Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C@@H:12]1[C:27](=[O:28])[N:14]2[C:15]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[C:16]([CH3:19])[CH2:17][S:18][C@H:13]12.C(OO)(=O)C.C(=O)([O-])O.[Na+]>CC(N(C)C)=O.C(#N)C>[CH3:19][C:16]1[CH2:17][S:18][C@@H:13]2[C@H:12]([NH:11][C:8](=[O:9])[CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:27](=[O:28])[N:14]2[C:15]=1[C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: CC(=O)OO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)N(C)C
Product: CC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1
Reaction time: 0.75 h

Procedure:
Phenylacetyl chloride (0.58 ml, 1.1 equiv.) was added to a stirred solution of t-butyl 7β-amino-3-methylceph-3-em-4-carboxylate (1.08 g, 4 mmole) in dimethylacetamide (2.5 ml) and acetonitrile (10 ml.) The mixture was stirred at ca. 25° for 45 minutes and the acetonitrile was removed in vacuo. Water (50 ml) and ethyl acetate (150 ml) were added and the organic phase was washed with water, 3% sodium hydrogen carbonate solution and water (50 ml of each), dried and evaporated. The residual colourless oil was dissolved in methylene chloride (10 ml) and cooled in an ice-bath while peracetic acid (40% w/v; 1.16 ml, 1.1 equiv.) was added dropwise. The solution was stirred at ca. 20° for 30 minutes and saturated sodium hydrogen carbonate solution (20 ml) was added. The organic phase was washed with water (50 ml), dried and evaporated to a white gelatinous solid, t.l.c. (acetone-methylene chloride; 1:4) Rf 0.49, 0.80, which was purified by chromatography on Kieselgel G (50g). Elution with acetonemethylene chloride (1:9) gave a pale yellow solid which was crystallised from acetone-light petroleum, b.p. 40°-60° (1:1; 10 ml) to give t-butyl 3-methyl-7β-phenylacetamidoceph-3-em-4-carboxylate, 1,1-dioxide (0.17 g, 11 %), m.p. 87 to 88°, [α]D + 36.5°, λmax. 259 nm (ε 8,150), νmax. (CHBr3) 3410 (NH), 1798 (acetidin-2-one), 1714 (CO2R) and 1680 and 1510 cm-1 (CONH), τ (CDCl3) 2.66 (5H,s; C6H5), 3.06 (1H,d, J 10.5 Hz; NH), 3.90 (1H,dd, J 10.5, 5Hz; C7 -H), 5.19 (1H,d, J 5 Hz; C6 -H), 6.09, 6.55 (2H, AB-q, J 18 Hz; C2 -H2), 6.34 (2H,s; C6H5CH2), 7.94 (3H,s; C3 -CH3), 8.49 (9H,s; CO2C(CH3)3). (Found: C, 56.9; 56.6; H, 5.8; 5.7; N, 6.3, 6.3; S, 7.4 C20H24N2O6S (420.5) requires C, 57.1; H, 5.75; N, 6.7; S, 7.6%). Further elution with acetone-methylene chloride (1:9) gave a white gelatinous solid which dissolved in acetone (10 ml) and reprecipitated by addition of light petroleum (b.p. 40°-60°; 10 ml) to give the title ester 1β-oxide (1.04 g, 67%), m.p. 181° to 182° (dec), [α]D + 164°, λmax. 265 nm (ε 7,900), νmax. (CHBr3) 3390 (NH), 1790 (azetidin-2-one), 1716 (CO2R), 1678 and 1510 (CONH) and 1050 cm-1 (S→O), τ (CDCl3 + 3 drops Me2SO-d6) 2.68 (5H,s; C6H5), 4.12 (1H,dd, J 9.5,4.5 Hz; C7 -H), 5.34 (1H,d, J 4.5 Hz; C6 -H), 6.37 (2H,s; C6H5CH2), 6.56 (2H,s; C2 -H2), 7.91 (3H,s; C3 -CH3), 8.47 (9H,s; CO2C(CH3)3) (Found: C, 60.0, 59.6; H, 6.1, 5.9; N, 6.7, 6.7; S, 7.8 C20H24N2O5S (404.5) requires C, 59.4; H, 6.0; N, 6.9; S, 7.9%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:7]=[CH:6][N:5]([CH2:8]O)[N:4]=1.S(Cl)([Cl:14])=O>ClCCl>[Cl:14][CH2:8][N:5]1[CH:6]=[CH:7][C:3]([C:2]([F:11])([F:10])[F:1])=[N:4]1
Reactant: O=S(Cl)Cl
Reactant: OCn1ccc(C(F)(F)F)n1
Solvent: ClCCl
Product: FC(F)(F)c1ccn(CCl)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.33 g of 3-(trifluoromethyl)-1H-pyrazole-1-ylmethanol was dissolved to 40 ml of dichloromethane. 2.7 ml of thionyl chloride was added to the solution, followed by stirring at room temperature for overnight. The reaction mixture was concentrated under reduced pressure to obtain 1.44 g of 1-(chloromethyl)-3-(trifluoromethyl)-1H-pyrazole.
Reaction SMILES: [Cl:1][CH:2]([CH2:6][OH:7])[C:3]([OH:5])=[O:4].[CH2:8](O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[Cl:1][CH:2]([CH2:6][OH:7])[C:3]([O:5][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH3:8])=[O:4]
Reactant: CCCCCCCCCCCCO
Reactant: O=C(O)C(Cl)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: c1ccccc1
Product: CCCCCCCCCCCCOC(=O)C(Cl)CO
Reaction time: 40 h

Procedure:
2-chloro-3-hydroxypropionic acid (4.80 g, 0.03 mol), dodecanol (6.00 g, 0.03 mol) were taken with 5 mL dry benzene in a (50 mL) RB, with a dean-stark apparatus and condenser; 25 mg (0.26 mmol) para-Toluene sulfonic acid (pTSA) was added to it and the mixture was stirred at 75° C.-80° C. for 40 h. 1H-NMR showed 85% conversion. More 2-chloro-3-hydroxypropionic acid (1.00 g, 8.00 mmol) was added to it and heated at 75° C.-80° C. for 20 h. 1H-NMR showed almost complete conversion. After cooling it down, the product was added with 100 mL of CH2Cl2. Organic phase was washed twice with 50 mL of dil. NaHCO3 aq. sol. and once with 50 mL of sat. NaCl aq. sol. and then dried over anhy. Na2SO4. After filtration and removing the solvent by rotary evaporation, yield=7.76 g (78%). It was used for the next reaction without further purification. 1H-NMR (CDCl3, 7.27 ppm): 2.18-2.40 (broad, —OH), 3.97 (m, —CH2OH), 4.21 (m, —CO2CH2), 4.39 (m, —CHCl).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:14]2[C:6]([N:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)=[CH:5][C:4]2[CH:15]=[C:16]3[C:21]([C:3]1=2)=[CH:20][CH2:19][CH:18]=[CH:17]3.Br[C:24]1[CH:36]=[CH:35][C:34]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]([CH3:38])([CH3:37])[C:26]=2[CH:25]=1.S(=O)(O)[O-].[Na+].C(C1C=C(C(C)(C)C)C=C(C(O)=O)C=1O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].C(C1C=CC=CC=1)CCCCCCCCCCC>[Cu]>[CH3:1][C:2]1([CH3:22])[C:14]2[C:6]([N:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)=[CH:5][C:4]2[CH:15]=[C:16]3[C:21]([C:3]1=2)=[CH:20][CH:19]([C:24]1[CH:36]=[CH:35][C:34]2[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:27]([CH3:38])([CH3:37])[C:26]=2[CH:25]=1)[CH:18]=[CH:17]3
Reactant: CC1(C)C2=C(C=C3C=CCC=C32)C=C2N=c3ccccc3=C21
Reactant: CC1(C)c2ccccc2-c2ccc(Br)cc21
Agent: [Cu]
Agent: CC(C)(C)c1cc(C(=O)O)c(O)c(C(C)(C)C)c1
Agent: CCCCCCCCCCCCc1ccccc1
Product: CC1(C)C2=C(C=C3C=CC(c4ccc5c(c4)C(C)(C)c4ccccc4-5)C=C32)C=C2N=c3ccccc3=C21
Temperature: 180 °C
Reaction time: 29 h
Yield: 80.2 %

Procedure:
12,12-Dimethyl-10,12-dihydroindeno[2,1-b]carbazole synthesized in Example 1 (5.5 g), 2-bromo-9,9-dimethyl-9H-fluorene (6.4 g), sodium bisulfite (0.3 g), a copper powder (0.1 g), 3,5-di(tert-butyl)salicylic acid (0.5 g), potassium carbonate (4.0 g), and dodecylbenzene (5 ml) were added to a nitrogen-substituted reaction vessel, heated, and stirred at 180° C. for 29 hours. The mixture was cooled to 100° C., and insoluble matter was removed by filtration after adding toluene (80 ml), and a filtrate was concentrated. Crystallization using n-hexane (20 ml) was performed to obtain an ocher powder of 12,12-dimethyl-10-(9,9-dimethyl-9H-fluorene-2-yl)-10,12-dihydroindeno[2,1-b]carbazole (7.4 g; yield 80.0%)
Reaction SMILES: C[O:2][CH:3]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])=[CH:17][C:16]=3[O:30][CH3:31])=[CH:12][CH:13]=2)[N:8]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[N:7]=1)OC>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:31][O:30][C:16]1[CH:17]=[C:18]([O:21][CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:19]=[CH:20][C:15]=1[C:11]1[CH:10]=[C:9]2[C:14]([C:6]([CH:3]=[O:2])=[N:7][N:8]2[CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])=[CH:13][CH:12]=1
Reactant: COc1cc(OCOCC[Si](C)(C)C)ccc1-c1ccc2c(C(OC)OC)nn(COCC[Si](C)(C)C)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(OCOCC[Si](C)(C)C)ccc1-c1ccc2c(C=O)nn(COCC[Si](C)(C)C)c2c1
Yield: 99.5 %

Procedure:
3-(1,1-Dimethoxy-methyl)-6-[2-methoxy-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole (1.1 g, 1.92 mmol) was stirred in 1% TFA/CH2Cl2 (20 mL) for 1 h at rt. Concentration in vacuo yielded 1.01 g (100%) of 6-[2-methoxy-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole-3-carbaldehyde as a clear oil. 1H NMR (300 MHz, CDCl3) δ 10.27 (s, 1H), 8.28 (d, 1H, J=8.4 Hz), 7.73 (s, 1H), 7.55 (dd, 1H, J=8.4, 1.2 Hz), 7.29 (d, 1H, J=8.4 Hz), 6.72–6.79 (m, 2H), 5.82 (s, 2H), 5.28 (s, 2H), 3.78–3.84 (m, 5H), 3.61 (t, 2H, J=8.1 Hz), 0.89–1.03 (m, 4H), 0.03 (s, 9H), −0.05 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6](=[O:14])[N:5]([CH3:15])[C:4](=[O:16])[C:3]=1[N:17]=O>CN(C=O)C.O=[Pt]=O>[NH2:17][C:3]1[C:4](=[O:16])[N:5]([CH3:15])[C:6](=[O:14])[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]=1[NH2:1]
Reactant: Cn1c(=O)c(N=O)c(N)n(-c2ccccc2)c1=O
Agent: O=[Pt]=O
Solvent: CN(C)C=O
Product: Cn1c(=O)c(N)c(N)n(-c2ccccc2)c1=O
Reaction time: 0.33 h

Procedure:
40.5 g of 6-amino-3-methyl-5-nitroso-1-phenyl-2,4-(1H, 3H)-pyrimidinedione (XVII) in 500 ml of DMF and in the presence of 0.3 g of PtO2 was the solution catalytically hydrogenated for 20 minutes at a pressure of 200 kPa. The reaction mixture was heated and the catalyst was filtered off. After cooling, crystals were filtered off and washed with DMF and water. Yield 21.4 g (XVIII). NMR
Reaction SMILES: [F:1][CH2:2][C@@H:3]1[C@@H:11]2[C@@:6]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])([N:7]=[C:8]([NH:12]C(=O)C3C=CC=CC=3)[S:9][CH2:10]2)[CH2:5][O:4]1.N12CCCN=C1CCCCC2>CO>[F:1][CH2:2][C@@H:3]1[C@@H:11]2[C@@:6]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])([N:7]=[C:8]([NH2:12])[S:9][CH2:10]2)[CH2:5][O:4]1
Reactant: O=C(NC1=N[C@@]2(c3ccccc3F)CO[C@H](CF)[C@H]2CS1)c1ccccc1
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: NC1=N[C@@]2(c3ccccc3F)CO[C@H](CF)[C@H]2CS1
Temperature: 80 °C
Yield: 89.2 %

Procedure:
N-((4aS,5S,7aS)-5-(fluoromethyl)-7a-(2-fluorophenyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)benzamide (70.56 g, 181.65 mmol) was dissolved in methanol (420 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (55.73 mL, 372.69) was added, and the solution was heated to reflux (heating block temperature 80° C.) for 5 h. The reaction mixture was concentrated under reduced pressure, and the residue purified by silica gel column chromatography (10% to 50% EtOAc in hexanes) to afford the title compound (46.05 g, 89%). 1H NMR (400 MHz, CDCl3) δ ppm 2.79 (dd, J=13.39, 4.04 Hz, 1H) 2.98-3.05 (m, 1H) 3.12 (dd, J=13.39, 3.54 Hz, 1H) 3.87 (dd, J=8.46, 2.65 Hz, 1H) 4.46 (br. s., 2H) 4.48-4.67 (m, 4H) 7.06 (ddd, J=12.57, 8.15, 1.26 Hz, 1H) 7.15 (td, J=7.58, 1.26 Hz, 1H) 7.24-7.31 (m, 1H) 7.44 (td, J=8.08, 2.02 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH3:18])[C:12]([C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][C:23]=3[OH:31])=O)=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH3:18])[C:12]([C:19]3[O:31][C:23]4[CH:24]=[C:25]([N+:28]([O-:30])=[O:29])[CH:26]=[CH:27][C:22]=4[N:21]=3)=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCCNc1nc(Nc2cccc(F)c2)ncc1C(=O)Nc1ccc([N+](=O)[O-])cc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: CCCNc1nc(Nc2cccc(F)c2)ncc1-c1nc2ccc([N+](=O)[O-])cc2o1
Temperature: 155 °C
Reaction time: 4 h

Procedure:
To 2-((3-fluorophenyl)amino)-N-(2-hydroxy-4-nitrophenyl)-4-(propylamino)pyrimidine-5-carboxamide (E24, 11 mg) and p-toluenesulfonic acid monohydrate (15 mg), xylene (1.5 mL) was added at room temperature, and the mixture was stirred at 155° C. for 4 hours. The reaction mixture was cooled to room temperature, and then purified by silica gel column chromatography (eluent, 100 to 80% ethyl acetate in methanol). To the obtained solid matter, saturated aqueous sodium hydrogencarbonate and ethyl acetate were added. The organic layer was separated, washed successively with saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To the obtained residue, ethyl acetate were added, and the solid matter was taken by filtration to obtain N2-(3-fluorophenyl)-5-(6-nitrobenzo[d]oxazol-2-yl)-N4-propylpyrimidine-2,4-diamine (E25) as yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][C:23](O)=[O:24])=[C:14]([N+:26]([O-:28])=[O:27])[CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+].[Cl-]>C1COCC1>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][CH2:23][OH:24])=[C:14]([N+:26]([O-:28])=[O:27])[CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1c([N+](=O)[O-])cc(NC(=O)OCc2ccccc2)c2ccccc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(Nc1cc([N+](=O)[O-])c(CCO)c2ccccc12)OCc1ccccc1
Reaction time: 8 h
Yield: 52.6 %

Procedure:
BH3-THF complex (1.0 M sol., 0.13 mL, 0.13 mmol) was added to a solution of [4-(N-benzyloxycarbonylamino)-2-nitronaphthalen-1-yl]acetic acid (40.0 mg, 0.11 mmol) in THF (5 mL) under N2 atmosphere and stirred overnight. The reaction mixture was treated with saturated aqueous NH4Cl (1 mL) and extracted with AcOEt (20 mL), The organic layer was washed with saturated aqueous NaCl (5 mL), dried (Na2SO4) and concentrated under reduced pressure. Flash chromatography (25% AcOEt-Petroleum ether) afforded 2-[4-(N-benzyloxycarbonylamino)-2-nitronaphthalen-1-yl]ethanol (21.2 mg, 53%) as a dark red solid. M.p. 128-130° C.; 1H NMR (CDCl3, 500 MHz) δ 8.24 (d, 9.0, 1H), 7.88 (d, 8.0, 1H), 7.66 (t, 7.5, 1H), 7.60 (t, 7.5, 1H), 7.45 (d, 7.5, 2H), 7.41 (t, 7.5, 2H), 7.35 (t, 7.5, 1H), 6.92 (s, 1H), 4.87 (brs, 1H), 4.50 (d, 5.0, 2H), 4.05 (t, 8.5, 2H), 3.40 (t, 7.0, 2H), 1.84 (brs, 1H); IR (neat) 3406, 2936, 2892, 1594, 1519, 1435, 1342, 1124, 1036, 912, 823, 752, 699 cm−1. FABMS (NBA) m/z 322 (M−CO2+), ESMS m/z 323 (M−CO2+H+), 645 ((M−CO2)×2+H+).
Reaction SMILES: [CH3:1][C:2]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)=O.C([O:14][CH:15](N(C)C)[N:16]([CH3:18])[CH3:17])(C)(C)C>>[CH3:17][N:16]([C:15](/[CH:1]=[CH:2]/[CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)=[O:14])[CH3:18]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: CC(=O)C1CCCCC1
Product: CN(C)C(=O)/C=C/C1CCCCC1
Reaction time: 8 h
Yield: 92.7 %

Procedure:
A mixture of 3.0 g (23.8 mmol) of cyclohexyl methyl ketone and 4.56 g (26.2 mmol) of t-butoxybis(dimethylamino)methane (Bredereck's reagent) was stirred at 60□C overnight. The reaction mixture was then concentrated to give 4.0 g (93% yield) of 1-cyclohexyl-3-dimethylamino-propenone as an orange oil as indicated by 1H NMR. This product was used in the next reaction without any further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[C:10]([C:17]1[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:19]([F:29])[CH:18]=1)[N:9]=[C:8]2[NH:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[N:36](C([O-])=O)[N:35]=[CH:34]2.[NH:43]1[CH2:47][CH2:46][CH2:45][CH2:44]1.O>CS(C)=O>[F:29][C:19]1[CH:18]=[C:17]([C:10]2[N:9]=[C:8]([NH:30][C:31]3[CH:32]=[C:33]4[C:37](=[CH:38][CH:39]=3)[NH:36][N:35]=[CH:34]4)[C:7]3[C:12](=[CH:13][C:14]([O:15][CH3:16])=[C:5]([O:4][CH2:3][CH2:2][N:43]4[CH2:47][CH2:46][CH2:45][CH2:44]4)[CH:6]=3)[N:11]=2)[CH:22]=[CH:21][C:20]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1cc2nc(-c3ccc(-c4ccccc4)c(F)c3)nc(Nc3ccc4c(cnn4C(=O)[O-])c3)c2cc1OCCCl
Reactant: C1CCNC1
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2nc(-c3ccc(-c4ccccc4)c(F)c3)nc(Nc3ccc4[nH]ncc4c3)c2cc1OCCN1CCCC1
Temperature: 75 °C
Yield: 84.2 %

Procedure:
A mixture of 5-(6-(2-chloroethoxy)-2-(3-fluoro-4-(phenyl)phenyl)-7-methoxyquinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.200 g, 0.31 mmol) and pyrrolidine (0.385 g, 5.41 mmol) in DMSO (1.5 mL) was heated at 75° C. for 1.5 h. The mixture was allowed to cool to RT, upon which it was poured into water (100 mL). The solid that formed was collected via filtration and purified by preparative TLC (SiO2, CH2Cl2:MeOH 9:1) to give the desired compound 2-(3-fluoro-4-(phenyl)phenyl)-N-(1H-indazol-5-yl)-7-methoxy-6-(2-(pyrrolidin-1-yl)ethoxy)quinazolin-4-amine (0.15 g, 0.261 mmol, 84%). MS 575.4 (M+1) HPLC retention time 5.40 mins.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][C:12]1[O:16][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:14][C:13]=1[CH2:23][CH2:24][OH:25].[H-].[Na+].O>C1COCC1>[CH3:11][C:12]1[O:16][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:14][C:13]=1[CH2:23][CH2:24][O:25][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCO
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc([N+](=O)[O-])cn1
Yield: 49.5 %

Procedure:
To a solution of 2-chloro-5-nitropyridine (25 g) and 2-(5-methyl-2-phenyl-4-oxazolyl)ethanol (32.1 g) in THF (250 ml) was added, in small portions, sodium hydride (60% in oil, 6.92 g), and the mixture was stirred. The reaction mixture was stirred, at room temperature, for further 15 hours, which was poured into water, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), then the solvent was distilled off under reduced pressure. The residual crystals are collected by filtration, followed by recrystallization from ethanol to afford 2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-5-nitropyridine (25.4 g, 49%) as yellowish brown crystals, m.p.110.5°-111.5° C.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][NH:4][C:5]([CH:7]1[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].C([N-]C(C)C)(C)C.[Li+].[Si:30]([O:37][CH2:38][CH2:39]Br)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31].[Cl-].[NH4+]>O1CCCC1>[F:1][C:2]([F:20])([F:21])[CH2:3][NH:4][C:5]([C:7]1([CH2:39][CH2:38][O:37][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: O=C(NCC(F)(F)F)C1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCC1(C(=O)NCC(F)(F)F)c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 129.8 %

Procedure:
9H-Fluorene-9-carboxylic acid (2,2,2-trifluoroethyl)amide (3.00 g) was dissolved in tetrahydrofuran (100 mL), and to this solution was added dropwise a 1.5M solution (13.7 mL) of lithium diisopropylamide under ice-cooling. The mixture was stirred for one hour under ice-cooling, and to this was added a solution of tert-butyldimethylsilanyloxyethyl bromide (2.46 g) in tetrahydrofuran (5 mL). The temperature was gradually raised from under ice-cooling to room temperature, and the mixture was stirred overnight. Saturated aqueous ammonium chloride was added to the reaction mixture under ice-cooling and then extracted with ethyl acetate (50 mL×2). The extract was washed with saturated brine, dried over sodium sulfate and purified by column chromatography on silica gel with ethyl acetate:hexane=1:2.5 to give the title compound (6.00 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:4]([CH3:13])[NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[H-].[Na+].[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[Cl:1][C:2]1[C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:4]([CH3:13])[N:5]([S:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:29])=[O:28])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)c1c(C)[nH]c(-c2ccccc2)c1Cl
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1c(Cl)c(-c2ccccc2)n(S(=O)(=O)c2ccccc2)c1C
Yield: 78.3 %

Procedure:
Using ethyl 4-chloro-2-methyl-5-phenyl-1H-pyrrole-3-carboxylate (509 mg), sodium hydride (60% in oil, 139 mg) and benzenesulfonyl chloride (511 mg), a procedure as in Reference Example 4 was performed to give the title compound as a pale-yellow oil (yield 610 mg, 78%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][N:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22](=O)[CH3:23])[N:20]=2)[N:15]=[N:14]1.Cl.[NH:26]([C:28]([NH2:30])=[O:29])[NH2:27]>CO>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][N:13]1[C:21]2=[N:20][C:19](/[C:22](=[N:27]/[NH:26][C:28]([NH2:30])=[O:29])/[CH3:23])=[CH:18][N:17]=[C:16]2[N:15]=[N:14]1
Reactant: CC(=O)c1cnc2nnn(Cc3cc4cccnc4cc3F)c2n1
Reactant: NNC(N)=O
Agent: Cl
Solvent: CO
Product: C/C(=N\NC(N)=O)c1cnc2nnn(Cc3cc4cccnc4cc3F)c2n1
Temperature: 45 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
To a solution of 1-[3-(7-fluoro-quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl]-ethanone (30.0 mg, 0.09 mmol) in MeOH (10 mL), was added hydrazinecarboxamide hydrochloride (31.0 mg, 0.28 mmol). The mixture was heated at 45° C. and stirred overnight. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography with gradient (DCM:MeOH=10:1) to give the title compound as a white solid (25.0 mg, 67%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.91 (s, 1H), 9.85 (s, 1H), 8.93 (dd, 1H), 8.42 (d, 1H), 8.185 (d, 1H), 7.83 (d, 1H), 7.54 (dd, 1H), 6.20 (s, 2H), 2.28 (s, 3H). LCMS (method A): [MH]+=380, tR=1.98 min.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([F:10])[C:5]([CH:6]=O)=[C:4](F)[CH:3]=1.C(O)(=O)C(O)=O.[CH2:18]([NH:20][NH2:21])[CH3:19]>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([CH:6]=[N:21][N:20]2[CH2:18][CH3:19])=[C:8]([F:10])[CH:9]=1
Reactant: CCNN
Reactant: O=Cc1c(F)cc(Br)cc1F
Agent: O=C(O)C(=O)O
Solvent: CN1CCCC1=O
Product: CCn1ncc2c(F)cc(Br)cc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 82.5 %

Procedure:
To a solution of 4-bromo-2,6-difluorobenzaldehyde (1000 mg, 4.5 mmol) in NMP (10 mL) was added ethyl hydrazine oxalate (747 mg, 5.0 mmol). The reaction mixture was stirred at r.t. for 72 h. The reaction mixture was heated under reflux for 15 h. After being cooled at r.t., the reaction mixture was partitioned between heptane and water. The aqueous layer was extracted with heptane. The combined organic extracts were washed with brine, dried over MgSO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0-20% EtOAc in heptanes) to afford 6-bromo-1-ethyl-4-fluoro-1H-indazole as a light yellow oil (902 mg, 84%).
Reaction SMILES: BrC1C=CSC=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)=O.O.[NH2:18][NH2:19]>C(O)CO>[CH3:16][O:15][C:11]1[CH:10]=[C:9]([CH:7]=[N:18][NH2:19])[CH:14]=[CH:13][CH:12]=1
Reactant: COc1cccc(C(=O)c2sccc2Br)c1
Reactant: NN
Solvent: O
Solvent: OCCO
Product: COc1cccc(C=NN)c1
Temperature: 130 °C

Procedure:
A mixture of (3-Bromothien-2-yl) (3-methoxyphenyl)methanone (10.0 g), hydrazine hydrate (10 ml, above 99% purity), and 75 ml of ethylene glycol was heated at 130° C. for three hours. The reaction mixture was then quenched with water and extracted with ether. The ether solution was washed three times with water and dried over anhydrous magnesium sulfate. The ether was then evaporated to give 5.5 g of an oil. This was then column chromatographed on a silica gel column packed in hexane using 15% ether/hexane as an eluent. The solid from the column was then recrystallized from ether/hexane.