Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C.[NH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([N:20]3[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)=[O:19])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.NC1C=C2C(=CC=1)CN(C(NC1C=C[C:45]([C:48](=[O:53])NCCC)=[CH:44][CH:43]=1)=O)C2>>[C:48]([N:5]1[CH2:6][CH2:7][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([N:20]3[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)=[O:19])=[CH:13][CH:12]=2)[CH2:9][CH2:10]1)(=[O:53])[CH2:45][CH2:44][CH3:43]
Reactant: O=C(Nc1ccc(C2CCNCC2)cc1)N1Cc2ccccc2C1
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(N)cc3C2)cc1
Solvent: CC(=O)Cl
Product: CCCC(=O)N1CCC(c2ccc(NC(=O)N3Cc4ccccc4C3)cc2)CC1

Procedure:
The title compound was prepared as described in Example 278, substituting butyryl chloride for acetyl chloride and N-[4-(piperidin-4-yl)phenyl]-1,3-dihydro-2H-isoindole-2-carboxamide for 5-amino-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.27 (s, 1H), 7.46-7.49 (m, 2H), 7.34-7.39 (m, 2H), 7.28-7.33 (m, 2H), 7.11-7.14 (m, 2H), 4.75-4.76 (bs, 4H), 4.52-4.57 (m, 1H), 3.94-4.00 (m, 1H), 3.03-3.11 (m, 1H), 2.64-2.75 (m, 1H), 2.51-2.63 (m, 1H), 2.31 (t, J=7.4 Hz, 2H), 1.73-1.81 (m, 2H), 1.47-1.59 (m, 3H), 1.32-1.47 (m, 1H), 0.85-0.95 (m, 3H); MS (ESI(+)) m/e 392 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[B-](F)(F)(F)[F:12].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C.CC(O)=O>[Cl:1][C:2]1[C:3]2[C:10]([F:12])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: F[B-](F)(F)F
Reactant: Clc1ncnc2[nH]ccc12
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Solvent: CC(=O)O
Product: Fc1c[nH]c2ncnc(Cl)c12
Temperature: 70 °C
Reaction time: 16 h

Procedure:
4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (F-1) (5.01 g, 32.6 mmol, 1 eq) and selectfluor (17.32 g, 48.9 mmol, 1.5 eq) are dissolved in a mixture of anhydrous acetonitrile (250 mL) and AcOH (50 mL). The resulting mixture is stirred at 70° C. under argon for 16 h. The mixture is concentrated in vacuo. The residue is dissolved in a mixture of DCM-ethyl acetate (v/v=1/1, 50 mL) and filtered through celite. The filtrate is concentrated in vacuo and the residue is purified by flash chromatography on silica gel (0-0.7% MeOH-DCM) to afford the product, 4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine (F-2).
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[CH3:29][C:30]([CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)([CH3:33])[CH2:31][OH:32]>>[CH3:33][C:30]([CH:34]1[CH2:35][CH2:36][N:37]([CH2:2][C:3]2[N:4]([CH3:28])[C:5]3[C:10]([N:11]=2)=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:8]=[C:7]([N:18]2[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[N:20]=[C:19]2[CH3:27])[N:6]=3)[CH2:38][CH2:39]1)([CH3:29])[CH2:31][OH:32]
Reactant: CC(C)(CO)C1CCNCC1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)CO)CC3)n(C)c2n1

Procedure:
Following General Procedure E for amine alkylation, 4-(8-(bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine and 2-methyl-2-(piperidin-4-yl)propan-1-ol were reacted to give 339. LCMS: M+H+=519.3
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH:5]=[CH:6][C:7]1[N:16]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:10]2=[N:11][C:12]([Cl:15])=[CH:13][CH:14]=[C:9]2[CH:8]=1)[CH3:2]>CCOC(C)=O.O=[Pt]=O>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH2:6][C:7]1[N:16]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:10]2=[N:11][C:12]([Cl:15])=[CH:13][CH:14]=[C:9]2[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1cc2ccc(Cl)nc2n1CC(=O)OC(C)(C)C
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1cc2ccc(Cl)nc2n1CC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
A mixture of 0.8 g of 3-(1-tert-butoxycarbonylmethyl-6-chloro-1H-pyrrolo[2,3-b]pyridin-2-yl)-acrylic acid ethyl ester and 80 mg of PtO2 in 60 mL of EtOAc was stirred under a balloon pressure of H2 for 1 h. The mixture was filtered through celite and concentrated to give crude product (0.8 g, white solid).
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][C:10]([F:13])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:14][C:15]1[CH:16]=[C:17]([OH:22])[CH:18]=[CH:19][C:20]=1[Cl:21].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[CH2:7]([O:6][C:4](=[O:5])[C:3]1[CH:9]=[C:10]([F:13])[CH:11]=[N:12][C:2]=1[O:22][C:17]1[CH:18]=[CH:19][C:20]([Cl:21])=[C:15]([Cl:14])[CH:16]=1)[CH3:8]
Reactant: CCOC(=O)c1cc(F)cnc1Cl
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(F)cnc1Oc1ccc(Cl)c(Cl)c1

Procedure:
Ethyl 2-chloro-5-fluoronicotinate (5.09 g, 25 mmol see reference J. Med. Chem., 1993, 36(18) 267-88) and 3,4-dichlorophenol (6.11 g, 37.5 mmol) were dissolved in 1,4-dioxane and the solution was purged with argon. Anhydrous caesium carbonate (12.21 g, 37.5 mmol) was added and the mixture was heated under reflux for 17 hours. The reaction mixture was partitioned between water (300 ml) and ethyl acetate (300 ml). The aqueous layer was acidified to pH 3 by addition of 2M hydrochloric acid and the phases were separated. The aqueous layer was extracted with ethyl acetate (2-fold 100 ml) and the combined organic solutions were dried over magnesium sulphate and concentrated in-vacuo to give a red oil. The material isolated was redissolved in ethyl acetate and was washed with 5% potassium carbonate solution (2-fold 200 ml), 0.5 M sodium hydroxide solution (2-fold 200 ml) and saturated sodium hydrogen carbonate solution (100 ml). The organic phase was dried over magnesium sulphate and concentrated in-vacuo. The residue was purified by chromatography on silica gel using ethyl acetate in pentane as eluant (4:96) to give 2-(3,4-dichloro-phenoxy)-5-fluoro-nicotinic acid ethyl ester as a colourless oil that crystallised on standing (4.95 g).
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH2:24][CH2:23][CH2:22]2>CN1C(=O)CCC1>[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]([C:2]1[C:3](=[O:16])[NH:4][C:5]3[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)[CH2:24][CH2:23][CH2:22]2
Reactant: COc1ccc2c(c1)CCCN2
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc2[nH]c(=O)c(N3CCCc4cc(OC)ccc43)nc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 42 %

Procedure:
To a solution of methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (700 mg, crude) in NMP (2 mL) was added 6-methoxy-1,2,3,4-tetrahydroquinoline (1.0 g, 6.13 mmol) with stifling for 3 h at 150° C. The reaction mixture was cooled to room temperature. The product was precipitated by the addition ethyl acetate and the solids were collected by filtration to afford methyl 3-(6-methoxy-1,2,3,4-tetrahydroquinolin-1-yl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a light yellow solid (450 mg), which was used to the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[CH3:13])(=[O:11])=[O:10])[CH:5]=[N:6][C:7]=1Cl.CC(C)([O-])C.[K+].CN(C)C(=O)C.[CH3:31][N:32]1[CH:36]=[CH:35][C:34]([NH:37][C:38]2[C:47]3[C:42](=[CH:43][CH:44]=[C:45]([OH:48])[CH:46]=3)[N:41]=[CH:40][N:39]=2)=[N:33]1>O>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[CH3:13])(=[O:11])=[O:10])[CH:5]=[N:6][C:7]=1[O:48][C:45]1[CH:46]=[C:47]2[C:42](=[CH:43][CH:44]=1)[N:41]=[CH:40][N:39]=[C:38]2[NH:37][C:34]1[CH:35]=[CH:36][N:32]([CH3:31])[N:33]=1
Reactant: Cn1ccc(Nc2ncnc3ccc(O)cc23)n1
Reactant: CN(C)CCN(C)S(=O)(=O)c1cnc(Cl)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN(C)CCN(C)S(=O)(=O)c1cnc(Oc2ccc3ncnc(Nc4ccn(C)n4)c3c2)c(Cl)c1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 59.9 %

Procedure:
5,6-Dichloro-N-[2-(dimethylamino)ethyl]-N-methylpyridine-3-sulfonamide (104 mg, 0.33 mmol) and potassium tert-butoxide (58 mg, 0.52 mmol) were added to an N,N-dimethylacetamide solution (1 ml) of 4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-ol (50 mg, 0.21 mmol), and stirred under a nitrogen atmosphere at 100° C. for 2.5 hours. The reaction solution was cooled with ice, saline water was added, and extracted with chloroform. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by amine-type silica gel column chromatography (Biotage NH, hexane:ethyl acetate:chloroform=2:5:1 to 2:5:2) to obtain the entitled compound (65 mg, yield: 61%) as a pale orange amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12](O)=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:15][C:16]1[CH:23]=[CH:22][C:19](C=O)=[CH:18][CH:17]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](/[CH:11]=[CH:12]/[C:19]2[CH:22]=[CH:23][C:16]([CH3:15])=[CH:17][CH:18]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)CS(=O)(=O)c1ccc(Cl)cc1
Reactant: Cc1ccc(C=O)cc1
Product: Cc1ccc(/C=C/S(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 60 %

Procedure:
A solution of 4-chlorophenyl sulfonylacetic acid (0.01 mol) and 4-methylbenzaldehyde (0.01 mol) was subjected to Procedure 1. The title compound was obtained in 60-64% yield.
Reaction SMILES: N1C=CN=C1.S(Cl)([Cl:8])=O.[F:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[C:18](O)([C:25]([F:28])([F:27])[F:26])[CH2:19][N:20]1[CH:24]=[N:23][CH:22]=[N:21]1.C(=O)(O)[O-].[Na+]>C(#N)C>[Cl:8][C:18]([C:12]1[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:11]=1[F:10])([C:25]([F:28])([F:27])[F:26])[CH2:19][N:20]1[CH:24]=[N:23][CH:22]=[N:21]1
Reactant: OC(Cn1cncn1)(c1ccc(F)cc1F)C(F)(F)F
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CC#N
Product: Fc1ccc(C(Cl)(Cn2cncn2)C(F)(F)F)c(F)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Imidazole (0.53 g, 7.8 mmole) was dissolved in dry acetonitrile (4 ml) and thionyl chloride (0.3 ml, 4.1 mmole) was added dropwise over 2 minutes followed by a solution of 2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3,3,3-trifluoropropan-2-ol (0.389 g, 1.25 mmole) in dry acetonitrile (12 ml). The mixture was stirred at room temperature for 24 hours and then heated to 70° C. for 1/2 hour. The cooled mixture was then poured into sodium bicarbonate solution and extracted with dichloromethane (3×100 ml). The combined dichloromethane extracts were washed once with water, dried over magnesium sulphate and evaporated. Chromatography of the residue on silica (230-400 mesh), eluting with 40:60 (by volume) ethyl acetate:hexane gave, after recrystallization from ethyl acetate/hexane, the title compound, 170 mg (41%), m.p. 87°-88° C.
Reaction SMILES: C(O[C@@H](C1C(C)=CC2N=C(C3C=C4C(C([C:29]5[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH:34]=5)=NN4C)=CC=3)SC=2C=1C1C=CC(Cl)=CC=1)C(OCC)=O)(C)(C)C.Br[C:47]1[C:55]2[C:50](=[CH:51][CH:52]=[C:53]([C:56]3[S:57][C:58]4[C:64]([C:65]5[CH:70]=[CH:69][C:68]([Cl:71])=[CH:67][CH:66]=5)=[C:63]([C@H:72]([O:78][C:79]([CH3:82])([CH3:81])[CH3:80])[C:73]([O:75][CH2:76][CH3:77])=[O:74])[C:62]([CH3:83])=[CH:61][C:59]=4[N:60]=3)[CH:54]=2)[N:49]([CH3:84])[N:48]=1>>[C:79]([O:78][C@@H:72]([C:63]1[C:62]([CH3:83])=[CH:61][C:59]2[N:60]=[C:56]([C:53]3[CH:54]=[C:55]4[C:50](=[CH:51][CH:52]=3)[N:49]([CH3:84])[N:48]=[C:47]4[C:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH:30]=3)[S:57][C:58]=2[C:64]=1[C:65]1[CH:70]=[CH:69][C:68]([Cl:71])=[CH:67][CH:66]=1)[C:73]([O:75][CH2:76][CH3:77])=[O:74])([CH3:82])([CH3:81])[CH3:80]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(c3)c(Br)nn4C)sc2c1-c1ccc(Cl)cc1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(C5=CCN(C)CC5)nn(C)c4c3)sc2c1-c1ccc(Cl)cc1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(c3)c(C3=CCN(C)CC3)nn4C)sc2c1-c1ccc(Cl)cc1

Procedure:
Prepared in a manner similar to (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(1-methyl-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indazol-6-yl)benzo[d]thiazol-6-yl)acetate except using (S)-ethyl 2-(2-(3-bromo-1-methyl-1H-indazol-5-yl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate instead of (S)-ethyl 2-(2-(3-bromo-1-methyl-1H-indazol-6-yl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate. LCMS-ESI+: calc'd for C36H39ClN4O3S: 643.2, 645.2 (M+H+); Found: 643.1, 645.0 (M+H+). 1H NMR (400 MHz, CD3OD): δ 8.65 (s, 1H), 8.13 (dd, J=8.9, 1.5 Hz, 1H), 7.84 (s, 1H), 7.71 (d, J=8.9 Hz, 1H), 7.65-7.47 (m, 4H), 6.66 (s, 1H), 5.25 (s, 1H), 4.37-4.15 (m, 2H), 4.11 (s, 3H), 4.03-3.87 (m, 2H), 3.87-3.63 (m, 2H), 3.57-3.37 (m, 2H), 3.07 (s, 3H), 2.60 (s, 3H), 1.26 (t, J=7.1 Hz, 3H), 1.00 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[O:13]1[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]1>C1COCC1>[OH:19][C:16]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:17][CH2:18][O:13][CH2:14][CH2:15]1
Reactant: Brc1ccccn1
Reactant: O=C1CCOCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2ccccn2)CCOCC1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 61.2 %

Procedure:
To a stirred, cooled solution of 2-bromopyridine (5 g, 31.65 mmol) in THF (75 mL) at −78° C. was added n-butyl lithium (2.5 M in hexanes, 12.66 mL, 31.65 mmol) dropwise and the solution stirred at −78° C. for 10 minutes. After this time, tetrahydro-4H-pyran-4-one (3.49 g, 34.81 mmol) was added, the reaction warmed to ambient temperature and stirred overnight. The reaction was then quenched with saturated aqueous ammonium chloride solution and the THF removed in vacuo. The resultant aqueous phase was twice extracted with ethyl acetate and the combined organic phases dried (magnesium sulfate) and filtered. After concentration in vacuo, purification by column chromatography (SiO2, eluting with 2:1 hexanes:ethyl acetate) gave a residue which was triturated from hexane to yield the title compound (3.47 g, 61%) as a white solid; NMR δH (400 MHz, CDCl3) 8.49 (1H, m), 7.81 (1H, td, J 7.8 Hz, 1.8 Hz), 7.68 (1H, m), 7.25 (1H, ddd, J 7.5 Hz, 4.9 Hz, 1.1 Hz), 3.85 (4H, m), 3.30 (1H, m), 2.30 (2H, td, J 13.3 Hz, 5.3 Hz), 1.54 (1H, dd, J 13.8 Hz, 1.9 Hz); LC-MS Retention time 0.51 min, (M+H)+ 180.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([CH2:12][S:13][C:14]2[NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]=2)[C:7]=1[CH3:23].ClC1C=CC=C(C(OO)=[O:32])C=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>ClCCl>[OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([CH2:12][S:13]([C:14]2[NH:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)=[O:32])[C:7]=1[CH3:23]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1c(OCCCO)ccnc1CSc1nc2ccccc2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(OCCCO)ccnc1CS(=O)c1nc2ccccc2[nH]1
Temperature: -20 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
1.0 g (3.04 mmol) of 2-[{4-(3-hydroxypropoxy)-3-methylpyridine-2-yl}methylthio]-1H-benzimidazole was dissolved in 100 ml of dichloromethane to obtain a solution. 580 mg of 90% m-chloroperbenzoic acid was added to this solution at -45° C. The obtained mixture was stirred for 2 hours. After the completion of the reaction, 470 mg of triethylamine was added to the reaction mixture. The obtained mixture was heated to -20° C., followed by the addition of 30 ml of a saturated aqueous solution of sodium hydrogencarbonate. The obtained mixture was stirred at a room temperature for 30 minutes and extracted with chloroform. The obtained chloroform layer was concentrated to obtain a crude product. This crude product was crystallized from dichloromethane/ether to obtain 830 mg of 2-[{4-(3-hydroxypropoxy)-3-methylpyridine-2-yl}methylsulfinyl]-1H-benzimidazole. This product was dissolved in 24 ml of 0.1N aqueous sodium hydroxide. The obtained solution was distilled together with ethanol to remove the water as an azeotropic mixture with ethanol and dried under vacuumizing with a vacuum pump. Ether was added to the obtained residue to precipitate a colorless crystal. This crystal was separated by filtration. Thus, 860 mg of the title compound was obtained (77%).
Reaction SMILES: [CH3:1][C:2]1([C:8]([NH:10][CH:11]([C:17](=[O:19])[CH3:18])[CH2:12][C:13]([O:15][CH3:16])=[O:14])=O)[CH2:7][CH2:6][CH:5]=[CH:4][CH2:3]1.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:18][C:17]1[O:19][C:8]([C:2]2([CH3:1])[CH2:7][CH2:6][CH:5]=[CH:4][CH2:3]2)=[N:10][C:11]=1[CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)CC(NC(=O)C1(C)CC=CCC1)C(C)=O
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)Cc1nc(C2(C)CC=CCC2)oc1C

Procedure:
A mixture of methyl 3-(1-methyl-3-cyclohexen-1-ylcarbonylamino)-4-oxovalerate (3.4 g), toluene (50 ml) and phosphorus oxychloride (3.5 ml) was refluxed for 3 hours and the solvent was distilled off. Aqueous sodium hydrogen carbonate was added, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off and the oily residue was further distilled under reduced pressure to give methyl 5-methyl-2-(1-methyl-3-cyclohexen-1-yl)-4-oxazoleacetate as an oil; yield 2.5 g (78.1%). Bp 120°-123° C. (0.3 mmHg).
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4](=[O:10])[CH2:5][CH2:6][C:7]([OH:9])=[O:8].[CH3:11]O>Cl>[ClH:1].[NH2:2][CH2:3][C:4](=[O:10])[CH2:5][CH2:6][C:7]([O:9][CH3:11])=[O:8]
Reactant: NCC(=O)CCC(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)CCC(=O)CN
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a 500 ml glass reactor containing 200 ml methanol, was added 1 g 5-amino-levulinic acid hydrochloride and 1 drop conc. HCl. The reaction mixture was then stirred overnight at 60° C. The progress of the esterification was followed by 1H-NMR. Excess methanol was removed by distillation, and the product further dried under vacuum at 30–40° C., giving methyl 5-aminolevulinate hydrochloride. The structure was confirmed by 1H-NMR in DMSO-d6.
Reaction SMILES: [NH2:1]CCCN1CCN(CCCN)CC1.[Cl:15][CH2:16][CH2:17][C:18]([N:20]=[C:21]=[O:22])=[O:19]>>[Cl:15][CH2:16][CH2:17][C:18]([NH:20][C:21]([NH2:1])=[O:22])=[O:19]
Reactant: NCCCN1CCN(CCCN)CC1
Reactant: O=C=NC(=O)CCCl
Product: NC(=O)NC(=O)CCCl
Yield: 318.8 %

Procedure:
In the same way as in Example 1, reaction of 10.0 g (50 mmols) of N,N'-bis(3-aminopropyl)piperazine with 14.3 g (106 mmols) of 3-chloropropionyl isocyanate gives 24.0 g of the 3-chloropropionylurea compound of the formula ##STR11##
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7](=[O:9])[NH2:8])=[C:4]([NH:10][C:11]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=O)[CH:3]=1.[OH-].[Na+].Cl>COCCOC>[Br:1][C:2]1[S:6][C:5]2[C:7](=[O:9])[NH:8][C:11]([C:13]3[S:14][CH:15]=[CH:16][N:17]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: NC(=O)c1sc(Br)cc1NC(=O)c1nccs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: O=c1[nH]c(-c2nccs2)nc2cc(Br)sc12
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a mixture of 3-amino-5-bromothiophene-2-carboxamide (200 mg) produced in Example 1, step D, triethylamine (0.19 mL) and tetrahydrofuran (4.0 mL) was added 1,3-thiazole-2-carbonyl chloride (0.22 g) at 0° C., and the mixture was stirred at room temperature for 2 hr. Water was poured into the reaction system, and the precipitate was collected by filtration to give N-(5-bromo-2-carbamoylthiophen-3-yl)-1,3-thiazole-2-carboxamide (290 mg) as a pale-yellow solid. To N-(5-bromo-2-carbamoylthiophen-3-yl)-1,3-thiazole-2-carboxamide produced above were added 2M aqueous sodium hydroxide solution (1.75 mL) and 1,2-dimethoxyethane (4.0 mL), and the mixture was stirred at 100° C. for 18 hr. The reaction system was neutralized with 1M hydrochloric acid at 0° C. The precipitate was collected by filtration to give the title compound (236 mg) as a white solid.
Reaction SMILES: [C:1]([N:9]1[CH2:15][CH2:14][CH:13](Br)[C:12](=O)[C:11]2[CH:18]=[CH:19][CH:20]=[CH:21][C:10]1=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([NH2:25])(=[S:24])[CH3:23]>C(O)C>[CH3:23][C:22]1[S:24][C:13]2[CH2:14][CH2:15][N:9]([C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:8])[C:10]3[CH:21]=[CH:20][CH:19]=[CH:18][C:11]=3[C:12]=2[N:25]=1
Reactant: O=C1c2ccccc2N(C(=O)c2ccccc2)CCC1Br
Reactant: CC(N)=S
Solvent: CCO
Product: Cc1nc2c(s1)CCN(C(=O)c1ccccc1)c1ccccc1-2
Reaction time: 16 h
Yield: 70 %

Procedure:
To a solution of 1-benzoyl-4-bromo-1,2,3,4-tetrahydrobenzo[b]azepin-5-one (11.0 g, 2.9 mmol) from Example E5.7 in ethanol (50 ml) was added thioacetamide (0.75 g, 10 mmol). The solution was stirred for 16 h. The resultant suspension was reduced in volume by evaporation and cooled. The precipitate was collected by filtration and the solid was washed with cold ethanol and dried to yield the title compound as a white solid (0.65 g, 70%).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][C:10]=2[C:21]([F:24])([F:23])[F:22])[CH2:5][CH2:4][N:3]1C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C@@H:2]1[NH:3][CH2:4][CH2:5][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][C:10]=2[C:21]([F:24])([F:22])[F:23])[CH2:7]1
Reactant: C[C@H]1CN(Cc2ccc(N3CCOCC3)cc2C(F)(F)F)CCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H]1CN(Cc2ccc(N3CCOCC3)cc2C(F)(F)F)CCN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
A 100 mL round-bottom flask was charged with tert-butyl (2S)-2-methyl-4-[[4-(morpholin-4-yl)-2-(trifluoromethyl)phenyl]methyl]piperazine-1-carboxylate (1.40 g, 3.16 mmol, 1.00 equiv), dichloromethane (15 mL). Trifluoroacetic acid (3.80 g, 33.3 mmol, 9.40 equiv) was added at 0° C. The resulting solution was stirred overnight at room temperature and concentrated under reduced pressure to yield 0.900 g (83% yield) of 4-(4-[[(3S)-3-methylpiperazin-1-yl]methyl]-3-(trifluoromethyl)phenyl)morpholine as colorless oil. LCMS (ESI, m/z): 294 [M+H]+.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]=1.[CH:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>O1CCCC1>[Cl:9][C:10]1[C:15]([CH:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[OH:27])=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[N:11]=1
Reactant: FC(F)(F)c1cccc(Cl)n1
Reactant: O=Cc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OC(c1ccccc1)c1ccc(C(F)(F)F)nc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
Lithium diisopropylamide (3.7 mL, 1.8 M tetrahydrofuran solution, manufactured by Tokyo Chemical Industry Co., Ltd.) was added to a solution of 2-chloro-6-(trifluoromethyl)pyridine (1.0 g, manufactured by Matrix Chemical LLC) in tetrahydrofuran (55 mL, manufactured by Kanto Chemical Co., Inc.) at −78° C., and the mixture was stirred for 30 minutes at the same temperature. Then, benzaldehyde (1.17 g, manufactured by Kokusan Chemical Co., Ltd.) was added thereto at −78° C., and the mixture was stirred overnight while gradually raising the temperature to room temperature. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3×10 mL), washed with brine (20 mL), and dried (MgSO4). The solvent was then evaporated. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=9:1), to give 1.58 g of the title compound. LC-MS: HPLC retention time 1.68 minutes, m/z 288 (M+H), condition C-1.
Reaction SMILES: [CH2:1]([CH:3]1[NH:7][C:6](=[O:8])[NH:5][CH:4]1[C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13](F)=[CH:12][CH:11]=1)[CH3:2].[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH2:1]([CH:3]1[CH:4]([C:9](=[O:17])[C:10]2[CH:15]=[CH:14][C:13]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:12][CH:11]=2)[NH:5][C:6](=[O:8])[NH:7]1)[CH3:2]
Reactant: CCC1NC(=O)NC1C(=O)c1ccc(F)cc1
Reactant: C1CCNCC1
Product: CCC1NC(=O)NC1C(=O)c1ccc(N2CCCCC2)cc1

Procedure:
A suspension of 10 g of 5-ethyl-4-(4-fluorobenzoyl)-2-imidazolidinone in 30 ml piperidine is stirred at reflux for 24 hours. Excess piperidine is evaporated under reduced pressure and the residue is purified by crystallization from alcohol.