Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[CH3:17].[NH2:18][C:19]1[C:23]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:22][NH:21][N:20]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:20]3[N:21]=[CH:22][C:23]([C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)=[C:19]3[N:18]=2)=[CH:4][C:3]=1[CH3:17]
Reactant: Nc1n[nH]cc1-c1cccnc1
Reactant: Cc1cc(C(=O)CC(=O)C(F)(F)F)ccc1Cl
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(-c4cccnc4)c3n2)ccc1Cl
Yield: 70.5 %

Procedure:
Reaction of 1-(4-chloro-3-methyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (265 mg, 1.0 mmol), prepared from commercially available 4-chloro-3-methyl-acetophenone according to general procedure A, and 3-amino-4-(3-pyridinyl)-pyrazole [CAS No. 40545-68-2; prepared from 3-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (160 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (274 mg, 70%). MS (ISP) 375.3 [(M+H)+]; mp 193° C.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:23][C@H:22]([CH2:24][O:25][CH2:26][CH3:27])[C@@H:17]([O:18]C(=O)C)[C@H:12]1[O:13]C(=O)C.[CH:28]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH:28]1([NH:33][C:2]2[C:3]3[N:4]=[CH:5][N:6]([C:7]=3[N:8]=[CH:9][N:10]=2)[C@@H:11]2[O:23][C@H:22]([CH2:24][O:25][CH2:26][CH3:27])[C@@H:17]([OH:18])[C@H:12]2[OH:13])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CCOC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: NC1CCCC1
Product: CCOC[C@H]1O[C@@H](n2cnc3c(NC4CCCC4)ncnc32)[C@H](O)[C@@H]1O

Procedure:
Method B. The reaction was carried out with 6-chloro-9-(2,3-di-O-acetyl-5-O-ethyl-β-D-ribofuranosyl)-purine (62, 502 mg, 1.26 mmol) and cyclopentylamine (1.89 mmol, 187 μL). The mixture was purified by column chromatography (eluens 5% MeOH in CH2Cl2). Yield 316 mg (0.87 mmol, 69%), mp 134–136° C.; Rf 0.49 (eluens 10% MeOH in CH2Cl2). The product was re-crystallized from CH3CN; 1H NMR (DMSO-d6) δ 8.31 (s, 1H, H-8), 8.19 (s, 1H, H-2), 7.72 (d, 1H, J=7.55 Hz, NH), 5.89 (d, 1H, J=5.15 Hz, H-1′), 5.55–5.25 (m, 2H, OH-2′,3′), 4.53 (t, 1H, J=4.81 Hz, H-2′), 4.15 (t, 1H, J=2.40 Hz, H-3′), 4.01–3.96 (m, 1H, H-4′), 3.62-3.48 (m, 2H, H-5′), 3.46 (q, 2H, J=7.21 Hz, CH2CH3), 1.99–1.82 (m, 2H, cyclopentyl), 1.78–1.52 (m, 4H, cyclopentyl), 1.11 (t, 3H, J=7.21 Hz, CH3); MS m/z 364 (M+H)+; Anal. (C17H25N5O4.0.6 CH3CN) C, H, N.
Reaction SMILES: [B]1OC2[C:3](=[CH:4]C=CC=2)O1.C(OC#C)C.[CH2:15]([O:17][C:18](=[O:28])[C:19]1[CH:24]=[C:23](I)[C:22]([NH2:26])=[N:21][C:20]=1[NH2:27])[CH3:16].[OH-].[Na+].Cl>O1CCCC1.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>[CH2:15]([O:17][C:18]([C:19]1[CH:24]=[C:23]2[CH:4]=[CH:3][NH:26][C:22]2=[N:21][C:20]=1[NH2:27])=[O:28])[CH3:16]
Reactant: CCOC(=O)c1cc(I)c(N)nc1N
Reactant: [B]1Oc2ccccc2O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C#COCC
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc[nH]c2nc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
Catechol borane (2.7 mL, 1M tetrahydrofuran solution, 2.7 mmol) was added dropwise to ethoxyacetylene (0.7 mL, 40% hexane solution, 2.83 mmol) on an ice bath, and the mixture was stirred for 1 hour at room temperature. The mixture was further heated at 70° C. and stirred for 2 hours, and allowed to room temperature. A solution of 2,6-diamino-5-iodo-nicotinic acid ethyl ester described in Preparation Example R-1 (415 mg, 1.35 mmol) in tetrahydrofuran (5.5 mL), tetrakis(triphenylphosphine)palladium(0) (48 mg, 0.042 mmol) and sodium hydroxide (160 mg, 4 mmol, powder) were added thereto, followed by stirring for 7 hours 30 minutes under reflux. The reaction mixture was allowed to room temperature, 2N hydrochloric acid (4.7 mL, 9.4 mmol) was added thereto, followed by stirring for 60 hours at room temperature. After the reaction was completed, the reaction mixture was evaporated, and extracted using diethyl ether. The aqueous layer was fractionated, neutralized on an ice bath with an aqueous solution of 5N sodium hydroxide, then, was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, then evaporated, the resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=2:1), and the title compound (97 mg, 0.47 mmol, 35%) was obtained.
Reaction SMILES: [O:1]1[C:6]2=[C:7]3[C:12](=[CH:13][CH:14]=C2OCC1)N=CC=C3.CC1C=C(C)C=CC=1S([O-])(=O)=O.[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28]1.C1(=O)CCC=C1>>[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([CH:13]2[CH2:12][CH2:7][C:6](=[O:1])[CH2:14]2)=[CH:28]1
Reactant: c1cnc2ccc3c(c2c1)OCCO3
Reactant: c1ccc2[nH]ccc2c1
Agent: Cc1ccc(S(=O)(=O)[O-])c(C)c1
Agent: O=C1C=CCC1
Product: O=C1CCC(c2c[nH]c3ccccc23)C1
Yield: 44 %

Procedure:
This compound was prepared in similar manner as for Intermediate 14, using indole (2.34 g, 20 mmol) and 2-cyclopenten-1-one (2.0 mL, 24.0 mmol) to give 1.7 g (44%) of the desired product as a thick oil: MS (ESI) m/z 200 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[C:21]1(C)C=CC(S(O)(=O)=O)=C[CH:22]=1>C1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:13][C:11]=3[N:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc2oc(-c3ccc(Cl)cc3)nc2c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1ccc2oc(-c3ccc(Cl)cc3)nc2c1

Procedure:
A suspension of 2-(p-chlorophenyl)-5-benzoxazolylacetic acid (26 g.) and p-toluene sulphonic acid (4.6 g.) in dry benzene (156 ml.) and dry absolute ethanol (78 ml.) was refluxed for 38 hours. Evaporation gave a solid which was dissolved in ethyl acetate (2 l) and washed with an aqueous saturated sodium bicarbonate solution (6 × 50 ml.). Evaporation of the organic phase gave ethyl 2-(2-p-chlorophenyl-5-benzoxazolyl)acetate as a solid (24.1 g.); m.pt. 133° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[N:9]2[CH2:12][CH:11]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH2:10]2)=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:33]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:23]2[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=2)[N:9]2[CH2:10][CH:11]([N:13]([CH3:33])[S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH2:12]2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(NC1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: CN(C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)S(=O)(=O)c1ccccc1

Procedure:
By carrying out the operation according to the procedure of Example 24, but starting with 0.21 g of N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-phenylsulfonamide, 17 mg of 80% sodium hydride and introducing iodomethane in two portions at an interval of 3 hours. 80 mg of N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-methylphenylsulfonamide are thus obtained in the form of a white lacquer [1H NMR spectrum (300 MHz, CDCl3, δ in ppm): 2.70 (s: 3H); 3.03 (broad t, J=7.5 Hz: 2H); 3.37 (broad t, J=7.5 Hz: 2H); 3.94 (mt: 1H); 4.28 (s: 1H); from 7.20 to 7.35 (mt: 8H); from 7.45 to 7.65 (mt: 3H); 7.74 (broad d, J=8 Hz: 2H)].
Reaction SMILES: Br[C:2]([CH3:14])([CH2:12]Br)[C:3](=[NH:11])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([O:25][CH:12]=[C:2]([CH3:14])[C:3](=[N:11][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: CC(Br)(CBr)C(=N)Oc1ccccc1
Reactant: COc1ccc(O)cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(OC=C(C)C(=Nc2ccccc2)Oc2ccccc2)cc1OC
Temperature: 70 °C
Reaction time: 5 h
Yield: 51.6 %

Procedure:
To a solution of 1.0 g (2.51 mmol) of phenyl 2,3-dibromo-2-methylpropanimidate and 466 mg (3.02 mmol) of 3,4-dimethoxyphenol in 5 ml of DMF was added 2.05 g (6.29 mmol) of cesium carbonate and stirred at 70° C. for 5 hours. After cooling to room temperature, the reaction solution was poured into water and extracted with tert-butyl methyl ether. The organic layer was washed sequentially with water and a saturated NaCl, dried over anhydrous MgSO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1) to obtain 252 mg of phenyl 3-(3,4-dimethoxyphenyloxy)-2-methyl-N-phenyl-2-propenimidate (hereinafter referred to as the present compound 99) and 145 mg of 3,4-dimethoxyphenyl 3-(3,4-dimethoxyphenyloxy)-2-methyl-N-phenyl-2-propenimidate (hereinafter referred to as the present compound 100).
Reaction SMILES: Cl.[CH2:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:34]=[CH:33][C:17]([CH2:18][NH:19][C:20]3[CH:32]=[CH:31][C:23]4[O:24][C:25]([CH3:30])([CH3:29])[O:26][C:27](=[O:28])[C:22]=4[CH:21]=3)=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].Cl[C:36](=[O:47])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]([O:45][CH3:46])=[O:44]>>[CH2:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]#[C:13][C:14]2[CH:34]=[CH:33][C:17]([CH2:18][N:19]([C:20]3[CH:32]=[CH:31][C:23]4[O:24][C:25]([CH3:30])([CH3:29])[O:26][C:27](=[O:28])[C:22]=4[CH:21]=3)[C:36](=[O:47])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]([O:45][CH3:46])=[O:44])=[CH:16][CH:15]=2)=[CH:10][CH:11]=1)[CH2:3][CH2:4][CH3:5]
Reactant: COC(=O)CCCCCCC(=O)Cl
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1
Agent: Cl
Product: CCCCc1ccc(C#Cc2ccc(CN(C(=O)CCCCCCC(=O)OC)c3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1

Procedure:
The titled compound was prepared following the procedure J using 6-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-2,2-dimethyl-4H-1,3-benzodioxin-4-one hydrochloride and methyl 8-chloro-8-oxooctanoate as a colorless oil (97%). 1H NMR (CDCl3, 300 MHz) δ 7.69 (br s, 1H), 7.44 (m, 4H), 7.18 (m, 4H), 7.04 (m, 1H), 6.92 (d, J=8.7 Hz, 1H), 4.88 (s, 2H), 3.66 (s, 3H). 2.63 (t, J=7.5 Hz, 2H), 2.28 (t, J=7.3 Hz, 2H), 2.05 (t, J=7.3 Hz, 2H), 1.75 (s, 6H), 1.61 (m, 6H), 1.38 (m, 2H), 1.26 (m, 4H), 0.94 (t, J=7.3 Hz, 3H). M+ (ESI): 610.2. HPLC, Rt: 5.81 min (Purity: 100%).
Reaction SMILES: [CH:1]([C@H:4]1[NH:9][CH2:8][CH2:7][N:6]2[C:10]3[CH:16]=[C:15]([S:17]([CH3:20])(=[O:19])=[O:18])[C:14]([C:21]([O:23][CH3:24])=[O:22])=[CH:13][C:11]=3[N:12]=[C:5]12)([CH3:3])[CH3:2].Cl[C:26]1[N:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[C:29]([C:36](=[O:38])[CH3:37])=[CH:28][N:27]=1.CCN(C(C)C)C(C)C.O>CC(O)C.C(Cl)Cl>[C:36]([C:29]1[C:30]([C:32]([F:34])([F:35])[F:33])=[N:31][C:26]([N:9]2[CH2:8][CH2:7][N:6]3[C:10]4[CH:16]=[C:15]([S:17]([CH3:20])(=[O:19])=[O:18])[C:14]([C:21]([O:23][CH3:24])=[O:22])=[CH:13][C:11]=4[N:12]=[C:5]3[C@H:4]2[CH:1]([CH3:3])[CH3:2])=[N:27][CH:28]=1)(=[O:38])[CH3:37]
Reactant: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN[C@@H]3C(C)C
Reactant: CC(=O)c1cnc(Cl)nc1C(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN(c1ncc(C(C)=O)c(C(F)(F)F)n1)[C@@H]3C(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 44.3 %

Procedure:
To a solution of (R)-methyl 1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate (220 mg, 0.627 mmol) in iPrOH (4 mL) and DCM (2 mL) was added 1-(2-chloro-4-(trifluoromethyl)pyrimidin-5-yl)ethanone (421 mg, 1.88 mmol) and DIEA (485 mg, 3.76 mmol). The mixture was stirred at 60° C. overnight. Water (5 mL) was added to the mixture and the aqueous layer was extracted with EtOAc (2×10 mL). The combined organic layers were washed with water (2×10 mL) and brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC to afford (R)-methyl 2-(5-acetyl-4-(trifluoromethyl)pyrimidin-2-yl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate (150 mg, 44.4% yield) as a yellow solid.
Reaction SMILES: [N:1]([C:4]1[N:11]=[CH:10][CH:9]=[C:8]([NH:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]=1[C:6]#[N:7])=[N+]=[N-].O>O1CCCC1.CP(C)C>[NH2:1][C:4]1[N:11]=[CH:10][CH:9]=[C:8]([NH:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:5]=1[C:6]#[N:7]
Reactant: N#Cc1c(NCCCc2ccccc2)ccnc1N=[N+]=[N-]
Agent: CP(C)C
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1c(NCCCc2ccccc2)ccnc1N
Yield: 34.6 %

Procedure:
Prepared according to the methods above using 2-azido-4-((3-phenylpropyl)amino)nicotinonitrile (35 mg, 0.126 mmol) in tetrahydrofuran (1.5 mL), trimethylphosphine 1.0 M in tetrahydrofuran (0.629 mL, 0.629 mmol) and water (0.011 mL, 0.629 mmol) at rt for 3.5 hours to give the desired product as an off-white solid (11 mg). LC/MS (253, [M+H]); 1H NMR (400 MHz, CHLOROFORM-d) δ 7.85-7.78 (m, 1H), 7.37-7.29 (m, 2H), 7.26-7.23 (m, 1H), 7.22-7.16 (m, 2H), 5.92 (d, J=6.0 Hz, 1H), 5.17 (br. s., 2H), 4.94 (br. s., 1H), 3.30-3.20 (m, 2H), 2.74 (t, J=7.5 Hz, 2H), 2.00 (quin, J=7.3 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]([Cl:12])=[CH:3][C@@H:4]1[C@H:6]([C:7](Cl)=[O:8])[C:5]1([CH3:11])[CH3:10].[C:13]1([C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH2:21][CH:22]([OH:28])[CH2:23]3)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]([Cl:12])=[CH:3][C@@H:4]1[C@H:6]([C:7]([O:28][CH:22]2[CH2:21][C:20]3[C:24](=[CH:25][CH:26]=[CH:27][C:19]=3[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:23]2)=[O:8])[C:5]1([CH3:11])[CH3:10]
Reactant: OC1Cc2cccc(-c3ccccc3)c2C1
Reactant: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)OC1Cc2cccc(-c3ccccc3)c2C1
Yield: 65.5 %

Procedure:
In a manner similar to Example 12A, the reaction of 1.54 g (0.007 mole) of (±)-cis-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarbonyl chloride and 1.5 g (0.007 mole) of (+)-4-phenyl-2-indanol (EE≥95%) in the presence of 0.7 g (0.009 mole) of pyridine and 20 ml of toluene gave 1.84 g of (+)-4-phenyl-2-indanyl(±)-cis-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylate as an oil, EE≥95% (alcohol moiety). The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][CH:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]#[CH:11])[C:5]2[CH:12]=[C:13]([N+:16]([O-])=O)[CH:14]=[CH:15][C:4]=2[O:3]1>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[NH2:16][C:13]1[CH:14]=[CH:15][C:4]2[O:3][CH:2]([CH3:1])[C:7](=[O:8])[N:6]([CH2:9][C:10]#[CH:11])[C:5]=2[CH:12]=1
Reactant: C#CCN1C(=O)C(C)Oc2ccc([N+](=O)[O-])cc21
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: C#CCN1C(=O)C(C)Oc2ccc(N)cc21
Yield: 50.1 %

Procedure:
A solution of 2-methyl-6-nitro-4-(2-propynyl)-2H-1,4-benzoxazin-3(4H)-one (5 g) in acetic acid (50 ml) and ethyl acetate (50 ml) was dropwise added to a mixture of iron powder (6 g) and 5% aqueous acetic acid (50 ml), and the resultant mixture was heated under reflux for 1 hour. After being allowed to cool, iron powder was removed by filtration and the filtrate was admixed with water. The aqueous layer was extracted with ethyl acetate, and the extract was combined with the organic layer, washed with a saturated sodium bicarbonate solution, dried and concentrated. The residue was crystallized from methanol to give 6-amino-2-methyl-4-(2-propynyl)-2H-1,4-benzoxazin-3(4H)-one (2.2 g). m.p., 158°-159° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]([CH3:18])=[C:14]([CH3:17])[N+:15]=2[O-])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].Cl.P(Cl)(Cl)([Cl:22])=O.N>C(Cl)(Cl)Cl>[Cl:22][CH2:17][C:14]1[N:15]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][CH:7]=2)[O:12][C:13]=1[CH3:18]
Reactant: Cc1oc(-c2ccc(OC(C)C)cc2)[n+]([O-])c1C
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Agent: N
Solvent: ClC(Cl)Cl
Product: Cc1oc(-c2ccc(OC(C)C)cc2)nc1CCl
Temperature: 0 °C
Yield: 60 %

Procedure:
To a solution of 2-(4-isopropoxy-phenyl)-4,5-dimethyl-oxazole 3-oxide; hydrochloride (2.5 g, 8.8 mmol) in chloroform (12 ml) was added a solution of phosphorous oxychloride (1 ml, 11 mmol) in chloroform (12 ml) within 5 min. The reaction mixture was heated under reflux for 45 min, cooled to 0° C. and made basic (pH 10) by carefully adding concentrated aqueous NH3 solution. The suspension was poured onto ice water and extracted two times with dichloromethane. The combined extracts were washed with ice water/brine and dried over sodium sulfate. Removal of the solvent under reduced pressure gave a brown oil which was purified by column chromatography (silica gel, dichloromethane) to yield 1.6 g (6 mmol, 60%) of the title compound as colorless oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][C:16]([NH:24][CH3:25])=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:26]>C(OCC)C.C(O)C>[ClH:26].[CH3:25][NH:24][C:16]1[S:15][C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[N:18][C:17]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)c1nc(N2CCN(C(=O)OC(C)(C)C)CC2)sc1NC
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)c1nc(N2CCNCC2)sc1NC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Ethyl 2-(4-tert-butoxycarbonylpiperazin-1-yl)-5-methylamino-thiazole-4-carboxylate (196 mg, 0.529 mmol) was dissolved in a mixture of diethylether (10 ml) and ethanol (absolute, 15 ml), hydrochloric acid (4N in dioxane, 5 ml) was added and the mixture was stirred at room temperature for two days. The resulting precipitate was collected by filtration, washed with diethylether and dried under reduced pressure to give 130 mg of a white solid (0.424 mmol, yield 80) MS (multi-mode) m/z=271.1 [M+1]+.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[C:20]1([CH2:19][N:13]2[C:12]3[CH2:11][CH2:10][CH2:9][C:8](=[O:18])[C:7]=3[C:6]3[C:14]2=[CH:15][CH:16]=[CH:17][C:5]=3[C:1]([O:3][CH3:4])=[O:2])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc2c1c1c(n2Cc2ccccc2)CCCC1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 79.4 %

Procedure:
A suspension of 5-carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one (300 mg, 1.23 mM), benzyl bromide (210 mg, 1.23 mM), and potassium carbonate (170 mg, 1.23 mM) in 15 mL DMF was stirred at room temperature for 6 hours. The mixture was diluted with 80 mL H2O and chilled in the refrigerator. The resultant white precipitate was collected by filtration, washed with H2O, and dried in vacuo to afford 325 mg (79%) of the 9-[(phenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one as a white solid. 1H NMR (DMSO-d6) δ 7.7 (dd, 1H, J=1 and 8 Hz), 7.45-7.0 (m, 7H), 5.6 (s, 2H), 3.8 (s, 3H), 3.05 (t, 2H, J=6 Hz), 2.5 (t, 2H, J=6 Hz), and 2.2 (m, 2H). IR (KBr, cm−1) 3421, 1726, 1676, 1636, 1473, 1450, 1435, 1288, 1122, 764, 745, and 706. MS (ES) m/e 334.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([OH:11])=[O:10])=[N:6][C:7]=1[CH3:8].OS(O)(=O)=O.[CH3:17]O>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([O:11][CH3:17])=[O:10])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1nc(C(=O)O)ccc1N
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(N)c(C)n1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of 5-amino-6-methylpicolinic acid (31D, 240 mg, 1.5 mmol) in methanol was added conc. H2SO4. The solution was stirred at 60° C. overnight, when LC-MS showed that s.m. was consumed. Then the mixture was concentrated and neutralized with Na2CO3 solution to pH=7. The mixture was extracted with DCM (10 mL×3). The organic layer was dried and concentrated to give the title compound 31E. LC-MS: m/z 167 (M+H)+
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1.Cl.Cl[CH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[CH:23][C:14]=1[CH2:13][O:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1
Reactant: COC(=O)c1cc(O)no1
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCc2ccc3ccccc3n2)no1
Temperature: 60 °C
Reaction time: 2 h
Yield: 78.2 %

Procedure:
A mixture of methyl 3-hydroxyisoxazole-5-carboxylate (5.01 g), 2-chloromethylquinoline hydrochloride (8.99 g), potassium carbonate (14.50 g) and N,N-dimethylformamide (100 ml) was stirred at 60° C. for 2 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-(2-quinolylmethoxy)-5-isoxazolecarboxylate (7.78 g, yield 78%) was obtained as colorless crystals from a fraction eluted with tetrahydrofuran. The crystals were recrystallized from tetrahydrofuran-hexane. melting point: 133–134° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C@@H:9]([CH3:12])[CH2:10][OH:11])[CH:5]=[CH:6][CH:7]=1.N1C=CN=C1.[C:18]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])([CH3:20])[CH3:19].O>CN(C)C=O>[Si:22]([O:11][CH2:10][C@@H:9]([NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH3:12])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@@H](CO)Nc1cccc(Cl)c1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)Nc1cccc(Cl)c1
Temperature: 50 °C
Reaction time: 14 h
Yield: 65.4 %

Procedure:
To a solution of (2S)-2-[(3-chlorophenyl)amino]propane-1-ol (7.00 g) in N,N-dimethylformamide (19 mL) were added imidazole (2.82 g) and tert-butyl(chloro)dimethylsilane (6.38 g), and the mixture was stirred at 50° C. for 14 hr. Water (200 mL) was added to the reaction solution, and the mixture was extracted with diethyl ether. The obtained organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=0→40%) to give the title compound as a colorless oil (yield: 7.40 g, 65%).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30]C(=O)OC(C)(C)C)[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.[CH3:38][O-:39].[Na+]>[Cu](I)I>[CH3:38][O:39][C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH2:30])[CH2:27][CH2:28][CH2:29]2)=[CH:22][CH:21]=1
Reactant: C[O-]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(Br)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: I[Cu]I
Agent: [Na+]
Product: COc1nc2n(c1-c1ccc(C3(N)CCC3)cc1)-c1cccnc1Nc1ccccc1-2
Temperature: 100 °C
Yield: 11 %

Procedure:
A mixture of tert-butyl {1-[4-(2-bromo-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (50 mg, 0.09 mmol) and copper iodide (1.7 mg, 0.01 mmol) in sodium methoxide solution (1 M, 5 mL) was heated at 100° C. for 24 hour. After cooling to room temperature, the precipitate was collected and purified by HPLC to give the title compound as a white solid (5 mg, 11%).