Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4]([NH2:13])[CH2:5][CH:6]1[CH2:11][CH:10]2[CH2:12][CH:7]1[CH2:8][CH2:9]2.C(N(CC)C(C)C)(C)C.C1(C[C@H](N2[CH2:49][C:48]([O:50][C:51]3[C:56]([F:57])=[CH:55][CH:54]=[CH:53][C:52]=3[F:58])=[CH:47][C:46]2=[O:59])C(NC2C=CN(CC(O)(C)C)N=2)=O)CCCCC1>C(#N)C>[CH3:1][O:2][C:3](=[O:14])[CH:4]([N:13]1[CH2:49][C:48]([O:50][C:51]2[C:56]([F:57])=[CH:55][CH:54]=[CH:53][C:52]=2[F:58])=[CH:47][C:46]1=[O:59])[CH2:5][CH:6]1[CH2:11][CH:10]2[CH2:12][CH:7]1[CH2:8][CH2:9]2
Reactant: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC(Oc3c(F)cccc3F)=CC2=O)n1
Reactant: COC(=O)C(N)CC1CC2CCC1C2
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)C(CC1CC2CCC1C2)N1CC(Oc2c(F)cccc2F)=CC1=O
Temperature: 140 °C
Yield: 21.4 %

Procedure:
In a round bottom flask was placed 2-amino-3-bicyclo[2.2.1]hept-2-yl-propionic acid methyl ester (206 mg, 1.04 mmol), N,N-diisopropylethylamine (390 μL, 2.24 mmol) and 4-bromo-3-(2,6-difluoro-phenoxy)-but-2-enoic acid ethyl ester (prepared as in Example 36, 390 mg, 2.24 mmol) in acetonitrile (10 mL). This mixture was then split into two 5 mL portions and placed in two sealed microwave reaction tubes and heated in a microwave reactor at 140° C. for 1 h. The contents of the two reaction tubes were combined, concentrated in vacuo and diluted with dichloromethane (20 mL) and washed with a 1N aqueous hydrochloric acid solution (10 mL), a saturated sodium bicarbonate solution (10 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by AnaLogix IntelliFlash flash chromatography (12 g column, 15% ethyl acetate/hexanes to 30% ethyl acetate/hexanes) afforded 3-bicyclo[2.2.1]hept-2-yl-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (87 mg, 15%) as a yellow oil.
Reaction SMILES: OCCO[CH:5]([CH2:9]OC(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:6][CH2:7][OH:8].C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>C(Cl)Cl>[CH3:37][S:38]([O:8][CH2:7][CH2:6][CH2:5][CH3:9])(=[O:40])=[O:39]
Reactant: CS(=O)(=O)Cl
Reactant: OCCOC(CCO)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCOS(C)(=O)=O
Temperature: 0 °C

Procedure:
3-(2-hydroxyethoxy)-4-(triphenylmethoxy)-1-butanol (14.0 g, 35.7 mmol) was dissolved in 140 mL of CH2Cl2, was cooled to 0° C. under N2, and triethylamine (10.8 g, 14.9 mL, 0.107 mol. 3.0 eq.) was added. Methanesulfonyl chloride (11.0 g, 7.46 mL, 96.4 mmol, 2.7 eq.) was then added dropwise at <5° C. The resultant reaction mixture was diluted with additional CH2Cl2 (300 mL) and was washed with 200 mL of water and 200 mL of an aqueous saturated solution of ammonium chloride. The aqueous layers were back-extracted with 50 mL of CH2Cl2 and the combined organic layer was washed with 100 mL of brine and was dried (MgSO4) and evaporated in vacuo to give 18.4 g (94%) of 3-(2-[(methylsulfonyl)oxy]ethoxy]-4-triphenylmethoxy)-1-butanol methane sulfonate as a white solid.
Reaction SMILES: [NH2:1][C:2]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[CH2:5][N:4]1[C:11](=[O:36])[C:12]([O:28]CC3C=CC=CC=3)=[C:13]([C:15]3[S:16][C:17]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)=[CH:18][N:19]=3)[N:14]=[C:3]21.[CH3:37][N:38]([CH3:44])[C:39](=[O:43])[C:40](O)=[O:41].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CN(C1C=CN=CC=1)C>[F:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][C:17]2[S:16][C:15]([C:13]3[N:14]=[C:3]4[C:2]5([NH:1][C:40](=[O:41])[C:39]([N:38]([CH3:44])[CH3:37])=[O:43])[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10]5)[CH2:5][N:4]4[C:11](=[O:36])[C:12]=3[OH:28])=[N:19][CH:18]=2)=[CH:26][CH:25]=1
Reactant: NC12CCC(CC1)Cn1c2nc(-c2ncc(Cc3ccc(F)cc3)s2)c(OCc2ccccc2)c1=O
Reactant: CN(C)C(=O)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CN(C)C(=O)C(=O)NC12CCC(CC1)Cn1c2nc(-c2ncc(Cc3ccc(F)cc3)s2)c(O)c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 15.32 %

Procedure:
To a stirred solution of 10-amino-3-(benzyloxy)-2-(5-(4-fluorobenzyl)-1,3-thiazol-2-yl)-7,8,9,10-tetrahydro-7,10-ethanopyrimido[1,2-a]azepin-4(6H)-one, Example 5 (35 mg, 0.085 mmol) in DMF (2 mL) was added 2-(dimethylamino)-2-oxoacetic acid (19.87 mg, 0.170 mmol), N,N-diisoproplylethylamine (0.119 mL, 0.679 mmol), HATU (64.5 mg, 0.170 mmol) and DMAP (5.18 mg, 0.042 mmol) and the resulting mixture stirred at room temperature for 16 h. The mixture was purified by preparative HPLC to afford the title compound (7 mg, 0.013 mmol, 15.32% yield) as a light green solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.17 (1H, br. s.), 9.04 (1H, br. s.), 7.87 (1H, br. s.), 7.36 (2H, dd, J=8.16, 5.65 Hz), 7.19 (2H, t, J=8.78 Hz), 4.29 (2H, s), 4.06 (2H, d, J=3.51 Hz), 3.04 (3H, s), 2.87 (3H, s), 2.33-2.45 (3H, m), 2.03-2.14 (2H, m), 1.79-1.90 (2H, m), 1.60-1.71 (2H, m). LCMS (M+H)=512.01.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[C:15]4[N:16]([N:25]=[CH:26][N:27]=4)[C:17]([C:20]4[CH:21]=[N:22][NH:23][CH:24]=4)=[CH:18][N:19]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5]OCC1.BrC1N2N=CN=C2C(NC2C=CC(N3CC[NH:48][CH2:47][C:46]3=[O:51])=CC=2)=NC=1.CC([O-])(C)C.[Na+]>CN(C=O)C.O.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>[NH:22]1[CH:21]=[C:20]([C:17]2[N:16]3[N:25]=[CH:26][N:27]=[C:15]3[C:14]([NH:13][C:10]3[CH:11]=[CH:12][C:7]([N:1]4[CH2:6][CH2:5][NH:48][CH2:47][C:46]4=[O:51])=[CH:8][CH:9]=3)=[N:19][CH:18]=2)[CH:24]=[N:23]1
Reactant: c1nc2c(Nc3ccc(N4CCOCC4)cc3)ncc(-c3cn[nH]c3)n2n1
Reactant: O=C1CNCCN1c1ccc(Nc2ncc(Br)n3ncnc23)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CNCCN1c1ccc(Nc2ncc(-c3cn[nH]c3)n3ncnc23)cc1

Procedure:
This compound may be prepared using methods as described for Compound 1, step 5 using 1-[4-(5-bromo-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino)-phenyl]-piperazin-2-one (70 mg, 0.18 mmol) 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (64 mg, 0.33 mmol), Pd(PPh3)4 (21 mg, 18 μmol) and NaOtBu (70 mg, 0.72 mmol) in 2 mL of 3:1 DMF/water. The reaction mixture is concentrated under vacuum and the residue is purified by silica gel column chromatography eluting with a gradient 99:1 to 90:10 DCM:NH3 (7M in MeOH). The title compound is isolated as a pale green solid (13 mg, 19%). 1H-NMR (400 MHz, d6-DMSO) δ(ppm) 3.05 (2H, m), 3.42 (2H, s), 3.62 (2H, m), 7.32 (2H, d), 8.07 (2H, d), 8.26 (1H, s), 8.39 (1H, br s), 8.67 (1H, br s), 8.81 (1H, s), 10.05 (1H, s), 13.32 (1H, br s). LCMS: Rt 6.98 min (92.4%), m/z (APCI) 376 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.C(N1CCOCC1)C.[NH2:46][C@H:47]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1[CH3:58])[CH2:48][C:49]([OH:51])=[O:50]>CN(C=O)C>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:5]=[C:4]([C:13]([NH:46][C@H:47]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=2[CH3:58])[CH2:48][C:49]([OH:51])=[O:50])=[O:15])[CH:3]=1
Reactant: Cc1ccccc1[C@@H](N)CC(=O)O
Reactant: Nc1cc(C(=O)O)nn1-c1ccccc1
Agent: CCN1CCOCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: Cc1ccccc1[C@H](CC(=O)O)NC(=O)c1cc(N)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg (0.492 mmol) of 5-Amino-1-phenyl-1H-pyrazole-3-carboxylic acid are dissolved in 5 ml of DMF, 194 mg (0.59 mmol) of TOTU and 142 mg (1.23 mmol) of N-ethyl-morpholine is added. After stirring for 10 minutes at RT 97 mg (1.1 Eq, 0.54 mmol) of (S)-3-amino-3-(2-methyl-phenyl)-propionic acid are added and the resulting mixture is stirred overnight at RT. Solvent is removed in vacuo and the obtained crude product is submitted to HPLC chromatography: Yield: 32 mg, 18%
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[C:21]3[C:16](=[C:17]([CH2:23][S:24][CH3:25])[CH:18]=[C:19]([F:22])[CH:20]=3)[NH:15][CH:14]=2)[CH2:9][CH2:10][C:11]#[N:12])=[C:4]([F:26])[CH:3]=1.ClCCl.ClC1C=CC=C(C(OO)=[O:38])C=1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[C:21]3[C:16](=[C:17]([CH2:23][S:24]([CH3:25])=[O:38])[CH:18]=[C:19]([F:22])[CH:20]=3)[NH:15][CH:14]=2)[CH2:9][CH2:10][C:11]#[N:12])=[C:4]([F:26])[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCc1cc(F)cc2c(C(CCC#N)c3ccc(Cl)cc3F)c[nH]c12
Solvent: CO
Solvent: ClCCl
Product: CS(=O)Cc1cc(F)cc2c(C(CCC#N)c3ccc(Cl)cc3F)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
80.0 mg (0.21 mmol) of the compound from Example 40 were introduced into 5 ml of dichloromethane at 0° C., 53.0 mg (0.22 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT overnight. Methanol was added, and the residue after concentration was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 58.8 mg (71% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:9]3[CH2:11][CH2:12][CH2:13][C:8]=3[S:7][C:6]=2[N:5]=[C:4]([CH3:14])[C:3]=1[C:15]([CH:17]1[CH2:19][CH2:18]1)=[O:16].[H-].[Na+].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]Br>CN(C=O)C>[CH:17]1([C:15]([C:3]2[C:4]([CH3:14])=[N:5][C:6]3[S:7][C:8]4[CH2:13][CH2:12][CH2:11][C:9]=4[C:10]=3[C:2]=2[N:1]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:16])[CH2:19][CH2:18]1
Reactant: BrCCCCCBr
Reactant: Cc1nc2sc3c(c2c(N)c1C(=O)C1CC1)CCC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc2sc3c(c2c(N2CCCCC2)c1C(=O)C1CC1)CCC3
Reaction time: 0.33 h
Yield: 53.4 %

Procedure:
To a stirred solution of 12 mg (0.044 mmol) of (4-amino-6-methyl-2,3-dihydro-1H-8-thia-7-aza-cyclopenta[a]inden-5-yl)-cyclopropyl-methanone in 2 ml DMF was added 3.0 mg (0.066 mmol) NaH (55% in oil). After 20 minutes, 10 □l (0.044 mmol) of 1,5-dibromo-pentane and stirring was continued at RT over the night. The mixture was poured onto water and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (heptane/ethyl acetate 6:1) afforded 8 mg (54%) cyclopropyl-(6-methyl-4-piperidin-1-yl-2,3-dihydro-1H-8-thia-7-aza-cyclopenta[a]inden-5-yl)-methanone as a white solid. ES-MS m/e (%): 341 (M+H+, 100).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)=[CH:15][CH:14]=2)[C:3]1=[O:31].C1CCN2C(=NCCC2)CC1.[O:43]=O>>[CH3:1][N:2]1[C:3](=[O:31])[C:4]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)=[CH:17][CH:18]=2)=[C:5]([C:7]2[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=2)[C:6]1=[O:43]
Reactant: CN1CC(c2ccncc2)=C(c2ccc(OCc3ccc4ccccc4n3)cc2)C1=O
Reactant: O=O
Solvent: C1CCC2=NCCCN2CC1
Product: CN1C(=O)C(c2ccncc2)=C(c2ccc(OCc3ccc4ccccc4n3)cc2)C1=O
Yield: 48 %

Procedure:
To a stirred solution of 1-methyl-4-(pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrrol-2(5H)-one (200 mg, 0.49 mmol) in AcN (10 mL) was added DBU (224.5 mg, 1.47 mmol) dropwise and then the reaction mixture was stirred for 6 h under a continuous flow of oxygen. The reaction mixture was quenched with 1N HCl and extracted with EtOAc (2×20 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo to afford 1-methyl-3-(pyridin-4-yl)-4-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrrole-2,5-dione (100 mg, 48%) as a solid. 1H NMR (500 MHz, CDCl3): δ 8.18-8.09 (m, 1H), 8.0-7.95 (m, 3H), 7.65-7.59 (m, 3H), 7.48-7.39 (m, 1H), 7.28-7.18 (m, 4H), 7.1-7.09 (m, 2H), 5.25 (s, 2H), 2.86 (s, 3H);
Reaction SMILES: C[O:2][C:3](=[O:23])[CH2:4][CH2:5][C:6]1([CH3:22])[CH2:15][CH2:14][C:13]2[C:8](=[C:9]3[CH:20]4[CH2:21][CH:17]([CH2:18][CH2:19]4)[C:10]3=[C:11]([OH:16])[CH:12]=2)[O:7]1.[OH-].[Na+].O1CCO[CH2:28][CH2:27]1>O>[OH:16][C:11]1[CH:12]=[C:13]2[C:8](=[C:9]3[CH:20]4[CH2:27][CH2:28][CH2:21][CH:17]([CH2:18][CH2:19]4)[C:10]=13)[O:7][C:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:23])([CH3:22])[CH2:15][CH2:14]2
Reactant: COC(=O)CCC1(C)CCc2cc(O)c3c(c2O1)C1CCC3C1
Reactant: C1COCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1(CCC(=O)O)CCc2cc(O)c3c(c2O1)C1CCCC3CC1
Reaction time: 15 h

Procedure:
To a solution of 3-(6-Hydroxy-2-methyl-3,4,7,8,9,10-hexahydro-7,10-methano-2H-benzo[h]chromen-2-yl)-propionic acid methyl ester (235 mg, 0.68 mmol) in 5 mL of dioxane was added a solution of NaOH (41 mg, 1.02 mmol) in 400 mL water. The resulting suspension was vigorously stirred for 15 h and quenched by adding 50 mL of saturated NaH2PO4 solution. The mixture was extracted with EtOAc (3×50 mL) and the organic layers were dried over Na2SO4 and concentrated. The crude product was purified by chromatography on silica gel to afford 3-(6-hydroxy-2-methyl-3,4,7,8,9,10-hexahydro-7,10-propano-2H-benzo[h]chromen-2-yl)-propionic acid as a white sticky solid (184 mg). 1H-NMR (CDCl3, 300 MHz) δ (ppm): 7.71 (ws, 1 H), 6.41 (s, 1 H), 3.54 (m, 1 H), 3.38 (m, 1 H), 2.73 (m, 2 H), 2.56 (m, 2 H), 2.10-1.62 (m, 12 H), 0.95 (m, 5 H); 13C-NMR δ (ppm): 180.1, 144.0, 142.9, 132.8, 128.9, 118.5, 112.7, 74.0, 34.48, 34.0, 32.0, 31.9, 31.8, 29.5, 28.7, 28.6, 26.4, 26.3, 26.0, 23.9, 23.3, 22.7, 22.3; MS (ESI) m/z: 331 (M+H+, 100%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N+:2]=1[O-].P(Cl)(Cl)([Cl:14])=O>C(Cl)(Cl)Cl>[Cl:14][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: [O-][n+]1ccc2ccccc2c1
Solvent: ClC(Cl)Cl
Product: Clc1nccc2ccccc12
Temperature: 17.5 °C
Yield: 48.4 %

Procedure:
69.3 g of isoquinoline N-oxide (448 mmol) manufactured by Tokyo Chemical Industry Co., Ltd. and 225 ml of chloroform were introduced into a 1 L-three-neck flask dissolved therein. Then, 219.6 g (1,432 mmol) of phosphorous oxychloride was slowly added dropwise therein and stirred under ice-cooling while maintaining the inner temperature at 15 to 20° C. Thereafter, the mixture was heated and stirred under reflux for 3 hours. The reaction product was left to cool to room temperature, and the resulting product was poured into ice water. The mixture was extracted with ethyl acetate, and the organic layer was washed with water until it was neutral. The solvent was then dried under reduced pressure. The residue was purified using silica gel column chromatography (eluent: chloroform/hexane: 5/1) to yield 35.5 g of 1-chloroisoquinoline white crystals (44.9% yield).
Reaction SMILES: O1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]3)=[O:8])[CH2:3][CH2:2]1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:25][NH2:26].[ClH:32]>>[ClH:32].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:25][N:26]1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]3)=[O:8])[CH2:3][CH2:2]1
Reactant: O=C1CCc2cc(C(=O)N3CCOCC3)ccc2N1
Reactant: COc1ccc(CN)cc1OC
Agent: Cl
Product: COc1ccc(CN2CCN(C(=O)c3ccc4c(c3)CCC(=O)N4)CC2)cc1OC

Procedure:
2.62 Grams of 6-morpholinocarbonyl-3,4-dihydrocarbostyril and 17.9 g of 3,4-dimethoxybenzylamine were placed in a sealed tube and heated at 170°-200° C. for 5 hours. Then 3,4-dimethoxybenzylamine was removed by distillation under a reduced pressure and the residue thus obtained was treated by means of a silica gel column chromatography, and the objective product was changed to a hydrochloride by adding concentrated hydrochloric acid. Recrystallized from methanol-water to obtain 0.35 g of 6-[4-(3,4-dimethoxybenzyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril monohydrochloride. Colorless granular crystals. Melting point: 240°-242° C. (decomposed)
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.O.O.[Sn](Cl)Cl>CN(C)C=O>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: Cl[Sn]Cl
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN(c2ccc(N)cc2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 73.9 %

Procedure:
0.999 g (4.5 mmol) of 1-methyl-4-(4-nitrophenyl)piperazine, 10.15 g (45 mmol) of tin(II)chloride dihydrate and 20 ml of dimethylformamide were mixed and stirred overnight at 80° C. Most of dimethylformamide was evaporated under vacuum. The remaining slurry was poured into ice water, neutralized with a sodium bicarbonate (sat.) solution, and filtered. The filtrate was extracted several times with ethylacetate and chloroform to provide 0.636 g (74%) of 4-(4-methylpiperazin-1-yl)aniline.
Reaction SMILES: C(OC([N:8]1[C@@H:13]([CH3:14])[CH2:12][N:11]([C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[N:24][C:25]([NH2:29])=[C:26]([OH:28])[CH:27]=3)=[CH:18][CH:17]=2)[CH2:10][C@H:9]1[CH3:31])=O)(C)(C)C.Br[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:40].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[NH2:29][C:25]1[N:24]=[CH:23][C:22]([C:19]2[CH:20]=[CH:21][C:16]([C:15]([N:11]3[CH2:10][CH:9]([CH3:31])[NH:8][CH:13]([CH3:14])[CH2:12]3)=[O:30])=[CH:17][CH:18]=2)=[CH:27][C:26]=1[O:28][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:40]
Reactant: C[C@@H]1CN(C(=O)c2ccc(-c3cnc(N)c(O)c3)cc2)C[C@H](C)N1C(=O)OC(C)(C)C
Reactant: Cc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1COc1cc(-c2ccc(C(=O)N3CC(C)NC(C)C3)cc2)cnc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.5 %

Procedure:
To a mixture of (2R,6S)-4-[4-(6-Amino-5-hydroxy-pyridin-3-yl)-benzoyl]-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (100 mg, 0.23 mmol) and 1-bromomethyl-2-methyl-benzene (47 mg, 0.25 mmol) in DMF(2 mL) was added 2 M Cs2CO3 (0.35 mL, 0.7 mmol) followed by water (0.5 mL). The mixture was stirred at room temperature overnight. LCMS showed the reaction was completed, DMF was removed, followed by addition of 4 N HCl in dioxane (2 mL) and the reaction was stirred at room temperature for 3 hr. The volatiles were removed followed by addition of methanol. This solution was purified by prep-HPLC to afford {4-[6-Amino-5-(2-methyl-benzyloxy)-pyridin-3-yl]-phenyl}-(3,5-dimethyl-piperazin-1-yl)-methanone (47 mg, yield 46.6%).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:11][C:12](=[O:31])[NH:13][C:14]([CH3:30])([CH3:29])[CH2:15][N:16]([C:25](=[O:28])[CH2:26]Br)[C:17]1[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=1[F:24])([CH3:10])([CH3:9])[CH3:8].C(O)(=O)C>O1CCCC1>[C:7]([O:11][C:12]([N:13]1[CH2:26][C:25](=[O:28])[N:16]([C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])[CH2:15][C:14]1([CH3:30])[CH3:29])=[O:31])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(CN(C(=O)CBr)c1c(F)cccc1F)NC(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CC(=O)N(c2c(F)cccc2F)CC1(C)C
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
A solution of 2.05 g of potassium t-butoxide (18.3 mmol) in tetrahydrofuran (120 ml) was added to a solution of 5.14 g of {2-[(2-bromoacetyl)-(2,6-difluorophenyl)amino]-1,1-dimethylethyl}carbamic acid t-butyl ester obtained in Example (60b) (12.2 mmol) in tetrahydrofuran (120 ml) under a nitrogen atmosphere and under cooling in a dry ice-acetone bath over 30 minutes, and the mixture was stirred at the same temperature for 30 minutes. 0.33 ml of acetic acid (6.10 mmol) was added to the reaction mixture. After returning to room temperature, the solvent was evaporated under reduced pressure. The residue was diluted with water, followed by extraction with ethyl acetate. Then, the organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:hexane/ethyl acetate=3/1) to obtain 3.43 g of the title compound (yield: 83%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][C@@H:6]([C:25]1[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=1)[CH:7]=[CH:8][CH2:9][N:10]1[C@H:14]([CH3:15])[CH2:13][C@H:12]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:11]1=[O:24])[CH3:2]>CO.C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:33])[CH2:5][C@@H:6]([C:25]1[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=1)[CH2:7][CH2:8][CH2:9][N:10]1[C@H:14]([CH3:15])[CH2:13][C@H:12]([NH:16][C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[C:11]1=[O:24])[CH3:2]
Reactant: CCOC(=O)C[C@H](C=CCN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C[C@H]1C)c1ccc(OC)nc1
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: CCOC(=O)C[C@H](CCCN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C[C@H]1C)c1ccc(OC)nc1
Reaction time: 1.5 h

Procedure:
To stirred solution of 4-6 (250 mg) in methanol (15 mL) was added a suspension of 10% Pd on carbon (90 mg) in ethanol (2 mL). The resulting suspension was stirred under an atmosphere of hydrogen for 1.5 hours. The mixture was filtered through Celite. The solvent was evaporated to give 4-7 as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[OH:24][CH2:25][C@H:26]1[NH:30][C:29](=[O:31])[CH2:28][CH2:27]1>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:30]3[C@H:26]([CH2:25][OH:24])[CH2:27][CH2:28][C:29]3=[O:31])=[CH:3][CH:4]=2)=[O:9])[CH2:11][CH2:12]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3)CC2)c(C)c1
Reactant: O=C1CC[C@@H](CO)N1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4C(=O)CC[C@H]4CO)cc3)CC2)c(C)c1
Yield: 50.8 %

Procedure:
Using (4-bromophenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (1.87 g) described in Preparation Example 170 and (S)-5-hydroxymethylpyrrolidin-2-one (556 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (1.00 g) was obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[N:5]2[N:25]=[CH:26][CH:27]=[C:4]2[N:3]=1.C([Sn]([C:41]#[N:42])(CCCC)CCCC)CCC>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[CH3:14][Si:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][O:10][CH2:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:6]1[N:5]2[N:25]=[CH:26][CH:27]=[C:4]2[N:3]=[C:2]([C:41]#[N:42])[CH:7]=1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2ccnn12
Reactant: CCCC[Sn](C#N)(CCCC)CCCC
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C#N)nc2ccnn12
Temperature: 150 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
5-chloro-N,N-bis((2-(trimethyl silyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (1.5 g, 3.5 mmol), tributyltin cyanide (1.7 g, 5.3 mmol), tetrakis(triphenylphosphine) palladium (0.8 g, 0.7 mmol), bis(tri-t-butylphosphine) palladium (0.4 g, 0.7 mmol) were charged in a pressure tube. The tube was evacuated and charged with argon for three cycles. Dioxane (20 ml) was added, and the tube was capped and heated at 150° C. with stirring for one hour. After cooling, the mixture was diluted with EtOAc (100 ml) and washed with brine (1×20 ml), dried over MgSO4. Solvent was removed in vacuo and the residue was purified by column chromatography on silica gel. Elution with EtOAc/Hexanes (0-35%) gave desired product, 7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidine-5-carbonitrile (1.3 g, 90%).