Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH2:6])=[O:5].C(N(CC)CC)C.[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24])([O-:16])=[O:15].Cl>ClCCl>[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([NH:2][CH2:3][C:4]([NH2:6])=[O:5])(=[O:25])=[O:24])([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: NCC(N)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)CNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.9 %

Procedure:
To a suspension of glycinamide hydrochloride (0.11 g) and triethylamine (0.35 mL) in dichloromethane (3 mL) was added 2-nitrobenzenesulfonyl chloride (0.27 g), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 0.5 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=20/1) to give the title compound (72 mg).
Reaction SMILES: [CH:1]([CH:4]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[CH2:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].[C:13]([Mg]Br)#[CH:14]>C1COCC1>[C:13]([C:9]1([OH:10])[CH:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6][CH2:7][C:8]1([CH3:12])[CH3:11])#[CH:14]
Reactant: C#C[Mg]Br
Reactant: CC(C)C1CCCC(C)(C)C1=O
Solvent: C1CCOC1
Product: C#CC1(O)C(C(C)C)CCCC1(C)C
Temperature: 60 °C
Reaction time: 48 h
Yield: 81 %

Procedure:
A solution of 6-isopropyl-2,2-dimethylcyclohexanone (12.6 g, 75.0 mmol) in THF (50 ml) was added within 10 min at room temperature to a stirred solution of ethynyl magnesium bromide in THF (0.5 M, 180 ml, 90 mmol), and the reaction mixture was stirred for 2 d at 60° C. The reaction mixture was allowed to cool to room temperature, quenched with satd. aq. NH4Cl solution (500 ml) and extracted with Et2O (3×300 ml). The combined organic extracts were dried (Na2SO4) and evaporated. Purification of the resulting residue by silica gel FC (pentane/Et2O, 98:2, Rf 0.21) furnished 1-ethynyl-6-isopropyl-2,2-dimethylcyclohexanol (11.8 g, 81%) as a colorless liquid.
Reaction SMILES: [OH:1][C@H:2]([CH2:36][O:37][Si:38]([CH:45]([CH3:47])[CH3:46])([CH:42]([CH3:44])[CH3:43])[CH:39]([CH3:41])[CH3:40])[C@H:3]([NH:5][C:6]([C:8]1[NH:9][C:10]([C:13]2[CH:18]=[C:17]([O:19][C:20]3[CH:21]=[N:22][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:24][CH:25]=3)[CH:16]=[C:15]([O:30][C@@H:31]([CH3:35])[CH2:32][O:33][CH3:34])[CH:14]=2)=[CH:11][CH:12]=1)=O)[CH3:4].CS(O)(=O)=O.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:34][O:33][CH2:32][C@H:31]([CH3:35])[O:30][C:15]1[CH:16]=[C:17]([CH:18]=[C:13]([C:10]2[NH:9][C:8]([C:6]3[O:1][C@@H:2]([CH2:36][O:37][Si:38]([CH:45]([CH3:47])[CH3:46])([CH:39]([CH3:41])[CH3:40])[CH:42]([CH3:44])[CH3:43])[C@@H:3]([CH3:4])[N:5]=3)=[CH:12][CH:11]=2)[CH:14]=1)[O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:27])=[O:28])=[N:22][CH:21]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C(=O)N[C@H](C)[C@H](O)CO[Si](C(C)C)(C(C)C)C(C)C)[nH]2)c1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C3=N[C@H](C)[C@H](CO[Si](C(C)C)(C(C)C)C(C)C)O3)[nH]2)c1
Temperature: 50 °C
Reaction time: 5 h
Yield: 74.7 %

Procedure:
N-[(1R,2S)-2-Hydroxy-1-methyl-3-[(triisopropylsilyl)oxy]propyl]-5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)-1H-pyrrole-2-carboxamide (1.69 g, 2.45 mmol) synthesized in Example (890 was dissolved in tetrahydrofuran (25 mL), and anhydrous methanesulfonic acid (0.88 g, 4.90 mmol) and triethylamine (1.37 mL, 9.80 mmol) were added, followed by stirring at 50° C. for 5 hours under nitrogen atmosphere. A saturated aqueous sodium hydrogencarbonate solution (40 mL) was added, and the solution was separated with ethyl acetate (60 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=10%-50%) to afford the desired compound (1.23 g, yield 75%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:41])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[S:10][C:11]([C:14]([CH2:38][CH:39]=[CH2:40])([CH2:18][O:19][C:20]2[CH:25]=[C:24]([CH3:26])[C:23]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)=[C:22]([CH3:37])[CH:21]=2)[CH2:15][CH:16]=[CH2:17])=[CH:12][CH:13]=1)=[O:8]>CCO.[Pd]>[CH3:1][O:2][C:3](=[O:41])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[S:10][C:11]([C:14]([CH2:18][O:19][C:20]2[CH:25]=[C:24]([CH3:26])[C:23]([C:27]3[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:31][CH:32]=3)=[C:22]([CH3:37])[CH:21]=2)([CH2:15][CH2:16][CH3:17])[CH2:38][CH2:39][CH3:40])=[CH:12][CH:13]=1)=[O:8]
Reactant: C=CCC(CC=C)(COc1cc(C)c(-c2ccc(C(F)(F)F)cc2)c(C)c1)c1ccc(C(=O)NCCC(=O)OC)s1
Agent: [Pd]
Solvent: CCO
Product: CCCC(CCC)(COc1cc(C)c(-c2ccc(C(F)(F)F)cc2)c(C)c1)c1ccc(C(=O)NCCC(=O)OC)s1
Reaction time: 2 h
Yield: 86.4 %

Procedure:
A solution of 3-({5-[1-allyl-1-(2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-yloxymethyl)-but-3-enyl]-thiophene-2-carbonyl}-amino)-propionic acid methyl ester (0.0679 g, 0.116 mmol) in EtOH (2.0 mL) is treated with 10% palladium on carbon (12 mg), flushed with H2, and stirred under 1 atm pressure for 2 h. The mixture is then filtered through Celite® and conc. to provide 3-({5-[1-(2,6-Dimethyl-4′-trifluoromethyl-biphenyl-4-yloxymethyl)-1-propyl-butyl]-thiophene-2-carbonyl}-amino)-propionic acid methyl ester (0.0591 g, 86%) as a white foam. MS (ES): 588.4 [M−H]−.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11](O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:35]>C1COCC1>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([Br:35])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Br)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.3 %

Procedure:
To N-Boc-4-hydroxy piperidine (20 g, 100 mmol) in THF (200 ml) at 0° C. was added triphenylphosphine (28.85 g, 110 mmol) followed by carbon tetrabromide (36.48 g, 110 mmol). The solution was stirred at room temperature for 2 h then filtered and concentrated under vacuum. Flash column chromatography using dichloromethane in hexane (10-70%) yielded the product as a colourless oil (23.6 g); δH (CDCl3) 1.47 (9H, s, t-Bu), 1.93 and 2.04 (4H, m, 3,5-piperidinyl CH2), 3.31 and 3.66 (4H, m, 2,6-piperidinyl CH2), and 4.39 (1H, m, 4-piperidinyl H).
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:13][NH2:14])[CH2:8][CH:7]1[CH2:9][CH:10]([CH3:12])[CH3:11])=[O:5])C.[ClH:15]>>[ClH:15].[NH2:14][CH2:13][C:6]1([C:4]([OH:5])=[O:3])[CH2:8][CH:7]1[CH2:9][CH:10]([CH3:12])[CH3:11]
Reactant: CCOC(=O)C1(CN)CC1CC(C)C
Agent: Cl
Product: CC(C)CC1CC1(CN)C(=O)O
Yield: 100 %

Procedure:
To 1-aminomethyl-2-isobutyl-cyclopropanecarboxylic acid ethyl ester (0.1 g, 0.50 mmol) was added 10 mL 3N HCl (aq), and the mixture was refluxed for 60 hours. The crude 1H NMR indicated the hydrolysis had proceeded to 100% completion. The solution was filtered while hot through a glass wool plug and concentrated. The solid residue was washed with Et2O (2×3 mL) to give 86 mg (100%) of 1-aminomethyl-2-isobutyl-cyclopropanecarboxylic acid hydrochloride as a colorless solid, mp>220° C. (dec): 1H NMR (D2O) δ 3.34 (d, J=13.7 Hz, 1H), 2.83 (d, J=13.9 Hz, 1H), 1.57 (m, 1H), 1.47 (m, 1H), 1.37 (m, 1H), 1.30 (m, 1H), 1.00 (m, 1H), 0.72 (m, 7H). LRMS: m/z 169.9 (M−1). Anal. Calcd for C9H17NO2.HCl: C, 52.05; H, 8.74; N, 6.74. Found: C, 50.32; H, 8.15; N, 6.53.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[NH2:6][CH:7]([CH2:11][CH3:12])[C:8]([OH:10])=[O:9]>C1COCC1>[Br:1][CH2:2][C:3]([NH:6][CH:7]([CH2:11][CH3:12])[C:8]([OH:10])=[O:9])=[O:4]
Reactant: CCC(N)C(=O)O
Reactant: O=C(Br)CBr
Solvent: C1CCOC1
Product: CCC(NC(=O)CBr)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 60 %

Procedure:
A solution of bromoacetyl bromide (50 g, 24 mmol 1 molar eq.) in dry THF (500 ml) was slowly added to a 2 L round-bottomed three-neck flask with a mechanical stirrer, a nitrogen gas purge and an addition funnel containing 2-aminobutyric acid (25 g, 24 mmol) in 500 mL dry THF. After stirring at room temperature for 12 hours the reaction mixture was filtered and the THF evaporated from the filtrate gave yellow oil, which crystallized upon cooling in 60% yield. 1H NMR (500 MHz, DMSO d6) δ (ppm): 8.30 (s, 1H), 3.8 (s, 2H), 1.5 (s, 6H). 13C NMR (500 MHz, DMSO d6) δ (ppm): 178, 177, 57, 29, 25. MS (m/z) (%) 224 (30), 208 (20), 178 (99), 121 (40), 88 (65), 58 (100).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[OH:9][CH2:10][C:11]([NH:13][CH2:14][C@H:15]([O:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[C:20]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[C:31]([CH3:36])[CH:30]=1)=[N:21][CH:22]=[N:23]2)[CH3:16])=[O:12]>>[OH:9][CH2:10][C:11]([NH:13][CH2:14][C@H:15]([O:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[C:20]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=3)=[C:31]([CH3:36])[CH:30]=1)=[N:21][CH:22]=[N:23]2)[CH3:16])=[O:12]
Reactant: ClCc1ccccn1
Reactant: Cc1cc(Nc2ncnc3cccc(O[C@H](C)CNC(=O)CO)c23)ccc1O
Product: Cc1cc(Nc2ncnc3cccc(O[C@H](C)CNC(=O)CO)c23)ccc1OCc1ccccn1
Yield: 29 %

Procedure:
The procedure described in Example 3 was repeated using 2-(chloromethyl)pyridine and 2-hydroxy-N-[(2R)-2-({4-[(4-hydroxy-3-methylphenyl)amino]quinazolin-5-yl}oxy)propyl]acetamide to give the title compound as a white solid in 29% yield; NMR spectrum (DMSO-d6) 1.40 (d, 3H), 2.27 (s, 3H), 3.43 (dt, 1H), 3.72 (dt, 1H), 3.80 (d, 2H), 4.94 (m, 1H), 5.20 (s, 2H), 5.46 (t, 1H), 7.00 (d, 1H), 7.21 (d, 1H), 7.30 (d, 1H), 7.34 (dd, 1H), 7.56 (m, 3H), 7.68 (t, 1H), 7.85 (td, 1H), 8.16 (t, 1H), 8.43 (s, 1H), 8.58 (d, 1H), 9.94 (s, 1H); Mass spectrum MH+ 474.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)([O-:22])=[O:21].CCN(C(C)C)C(C)C.C(Cl)Cl>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:29][C:26]3[CH:27]=[CH:28][C:23]([N+:20]([O-:22])=[O:21])=[CH:24][CH:25]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccnc2cc(OCc3ccccc3)ccc12
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(Oc2ccnc3cc(OCc4ccccc4)ccc23)cc1
Temperature: 115 °C
Yield: 95.5 %

Procedure:
To a suspension of 7-(benzyloxy)-4-chloroquinoline (10 g, 37.1 mmol) and 4-nitrophenol (6.2 g, 44.5 mmol) in toluene (10 mL) was added DIPEA (6.2 g, 48.2 mmol). The reaction mixture was refluxed at 115° C. for 12 hours, then cooled down to room temperature. DCM (50 mL) was added to the mixture, and the resulted solution was washed with 1 M NaOH (30 mL each) several times till the water phase was colorless. The organic phase was concentrated in vacuo to afford a brown solid (13.2 g, 95.7%). The solid was stirred in 95% EtOH (30 mL) at room temperature for 12 hours, and filtered to give the title compound as a gray-brown solid (12.1 g, 91.7%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([CH2:12][S:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[C:7]=1[CH3:20].[SH:21][C:22]1[N:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([OH:26])=[O:25]>>[CH3:20][C:7]1[C:8]([CH2:12][S:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[N:9][CH:10]=[CH:11][C:6]=1[S:5][CH2:4][CH2:3][CH2:2][S:21][C:22]1[C:23]([C:24]([OH:26])=[O:25])=[CH:27][CH:28]=[CH:29][N:30]=1
Reactant: O=C(O)c1cccnc1S
Reactant: Cc1c(SCCCCl)ccnc1CSc1ccncc1
Product: Cc1c(SCCCSc2ncccc2C(=O)O)ccnc1CSc1ccncc1
Yield: 57 %

Procedure:
According to the procedure indicated in Example 21, reaction of 4-(3-chloropropylthio)-3-methyl-2-[(4-pyridinylthio)methyl]pyridine with 2-mercaptonicotinic acid, and subsequent establishment of a pH of about 6 gives the title compound as a colorless solid; m.p. 219° C., dec.; yield 57% of theory.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([OH:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:25][S:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33]Br)=[CH:29][CH:28]=1>>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([O:21][CH2:33][C:30]4[CH:31]=[CH:32][C:27]([S:26][CH3:25])=[CH:28][CH:29]=4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1c(C)c2c(c(C)c1O)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Reactant: CSc1ccc(CBr)cc1
Product: CSc1ccc(COc2c(C)c(C)c3c(c2C)C(c2ccc(C(C)C)cc2)C(C)(C)O3)cc1
Yield: 70 %

Procedure:
Using 3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-ol and 4-(bromomethyl)phenyl methyl sulfide, the title compound was obtained in the same manner as in Example 1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[I:12][C:13]1[C:21]2[C:16](=[CH:17][C:18]([CH:22]=O)=[CH:19][CH:20]=2)[NH:15][N:14]=1>N1CCCCC1.CO>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:22]\[C:18]1[CH:17]=[C:16]2[C:21]([C:13]([I:12])=[N:14][NH:15]2)=[CH:20][CH:19]=1
Reactant: O=Cc1ccc2c(I)n[nH]c2c1
Reactant: O=C1Cc2cc(F)ccc2N1
Solvent: C1CCNCC1
Solvent: CO
Product: O=C1Nc2ccc(F)cc2/C1=C/c1ccc2c(I)n[nH]c2c1
Temperature: 60 °C
Yield: 97.1 %

Procedure:
A round bottom flask was charged with 5-fluoroindolin-2-one (100 mg, 0.661 mmol), 3-iodo-1H-indazole-6-carbaldehyde (180 mg, 0.661 mmol), piperidine (13 uL, 0.027 mmol) and methanol (7.5 mL). The reaction was then heated to 60° C. for 3 h prior to cooling the reaction mass to room temperature. Filtration and washing with methanol (0.50 mL×2) gave the title compound as a yellow solid (260 mg, 96%). 1H NMR (400 MHz, DMSO-d6) δ 13.82 (s, 1H), 10.72 (s, 1H), 9.00 (s, 1H), 8.06 (s, 1H), 7.98 (d, J=8.8 Hz, 1H), 7.71 (s, J=8.8 Hz, 1H), 7.48 (d, J=8.8 Hz, 1H), 7.07-7.02 (m, 1H), 6.81 (d, J=4.4 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:38])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[N:10]=[C:11]([NH:17][C:18]([C:20]2[N:21]([CH3:37])[CH:22]=[C:23]([NH:25][C:26]([C:28]3[N:29]([CH3:36])[CH:30]=[C:31]([N+:33]([O-])=O)[CH:32]=3)=[O:27])[CH:24]=2)=[O:19])[S:12][C:13]=1[CH:14]([CH3:16])[CH3:15])=[O:8].[CH2:39]([OH:41])C>[Pd]>[CH3:1][N:2]([CH3:38])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[N:10]=[C:11]([NH:17][C:18]([C:20]2[N:21]([CH3:37])[CH:22]=[C:23]([NH:25][C:26]([C:28]3[N:29]([CH3:36])[CH:30]=[C:31]([NH:33][CH:39]=[O:41])[CH:32]=3)=[O:27])[CH:24]=2)=[O:19])[S:12][C:13]=1[CH:14]([CH3:16])[CH3:15])=[O:8]
Reactant: CC(C)c1sc(NC(=O)c2cc(NC(=O)c3cc([N+](=O)[O-])cn3C)cn2C)nc1C(=O)NCCCN(C)C
Reactant: CCO
Agent: [Pd]
Product: CC(C)c1sc(NC(=O)c2cc(NC(=O)c3cc(NC=O)cn3C)cn2C)nc1C(=O)NCCCN(C)C
Reaction time: 5 h
Yield: 51 %

Procedure:
N-[3-(Dimethylamino)propyl]-5-isopropyl-2-{[(1-methyl-4-{[(1-methyl-4-nitro-1H-pyrrol-2-yl)carbonyl]amino}-1H-pyrrol-2-yl)carbonyl]amino}-1,3-thiazole-4-carboxamide (90 mg, 0.165 mmol; see step (v) above) was suspended in ethanol (20 mL) then Pd/C (97 mg, 10%) was added at 0° C. under nitrogen. The reaction mixture was hydrogenated at room temperature and atmospheric pressure for 5 h. The catalyst was removed under reduced pressure then ethyl formate (20 mL) was added to the ethanolic solution of the amine. The reaction mixture was heated under reflux for 3 days, then the solvent was removed under reduced pressure. The crude product was dissolved in water (2 mL) containing 0.1% TFA, then purified by HPLC. The fractions collected were freeze-dried to give the desired product as pale yellow solid (55 mg, 51%) with no distinct m.p.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:11])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[Cl:12][C:13]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15]Cl.C(N1C2C(=CC=C(C(O)=O)C=2)C=C1)C1C=CC=CC=1>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:11])=[N:7][N:8]2[CH2:15][C:14]2[CH:17]=[CH:18][CH:19]=[C:20]([Cl:21])[C:13]=2[Cl:12])=[CH:4][CH:3]=1
Reactant: ClCc1cccc(Cl)c1Cl
Reactant: Cc1n[nH]c2cc(Br)ccc12
Agent: O=C(O)c1ccc2ccn(Cc3ccccc3)c2c1
Product: Cc1nn(Cc2cccc(Cl)c2Cl)c2cc(Br)ccc12
Yield: 85.5 %

Procedure:
The titled compound (228 mg) as a white solid was prepared from the 6-bromo-3-methyl-1H-indazole (152 mg) obtained with the method described in the document (JP 2009-528363 W) and 2,3-dichlorobenzyl chloride (215 mg) according to the method of the process (1) of Example 66.
Reaction SMILES: [CH3:1][NH:2][C:3]([CH:5]1[O:10][CH2:9][CH2:8][N:7]([C:11](OC(C)(C)C)=O)[CH2:6]1)=[O:4].C([O-])([O-])=O.[K+].[K+].[CH2:24]([O:31][C:32](=[O:35])CBr)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O.C(OCC)(=O)C.O>[CH3:1][NH:2][C:3]([CH:5]1[CH2:6][N:7]([CH2:11][C:32]([O:31][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:35])[CH2:8][CH2:9][O:10]1)=[O:4]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CNC(=O)C1CN(C(=O)OC(C)(C)C)CCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)C1CN(CC(=O)OCc2ccccc2)CCO1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
tert-butyl 2-(methylcarbamoyl)morpholine-4-carboxylate prepared above (0.5 g, 0.20 mmol) was dissolved in DCM (10 mL) and TFA (2 mL). The reaction mixture was stirred at room temperature for 4 h and then concentrated; excess 1N HCl solution in ether was added to the residue and concentrated under high vacuum. The residue was dissolved in acetonitrile (20 mL) and K2CO3 (0.56 g, 40.8 mmol) was added followed by bromo-acetic acid benzyl ester (0.7 g, 3.07 mmol). The reaction mixture was heated at 60° C. overnight. The solution was cooled to room temperature and diluted with Ethyl acetate (50 mL) and water (50 mL), organic layer was separated, dried (MgSO4) and concentrated to give an oil which was purified by column chromatography using ethyl acetate-hexanes (1:1) to give benzyl 2-(2-(methylcarbamoyl)morpholino)acetate. MS (APCI) 293 (M+).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.[CH3:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[CH3:22])[C:16](O)=[O:17].C(OC(OC)=O)(OC)=O.C(=O)([O-])[O-].[K+].[K+]>[Pd].O1CCOCC1.O>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:16]([C:15]1[CH:19]=[CH:20][C:21]([CH3:22])=[C:13]([CH3:12])[CH:14]=1)=[O:17]
Reactant: Cc1cccc(B(O)O)c1C
Reactant: Cc1ccc(C(=O)O)cc1C
Agent: [Pd]
Agent: COC(=O)OC(=O)OC
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)c2cccc(C)c2C)cc1C
Temperature: 80 °C
Yield: 42 %

Procedure:
To a 250 ml 3-necked round-bottom flask, 2,3-dimethylphenylboronic acid (3.6 g. 24 mmol). 3,4-dimethylbenzoic acid (3.0 g. 20 mmol), a selected palladium catalyst (0.6 mmol), dimethyl dicarbonate (2.7 g. 30 mmol) and potassium carbonate (6.22 g. 45 mmol) were mixed with 150 ml of dry dioxane. The reaction mixture was heated at 80° C. overnight to become a viscous reaction mixture. 20 ml of water was added to dissolve the heterogeneous reaction mixture, and dioxane was evaporated to dryness. The aqueous solution was extracted with 20 ml of ethyl acetate, dried over anhydrous magnesium sulfate and then evaporated to dryness. The crude product was purified by silica gel column chromatography eluted by hexane/ethyl acetate=20/80 to afford 2.0 g (33%) of the product.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:9])[CH:6]([CH3:8])[CH3:7].ClCCl.O.[S:15]1[CH:19]=[CH:18][N:17]2[CH:20]=[N:21][CH:22]=[C:16]12>C(=S)=S>[C:5]([C:22]1[N:21]=[CH:20][N:17]2[CH:18]=[CH:19][S:15][C:16]=12)(=[O:9])[CH:6]([CH3:8])[CH3:7]
Reactant: c1cn2cncc2s1
Reactant: CC(C)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Solvent: O
Solvent: ClCCl
Product: CC(C)C(=O)c1ncn2ccsc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Aluminum chloride (16.2 g) was added to a solution of 15.0 ml of isobutyryl chloride in 100 ml of carbon disulfide. A solution of 40 ml of dichloromethane in 2.50 g of imidazo[5,1-b]thiazole was added dropwise to the mixture. The mixture was stirred at room temperature for 20 hr. Dichloromethane (100 ml) was added to the reaction solution. Water (60 ml) was added dropwise thereto with stirring. The organic layer was then separated. Dichloromethane (200 ml) and 100 g of sodium carbonate were added to the aqueous layer. The mixture was stirred. The insolubles were removed by filtration, and washed with dichloromethane. The filtrate was combined with the organic layer. The combined organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane:ethyl acetate=1:1) to give 2.75 g of 7-isobutyrylimidazo[5,1-b]thiazole.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([OH:19])=[O:18])[CH2:12]1>>[B:8]([C:5]1[CH:4]=[N:3][C:2]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([OH:19])=[O:18])[CH2:12]2)=[N:7][CH:6]=1)([OH:10])[OH:9]
Reactant: O=C(O)[C@@H]1CCCNC1
Reactant: OB(O)c1cnc(Cl)nc1
Product: O=C(O)[C@@H]1CCCN(c2ncc(B(O)O)cn2)C1

Procedure:
The title compound was synthesised from (2-chloropyrimidin-5-yl)boronic acid and (3R)-piperidine-3-carboxylic acid in accordance with General Method C.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[S:30][C:29]([CH3:31])=[N:28][C:27]=4[CH3:32])[CH2:23][CH2:22][C:21]([C:33]([O:35]C)=[O:34])=[CH:20][C:19]=3[CH:37]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].Cl>C1COCC1.CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[S:30][C:29]([CH3:31])=[N:28][C:27]=4[CH3:32])[CH2:23][CH2:22][C:21]([C:33]([OH:35])=[O:34])=[CH:20][C:19]=3[CH:37]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2sc(C)nc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2sc(C)nc2C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.1 %

Procedure:
In THF (5.0 ml)/methanol (2.5 ml) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(2,4-dimethyl-1,3-thiazol-5-ylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylate (0.25 g). To the solution was added 1N sodium hydroxide solution (2.5 ml), and the mixture was stirred at room temperature for 16 hours. pH was adjusted to approximate with 1N hydrochloric acid, and the solvent was concentrated to half under reduced pressure. The concentrated material was extracted with ethyl acetate/THF, and the extract was washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was washed with hexane/ethyl acetate (8/1) to give 7-(4-(2-butoxyethoxy)phenyl]-1-(2,4-dimethyl-1,3-thiazol-5-ylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (190 mg).