Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:23][C:24]1[CH:32]=[C:31]2[C:27]([CH:28]=[C:29]([CH3:33])[NH:30]2)=[CH:26][CH:25]=1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[N:5]=[CH:4][N:3]=[C:2]2[O:23][C:24]1[CH:32]=[C:31]2[C:27]([CH:28]=[C:29]([CH3:33])[NH:30]2)=[CH:26][CH:25]=1
Reactant: Cc1cc2ccc(O)cc2[nH]1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCC1
Product: COc1cc2c(Oc3ccc4cc(C)[nH]c4c3)ncnc2cc1OCCCN1CCCC1
Yield: 83.6 %

Procedure:
Using an analogous procedure to that described for Example 121, 4-chloro-6-methoxy-7-(3-pyrrolidinopropoxy)quinazoline (150 mg, 0.47 mmol), (prepared as described for the starting material in Example 9), was reacted with 6-hydroxy-2-methylindole (83 mg, 0.56 mol), (Eur. J. Med. Chem. 1975, 10, 187), to give 6-methoxy-4-(2-methylindol-6-yloxy)-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (170 mg, 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:13]([OH:15])[CH3:14]>>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([O:15][CH2:13][CH3:14])=[O:5]
Reactant: CCO
Reactant: O=C(Cl)c1cc(F)c(Cl)cc1Cl
Product: CCOC(=O)c1cc(F)c(Cl)cc1Cl
Temperature: 0 °C
Yield: 97 %

Procedure:
84 g of 2,4-dichloro-5-fluoro-benzoyl chloride are added dropwise to 250 ml of anhydrous ethanol at 50° to 60° C., the temperature being maintained by occasional cooling with ice-water. The mixture is then refluxed for about a further hour, the excess alcohol is distilled off and the residue is fractionated in vacuo. 84.9 g (~97%) of ethyl 2,4-dichloro-5-fluoro-benzoate are obtained at 132°-135° C./8 mbar.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=1[C:20]([F:23])([F:22])[F:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:2]2[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=2[C:4]#[N:5])=[CH:15][C:14]=1[C:20]([F:21])([F:22])[F:23]
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cc(C=O)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
A mixture of 2-fluoro-5-formylbenzonitrile (5.0 g, 33.5 mmol), 4-chloro-3-(trifluoromethyl)phenol (6.59 g, 33.5 mmol) and potassium carbonate (13.9 g, 101 mmol) in N,N-dimethyl formamide (DMF) (10 mL) was stirred at 60° C. overnight and filtered. Purification via Biotage-C18 system afforded the title product (6 g) as a pale solid. LC-MS (ESI): m/z 326 [M+H]+; 3.51 min (ret time).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrC[CH2:45][O:46]C>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH2:15][O:46][CH3:45])[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COCCBr
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: COCCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-bromo-2-methoxyethane and isolated as light-yellow gum (4.5 mg, 32%). MS (m/e): 341.3 (MH+).
Reaction SMILES: C([NH:8][C:9]([C:14]1[CH2:23][CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:24]CC3C=CC=CC=3)[CH:20]=2)[CH:15]=1)([CH2:12][OH:13])[CH2:10][OH:11])C1C=CC=CC=1.C(O)C.C(OCC)(=O)C.C(O)(=O)C>[Pd]>[NH2:8][C:9]([CH:14]1[CH2:23][CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([OH:24])[CH:20]=2)[CH2:15]1)([CH2:12][OH:13])[CH2:10][OH:11]
Reactant: OCC(CO)(NCc1ccccc1)C1=Cc2ccc(OCc3ccccc3)cc2CC1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: NC(CO)(CO)C1CCc2cc(O)ccc2C1
Reaction time: 6 h

Procedure:
A 1 L pressure vessel was charged 10% Pd—C, dry Engelhard (10:90, palladium:carbon black, 0.966 g, 0.000908 mol) under an atmosphere of nitrogen. The solution of 2-benzylamino-2-(6-benzyloxy-3,4-dihydro-naphthalen-2-yl)-propane-1,3-diol (23.75 g, 0.05716 mol) in ethanol (300 mL, 5 mol) and ethyl acetate (300 mL, 3 mol) was added under an atmosphere of nitrogen. The mixture was connected to a H2 line, flashed with 50 psi of H2 three times, then stirred under 50 psi of H2 for 6 hours. The mixture was continuously stirred under 50 psi of H2 overnight. Acetic acid (18.0 mL, 0.316 mol) was added and the mixture was stirred under 50 psi of H2 for 30 hours. 10% Pd—C, dry Engelhard (10:90, palladium:carbon black, 1.01 g, 0.000949 mol) suspended in 10 mL of EtOAc was added and the mixture was continuously stirred under 50 psi of H2 for 45 hours. The mixture was filtered through Celite, concentrated to 54 g. The material was dissolved in ethanol (300 mL, 5 mol) and acetic acid (10.0 mL, 0.176 mol). The resulted solution was added to a pressure hydrogenation flask charged with 10% Pd—C, dry Engelhard(10:90, palladium:carbon black, 2.10 g, 0.00197 mol) under an atmosphere of Nitrogen. The mixture was flashed with 50 psi of H2 three times then stirred under 50 psi of H2 for 3 days. Acetic acid (10.0 mL, 0.176 mol) was added and the mixture was continuously stirred under 50 psi of H2 for 24 more hours. The reaction mixture was released from the H2 pressure, filtered through Celite, concentrated and dried in high vacuum to give a crude product. The material was used for next step without further purification. 1H NMR (MeOD) δ: 6.84-6.99 (m, 1H), 6.43-6.61 (m, 2H), 3.62-3.88 (m, 4H), 2.55-2.94 (m, 4H), 2.17-2.35 (m, 1H), 1.91-2.11 (m, 1H), 1.68-1.82 (m, 1H). MS (M+1): 238.0.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=1>C(OCC)(=O)C>[N+:8]([C:7]1[C:2]([NH:11][C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Cc1cccc(N)c1
Solvent: CCOC(C)=O
Product: Cc1cccc(Nc2ncccc2[N+](=O)[O-])c1
Temperature: 100 °C
Yield: 36.4 %

Procedure:
A mixture of 2-chloro-3-nitropyridine (1.59 g) and m-toluidine (1.07 g) was heated at 100° C. for 20 minutes. The mixture was cooled and dissolved in ethyl acetate. The organic solution was washed with water and brine, dried over magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate, 4:1) to afford 3-nitro-2-[(m-tolyl)amino]pyridine (834 mg) as an orange solid.
Reaction SMILES: [C:1]([OH:11])(=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[Cl-].[Cl-].[Al+3]>>[C:12]1([CH:3]2[C:4]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:1](=[O:11])[CH2:2]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)C=Cc1ccccc1
Reactant: c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C1CC(c2ccccc2)c2ccccc21
Yield: 600.2 %

Procedure:
To the solution of 90 g (0.0608 moles) of cinnamic acid in 400 ml of benzene 300 g (2.25 moles) of aluminium trichloride is added, beginning with a very slow addition rate. At the end, the mixture is kept refluxing for 22 hours. The resulting reaction mixture is hydrolysed with ice and is extracted with ethyl ether which is washed first with water until neutral, and then with a solution of 10% sodium hydroxide. The organic extract is then desiccated and evaporated. The residue is triturated with petroleum ether, is then filtered and is then washed with a small amount of diisopropyl ether, then once more with petroleum ether and is dried yielding 76 g (yield of 60%) of 3-phenyl-1-indanone.
Reaction SMILES: [C:1]1([CH:11]=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.CC(C)([O-:16])C.[K+].[O:19]1[CH2:23][CH2:22][CH2:21]C1>>[C:1]1([CH2:11][CH:21]=[CH:22][C:23]([OH:19])=[O:16])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1cccc2ccccc12
Reactant: C1CCOC1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Product: O=C(O)C=CCc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 3-triphenylphosphorylpropionic acid chloride (12.40 g) and 1-naphthaldehyde in dry tetrahydrofuran (30 cm3) at 0° C. under an atmosphere of nitrogen was added a solution of potassium tert-butoxide (7.54 g) in tetrahydrofuran (30 cm3) over a period of 1 h. The reaction was allowed to warm to room temperature and stirred for a further 12 h before it was quenched with water (40 cm3) and extracted with diethyl ether (2×40 cm3). The aqueous portion was acidified with hydrochloric acid (5 M) and extracted into dichloromethane (3×40 cm3). The organic extracts were dried (Na2SO4) and the solvent was removed under reduced pressure to give a brown oil that crystallised on standing. The product was re-crystallised from aqueous ethyl alcohol to afford the title compound (3.96 g).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH2:11][CH3:12])[CH:3]=1.NC(N)=[S:15]>C(O)C>[CH2:11]([C:4]1[CH:3]=[C:2]([SH:15])[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=1)[CH3:12]
Reactant: NC(N)=S
Reactant: CCc1cc(Cl)n2nccc2n1
Solvent: CCO
Product: CCc1cc(S)n2nccc2n1

Procedure:
5.0 g (27.5 mmol) of the chloride from Example 1, Step B and 4.2 g (55.2 mmol) thiourea were heated in 100 ml dry ethanol for 5 h. The solvent was distilled off in vacuo and the residue crystallized from ethanol/water to give the title compound in yellow crystals, m.p. 178°-180° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]1[C:14](=[O:23])[NH:15][C:16]3[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:7]2)(=O)[CH3:2].[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.O1CCOCC1>[N:24]1([CH:1]([C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[NH:9][C:8]([C:13]2[C:14](=[O:23])[NH:15][C:16]4[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:7]3)[CH3:2])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: C1COCCN1
Reactant: CC(=O)c1ccc2[nH]c(-c3cc4ccccc4[nH]c3=O)cc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Solvent: CC(=O)O
Product: CC(c1ccc2[nH]c(-c3cc4ccccc4[nH]c3=O)cc2c1)N1CCOCC1
Temperature: 50 °C

Procedure:
A mixture of 3-(5-acetyl-1H-indol-2-yl)-2(1H)-quinolinone (8-4, 50.0 mg, 0.165 mmol, 1 equiv), morpholine (0.070 mL, 0.83 mmol, 5.0 equiv), acetic acid (0.050 mL, 0.83 mmol, 5.0 equiv), sodium cyanoborohydride (52 mg, 0.83 mmol, 5.0 equiv), and activated powdered 3 angstrom molecular sieves in anhydrous 20% dioxane in methanol (15 mL) was heated at 50° C. for 8 h. Additional morpholine (0.070 mL, 0.83 mmol, 5.0 equiv), acetic acid (0.050 mL, 0.83 mmol, 5.0 equiv), and sodium cyanoborohydride (52 mg, 0.83 mmol, 5.0 equiv) was added, and this was repeated (3×) every 8-12 hours over the course of two days. The reaction mixture was partitioned between a 1:1 mixture of saturated sodium carbonate solution and brine and ethyl acetate (100 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by reverse-phase liquid chromatography (H2O/CH3CN gradient w/0.1% TFA present) to provide 3-{5-[1-(4-morpholinyl)ethyl]-1H-indol-2-yl}-2(1H)-quinolinone (8-5) as a yellow solid. 1H NMR (500 MHz, CDCl3) δ 11.15 (s, 1H), 9.28 (br s, 1H), 8.37 (s, 1H), 7.72 (d, 1H, J=8.0 Hz), 7.57 (s, 1H), 7.54 (br t, 1H, J=7.6 Hz), 7.43 (d, 1H, J=8.0 Hz), 7.32 (t, 1H, J=7.6 Hz), 7.27 (d, 1H, J=7.8 Hz), 7.22 (d, 1H, J=7.9 Hz), 7.04 (s, 1H), 3.72 (m, 4H), 3.41 (q, 1H, J=6.6 Hz), 2.56 (m, 2H), 2.43 (m, 2H), 1.46 (d, 3H, J=6.6 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:27]([F:30])([F:29])[F:28])[CH2:14][CH2:13][N:12]([C:15]3[N:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[C:18]([CH2:25]O)=[CH:17][N:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].[C:31]1(=[O:41])[NH:35][C:34](=[O:36])[C:33]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:32]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:9][C:6]1[CH:5]=[C:4]([C:10]2([C:27]([F:28])([F:29])[F:30])[CH2:14][CH2:13][N:12]([C:15]3[N:20]=[C:19]([C:21]([F:24])([F:22])[F:23])[C:18]([CH2:25][N:35]4[C:31](=[O:41])[C:32]5[C:33](=[CH:37][CH:38]=[CH:39][CH:40]=5)[C:34]4=[O:36])=[CH:17][N:16]=3)[CH2:11]2)[CH:3]=[C:2]([Cl:1])[C:7]=1[Cl:8]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCc1cnc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)nc1C(F)(F)F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1cnc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)nc1C(F)(F)F
Reaction time: 3 h
Yield: 84.7 %

Procedure:
{2-({2-[3-(3,4,5-Trichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)pyrimidin-5-yl}methanol (Reference document: WO 2010/043315) (2.20 g), phthalimide (0.72 g) and triphenylphosphine (1.40 g) were dissolved in tetrahydrofuran (50 ml), and to the solution was added diethyl azodicarboxylate (40% toluene solution, 2.43 ml) at room temperature. After stirring the reaction solution for 3 hours, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the target compound (2.35 g).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([N:15]([CH2:29][C:30]3[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=3)[C:16]3[CH:28]=[CH:27][CH:26]=[CH:25][C:17]=3[C:18]([O:20]C(C)(C)C)=[O:19])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)=O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([N:15]([CH2:29][C:30]3[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=3)[C:16]3[CH:28]=[CH:27][CH:26]=[CH:25][C:17]=3[C:18]([OH:20])=[O:19])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(N(Cc2cccnc2)c2ccccc2C(=O)OC(C)(C)C)cc1OC1CCCC1
Solvent: O=CO
Product: COc1ccc(N(Cc2cccnc2)c2ccccc2C(=O)O)cc1OC1CCCC1
Temperature: 40 °C
Yield: 29.4 %

Procedure:
Tert-Butyl N-(3-cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-2-aminobenzoate (60 mg, 0.13 mmol) was taken up in 0.2 mL 98% formic acid and heated at 40° C. for 4 h. The formic acid was removed in vacuo and the residue was loaded onto a column of silica gel (RediSep, 4.2 g). The product was eluted with a linear gradient from 40% EtOAc in hexanes to 60% EtOAc in hexanes over 15 min to yield 16 mg of product as a brown solid. 1H NMR (CDCl3) □ 8.47 (d, 1H, J=4.9), 8.43 (s, 1H), 8.10 (d, 1H, J=7.8), 7.67 (d, 1H, J=7.8 Hz), 7.56 (m, 1H), 7.40-7.20 (m, 3H), 6.75 (d, 1H, J=8.7), 6.57 (d, 1H, J 8.7), 6.47 (s, 1H), 4.72 (s, 2H), 4.54 (p, 1H, J=4.3), 3.77 (s, 3H), 1.80-1.60 (m, 6H), 1.60-1.40 (m, 2H).
Reaction SMILES: C(OC(O[CH2:8][CH3:9])CBr)C.C(O)C.C(=O)([O-])O.[Na+].[NH2:18][C:19]1[N:20]=[N:21][CH:22]=[C:23]([C:25]([F:28])([CH3:27])[CH3:26])[N:24]=1>Br.O>[F:28][C:25]([C:23]1[CH:22]=[N:21][N:20]2[CH:8]=[CH:9][N:18]=[C:19]2[N:24]=1)([CH3:27])[CH3:26]
Reactant: CC(C)(F)c1cnnc(N)n1
Reactant: CCOC(CBr)OCC
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(F)c1cnn2ccnc2n1
Temperature: 75 °C
Reaction time: 17 h
Yield: 17.3 %

Procedure:
A stirred mixture of bromoacetaldehyde diethyl acetal (1.20 ml, 7.73 mmol) in concentrated hydrobromic acid (0.38 ml) and water (0.38 ml) was heated at reflux for 40 min, then poured into ethanol (3 ml). The solution was neutralised to pH 7 with solid sodium hydrogencarbonate, then filtered, washing the solid with more ethanol (3 ml). To the filtrate was added 3-amino-5-(1-fluoro-1-methylethyl)-1,2,4-triazine (1.0046 g, 6.43 mmol) and the mixture was stirred at 70-80° C. for 17 h. The mixture was evaporated in vacuo, and the residue was purified by flash chromatography (silica gel, 70% EtOAc/isohexane to 15% MeOH/EtOAc, then 20% EtOAc/CH2Cl2) to give 0.2000 g (17%) of the title compound as a pale yellow solid: 1H NMR (360 MHz, CDCl3) δ1.82 (6H, d, J 22.1 Hz), 7.97 (1H, d, J 1.3 Hz), 7.99 (1H, d, J 1.2 Hz), 8.69 (1H, d, J 1.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:31])[C:6]=1[C:7]1[CH:17]=[C:16]([NH:18][C:19](=[O:30])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)[CH:15]=[CH:14][C:8]=1[O:9][CH2:10][C:11](O)=[O:12].C(N(CC)C(C)C)(C)C.[CH3:41][O:42][CH2:43][CH2:44][NH2:45]>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:31])[C:6]=1[C:7]1[CH:17]=[C:16]([NH:18][C:19](=[O:30])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=2)[CH:15]=[CH:14][C:8]=1[O:9][CH2:10][C:11]([NH:45][CH2:44][CH2:43][O:42][CH3:41])=[O:12]
Reactant: COCCN
Reactant: Cn1ncc(Cl)c1-c1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1OCC(=O)O
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCNC(=O)COc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1c(Cl)cnn1C
Yield: 85.8 %

Procedure:
To a solution of 2-(2-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-(3-(trifluoromethyl)benzamido)phenoxy)acetic acid (0.060 g, 0.13 mmol) and N,N-diisopropylethylamine (0.034 g, 0.26 mmol) in dichloromethane (1.3 mL) was added BTU (0.075 g, 0.20 mmol) followed by 2-methoxyethylamine (0.015 g, 0.2 mmol). After 1.5 hours the reaction was diluted with ethyl acetate, washed with water, 1 M HCl (×3) and brine, dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography (1:1-1:0 EtOAc/hexane) to give a white solid (57.0 mg, 84%). LCMS m/z (%)=511 (M+H, 35Cl, 100), 513 (M+H, 37Cl, 30). 1H NMR (400 MHz, CDCl3) δ 3.35 (s, 3H) 3.39-3.52 (m, 4H) 3.78 (s, 3H) 4.52 (s, 2H) 6.60 (br. s., 1H) 7.02 (d, J=9.09 Hz, 1H) 7.55 (s, 1H) 7.63-7.67 (m, 2H) 7.74 (dd, J=8.97, 2.91 Hz, 1H) 7.84 (d, J=6.82 Hz, 1H) 7.92 (s, 1H) 8.08 (d, J=6.57 Hz, 1H) 8.14 (s, 1H).
Reaction SMILES: [N+](C1C=CC2C(=O)C3C(=CC=CC=3)C(=O)C=2C=1)([O-])=O.[N+:20]([C:23]1[C:36]2[C:35](=[O:37])[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([N+]([O-])=O)[CH:33]=3)[C:28](=[O:41])[C:27]=2[CH:26]=[CH:25][CH:24]=1)([O-])=O>>[NH2:20][C:23]1[C:36]2[C:35](=[O:37])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28](=[O:41])[C:27]=2[CH:26]=[CH:25][CH:24]=1
Reactant: O=C1c2ccc([N+](=O)[O-])cc2C(=O)c2c1cccc2[N+](=O)[O-]
Agent: O=C1c2ccccc2C(=O)c2cc([N+](=O)[O-])ccc21
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O

Procedure:
The product obtained by the nitration process is accompanied by 2-nitroanthraquinone and 1,5-, 1,8-, 1,6-, and 1,7-dinitroanthraquinone, undesirable contaminants. In order to obtain high quality 1-aminoanthraquinone from this product, multiple purification steps are required after the nitration and reduction reactions.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:22]=[C:21]([CH2:23][C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)[C:20](=[O:30])[C:8]4[CH:9]=[C:10]([O:15][CH2:16][C:17]([OH:19])=[O:18])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.S(Cl)(Cl)=O>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:22]=[C:21]([CH2:23][C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)[C:20](=[O:30])[C:8]4[CH:9]=[C:10]([O:15][CH2:16][C:17]([O:19][CH2:13][CH2:14][CH2:2][CH2:3][CH3:4])=[O:18])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: O=C(O)COc1cc2c(=O)c(Cc3cccnc3)cn3c4ccc(Br)cc4c(c1)c23
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CCCCCOC(=O)COc1cc2c(=O)c(Cc3cccnc3)cn3c4ccc(Br)cc4c(c1)c23
Reaction time: 0.33 h
Yield: 115.8 %

Procedure:
10-bromo-2-carboxymethyloxy-5-(3-pyridylmethyl)-4H-pyrido [3,2,1-jk]carbazole-4-one (300 mg) obtained in Example 6 was suspended in anhydrous benzene (10 ml), and to the suspension was added thionyl chloride (0.95 ml) at room temperature. The mixture was heated under reflux in an argon atmosphere for 3 hours and allowed to cool. The solvent was evaporated under reduced pressure, and after adding anhydrous benzene (5 ml), the solvent was evaporated again. The resulting residue was dissolved in anhydrous methylene chloride (3 ml), and the solution was added dropwise to a solution of 1-pentanol (0.065 ml) and triethylamine (0.18 ml) dissolved in methylene chloride (30 ml) in an ice bath, and the solution was stirred for 20 minutes. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride. The methylene chloride layer was repeatedly washed with saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The residual crude crystals were washed with ether, and recovered by filtration to obtain the title compound (200 mg, 58%).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].[OH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:14])[CH3:13].C(N(CC)CC)C>C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.C(Cl)Cl>[C:1]([O:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:14])[CH3:13])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)Cl
Reactant: CC(=O)NCCCO
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)OCCCNC(C)=O
Temperature: -72 °C
Reaction time: 2 h
Yield: 53.4 %

Procedure:
184.0 g (1.76 mol) of methacryloyl chloride were added dropwise in the course of 2 hours to an initial mixture, cooled to -72° C., consisting of 206.2 g (1.76 mol) of N-(3-hydroxypropyl)-acetamide, 750 ml of methylene chloride, 228 g (2.25 mol) of triethylamine and 250 mg of 2,6-di-tert.butyl-4-methylphenol. The mixture was stirred for a further 2 hours at -52° C. and the precipitated pale precipitate was then filtered off with suction at 0° C. The filtrate was subjected to aqueous work-up and the product was dried and, after concentrating on a rotary evaporator, distilled first at 100° C., and then the residue at 130° C. (in each case 0.1 mm Hg). 174.1 g (53% of theory) of 3- acetamidopropyl methacrylate were obtained in the form of a colorless oil.
Reaction SMILES: C(O)(=O)C.[NH2:5][C:6]1[N:11]([CH3:12])[C:10](=[O:13])[NH:9][C:8](=[O:14])[CH:7]=1.[N:15]([O-])=O.[Na+]>O>[NH2:15][C:7]1[C:8](=[O:14])[NH:9][C:10](=[O:13])[N:11]([CH3:12])[C:6]=1[NH2:5]
Reactant: O=N[O-]
Reactant: Cn1c(N)cc(=O)[nH]c1=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cn1c(N)c(N)c(=O)[nH]c1=O
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Glacial acetic acid (4.5 ml 75 mmol) was added to a suspension of 6-amino-1-methyluracil (5.66 g, 50 mmol) in hot water (100 ml). Sodium nitrite (4.14 g) was added in portions and the reaction mixture was stirred for 1 hour. The resulting solid was collected by filtration, washed with water (75 ml) and resuspended in water (100 ml). After warming to 50° C., sodium dithionite (10 g) was added in portions maintaining the reaction temperature between 50° C. and 55° C. After stirring at 50° C. for an additional 1 hour, the mixture was cooled to room temperature and filtered. The solid was washed with water (2×25 ml), with acetone (2×25 ml) and then dried under vacuum. Yield=5.6 g.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:31][C:32]1[C:40]([CH3:41])=[CH:39][CH:38]=[C:37]([F:42])[C:33]=1[C:34](Cl)=[O:35].C1C2C(=CC=C(NC3N=C(C4C(C5C=C(NC(=O)C6C=CC=CC=6)C=CC=5)=NN5C=CC=CC=45)C=CN=3)C=2)CCN1>>[F:31][C:32]1[C:40]([CH3:41])=[CH:39][CH:38]=[C:37]([F:42])[C:33]=1[C:34]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:3]=1)=[O:35]
Reactant: Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(F)c3)n2)c1
Reactant: Cc1ccc(F)c(C(=O)Cl)c1F
Agent: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CNCC4)n2)c1)c1ccccc1
Product: Cc1ccc(F)c(C(=O)Nc2cccc(-c3nn4ccccc4c3-c3ccnc(Nc4cccc(F)c4)n3)c2)c1F

Procedure:
In a manner analogous to Example 66, 4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(3-fluorophenyl)-2-pyrimidinamine and 2,6-difluoro-3-methylbenzoyl chloride are used to prepare the title compound. HRMS calcd for C31H21F3N6O: 550.1729, found: 551.1803 (M+H+).