Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[SH:11].C(N(CC)CC)C.Cl[CH2:20][C:21](=O)[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>O1CCCC1>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][C:21]1[NH:1][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[S:11][CH:20]=1)[CH3:27]
Reactant: Nc1ccc([N+](=O)[O-])cc1S
Reactant: CCOC(=O)CC(=O)CCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CC1=CSc2cc([N+](=O)[O-])ccc2N1
Temperature: 25 °C
Reaction time: 12 h
Yield: 86.6 %

Procedure:
A solution of 2-amino-5-nitro-benzenethiol (4.1 g, 23.9 mmol) in tetrahydrofuran (60 mL) was treated with triethylamine (4.8 g, 47.8 mmol) and ethyl chloroacetoacetate (4.3 g, 26.3 mmol). The reaction mixture was stirred at 25° C. for 12 h, concentrated in vacuo, taken up in ethyl acetate, and heated at 80° C. for 3 h. The reaction mixture was allowed to cool to 25° C., washed with saturated aqueous brine solution, dried over sodium sulfate, and concentrated in vacuo. The resulting brown solid was triturated with diethyl ether to afford the desired product, (7-nitro-4H-benzo[1,4]thiazin-3-yl)-acetic acid ethyl ester (5.8 g, 20.7 mmol, 87%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 1.32 (t, 3H, J=7.1 Hz), 3.49 (s, 2H), 4.21 (q, 2H, J=7.0 Hz), 4.89 (s, 1H), 6.91 (d, 1H, J=8.7 Hz), 8.00 (dd, 1H, J1=9.5 Hz, J2=2.3 Hz), 8.12 (d, 1H, J=3.1 Hz), 10.95 (bs, 1H). LC-MS (ESI) calcd for C12H12N2O4S [M+H+] 281.05, found 281.23 [M+H+].
Reaction SMILES: C(CC[O:12][C:13]([CH2:15][NH:16][C:17]1[C:25]2[C:20](=[CH:21][C:22]([Cl:27])=[CH:23][C:24]=2[Cl:26])[NH:19][C:18]=1[C:28]([O:30]CC)=[O:29])=[O:14])C(C1C=CC=CC=1)=O.[OH2:33].[OH-].[Li+]>O1CCCC1.O>[CH2:18]([N:16]([CH2:15][C:13]([OH:12])=[O:14])[C:17]1[C:25]2[C:20](=[CH:21][C:22]([Cl:27])=[CH:23][C:24]=2[Cl:26])[NH:19][C:18]=1[C:28]([OH:30])=[O:29])[C:17]([C:25]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:33]
Reactant: O
Reactant: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1NCC(=O)OCCCC(=O)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CN(CC(=O)c1ccccc1)c1c(C(=O)O)[nH]c2cc(Cl)cc(Cl)c12
Yield: 113.8 %

Procedure:
Dissolve 3-[(phenacyl)carbethoxymethyl-amino]-2-carbethoxy-4,6-dichloroindole (0.29g, 0.626 mmol) in tetrahydrofuran (27 mL) and water (13 mL). Add lithium hydroxide monohydrate (0.158 g, 3.76 mmol) and stir overnight. Pour into 1N hydrchloric acid (100 mL) and extract into ethyl acetate. Dry (MgSO4) and evaporate the solvent in vacuo. Recrystallize (ethyl acetate/hexane) to give the title compound (0.15 g, 59%); mp 235°-7° C.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=O)=[CH:2]1.[S:12]1[CH2:18][C:16](=[O:17])[NH:15][C:13]1=[S:14].C([O-])(=O)C.[Na+].O>C(O)(=O)C>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:18]2[S:12][C:13](=[S:14])[NH:15][C:16]2=[O:17])=[CH:2]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: O=C1CSC(=S)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C1NC(=S)SC1=Cc1c[nH]c2ncccc12
Temperature: 25 °C
Yield: 102.4 %

Procedure:
The suspension of 1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (example 1b, 1.2 g, 8.22 mmol), rhodanine (1.09 g, 8.22 mmol) and sodium acetate (2.69 g, 32.8 mmol) in acetic acid (12 mL) was stirred under reflux for 12 h. After cooling to room temperature, water (150 mL) was added. The solid was collected by filtration, washed with water and dried to obtain 5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethylene)-2-thioxo-thiazolidin-4-one (2.2 g, 100%) as a brawn solid. LC-MS m/e 262 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][N:7]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:19]=[CH:20][C:21]=1[Cl:22])[O:14][CH2:15][C:16](N)=[NH:17].C(O)C.CN(C)C=O>C(O)C>[NH2:9][C:8]1[C:3]2[C:2](=[N:7][CH:6]=[CH:5][N:4]=2)[N:1]=[C:16]([CH2:15][O:14][C:13]2[CH:19]=[CH:20][C:21]([Cl:22])=[C:11]([Cl:10])[CH:12]=2)[N:17]=1
Reactant: N=C(N)COc1ccc(Cl)c(Cl)c1
Reactant: N#Cc1nccnc1N
Solvent: CN(C)C=O
Solvent: CCO
Product: Nc1nc(COc2ccc(Cl)c(Cl)c2)nc2nccnc12

Procedure:
Obtained using the procedure described in section c of Example 2, starting with 9.6 g (0.080 mole) of 3-amino-2-pyrazinecarbonitrile and 26.3 g (0.12 mole) of 2-(3,4-dichlorophenoxy)acetamidine in 520 ml of absolute ethanol. Refluxing time: 3 hours. Yld: 18.0 g (70%), m.p. 261°-263° C. (ethanol/N,N-dimethylformamide).
Reaction SMILES: [Li]CCCC.CCCCCC.[CH2:12]([C@H:19]1[CH2:23][O:22][C:21](=[O:24])[NH:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:25](Cl)(=[O:30])[CH2:26][CH2:27][CH:28]=[CH2:29]>C1COCC1>[CH2:12]([C@H:19]1[CH2:23][O:22][C:21](=[O:24])[N:20]1[C:25](=[O:30])[CH2:26][CH2:27][CH:28]=[CH2:29])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C=CCCC(=O)Cl
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=CCCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 59.5 %

Procedure:
In a 250 mL round-bottomed flask was (S)-4-benzyloxazolidin-2-one (5 g, 28.2 mmol) and THF (30 mL) to give a colorless solution. Cooled in −78° C. bath. 2.5M BuLi in hexane (11.29 mL, 28.2 mmol) was added slowly to the oxazolidinone. Initially a thick white precipitate formed, added another 10 mL THF. At the end of the addition the reaction mixture became light orange and contained white solid material. The reaction mixture was stirred at −78° C. for 1 h, and then pent-4-enoyl chloride (3.11 mL, 28.2 mmol) was added dropwise to the oxazolidinone anion at −78° C. The orange color immediately discharged and the reaction became a pale yellow color. Still several large white chunks in the reaction. After 30 min. The reaction mixture was removed from −78° C. bath and let warm to room temperature. All the white chunks have dissolved. The reaction mixture was then stirred at room temperature for 4 h. The reaction was quenched with saturated NH4Cl. The reaction mixture was diluted with 10% aqueous LiCl and Et2O. The organic layer was separated and washed with saturated aqueous NaHCO3 and then washed with brine. The organic layer was dried over MgSO4, filtered and concentrated to give a crude material. This crude material was purified on silica gel column (120 g ISCO) eluting with a gradient from 100% hexane/EtOAc to 50% hexane/EtOAc. The product came off ˜20% EtOAc/hexane. The product was collected in tubes and concentrated to afford (S)-4-benzyl-3-(pent-4-enoyl)oxazolidin-2-one, Intermediate S8A (4.35 g, 16.78 mmol, 59.5% yield) as thick colorless oil. 1H NMR (400 MHz, chloroform-d) δ 7.43-7.22 (m, 5H), 6.01-5.81 (m, 1H), 5.20-5.02 (m, 2H), 4.78-4.62 (m, 1H), 4.29-4.16 (m, 2H), 3.34 (dd, J=13.4, 3.3 Hz, 1H), 3.19-3.02 (m, 2H), 2.80 (dd, J=13.3, 9.6 Hz, 1H), 2.50 (d, J=7.3 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][C:17]([C:23](OC)=[O:24])=[CH:18][CH:19]=3)[CH2:14]2)(=[O:12])=[O:11])=[C:5]([CH3:27])[CH:4]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].C1COCC1.O>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][C:17]([CH2:23][OH:24])=[CH:18][CH:19]=3)[CH2:14]2)(=[O:11])=[O:12])=[C:5]([CH3:27])[CH:4]=1
Reactant: COC(=O)c1ccc2c(c1)CN(S(=O)(=O)c1c(C)cc(OC)cc1C)CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C)c(S(=O)(=O)N2CCc3ccc(CO)cc3C2)c(C)c1
Reaction time: 1 h

Procedure:
A solution of methyl 2-(4-methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxylate (3.85 mmol, 1 equiv.) in THF (10 ml) was added dropwise to a cold suspension of LAH (7.7 mmol, 2 equiv.) in THF (30 ml), and the resulting mixture was stirred for 1 h. THF/water was added to the reaction mixture, and filtration over Celite was carried out. The filtrate was concentrated and the yellow oil so obtained was used in the following stage without further purification.
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@@H:24]([O:25][C@@H:26]2[O:55][C@@H:54]([CH3:56])[C@@H:45]([O:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C@@H:36]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C@@H:27]2[O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@H:23]([O:57][C@@H:58]2[O:74][C@H:73]([CH2:75][O:76][C:77](=[O:84])[C:78]3[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=3)[C@H:71]([OH:72])[C@H:69]([OH:70])[C@H:59]2[O:60][C:61](=[O:68])[C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[C@@H:22]([CH2:85][O:86][C:87](=[O:94])[C:88]2[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=2)[O:21][C@H:11]1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC=CC=1.C([C:103](CC)(CC)[C:104]([O-])([O-])[O-:105])C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(N(CC)CC)C>[C:1]([O:9][C@@H:10]1[C@@H:24]([O:25][C@@H:26]2[O:55][C@@H:54]([CH3:56])[C@@H:45]([O:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C@@H:36]([O:37][CH2:38][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[C@@H:27]2[O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@H:23]([O:57][C@@H:58]2[O:74][C@H:73]([CH2:75][O:76][C:77](=[O:84])[C:78]3[CH:79]=[CH:80][CH:81]=[CH:82][CH:83]=3)[C@H:71]([O:72][C:104](=[O:105])[CH3:103])[C@H:69]([OH:70])[C@H:59]2[O:60][C:61](=[O:68])[C:62]2[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=2)[C@@H:22]([CH2:85][O:86][C:87](=[O:94])[C:88]2[CH:89]=[CH:90][CH:91]=[CH:92][CH:93]=2)[O:21][C@H:11]1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCO[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](O[C@@H]2O[C@H](COC(=O)c3ccccc3)[C@H](O)[C@H](O)[C@H]2OC(=O)c2ccccc2)[C@H](O[C@@H]2O[C@@H](C)[C@@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)[C@H]1OC(=O)c1ccccc1
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCCO[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](O[C@@H]2O[C@H](COC(=O)c3ccccc3)[C@H](OC(C)=O)[C@H](O)[C@H]2OC(=O)c2ccccc2)[C@H](O[C@@H]2O[C@@H](C)[C@@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)[C@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
Compound 22 (5 g) was dissolved a 1:1 mixture of benzene and triethylorthoacetate (110 mL), containing 4-toluenesulfonic acid (0.2 g), and the mixture was stirred for 1 h at room temperature. The acid was neutralized with triethylamine, and the mixture evaporated to dryness. The residue was dissolved in 80% aqueous acetic acid (75 mL) and stirred for 40 min at room temperature. The acetic acid was evaporated under diminished pressure and the last traces were removed by co-evaporation with toluene to yield 23 (4.7 g, 91.3%); [α]D, -4.5° (c 0.8, chloroform), t.l.c. (5:1 ethyl acetate-toluene). 13C NMR (CDCl3): δ170.98 (COCH3), 166.75, 166.33, 166.18, 165.07 (4×PhCO), 102.03, 101.08 (C-1, C-1'), 98.16 (C-1 fuc), 80.07, 78.23 (C-3, C-4), 74.69, 73.53, 73.24 (3×PhCH2), 70.66 [OCH2 (CH2)6 ], 63.23, 61.42 (C-6, C-6'), 32.25-23.14 [(CH2)6CH3 ], 21.20 (COCH3), 17.49 (C-6 fuc), and 14.63 (CH3).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[NH:19][N:18]=3)[N:15]=2)[N:10]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].Cl[CH2:40][CH2:41][CH2:42][NH+:43]([CH3:45])[CH3:44].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:28])[F:29])[CH:24]=4)[N:19]([CH2:40][CH2:41][CH2:42][N:43]([CH3:45])[CH3:44])[N:18]=3)[N:15]=2)[N:10]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4ccc(OC(F)F)cc34)nc12
Reactant: C[NH+](C)CCCCl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C)CCCn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c2cc(OC(F)F)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77.1 %

Procedure:
In a 2-(5 mL Biotage microwave vial were mixed N-tert-butyl-2-(5-(difluoromethoxy)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (109 mg, 205 μmol), 3-chloro-N,N-dimethylpropan-1-aminium chloride (97.4 mg, 616 μmol, Eq: 3.0) and Cs2CO3 (402 mg, 1.23 mmol, Eq: 6.00) in DMF (2 mL). The mixture was stirred ˜10 min at 25° C. then heated to 100° C. in the Biotage microwave reactor for 30 min, diluted with 10 mL of dichloromethane and filtered through a celite pad, filtrate concentrated under high vacuum at 65° C. and residue dissolved in dichloromethane and purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco) eluting with 0 to 5% over 20 min (MeOH containing 10% ammonium hydroxide)/dichloromethane to give N-tert-butyl-2-(5-(difluoromethoxy)-1-(3-(dimethylamino)propyl)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (97 mg, 158 μmol, 76.7%) as a light brown solid. MS (M+H)+=616 (>90% purity); 1H NMR (CDCl3) δ: 9.24 (s, 1H), 8.36 (s, 1H), 8.32 (d, J=2.3 Hz, 1H), 8.06 (s, 1H), 7.60 (d, J=8.7 Hz, 1H), 7.35 (dd, J=9.1, 2.3 Hz, 1H), 6.55 (t, J=74.8 Hz, 1H), 5.75 (s, 2H), 4.60 (t, J=6.6 Hz, 2H), 3.53-3.74 (m, 2H), 2.33-2.42 (m, 2H), 2.29 (s, 6H), 2.14-2.27 (m, 2H), 1.65 (s, 9H), 0.90-1.07 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: [O-:1][S:2]([O-:4])=[O:3].[Na+].[Na+].Cl[CH2:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1>O>[S:2]([CH2:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)([OH:4])(=[O:1])=[O:3]
Reactant: ClCCc1cccnc1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=S(=O)(O)CCc1cccnc1

Procedure:
A mixture of Na2SO3 (2.7 g., 21 m.moles) and (3-(2-chloroethyl)pyridine (1.2 g., 8.5 m.moles) in water (10 ml.) was heated under reflux overnight with stirring and column chromatographed on IR-120 resin (H+, 100 ml.) by eluting with water. The eluate containing the desired product was collected and concentrated to give colorless plates (1.1 g., 69%), melting at 275°-278° C.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[C:14](=[O:25])[NH:15][C:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:18])[CH3:17])([O-])=O>CO.C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[C:14](=[O:25])[NH:15][C:16]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([CH3:18])[CH3:17]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(C(=O)NC(C)(C)c2ccccc2)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(N)c(C(=O)NC(C)(C)c2ccccc2)c1
Reaction time: 5 h
Yield: 100.6 %

Procedure:
To a solution of methyl 4-nitro-3-[(2-phenylpropan-2-yl)carbamoyl]benzoate (0.12 g, 0.35 mmol) in methanol (2.5 mL) and ethyl acetate (2.5 mL) was added 10% palladium on carbon (12 mg). The mixture was purged with H2 gas (3×) and stirred under an atmosphere of H2 for 5 h. The reaction mixture was then filtered through Celite, washed with MeOH and concentrated. The residue was purified by flash silica gel chromatography (50% to 100% EtOAc/hexanes) to afford methyl 4-amino-3-[(2-phenylpropan-2-yl)carbamoyl]benzoate (0.11 g, 99%). LC-MS: (FA) ES+ 313.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.[Cl:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([CH:21]=[C:22]([CH2:24]Cl)[N:23]=2)[CH:20]=1.C(N(CC)CC)C>C(O)CO>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([CH:21]=[C:22]([CH2:24][N:11]3[CH2:10][CH2:9][N:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=4)[CH2:13][CH2:12]3)[N:23]=2)[CH:20]=1
Reactant: ClCc1cn2cc(Cl)ccc2n1
Reactant: Clc1ccc(N2CCNCC2)nc1
Solvent: CCN(CC)CC
Solvent: OCCO
Product: Clc1ccc(N2CCN(Cc3cn4cc(Cl)ccc4n3)CC2)nc1

Procedure:
Following the general procedure of Example 33, Step 2, and making non-critical variations, 1-(5-chloropyridin-2-yl)piperazine (0.424 g), 6-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine (Example 4, Step 1; 0.517 g), triethylamine (0.282 g), and ethylene glycol (2 mL) give, after crystallization from dichloromethane/ethyl ether, 0.621 g of the title compound; mp 137-138° C.; MS m/z 361, 363; IR 1593, 1480, 1245, 1324, 801, 1304 cm-1 ; 1H NMR (CDCl3) δ2.67, 3.55, 3.75, 6.57, 7.13, 7.41, 7.52, 7.53, 8.10, 8.14.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:16]([C:20]1[Se:24][C:23]([C:25]([NH2:27])=[O:26])=[C:22]([OH:28])[CH:21]=1)([CH3:19])([CH3:18])[CH3:17].[OH-].[Na+].Cl>CN(C=O)C.O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][N:3]=[C:2]2[O:28][C:22]1[CH:21]=[C:20]([C:16]([CH3:19])([CH3:17])[CH3:18])[Se:24][C:23]=1[C:25]([NH2:27])=[O:26]
Reactant: CC(C)(C)c1cc(O)c(C(N)=O)[se]1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2ncnc(Oc3cc(C(C)(C)C)[se]c3C(N)=O)c2cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.4 %

Procedure:
To a solution of 4-chloro-6,7-dimethoxyquinazoline (200 mg, 0.89 mmol) in DMF (5 mL) was added sequentially 5-tert-butyl-3-hydroxyselenophene-2-carboxamide (220 mg, 0.89 mmol), powdered NaOH (147 mg, 3.568 mmol) and catalytic amount of KI at rt and the mixture was stirred at rt for 3 h. The mixture was poured into ice cooled water, neutralized with dil. HCl and stirred for 15 min. The precipitated solid was filtered, washed with water and dried. The crude product was chromatographed over silica gel column using chloroform-methanol (95:5) as eluents to give the product as an yellow color solid (245 mg, 63%), mp 220-224° C. 1H NMR (400 MHz, CDCl3): δ 15.16 (1H, br s, exchangeable with D2O), 13.63 (1H, br s, exchangeable with D2O), 8.17 (1H, s), 7.51 (1H, s), 7.21 (1H, s), 6.87 (1H, s), 4.05 (6H, s), 1.38 (9H, s); 13C NMR (100 MHz, CDCl3): δ 175.5, 172.0, 164.8, 156.6. 155.1, 150.7, 145.9, 139.9, 118.7, 113.1, 112.7, 108.4, 103.3, 56.5, 56.3, 37.1, 32.2; LC-MS (positive ion mode): m/z 434, 436 (M+H)+.
Reaction SMILES: [H][H].[Cl:3][C:4]1[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][C:5]=1[CH2:6][N:7]1[CH2:11][CH2:10][CH:9]([CH2:12][NH:13][C:14](=[O:32])[CH2:15][CH2:16][C:17]2[N:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][CH:24]=3)=[CH:19][N:18]=2)[CH2:8]1>CO.[Pd]>[Cl:3][C:4]1[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][C:5]=1[CH2:6][N:7]1[CH2:11][CH2:10][CH:9]([CH2:12][NH:13][C:14](=[O:32])[CH2:15][CH2:16][C:17]2[N:18]=[CH:19][C:20]([C:23]3[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=3)=[CH:21][N:22]=2)[CH2:8]1
Reactant: O=C(CCc1ncc(-c2ccc([N+](=O)[O-])cc2)cn1)NCC1CCN(Cc2cccc(Cl)c2Cl)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(-c2cnc(CCC(=O)NCC3CCN(Cc4cccc(Cl)c4Cl)C3)nc2)cc1
Reaction time: 1.5 h
Yield: 59.1 %

Procedure:
Hydrogen gas (balloon pressure) was introduced into a vessel containing Pd/C (10%, 100 mg, 0.1 mmol, 0.05 equiv.) in a solution of N-[1-(2,3-dichlorobenzyl)-pyrrolidin-3-(RS)-ylmethyl]-3-[5-(4-nitrophenyl)pyrimidin-2-yl]propionamide (1.0 g, 2.2 mmol) in methanol (30 mL). After 1.5 h, the reaction was terminated by purging with N2 and the reaction mixture was filtered through celite® and concentrated. The yellow residue was dissolved in ethyl acetate, then taken into the aqueous phase using 1 M hydrochloric acid. The aqueous phase was basified to pH 11, then extracted thoroughly with ethyl acetate. The organic fractions were combined and washed with brine, then dried sodium sulfate and concentrated to afford N-[1-(2,3-dichlorobenzyl)pyrrolidin-3-(RS)-ylmethyl]-3-[5-(4-aminophenyl)pyrimidin-2-yl]propionamide as a yellow crystalline solid (630 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.C(N(C(C)C)CC)(C)C.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][CH2:28][C@@H:27]([OH:31])[CH2:26]2)=[CH:21][CH:20]=1>O1CCOCC1>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][CH2:28][C@@H:27]([OH:31])[CH2:26]3)=[CH:21][CH:20]=2)[N:7]=1
Reactant: Clc1ncnc(Cl)n1
Reactant: Nc1ccc(N2CCC[C@@H](O)C2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O[C@@H]1CCCN(c2ccc(Nc3ncnc(Cl)n3)cc2)C1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
To a solution of 2,4-dichloro-1,3,5-triazine in dioxane was added diisopropylethylamine, followed by the addition of (R)-1-(4-aminophenyl)piperidin-3-ol. The reaction mixture was stirred at 110° C. for 1 hour, and LCMS (liquid chromatography-mass spectrometry) showed the reaction was completed. The solvents were removed under reduced pressure, and the residue was purified by silica gel chromatography, eluting with petroleum ether:ethyl acetate=5:1, to afford (R)-1-(4-((4-chloro-1,3,5-triazin-2-yl)amino)phenyl)piperidin-3-ol.
Reaction SMILES: [NH2:1][CH:2]([CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:9][CH:8]=1)[CH2:3][OH:4].C(N(CC)CC)C.[CH3:28][O:29][C@@:30]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:34]([F:37])([F:36])[F:35])[C:31](Cl)=[O:32]>C(Cl)Cl>[CH3:28][O:29][C@:30]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:34]([F:37])([F:36])[F:35])[C:31]([NH:1][CH:2]([CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:11][CH:12]=1)[CH2:3][OH:4])=[O:32]
Reactant: CCCCCCCCc1ccc(CCC(N)CO)cc1
Reactant: CO[C@@](C(=O)Cl)(c1ccccc1)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCc1ccc(CCC(CO)NC(=O)[C@@](OC)(c2ccccc2)C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
2-Amino-4-(4-octylphenyl)butanol (30 mg), N,N-dimethyl-p-aminopyridine (52.6 mg), anhydrous triethylamine (34.2 μl) and anhydrous methylene chloride (1 ml) were mixed and the mixture was stirred under a nitrogen atmosphere at room temperature. Thereto was added (S)-α-methoxy-α-trifluoromethylphenylacetyl chloride (50.4 μl) and the mixture was stirred at room temperature for 10 hours. The reaction mixture was concentrated under reduced pressure and the residue obtained was purified by thin layer chromatography (eluent; chloroform:methanol=9:1) to give the two diastereomer mixtures. Moreover, the mixture was purified by high performance liquid chromatography (eluent; methanol:water=88:12, flow rate; 8.0 ml /minute) to give the subject oily substance (31.6 mg) of 67.8 minutes at retention time and the subject oily substance (31.9 mg) of 71.6 minutes at retention time.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:27]([CH3:28])=[CH:26][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21](Cl)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:36][N:37]1[C:45]2[C:40](=[CH:41][CH:42]=[C:43]([Sn](CCCC)(CCCC)CCCC)[CH:44]=2)[C:39](=[O:59])[N:38]1[CH3:60]>O1CCOCC1.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.[Cu]I>[C:1]([O:5][C@@H:6]([C:12]1[C:27]([CH3:28])=[CH:26][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:43]4[CH:44]=[C:45]5[C:40]([C:39](=[O:59])[N:38]([CH3:60])[N:37]5[CH3:36])=[CH:41][CH:42]=4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)c3)sc2c1-c1ccc(Cl)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc2c(=O)n(C)n(C)c2c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4ccc5c(=O)n(C)n(C)c5c4)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
To a solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (32.0 mg, 0.061 mmol) and 1,2-dimethyl-6-(tributylstannyl)-1H-indazol-3(2H)-one (33.0 mg, 0.073 mmol) in dioxane (0.8 mL) was added Pd(PPh3)4 (4.0 mg, 0.003 mmol) and CuI (4.0 mg, 0.018 mmol). The reaction was degassed for 5 minutes with N2 and then heated at 100° C. for 2 days. Concentrated in vacuo and then purified by flash column chromatography (silica gel, 0 to 100% ethyl acetate/hexanes) to give the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C36H36ClN4O4S: 655.2; found: 655.3.