Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([F:32])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][CH2:28][CH2:29][CH2:30][OH:31].[CH3:33][S:34](Cl)(=[O:36])=[O:35].O>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([F:32])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][CH2:28][CH2:29][CH2:30][O:31][S:34]([CH3:33])(=[O:36])=[O:35]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NCCCO)c(F)cc(F)c3o2)cc1F
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NCCCOS(C)(=O)=O)c(F)cc(F)c3o2)cc1F
Reaction time: 0.83 h
Yield: 98.8 %

Procedure:
2.98 g (6.65 mmol) of the above 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-(3-hydroxypropylamino)-4H-1-benzopyran-4-one was dissolved in 100 mL of pyridine, 1.1 mL (14 mmol) of methanesulfonyl chloride was added under ice-cooling and the mixture was stirred for 50 minutes. Water was added to the reaction solution and the precipitated crystals were collected by filtration to give 3.46 g of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-(3-methanesulfonyloxypropylamino)-4H-1-benzopyran-4-one (yield: 99%).
Reaction SMILES: C([O:8][N:9]1[C:13](=[O:14])[CH2:12][C@H:11]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[C:10]1=[O:30])C1C=CC=CC=1>C(OCC)(=O)C.CO.[Pd]>[CH2:26]([O:25][C:22]1[CH:23]=[CH:24][C:19]([S:16]([NH:15][C@H:11]2[CH2:12][C:13](=[O:14])[N:9]([OH:8])[C:10]2=[O:30])(=[O:17])=[O:18])=[CH:20][CH:21]=1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCCOc1ccc(S(=O)(=O)N[C@H]2CC(=O)N(OCc3ccccc3)C2=O)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCOc1ccc(S(=O)(=O)N[C@H]2CC(=O)N(O)C2=O)cc1
Yield: 74.9 %

Procedure:
N-(1-Benzyloxy-2,5-dioxo-pyrrolidin-3(S)-yl)-4-butoxy-benzenesulfonamide (100 mg, 0,23 mmol) was hydrogenated at atmospheric pressure for 1 h in ethyl acetate/methanol (1:1, 4 mL) with palladium on activated charcoal (50 mg, 10%). The mixure was filtered through Celite® and concentrated. The residue was purified by silica gel chromatography (ethyl acetate-acetic acid, 100:2) to give 59 mg (75%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[CH:16][C:17]([Br:20])=[CH:18][C:19]=3[C:11]=2[CH2:10][CH2:9][NH:8][CH:7]=1)=[O:5])[CH3:2].[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[CH:16][C:17]([Br:20])=[CH:18][C:19]=3[C:11]=2[CH2:10][CH2:9][N:8]([C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([F:21])=[CH:23][CH:24]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=CNCCc2c1[nH]c1ccc(Br)cc21
Reactant: O=C(Cl)c1ccc(F)cc1
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CCc2c1[nH]c1ccc(Br)cc21

Procedure:
The title compound was prepared in a manner similar to that described in Example 2A by using 9-bromo-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylic acid ethyl ester and 4-fluorobenzoyl chloride; 1H-NMR (CDCl3): δ 10.56 (1H, s), 7.98 (1H, s), 7.56 (3H, m), 7.19 (1H, m), 7.09 (2H, m), 4.17 (4H, m), 3.13 (2H, m), 1.13 (3H, t). MS (ESI): 457, 459 (MH+).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:14]([O-:16])=[O:15])=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:7]=1.[NH3:17].CO>>[N+:14]([C:5]1[CH:4]=[CH:3][C:2]([NH2:17])=[CH:7][C:6]=1[N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(F)cc1N1CCCCC1
Reactant: N
Solvent: CO
Product: Nc1ccc([N+](=O)[O-])c(N2CCCCC2)c1
Yield: 47 %

Procedure:
A solution of 1-(5-fluoro-2-nitro-phenyl)-piperidine (514 mg, 2.29 mmol) in 10 mL of saturated NH3-MeOH were heated in a sealed tube at 110° C. for 48 h. The result was concentrated in vacuo and purified by preparative thin layer chromatography to afford 240 mg (47%) of the title compound. Mass spectrum (ESI, m/z): Calcd. for C11H15N3O2, 222.1 (M+H), found 222.2.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([OH:14])=O)[CH:3]=1.Cl.[CH3:16][O:17][C:18](=[O:30])[C@@H:19]([NH2:29])[CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.O>[CH3:16][O:17][C:18](=[O:30])[C@@H:19]([NH:29][C:12]([C:4]1[CH:3]=[C:2]([OH:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)=[O:14])[CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23]
Reactant: COC(=O)[C@@H](N)CCC(=O)OC(C)(C)C
Reactant: O=C(O)c1cc(O)c2ccccc2n1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCCl
Product: COC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c1cc(O)c2ccccc2n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5 g 4-Hydroxy-quinoline-2-carboxylic acid and 5 g of (S)-2-Amino-pentanedioic acid 5-tert-butyl ester 1-methyl ester hydrochloride in 50 ml of DMF, 4.0 g of HOBT, 5.1 g of EDC and 6 g of NEM was added and the reaction mixture was stirred for 16 h at RT. Then, the reaction mixture was diluted with water and extracted with DCM. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by re-crystallisation from ethyl acetate and dried under reduced pressure. Yield: 6.5 g.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH:1][C:2]2[O:6][N:5]=[C:4]([CH3:7])[C:3]=2[Br:8])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Product: Cc1noc(NS(=O)(=O)c2ccc(Br)cc2)c1Br
Yield: 74 %

Procedure:
4-Bromo-N-(4-bromo-3-methy l-5-isoxazolyl)benzenesulfonamide was prepared in the same manner as described in Example 30 from 5-amino-4-bromo-3-methylisoxazole and 4-bromobenzenesulfonyl chloride in 74% yield. Purification was achieved by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 146-149° C.
Reaction SMILES: FC1C(O[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[C:14]3=[N:21][NH:22][C:23]2[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=2)=[O:10])=C(F)C(F)=C(F)C=1F.[OH:37][CH2:38][C:39]([CH3:43])([CH3:42])[CH2:40][NH2:41]>>[OH:37][CH2:38][C:39]([CH3:43])([CH3:42])[CH2:40][NH:41][C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[C:14]2=[N:21][NH:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=1)=[O:10]
Reactant: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc(C(=O)Oc4c(F)c(F)c(F)c(F)c4F)cc32)cc1
Reactant: CC(C)(CN)CO
Product: CC(C)(CO)CNC(=O)c1ccc2c(c1)C(=NNc1ccc(S(N)(=O)=O)cc1)C(=O)N2

Procedure:
The title compound was prepared from 2-oxo-3[(4-sulfamoyl-phenyl)-hydrazono]-2,3-dihydro-1H-indole-5-carboxylic acid pentafluorophenyl ester and 3-hydroxy-2,2-dimethylpropylamine according to Procedure K: mp>230° C.; Anal. Calcd for C20H23N5O5S: C, 53.92; H, 5.20; N, 15.72. Found: C, 54.04; H, 5.17; N, 15.77.
Reaction SMILES: N.[CH3:2][NH:3][CH2:4][CH:5]1[C:10]2[N:11](CC3C=CC=CC=3)[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:9]=2[S:8][CH2:7][CH2:6]1.[Na].[Cl-].[NH4+]>CCOCC>[CH3:2][NH:3][CH2:4][CH:5]1[C:10]2[NH:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:9]=2[S:8][CH2:7][CH2:6]1
Reactant: CNCC1CCSc2c1n(Cc1ccccc1)c1ccccc21
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CNCC1CCSc2c1[nH]c1ccccc21
Temperature: -70 °C
Reaction time: 1.5 h
Yield: 91.9 %

Procedure:
Liquid ammonia (ca. 100 ml) is trapped in a solution of 4-methylaminomethyl-5-benzyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole (1.6 g) in ether (20 ml) under cooling at -70° C. A piece of sodium metal is added occasionally under refluxing. The refluxing is continued for 1.5 hours after the dark green color of the reaction mixture disappears. The reaction mixture is neutralized with ammonium chloride, the excess ammonia removed, and then the residue extracted with methylene chloride after addition of water. The extract is washed with water, dried and evaporated to give the title compound (1.06 g): Yield 91.4%. Recrystallization from benzene-petroleum benzine gives crystals melting at 100°-101° C.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:5].CS(O[CH:20]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21]1)(=O)=O.O>CN(C=O)C>[CH3:5][N:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:20]2[CH2:21][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23]2)=[CH:9][C:8]=1[CH3:14])[CH3:3]
Reactant: Cc1cc(O)ccc1CN(C)C
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OC2CN(C(=O)OC(C)(C)C)C2)ccc1CN(C)C
Temperature: 80 °C
Reaction time: 1 h
Yield: 53.7 %

Procedure:
A mixture of NaH (55-65% disp. in oil, 1.0 g, 23 mmol) in dry DMF (25 mL) under nitrogen was cooled by an ice-bath. A solution of 20A (2.9 g, 18 mmol) in DMF (20 mL) was added drop-wise over 10 minutes. The mixture was stirred for one hour and then tert-butyl 3-[(methylsulfonyl)oxy]azetidine-1-carboxylate (5.3 g, 21 mmol) in DMF (15 mL) was added. The mixture was heated to 80° C. over night and then cooled to RT. Water (200 mL) was added and the mixture was extracted three times with EtOAc (100 mL). The combined organic phases were dried (MgSO4) and the solvent was removed by evaporation. The residue was purified by column chromatography on SiO2 using 5-75% EtOAc/heptane as eluent. The product was further purified using 0.5% NH3 in MeOH/DCM as eluent. There was obtained 3.1 g (55%) of 20B as a semi-solid. 1H NMR (600 MHz, CDCl3): δ 1.44 (s, 9H), 2.21 (s, 6H), 2.32 (s, 3H), 3.29 (s, 2H), 3.93-4.02 (m, 2H), 4.21-4.32 (m, 2H), 4.79-4.89 (m, 1H), 6.48 (d, 1H), 6.55 (s, 1H), 7.12 (d, 1H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C@H:9]([OH:22])[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[C:4](=[O:23])[CH2:3]1.[O:24]=[C:25]1[NH:30][C:29]2[CH:31]=[C:32]([CH:35]=O)[CH:33]=[CH:34][C:28]=2[S:27][CH2:26]1.[O-]S([O-])(=O)=O.[Na+].[Na+].[BH4-].[Na+]>CN(C=O)C>[OH:22][C@H:9]([C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1)[CH2:8][N:5]1[CH2:6][CH2:7][CH:2]([NH:1][CH2:35][C:32]2[CH:33]=[CH:34][C:28]3[S:27][CH2:26][C:25](=[O:24])[NH:30][C:29]=3[CH:31]=2)[CH2:3][C:4]1=[O:23]
Reactant: O=Cc1ccc2c(c1)NC(=O)CS2
Reactant: COc1ccc2nccc([C@@H](O)CN3CCC(N)CC3=O)c2c1
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2nccc([C@@H](O)CN3CCC(NCc4ccc5c(c4)NC(=O)CS5)CC3=O)c2c1

Procedure:
A mixture of 4-amino-1-[(R)-2-hydroxy-2-(6-methoxyquinolin-4-yl)ethyl]piperidin-2-one (4e) (1 equiv.), 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbaldehyde (in) (1.1 equiv.), and Na2SO4 in DMF is stirred until the imine has formed, then is filtered through a sintered glass funnel. The filtrate is concentrated to dryness in vacuo, and the residue is dissolved in MeOH. NaBH4 (1 equiv.) is added, and the reaction is stirred until the imine is consumed. The solvent is removed in vacuo and the residue is taken up in dilute HCl. The mixture is neutralized with dilute NaOH and extracted with CH2Cl2. Drying (Na2SO4), concentration, and flash chromatography on silica gel gives the title compound.
Reaction SMILES: C(C1C=C(CCC(NCCCCNC(=O)CCC2C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=2)=O)C=C(C(C)(C)C)C=1O)(C)(C)C.C(C1C=C(CCC(NCCCCCCCCNC(=O)CCC2C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=2)=O)C=C(C(C)(C)C)C=1O)(C)(C)C.C(C1C=C(CCC(Cl)=O)C=C(C(C)(C)C)C=1O)(C)(C)C.NCCCCN.NCCCCCCCCN.N[CH2:130][CH2:131][CH2:132][CH2:133][CH2:134][CH2:135][CH2:136][CH2:137][CH2:138][CH2:139][CH2:140][CH2:141]N>>[CH3:141][CH2:140][CH2:139][CH2:138][CH2:137][CH2:136][CH2:135][CH2:134][CH2:133][CH2:132][CH2:131][CH3:130]
Reactant: NCCCCCCCCCCCCN
Agent: CC(C)(C)c1cc(CCC(=O)Cl)cc(C(C)(C)C)c1O
Agent: CC(C)(C)c1cc(CCC(=O)NCCCCCCCCNC(=O)CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Agent: CC(C)(C)c1cc(CCC(=O)NCCCCNC(=O)CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Product: CCCCCCCCCCCC

Procedure:
Using techniques similar to the one described above 1,4-bis[β-(3,5-di-t-butyl-4-hydroxy phenyl) propionamido] butane (M.P. 203°-205° C); 1,8-bis[β-(3,5-di-t-butyl-4-hydroxy phenyl) propionamido] octane (M.P. 94.5°-96° C); and 1,12-bis[β-3,5-di-t-butyl-4-hydroxy phenyl) propionamido] dodecane (M.P. 89°-92° C) were prepared by reaction of β-(3,5-di-t-butyl-4-hydroxy phenyl) propionyl chloride with respectively 1,4 diamino butane, 1,8-diamino octane and 1,12-diamino dodecane.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)[N:14]=[CH:13][NH:12][C:11]2=O.CN(C)C1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:3][C:11]1[C:10]2[C:15](=[CH:16][C:17]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[C:8]([O:7][CH3:6])[CH:9]=2)[N:14]=[CH:13][N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCc1ccncc1
Solvent: Cc1ccccc1
Solvent: CN(C)c1ccccc1
Product: COc1cc2c(Cl)ncnc2cc1OCc1ccncc1
Yield: 41 %

Procedure:
Phosphorus oxytrichloride (0.1 ml) was added to a mixture of 6-methoxy-7-(4-pyridylmethoxy)-3,4-dihydroquinazolin-4-one (81 mg, 0.29 mmol) and N,N-dimethylaniline (0.1 ml) in toluene (5 ml), and the mixture heated at reflux for 1 hour. The volatiles were removed by evaporation and the residue partitioned between methylene chloride and aqueous ammnonia. The organic extract was separated, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by chromatography on silica eluting with ethyl acetate progressing through increasingly polar mixtures to methanol/methylene chloride (1/9) to give 4-chloro-6-methoxy-7-(4-pyridylmethoxy)quinazoline (40 mg, 41%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[CH2:5][CH2:6][NH:7][C:8]1[N:13]=[C:12]([C:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH:15]=2)[CH:11]=[CH:10][C:9]=1[C:27](=[O:36])[NH:28][CH2:29][C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1.Cl>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[CH2:5][CH2:6][NH:7][C:8]1[N:13]=[C:12]([C:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH:15]=2)[CH:11]=[CH:10][C:9]=1[C:27]([NH:28][CH2:29][C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1)=[O:36]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(C(=O)NCc3cccnc3)c(NCCc3cccc(F)c3)n2)CC1
Agent: Cl
Solvent: CO
Product: O=C(NCc1cccnc1)c1ccc(C2=CCNCC2)nc1NCCc1cccc(F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl 4-(6-(3-fluorophenethylamino)-5-(pyridin-3-ylmethylcarbamoyl)pyridin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (200 mg, 0.377 mmol) in MeOH (8 mL) at 0° C. was added HCl (2.0 mL, 8 mmol, 4 M in dioxane) under nitrogen. The reaction mixture was warmed to room temperatures stirred at r.t. for 4 h. LC/MS indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure to give 2-(3-fluorophenethylamino)-N-(pyridin-3-ylmethyl)-6-(1,2,3,6-tetrahydropyridin-4-yl)nicotinamide which was used for next step without further purification. LRMS (M+H+) m/z 444.2.
Reaction SMILES: [C:1](O)(=O)[CH:2]([CH3:4])[CH3:3].[NH2:7][CH2:8][CH:9]([NH2:11])[CH3:10]>>[CH:2]([C:1]1[NH:7][CH2:8][C@H:9]([CH3:10])[N:11]=1)([CH3:4])[CH3:3]
Reactant: CC(N)CN
Reactant: CC(C)C(=O)O
Product: CC(C)C1=N[C@@H](C)CN1
Yield: 80 %

Procedure:
The procedure described in Example 5 is followed except that 176 parts of isobutyric acid and 162.8 parts of 1,2-diaminopropane are employed. 201 parts of 2-isopropyl-4(5)-methylimidazoline (80% of theory, based on isobutyric acid employed) of boiling point 105°-106° C./32 mbar are obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=O)O[C:8](=O)[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2].[NH2:15][C:16]([CH3:20])([CH3:19])[CH2:17][OH:18].O>C(Cl)Cl>[CH3:19][C:16]([N:15]1[CH2:11][C:6]2[C:7](=[CH:13][CH:14]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:8]1)([CH3:20])[CH2:17][OH:18]
Reactant: CC(C)(N)CO
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Solvent: O
Solvent: ClCCl
Product: CC(C)(CO)N1Cc2ccc([N+](=O)[O-])cc2C1

Procedure:
20 g of 4-Nitro-phthalic anhydride and 8.94 g of 2-amino-2-methylpropanol were heated to 170° C. for 30 min. After cooling, water and CH2Cl2 were added, and the organic phase separated, concentrated and purified by chromatography on silica (eluent CH2Cl2/MeOH 97/3).
Reaction SMILES: [NH2:1][C:2]1[S:3]C2C(F)=CC=CC=2N=1.[F:12][C:13]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15].FC1C(F)=CC=C(F)C=1N>>[NH2:1][C:2]1[S:3][C:16]2[CH:17]=[CH:18][C:19]([F:20])=[C:13]([F:12])[C:14]=2[N:15]=1
Reactant: Nc1nc2cccc(F)c2s1
Reactant: Nc1cccc(F)c1F
Agent: Nc1c(F)ccc(F)c1F
Product: Nc1nc2c(F)c(F)ccc2s1

Procedure:
The title compound was prepared following the route for 2-amino-7-fluoro-1,3-benzothiazole from 2,3-difluoroaniline, starting from 2,3,6-trifluoroaniline and conducting the first step at 100° C. for 4 h.
Reaction SMILES: [H-].[Na+].Cl.[NH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([OH:11])[CH2:7][CH2:6]1.Cl[C:13]1[N:18]=[CH:17][CH:16]=[CH:15][N:14]=1>O1CCCC1>[N:14]1[CH:15]=[CH:16][CH:17]=[N:18][C:13]=1[O:11][C@H:8]1[CH2:9][CH2:10][C@H:5]([NH2:4])[CH2:6][CH2:7]1
Reactant: Clc1ncccn1
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N[C@H]1CC[C@H](Oc2ncccn2)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
60% sodium hydride was added to 10 ml of a tetrahydrofuran suspension containing 1.00 g of trans-4-aminocyclohexanol hydrochloride and the mixture was refluxed for 1 hour. After cooling to room temperature, 2-chloropyrimidine was slowly added thereto and the mixture was stirred at room temperature for 6 hours. The reaction mixture was poured into ice-cold water and extracted with chloroform. The extract was washed with brine and dried over anhydrous sodium sulfate, and then, the solvent was removed under reduced pressure. The residue was purified by NH-silica gel column chromatography (solvent: ethyl acetate-hexane (1:4) to chloroform alone) to obtain 788 mg of trans-4-(2-pyrimidinyloxy)cyclohexylamine (Reference Example 9-46 in Table 6).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Br:5][CH:6]([CH3:10])[C:7](Cl)=[O:8].BrC(C)C(O)=O.S(Cl)(Cl)=O.[Br:21][C:22]1[CH:23]=[C:24]([CH3:28])[CH:25]=[CH:26][CH:27]=1.[NH4+].[Cl-]>ClC(Cl)C.CN(C)C=O>[Br:5][CH:6]([CH3:10])[C:7]([C:25]1[CH:26]=[CH:27][C:22]([Br:21])=[CH:23][C:24]=1[CH3:28])=[O:8]
Reactant: CC(Br)C(=O)Cl
Reactant: Cc1cccc(Br)c1
Agent: CC(Br)C(=O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1cc(Br)ccc1C(=O)C(C)Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of AlCl3 (20.4 g, 153 mmol) in dichloroethane (150 mL, DCE) was added 2-bromopropionyl chloride, freshly prepared from 2-bromopropionic acid (23.4 g, 153 mmol), excess thionyl chloride, and catalytic N,N-dimethylformamide, at 25° C. To the resulting mixture was added 3-bromotoluene (20.2 g, 118 mmol) at 17° C., and the dark solution was stirred at room temperature for 2 h. The reaction was cooled to 0° C. and satd aq NH4Cl was slowly added. The phases were separated and the organic layer was washed with additional satd aq NH4Cl, dried (Na2SO4), filtered, and concentrated in vacuo to give crude 2-bromo-1-(4-bromo-2-methylphenyl)propan-1-one as a dark oil. Flash chromatography (SiO2; 0-5% Et2O/Hexanes) afforded the desired product as the major component in a mixture of isomeric products (32.3 g crude). The resulting gold oil (10.0 g, 32.7 mmol) was dissolved in 1,2-dichloroethane (120 mL), and potassium acetate (4.8 g, 49 mmol) and benzyltriethylammonium chloride (0.37 g, 1.6 mmol) were added. The resulting mixture was heated to reflux and stirred for 6 h and then at 25° C. for 16 h. The reaction mixture was washed with water, and the organic phase was dried (Na2SO4), filtered, and concentrated in vacuo to give crude product as a yellow oil. Flash chromatography (SiO2; 0-20% Et2O/Hexanes) afforded the racemic product (5.0 g, 54%) as a yellow oil: 1H NMR (CDCl3) δ 1.42 (d, 3H, J=7.3 Hz), 2.11 (s, 3H), 2.41 (s, 3H), 5.69 (q, 1H, J=7.3 Hz), 7.38-7.44 (m, 2H), 7.52 (d, 1H, J=8.4 Hz); EI/MS 285 m/e (M+).
Reaction SMILES: [C:1]1([C@H:7]2[CH2:11][N:10]([S:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][CH2:19][CH2:18]4)(=[O:14])=[O:13])[C:9](=[O:24])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[N+:31]([C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1)([O-:33])=[O:32].C(OC(=O)C)C.CCCCCC>ClCCl>[C:1]1([C@H:7]2[CH2:11][N:10]([S:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([C:38](=[O:39])[C:37]3[CH:36]=[CH:35][C:34]([N+:31]([O-:33])=[O:32])=[CH:42][CH:41]=3)[CH2:19][CH2:18]4)(=[O:14])=[O:13])[C:9](=[O:24])[NH:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1N[C@@H](c2ccccc2)CN1S(=O)(=O)c1ccc2c(c1)CCN2
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: CCCCCC
Solvent: ClCCl
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1CCc2cc(S(=O)(=O)N3C[C@H](c4ccccc4)NC3=O)ccc21
Temperature: 5 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
(S)-(+)-4-phenyl-1-(indoline-5-sulfonyl)-4,5-dihydro-2-imidazolone (0.72 g, 2.09 mmol) prepared in Preparation 8 was dissolved in 20 ml of dichloromethane. Then, pyridine (186 μl, 2.23 mmol) and 4-nitrobenzoyl chloride (413 mg, 2.23 mmol) were added thereto at 0° C. under nitrogen atmosphere one after another. The reaction mixture was stirred at 5° C. for 2 hours and further stirred at room temperature for 3 hours. Then, the reaction mixture was diluted with 20 ml of dichloromethane, washed with water, dried over anhydrous magnesium sulfate, concentrated and finally purified by silica gel column chromatography (eluent:ethylacetate/hexane=2/1, v/v) to afford 0.97 g (Yield: 93%) of (S)-(+)-4-phenyl-1-[N-(4-nitrobenzoyl)-indoline-5-sulfonyl]-4,5-dihydro-2-imidazolone.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=1.[CH3:13][O:14][CH:15]([O:23][CH3:24])[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[CH3:13][O:14][CH:15]([O:23][CH3:24])[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[O:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)c1cccc(CO)n1
Reactant: COC(OC)c1ccncc1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cccc(COc2cnccc2C(OC)OC)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.7 %

Procedure:
Into a 50-mL round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of methyl 6-(hydroxymethyl)pyridine-2-carboxylate (300 mg, 1.79 mmol, 1.00 equiv) in tetrahydrofuran (15 mL). 4-(Dimethoxymethyl)pyridin-3-ol (304.2 mg, 1.80 mmol, 1.00 equiv), and triphenylphosphane (615 mg, 2.34 mmol, 1.30 equiv) was added to the reaction mixture. This was followed by the addition of DIAD (473.1 mg, 2.34 mmol, 1.30 equiv) dropwise at 0° C. The resulting solution was stirred overnight at room temperature, and then it was quenched by the addition of 10 mL of water. The resulting solution was extracted with 2×50 mL of ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5-1:1) as eluent to yield 340 mg (60%) of methyl 6-([[4-(dimethoxymethyl)pyridin-3-yl]oxy]methyl)pyridine-2-carboxylate as a white solid.