Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([NH:17][C:18](=[O:20])[CH3:19])=[N:14][C:13]=2[CH3:21])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[NH:22]1[CH:26]=[CH:25][N:24]=[CH:23]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1>[N:22]1([C:2]2[CH:3]=[C:4]([C:12]3[S:16][C:15]([NH:17][C:18](=[O:20])[CH3:19])=[N:14][C:13]=3[CH3:21])[CH:5]=[CH:6][C:7]=2[S:8]([CH3:11])(=[O:10])=[O:9])[CH:26]=[CH:25][N:24]=[CH:23]1
Reactant: c1c[nH]cn1
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(F)c2)s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(-n3ccnc3)c2)s1
Temperature: 135 °C

Procedure:
A stirred mixture of N-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide (AF1) (5.0 g, 15 mmol), imidazole (2.07 g, 30 mmol) and caesium carbonate (9.93 g, 30 mmol) in dry NMP (30 ml) is heated under argon at 135° C. for 18 hours. The reaction mixture is then poured onto water (50 ml) whereupon the titled product precipitates and is recrystalfised from ethanol-water.
Reaction SMILES: [C:1]([O:8]CC)(=O)[C:2]([O:4]CC)=O.[Cl:11][C:12]1[C:13]([NH2:20])=[C:14]([NH2:19])[CH:15]=[C:16]([Cl:18])[CH:17]=1>>[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]2[C:13]=1[NH:20][C:2](=[O:4])[C:1](=[O:8])[NH:19]2
Reactant: Nc1cc(Cl)cc(Cl)c1N
Reactant: CCOC(=O)C(=O)OCC
Product: O=c1[nH]c2cc(Cl)cc(Cl)c2[nH]c1=O
Temperature: 25 °C

Procedure:
The title compound (Leeson, P. D. et al., J. Med. Chem 34: 1243 (1991)) was prepared using an adaptation of the method of Cheeseman. (Cheeseman, G. W. H. J. Chem. Soc. 1171 (1962)). A mixture of diethyl oxalate (4.12 g, 28.2 mmol) and 3,5-dichloro-1,2-diaminobenzene (500 mg, 2.82 mmol) was heated to reflux under N2 for 6 h. The reaction was allowed to cool to room temperature and the pale yellow shiny solid collected by vacuum filtration and rinsed with EtOH (20 mL) and air dried to give 286 mg (44%). mp 326°-328° C. (dec) Lit 337°-340° C.). 1H NMR (d6 -DMSO) δ 7.05 (d, 1H, J=1.8, H-8), 7.32 (d, 1H, J=1.8, H-6), 11.5 (br s, 1H, NH), 12.1 (br s, 1H, NH). EIMS m/e 234 (M+4, 12), 232 (M+2, 67), 230 (M+, bp), 204 (52), 202 (77), 141 (19), 142 (59) EIHRMS calc. for C8H4Cl2N2O: 229.9650, found 229.9646.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]3[S:24](=[O:26])(=[O:25])[CH2:23][CH2:22][C:21]([C:27]([O:29]C)=[O:28])=[CH:20][C:19]=3[CH:31]=2)[CH:8]=[CH:9][CH:10]=1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].Cl>C1COCC1.CO>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]3[S:24](=[O:26])(=[O:25])[CH2:23][CH2:22][C:21]([C:27]([OH:29])=[O:28])=[CH:20][C:19]=3[CH:31]=2)[CH:8]=[CH:9][CH:10]=1)[CH2:2][CH3:3]
Reactant: CCCOc1cccc(CCCOc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: CCCOc1cccc(CCCOc2ccc3c(c2)C=C(C(=O)O)CCS3(=O)=O)c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 63.4 %

Procedure:
To methyl 7-[3-(3-propoxyphenyl)propoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (765 mg) dissolved in THF-methanol (15-7.5 ml) was added a 2 M aqueous solution of potassium carbonate (1.5 ml), and the resulting mixture was stirred at 60° C. for 18 hours. The reaction mixture was treated with 1 N hydrochloric acid to bring the pH to 2. The resulting mixture was extracted with ethyl acetate and the organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with anhydrous magnesium sulfate. After concentration under reduced pressure to remove the solvent, the precipitated crystals were washed with hexane-ethyl acetate to obtain 7-[3-(3-propoxyphenyl)propoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (470 mg) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]([OH:15])=O)[N:3]=1.C([O:18][C:19](=[O:28])[CH2:20][NH:21][CH2:22][C:23]([O:25]CC)=[O:24])C>>[C:19]([CH2:20][N:21]([CH2:22][C:23]([OH:25])=[O:24])[C:13]([C:4]1[N:3]=[C:2]([Cl:1])[C:11]2[C:6]([C:5]=1[OH:12])=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:15])([OH:28])=[O:18]
Reactant: CCOC(=O)CNCC(=O)OCC
Reactant: O=C(O)c1nc(Cl)c2ccccc2c1O
Product: O=C(O)CN(CC(=O)O)C(=O)c1nc(Cl)c2ccccc2c1O

Procedure:
Prepared from 1-chloro-4-hydroxy-isoquinoline-3-carboxylic acid and (ethoxycarbonylmethyl-amino)-acetic acid ethyl ester analogously to Example D-49: MS-(+)-ion: 339.0 amu.
Reaction SMILES: [CH:1]1([N:4]2[C:8]([N:9]3[CH2:15][CH2:14][CH:13]([O:16][CH3:17])[CH:12]([NH:18]C(=O)OC(C)(C)C)[CH2:11][CH2:10]3)=[C:7]([N+:26]([O-])=O)[CH:6]=[N:5]2)[CH2:3][CH2:2]1.C(OC([NH:36][C:37]1[S:41][C:40]([C:42]2[C:47]([F:48])=[CH:46][CH:45]=[CH:44][C:43]=2[F:49])=[N:39][C:38]=1[C:50](O)=[O:51])=O)(C)(C)C>>[NH2:36][C:37]1[S:41][C:40]([C:42]2[C:47]([F:48])=[CH:46][CH:45]=[CH:44][C:43]=2[F:49])=[N:39][C:38]=1[C:50]([NH:26][C:7]1[CH:6]=[N:5][N:4]([CH:1]2[CH2:2][CH2:3]2)[C:8]=1[N:9]1[CH2:15][CH2:14][C@@H:13]([O:16][CH3:17])[C@@H:12]([NH2:18])[CH2:11][CH2:10]1)=[O:51]
Reactant: COC1CCN(c2c([N+](=O)[O-])cnn2C2CC2)CCC1NC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Product: CO[C@@H]1CCN(c2c(NC(=O)c3nc(-c4c(F)cccc4F)sc3N)cnn2C2CC2)CC[C@@H]1N
Yield: 23 %

Procedure:
Following the procedure for Example 101 starting from tert-butyl 1-(1-cyclopropyl-4-nitro-1H-pyrazol-5-yl)-5-methoxyazepan-4-ylcarbamate and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)-thiazole-4-carboxylic acid gave 386 as an off-white solid (29 mg, 23% over three steps). 1H NMR (400 MHz, CDCl3) δ 8.96 (s, 1H), 7.86 (s, 1H), 7.36-7.28 (m, 1H), 7.02 (t, J=8.9 Hz, 2H), 6.19-6.10 (m, 2H), 3.50-3.35 (m, 4H), 3.33 (s, 3H), 3.25-3.11 (m, 2H), 2.19-2.05 (m, 1H), 2.03-1.96 (m, 1H), 2.01-1.60 (m, 2H), 1.57 (s, 3H), 1.27-1.12 (m, 2H), 0.97 (d, J=7.1 Hz, 2H). LCMS (ES+) m/z 504 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[CH3:20][C:21]([CH3:26])([CH3:25])[C:22](Cl)=[O:23]>O1CCCC1>[CH3:20][C:21]([CH3:26])([CH3:25])[C:22]([O:11][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)=[O:23]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)OC(=O)Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C

Procedure:
Combine 3,4-dichlorophenyl acetic acid (31.5 g, 154 mmol) and triethylamine (25.7 ml, 184 mmol) and tetrahydrofuran (300 ml). Cool in a dry-ice/acetone bath. Add trimethylacetyl chloride (18.5 grams, 154 mmol) and tetrahydrofuran (200 ml). Warm to ambient temperature to give the title compound in solution.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[F:15][C:16]([F:25])([F:24])[C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1.N1C=CC=CC=1.CCCCCC>ClCCl>[F:15][C:16]([F:24])([F:25])[C:17]1[CH:18]=[CH:19][C:20]([NH:21][S:2]([C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[NH:10][C:9](=[O:14])[CH2:8]3)(=[O:4])=[O:3])=[CH:22][CH:23]=1
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Reactant: Nc1ccc(C(F)(F)F)cc1
Solvent: CCCCCC
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C1Cc2cc(S(=O)(=O)Nc3ccc(C(F)(F)F)cc3)ccc2N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 37.2 %

Procedure:
A suspension of 2.1 g of 5-chlorosulphonyl-2-oxindole, 1.6 g of 4-trifluoromethylaniline and 1.4 g of pyridine in 20 mL of dichloromethane was stirred at room temperature for 4 hours. The precipitate which formed was collected by vacuum filtration, washed twice with 5 mL of water and dried under vacuum at 40° C. overnight to give 2.4 g of crude product containing some impurities by thin layer chromatography. The crude product was chromatographed on silica gel eluting with ethyl acetate:hexane (1,2) to give 1.2 g (37% yield) of 5-(4-trifluoromethylphenyl-aminosulfonyl)-2-oxindole.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]1([CH2:13][CH2:14][CH2:15][N:16]2[C@@H:24]3[C@@H:19]([C:20]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[C:21]=4[CH2:22][CH2:23]3)[CH2:18][C:17]2=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.C(OCC)(=O)C.[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH:7]1([CH2:13][CH2:14][CH2:15][N:16]2[C@@H:24]3[C@@H:19]([C:20]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[C:21]=4[CH2:22][CH2:23]3)[CH2:18][CH2:17]2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: COc1cccc2c1CC[C@H]1[C@@H]2CC(=O)N1CCCC1CCCCC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cccc2c1CC[C@H]1[C@@H]2CCN1CCCC1CCCCC1
Yield: 84.4 %

Procedure:
0.38 g (0.010 mol) of lithium aluminum hydride was suspended in 40 ml of THF under argon. A solution of 3.26 g (0.00955 mol) of rac-cis-3-(3-cyclohexyl-propyl)-1,3,3a,4,5,9b-hexahydro-6-methoxy-2H-benzo[e]indol-2-one in 30 ml of THF was added dropwise thereto and the mixture was boiled under reflux for 2 hours. Then, 10 ml of ethyl acetate and a saturated aqueous Na2SO4 solution were cautiously added dropwise thereto in succession until a complete white precipitate had resulted. After filtration and concentration there was obtained an oil which was chromatographed over silica gel with cyclohexane/ethyl acetate 1:1. There were obtained 2.64 g (84%) of oily rac-cis-3-(3-cyclohexyl-propyl)-2,3,3a,4,5,9b-hexahydro-6-methoxy-1H-benzo[e]indole.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([I:8])[N:5]=[CH:4][N:3]=1.[F:9][C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][CH:16]=1)[NH2:13].C(N(CC)C(C)C)(C)C.C(O)CCC>O>[F:9][C:10]1[CH:11]=[C:12]([NH:13][C:2]2[CH:7]=[C:6]([I:8])[N:5]=[CH:4][N:3]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: Nc1cccc(F)c1
Reactant: Ic1cc(I)ncn1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Fc1cccc(Nc2cc(I)ncn2)c1
Temperature: 120 °C
Reaction time: 4 h
Yield: 71.7 %

Procedure:
A mixture of 4,6-diiodopyrimidine (1.0 g, 3.01 mmol), 3-fluoroaniline (290 μL, 3.01 mmol), N,N-diisopropylethylamine (782 μL, 4.52 mmol) and n-butanol (3 mL) under nitrogen was stirred at 120° C. for 4 h. After cooling to room temperature, the solution was poured into water and extracted with ethyl acetate. The organic layer was washed once with 1 N hydrochloric acid, followed by brine, dried and concentrated to yield 0.68 g of title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:18][CH2:17][C@H:16]([NH:19][C:20]4[CH:25]=[C:24]([CH3:26])[C:23]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:22][C:21]=4[F:31])[C:15]3=[O:32])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH2:39]([Zn]CC)[CH3:40]>C1COCC1.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]>[CH2:39]([C:2]1[N:3]=[CH:4][C:5]([N:8]2[CH2:9][CH2:10][CH:11]([N:14]3[CH2:18][CH2:17][C@H:16]([NH:19][C:20]4[CH:25]=[C:24]([CH3:26])[C:23]([S:27]([CH3:30])(=[O:28])=[O:29])=[CH:22][C:21]=4[F:31])[C:15]3=[O:32])[CH2:12][CH2:13]2)=[N:6][CH:7]=1)[CH3:40]
Reactant: CC[Zn]CC
Reactant: Cc1cc(N[C@H]2CCN(C3CCN(c4cnc(Cl)cn4)CC3)C2=O)c(F)cc1S(C)(=O)=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: CCc1cnc(N2CCC(N3CC[C@H](Nc4cc(C)c(S(C)(=O)=O)cc4F)C3=O)CC2)cn1
Temperature: 60 °C
Yield: 55.4 %

Procedure:
(S)-1-(1-(5-Chloropyrazin-2-yl)piperidin-4-yl)-3-(2-fluoro-5-methyl-4-(methylsulfonyl)phenylamino)pyrrolidin-2-one (Example 1; 320 mg, 0.664 mmol) was dissolved in THF (6 mL) and K2CO3 (275 mg, 1.99 mmol) and PdCl2(dppf)*CH2Cl2 (54.2 mg, 0.0664 mmol) were added and purged with nitrogen. Diethylzinc (1 M in THF; 797 μL, 0.797 mmol) was added and the reaction heated to 60° C. for 1 hour. The reaction was cooled to ambient temperature, partitioned between water and EtOAc, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified over silica gel (100% EtOAc) to afford (S)-1-(1-(5-ethylpyrazin-2-yl)piperidin-4-yl)-3-(2-fluoro-5-methyl-4-(methylsulfonyl)phenylamino)pyrrolidin-2-one (175 mg, 0.368 mmol, 55.4% yield) as a tan solid. Mass spectrum (apci) m/z=476.3 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:27]([C:24]2[CH:25]=[CH:26][C:21]([CH3:20])=[CH:22][CH:23]=2)(=[O:29])=[O:28])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: Nc1cnc(Oc2cnc3ccccc3c2)c(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)Nc2cnc(Oc3cnc4ccccc4c3)c(Cl)c2)cc1

Procedure:
The title compound was prepared by reacting 5-chloro-6-(quinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 1) and 4-methylbenzene-1-sulfonyl chloride.
Reaction SMILES: C(Cl)Cl.[C:4]([O:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[O:18][C:17](=[O:22])[CH2:16][CH2:15]2)=[O:10])([CH3:7])([CH3:6])[CH3:5].[H-].C([Al+]CC(C)C)C(C)C.CO>O>[C:4]([O:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[O:18][CH:17]([OH:22])[CH2:16][CH2:15]2)=[O:10])([CH3:7])([CH3:5])[CH3:6]
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)CCC(=O)O2
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc2c(c1)CCC(O)O2
Temperature: -55 °C
Reaction time: 1.5 h

Procedure:
A 22-L three-neck round-bottom flask equipped with an overhead stirrer and an addition funnel was charged under nitrogen with 7 L of anhydrous methylene chloride and 800 g of 6-(tert-butyloxycarbonylamino)chroman-2-one (Example 1). The solution was cooled to about −55° C., and 2.66 L of diisobutylaluminum hydride (1.58 M solution in toluene, 4.2 mol) was slowly added through the addition funnel to the well-stirred solution. The addition rate was adjusted to keep the temperature of the reaction was between −50° C. and −65° C. requiring about 1.5 h overall. After an additional 1 h stirring, the reaction was complete by TLC. Methanol (870 mL) of was slowly added, keeping the temperature below −50° C. The reaction mixture was warmed up to about −20° C., and 790 g of Celite and 970 mL of water were added. The mixture was warmed to room temperature and stirred vigorously for 40 minutes. The mixture was filtered and the filter cake washed with 10.0 L of methylene chloride. The filtrate and the washings were combined and the solvent removed under reduced pressure at 50° C. The residue was transferred with 8.0 L of toluene into a 22-L three-neck round-bottom flask and dried azeotropically by distilling off 6 L of toluene under reduced pressure at 50° C. The volume of the remaining solution was adjusted to about 8 L with anhydrous toluene to provide a toluene solution of 6-(tert-butyloxycarbonylamino)chroman-2-ol.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[F:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][C:21]=1[O:27][CH3:28]>>[F:19][C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)=[CH:22][C:21]=1[O:27][CH3:28]
Reactant: COc1cc(N)ccc1F
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Na+]
Product: COc1cc(NC(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)ccc1F
Yield: 75.5 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 250 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 520 mg of 4-fluoro-3-methoxyaniline in place of the 2,4-difluoroaniline. 262 mg of N-(4-fluoro-3-methoxyphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:18])[CH:15]=2)[CH2:10]1)=O)(C)(C)C.[ClH:19].O1CCOCC1>C(O)(=O)C>[ClH:19].[NH2:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:18])[CH:15]=2)[CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1Cc2ccc(O)cc2C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: NC1Cc2ccc(O)cc2C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To 2-(tert-butoxycarbonylamino)-5-hydroxyindan (130 mg, 0.50 mmol) synthesized in the above Reference Production Example 1 was added 4N hydrochloric acid-dioxane (2.3 ml) and acetic acid (6.9 ml), and the mixture was stirred at room temperature for 10 minutes. By distilling off the solvent under reduced pressure, 2-amino-5-hydroxyindan hydrochloride was obtained as a crude product. This was dissolved in ethanol (3 ml). Using triethylamine (0.14 ml, 1.0 mmol), 4-chloro-5-methylthieno[2,3-d]pyrimidine (83 mg, 0.60 mmol), a similar procedure to b) in Production Example 208 was carried out. The product obtained was purified by silica gel chromatography (methylene chloride:ethyl acetate=2:1) to obtain the title compound (17 mg, 0.057 mmol) having the following physical properties:
Reaction SMILES: [CH3:1][N:2]1[CH2:8][C:6](=[O:7])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)[C:3]1=[O:4].[BH4-].[Na+]>CO>[CH3:1][N:2]1[CH2:8][CH:6]([OH:7])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)[C:3]1=[O:4]
Reactant: CN1CC(=O)N(c2ccc(Cl)c(Cl)c2)C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN1CC(O)N(c2ccc(Cl)c(Cl)c2)C1=O
Temperature: 10 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
A 10.4 g (0.04 mole) quantity of 1-methyl-3-(3,4-dichlorophenyl)hydantoin was suspended in 80 ml of methanol. The suspension was cooled to 10° C. and 1.5 g of sodium borohydride was added thereto with stirring. After the addition, the mixture was stirred for 30 minutes and warmed to room temperature, followed by further agitation for 2 hours. After completion of the reaction, the reaction mixture was concentrated and water was added to the residue to deposit crystals. The crystals were filtered and recrystallized from ethanol, affording 9.2 g of white crystals in 88% yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][N:20]=[N+:21]=[N-:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCCC(COS(C)(=O)=O)C1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(CN=[N+]=[N-])C1
Temperature: 50 °C
Reaction time: 22 h
Yield: 98.1 %

Procedure:
A solution of 3-methanesulfonyloxymethylpiperidine-1-carboxylic acid tert-butyl ester (19.11 g, 65.1 mmol) in N,N-dimethylformamide (125 mL) was treated with sodium azide (12.70 g, 195 mmol) and the mixture was stirred at 50° C. for 22 hours. The mixture was cooled and filtered, and the filtrate was concentrated under vacuum. The residue was dissolved in ethyl acetate, washed with water, dried over sodium sulfate, and concentrated under vacuum to provide a colorless liquid (15.34 g, 98%) which was used without further purification. 1H NMR (300 MHz, CDCl3) δ3.95 (bd, J=12 Hz, 1H), 3.86 (dt, J=13, 4 Hz, 1H), 3.22 (d, J=7 Hz, 2H), 2.87 (ddd, J=14, 11, 3 Hz, 1H), 2.68 (m, 1H), 1.9-1.6 (3H), 1.49 (m, 1H), 1.47 (s, 9H), 1.26 (m, 1H).
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[C:6]([O:10][C:11](=[O:14])[CH2:12]Br)([CH3:9])([CH3:8])[CH3:7]>COC(C)(C)C>[C:6]([O:10][C:11](=[O:14])[CH2:12][NH:5][CH2:1][CH2:2][CH2:3][CH3:4])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCCCN
Solvent: COC(C)(C)C
Product: CCCCNCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
N-Butylamine (5 mL, 51 mmol) was dissolved in t-butyl methyl ether (100 mL), and bromoacetic acid t-butyl ester (3.7 mL, 25 mmol) was then added to the solution. The obtained mixture was stirred at room temperature overnight. The generated precipitate was filtered, and the filtrate was then concentrated under reduced pressure, so as to obtain the title compound (4.67 g, yield: 100%) in the form of a colorless oily substance.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]([OH:10])=[O:9].[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18](O)[CH:19]=[CH2:20])=[CH:14][C:13]=1[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH:8]([O:10][CH:18]([C:15]1[CH:16]=[CH:17][C:12]([F:11])=[C:13]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:14]=1)[CH:19]=[CH2:20])=[O:9]
Reactant: O=CO
Reactant: C=CC(O)c1ccc(F)c(Oc2ccccc2)c1
Solvent: CC(=O)OC(C)=O
Product: C=CC(OC=O)c1ccc(F)c(Oc2ccccc2)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 97.4 %

Procedure:
To 28 mL (0.30 mole) of acetic anhydride that had been cooled to 0° C. was added slowly 16.75 g (0.36 mole) of 100% formic acid. Upon completion of addition this mixture was heated at 50° C. for 15 minutes. After the mixture was cooled to 0° C., 72.0 g of 1-(4-fluoro-3-phenoxyphenyl)-2-propen-1-ol was added during a 20 minute period. Upon completion of addition, the reaction mixture was allowed to stand at room temperature overnight and was then poured into an ice/water mixture. This mixture was extracted with diethyl ether, and the ether extract was separated, washed four times with water and four times with a saturated, aqueous solution of sodium bicarbonate, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, leaving 78.2 g of 1-(4-fluoro-3-phenoxyphenyl)-2-propen-1-yl formate as a residue. The ir and nmr spectra were consistent with the proposed structure.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[CH:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=3)[C:15]2=[O:30])[CH2:10][CH2:9]1)C1C=CC=CC=1>C(O)C.[Pd]>[CH3:29][S:26]([C:23]1[CH:22]=[CH:21][C:20]([CH2:19][N:16]2[CH2:17][CH2:18][N:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[C:15]2=[O:30])=[CH:25][CH:24]=1)(=[O:28])=[O:27]
Reactant: CS(=O)(=O)c1ccc(Cn2ccn(C3CCN(Cc4ccccc4)CC3)c2=O)cc1
Agent: [Pd]
Solvent: CCO
Product: CS(=O)(=O)c1ccc(CN2CCN(C3CCNCC3)C2=O)cc1

Procedure:
A solution of 1-(1-benzylpiperidin-4-yl)-3-[4-(methylsulphonyl)benzyl]-1,3-dihydro-2H-imidazol-2-one (1.2 g) in ethanol was hydrogenated under a hydrogen filled balloon using 20% palladium on charcoal as catalyst. The catalyst was filtered and the filtrate evaporated to dryness to give the title compound, yield 0.6 g, NMR CDCl3 1.6-2 (m, 5H) 2.8 (m, 1H) 3.05 (s, 3H) 3.2-4.5 (m, 7H) 4.45 (s, 2H) 7.5 (d, 2H) 7.9 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.[Br:21][C:22]1[CH:23]=[C:24]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:36])[CH:25]=[C:26]([CH2:28]Br)[CH:27]=1>>[Br:21][C:22]1[CH:27]=[C:26]([CH2:28][N:11]2[C:10](=[O:13])[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[N:12]2)[CH:25]=[C:24]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:36])[CH:23]=1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Reactant: Clc1ccccc1-c1cc(Br)cc(CBr)c1
Product: O=c1n(Cc2cc(Br)cc(-c3ccccc3Cl)c2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F

Procedure:
Analogously to the preparation of Example 91, 109 mg (0.36 mmol) of the compound from Example 5A were reacted with 128 mg (0.36 mmol) of the compound from Example 117A. This gave 148 mg (68% of theory) of the target compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][NH:7][CH2:6][CH2:5]2.B(O)O>>[N:7]1[CH:8]=[CH:9][CH:4]=[C:5]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH2:8][NH:7][CH2:6][CH2:5]3)[CH:6]=1
Reactant: Brc1ccc2c(c1)CCNC2
Agent: OBO
Product: c1cncc(-c2ccc3c(c2)CCNC3)c1

Procedure:
In close analogy to the procedure described above, 6-Bromo-1,2,3,4-tetrahydro-isoquinoline is reacted with the corresponding boronic acid to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.[Br:13][CH2:14][CH2:15]Br>>[Br:13][CH2:14][CH2:15][NH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: BrCCBr
Reactant: COC(=O)Cc1cccc(N)c1
Product: COC(=O)Cc1cccc(NCCBr)c1

Procedure:
Methyl (3-aminophenyl)acetate (1 g) and 1,2-dibromoethane (5 ml) were heated at 100° C. for 5 hours. After cooling, the resultant was purified by column chromatography (ethyl acetate:isohexane 7:3) to give the titled compound as an oil. Yield: 280 mg (17%).