60/35/5) to afford 0.573 g (60% yield) as a light brown solid.
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH:16]=2)[C:11]([OH:13])=O)=[CH:5][CH:4]=1)#[N:2].[NH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][CH2:30][CH2:29]1>>[C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=3)[CH:16]=2)[C:11]([N:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:31][CH2:30][CH2:29]2)=[O:13])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)O)c2)cc1
Reactant: c1ccc2c(c1)CCCN2
Product: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)N3CCCc4ccccc43)c2)cc1
Yield: 82.1 %

Procedure:
Following the procedure of Example 5(c) 3,5-bis-(4-cyano-phenoxy)-benzoic acid 1.2 g (3.36 mmol) and 1,2,3,4-tetrahydro-quinoline (0.44 g, 3.36 mmol) were used to afford 1.3 g of the required product. 1H NMR (DMSO-d6): δ 1.92 (2H, t), 2.54 (2H, m) 3.75 (2H, t), 6.92 (2H, d), 7.08 (7H, m), 7.82 (4H, d).
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([CH2:22][N:23]4[CH2:26][CH2:25][CH2:24]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:29])[CH:3]=1.[C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[C:45]1([CH2:51][C:52]([N:54]=[C:55]=[S:56])=[O:53])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.C(OCC)C>C(O)C.C1(C)C=CC=CC=1.CCCCCC>[F:29][C:4]1[CH:3]=[C:2]([NH:1][C:55]([NH:54][C:52](=[O:53])[CH2:51][C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)=[S:56])[CH:28]=[CH:27][C:5]=1[O:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][N:23]3[CH2:26][CH2:25][CH2:24]3)[CH2:18][CH2:17]2)=[O:15])[CH:8]=1
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: Nc1ccc(Oc2cc(NC(=O)N3CCC(CN4CCC4)CC3)ncn2)c(F)c1
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CCO
Solvent: CCCCCC
Solvent: CCOCC
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2cc(NC(=O)N3CCC(CN4CCC4)CC3)ncn2)c(F)c1
Reaction time: 0.08 h

Procedure:
4-(Azetidin-1-ylmethyl)piperidine-1-carboxylic acid [6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl]amide (110 mg) was dissolved in ethanol (3 ml) under a nitrogen atmosphere, and then (S)-(+)-10-camphorsulfonic acid (64 mg) was added thereto, followed by stirring for 5 min. A 0.25 M solution of phenylacetyl isothiocyanate in toluene (1.65 ml) was added thereto, followed by stirring for 1 hr. The reaction mixture was partitioned between ethyl acetate (50 ml) and a saturated aqueous solution of sodium hydrogencarbonate (30 ml). The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (30 ml), water (30 ml), brine (30 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (FUJI Silysia NH, eluent; heptane:ethyl acetate=1:8, then ethyl acetate). Fractions containing the target compound were concentrated under reduced pressure to give a residue, to which diethyl ether (4 ml) and hexane (4 ml) were then added to suspend. The solid was filtered off, and dried under aeration to provide the titled compound (76.1 mg) as white powder.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][CH2:5][CH:6]([C:8]1[C:16]([F:17])=[CH:15][C:11]2[S:12][CH:13]=[CH:14][C:10]=2[CH:9]=1)[OH:7].[CH2:18]([NH:20][CH2:21][CH3:22])[CH3:19].[I-].[K+].Cl.Cl.C(O)C>C(O)C.C(OCC)C.O.C(OCC)(=O)C>[ClH:1].[CH2:18]([N:20]([CH2:2][CH2:3][O:4][CH2:5][CH:6]([C:8]1[C:16]([F:17])=[CH:15][C:11]2[S:12][CH:13]=[CH:14][C:10]=2[CH:9]=1)[OH:7])[CH2:21][CH3:22])[CH3:19]
Reactant: CCNCC
Reactant: OC(COCCCl)c1cc2ccsc2cc1F
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCOCC
Product: CCN(CC)CCOCC(O)c1cc2ccsc2cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 0.61 g of 2-(2-chloroethoxy)-1-(6-fluorobenzo[b]thiophen-5-yl)ethanol, 3 ml of 50% aqueous diethylamine solution, 0.45 mg of potassium iodide and 20 ml of ethanol is refluxed for three hours. Subsequently, 3 ml of 50% aqueous diethylamine solution is added to the thus refluxed reaction mixture, and the resulting reaction mixture is further refluxed for three hours. The solvent is removed from the thus refluxed mixture by distillation under reduced pressure. To the residue obtained are added 30 ml of ethyl acetate and 30 ml of water, after which the resulting mixture is adjusted to pH 1.5 with 6N hydrochloric acid. Thereafter, the aqueous layer is separated and washed with 10 ml of ethyl acetate. 30Milliliters of ethyl acetate is then added to the thus washed layer, after which the resulting mixture is adjusted to pH 10.5 with potassium carbonate. The organic layer is separated again, washed successively with 10 ml of water and 10 ml of a saturated saline solution, and then dried over anhydrous magnesium sulfate. The solvent is then removed from the thus dried layer by distillation under reduced pressure. The residue obtained is dissolved in 6 ml of ethanol. To the resulting solution are added 0.6 ml of 5N dried hydrochloric acid-ethanol solution and 6 ml of diethyl ether. The mixture thus obtained is stirred at room temperature for one hour. The crystals precipitated are collected by filtration and washed with 2 ml of a liquid mixture of diethyl ether and ethanol (1:1) and then dried, to obtain 0.28 g of 2-[2-(N,N-diethylamino)ethoxy]-1-(6-fluorobenzo[b]thiophen-5-yl)ethanol hydrochloride.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[N:5]=[C:4]([N:11]2[CH2:16][CH2:15][S:14](=[O:17])[CH2:13][CH2:12]2)[N:3]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>O1CCOCC1>[C:8]([C:7]1[C:2]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[N:3][C:4]([N:11]2[CH2:16][CH2:15][S:14](=[O:17])[CH2:13][CH2:12]2)=[N:5][C:6]=1[CH3:10])#[N:9]
Reactant: Cc1nc(N2CCS(=O)CC2)nc(Cl)c1C#N
Reactant: C1CNCCN1
Solvent: C1COCCO1
Product: Cc1nc(N2CCS(=O)CC2)nc(N2CCNCC2)c1C#N

Procedure:
2.7 gm (0.01 mol) of 4-chloro-5-cyano-6-methyl-2-(1-oxido-thiomorpholino)-pyrimidine (m.p. 251°-253°C, obtained from 5-cyano-2,4-dichloro-6-methyl-pyrimidine and thiomorpholine-1-oxide in acetone while cooling) were refluxed with a solution of 8.6 gm (0.1 mol) of piperazine in 80 ml of dioxane for about 30 minutes. The major part of the solvent was distilled off in vacuo, the residue was dissolved in about 80 ml of water, and a small quantity of 8 N sodium hydroxide was added, whereby the reaction product was first obtained as greasy, but soon solidifying precipitate. The product was suction-filtered off, washed with water and dried. Yield: 2.8 gm (87% of theory).