Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[CH2:4]CC1(C)CCCCC1=O.COC(=O)CCC1(CC)CCCCC1=O.[CH3:30][O:31][C:32](=[O:45])[CH2:33][CH2:34][C:35]1([CH2:42][CH2:43][CH3:44])[CH2:40][CH2:39][CH2:38][CH2:37][C:36]1=[O:41].COC(=O)CCC1(CC)CCCCC21OCCO2>>[CH3:30][O:31][C:32](=[O:45])[CH2:33][CH2:34][C:35]1([CH2:42][CH2:43][CH3:44])[CH2:40][CH2:39][CH2:38][CH2:37][C:36]21[O:2][CH2:3][CH2:4][O:41]2
Reactant: CCCC1(CCC(=O)OC)CCCCC1=O
Reactant: COC(=O)CCC1(C)CCCCC1=O
Agent: CCC1(CCC(=O)OC)CCCCC12OCCO2
Agent: CCC1(CCC(=O)OC)CCCCC1=O
Product: CCCC1(CCC(=O)OC)CCCCC12OCCO2

Procedure:
In the same manner but replacing 1-methyl-2-oxocyclohexanepropionic acid methyl ester with an equivalent amount of 1-ethyl-2-oxocyclohexanepropionic acid methyl ester or 1-propyl-2-oxocyclohexanepropionic acid methyl ester, described in Example 6, 6-ethyl-1,4-dioxaspiro[4.5]decane-6-propionic acid methyl ester, νmaxCHCl3 1730 cm-1 and 6-propyl-1,4-dioxaspiro[4.5]decane-6-propionic acid methyl ester, νmaxCHCl3 1735 cm-1, are obtained, respectively.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=2)[CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[C:4]([CH3:26])[CH:3]=1.[CH:27]([C:30]1[CH:34]=[CH:33][NH:32][N:31]=1)([CH3:29])[CH3:28].CN[C@@H]1CCCC[C@H]1NC.C(=O)([O-])[O-].[K+].[K+]>[Cu]I.O.C1(C)C=CC=CC=1>[F:12][C:11]([F:14])([F:13])[CH2:10][CH2:9][CH:8]([NH:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1)[C:5]1[CH:6]=[CH:7][C:2]([N:32]2[CH:33]=[CH:34][C:30]([CH:27]([CH3:29])[CH3:28])=[N:31]2)=[CH:3][C:4]=1[CH3:26]
Reactant: COC(=O)c1ccc(NC(CCC(F)(F)F)c2ccc(Br)cc2C)cc1
Reactant: CC(C)c1cc[nH]n1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccc(NC(CCC(F)(F)F)c2ccc(-n3ccc(C(C)C)n3)cc2C)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
Under a nitrogen atmosphere, a mixture of methyl 4-((1-(4-bromo-2-methylphenyl)-4,4,4-trifluorobutyl)amino)benzoate (racemate) (400 mg), 3-isopropylpyrazole (154 mg), copper(I) iodide (212 mg), trans-N,N′-dimethylcyclohexane-1,2-diamine (0.352 mL), potassium carbonate (385 mg) and toluene (1.8 mL) was stirred at 110° C. overnight, water was added at room temperature, and the insoluble material was filtered off through celite. The filtrate was extracted with ethyl acetate, and the extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (316.2 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:24]3[CH:25]=[CH:26][C:27]4[C:31]([CH:32]=3)=[N:30][N:29]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:28]=4)[CH:9]=[C:10]([CH:11]3[O:16][CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.FC(F)(F)C(O)=O.CCOCC>ClCCl>[CH2:33]([N:29]1[CH:28]=[C:27]2[C:31]([CH:32]=[C:24]([C:8]3[CH:9]=[C:10]([CH:11]4[O:16][CH2:15][CH2:14][NH:13][CH2:12]4)[N:6]4[C:7]=3[C:2]([NH2:1])=[N:3][CH:4]=[N:5]4)[CH:25]=[CH:26]2)=[N:30]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CCOC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: Nc1ncnn2c(C3CNCCO3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reaction time: 0.17 h
Yield: 101.2 %

Procedure:
A suspension of tert-butyl 2-[4-amino-5-(2-benzyl-2H-indazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]morpholine-4-carboxylate (680 mg, 1.3 mmol) in dichloromethane (6 mL) was treated with trifluoroacetic acid (4 mL) and the solution allowed to stir for 10 min. Volatiles were removed in vacuo and the residue taken up in 25 mL of 1,2-dichloroethane. This solution was again dissolved in 1,2-dichloroethane and concentrated in vacuo. This process was repeated 2 additional times, yielding a brown semi-solid. Trituration with ether:hexanes provided the desired product 560 mg (99%) as a brown solid; 1H NMR (300 MHz, DMSO-d6) δ 8.55 (s, 1 H), 7.93 (s, 1 H), 7.81 (d, 1 H, J=9 Hz), 7.65 to 7.73 (m, 1H), 7.59 (s, 1H), 7.26 to 7.41 (m, 5H), 7.13 (d, 1H, J=9 Hz), 6.76 (s, 1H), 5.65 (s, 2H), 5.09 (dd, 1H, J=10, 2 Hz), 4.12 (dd, 1H, J=6, 2 Hz), 3.85 to 3.94 (m, 1H), 3.65 to 3.76 (m, 1H), 3.15 to 3.23 (m, 1H), 2.98 to 3.08 (m, 1H), 2.80-2.96 (m, 2H); ES-MS m/z 426.2 [M+H]+, HPLC RT (min) 2.11.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[C:11](OS(C(F)(F)F)(=O)=O)[C:10]=2[N+:23]([O-:25])=[O:24])=[C:5]([CH3:26])[CH:4]=1.[CH3:27][O:28][CH2:29][CH:30]([NH2:33])[CH2:31][CH3:32]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:33][CH:30]([CH2:29][O:28][CH3:27])[CH2:31][CH3:32])[C:10]=2[N+:23]([O-:25])=[O:24])=[C:5]([CH3:26])[CH:4]=1
Reactant: COc1ccc(-c2ccnc(OS(=O)(=O)C(F)(F)F)c2[N+](=O)[O-])c(C)c1
Reactant: CCC(N)COC
Product: CCC(COC)Nc1nccc(-c2ccc(OC)cc2C)c1[N+](=O)[O-]
Yield: 3.9 %

Procedure:
Trifluoro-methanesulfonic acid 4-(4-methoxy-2-methyl-phenyl)-3-nitro-pyridin-2-yl-ester (0.78 g, 1.98 mmol), prepared substantially as described in Part C of Example 67a, and 1-methoxymethyl-propylamine (0.45 g, 4.36 mmol) were treated substantially as described in Part C of Example 67a to produce 27 mg (40%) of [4-(4-methoxy-2-methyl-phenyl)-3-nitro-pyridin-2-yl]-(1-methoxymethyl-propyl)-amine; MS (EI) m/z 346.33 [(M+H)+, 100].
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[NH:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].[Cl:24][C:25]([Cl:31])([Cl:30])[C:26](=N)OC>C(O)(=O)C>[C:20]([O:19][C:17]([NH:16][CH2:15][CH2:14][CH2:13][N:12]1[C:3]2[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:2]=2[N:1]=[C:26]1[C:25]([Cl:31])([Cl:30])[Cl:24])=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: COC(=O)c1ccc(N)c(NCCCNC(=O)OC(C)(C)C)c1
Reactant: COC(=N)C(Cl)(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)c1ccc2nc(C(Cl)(Cl)Cl)n(CCCNC(=O)OC(C)(C)C)c2c1
Reaction time: 3 h
Yield: 79.6 %

Procedure:
To a stirred solution of methyl 4-amino-3-({3-[(tert-butoxycarbonyl)amino]propyl}amino)benzoate (4.7 g, 14.5 mmol) in acetic acid (50 mL) is added methyl trichloroacetimidate (3.1 g, 17.4 mmol). After 3 h at room temperature, the solvent is evaporated, the residue is dissolved in EtOAc, and is washed with Na2CO3 and brine. The organic layer is dried (Na2SO4) and evaporated. The residue is triturated with hexanes to afford the title compound (5.2 g, 80%) as a fine powder. LCMS (Method T), 1.85 min, 450.63 (MH+).
Reaction SMILES: C([N:20]1[CH:24]=[C:23]([CH2:25][NH:26][C:27]2[C:28]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[C:29]([CH:41]=[CH:42][CH:43]=2)[C:30]([C:32]([CH3:40])([CH3:39])[CH2:33][C@@H:34]([C:36]([OH:38])=[O:37])[NH2:35])=[O:31])[N:22]=[CH:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[NH:20]1[CH:24]=[C:23]([CH2:25][NH:26][C:27]2[C:28]([C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)=[C:29]([CH:41]=[CH:42][CH:43]=2)[C:30]([C:32]([CH3:40])([CH3:39])[CH2:33][C@@H:34]([C:36]([OH:38])=[O:37])[NH2:35])=[O:31])[N:22]=[CH:21]1
Reactant: CC(C)(C[C@H](N)C(=O)O)C(=O)c1cccc(NCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1-c1ccccc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C[C@H](N)C(=O)O)C(=O)c1cccc(NCc2c[nH]cn2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound of Example 387B (0.25 g, 0.38 mmol) was dissolved in 10 mL dichloromethane and 3 mL trifluoroacetic acid followed by the addition of 1.5 mL of triethylsilane and the reaction stirred at room temperature for 2 hours. The solvents were evaporated and ether added followed by the addition of 6 N HCl in ether to precipitate the desired compound (0.12 g, 77%) which was collected by rapid filtration. 1H NMR (300 MHz, DMSO-d6) 0.76 (dd, 6H), 1.38 (m, 2H), 1.55 (m, 1H), 4.19 (m, 1H), 4.42 (d, 2H), 6.63 (s, 1H), 6.73 (d, 1H), 7.31-7.36 (m, 6H), 7.63 (s, 1H), 8.23 (d, 1H), 9.09 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]([O:12][CH2:13][CH3:14])(=[O:11])[CH:9]=[CH2:10].C([O-])(=O)C.[Na+].C(CC(=O)C)(=O)C.C(O)(=O)CC.O=O.C([O-])(=O)C=C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:8]([O:12][CH2:13][CH3:14])(=[O:11])[CH:9]=[CH:10][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccccc1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: C=CC(=O)[O-]
Agent: CC(=O)[O-]
Solvent: CCC(=O)O
Solvent: CC(=O)CC(C)=O
Product: CCOC(=O)C=Cc1ccccc1

Procedure:
In a flask, 30 mmol of bromobenzene, 1.5 mmol of ethyl acrylate, 0.1 mmol of palladium(II) acetate, 0.02 mmol of H7PMo8V4O40, 0.08 mmol of sodium acetate, 0.1 mmol of acetylacetone, and 5 ml of propionic acid were placed and were stirred at a constant temperature of 90° C. in an atmosphere of oxygen gas at 1 atm (0.1 MPa) for 7 hours. The resulting reaction mixture was analyzed by gas chromatography to find that ethyl 3-[(o, m, or p)-bromophenyl]acrylate (o-isomer:m-isomer:p-isomer=38:35:27) and ethyl cinnamate were produced in yields of 49% and 4%, respectively.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[C:16]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:17][CH:18]=[CH:19][CH:20]=1)=O)(C)(C)C.[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29]>ClCCl>[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].[NH:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[C:16]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)c1ncccc1OC[C@H]1CCCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1ncccc1OC[C@H]1CCCN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-ethyl 3-((1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methoxy)picolinate (1.00 g, 285 mmol, EXAMPLE 33 Step 1) in dichloromethane (10 mL) was added trifluoroacetic acid (3 mL) at room temperature. After being stirred at room temperature for 8 h, the volatile was evaporated to afford 1.36 g (quant.) of the title compound that was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[C@@H:19]([O:20][C:21]([C@H:23]([OH:40])[C@@H:24]([NH:31][C:32]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:33])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[CH2:18][C@:14]2([OH:41])[C:15]([CH3:17])([CH3:16])[C:3]=1[C@@H:4]([O:59][C:60]([CH3:62])=[O:61])[C:5]([C@@:7]1([CH3:58])[C@H:12]([C@@H:13]2[O:42][C:43]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)=[O:44])[C@:11]2([O:53][C:54]([CH3:56])=[O:55])[CH2:51][O:52][C@@H:10]2[CH2:9][C@@H:8]1[OH:57])=[O:6].Cl.[C:64](Cl)(=[O:71])[C:65]1[CH:70]=[CH:69][CH:68]=[N:67][CH:66]=1>N1C=CC=CC=1.ClCCl>[C:60]([O:59][C@@H:4]1[C:3]2[C:15]([CH3:16])([CH3:17])[C@@:14]([OH:41])([CH2:18][C@H:19]([O:20][C:21](=[O:22])[C@H:23]([O:40][C:64](=[O:71])[C:65]3[CH:70]=[CH:69][CH:68]=[N:67][CH:66]=3)[C@@H:24]([NH:31][C:32](=[O:33])[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:2]=2[CH3:1])[C@@H:13]([O:42][C:43](=[O:44])[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C@@H:12]2[C@:11]3([O:53][C:54](=[O:55])[CH3:56])[CH2:51][O:52][C@@H:10]3[CH2:9][C@H:8]([OH:57])[C@@:7]2([CH3:58])[C:5]1=[O:6])(=[O:61])[CH3:62]
Reactant: O=C(Cl)c1cccnc1
Reactant: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](OC(=O)c4cccnc4)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.6 %

Procedure:
4 drops of pyridine were added to a solution of paclitaxel [4114] (0.10 g, 0.117 mmol 1.0 eq) of in dry dichloromethane under argon atmosphere. At 0° C., nicotinoyl chloride hydrochloride [296] (0.17 g, 1.17 mmol 10.0 eq) was added. The reaction mixture was stirred at room temperature for 24 hours. After 24 hours, the mixture was diluted with dichloromethane (25 ml) and washed with a 10% solution of NaHCO3 (15 ml) and brine (10 ml) followed by drying over anhydrous sodium sulfate. Evaporation of the solvents provided residual yellow solid which was purified by silica gel column chromatography (30% ethyl acetate: cyclohexane, 100-200 mesh silica) to get a white solid [310], (2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-9-(((2R,3S)-3-benzamido-2-(nicotinoyloxy)-3-phenylpropanoyl)oxy)-12-(benzoyloxy)-4,11-dihydroxy-4a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-1H-7,11-methanocyclodeca[3,4]benzo[1,2-b]oxete-6,12b-diyl diacetate, (0.05 g, 45%)
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]([CH2:11][CH2:12][OH:13])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=1)[NH2:18].C(OCC)(=O)C>CN1CCCC1=O>[Cl:14][C:15]1[CH:16]=[C:17]([NH:18][C:2]2[C:3]3[N:10]([CH2:11][CH2:12][OH:13])[CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:19]=[CH:20][C:21]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=1
Reactant: OCCn1ccc2ncnc(Cl)c21
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: OCCn1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c21
Temperature: 120 °C
Reaction time: 2 h
Yield: 75.9 %

Procedure:
To a solution of 2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethanol (130 mg) in 1-methyl-2-pyrrolidone (1.3 mL) was added 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (193 mg), and the reaction mixture was stirred at 120° C. for 2 hrs. The reaction mixture was allowed to cool to room temperature and ethyl acetate (20 mL) was added. The resultant precipitate was recrystallized from a mixed solvent of hexane/methanol (3/7), collected by filtration and dried under reduced pressure to give the title compound (206 mg) as pale purple crystals.
Reaction SMILES: COC(=O)C1C=CC(C(=O)C)=CC=1.C([O-])(=O)C1C=CC=CC=1.BrBr.COC(=O)C1C=CC(C(=O)CBr)=CC=1.C(N)(=S)C.C[O:44][C:45](=[O:58])[C:46]1[CH:51]=[CH:50][C:49]([C:52]2[N:53]=[C:54]([CH3:57])[S:55][CH:56]=2)=[CH:48][CH:47]=1.[OH-].[Li+]>CO.O.O1CCCC1.C(O)C.C(O)(=O)C>[CH3:57][C:54]1[S:55][CH:56]=[C:52]([C:49]2[CH:50]=[CH:51][C:46]([C:45]([OH:58])=[O:44])=[CH:47][CH:48]=2)[N:53]=1
Reactant: COC(=O)c1ccc(-c2csc(C)n2)cc1
Agent: BrBr
Agent: CC(N)=S
Agent: COC(=O)c1ccc(C(=O)CBr)cc1
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Cc1nc(-c2ccc(C(=O)O)cc2)cs1
Temperature: 70 °C
Reaction time: 19 h
Yield: 93.9 %

Procedure:
A mixture of methyl-4-acetylbenzoate (7.59 g, 43 mmol) and acetic acid (100 mL) was heated to 70° C. The reaction was cooled to 30° C. once the benzoate was dissolved. Bromine (2.2 mL, 43 mmol) was added dropwise over a period of 30 mins. The reaction was stirred at ambient temperature under nitrogen for 19 hrs. Precipitates formed upon cooling with an ice bath. The precipitate was filtered and washed with a cold solution of 1:1 MeOH/H2O. The crude material (5.05 g) was taken to the next reaction without further purification. A solution of 4-bromoacetyl-benzoic acid methyl ester (0.50 g, 1.9 mmol), ethanol (6.5 mL), and thioacetamide (0.29 mg, 3.9 mmol) was refluxed under nitrogen for 5 hrs. After cooling, the reaction was poured onto water (75 mL) and stirred for 10 mins. The precipitate was filtered and washed with water. The product was collected as a pale yellow powder 0.43 g (95%). A solution of 4-(2-methyl-thiazol-4-yl)-benzoic acid methyl ester (400 mg, 1.7 mmol), lithium hydroxide (108 mg, 2.6 mmol), tetrahydrofuran (2 mL), water (2 mL), and methanol (1.5 mL) was stirred at ambient temperature under nitrogen for 16 hrs. The reaction was concentrated, diluted with water (10 mL), acidified with HCl (4 mL, 1M), and extracted with ethyl acetate and methylene chloride. The organic layers were combined, dried on sodium sulfate, and concentrated to give 0.35 g (94%) of 4-(2-methyl-thiazol-4-yl)-benzoic acid, which was used in the preparation of compound 47 of Table 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH2:23])=[C:16]2[N:15]=1.C1N=[CH:27][N:26]([C:29](N2C=NC=C2)=[O:30])[CH:25]=1.CNC>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH:23][C:29](=[O:30])[N:26]([CH3:27])[CH3:25])=[C:16]2[N:15]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Agent: CNC
Solvent: ClCCl
Product: CN(C)C(=O)Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Reaction time: 2 h
Yield: 89.9 %

Procedure:
To a DCM (0.8 mL) solution of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (Preparation B; 30 mg, 0.095 mmol) was added CDI (31 mg, 0.19 mmol) at ambient temperature in one portion. After stirring two hours, dimethylamine (0.095 mL×2 N THF, 0.19 mmol) was added in one portion. The reaction was stirred for 5 minutes, then concentrated, and the residue was directly purified by reverse-phase column chromatography, eluting with 0 to 60% acetonitrile/water to yield the final product as a yellowish foamy powder (33 mg, 90% yield). MS (apci) m/z=387.2 (M+H).
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[N:5]([C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:4][CH:3]1[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].[H-].[Na+].Br[CH2:31][C:32]([C:34]1[CH:38]=[CH:37][S:36][CH:35]=1)=[O:33]>O1CCCC1>[S:36]1[CH:37]=[CH:38][C:34]([C:32]([CH2:31][N:8]2[C:7]3[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=3[N:5]([C:14](=[O:19])[C:15]([CH3:18])([CH3:16])[CH3:17])[CH2:4][CH:3]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:2]2=[O:1])=[O:33])=[CH:35]1
Reactant: O=C(CBr)c1ccsc1
Reactant: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2C(=O)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)N(CC(=O)c1ccsc1)C(=O)C(NC(=O)OC(C)(C)C)CN2C(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.6 %

Procedure:
2-Oxo-3-tert-butoxycarbonylamino-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (1.0 g) obtained from Step 1 of Example 89 was dissolved in tetrahydrofuran (10 ml), 60% sodium hydride (0.16 g) was added under argon atmosphere, the mixture was stirred for 30 minutes at room temperature. A solution of 3-bromoacetylthiophene (0.90 g) in tetrahydrofuran (5 ml) was added,stirred for one hour. The reaction mixture was poured into ice-water, extracted with ethyl acetate, the organic layer was successively washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=2:1), to thereby obtain 0.94 g of the titled compound (Yield: 71%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:14]([OH:16])=O)[S:10][C:11]=1[O:12][CH3:13].[NH2:18][C@@H:19]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)[CH2:20][N:21]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:31].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:14]([NH:18][C@@H:19]([CH2:32][C:33]2[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=2)[CH2:20][N:21]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]2=[O:31])=[O:16])[S:10][C:11]=1[O:12][CH3:13]
Reactant: COc1sc(C(=O)O)cc1-c1c(Cl)cnn1C
Reactant: N[C@@H](Cc1ccc(F)cc1)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COc1sc(C(=O)N[C@@H](Cc2ccc(F)cc2)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Cl)cnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.6 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-(methyloxy)-2-thiophenecarboxylic acid (208 mg, 0.76 mmol) [prepared according to the procedure of Example 188], 2-[(2S)-2-amino-3-(4-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (257 mg, 0.77 mmol) [prepared according to the procedure of Preparation 6, except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-4-fluoro-L-phenylalanine (4.95 g, 17.5 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (435 mg, 0.93 mmol) in chloroform (7.6 mL). DIEA (670 μL, 3.84 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (238 mg, 0.43 mmol, 56%): LC-MS (ES) m/z=553 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]2=[C:7]([CH2:10][OH:11])[N:8]=[CH:9][N:4]2[CH:3]=1>ClCCl.[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[S:6][C:5]2=[C:7]([CH:10]=[O:11])[N:8]=[CH:9][N:4]2[CH:3]=1
Reactant: OCc1ncn2cc(Br)sc12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1ncn2cc(Br)sc12
Yield: 92.8 %

Procedure:
Manganese dioxide (content 75%; 5.3 g, 46.11 mmol) was added to a solution of 2-bromo-7-hydroxymethylimidazo[5,1-b]thiazole (1.1 g, 4.61 mmol) in dichloromethane (100 ml), and the mixture was heated under reflux for 30 min. After the completion of the reaction, the reaction mixture was filtered through Celite, followed by washing with dichloromethane. The solvent was then removed by distillation under the reduced pressure to give 2-bromoimidazo[5,1-b]thiazole-7-carbaldehyde (989 mg, 93%) as a white solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14]([F:15])=[C:13](F)[C:12]([CH3:17])=[C:11]2[C:6]=1[C:7](=[O:24])[C:8]([C:21]([OH:23])=[O:22])=[CH:9][N:10]2[CH:18]1[CH2:20][CH2:19]1)(=[O:3])[CH3:2].[C:25]([O:29][C:30]([NH:32][C@H:33]1[C:37]2([CH2:39][CH2:38]2)[CH2:36][NH:35][CH2:34]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>CS(C)=O>[C:1]([NH:4][C:5]1[C:14]([F:15])=[C:13]([N:35]2[CH2:34][C@@H:33]([NH:32][C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[C:37]3([CH2:38][CH2:39]3)[CH2:36]2)[C:12]([CH3:17])=[C:11]2[C:6]=1[C:7](=[O:24])[C:8]([C:21]([OH:23])=[O:22])=[CH:9][N:10]2[CH:18]1[CH2:20][CH2:19]1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNCC12CC2
Reactant: CC(=O)Nc1c(F)c(F)c(C)c2c1c(=O)c(C(=O)O)cn2C1CC1
Solvent: CS(C)=O
Product: CC(=O)Nc1c(F)c(N2C[C@@H](NC(=O)OC(C)(C)C)C3(CC3)C2)c(C)c2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 95 °C
Reaction time: 20 h

Procedure:
A mixture consisting of 5-acetylamino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (51.2 mg), (7S)-7-tert-butoxycarbonylamino-5-azaspiro(2.4)heptane (48.2 mg) and dimethyl sulfoxide (0.25 ml) was stirred at an outer temperature of 95° C. for 20 hours. When quantitative analysis was carried out by a high performance liquid chromatography after completion of the reaction, formed amount of the compound of interest 5-acetylamino-7-[(7S)-7-tert-butoxycarbonylamino-5-azaspiro[2.4]hept-5-yl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid corresponded to 68.9 mg. The formation ratio was 85.6%.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:8]2[CH:9]=[C:10]([CH2:14][CH2:15][C:16](O)=[O:17])[CH:11]=[CH:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1.S(Cl)([Cl:23])=O>>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:8]2[CH:9]=[C:10]([CH2:14][CH2:15][C:16]([Cl:23])=[O:17])[CH:11]=[CH:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCc1cccc(C(=O)c2ccc(Cl)cc2)c1
Product: O=C(Cl)CCc1cccc(C(=O)c2ccc(Cl)cc2)c1

Procedure:
6.96 g of 3-(3'-p-chlorobenzoyl-phenyl)-propionic acid and 70 ml of thionyl chloride were refluxed for 3 hours and then evaporated to dryness. The residue was taken up in 100 ml of benzene and evaporated to dryness to obtain 8.7 g of 3-(3'-p-chlorobenzoyl-phenyl)-propionyl chloride which was used as is.