Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([S:7](O)(=[O:9])=[O:8])=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:18]>O>[C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([S:7]([Cl:18])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=S(=O)(O)c1ccc(-c2ccccc2)cc1
Solvent: O
Product: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C

Procedure:
4-Biphenyl sulfonic acid (2.4 g, 10 mmol) was heated to 100 C. with phosphorus pentachloride (2.1 g, 10 mmol) overnight. The reaction was cooled to RT, diluted with water, filtered and washed with water. The solid was then triturated with EtOAc-ether and the beige solid was used in the next reaction without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][CH:12]([CH2:14][O:15][C:16]3[CH:20]=[CH:19][O:18][N:17]=3)[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1F.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][CH:12]([CH2:14][O:15][C:16]3[CH:20]=[CH:19][O:18][N:17]=3)[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: C1CNCCN1
Reactant: Fc1ccc(C2=NOC(COc3ccon3)C2)cc1F
Product: Fc1cc(C2=NOC(COc3ccon3)C2)ccc1N1CCNCC1
Reaction time: 4 h

Procedure:
(5RS)-3-(3,4-Difluorophenyl)-5-isoxazol-3-yloxymethyl-4,5-dihydroisoxazole (530 mg, 1.89 mM) was treated with piperazine using essentially the conditions of Example 4, except that the reaction conditions were 140° for 4 hours, and work-up did not include an acid wash. Crude product was chromatographed on a 50 g silica Mega Bond Elut® column, eluting with a mixture of dichloromethane/methanol/ammonia 90:10:1. Relevant fractions were combined to give the desired product (601 mg). MS (ESP): 347 (MH+) for C17H11FN4O3
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:33]1[CH:34]=[N+:35]([O-])[CH:36]=[CH:37][CH:38]=1)[C@H:10]1[CH2:14][CH2:13][C@@H:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:17]=2)[N:11]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:40]([NH2:44])([CH3:43])([CH3:42])[CH3:41].C1(C)C=CC(S(OS(C2C=CC(C)=CC=2)(=O)=O)(=O)=O)=CC=1>FC(F)(F)C1C=CC=CC=1.CCOC(C)=O>[C:40]([NH:44][C:36]1[N:35]=[CH:34][C:33]([C@@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[C@H:10]2[CH2:14][CH2:13][C@@H:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:17]=3)[N:11]2[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:38][CH:37]=1)([CH3:43])([CH3:42])[CH3:41]
Reactant: COC(=O)c1ccc(C[C@@H]2CC[C@H]([C@H](O[Si](C)(C)C(C)(C)C)c3ccc[n+]([O-])c3)N2C(=O)OC(C)(C)C)cc1
Reactant: CC(C)(C)N
Agent: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: FC(F)(F)c1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C[C@@H]2CC[C@H]([C@H](O[Si](C)(C)C(C)(C)C)c3ccc(NC(C)(C)C)nc3)N2C(=O)OC(C)(C)C)cc1
Reaction time: 1 h
Yield: 88.3 %

Procedure:
A solution of tert-butyl (2R,5S)-2-[(R)-{[tert-butyl(dimethyl)silyl]oxy}(1-oxidopyridin-3-yl)methyl]-5-[4-(methoxycarbonyl)benzyl]pyrrolidine-1-carboxylate (0.049 g, 0.087 mmol) in trifluorotoluene (2 mL) was cooled to 0° C. Tert-butylamine (0.046 mL, 0.44 mmol) was added, followed by p-toluenesulfonic anhydride (0.057 g, 0.18 mmol). After 1 hour, the reaction was diluted with EtOAc (50 mL) and washed with water (15 mL) and brine (15 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography with 0-45% EtOAc/hexanes to afford 47 mg of impure tert-butyl (2R,5S)-2-[(R)-[6-(tert-butylamino)pyridin-3-yl]{[tert-butyl(dimethyl)silyl]oxy}methyl]-5-[4-(methoxycarbonyl)benzyl]pyrrolidine-1-carboxylate. LC-MS=6123 (M−H)+.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[F:8][C:9]([F:38])([F:37])[O:10][C:11]1[CH:36]=[CH:35][C:14]([CH2:15][C@:16]23[CH2:23][C@H:22]([NH2:24])[CH2:21][N:20]2[C:19](=[O:25])[N:18]([C:26]2[CH:31]=[C:30]([Cl:32])[N:29]=[C:28]([Cl:33])[CH:27]=2)[C:17]3=[O:34])=[CH:13][CH:12]=1.CCN(C(C)C)C(C)C>C1COCC1>[F:38][C:9]([F:37])([F:8])[O:10][C:11]1[CH:36]=[CH:35][C:14]([CH2:15][C@:16]23[CH2:23][C@H:22]([NH:24][C:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5])[CH2:21][N:20]2[C:19](=[O:25])[N:18]([C:26]2[CH:31]=[C:30]([Cl:32])[N:29]=[C:28]([Cl:33])[CH:27]=2)[C:17]3=[O:34])=[CH:13][CH:12]=1
Reactant: CCCCC(=O)Cl
Reactant: N[C@@H]1CN2C(=O)N(c3cc(Cl)nc(Cl)c3)C(=O)[C@@]2(Cc2ccc(OC(F)(F)F)cc2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCCC(=O)N[C@@H]1CN2C(=O)N(c3cc(Cl)nc(Cl)c3)C(=O)[C@@]2(Cc2ccc(OC(F)(F)F)cc2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 63.7 %

Procedure:
Valeryl chloride (0.031 g) was added to a solution of the compound from Example 63 (0.1 g) and DIEA (0.84 g) in THF (5 mL) and the reaction mixture was stirred at room temperature for 24 hours. The mixture was concentrated and the residue was purified via HPLC (CH3CN/0.1 M AcOH) to yield 0.075 g of the titled compound. MS (m/z) 559 (MH+) and 581 (MNa+). mp 66.8° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:9]=[O:10])[C:7]=1[OH:8].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(C(C)C)C(C)C)C>ClCCl>[CH3:15][O:14][C:12](=[O:13])[CH2:11][C:4]1[CH:5]=[C:6]([CH:9]=[O:10])[C:7]([O:8][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:2]([Br:1])[CH:3]=1
Reactant: COC(=O)Cc1cc(Br)c(O)c(C=O)c1
Reactant: BrCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cc1cc(Br)c(OCc2ccccc2)c(C=O)c1
Temperature: 25 °C

Procedure:
To a 250 mL round-bottomed flask with a teflon stir bar and a reflux condensor were added methyl (3-bromo-5-formyl-4-hydroxyphenyl)acetate (23.3 g, 85.3 mmol, prepared as described in Reference A above), dichloromethane (100 mL), benzyl bromide (15.32 g, 10.64 mL, 89.59 mmol), and N-ethyldiisopropylamine (11.6 g, 15.6 mL, 89.5 mmol). The reaction mixture was heated to reflux for 14 h and then allowed to cool to room temperature. Dichloromethane (100 mL) was added and the organic layer was separated and washed with 200 mL of a 3% solution of NaOH in water. The organic layer was concentrated to give (4-benzyloxy-3-bromo-5-formyl-phenyl) acetic acid methyl ester (30.65 g) as oil.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:14])=O>>[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:14])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cccnc1Cl
Product: O=C(Cl)c1cccnc1Cl
Yield: 98 %

Procedure:
2-Chloronicotinic acid (317 mmol) was diluted with oxalyl chloride (130 mL) and the resulting solution was heated at reflux for 18 h. The volatiles were removed by evaporation to provide 2-chloronicotinoyl chloride in 98% yield as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Br:16][C:17]1[CH:22]=[CH:21][C:20](/[C:23](=[CH:26]/[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=2[F:34])/[C:24]#[N:25])=[CH:19][CH:18]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:26]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=2[F:34])[C:23]([C:20]2[CH:19]=[CH:18][C:17]([Br:16])=[CH:22][CH:21]=2)([C:24]#[N:25])[CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[NH:8]1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Reactant: N#C/C(=C\c1cccc(Cl)c1F)c1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Br)cc1
Yield: 55.6 %

Procedure:
In a manner similar to the method described in Example 1c, [3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 1a (1.1 g, 5 mmol) was reacted with (Z)-2-(4-bromo-phenyl)-3-(3-chloro-2-fluoro-phenyl)-acrylonitrile (1.2 g, 3.6 mmol) prepared in Example 54a, AgF (1.3 g, 10 mmol), and triethylamine (2 g, 20 mmol) in dichloromethane (100 mL) at room temperature for 3 h to give rac-(2R,3S,4R,5S)-4-(4-bromo-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.1 g, 56%).
Reaction SMILES: C(OC([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17](NCCN3CCCC3)[CH:18]=2)[NH:13][C:12]=1C)=O)C1C=CC=CC=1.C([N:31](CC)CC)C.C(Cl)(=O)C>C(#N)C>[NH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=[C:12]1[NH2:31]
Reactant: Cc1[nH]c2ccc(NCCN3CCCC3)cc2c1C(=O)OCc1ccccc1
Reactant: CCN(CC)CC
Solvent: CC#N
Solvent: CC(=O)Cl
Product: Nc1cc2ccccc2[nH]1
Yield: 33 %

Procedure:
To a stirred solution of the 2-methyl-5-(2-pyrrolidine-1-yl-ethylamino)-1H-indole-3-carboxylic acid benzyl ester (147 mg, 0.39 mmol, 1.0 eq) and triethylamine (47.6 mg, 0.47 mmol, 1.2 eq) in acetonitrile in an ice-water bath was added dropwise a solution of acetyl chloride in acetonitrile. After the ice-water bath was removed, the reaction mixture was heated to reflux for overnight. After the mixture was concentrated, the residue was purified by preparative HPLC (reverse-phase, 10-100 CH3CN:H2O, 0.1% TFA) to yield the desire indole amine in 33.0% yield. Elemental Analysis: C25H29N3O3.2HCl.0.3H2O Calcd: C: 60.31; H: 6.40; N: 8.44. Found: C: 60.63; H: 6.40; N: 8.04. ESI-MS: m/z 420.78 (M+H)+.
Reaction SMILES: [S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=[C:2]1[NH:10]C(=O)C.O.[OH-].[Li+]>CO>[S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=[C:2]1[NH2:10]
Reactant: CC(=O)Nc1nc2cnccc2s1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Nc1nc2cnccc2s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of N-(thiazolo[4,5-c]pyridin-2-yl)acetamide, prepared in the previous step, in MeOH (200 mL) at room temperature was added lithium hydroxide hydrate (7.08 g, 169 mmol). The reaction mixture was stirred at room temperature for 30 min and then warmed to 40° C. After 3 h, additional lithium hydroxide hydrate (7.48 g) was added. The reaction mixture was heated to 50° C. for 20 h and concentrated. The reaction mixture was diluted with DCM/MeOH (˜10:1, 500 mL). The undissolved material was removed by filtration and the filtrate was concentrated. Purification by flash column chromatography on silica gel (eluted with 2% to 10% MeOH in DCM) gave thiazolo[4,5-c]pyridin-2-amine.
Reaction SMILES: C(OC([N:8]([C:13]1[CH:14]=[C:15]([C:21]2[CH:22]=[C:23]3[C:29](I)=[CH:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:24]3=[N:25][CH:26]=2)[CH:16]=[N:17][C:18]=1[O:19][CH3:20])[S:9]([CH3:12])(=[O:11])=[O:10])=O)(C)(C)C.[F:38][C:39]1[CH:40]=[C:41]([CH:59]=[CH:60][CH:61]=1)[CH2:42][N:43]1[C:47]([CH3:48])=[C:46](B2OC(C)(C)C(C)(C)O2)[C:45]([CH3:58])=[N:44]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[F:38][C:39]1[CH:40]=[C:41]([CH:59]=[CH:60][CH:61]=1)[CH2:42][N:43]1[C:47]([CH3:48])=[C:46]([C:29]2[C:23]3[C:24](=[N:25][CH:26]=[C:21]([C:15]4[CH:16]=[N:17][C:18]([O:19][CH3:20])=[C:13]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:14]=4)[CH:22]=3)[N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH:28]=2)[C:45]([CH3:58])=[N:44]1
Reactant: COc1ncc(-c2cnc3c(c2)c(I)cn3C(=O)OC(C)(C)C)cc1N(C(=O)OC(C)(C)C)S(C)(=O)=O
Reactant: Cc1nn(Cc2cccc(F)c2)c(C)c1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ncc(-c2cnc3c(c2)c(-c2c(C)nn(Cc4cccc(F)c4)c2C)cn3C(=O)OC(C)(C)C)cc1NS(C)(=O)=O
Yield: 63.4 %

Procedure:
Using similar reaction conditions as described in step-i of example-1, tert-butyl 5-(5-(N-(tert-butoxycarbonyl)methylsulfonamido)-6-methoxypyridin-3-yl)-3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (intermediate 66) (100 mg, 0.155 mmol) was coupled with 1-(3-fluorobenzyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 16) (61 mg, 0.186 mmol) using Pd(PPh3)2Cl2 (5 mg, 0.0077 mol) and sodium carbonate (49 mg, 0.465 mmol) in DME/water (10/1 ml) to afford 61 mg (54.5% yield) of the titled compound. MS: m/z=621.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[CH:25]([C:28]1[CH:29]=[C:30]([OH:34])[CH:31]=[CH:32][CH:33]=1)([CH3:27])[CH3:26]>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:34][C:30]3[CH:31]=[CH:32][CH:33]=[C:28]([CH:25]([CH3:27])[CH3:26])[CH:29]=3)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(C)c1cccc(O)c1
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Product: CC(C)c1cccc(Oc2nc(C(=O)NC(C)c3cc(F)c(NS(C)(=O)=O)c(F)c3)co2)c1
Yield: 79.6 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (40 mg, 0.11 mmol) was reacted with 3-isopropyl phenol (18 mg, 0.12 mmol) to give the title compound (42 mg, 83%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: [Tl].Cl[C:3]1[C:4]([I:14])=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:12]=[O:13].[H-].[Na+].IC.CN([CH:22]=[O:23])C>>[I:14][C:4]1[C:3]([O:23][CH3:22])=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6]([CH:12]=[O:13])=[CH:7][NH:8]2
Reactant: CN(C)C=O
Reactant: O=Cc1c[nH]c2ccc(Cl)c(I)c12
Agent: [H-]
Agent: [Na+]
Agent: [Tl]
Solvent: CI
Product: COc1ccc2[nH]cc(C=O)c2c1I

Procedure:
By employing thallium chemistry, the 4-iodo-5-methoxy-indole-3-carboxaldehyde was prepared according to the procedure of Moody, C. J.; Swann, E. J. Chem. Soc. Perkin 1 1993, 21, 2561 and the 5-chloro-4-iodo-indole-3-carboxaldehyde according to the procedure of Ohta, T.; Yamato, Y.; Tahira, H.; Somei M., Heterocycles 1987, 11, 2817 (and references therein). These derivatives were subsequently reacted with NaH and iodomethane in DMF to provide the corresponding N-methyl derivatives, which were then used for the preparation of compounds 190, 280 and 212 following a procedure analogous to that described in example 1. Following the general procedure of Ohta, T.; Yamato, Y.; Tahira, H.; Somei M., Heterocycles 1987, 11, 2817 (and references therein), as used above for the preparation of the 5-chloro-4-iodo-indole-3-carboxaldehyde, the 4-halogenated derivatives for a number of commercially available 5 or 6 substituted indole-3-carboxyladehydes were prepared via thallium-mediated chemistry, using (i) reaction with thallium tris-trifluoro acetate, followed by (ii) reaction an electrophile, such as KI or CuBr2. The resulting 4,5- or 4,6-disubstituted indole-3-carboxaldehydes were subsequently methylated at the indole N-position, as described in examples 13 and 16. The products were used for condensation with appropriate pyrazolones as described in example 1, to provide the desired compounds. Compounds 203, 266, 267, 281, 214, 221, 220, 222, 223, 289, 218, 219, 225, 226, 227, 228, 229, and 230 were derived following the sequence of steps described above.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Br:17][CH2:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc2sc(-c3ccccc3)nc12
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cccc2sc(-c3ccccc3)nc12
Reaction time: 8 h

Procedure:
42.8 g (190 mmol) of 4-methyl-2-phenyl-benzothiazole [compare Perregaard, Lawesson, Acta Chem. Scand. Ser. B, 31, 203 (1977)] were dissolved in 1 l of carbon tetrachloride, and catalytic amounts of 2,2'-azoisobutyronitrile were added. 40.6 g (0.228 mol) of N-bromosuccinimide (NBS) were added under reflux in portions and the mixture was boiled overnight. A further 40.6 g of NBS were added and the mixture was boiled for 2 h. After cooling, the mixture was diluted with methylene chloride, washed with water, dried and concentrated, and the residue was crystallized using petroleum ether.
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]=[CH:3]1.[NH:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:17]=[O:18])[C:11]=2[CH:10]=[CH:9]1>>[CH:2]1([N:8]2[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([CH:17]=[O:18])[C:11]=3[CH:10]=[CH:9]2)[CH2:7][CH2:6][CH2:5][CH:4]=[CH:3]1
Reactant: BrC1C=CCCC1
Reactant: O=Cc1cccc2[nH]ccc12
Product: O=Cc1cccc2c1ccn2C1C=CCCC1
Yield: 17.9 %

Procedure:
The same procedures used in Example 1 were repeated except for using 2.44 g of 3-bromocyclohexene and 2.00 g of indole-4-carbaldehyde as a starting material to give 556 mg of 1-(2-cyclohexenyl)indole-4-carbaldehyde as a yellow-colored oily substance. The yield thereof was found to be 18%.
Reaction SMILES: [NH2:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]3[C:14]([C:5]2=[N:4][C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])=[CH:13][CH:12]=[CH:11][CH:10]=3.[C:22]1([CH3:30])[CH:27]=[CH:26][C:25]([CH:28]=O)=[CH:24][CH:23]=1.O>CO>[CH3:30][C:22]1[CH:27]=[CH:26][C:25]([CH:28]=[N:1][C:2]2[N:6]3[CH:7]=[CH:8][C:9]4[C:14]([C:5]3=[N:4][C:3]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][CH:12]=[CH:11][CH:10]=4)=[CH:24][CH:23]=1
Reactant: Cc1ccccc1-c1nc2c3ccccc3ccn2c1N
Reactant: Cc1ccc(C=O)cc1
Solvent: CO
Solvent: O
Product: Cc1ccc(C=Nc2c(-c3ccccc3C)nc3c4ccccc4ccn23)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 78.6 %

Procedure:
To a solution of 5 g of 3-amino-2-(2-methylphenyl)imidazo[2,1-a]isoquinoline (Compound 3) in 50 ml of methanol was added 2.2 g of p-tolualdehyde. After the mixture was stirred at room temperature for 22 hours, it was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel, and recrystallization from ethyl acetate/petroleum ether gave 5.4 g of the title compound as yellow crystals.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:34][CH2:33][C:18]3([O:23][CH2:22][C:21](=[O:24])[N:20]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)[CH2:19]3)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>CO.O1CCCC1.[C].[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:34][CH2:33][C:18]3([O:23][CH2:22][C:21](=[O:24])[N:20]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)[CH2:19]3)[CH2:17][CH2:16]2)=[CH:13][CH:14]=1
Reactant: COc1ccc(N2CC3(CCN(c4ccc(OCc5ccccc5)cc4)CC3)OCC2=O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(N2CC3(CCN(c4ccc(O)cc4)CC3)OCC2=O)cc1
Yield: 82 %

Procedure:
The benzyloxy compound (529 mg, 1.15 mmol) obtained in (a) was dissolved in a mixed solvent of methanol/tetrahydrofuran (1/1), then 10% palladium-carbon (110 mg, 0.103 mmol) was added thereto and stirred overnight in a hydrogen atmosphere. The reaction solution was filtered through Celite, the Celite was washed with mixed solvent of chloroform/methanol, and the mother liquid was concentrated to obtain the entitled compound (350 mg, 82%) as a violet solid.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=2)[N:3]=[CH:2]1.S1C=CN=C1C1C=CC(C=O)=CC=1>>[S:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[CH:8][C:9]([CH2:10][OH:11])=[CH:12][CH:13]=2)[N:3]=[CH:2]1
Reactant: O=Cc1ccc(-c2cscn2)cc1
Agent: O=Cc1ccc(-c2nccs2)cc1
Product: OCc1ccc(-c2cscn2)cc1
Yield: 82.8 %

Procedure:
Reaction and post-treatment were carried out in the same manner as in Reference Example 4-(a) except for using 4-(thiazol-4-yl)benzaldehyde (1.28 g, 6.76 mmol) obtained in Reference Example 15-(a) in place of 4-(thiazol-2-yl)benzaldehyde to afford the title compound (1.07 g) as a white solid. (Yield: 83%)
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]([C:14]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)([CH3:16])[OH:15])[CH:10]=[C:11]([Br:13])[CH:12]=1.CN(C)[CH:26]=[O:27]>CCCCCC.C(OCC)C>[Br:13][C:11]1[CH:12]=[C:7]([CH:8]=[C:9]([C:14]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)([OH:15])[CH3:16])[CH:10]=1)[CH:26]=[O:27]
Reactant: CC(O)(c1ccc(F)cc1)c1cc(Br)cc(Br)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(O)(c1ccc(F)cc1)c1cc(Br)cc(C=O)c1
Reaction time: 0.5 h
Yield: 41.2 %

Procedure:
A 2.5M solution of n-butyllithium in hexane (10.7 ml) was added dropwise to a stirred suspension of 3,5-dibromo-α-(4-fluorophenyl)-α-methylbenzenemethanol (5.90 g) in dry diethyl ether (160 ml) at -78° C. under an atmosphere of dry nitrogen. The resulting mixture was stirred at this temperature for 30 minutes and then N,N-dimethylformamide (2.93 g) was added dropwise. Stirring at -78° C. was continued for 1 hour and then the reaction was quenched by the addition of water. The temperature was allowed to reach room temperature and the organic layer was separated, washed with water and dried (MgSO4). Evaporation of the solvent gave an oil which was chromatographed on silica gel. Elution was commenced with hexane/dichloromethane (1:1), and the ratio was gradually changed to hexane/dichloromethane (1:5). The later product fractions were combined and evaporated to give the title compound as an oil (2.10 g), Rf 0.15 (SS 1). Found: C,55.39; H,3.78. C15H12BrO2F requires C,55.75; H,3.74%.
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([O:7][CH:8]1[CH2:25][CH2:24][C:11]2([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[CH2:10][CH2:9]1)[CH:5]=C.CSC>CO>[O:1]=[CH:5][CH2:4][O:7][CH:8]1[CH2:9][CH2:10][C:11]2([CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])[CH2:15][CH2:16]2)[CH2:24][CH2:25]1
Reactant: O=[O+][O-]
Reactant: C=CCOC1CCC2(CC1)CCN(C(=O)OC(C)(C)C)CC2
Solvent: CSC
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2(CCC(OCC=O)CC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
O3 gas was passed through a stirred solution of tert-butyl 9-(allyloxy)-3-azaspiro[5.5]undecane-3-carboxylate (6.47 mmol, 1.0 eq.) in MeOH (40 ml) for 45 min at −78° C. Dimethylsulfide (77.64 mmol, 12.0 eq.) was added dropwise to the reaction mixture at 0° C. and it was stirred for 30 min at 25° C. The reaction mixture was concentrated under reduced pressure to yield the crude product as a light yellow oil which was used in next step without further purification. Yield: 99%
Reaction SMILES: Cl.[CH:2]([C:5](C(C)C)([CH:8]([CH3:10])C)[CH2:6][NH2:7])([CH3:4])[CH3:3].[N:14](C1C=CC(B2OC(C)(C)C(C)(C)O2)=CC=1)=C=O>CN(C)C=O.O1CCCC1>[CH2:6]1[C:5]2[CH:8]=[CH:10][N:14]=[CH:4][C:2]=2[CH2:3][NH:7]1
Reactant: CC(C)C(CN)(C(C)C)C(C)C
Reactant: CC1(C)OB(c2ccc(N=C=O)cc2)OC1(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: c1cc2c(cn1)CNC2
Temperature: -15 °C
Reaction time: 0.33 h

Procedure:
HCl (1.55 g, 8.03 mmol) was suspended in dimethylformamide (30 ml) and treated with triisopropylethylamine (4.21 ml, 24.08 mmol). After stirring for 20 minutes, the mixture was cooled to −15° C. 2-(4-Isocyanatophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.028 g, 8.03 mmol) was dissolved in 10 ml tetrahydrofuran and added via syringe over 10 minutes. The mixture was allowed to warm to room temperature, and it was stirred for 3 hours and concentrated under a stream of nitrogen to minimal volume. The residue was diluted with cold water to give a turbid mixture which was filtered with water washes to provide the title compound after drying.