Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=1.CN([CH:24]=[O:25])C.[OH-].[Na+]>C1COCC1.O>[Br:13][C:14]1[CH:19]=[C:18]([CH:24]=[O:25])[C:17]([Cl:20])=[CH:16][N:15]=1
Reactant: Clc1ccc(Br)nc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=Cc1cc(Br)ncc1Cl
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 75.2 %

Procedure:
To a stirred sol. of diisopropylamine (20.9 mL, 148 mmol) in dry THF (350 mL) at −5° C. was added dropwise BuLi (1.6M in hexane, 89.5 mL, 143 mmol), and the resulting sol. was stirred for 30 min at −5° C. The sol. was allowed to cool to −70° C., and a sol. of 2-bromo-5-chloropyridine (25.0 g, 130 mmol) in THF (100 mL) was added dropwise at −70° C. over 15 min, such that the internal temperature did not exceed −65° C. The mixture was stirred at −70° C. for 30 min. DMF (10.52 mL, 136 mmol) was added dropwise over 20 min such that the internal temperature did not exceed −70° C. The orange mixture was stirred at −70° C. for 40 min. The mixture was allowed to warm up to rt, and was poured onto a mixture of water (200 mL) and aq. 1 M NaOH (50 mL). The mixture was extracted with EtOAc (2×), and the combined org. extracts were washed back with aq. 1M NaOH (2×). The org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 1:9→1:8→1:6→1:4→1:2→1:1) yielded the title compound (21.55 g, 72%). LC-MS: tR=0.74 min; ES+: 295.01.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=O.[S:13]1[C:17]2[CH:18]=[CH:19][C:20]([CH:22]([N:33]3[C@H:38]([CH2:39][CH:40]([CH3:42])[CH3:41])[C:37](=[O:43])[NH:36][C@H:35]([CH:44]4[CH2:52][C:51]5[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=5)[CH2:45]4)[C:34]3=[O:53])[C:23]([NH:25][C:26]3C=CC=CC=3O)=[O:24])=[CH:21][C:16]=2[CH:15]=[CH:14]1.CNC.O1CCCC1>ClCCl>[S:13]1[C:17]2[CH:18]=[CH:19][C:20]([C@@H:22]([N:33]3[C@H:38]([CH2:39][CH:40]([CH3:41])[CH3:42])[C:37](=[O:43])[NH:36][C@H:35]([CH:44]4[CH2:52][C:51]5[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=5)[CH2:45]4)[C:34]3=[O:53])[C:23]([N:25]([CH3:26])[CH3:1])=[O:24])=[CH:21][C:16]=2[CH:15]=[CH:14]1
Reactant: CC(C)C[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1C(C(=O)Nc1ccccc1O)c1ccc2sccc2c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)C[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1[C@@H](C(=O)N(C)C)c1ccc2sccc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50.7 %

Procedure:
Carbonyldiimidazole (100 mg) was suspended in anhydrous dichloromethane (1 mL) and the suspension was left at room temperature for 15 minutes. 2RS)-2-(1-benzothien-5-yl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-(2-hydroxyphenyl)ethanamide (200 mg) was then added and the mixture was stirred at room temperature for 5 hours 20 minutes. The resulting brown solution was then treated with a 2.0M solution of dimethylamine in tetrahydrofuran (1.0 mL, 6 equiv.) and the resulting mixture was stirred for 30 minutes and then left to stand at room temperature for 18 hours 15 minutes. The reaction mixture was evaporated under reduced pressure. The crude product was purified by silica column chromatography eluting with 1:1 v/v ethyl acetate:cyclohexane. The required fractions were combined and evaporated in vacuo to give (2R)-2-(benzothien-5-yl) -2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-dimethylethanamide as a white solid (90 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[CH2:12]([O:14][C:15](=[O:23])[N:16]([CH2:20][CH2:21]Br)[CH2:17][CH2:18]Br)[CH3:13].[H-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[C:6]1([CH2:21][CH2:20][N:16]([C:15]([O:14][CH2:12][CH3:13])=[O:23])[CH2:17][CH2:18]1)[CH2:5]2
Reactant: O=C1CCc2cc(F)ccc21
Reactant: CCOC(=O)N(CCBr)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC2(CC1)Cc1cc(F)ccc1C2=O
Temperature: 50 °C
Reaction time: 16 h
Yield: 32.1 %

Procedure:
To a stirred solution of 5-fluoro-1-indanone (302 mg, 2.013 mmol) and bis-(2-bromo-ethyl)-carbamic acid ethyl ester (610 mg, 2.01 mmol) in DMF (5 mL) at 50° C. was added NaH (121 mg, 5.03 mmol) by small portions. After being stirred at 50° C. for 16 hr, the reaction was cooled to 25° C. The reaction was diluted with 15 mL of ethyl acetate and washed twice with 10 mL of water, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash column (gradient of 85:15 to 60:40 heptane/ethyl acetate in 20 min to give the title compound (188 mg, 0.645 mmol, 32.1% yield). MS (ESI) [m/e, (M+H)+]=292.4. HPLC retention time=1.46 minutes (Agilent 1100 HPLC system; 3.0 cm×3.0 mm×3.0 um C8 column; flow rate of 2.0 mL/min; gradient of 5-95% acetonitrile/water with 0.1% formic acid over 2 minutes).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[NH:4][C@H:5]([C:9]([N:11]1[C@H:15]([C:16]2[NH:17][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24](B4OC(C)(C)C(C)(C)O4)=[CH:23][CH:22]=3)[N:20]=2)[CH2:14][Si:13]([CH3:37])([CH3:36])[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7].[C:39]([O:43][C:44]([N:46]1[CH2:51][CH2:50][N:49]([C:52]2[CH:57]=[CH:56][C:55]([C:58](=[O:73])[NH:59][C:60]3[CH:65]=[C:64]([O:66][C:67]([F:70])([F:69])[F:68])[C:63](Br)=[CH:62][C:61]=3[Cl:72])=[CH:54][N:53]=2)[C@H:48]([CH3:74])[CH2:47]1)=[O:45])([CH3:42])([CH3:41])[CH3:40].O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[C:39]([O:43][C:44]([N:46]1[CH2:51][CH2:50][N:49]([C:52]2[CH:57]=[CH:56][C:55]([C:58](=[O:73])[NH:59][C:60]3[C:61]([Cl:72])=[CH:62][C:63]([C:24]4[CH:23]=[CH:22][C:21]([C:19]5[N:20]=[C:16]([C@H:15]6[N:11]([C:9](=[O:10])[C@@H:5]([NH:4][C:3]([O:2][CH3:1])=[O:38])[CH:6]([CH3:7])[CH3:8])[CH2:12][Si:13]([CH3:37])([CH3:36])[CH2:14]6)[NH:17][CH:18]=5)=[CH:26][CH:25]=4)=[C:64]([O:66][C:67]([F:70])([F:69])[F:68])[CH:65]=3)=[CH:54][N:53]=2)[C@H:48]([CH3:74])[CH2:47]1)=[O:45])([CH3:42])([CH3:40])[CH3:41]
Reactant: COC(=O)N[C@H](C(=O)N1C[Si](C)(C)C[C@H]1c1nc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c[nH]1)C(C)C
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(C(=O)Nc2cc(OC(F)(F)F)c(Br)cc2Cl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)N[C@H](C(=O)N1C[Si](C)(C)C[C@H]1c1nc(-c2ccc(-c3cc(Cl)c(NC(=O)c4ccc(N5CCN(C(=O)OC(C)(C)C)C[C@H]5C)nc4)cc3OC(F)(F)F)cc2)c[nH]1)C(C)C
Temperature: 90 °C
Yield: 25.8 %

Procedure:
To a solution of [[(5)-1-((R)-3,3-dimethyl-5-{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-[1,3]azasilolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methylester (51.6 mg, 0.096 mmol; Preparation 11) and (R)-4-[5-(4-bromo-2-chloro-5-trifluoromethoxy-phenylcarbamoyl)-pyridin-2-yl]-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (56.7 mg, 0.096 mmol) dissolved in toluene (0.61 mL) and water (0.24 mL) was added potassium carbonate (66.0 mg, 0.48 mmol). The reaction mixture was sparged under nitrogen for 15 min and Pd(dppf)Cl2CH2Cl2 (7.02 mg, 0.009 mmol) was added. The reaction mixture was sparged with nitrogen and heated to 90° C. overnight, cooled to RT, diluted with EtOAc, and washed with water and brine to produce a dark colored oil. The residue was purified by silica gel chromatography (12 g silica, 0% to 100% EtOAc/hexane) to produce the title intermediate as a yellowish solid (23 mg; 26% yield) (m/z): [M+H]+ calcd for C44H54ClF3N8O7Si, 927.35 found 927.4.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][CH3:7])=[O:3].[NH2:8][C:9]1[N:14]=[N:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]([F:32])([F:31])[F:30])=[O:22])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1>>[CH2:5]([O:4][C:2](=[O:3])[NH:8][C:9]1[N:14]=[N:13][C:12]([N:15]2[CH2:16][CH2:17][N:18]([C:21](=[O:22])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]([F:32])([F:31])[F:30])[CH2:19][CH2:20]2)=[CH:11][CH:10]=1)[CH2:6][CH3:7]
Reactant: CCCOC(=O)Cl
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Product: CCCOC(=O)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 7, making variations only as required to use propyl chloroformate in place of n-butyl chloroformate to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)methanone, the title compound was obtained as a white solid (72% yield). 1H NMR (500 MHz, CDCl3) δ 8.10, 7.73, 7.62, 7.55, 7.37, 7.04, 4.14, 3.96-4.02, 3.88-3.94, 3.61-3.66, 3.52-3.56, 3.32, 1.66-1.75, 0.98. MS (ES+) m/z 438 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:10]([S:12](Cl)(=[O:14])=[O:13])=[CH:9][CH:8]=[CH:7][C:6]=2[CH:5]=[N:4][CH:3]=1.[H][H].[C:18]([O:22][C:23]([NH:25][CH:26]([CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[CH3:27])=[O:24])([CH3:21])([CH3:20])[CH3:19].BrC1C2C(S(Cl)(=O)=O)=CC=CC=2C=NC=1.C(OC(N[C@H]1CCNC1)=O)(C)(C)C>>[C:18]([O:22][C:23]([NH:25][CH:26]([CH:28]1[CH2:29][CH2:30][N:31]([S:12]([C:10]2[C:11]3[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=3[CH:7]=[CH:8][CH:9]=2)(=[O:14])=[O:13])[CH2:32][CH2:33]1)[CH3:27])=[O:24])([CH3:19])([CH3:20])[CH3:21]
Reactant: O=S(=O)(Cl)c1cccc2cncc(Cl)c12
Reactant: [H][H]
Reactant: CC(NC(=O)OC(C)(C)C)C1CCNCC1
Agent: CC(C)(C)OC(=O)N[C@H]1CCNC1
Agent: O=S(=O)(Cl)c1cccc2cncc(Br)c12
Product: CC(NC(=O)OC(C)(C)C)C1CCN(S(=O)(=O)c2cccc3cncc(Cl)c23)CC1

Procedure:
4-Chloro-5-isoquinolinesulfonyl chloride obtained in Reference Example 7 (131 mg) and 4-[1-(tert-butoxycarbonylamino)ethyl]piperidine (134 mg) prepared according to the method described in WO05/080394 were used in the method of Example 1-1, Step A instead of 4-bromo-5-isoquinolinesulfonyl chloride and (S)-3-(tert-butoxycarbonylamino)pyrrolidine, respectively, to obtain the title compound (211 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:43]=[CH:42][CH:41]=[CH:40][C:4]=2[S:5][C:6]=1[C:7]([N:9]([CH2:25][C:26]1[CH:31]=[C:30]([C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)[CH:29]=[CH:28][C:27]=1[O:38][CH3:39])[CH:10]1[CH2:15][CH2:14][CH:13]([N:16](C)[C:17](=O)OC(C)(C)C)[CH2:12][CH2:11]1)=[O:8]>O>[ClH:1].[ClH:1].[CH3:39][O:38][C:27]1[CH:28]=[CH:29][C:30]([C:32]2[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=2)=[CH:31][C:26]=1[CH2:25][N:9]([CH:10]1[CH2:15][CH2:14][CH:13]([NH:16][CH3:17])[CH2:12][CH2:11]1)[C:7]([C:6]1[S:5][C:4]2[CH:40]=[CH:41][CH:42]=[CH:43][C:3]=2[C:2]=1[Cl:1])=[O:8]
Reactant: COc1ccc(-c2ccncc2)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Solvent: O
Product: CNC1CCC(N(Cc2cc(-c3ccncc3)ccc2OC)C(=O)c2sc3ccccc3c2Cl)CC1
Product: Cl

Procedure:
tert-Butyl carbamate 116 (75 mg, 0.12 mmol) is deprotected using Method E. On removal of the solvent in vacuo, the residue obtained is dissolved in water (5 mL) and washed with TBME (3×5 mL). Reduction of the aqueous phase in vacuo affords the title product.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][NH2:20].[NH:25]1[CH:29]=[CH:28][C:27]([CH:30]=O)=[N:26]1>>[CH3:15][O:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][NH:20][C:8]1[CH:7]=[CH:6][C:5]2[C:4]([NH:1][CH2:30][C:27]3[CH:28]=[CH:29][NH:25][N:26]=3)=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: COc1ccccc1CN
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: O=Cc1cc[nH]n1
Product: COc1ccccc1CNc1ccc2c(NCc3cc[nH]n3)cccc2n1

Procedure:
The title compound, MS: m/e=360.4 (M+H+), was prepared from 5-nitro-2-chloroquinoline, 2-methoxybenzylamine and pyrazole-3-carbaldehyde as described in example 26.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH2:9])=[C:7]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[CH:6]=[CH:5][CH:4]=1.[C:17]([O:21][C:22]([N:24]1[CH2:29][C@H:28]([C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:31])[CH2:27][C@H:26]([N:38]([C:43](=[O:47])[C:44](O)=[O:45])[CH2:39][CH:40]([CH3:42])[CH3:41])[CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>ClCCCl.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[C:8]=1[NH:9][C:44](=[O:45])[C:43]([N:38]([CH2:39][CH:40]([CH3:41])[CH3:42])[C@H:26]1[CH2:27][C@@H:28]([C:30]([N:32]2[CH2:33][CH2:34][O:35][CH2:36][CH2:37]2)=[O:31])[CH2:29][N:24]([C:22]([O:21][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:23])[CH2:25]1)=[O:47]
Reactant: COCCCCNc1cccc(OC)c1N
Reactant: CC(C)CN(C(=O)C(=O)O)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COCCCCNc1cccc(OC)c1NC(=O)C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 53.1 %

Procedure:
6-Methoxy-2-(4-methoxybutylamino)aniline (210 mg), {{(3S,5R)-1-(tert-butoxycarbonyl)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl}(2-methylpropyl)amino}(oxo)acetic acid (308 mg), HOBt (97 mg) and triethylamine (370 μl) were dissolved in 1,2-dichloroethane (15 ml), WSC.HCl (430 mg) was added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, diluted with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (2:8)-ethyl acetate was concentrated under reduced pressure to give the object product (240 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[OH:11][C:12]1[C:21]([C:22](=[O:25])[CH2:23][CH3:24])=[CH:20][CH:19]=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15]>>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:11][C:12]2[C:21]([C:22](=[O:25])[CH2:23][CH3:24])=[CH:20][CH:19]=[CH:18][C:13]=2[C:14]([O:16][CH3:17])=[O:15])=[O:7])=[CH:4][CH:3]=1
Reactant: CCC(=O)c1cccc(C(=O)OC)c1O
Reactant: Cc1ccc(C(=O)Cl)cc1
Product: CCC(=O)c1cccc(C(=O)OC)c1OC(=O)c1ccc(C)cc1
Reaction time: 4 h

Procedure:
This compound was prepared in three steps according to the methods described for Intermediate XC (first step) and Intermediate LXXX (second and third steps). In the first step, 4-methylbenzoyl chloride was used instead of 2-furanecarbonyl chloride and methyl 2-hydroxy-3-propionylbenzoate was used instead of ethyl 2-hydroxy-3-propionylbenzoate. The reaction lasted 4 hours at room temperature, yielding methyl 2-(4-methylbenzoyloxy)-3-propionylbenzoate. This compound was used without purification by column chromatography for the second step, that lasted 1.5 hours at 100° C. In the third step, 96% sulfuric acid was used instead of 37% hydrochloric acid. The title compound melted at 174°-175° C. after crystallization from ethanol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4](=[CH:8]N(C)C)[C:5](=O)[CH3:6].Cl.[C:14]([NH:18][NH2:19])([CH3:17])([CH3:16])[CH3:15].C([O-])(=O)C.[Na+].ClCCl>C(O)C>[CH3:1][O:2][C:3]([C:4]1[CH:8]=[N:19][N:18]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:5]=1[CH3:6])=[O:12]
Reactant: COC(=O)C(=CN(C)C)C(C)=O
Reactant: CC(C)(C)NN
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: COC(=O)c1cnn(C(C)(C)C)c1C
Temperature: 90 °C
Yield: 70.9 %

Procedure:
A solution of 2-dimethylaminomethylene-3-oxo-butyric acid methyl ester (7.43 g, 43.40 mmol) in absolute ethanol (70 mL) was treated with tert-butylhydrazine hydrochloride (5.52 g, 44.29 mmol) and sodium acetate (4.42 g, 53.88 mmol). The resulting mixture was heated to 90° C. for 18 h. At this time, the reaction was cooled to 25° C. The reaction was poured onto ice using dichloromethane to assist the transfer (50 mL). The mixture was transferred to a separatory funnel at which time the layers were shaken and separated. The aqueous layer was further extracted with dichloromethane (1×50 mL). The combined organics were washed with a saturated aqueous sodium bicarbonate solution (1×50 mL), water (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. ISCO CombiFlash (120 g column; 0-10% ethyl acetate/hexanes) afforded 1-tert-butyl-5-methyl-1H-pyrazole-4-carboxylic acid methyl ester (6.04 g, 71%) as a yellow oil.
Reaction SMILES: [Cl:1][CH2:2][CH:3]=O.Cl[C:6]1[N:11]=[N:10][C:9]([NH2:12])=[CH:8][CH:7]=1.C([O-])(O)=O.[Na+].Cl>CCO.O>[Cl:1][C:2]1[N:12]=[C:9]2[CH:8]=[CH:7][CH:6]=[N:11][N:10]2[CH:3]=1
Reactant: O=CCCl
Reactant: Nc1ccc(Cl)nn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Clc1cn2ncccc2n1
Temperature: 0 °C
Reaction time: 14 h

Procedure:
Chloro-imidazo[1,2-b]pyridazine (10-1) was synthesized as shown in scheme 10, wherein chloracetaldehyde (55% in water, 126 ml, 880 mmol) was added to a solution of 6-chloro-pyridazin-3-ylamine (25.43 g, 196 mmol) and NaHCO3 (28 g, 334 mmol) in EtOH (600 ml) and then the reaction mixture was heated to reflux while stirring for 14 hours. The resulting dark brown reaction mixture was then concentrated under vacuum and the resulting residue reconstituted with dichloromethane (DCM). This solution was filtered through a celite pad and the solid washed with DCM and the solvent was then removed to yield a dark brown oil. 2M HCl (290 ml) and water (300 ml) was added to the residue and the resulting slurry was stirred at room temperature for 15 minutes. The solution was filtered through a celite pad and the filter cake was washed with water. The filtrate was extracted with diethyl ether (3×200 ml). The aqueous layer was cooled to 0° C. (ice bath) and neutralized using NaOH (24 g). The resulting slurry was extracted with diethyl ether (6×300 ml), dried using sodium sulfate and the diethyl ether was removed using a rotary evaporator to yield chloro-imidazo[1,2-b]pyridazine (10-1) as a light orange solid. MS: 155.1 [M+1]+.
Reaction SMILES: C1([C:4]2[N:5]=[C:6]3[C:12]([C:13]([OH:15])=O)=[CH:11][N:10](COCC[Si](C)(C)C)[C:7]3=[N:8][CH:9]=2)CC1.C([N:31]1CCC(C)(C)C(N)C1)C1C=CC=CC=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[N:5]1[CH:4]=[CH:9][N:8]=[C:7]2[NH:10][CH:11]=[C:12]([C:13]([NH2:31])=[O:15])[C:6]=12
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(C3CC3)cnc21
Reactant: CC1(C)CCN(Cc2ccccc2)CC1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1c[nH]c2nccnc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a 25 mL flask were combined 2-cyclopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (150 mg, 0.45 mmol), 1-benzyl-4,4-dimethylpiperidin-3-amine (147 mg, 0.68 mmol), and HATU (188 mg, 0.50 mmol). Then added DMF (3 mL) followed by N,N-diisopropylethylamine (0.24 mL 1.35 mmol). The yellow reaction mixture was stirred at room temperature for 3 h then quenched with H2O and extracted with EtOAc (3×). The combined organics were washed with H2O (3×), dried over MgSO4 and concentrated. The crude residue was purified by SiO2 chromatography (30% to 80% EtOAc/hexanes) to afford 197 mg (82%) of N-(1-benzyl-4,4-dimethylpiperidin-3-yl)-2-cyclopropyl-5-(2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide as a white foam.
Reaction SMILES: C([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[N:10]=2)[CH2:5][CH2:4]1)=O.[OH-].[Na+]>C(O)C>[N:6]1([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[N:10]=2)[CH2:7][CH2:8][NH:3][CH2:4][CH2:5]1
Reactant: COc1ccc(-c2cc3ccccc3c(N3CCN(C=O)CC3)n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-c2cc3ccccc3c(N3CCNCC3)n2)cc1
Yield: 61.7 %

Procedure:
1-(4-Formylpiperazinyl)-3-(4-methoxyphenyl)isoquinoline (4.797 g) was dissolved in ethanol (85 ml), followed by the addition of 2N sodium hydroxide (35 ml), and the mixture was heated under reflux for 4 hr. The reaction mixture was evaporated, water was added thereto, and extracted with chloroform. The resulting organic layer was washed with water, dried (over MgSO4) and evaporated. The resulting residue was purified by (NH) silica gel column chromatography (ethyl acetate/hexane system), to give the title compound as a colorless solid (2.720 g, yield; 63%).
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([C:12]3[C:13]([NH2:24])=[N:14][CH:15]=[C:16]([C:18]4[CH2:19][CH2:20][NH:21][CH2:22][CH:23]=4)[N:17]=3)=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.[CH2:32]([S:34](Cl)(=[O:36])=[O:35])[CH3:33]>C(Cl)Cl>[CH2:32]([S:34]([N:21]1[CH2:20][CH:19]=[C:18]([C:16]2[N:17]=[C:12]([C:10]3[O:11][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:8][N:9]=3)[C:13]([NH2:24])=[N:14][CH:15]=2)[CH2:23][CH2:22]1)(=[O:36])=[O:35])[CH3:33]
Reactant: Nc1ncc(C2=CCNCC2)nc1-c1nnc(-c2ccccc2)o1
Reactant: CCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)N1CC=C(c2cnc(N)c(-c3nnc(-c4ccccc4)o3)n2)CC1
Reaction time: 0.5 h
Yield: 100 %

Procedure:
3-(5-phenyl-1,3,4-oxadiazol-2-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrazin-2-amine (50 mg, 0.1151 mmol) was dissolved in DCM (3 mL) and Et3N (34.94 mg, 48.13 μL, 0.3453 mmol) followed by ethanesulfonyl chloride (16.28 mg, 12.00 μL, 0.1266 mmol) were added. The reaction was allowed to stir for 30 mins and then diluted with dichloromethane and washed with water. The aqueous layer was extracted further with dichloromethane and the organics washed with saturated aqueous NaHCO3, dried over MgSO4 and concentrated in vacuo. The resultant residue was purified on silica gel by flash column chromatography (0-5% MeOH/DCM) to afford the title compound (47.47 mg, 60% Yield).
Reaction SMILES: C([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH2:18])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[Cl:20][C:21]1[N:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:22]=1[C:23]#[N:24].Cl.O1[CH2:36][CH2:35]OCC1>O1CCOCC1>[ClH:20].[Cl:29][C:26]1[CH:25]=[C:22]([C:23]#[N:24])[C:21]([N:18]([CH2:21][CH2:22][CH2:25][CH2:26][CH2:27][CH2:35][CH3:36])[CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:19])[S:12][CH:13]=2)=[N:28][CH:27]=1
Reactant: C1COCCO1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCN)cs1
Reactant: N#Cc1cc(Cl)cnc1Cl
Agent: Cl
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1ncc(Cl)cc1C#N
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A compound obtained by using, as starting materials, 2-{[4-(2-aminoethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester synthesized in Example 7 and 2,5-dichloronicotinonitrile synthesized in reference to non-patent reference [Liebigs Ann. Chem., 487, 127 (1931)] and the like, and by operations similar to those of Example 265-1 and Example 265-2, was dissolved in dioxane, an excess amount of 4 mol/L hydrochloric acid-dioxane was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; chloroform:methanol=10:1) to give the title compound as a colorless oil.