Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([NH:20][CH2:21][CH3:22])[CH2:16][CH2:15]2)=[C:10]([CH2:23][NH:24][CH3:25])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:26]1([CH:32]=[CH:33][CH2:34][C:35](Cl)=[O:36])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[CH2:15][CH2:16][C@H:17]([N:20]([CH2:21][CH3:22])[C:35](=[O:36])[CH2:34][CH:33]=[CH:32][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:18][CH2:19]2)=[C:10]([CH2:23][NH:24][CH3:25])[CH:9]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: O=C(Cl)CC=Cc1ccccc1
Reactant: CCN[C@H]1CC[C@H](c2ccc(C(=O)OC(C)(C)C)cc2CNC)CC1
Product: CCN(C(=O)CC=Cc1ccccc1)[C@H]1CC[C@H](c2ccc(C(=O)OC(C)(C)C)cc2CNC)CC1

Procedure:
from trans-4-(4-tert.butoxycarbonyl-methylaminomethylphenyl)-N-ethylcyclohexylamine and 4-phenyl-3-butenoylchloride. Colourless oil. Rf value: 0.74 (alumina, petroleum ether/ethyl acetate=2:1, v:v).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@H:6]2[C@H:5]([N:13]2[C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:22][CH2:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=4[O:32][CH3:33])[C:16]=3[CH:15]=[CH:14]2)[CH2:4]1.[Cl:34][C:35]1[C:36]([C:51]([F:54])([F:53])[F:52])=[CH:37][C:38]2[N:42]=[C:41]([CH2:43][CH2:44][CH:45]3[CH2:48][C:47](=O)[CH2:46]3)[NH:40][C:39]=2[CH:50]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[Cl:34][C:35]1[C:36]([C:51]([F:54])([F:52])[F:53])=[CH:37][C:38]2[N:42]=[C:41]([CH2:43][CH2:44][CH:45]3[CH2:46][CH:47]([NH:1][CH2:2][C@@H:3]4[C@H:7]5[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@H:6]5[C@H:5]([N:13]5[C:17]6[N:18]=[CH:19][N:20]=[C:21]([NH:22][CH2:23][C:24]7[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=7[O:32][CH3:33])[C:16]=6[CH:15]=[CH:14]5)[CH2:4]4)[CH2:48]3)[NH:40][C:39]=2[CH:50]=1
Reactant: O=C1CC(CCc2nc3cc(C(F)(F)F)c(Cl)cc3[nH]2)C1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CNC3CC(CCc4nc5cc(C(F)(F)F)c(Cl)cc5[nH]4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
A solution of 7-((3aS,4R,6R,6aR)-6-(aminomethyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-N-(2,4-dimethoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (80 mg, 0.18 mmol) and 3-(2-(6-chloro-5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutanone (45 rug, 0.14 mmol) in 1,2-dichloroethane (2.4 mL) was treated dropwise with acetic acid (10 uL, 0.18 mmol). The solution was treated with sodium triacetoxyborohydride (53 mg, 0.25 mmol) in one portion and allowed to stir at room temperature till complete by HPLC. After 4 h, the reaction mixture was diluted with 10 mL CH2Cl2 and washed with 10 mL sat NaHCO3. The aqueous phase was washed with 10 mL CH2Cl2 and the combined organic phase was dried over Na2SO4. The solution was filtered and concentrated to yield a light tan glass/stiff foam. The crude material was purified by flash chromatography (25 g silica gel; 5% 7N NH3 in CH3OH/CHCl3) to yield the title compound (76 mg, 71%) as a colorless glass/stiff foam: MS (ESI+) for C38H43ClF3N7O4 m/z 754.3 (M+H)+; MS (ESI−) for C38H43ClF3N7O4 m/z 752.3 (M−H)−; HPLC purity 90.5% (ret. time, 3.24 min).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[F:9][C:10]1[CH:11]=[CH:12][C:13]([O:17][CH3:18])=[C:14]([OH:16])[CH:15]=1.O>ClCCCl>[F:9][C:10]1[CH:15]=[C:14]([OH:16])[C:13]([O:17][CH3:18])=[CH:12][C:11]=1[C:5](=[O:7])[CH3:6]
Reactant: COc1ccc(F)cc1O
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: O
Product: COc1cc(C(C)=O)c(F)cc1O
Reaction time: 0.17 h
Yield: 89.8 %

Procedure:
To a suspension of AlCl3 (1.17 g; 8.79 mmol) in 1,2-dichloroethane (2 mL) was added acetyl chloride (0.55 g; 7.03 mmol). After 10 min stirring was added dropwise a solution of 5-fluoro-2-methoxyphenol (0.50 g; 3.52 mmol) in 1,2-dichloroethane (2 mL). The reaction mixture was stirred overnight at 40° C. The mixture was then poured on iced water and extracted with diethylether. The organic phases were combined, washed with brine, dried (Na2SO4) and concentrated to afford 582 mg (90%) of the title compound as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.[CH3:14][O:15][C:16](=[O:31])[CH:17]([NH2:30])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[NH:26][CH2:27][CH2:28][N:29]=2)=[CH:21][CH:20]=1>>[CH3:14][O:15][C:16](=[O:31])[CH:17]([NH:30][C:11]([C:6]1[NH:7][C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)=[O:13])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[NH:29][CH2:28][CH2:27][N:26]=2)=[CH:21][CH:20]=1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: COC(=O)C(N)Cc1ccc(C2=NCCN2)cc1
Product: COC(=O)C(Cc1ccc(C2=NCCN2)cc1)NC(=O)c1cc2cc(Cl)ccc2[nH]1

Procedure:
From 5-chloro-1H-indole-2-carboxylic acid and (±)-2-amino-3-[4-(4,5-dihydro-1H-imidazol-2-yl)-phenyl]-propionic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-])[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH2:20]([N:22](CC)CC)C.C[Si](C#N)(C)C>C(#N)C>[Cl:1][C:2]1[C:3]([C:20]#[N:22])=[N:4][C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Cl)c[n+]([O-])c1-c1cccc(F)c1
Reactant: CCN(CC)CC
Agent: C[Si](C)(C)C#N
Solvent: CC#N
Product: COC(=O)c1cc(Cl)c(C#N)nc1-c1cccc(F)c1
Temperature: 70 °C
Yield: 92.9 %

Procedure:
Methyl 5-chloro-2-(3-fluorophenyl)nicotinate 1-oxide (2.9 g, 10 mmol) was stirred in acetonitrile (30 mL) with triethylamine (2.2 mL, 16 mmol) and trimethylsilyl cyanide (3.4 mL, 26 mmol) was added. The mixture was heated at 70° C. for 1 hour. Evaporation and purification by flash column chromatography using ethyl acetate in hexanes (0-20%) gave the desired compound (2.7 g, 90%). LCMS calculated for C14H9ClFN2O2 (M+H)+: m/z=291.1. found: 290.8.
Reaction SMILES: BrCCBr.Cl[Si](C)(C)C.C(OC([N:17]1[CH2:22][CH2:21][CH:20](I)[CH2:19][CH2:18]1)=O)(C)(C)C.Br[C:25]1[N:30]=[CH:29][CH:28]=[CH:27][N:26]=1>C1COCC1.CN(C)C(=O)C.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>[N:26]1[CH:27]=[CH:28][CH:29]=[N:30][C:25]=1[CH:20]1[CH2:19][CH2:18][NH:17][CH2:22][CH2:21]1
Reactant: Brc1ncccn1
Reactant: CC(C)(C)OC(=O)N1CCC(I)CC1
Agent: [Pd]
Agent: C[Si](C)(C)Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: BrCCBr
Product: c1cnc(C2CCNCC2)nc1
Temperature: 25 °C
Yield: 104.7 %

Procedure:
A 3-neck round bottomed flask equipped with an addition funnel and condenser and containing zinc dust (2.45 g, 37.4 mmol) was flame dried. After cooling, and purging the system with nitrogen gas, 6 mL of THF was added, followed by 1,2-dibromoethane (0.298 mL, 3.46 mmol). The mixture was warmed to a vigorous reflux using a heat gun and stirred at reflux for ˜30 seconds (gas evolution was observed), then cooled to room temperature. The warming and cooling was repeated two more times. Then chlorotrimethylsilane (0.402 mL, 3.17 mmol) was added and the mixture was stirred at room temperature for 20 minutes. N-t-butoxycarbonyl-4-iodo-piperidine (known: Billotte, S. Synlett (1998), 379, 8.97 g, 28.8 mmol) in 15 mL of THF was added over a period of about 1 minutes. The reaction mixture was stirred at 50° C. for 1.5 h, then was cooled to room temperature. Meanwhile, a mixture of tri-2-furylphosphine (267 mg, 1.15 mmol) and Tris(dibenzylideneacetone)-dipalladium(0) chloroform adduct (298 mg, 0.288 mmol) was dissolved in 6 mL of THF under a nitrogen atmosphere, stirred for 15 minutes at room temperature, and added to the organozinc solution. Then a solution of 2-bromopyrimidine (5.50 g, 34.6 mmol) in a mixture of 58 mL of THF and 20 mL of N,N-dimethylacetamide was added. The reaction mixture was warmed to 80° C. and stirred for 3.5 h, then was cooled to room temperature and stirred for 36 h. The reaction mixture was filtered through celite and the filter cake was washed with ethyl acetate. The filtrate was diluted further with ethyl acetate, and washed with saturated NaHCO3 solution. The aqueous layer was back extracted with ethyl acetate, the organic layers were combined and washed twice with water and once with brine. The organic phase was dried over anhydrous MgSO4, filtered, and concentrated. Purification by flash chromatography (silica, stepwise gradient: 25% ethyl acetate/hexane, 40% ethyl acetate/hexane, 60% ethyl acetate/hexane, 80% ethyl acetate/hexane, 100% ethyl acetate) to afford 4.92 g of pure 4-(2-pyrimidyl)-piperidine product (65%). 1H NMR (500 MHz, CDCl3): δ 8.70 (d, J=5.0 Hz, 2H), 7.16 (app t, J=4.5 Hz, 1H), 4.24 (br s, 2H), 3.05 (m, 1H), 2.89 (br m, 2H), 2.01 (br d, J=13 Hz, 2H), 1.84 (dq, J=4.5, 12.5 Hz, 2H), 1.49 (s, 9H).
Reaction SMILES: [C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH:12]=O)=[CH:8][C:7]([CH2:14][CH2:15][CH3:16])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[C:17]1([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH2:12][N:26]2[CH2:27][CH2:28][N:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:24][CH2:25]2)=[CH:8][C:7]([CH2:14][CH2:15][CH3:16])=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCc1cc(CCC=O)n(C(C)(C)C)n1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(c3ccccc3)CC2)n(C(C)(C)C)n1

Procedure:
132 mg (73%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-3-propyl-1H-pyrazol-5-yl)propanal (100 mg, 0.450 mmol), 1-phenylpiperazine (0.067 mL, 0.450 mmol), DIPEA (0.118 mL, 0.675 mmol) and NaBH(OAc)3 (286 mg, 1.350 mmol).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2onc3ccccc23)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(-c2onc3ccccc23)cc1
Yield: 59.1 %

Procedure:
A mixture of 14.9 g (0.071 mole) of 3-(4'-methylphenyl)-2,1-benzisoxazole, 12.7 g (0.071 mole) of N-bromosuccinimide, 0.1 g of dibenzoyl peroxide and 200 ml of carbon tetrachloride was heated at reflux under illumination by a flood lamp for 20 hr. The mixture was filtered while hot and the filtrate was washed twice with 5% aqueous sodium hydroxide, dried over sodium sulfate and concentrated. The residue was dissolved in acetonitrile and filtered to remove insoluble material. The filtrate was concentrated and the residue was recrystallized twice from ethanol and once from 2-propanol (charcoal) to yield 12.1 g (59%) of solid, m.p. 146°-147° C. with decomposition.
Reaction SMILES: [O:1]=[C:2]1[C:6]([C:7]([O-:9])=O)=[CH:5][C:4]2([CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[O:3]1.[NH2:15][C:16]1[CH2:24][C:20]2([CH2:23]C[CH2:21]2)[CH2:19][C:18](=[O:25])[CH:17]=1>>[OH:9][C:7]1[C:6]2[C:2](=[O:1])[O:3][C:4]3([CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)[C:5]=2[C:17]2[C:18](=[O:25])[CH2:19][C:20]([CH3:23])([CH3:21])[CH2:24][C:16]=2[N:15]=1
Reactant: NC1=CC(=O)CC2(CCC2)C1
Reactant: O=C([O-])C1=CC2(CCOCC2)OC1=O
Product: CC1(C)CC(=O)c2c(nc(O)c3c2C2(CCOCC2)OC3=O)C1

Procedure:
Obtained by starting from 2-oxo-1,8-dioxaspiro[4.5]dec-3-ene-3-carboxylate and 8-aminospiro[3.5]non-7-en-6-one.
Reaction SMILES: Cl[C:2](OC(Cl)(Cl)Cl)=[O:3].[NH2:9][C@@H:10]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:11]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[OH:12].C(N(CC)CC)C>C(Cl)Cl>[CH2:25]([C@H:10]1[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:12][C:2](=[O:3])[NH:9]1)[CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)C[C@H](N)C(O)(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C[C@@H]1NC(=O)OC1(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 89.5 %

Procedure:
Trichloromethyl chloroformate (13.0 g, 65.8 mmol) was added to a mixture of (S)-2-amino-1,1-diphenyl-4-methylpentan-1-ol 16 (12.4 g of 65%, 29.9 mmol) and triethylamine (12.7 g, 125.5 mmol) in CH2Cl2 at 0° C. The reaction mixture was stirred for 15 h, allowing to warm to room temperature. The mixture was then washed with HCl (3×200 ml) and water (2×200 ml), and dried over MgSO4. Concentration gave a crude product, which was washed with diethyl ether to afford the title compound 17 (7.9 g, 90%) as a white solid. m.p. 212–214° C. [α]D25=−286.1° (c, 4.32 in CHCl3). δH 0.85 (3H, d, J=6.6 Hz, CH3), 0.91 (3H, d, J=6.6 Hz, CH3), 0.96–1.08 (2H, m, CH2), 1.53–1.73 (1H, m, CH—Me2), 4.57 (1H, dd, J=10.5 and 3.60 Hz, CH—NH), 7.05 (1H, s, NH), 7.16–7.50 (10H, m, Ar—H). δC 20.8, 23.7, 24.9, 41.8, 58.8, 89.1, 125.9, 126.3, 127.6, 127.8, 128.1, 128.3, 139.3, 142.5 (Ar), 158.8 (C═O). νmax (cm−1): 3261, 3160 (N—H), 2955, 2869 (methyl and methylene C—H), 1752, 17235 (C═O), 1495, 1447 (Ar C═C), 1251 (C—O). m/e 313 (MNH4+, 12%), 296 (MH+, 15%), 237 (100%).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH:3]([CH3:7])[C:4](O)=[O:5].[CH3:10][O:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:32])[C:23]2[CH:28]=[C:27]([CH2:29][NH2:30])[CH:26]=[CH:25][C:24]=2[Cl:31])=[CH:17][C:16]=1[C:33]([NH:35][C:36]1[CH:41]=[CH:40][C:39]([Br:42])=[CH:38][CH:37]=1)=[O:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:10][O:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:32])[C:23]2[CH:28]=[C:27]([CH2:29][NH:30][C:4]([CH:3]([CH3:7])[C:2]([F:9])([F:8])[F:1])=[O:5])[CH:26]=[CH:25][C:24]=2[Cl:31])=[CH:17][C:16]=1[C:33]([NH:35][C:36]1[CH:41]=[CH:40][C:39]([Br:42])=[CH:38][CH:37]=1)=[O:34]
Reactant: CC(C(=O)O)C(F)(F)F
Reactant: COCCOc1ccc(NC(=O)c2cc(CN)ccc2Cl)cc1C(=O)Nc1ccc(Br)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COCCOc1ccc(NC(=O)c2cc(CNC(=O)C(C)C(F)(F)F)ccc2Cl)cc1C(=O)Nc1ccc(Br)cc1

Procedure:
Prepared analogously to example 53d with 3,3,3-trifluoro-2-methyl-propionic acid (10 mg; 0.07 mmol); N-[4-methoxyethoxy-3-(4-bromphenyl)aminocarbonyl-phenyl]-2-chloro-5-aminomethyl-benzamide (32 mg; 0.06 mmol); TBTU (21 mg; 0.07 mmol) in TEA (25 μL; 0.18 mmol) and 3 mL DMF.
Reaction SMILES: Cl.C([NH:6][C:7]1[C:12]([F:13])=[CH:11][N:10]=[C:9]([N:14]2[C:23]3[C:18](=[CH:19][C:20]([F:26])=[C:21]([F:25])[C:22]=3[Cl:24])[C:17](=[O:27])[C:16]([C:28]([O:30]CC)=[O:29])=[CH:15]2)[N:8]=1)(C)(C)C>C(O)(=O)C>[NH2:6][C:7]1[C:12]([F:13])=[CH:11][N:10]=[C:9]([N:14]2[C:23]3[C:18](=[CH:19][C:20]([F:26])=[C:21]([F:25])[C:22]=3[Cl:24])[C:17](=[O:27])[C:16]([C:28]([OH:30])=[O:29])=[CH:15]2)[N:8]=1
Reactant: CCOC(=O)c1cn(-c2ncc(F)c(NC(C)(C)C)n2)c2c(Cl)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: CC(=O)O
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)ncc1F
Yield: 65.4 %

Procedure:
To a mixed solution (1:1, v/v) of 0.4 ml of 4N hydrochloric acid and 1 ml of acetic acid was added 90 mg of ethyl 1-[4-(t-butylamino)-5-fluoropyrimidin-2-yl]-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate, and the mixture was heated under reflux with stirring for 3 and half hours and allowed to cool. The precipitate was collected by filtration, and washed with ethanol and diisopropylether successively to obtain 48 mg of the title compound as a colorless powder.
Reaction SMILES: [C:1]1([C:7](=[O:19])[CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]([O:22][C:23](=[O:26])[CH2:24]Br)[CH3:21]>>[CH2:20]([O:22][C:23](=[O:26])[CH2:24][CH:8]([C:7](=[O:19])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:9](=[O:10])[C:11]1[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=1)[CH3:21]
Reactant: COc1ccc(C(=O)CC(=O)c2ccccc2)cc1
Reactant: CCOC(=O)CBr
Product: CCOC(=O)CC(C(=O)c1ccccc1)C(=O)c1ccc(OC)cc1

Procedure:
By a method analogous to that described in Example 28, 1-phenyl-3-(p-methoxyphenyl)-1,3-propanedione was reacted with bromoacetic acid-ethyl ester to form 3-benzoyl-3-p-anisoyl-propionic acid-ethyl ester, which was further reacted with phenylhydrazine to form 1,3-diphenyl-5-(p-methoxyphenyl)-pyrazol-4-acetic acid-ethyl ester, from which was obtained by saponification 1,3-diphenyl-5-(p-methoxyphenyl)-pyrazol-4-acetic acid having a melting point of 160°-163° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.S(Cl)([Cl:14])(=O)=O>C(O)(=O)C>[Cl:14][C:3]1[NH:4][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:10]2[C:2]=1[CH3:1]
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1c[nH]c2ncccc12
Solvent: CC(=O)O
Product: Cc1c(Cl)[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
3-methylpyrrolo[2,3-b]pyridine (0,5 g 0.0038 mol) was treated in 2 ml acetic acid with an equimolecular amount of sulfuryl chloride at 0° C. for 5 min. The mixture was allowed to warm to room temperature and was stirred for 5 min. After evaporation the residue was dissolved in methylene chloride and was treated with bicarbonate. The organic layer was separated, dried and removed under reduced pressure. Chromatography on silica gel eluting with ethyl acetate gave the desired product. (0,18 g 29%).
Reaction SMILES: O[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]([CH3:10])[CH3:9])[CH:3]=1.P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]([CH3:10])[CH3:9])[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)c1cc(O)n(C)n1
Product: CC(C)c1cc(Cl)n(C)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The 5-hydroxy-3-isopropyl-1-methylpyrazole (20.5 g) was added in small portions over five minutes to 60 ml of phosphorus oxychloride cooled at 10 C. No significant exotherm resulted and after five minutes the cooling bath was removed. After stirring for one hour, the reaction was heated to 70 C. overnight and then 90 C. for four hours. The cooled reaction was cautiously added to 500 g of ice. The desired product was extracted with two 200 ml portions of ethyl acetate and the combined extracts were concentrated under reduced pressure to yield 13.7 g of the desired product as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7]2[CH:8]=[C:9](B(O)O)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:15])[O:3]1.C(=O)([O-])[O-].[Na+].[Na+].[Br-].[Li+].O.CO[CH2:28][CH2:29][O:30][CH3:31]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:16])[O:3][C:4](=[O:15])[NH:5][C:6]2[CH:11]=[CH:10][C:9]([C:9]3[CH:8]=[C:7]([CH:28]=[C:29]([O:30][CH3:31])[CH:10]=3)[C:6]#[N:5])=[CH:8][C:7]1=2
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Reactant: COCCOC
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(C#N)cc(-c2ccc3c(c2)C(C)(C)OC(=O)N3)c1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 53 %

Procedure:
A mixture of (4,4-dimethyl-1,4-dihydro-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid (4.2 g, 19.0 mmol), 3-cyano-5-methoxybenzyltriflate (5.1 g, 19.0 mmol), tetrakis(triphenylphosphine)-palladium (0) (1.1 g, 0.95 mmol), sodium carbonate (4.0 g, 38.0 mmol), lithium bromide (5 g, 57 mmol) in DME (50 mL), and water (25 mL) under a blanket of nitrogen, was stirred for 15 minutes at 50° C. This solution was then was heated at 85° C. for 1 hour. The reaction mixture was cooled to room temperature and ethyl acetate (100 mL) was added. The organic layers were washed twice with aqueous ammonium chloride (100 mL) and once with brine (100 mL), dried over magnesium sulfate and concentrated. Purification via chromatography (silica gel, 40% ethyl acetate/hexane) gave 3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-methoxy-benzonitrile as a white solid (0.69 g, 53%): mp 254-255° C.; 1H-NMR (DMSO-d6) δ 10.4 (s, 1H), 7.84 (s, 1H), 7.67-7.61 (m, 2H), 7.55 (bs, 1H), 7.4 (bs 1H) 6.99 (d, 1H, J=7.94 Hz), 3.88 (s, 3H), 1.67 (s, 6H); MS (EI) m/z 308 ([M+H]+, 30%); Anal. Calcd. For C18H16N2O3: C, 68.13; H, 5.40; N, 8.83. Found: C, 68.03; H, 5.22; N, 8.46.
Reaction SMILES: [P:1](=[O:5])([OH:4])([OH:3])[OH:2].[O-2].[Nb+5:7].[O-2].[O-2].[O-2].[O-2].[Nb+5]>>[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[Nb+5:7].[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[Nb+5:7].[Nb+5:7]
Reactant: O=P(O)(O)O
Agent: [Nb+5]
Agent: [O-2]
Product: O=P([O-])([O-])[O-]
Temperature: 25 °C

Procedure:
Niobic acid, Nb2O5 xH2O (60.33 g; 0.211 mole) is stirred in 85 percent phosphoric acid (602.20 g; 5.22 moles) at 150° C. The niobium oxide dissolves to form a pink solution, and upon further heating a precipitate forms. The precipitate is boiled in the phosphoric acid solution for about 2 hours with stirring. The mixture is cooled to room temperature, and the liquid is decanted from the precipitate. Water (500 ml) is added to the precipitate with stirring, and the precipitate is filtered. The washing and filtering cycle is repeated five times. The filtered solid is dried at 110° C. under air for 21/2 days to yield a niobium phosphate catalyst. The elemental analysis of the catalyst is consistent with the composition NbOPO4.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:8]=2)[N:3]=1.Br[CH2:30][CH:31]([CH2:39]Br)[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].[H-].[Na+].[Cl-].[NH4+]>CN(C=O)C>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:15][C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:22]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:39][C:31](=[CH2:30])[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH:8]=2)[N:3]=1
Reactant: CC(C)(C)OC(=O)C(CBr)CBr
Reactant: CCOC(=O)Cc1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: C=C(CC(C(=O)OCC)c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1)C(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
1 g of ethyl 2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]acetate are suspended in 10 ml of DMF, and 1 g of tert-butyl 3-bromo-2-(bromomethyl)propanoate is added. 324 mg of sodium hydride are subsequently added with ice-cooling, and the mixture is stirred with cooling for a further 30 min. After 1 h at 23° C., the mixture is poured into 50 ml of saturated ammonium chloride solution, with a precipitate forming. This is filtered off, washed with water and dried at 50° C. for 12 h. Yield: 900 mg (66%) of O1-tert-butyl O5-ethyl 4-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-2-methylenepentanedioate;