Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20](Cl)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:35][N:36]1[C:40]([CH3:41])=[C:39]2[S:42][C:43]([Sn](CCCC)(CCCC)CCCC)=[CH:44][C:38]2=[N:37]1>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([C:43]2[S:42][C:39]3[C:38](=[N:37][N:36]([CH3:35])[C:40]=3[CH3:41])[CH:44]=2)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2nn(C)c(C)c2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1c2sc(-c3nc(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)c(F)c4c3C(=O)N(C(=O)OC(C)(C)C)C4)cc2nn1C
Temperature: 90 °C

Procedure:
In a 30 mL sealed cap glass tube, tert-butyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (150 mg, 0.301 mmol), 2,3-dimethyl-5-(tributylstannyl)-2H-thieno[3,2-c]pyrazole (265 mg, 0.601 mmol) and tetrakis(triphenylphosphine)palladium(0) (174 mg, 0.150 mmol) were dissolved in toluene (5 mL). The cap was sealed and the reaction mixture was heated at 90° C. in an oil bath for 2 hours. The mixture was concentrated to give the intermediate, tert-butyl 6-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-4-(2,3-dimethyl-2H-thieno[3,2-c]pyrazol-5-yl)-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate. The intermediate was dissolved in TFA (5 mL) and the reaction mixture was stirred for 90 minutes. The mixture was concentrated, dissolved in DMSO (5 mL), and purified via preparatory HPLC eluting with a gradient of 20-30% ACN (0.035% TFA) and H2O (0.05% TFA). The pure fractions were combined, evaporated to a minimal volume, and lyophilized to give a TFA salt of the title compound as a white solid (108 mg, 68.0%). 1H NMR (400 MHz, DMSO-d6) ppm 1.49-2.04 (m, 8H), 2.45 (s, 3H), 3.84 (br s, 1H), 3.92 (s, 3H), 4.27 (br s, 1H), 4.35-4.51 (m, 2H), 7.08 (d, J=6.06 Hz, 1H), 7.78 (br s, 3H), 8.60 (s, 1H), 9.25 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C20H23FN6OS, 415. found, 415.
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([N+:29]([O-])=O)[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[N:11](C(OC(C)(C)C)=O)[CH:12]=[C:13]([C:14]#[C:15][CH2:16][OH:17])[C:6]=12>C1COCC1.CO.[Pd]>[NH2:29][C:27]1[CH:26]=[CH:25][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]3[NH:11][CH:12]=[C:13]([CH2:14][CH2:15][CH2:16][OH:17])[C:6]=23)=[C:2]([F:1])[CH:28]=1
Reactant: CC(C)(C)OC(=O)n1cc(C#CCO)c2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc21
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(Oc2ccnc3[nH]cc(CCCO)c23)c(F)c1
Reaction time: 5 h
Yield: 13.3 %

Procedure:
A mixture of tert-butyl 4-(2-fluoro-4-nitrophenoxy)-3-(3-hydroxyprop-1-ynyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (50 mg, 0.15 mmol) and 10% Pd/C (containing 50% H2O, 120 mg) in THF (10 mL) and MeOH (2 mL) was hydrogenated at 1 atm for 5 h. The mixture was diluted with MeOH and filtered through a pad of Celite®. The crude mixture was purified by preparative HPLC to afford the desired product (6 mg, 13% yield) as a white solid. LC/MS (ESI+) m/z 302 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:12][CH:13]2[CH2:17][CH2:16][O:15][CH2:14]2)=[C:9]([CH:11]=1)[NH2:10])([CH3:4])([CH3:3])[CH3:2].[C:18]1([CH3:27])[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:12][CH:13]2[CH2:17][CH2:16][O:15][CH2:14]2)=[C:9]([NH:10][C:25]([NH:24][C:21]2[CH:22]=[CH:23][C:18]([CH3:27])=[CH:19][CH:20]=2)=[O:26])[CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(OC2CCOC2)c(N)c1
Reactant: Cc1ccc(N=C=O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(NC(=O)Nc2cc(C(C)(C)C)ccc2OC2CCOC2)cc1
Reaction time: 8 h
Yield: 74.8 %

Procedure:
To a solution of 5-tert-butyl-2-(3-tetrahydrofuranyloxy)aniline (0.078 g, 0.33 mmol) in toluene (2.0 mL) was added p-tolyl isocyanate (0.048 g, 0.36 mmol) and the resulting mixture was allowed to stir at room temp. for 8 h to produce a precipitate. The reaction mixture was filtered and the residue was sequentially washed with toluene and hexanes to give the desired urea as a white solid (0.091 g, 75%): mp 229-231° C.; 1H-NMR (DMSO-d6) δ 1.30 (s, 9H), 1.99-2.03 (m, 1H), 2.19-2.23 (m, 4H), 3.69-3.76 (m, 1H), 3.86-3.93 (m, 3H), 4.98-5.01 (m, 1H), 6.81-6.90 (m, 2H), 7.06 (d, J=8.09 Hz, 2H, 7.32 (d, J=8.09 Hz, 2H), 7.84 (s, 1H), 8.22 (d, J=2.21 Hz, 1H), 9.26 (s, 1H). B1b. General Method for the Reaction of an Aryl Amine with an Aryl Isocyanate
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][CH:3]=1.CO[C:20]1(OC)[CH2:24][CH2:23][CH2:22]O1>C(O)(=O)C>[N:1]1([C:2]2[CH:11]=[C:10]3[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]3[CH2:12][CH3:13])=[CH:4][CH:3]=2)[CH:20]=[CH:24][CH:23]=[CH:22]1
Reactant: CCn1cc(C(=O)O)c(=O)c2ccc(N)cc21
Reactant: COC1(OC)CCCO1
Solvent: CC(=O)O
Product: CCn1cc(C(=O)O)c(=O)c2ccc(-n3cccc3)cc21

Procedure:
0.3 Gram of 7-amino-1-ethyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is suspended in 10 ml of acetic acid, 0.17 gram of dimethoxytetrahydrofuran is added and the mixture is heated until the solid has dissolved. The mixture is filtered, and water is added to the filtrate until it becomes turbid. The filtrate is allowed to cool, and the precipitate obtained is filtered off and washed with ethanol. 0.12 gram of a solid is obtained, of melting point 235°-238° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[O:20][N:19]=[C:18]([CH3:21])[CH:17]=1.[OH-].[K+]>C(#N)C>[CH3:21][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[O:20][N:19]=1
Reactant: Cc1cc(CCCCCBr)on1
Reactant: O=Cc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: Cc1cc(CCCCCOc2ccc(C=O)cc2)on1
Yield: 67 %

Procedure:
A solution of 7.2 g 4-hydroxybenzaldehyde, 14.6 g 5-(5-bromopentyl)-3-methylisoxazole, 4 g potassium hydroxide in 100 ml acetonitrile was heated at reflux for 1.5 hours. The reaction mixture was cooled and filtered the solvent removed, and the residue recrystallized from isopropyl acetate-hexane to give 10.8 g 4-[5-(3-methyl-5-isoxazolyl)pentyloxy]benzaldehyde as a pale-yellow powder.
Reaction SMILES: I[C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[F:14][CH:15]1[CH:20]([OH:21])[CH2:19][CH2:18][N:17]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:16]1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.[Cu]I>[F:14][C@H:15]1[C@H:20]([O:21][C:2]2[C:10]3[O:9][CH:8]=[CH:7][C:6]=3[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=2)[CH2:19][CH2:18][N:17]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C(F)C1
Reactant: O=[N+]([O-])c1cc(I)c2occc2c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC[C@@H](Oc2cc([N+](=O)[O-])cc3ccoc23)[C@H](F)C1

Procedure:
7-Iodo-5-nitrobenzofuran (2.0 g, 6.9 mmol), tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate* (3.8 g, 17.3 mmol; mixture of cis/trans isomers), 1,10-phenanthroline (0.50 g, 2.8 mmol), CuI (0.26 g, 1.4 mmol) and Cs2CO3 (4.5 g, 13.8 mmol) were heated in toluene (20 mL) at 120° C. for 72 h. The reaction mixture was filtered through Celite and evaporated. The resulting diastereomers were separated by flash chromatography using heptane/EtOAc [(4:1)→(2:1)] to yield 255 mg of the cis-isomer and 919 mg of the trans-isomer. *Prepared according to the procedure described in WO2001085728.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:12])=[C:4]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[CH:5]=O.Br[CH:14](C(OC)=O)[C:15]([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:1][C:2]1[C:3]2[O:12][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:5][C:4]=2[CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1
Reactant: COC(=O)C(Br)C(=O)OC
Reactant: COc1cc(Br)c(O)c(C=O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc2cc(OC)cc(Br)c2o1
Yield: 54.8 %

Procedure:
To a solution containing 3-Bromo-2-hydroxy-5-methoxy-benzaldehyde (94.7 g, 0.410 mol) and dimethyl bromomalonate (103 g, 0.492 mol) in toluene (1.2 L) was added freshly powdered potassium carbonate (85 g, 0.615 mol) and tetra-n-butylammonium bromide (13.2 g, 0.041 mol). The reaction was heated at reflux under a Dean-Stark trap for 48 h. The reaction was concentrated and the residue dissolved with dichloromethane (−0.5 L) and filtered through Celite, washing with dichloromethane (˜0.5 L). The filtrate was washed with 1 L of 1M sodium hydroxide and water (2×1 L). The organic phase was then passed through a 400 g pad of silica gel washing with dichloromethane (˜1 L) and the filtrate was concentrated to give the desired benzofuran (64 g, 56%) as an orange solid, mp 107–111° C. 1H NMR δ (CDCl3) 7.50 (s, 1H), 7.23 (d, 1H), 7.03 (d, 1H), 3.98 (s, 3H), 3.82 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][CH2:9][C:8](=O)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[C:13]([CH:15]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:14]>CC1C=CC(C)=CC=1>[CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH2:15][C:13]#[N:14])=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: N#CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1cccc2c1OCC2=O
Solvent: Cc1ccc(C)cc1
Product: COc1cccc2cc(CC#N)oc12
Yield: 68.5 %

Procedure:
A mixture of 14.16 g of 7-methoxy-3-benzofuranone, 39.4 g of cyanomethylenetriphenylphosphorane and 70 ml of p-xylene was heated at reflux under nitrogen for 16 hours. The solvent was removed, the solid washed repeatedly with ether and the product obtained on removal of the solvent from the ether washings sublimed (145° bath, 1 micron). Crystallization of the sublimate from 20 ml of isopropyl alcohol gave 11.06 g (69% yield) of 7-methoxy-3-benzofuranacetonitrile. Nmr spectrum (in CDCl3): τ2.4 (t, J=1-2 Hz, 1); 2.8-3.3 (m, 3); 6.0 (s, 3) and 6.3 (d, J=1-2 Hz, 2).
Reaction SMILES: C(OC([O:8][NH:9][C:10]([C:12]1[CH:13]=[N:14][C:15]([N:18]2[CH2:25][CH:24]3[CH:20]([CH2:21][N:22]([S:26]([C:29]4[CH:38]=[CH:37][C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[CH:30]=4)(=[O:28])=[O:27])[CH2:23]3)[CH2:19]2)=[N:16][CH:17]=1)=[O:11])C)C(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl.CO>>[OH:8][NH:9][C:10]([C:12]1[CH:13]=[N:14][C:15]([N:18]2[CH2:25][CH:24]3[CH:20]([CH2:21][N:22]([S:26]([C:29]4[CH:38]=[CH:37][C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[CH:30]=4)(=[O:28])=[O:27])[CH2:23]3)[CH2:19]2)=[N:16][CH:17]=1)=[O:11]
Reactant: CC(C)COC(C)ONC(=O)c1cnc(N2CC3CN(S(=O)(=O)c4ccc5ccccc5c4)CC3C2)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: O=C(NO)c1cnc(N2CC3CN(S(=O)(=O)c4ccc5ccccc5c4)CC3C2)nc1
Reaction time: 2 h
Yield: 43.2 %

Procedure:
To N-(1-isobutoxyethoxy) 2-[5-(naphthalene-2-sulfonyl)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-pyrimidine-5-carboxamide (0.255 g, 0.5 mmol) was added TFA/DCM/MeOH (5 ml, 1:2:2 mixture). The solution was stirred for 2 h, then concentrated under vacuum. The residue was purified by reverse phase HPLC to yield the desired product (95 mg, 50%). LCMS purity >98%, m/z 440 [M+H]+, 1H NMR (300 MHz, d6-DMSO) δ: 2.90 (2H, br s), 3.24 (4H, dd, J=3.3, 10 Hz), 3.45 (2H, dd, J=6.8, 9.8 Hz), 3.61 (2H, dd, J=6.7, 11.4 Hz), 7.62-7.77 (2H, m), 7.83 (1H, dd, J=1.1, 8.5 Hz), 8.06 (1H, d, J=7.8 Hz), 8.13 (1H, d, J=8.8 Hz), 8.17 (1H, d, J=8.2 Hz), 8.47 (1H, s), 8.55 (2H, s), 11.02 (1H, s).
Reaction SMILES: [N:1]1([CH2:7][CH2:8]O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(Br)(Br)(Br)[Br:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:11][CH2:8][CH2:7][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: OCCN1CCOCC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCN1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.8 %

Procedure:
To a mixture of 0.656 g (5 mmole) of 2-morpholin-4-yl-ethanol and 20 mL of dichloromethane at 0 degrees was added 2.49 g (7.5 mmole) of carbon tetrabromide and then 1.57 g (6 mmole) of triphenylphosphine. The mixture was stirred at ambient temperature overnight. The mixture was concentrated under reduced pressure and 50 mL of hexanes was added. The solid was removed by filtration and the filtrate was concentrated under reduced pressure. Purification of the residue by silica gel chromatography, eluting with ethyl acetate-hexanes (gradient 0:100-30:70) gave 0.580 g of 4-(2-bromo-ethyl)-morpholine as a colorless oil.
Reaction SMILES: [O:1]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:16][C:17]([CH3:23])([CH2:21][CH3:22])[C:18](Cl)=[O:19]>>[CH3:16][C:17]([CH3:23])([CH2:21][CH3:22])[C:18]([N:13]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8][N:7]([C:18](=[O:19])[C:17]([CH3:23])([CH3:16])[CH2:21][CH3:22])[CH2:6][CH2:5][O:4][CH2:3][CH2:2][O:1][CH2:15][CH2:14]1)=[O:19]
Reactant: C1COCCNCCOCCOCCN1
Reactant: CCC(C)(C)C(=O)Cl
Product: CCC(C)(C)C(=O)N1CCOCCOCCN(C(=O)C(C)(C)CC)CCOCC1

Procedure:
Analogously to Example 2 from 1,4,10-trioxa-7,13-diazacyclopentadecane and 2,2-dimethylbutyryl chloride.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.Cl[CH2:40][C:41]1[N:42]2[CH2:48][CH2:47][N:46]=[C:43]2[S:44][CH:45]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:40][C:41]2[N:42]3[CH2:48][CH2:47][N:46]=[C:43]3[S:44][CH:45]=2)[CH:28]=1)[C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: ClCC1=CSC2=NCCN12
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Agent: Cl
Product: CC(C)c1ccc(N(Cc2cnn(CC3=CSC4=NCCN34)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Yield: 106.8 %

Procedure:
By the reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.72 g) and 3-chloromethyl-5,6-dihydroimidazo[2,1-b]thiazole hydrochloride (0.38 g) as starting materials, 5-benzyloxy-N-({1-[(5,6-dihydroimidazo[2,1-b]thiazol-3-yl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.92 g) was obtained. By the reaction and treatment of this compound in the same manner as in Example 139, N-({1-[(5,6-dihydroimidazo[2,1-b]thiazol-3-yl)methyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide dihydrochloride (0.50 g) was obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]2[CH2:16][CH2:15][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([CH:14]=1)[C:8]2=3)=[O:5])C.O.Cl>C(O)C.[OH-].[Na+]>[CH:14]1[C:13]2[C:8]3=[C:9]([CH2:15][CH2:16][N:7]3[C:6]=1[C:4]([OH:5])=[O:3])[CH:10]=[CH:11][CH:12]=2
Reactant: CCOC(=O)c1cc2cccc3c2n1CC3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc2cccc3c2n1CC3
Temperature: 25 °C
Yield: 91 %

Procedure:
A solution of 4,5-dihydro-pyrrolo[3,2,1-hi]indole-2-carboxylic acid ethyl ester (1.117 g) in ethanol (25 ml) and 2M sodium hydroxide (25 ml) was heated to reflux for 1 hour. The mixture was cooled to room temperature and poured into water (300 ml). 1M hydrochloric acid was added until pH1 and the precipitate formed filtered off and washed with water (50 ml). After drying under reduced pressure 4,5-dihydro-pyrrolo[3,2,1-hi]indole-2-carboxylic acid was obtained as a pale yellow powder (884 mg). 400 MHz 1H NMR (DMSO-d6) δ: 12.94 (s, 1H), 7.31 (d, J=7.2 Hz, 1H), 7.01-6.96 (m, 3H), 4.67 (t, J=6.8 Hz, 2H), 3.74 (t, J=6.8 Hz, 2H); LCMS: 188 [M+H].
Reaction SMILES: [C:1]12([C:11]3[CH:16]=[C:15]([Br:17])[C:14]([O:18][CH3:19])=[CH:13][C:12]=3[OH:20])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:1]12([C:11]3[C:12]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:13][C:14]([O:18][CH3:19])=[C:15]([Br:17])[CH:16]=3)[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: COc1cc(O)c(C23CC4CC(CC(C4)C2)C3)cc1Br
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(OCc2ccccc2)c(C23CC4CC(CC(C4)C2)C3)cc1Br
Yield: 76.2 %

Procedure:
To a stirred solution of 2-(1-adamantyl)-4-bromo-5-methoxyphenol (2.59 g, 7.68 mmol) in acetone (26 mL) was added benzyl bromide (1.31 g, 7.68 mmol) followed by K2CO3 (1.33 g, 9.60 mmol). The mixture was stirred and heated at reflux for 17.25 h under argon. Acetone was removed at reduced pressure before 1 N HCl (40 mL) was added. The mixture was extracted with EtOAc (100 mL), and the organic layer was washed with H2O and brine and dried. After removal of solvent at reduced pressure, the residue was purified on silica gel (0% to 4% EtOAc/hexane) to give 2.50 g (76%) of 5-(1-adamantyl)-4-benzyloxy-2-methoxyphenyl bromide as a white solid, mp 124-126° C. IR 2902, 2847, 1498, 1161 cm−1; 1H NMR (CDCl3) δ 1.71 (bs, 6H, AdCH2), 2.02 (bs, 311, AdCH), 2.08 (bs, 6H, AdCH2), 3.82 (s, 3H, OCH3), 5.12 (s, 2H, C6H5CH2), 6.53 (s, 1H, 3-ArH), 7.34 (s, 1H, 6-ArH), 7.31-7.50 ppm (m, 5H, C6H5).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:3]=1[NH2:4].[O:10]=[C:11]([CH3:18])[CH2:12][C:13](OCC)=[O:14]>>[CH3:1][C:2]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:3]=1[NH:4][C:13](=[O:14])[CH2:12][C:11](=[O:10])[CH3:18]
Reactant: Cc1ccc(C)c(N)c1
Reactant: CCOC(=O)CC(C)=O
Product: CC(=O)CC(=O)Nc1cc(C)ccc1C
Temperature: 25 °C

Procedure:
A mixture of 2,5-dimethylaniline (1.00 g, 8.25 mmol) and ethyl 3-oxobutanoate (1.0 mL, 1.0 eq) was microwaved at 180° C. for 5 minutes. After the reaction mixture was cooled to room temperature, it was triturated with hexane. The resulting precipitate was filtered and dried under high vacuum to yield the desired title compound. Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ ppm 2.28 (s, 3 H) 2.32 (s, 3 H) 2.34 (s, 3 H) 3.63 (s, 2 H) 6.88 (d, J=7.62 Hz, 1 H) 7.07 (d, J=7.62 Hz, 1 H) 7.75 (s, 1 H) 9.00-9.12 (m, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:26]=[CH:25][CH:24]=[C:23](OS(C(F)(F)F)(=O)=O)[C:13]=2[C:14]([O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])=[O:15])[N:4]=1.[C:35](C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)[CH3:36].C([Sn](CCCC)(CCCC)CCCC)=C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][C:12]2[CH:26]=[CH:25][CH:24]=[C:23]([CH:35]=[CH2:36])[C:13]=2[C:14]([O:16][CH2:17][CH2:18][Si:19]([CH3:20])([CH3:22])[CH3:21])=[O:15])[N:6]=1
Reactant: COc1cc(OC)nc(Oc2cccc(OS(=O)(=O)C(F)(F)F)c2C(=O)OCC[Si](C)(C)C)n1
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C=C[Sn](CCCC)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: C=Cc1cccc(Oc2nc(OC)cc(OC)n2)c1C(=O)OCC[Si](C)(C)C
Yield: 20.8 %

Procedure:
In a 100 ml flask equipped with a thermometer, a cooling tube and a nitrogen-introducing tube, there were charged 2-trimethylsilylethyl 2-[(4,6-dimethoxypyrimidin-2-yl)oxy]-6-trifluoromethylsulfonyloxybenzoate (3.15 g, 6.0 mmol), tetrakis(triphenylphosphine)palladium(0) (400 mg, 0.34 mmol) and toluene (30 ml), and the resultant mixture was stirred at room temperature for 1 hour under nitrogen stream. After adding 2,6-di-tert-butyl-4-methylphenol (catalytic amount) to the resultant mixture, vinyl tributyl tin (3.17 g, 10.0 mmol) was further added and the mixture was reacted at 80°-90° C. for 3 hours. After cooling the mixture, toluene was added thereto and the organic layer was washed with water and a saturated salt water, dried with anhydrous sodium sulfate and concentrated. The residue thus obtained was purified by silica gel column chromatography to obtain 0.50 g (yield: 20.8%) of the aimed product (transparent viscous orange color liquid).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:4]=1[NH2:5].C(N(CC)CC)C.[C:19]([O:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]([C:39]2[CH:44]=[CH:43][C:42]([O:45][C:46](=[O:48])[CH3:47])=[CH:41][CH:40]=2)[C:30]2[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=2[C:32](Cl)=[O:33])=[CH:25][CH:24]=1)(=[O:21])[CH3:20].O>C(Cl)Cl>[C:19]([O:22][C:23]1[CH:24]=[CH:25][C:26]([CH:29]([C:39]2[CH:40]=[CH:41][C:42]([O:45][C:46](=[O:48])[CH3:47])=[CH:43][CH:44]=2)[C:30]2[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=2[C:32]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([O:10][CH3:11])=[CH:9][C:3]=2[O:2][CH3:1])=[O:33])=[CH:27][CH:28]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)Oc1ccc(C(c2ccc(OC(C)=O)cc2)c2ccccc2C(=O)Cl)cc1
Reactant: COc1ccc(N)c(OC)c1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)c2ccccc2C(c2ccc(OC(C)=O)cc2)c2ccc(OC(C)=O)cc2)c(OC)c1
Reaction time: 7 h

Procedure:
In 20 ml of methylene chloride were dissolved 1.08 g of 2,4-dimethoxyaniline and 4.5 ml of triethylamine. To this solution was dropwise added under ice cooling 20 ml of methylene chloride containing 3 g of 2-[bis(4-acetoxyphenyl)methyl]benzoyl chloride obtained in Reference Example 2. After stirring for 7 hours, water was added thereto. The organic layer was separated off, and the aqueous layer was extracted with chloroform. The chloroform layer was combined with the organic layer, and the combined organic layer was washed with 2N aqueous hydrochloric acid solution and dried over anhydrous magnesium sulfate. The resulting solution was concentrated under reduced pressure to give 2.6 g of the desired product (Compound 2) as an oily matter.
Reaction SMILES: [C:1]1(=[N:13][OH:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:17][N:18]([CH3:23])[CH2:19][CH2:20][CH2:21]Cl.Cl.[OH-].[NH4+]>C1(C)C=CC=CC=1>[CH3:17][N:18]([CH2:19][CH2:20][CH2:21][O:14][N:13]=[C:1]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH3:23]
Reactant: ON=C1CCCCCCCCCCC1
Reactant: CN(C)CCCCl
Agent: Cl
Agent: [H-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: CN(C)CCCON=C1CCCCCCCCCCC1
Temperature: 25 °C

Procedure:
A solution of 19.73 g. (0.1 moles) of cyclododecanone oxime in 200 ml. of anhydrous toluene is dropwise added at 85° C. under continuous stirring to a suspension of 2.4 g. (0.1 moles) of sodium hydride in 50 ml. of anhydrous toluene, and the mixture is refluxed for 2 hours. Then 13.3 g. (0.11 moles) of 1-dimethylamino-3-chloropropane is added to the reaction mixture. After refluxing for 10 hours the mixture is cooled to room temperature, washed with 100 ml of water and extracted with a 10% solution of hydrochloric acid containing 0.11 moles of hydrochloric acid. Then the solution cooled to 0° C. is made alkaline to pH 10 with an aqueous solution of ammonium hydroxide. The base separated as an oil is extracted with dichloromethane and the solvent is removed. Yield: 21.2 g. (75.07%). Hydrogen fumarate, m.p.: 116°-118° C.