Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Ba+2].[CH3:6][CH2:7][CH2:8][CH2:9][CH:10]1[C:45](=[O:46])[O:44][CH:43]([CH:47]([CH:49]([OH:57])[CH2:50][CH2:51][CH2:52][NH:53][C:54]([NH2:56])=[NH:55])[CH3:48])[CH:42]([CH3:58])[CH:41]=[C:40]([CH3:59])[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]([OH:60])[CH2:34][CH:33]([OH:61])[CH2:32][CH:31]([OH:62])[CH2:30][CH:29]([OH:63])[CH2:28][CH:27]([OH:64])[CH:26]([O:65][C@H:66]2[O:70][C@H:69]([CH2:71][OH:72])[C@@H:68]([OH:73])[C@@H:67]2[OH:74])[CH:25]=[C:24]([CH3:75])[CH:23]([OH:76])[CH2:22][CH2:21][CH2:20][CH:19]([OH:77])[CH2:18][CH2:17][CH2:16][CH:15]([OH:78])[CH2:14][CH2:13][CH:12]([CH3:79])[CH:11]1[OH:80].S([O-])([O-])(=O)=O.CO.[BrH:88]>>[CH3:6][CH2:7][CH2:8][CH2:9][CH:10]1[C:45](=[O:46])[O:44][CH:43]([CH:47]([CH:49]([OH:57])[CH2:50][CH2:51][CH2:52][NH:53][C:54]([NH2:56])=[NH:55])[CH3:48])[CH:42]([CH3:58])[CH:41]=[C:40]([CH3:59])[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]([OH:60])[CH2:34][CH:33]([OH:61])[CH2:32][CH:31]([OH:62])[CH2:30][CH:29]([OH:63])[CH2:28][CH:27]([OH:64])[CH:26]([O:65][C@H:66]2[O:70][C@H:69]([CH2:71][OH:72])[C@@H:68]([OH:73])[C@@H:67]2[OH:74])[CH:25]=[C:24]([CH3:75])[CH:23]([OH:76])[CH2:22][CH2:21][CH2:20][CH:19]([OH:77])[CH2:18][CH2:17][CH2:16][CH:15]([OH:78])[CH2:14][CH2:13][CH:12]([CH3:79])[CH:11]1[OH:80].[Br-:88]
Reactant: Br
Agent: CCCCC1C(=O)OC(C(C)C(O)CCCNC(=N)N)C(C)/C=C(\C)CCCCC(O)CC(O)CC(O)CC(O)CC(O)C(O[C@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)/C=C(\C)C(O)CCCC(O)CCCC(O)CCC(C)C1O
Agent: CCCCC1C(=O)OC(C(C)C(O)CCCNC(=N)N)C(C)C=C(C)CCCCC(O)CC(O)CC(O)CC(O)CC(O)C(O[C@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)C=C(C)C(O)CCCC(O)CCCC(O)CCC(C)C1O
Agent: O=C([O-])[O-]
Solvent: CO
Product: [Br-]
Reaction time: 0.33 h

Procedure:
0.087 g (0.444 millimoles) of barium carbonate is dissolved in 1 ml of 48% hydrogen bromide under slight warming. The solvent is removed in vacuo and the residue is rubbed with ether. The barium bromide is filtered and washed with dichloro methane until all the traces of bromine are removed. The yellow color of barium bromide turns into light beige. This salt is dissolved in 10 ml of methanol and the solution is added to a solution of 1.0 g (0.887 millimoles) of primycin sulfate and 80 ml of methanol. The suspension thus obtained is heated to boiling for 20 minutes under stirring. The precipitated barium sulfate is filtered and the filtrate is evaporated in vacuo. The residue is treated with ether and filtered. The solid is washed on the filter first with 10 ml of a 2:1 mixture of acetone and water and later with 10 ml of a dichloro methane. Thus 0.91 g of beige primycin bromide is obtained, yield 87.2%. Mp.: 138° C., /α/D25 =-20°.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:22][C:21]([C:23]([O:25]C)=[O:24])=[C:20]([CH3:27])[CH:19]=3)[CH2:14][C@H:13]2[O:28][CH3:29])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].C1COCC1.O>CO>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:22][C:21]([C:23]([OH:25])=[O:24])=[C:20]([CH3:27])[CH:19]=3)[CH2:14][C@H:13]2[O:28][CH3:29])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(c3cc(C)c(C(=O)OC)s3)C[C@H]2OC)nc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3cc(C)c(C(=O)O)s3)C[C@H]2OC)nc1Cl
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 35.9 %

Procedure:
Methyl cis(±)-5-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-3-methylthiophene-2-carboxylate obtained in Example (245d) (65 mg, 0.15 mmol) was dissolved in methanol (1.5 mL). A 2 N aqueous lithium hydroxide solution (0.74 mL, 1.47 mmol) was added, and the mixture was stirred at room temperature for 50 minutes. THF (1 mL) was added, and the mixture was stirred for 19 hours, and then further stirred at 40° C. for 6.5 hours and at 70° C. for two hours. Water was added to the reaction solution, and then the mixture was washed with ethyl acetate. A 1 N aqueous hydrochloric acid solution (2.5 mL) was added to the aqueous layer, followed by extraction with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The resulting solid was suspended and washed in diethyl ether to obtain 23 mg of the title compound as a pale blue solid (37%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([CH:21]3OCC[O:22]3)[CH:15]=2)[C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[CH3:26].Cl>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([CH:15]=2)[CH:21]=[O:22])[C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[CH3:26]
Reactant: Cc1cc([C@H](Nc2ccc(C)c(C3OCCO3)c2)C(F)(F)F)ccc1Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc([C@H](Nc2ccc(C)c(C=O)c2)C(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 1.67 h

Procedure:
To a solution of acetal INT 32 (4.91 g, 12.73 mmol) in THF (127 mL) at 0° C. was added HCl (2 M in H2O, 25.5 mL, 50.92 mmol). The reaction mixture was stirred at room temperature for 100 minutes. The mixture was diluted with EtOAc and washed with saturated aqueous NaHCO3 (2×), water (2×) and brine (1×). The organic layer was dried over MgSO4, filtered and concentrated to give INT 33.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][C:17](=[O:19])[N:16]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:15][CH:14]2[C:28]([O:30][CH3:31])=[O:29])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.O.O.Cl[Sn]Cl.C([O-])(O)=O.[Na+].CO[CH:44]1[CH2:48][CH2:47][CH:46](OC)O1>CO.C(OCC)(=O)C.C(O)(=O)C>[CH2:20]([N:16]1[C:17](=[O:19])[CH2:18][N:13]([S:10]([C:7]2[CH:8]=[CH:9][C:4]([N:1]3[CH:44]=[CH:48][CH:47]=[CH:46]3)=[CH:5][CH:6]=2)(=[O:12])=[O:11])[CH:14]([C:28]([O:30][CH3:31])=[O:29])[CH2:15]1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: COC1CCC(OC)O1
Reactant: CCCCCCCCN1CC(C(=O)OC)N(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1=O
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCCCCCN1CC(C(=O)OC)N(S(=O)(=O)c2ccc(-n3cccc3)cc2)CC1=O
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 26.6 %

Procedure:
The compound of Example 56 (0.69 g, 1.5 mmol) was put in 10 mL of a MeOH solution to which SnCl2.2H2O (1.37 g, 6.4 mmol) was added, and stirred for 1.5 hours while maintaining the temperature at 50° C. A saturated NaHCO3 aqueous solution was introduced and stirred for 2 hours, and then it was extracted with ethyl acetate. After distillation under reduced pressure, 2,5-dimethoxytetrahydrofuran (0.20 mLo, 1.5 mmol) and 1 mL of acetic acid were introduced and refluxed for 2 hours. 50 mL of ethyl acetate was introduced and the reactant was washed with 50 mL of a saturated NaHCO3 aqueous solution and 50 mL of a 1 N HCl aqueous solution, and dried and then concentrated under reduced pressure. The mixture was separated with hexane and ethyl acetate (3:1) in a silica gel column to obtain a yellow oily title compound (0.19 g, 26%).
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([OH:13])=O)[C:5]=2[CH:4]=[CH:3][N:2]=1.S(Cl)(Cl)=O.[CH3:18][O:19][CH2:20][CH2:21][N:22]1[C:26]([CH3:27])=[C:25]([CH3:28])[S:24][C:23]1=[NH:29].CCN(CC)CC>C1COCC1>[CH3:18][O:19][CH2:20][CH2:21][N:22]1[C:26]([CH3:27])=[C:25]([CH3:28])[S:24]/[C:23]/1=[N:29]\[C:11]([C:6]1[C:5]2[CH:4]=[CH:3][N:2]=[CH:1][C:10]=2[CH:9]=[CH:8][CH:7]=1)=[O:13]
Reactant: O=C(O)c1cccc2cnccc12
Reactant: COCCn1c(C)c(C)sc1=N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: COCCn1c(C)c(C)s/c1=N\C(=O)c1cccc2cnccc12
Yield: 26.4 %

Procedure:
The isoquinoline-5-carboxylic acid (Lancaster, 0.25 g, 1.4 mmol) was converted to the corresponding acid chloride with 5 mL of thionyl chloride using the method described in Example 134A. The product of Example 126A (0.20 g, 1.1 mmol), Et3N (0.3 mL, 2.2 mmol) and the acid chloride in 30 mL THF were processed as in Example 134B to afford the title compound (98 mg, 0.29 mmol, 27% yield). 1H NMR (300 MHz, CD3OD) δ ppm 2.31 (s, 3H), 2.35 (s, 3H), 3.31 (s, 3H), 3.81 (t, J=5.3 Hz, 2H), 4.50 (t, J=5.3 Hz, 2H), 7.76 (dd, J=7.5, 7.5 Hz, 1H), 8.23 (d, J=8.1 Hz, 1H), 8.48 (d, J=6.4 Hz, 1H), 8.61 (dd, J=7.1, 1.4 Hz, 1H), 9.03 (d, J=6.1 Hz, 1H), 9.27 (d, J=1.0 Hz, 1H); MS (DCI/NH3) m/z 342 (M+H)+; Anal. calculated for C18H19N3O2S: C, 63.32; H, 5.61; N, 12.31. Found: C, 62.97; H, 5.54; N, 12.07.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)=[CH:10][C:9]([C@H:22]2[C@H:27]([O:28]CC3C=CC=CC=3)[C@@H:26]([O:36]CC3C=CC=CC=3)[C@H:25]([O:44]CC3C=CC=CC=3)[C@@H:24]([CH2:52][O:53]CC3C=CC=CC=3)[O:23]2)=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][O:7]2>C1COCC1.CO.[Pd]>[Cl:1][C:2]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)=[CH:10][C:9]([C@H:22]2[C@H:27]([OH:28])[C@@H:26]([OH:36])[C@H:25]([OH:44])[C@@H:24]([CH2:52][OH:53])[O:23]2)=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][O:7]2
Reactant: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2Cl)CCCO3)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c3c(c2Cl)CCCO3)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of compound 30 (255 mg, 0.309 mmol) in THF/MeOH (15 mL/15 mL) was added 10% Pd/C (71 mg) at rt. The reaction mixture was stirred at r.t. for 15 hours under hydrogen and filtered off. The filtrate was concentrated in vacuo and the residue was purified using reverse phase preparative HPLC to provide the title compound E012 (51 mg, 36%).
Reaction SMILES: CO[C:3]([CH:5]1[CH2:9][CH:8]([OH:10])[CH:7]([CH2:11][NH:12][C:13]([C:15]2[S:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[O:14])[CH2:6]1)=[O:4].[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][C:29]2=[O:34])=[CH:24][CH:23]=1>>[OH:10][CH:8]1[CH2:9][CH:5]([C:3](=[O:4])[NH:21][C:22]2[CH:23]=[CH:24][C:25]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][C:29]3=[O:34])=[CH:26][CH:27]=2)[CH2:6][CH:7]1[CH2:11][NH:12][C:13]([C:15]1[S:16][C:17]([Cl:20])=[CH:18][CH:19]=1)=[O:14]
Reactant: Nc1ccc(N2CCOCC2=O)cc1
Reactant: COC(=O)C1CC(O)C(CNC(=O)c2ccc(Cl)s2)C1
Product: O=C(NCC1CC(C(=O)Nc2ccc(N3CCOCC3=O)cc2)CC1O)c1ccc(Cl)s1

Procedure:
In analogy to example 15C, (1SR,3RS,4SR)-3-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-4-hydroxy-cyclopentanecarboxylic acid methyl ester was reacted with 4-(4-amino-phenyl)-morpholin-3-one (CAS 438056-69-0) to give 5-chloro-thiophene-2-carboxylic acid {(1RS,2SR,4SR)-2-hydroxy-4-[4-(3-oxo-morpholin-4-yl)-phenylcarbamoyl]-cyclopentylmethyl}-amide. Orange solid. MS: 478.3 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[C:13]2[C:6]([NH:7][CH:8]=[C:9]2[CH2:10][CH2:11][NH2:12])=[CH:5][CH:4]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>C(Cl)Cl>[CH3:16][C:15]([NH:12][CH2:11][CH2:10][C:9]1[C:13]2[CH:14]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[NH:7][CH:8]=1)=[O:17]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc2[nH]cc(CCN)c2c1
Solvent: ClCCl
Product: COc1ccc2[nH]cc(CCNC(C)=O)c2c1
Reaction time: 1 h
Yield: 98 %

Procedure:
To a suspension, cooled in ice, of 20 g (0.105 moles) of pure 5-methoxytryptamine in 400 ml methylene chloride there is slowly added, under stirring, a cold solution of 20 ml (0.21 moles) of acetic anhydride in 200 ml methylene chloride. Stirring and cooling are continued for 1 hour (the reaction progression can be controlled by TCL) so as to obtain a full solution; then the solution is washed with Na2CO3 ×2, under long stirring, and then with water. The organic phase, dried on Na2SO4 and evaporated, provides 24 g (yield 98%) of lightly colored melatonine.
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]([O:6][CH:7]([CH3:16])[CH2:8][NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[CH:4][CH:3]=1.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC>[CH3:14][CH:13]([S:10]([NH:9][CH2:8][CH:7]([O:6][C:5]1[CH:17]=[CH:18][C:2]([C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([C:20]3[S:19][CH:23]=[CH:22][CH:21]=3)[CH:25]=2)=[CH:3][CH:4]=1)[CH3:16])(=[O:12])=[O:11])[CH3:15]
Reactant: CC(CNS(=O)(=O)C(C)C)Oc1ccc(Br)cc1
Reactant: OB(O)c1cccc(-c2cccs2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2cccc(-c3cccs3)c2)cc1
Yield: 63.4 %

Procedure:
The title compound (243 mg, 77.6%, yellow foam) was prepared from [2-(4-Bromophenoxy)propyl][(methylethyl)sulfonyl]amine (310 mg, 0.922 mmol, prepared in example 1), 3-(2-thienyl)benzeneboronic acid (145 mg, 1.13 mmol), dichlorobis(triphenylphosphine)palladium(II) (26 mg, 0.037 mmol), 2 M sodium carbonate (335 mg in 1.6 mL water), and 1,2-dimethoxyethane (6 mL) in a manner analogous to the procedure described in Example 8.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]([CH3:10])[C@@H:5]1[CH2:9][CH2:8][NH:7][CH2:6]1.[Cl:11][C:12]1[C:13]([C:31]2[CH:32]=[N:33][N:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=23)=[N:14][C:15]([NH:18][C:19]2[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[C:22](F)=[CH:21][C:20]=2[O:29][CH3:30])=[N:16][CH:17]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O.CO>[Cl:11][C:12]1[C:13]([C:31]2[CH:32]=[N:33][N:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=23)=[N:14][C:15]([NH:18][C:19]2[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[C:22]([N:7]3[CH2:8][CH2:9][C@@H:5]([N:4]([CH3:10])[CH3:3])[CH2:6]3)=[CH:21][C:20]=2[O:29][CH3:30])=[N:16][CH:17]=1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Reactant: CN(C)[C@@H]1CCNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CC(=O)N(C)C
Product: COc1cc(N2CC[C@@H](N(C)C)C2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Temperature: 140 °C
Yield: 61 %

Procedure:
(3R)—N,N-Dimethylpyrrolidin-3-amine dihydrochloride (90 mg, 0.48 mmol) was added to a suspension of 5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine (Intermediate 20, 200 mg, 0.48 mmol) and DIPEA (0.250 mL, 1.45 mmol) in DMA (3 mL). This mixture was heated at 140° C. in a microwave for 0.5 h. The mixture was then diluted with CH3OH and absorbed onto an SCX column, washed with CH3OH and eluted with 1:1 methanolic ammonia in CH2Cl2. Fractions containing the product were combined and concentrated in vacuo. Purification by FCC, eluting with 1.5% 7N methanolic ammonia in CH2Cl2 gave the title compound (149 mg, 61%) as an orange foam; 1H NMR: 1.76-1.89 (1H, m), 2.14-2.25 (7H, m), 2.69-2.84 (1H, m), 3.12-3.27 (3H, m), 3.41-3.53 (1H, m), 3.89 (3H, s), 6.56 (1H, s), 7.13 (1H, td), 7.26-7.38 (1H, m), 8.06 (1H, s), 8.40-8.43 (2H, m), 8.73 (1H, s), 8.85 (1H, d), 8.95 (1H, s); m/z: ES+ MH+ 509.5.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([I:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Hg](C#N)[C:16]#[N:17].N1C=CC=CC=1.Cl>CN(C)C=O>[I:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:16]#[N:17])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1
Reactant: N#C[Hg]C#N
Reactant: Ic1ccc(-c2ccc(I)cc2)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: N#Cc1ccc(-c2ccc(I)cc2)cc1
Temperature: 200 °C
Yield: 86.8 %

Procedure:
A mixture of 15 g (33.2.10-3 mol) of 4,4'-diiodo-1,1'-biphenyl, 3.13 g (34.9.10-3 mol) of mercuric cyanide and 2.75 g (34.9.10-3 mol) of pyridine is heated at 200° C. for 15 minutes and 6 ml of dimethylformamide are then added to the mixture. After cooling, the reaction medium is hydrolyzed with a 1N aqueous solution of hydrochloric acid. The expected product is extracted with ethyl acetate. The organic phase obtained is washed with water until the pH of the washings is neutral, dried over magnesium sulfate and evaporated under vacuum. 3.28 g (yield: 33%) of a yellow solid are obtained after purification by flash chromatography using a chloroform/toluene mixture (1/1 v/v) as the eluent.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:14])=[C:4]([C:11]([OH:13])=O)[C:5](=[O:10])[N:6]([CH3:9])[C:7]=1[CH3:8].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:27][C:28]1[S:29][CH:30]=[C:31]([CH3:33])[N:32]=1>C(#N)C>[F:1][C:2]1[C:3]([OH:14])=[C:4]([C:11]([NH:27][C:28]2[S:29][CH:30]=[C:31]([CH3:33])[N:32]=2)=[O:13])[C:5](=[O:10])[N:6]([CH3:9])[C:7]=1[CH3:8]
Reactant: Cc1c(F)c(O)c(C(=O)O)c(=O)n1C
Reactant: Cc1csc(N)n1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: Cc1csc(NC(=O)c2c(O)c(F)c(C)n(C)c2=O)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.4 %

Procedure:
200 mg of 5-fluoro-1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid was dissolved in 3 ml of acetonitrile, and 162 mg of carbonyldiimidazole was added to this. The mixture was stirred for 1 hour under heat refluxing condition, then, 114 mg of 2-amino-4-methylthiazole was added, and the resulting mixture was further stirred for 1 hour under heat refluxing condition. Thereafter, the reaction mixture was cooled to room temperature. As a result, a crystal was produced. The produced crystal was collected by filtration, to obtain 90 mg of 5-fluoro-1,6-dimethyl-4-hydroxy-2-oxo-N-(4-methyl-2-thiazolyl)-1,2-dihydropyridine-3-carboxamide (hereinafter, referred to as present compound 31) represented by the formula:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28]Cl)=[CH:21][CH:20]=1)[C:13]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:32][CH:31]=1)=[C:12]2[CH3:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[K+].[NH:47]1[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1.O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][N:47]3[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]3)=[CH:21][CH:20]=1)[C:13]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:32][CH:31]=1)=[C:12]2[CH3:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(-c2ccc(OCc3ccccc3)cc2)n(Cc2ccc(OCCCCl)cc2)c2ccc(OCc3ccccc3)cc12
Reactant: C1CCNCC1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(-c2ccc(OCc3ccccc3)cc2)n(Cc2ccc(OCCCN3CCCCC3)cc2)c2ccc(OCc3ccccc3)cc12

Procedure:
A solution of 5-Benzyloxy-2-(4-benzyloxy-phenyl)-1-[4-(3-chloro-propoxy)-benzyl]-3-methyl-1H-indole No. 164 (3 g, 5.1 mmol), potassium iodide (2.5 g, 15.3 mmol) and piperidine (3.0 mL, 30.6 mmol) were heated in DMF (30 mL) at 100° C. for 18 hours. The reaction was worked up by pouring into water and extracting with ethyl acetate. The organic layer was washed with water, brine and dried over magnesium sulfate. The solution was concentrated to an oil and the product precipitated out by adding methanol. The product was obtained as a white solid: Mp=104-106° C.; 1H NMR (DMSO) 7.47 (d, 4H, J=7.5 Hz), 7.38 (q, 4H, J=7.9 Hz), 7.36-7.30 (m, 1H), 7.28 (d, 2H, J=8.3 Hz), 7.19 (d, 1H, J=8.8 Hz), 7.12-7.10 (m, 4H), 6.80 (dd, 1H, J=8.8, 2.0 Hz), 6.72 (s, 4H), 5.14 (s, 2H), 5.13 (s, 2H), 5.11 (s, 2H), 3.86 (t, 2H, J=6.4 Hz), 2.35-2.20 (m, 6H), 2.14 (s, 3H), 1.78-1.75 (m, 2H), 1.47-1.42 (m, 4H), 1.40-1.31 (m, 2H); MS eI m/z 650.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2=O.C([O:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)(=O)C.C([O-])([O-])=O.[Na+].[Na+]>CO>[CH:23]1[CH:22]=[CH:21][C:20]2[N:19]=[C:18]([C:7]3[C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[C:10]=4[NH:9][C:8]=3[OH:11])[C:17](=[O:16])[C:25]=2[CH:24]=1
Reactant: CC(=O)Oc1c[nH]c2ccccc12
Reactant: O=C1Nc2c(F)cccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1C(c2c(O)[nH]c3c(F)cccc23)=Nc2ccccc21
Reaction time: 0.08 h
Yield: 75.4 %

Procedure:
Methanol (25 mL) was vigorously stirred under nitrogen for 20 min and then 7-fluoroisatin (IIIa) (150 mg, 0.91 mmol) and 3-acetoxyindole (106 mg, 0.61 mmol) were added and stirring was Continued for 5 min. Anhydrous Na2CO3 (155 mg) was added and the stirring was continued for 3 h. The dark precipitate was filtered and washed with aqueous methanol (1:1, 20 mL) to give 7 (130 mg, 0.46 mmol, 77%) selectively in a Z form. 1H NMR (DMSO, 400 MHz, δ ppm, J in Hz) 11.37 (1H, s, N′—H), 11.12 (1H, s, N—H), 8.58 (1H, d, J=7.7 Hz, H-4), 7.64 (1H, d, J=7.5 Hz, H-4′), 7.57 (1H, t, J=7.5 Hz H-6′), 7.42 (1H, d, J=7.5 Hz, H-7′), 7.15 (1H, t, J=8.0 Hz, H-5), 7.02 (2H, m, H-5′, 6); CI-MS m/z 281 (M+H)+. Anal. (C16H9N2O2F) C, H, N.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([C@@H:11]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)[CH2:12][CH2:13]O)[C:8](=[O:22])[C:7]2([CH3:24])[CH3:23].C1(C)C(S(Cl)(=O)=O)=CC=CC=1.[N:36]1C=CC=C[CH:37]=1>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([C@@H:11]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)[CH2:12][CH2:13][NH:36][CH3:37])[C:8](=[O:22])[C:7]2([CH3:24])[CH3:23]
Reactant: CC1(C)C(=O)N([C@H](CCO)c2cccc(F)c2)c2c(F)cccc21
Reactant: c1ccncc1
Agent: Cc1ccccc1S(=O)(=O)Cl
Solvent: CCOC(C)=O
Product: CNCC[C@H](c1cccc(F)c1)N1C(=O)C(C)(C)c2cccc(F)c21
Reaction time: 6 h

Procedure:
7-fluoro-1-[(1R)-1-(3-fluorophenyl)-3-hydroxypropyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (0.24 g, 0.73 mmol) was dissolved in pyridine (5 mL) and toluenesufonyl chloride (0.18 g, 0.94 mmol) was added. Stirred for 6 hours then the reaction mixture was diluted with ethyl acetate and washed with water, 2N hydrochloric acid, saturated copper sulfate, 2N hydrochloric acid, and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was immediately dissolved in methylamine (8M in ethanol, 25 mL) and stirred for 16 hours. The mixture was concentrated in vacuo and purified via chromatography (silica, 3% methanol saturated with ammonia in chloroform) to give 7-fluoro-1-[(1R)-1-(3-fluorophenyl)-3-(methylamino)propyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one as a colorless oil (0.22 g). The freebase was dissolved in ether (5 mL) and treated with 1N hydrochloric acid in ether (0.64 mL, 1.0 equivalent). The white precipitate was collected and dried under vacuum to give 120 mg (43% over three steps) 7-fluoro-1-[(1R)-1-(3-fluorophenyl)-3-(methylamino)propyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one hydrochloride.
Reaction SMILES: [Cl:1][C:2]([F:27])([F:26])[CH2:3][CH:4]1[CH2:8][N:7]([CH2:9][C:10]2[N:17]3[C:13]([S:14][C:15]([CH2:18][O:19][CH3:20])=[N:16]3)=[N:12][C:11]=2[C:21]([F:24])([F:23])[F:22])[C:6](=[O:25])[NH:5]1.[OH-].[Na+].I[CH3:31].O>C(Cl)Cl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]([F:26])([F:27])[CH2:3][CH:4]1[CH2:8][N:7]([CH2:9][C:10]2[N:17]3[C:13]([S:14][C:15]([CH2:18][O:19][CH3:20])=[N:16]3)=[N:12][C:11]=2[C:21]([F:22])([F:23])[F:24])[C:6](=[O:25])[N:5]1[CH3:31]
Reactant: CI
Reactant: COCc1nn2c(CN3CC(CC(F)(F)Cl)NC3=O)c(C(F)(F)F)nc2s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COCc1nn2c(CN3CC(CC(F)(F)Cl)N(C)C3=O)c(C(F)(F)F)nc2s1
Temperature: 25 °C
Reaction time: 120 h
Yield: 43 %

Procedure:
To a solution of (+4-(2-chloro-2,2-difluoroethyl)-1-{[2-(methoxymethyl)-6-(trifluoro-methyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}imidazolidin-2-one 14 (120 mg, 0.277 mmol) in CH2Cl2 (12 ml) is added, at 0° C., sodium hydroxide (3.96 ml, 1M solution), tetrabutylammonium bromide (82 mg, 0.1 eq.) and iodomethane (0.035 ml, 2 eq.). The mixture is stirred at room temperature for 120 h. Iodomethane (0.060 ml) is added and the mixture is stirred at room temperature for 24 h. Iodomethane is added (2×0.060 ml) and the mixture is stirred for 72 h. Water is added and the reaction mixture is extracted with CH2Cl2 (2 times), dried over MgSO4, filtered and condensed under reduced pressure. The residue is purified by chromatography (basic conditions; gradient; eluent: H2O/CH3CN/NH4OH 60/40/0.1 to 30/70/0.1; 10 min) to afford 54 mg of pure (+)-4-(2-chloro-2,2-difluoroethyl)-1-{[2-(methoxymethyl)-6-(trifluoromethyl) imidazo[2,1-b][1,3,4]-thiadiazol-5-yl]methyl}-3-methylimidazolidin-2-one 22.