Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:23]([O:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[CH3:24].C(N(CC)CC)C>CN(C=O)C>[CH2:23]([O:25][CH:26]1[CH2:31][CH2:30][N:29]([C:4]([C:3]2[CH:7]=[C:8]([CH:9]=[CH:10][CH:2]=2)[CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[O:6])[CH2:28][CH2:27]1)[CH3:24]
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: CCOC1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC1CCN(C(=O)c2cccc(Cc3n[nH]c(=O)c4ccccc34)c2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 63 %

Procedure:
2-(1H-Benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.379 g, 1.00 mmol) was added to 3-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1b) (0.200 g, 0.71 mmol), 4-ethoxypiperidine (0.101 g, 0.78 mmol) and triethylamine (0.249 mL, 1.78 mmol) in DMF (3 mL). The resulting solution was stirred at room temperature for 3 days. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired compound (0.175 g, 62.6% yield); 1H NMR (400.132 MHz, DMSO) δ 1.11 (3H, t), 1.20-1.93 (4H, m), 2.98-3.27 (2H, m), 3.33-3.41 (1H, m), 3.42-3.54 (3H, m), 3.93 (1H, s), 4.35 (2H, s), 7.21 (1H, m), 7.31 (1H, s), 7.33-7.42 (2H, m), 7.79-7.90 (2H, m), 7.95 (1H, m), 8.26 (1H, m), 12.58 (1H, s); m/z (LC-MS, ESI+), RT=1.81 min (M+H=392.13).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[CH:12]=[C:13]([C:15](=O)[NH:16][CH2:17][CH3:18])[CH:14]=1)=[O:8].[Si](Cl)(Cl)(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>C(#N)C>[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]([C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)[CH:12]=[C:13]([C:15]2[N:16]([CH2:17][CH3:18])[N:3]=[N:2][N:1]=2)[CH:14]=1)=[O:8]
Reactant: CCNC(=O)c1cc(C(=O)OC)cc(-c2ccc(C)cc2)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl[Si](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCn1nnnc1-c1cc(C(=O)OC)cc(-c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.6 %

Procedure:
Sodium azide (145.8 mg, 16.2 mmol) was added into a solution of 5-ethylcarbamoyl-4′-methyl-biphenyl-3-carboxylic acid methyl ester (210 mg, 0.7 mmol) and SiCl4 (0.62 mL, 5.4 mmol) in dry acetonitrile (14 mL). After the reaction was stirred at room temperature for 24 hours, the reaction mixture was poured into cold saturated aqueous Na2CO3 solution. This mixture was extracted with ethyl acetate and dried with anhydrous Na2SO4. Solvent was removed under reduced pressure to afford 200 mgs of 5-(1-ethyl-1H-tetrazol-5-yl)-4′-methyl-biphenyl-3-carboxylic acid methyl ester (yield 89%). MS (M+H)=323.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([NH2:13])[CH:7]=1.[CH3:15][S:16]([C:19]1[CH:34]=[CH:33][C:22]([CH2:23][CH:24]([C:29](=O)[CH2:30][CH3:31])[C:25](=O)[CH2:26][CH3:27])=[CH:21][CH:20]=1)(=[O:18])=[O:17]>O>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]2[C:7]=1[C:25]([CH2:26][CH3:27])=[C:24]([CH2:23][C:22]1[CH:21]=[CH:20][C:19]([S:16]([CH3:15])(=[O:18])=[O:17])=[CH:34][CH:33]=1)[C:29]([CH2:30][CH3:31])=[N:13]2
Reactant: CCC(=O)C(Cc1ccc(S(C)(=O)=O)cc1)C(=O)CC
Reactant: COC(=O)COc1ccc(Cl)c(N)c1
Solvent: O
Product: CCc1nc2c(Cl)ccc(OCC(=O)OC)c2c(CC)c1Cc1ccc(S(C)(=O)=O)cc1
Temperature: 100 °C

Procedure:
A mixture of (3-amino-4-chlorophenoxy)acetic acid methyl ester (0.35 g), 4-(4-methanesulfonylbenzyl)heptane-3,5-dione (0.49 g) and polyphosphoric acid (5.0 g) was heated at 100° C. for 2 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (99.5:0.5 by volume) to afford title compound, 0.20 g.
Reaction SMILES: [F:1][C:2]1[C:32]([F:33])=[CH:31][C:5]2[NH:6][C:7]([CH2:9][CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][N:11]3[C:16]([C:18]3[N:19]=[C:20]([CH3:30])[S:21][C:22]=3[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[O:17])=[N:8][C:4]=2[CH:3]=1.[H-].[Na+].I[CH2:37][CH2:38][CH3:39]>CN(C=O)C>[F:1][C:2]1[C:32]([F:33])=[CH:31][C:5]2[N:6]([CH2:37][CH2:38][CH3:39])[C:7]([CH2:9][CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][N:11]3[C:16]([C:18]3[N:19]=[C:20]([CH3:30])[S:21][C:22]=3[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[O:17])=[N:8][C:4]=2[CH:3]=1
Reactant: CCCI
Reactant: Cc1nc(C(=O)N2CCCCC2Cc2nc3cc(F)c(F)cc3[nH]2)c(-c2ccc(F)cc2)s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1c(CC2CCCCN2C(=O)c2nc(C)sc2-c2ccc(F)cc2)nc2cc(F)c(F)cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(RS)-1-[2-(5,6-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone, E35 (150 mg, 0.32 mmol) was added slowly to an ice-cooled slurry of sodium hydride (26 mg, 0.64 mmol, 60% dispersion in mineral oil) in DMF (10 ml). After stirring for a further 0.5 h, 1-iodopropane (60 mg, 0.35 mmol) was added. The mixture was stirred at room temperature for 16 h then partitioned between water and ethyl acetate. The organic phase was washed with water, brine, dried (Na2SO4) and the solvent removed in vacuo. Chromatography (silica gel, 50-100% ethyl acetate-pentane then 0-5% methanol-ethyl acetate) afforded the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[C:8](NCCC[N+]12CCC(CC1)[C@@H](OC(=O)C(O)(C1C=CC=CC=1)C1C=CC=CC=1)C2)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl.[Cl-].[NH2:47][CH:48]([CH3:75])[CH2:49][N+:50]12[CH2:57][CH2:56][CH:53]([CH2:54][CH2:55]1)[C@@H:52]([O:58][C:59](=[O:74])[C:60]([OH:73])([C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[CH2:51]2>>[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[C:8]([NH:47][CH:48]([CH3:75])[CH2:49][N+:50]12[CH2:57][CH2:56][CH:53]([CH2:54][CH2:55]1)[C@@H:52]([O:58][C:59](=[O:74])[C:60]([OH:73])([C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1)[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)[CH2:51]2)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(N)C[N+]12CCC(CC1)[C@@H](OC(=O)C(O)(c1ccccc1)c1ccccc1)C2
Reactant: O=C(NCCC[N+]12CCC(CC1)[C@@H](OC(=O)C(O)(c1ccccc1)c1ccccc1)C2)c1ccccc1
Agent: Cl
Agent: O=C([O-])C(F)(F)F
Agent: [Cl-]
Product: CC(C[N+]12CCC(CC1)[C@@H](OC(=O)C(O)(c1ccccc1)c1ccccc1)C2)NC(=O)c1ccccc1

Procedure:
This compound is prepared analogously to (R)-1-(3-benzoylamino-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]-octane trifluoroacetate [Example 2] but by replacing (R)-1-(3-amino-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo-[2.2.2]octane chloride hydrochloride [Example 1(ii)] with (R)-1-((R/S)-2-amino-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azoniabicyclo[2.2.2]octane chloride hydrochloride.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([CH:10]=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9])[CH3:2].Cl([O-])=[O:13].[Na+].P([O-])(O)(O)=O.[Na+].CC(=CC)C>>[CH2:8]([C:7]1[N:6]=[C:5]([C:10]([OH:13])=[O:11])[NH:4][C:3]=1[CH2:1][CH3:2])[CH3:9]
Reactant: CCc1nc(C=O)[nH]c1CC
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Product: CCc1nc(C(=O)O)[nH]c1CC
Yield: 9.4 %

Procedure:
The same operation as in Example (33c) was performed using 4,5-diethyl-1H-imidazole-2-carbaldehyde obtained in Example (43b) (352 mg, 2.31 mmol), sodium chlorite (420 mg, 4.64 mmol), sodium dihydrogenphosphate (725 mg, 4.64 mmol) and 2-methyl-2-butene (1 mL, 9.45 mmol), to obtain 36.7 mg of the title compound as a white solid (9.4%).
Reaction SMILES: [CH:1](=[C:8]([CH2:13][OH:14])[C:9]([O:11][CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.[C].[Pd]>[OH:14][CH2:13][CH:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)C(=Cc1ccccc1)CO
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(CO)Cc1ccccc1
Yield: 99.2 %

Procedure:
Methyl 2-benzylidene-3-hydroxypropionate (847.2 mg, 4.408 mmols) was dissolved in 8 ml of methanol, and 21.7 mg (water content 2.7%) of 5% palladium-carbon were added thereto to conduct catalytic reduction in a hydrogen atmosphere for 140 minutes. After the completion of the reaction, the reaction solution was filtered with Celite to remove the palladium-carbon. The resulting solution was concentrated under reduced pressure to obtain 849.2 mg of a crude product of the above title compound.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:48]=[CH:47][C:26]([C:27]([N:29]2[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3/[C:33](=[CH:40]/[C:41]([O:43][CH3:44])=[O:42])/[C:32]([F:46])([F:45])[CH2:31][CH2:30]2)=[O:28])=[CH:25][CH:24]=1>>[F:46][C:32]1([F:45])[CH2:31][CH2:30][N:29]([C:27](=[O:28])[C:26]2[CH:25]=[CH:24][C:23]([NH:22][C:9](=[O:11])[C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:48][CH:47]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2/[C:33]/1=[CH:40]/[C:41]([O:43][CH3:44])=[O:42]
Reactant: O=C(O)c1ccccc1-c1ccccc1
Reactant: COC(=O)/C=C1/c2ccccc2N(C(=O)c2ccc(N)cc2)CCC1(F)F
Agent: O=C(Cl)C(=O)Cl
Product: COC(=O)/C=C1/c2ccccc2N(C(=O)c2ccc(NC(=O)c3ccccc3-c3ccccc3)cc2)CCC1(F)F
Yield: 95.4 %

Procedure:
Using 396 mg of o-phenylbenzoic acid, 0.290 ml of oxalyl chloride and 620 mg of methyl (Z)-[1-(4-aminobenzoyl)4,4-difluoro-2,3,4,5-tetrahydro-1H-1-benzazepin-5ylidene]acetate, a similar procedure as in Reference Example 8 was repeated to obtain 878 mg of methyl (Z)-[4,4-difluoro-1-[4-(2-phenylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ylidene]acetate.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[N:5][CH:4]=[N:3]1.[F:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1>O1CCCC1.C(OCC)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[F:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[N:1][N:2]2[CH:6]=[N:5][CH:4]=[N:3]2)=[CH:10][CH:9]=1
Reactant: Nn1cncn1
Reactant: O=Cc1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Fc1ccc(C=Nn2cncn2)cc1
Yield: 68.3 %

Procedure:
A solution of 42.3 g (0.377 mol) of 75% pure 1-amino-1H-1,2,4-triazole, 40.0 mL (0.372 mol) of 4-fluorobenzaldehyde and 2.0 g of p-toluenesulfonic acid in 600 mL of tetrahydrofuran was stirred at room temperature for 21/2 days. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous Na2CO3, water and brine and dried (MgSO4). Removal of solvent gave a white solid which was recrystallized from n-butylchloride to afford 48.3 g (67%) of desired product as white needles; mp 118°-120° C. Concentration of the filtrate and recrystallization of the residue afforded 12.8 g (18%) more of product; mp 118°-120° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][C:3]=1[CH:4]=[O:5].Cl[CH2:18][CH:19]1[CH2:21][CH2:20]1>>[CH:19]1([CH2:18][O:1][C:2]2[CH:9]=[C:8]([O:10][CH3:11])[C:7]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)=[CH:6][C:3]=2[CH:4]=[O:5])[CH2:21][CH2:20]1
Reactant: COc1cc(O)c(C=O)cc1-c1cccs1
Reactant: ClCC1CC1
Product: COc1cc(OCC2CC2)c(C=O)cc1-c1cccs1
Yield: 18 %

Procedure:
Ex-32A: 2-Cyclopropylmethoxy-4-methoxy-5-thiophen-2-yl-benzaldehyde was prepared in a similar manner as described in Ex-29C from 2-hydroxy-4-methoxy-5-thiophen-2-yl-benzaldehyde (Ex. 29B) and chloromethyl-cyclopropane, 18% yield. 1H-NMR (CDCl3) δ 10.41 (s, 1H), 8.24 (s, 1H), 7.43 (d, 1H), 7.29 (d, 1H), 7.06 (t, 1H), 6.45 (s, 1H), 3.95 (m, 5H), 1.31 (m, 1H), 0.68 (m, 2H), 0.40 (q, 2H).
Reaction SMILES: [C:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=2)[CH:10]=[N:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N1C=CC=CC=1.[N+:24]([C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30])([O-:26])=[O:25]>ClCCl>[C:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:29](=[O:30])[C:28]3[CH:32]=[CH:33][CH:34]=[CH:35][C:27]=3[N+:24]([O-:26])=[O:25])[CH:15]=2)[CH:10]=[N:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)n1ncc2ccc(N)cc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1ncc2ccc(NC(=O)c3ccccc3[N+](=O)[O-])cc21
Reaction time: 12 h
Yield: 107.9 %

Procedure:
To a stirring solution of 1-Boc-6-aminoindazole (1.5 g, 6.4 mmol) in dichloromethane (25 mL) was added pyridine (1.55 mL, 19.2 mmol) followed by 2-nitrobenzoyl chloride (1 mL, 7.1 mmol). After stirring for 12 h, the solvent was removed by rotary evaporation and the residue was partitioned between ethyl acetate (250 mL) and water (250 mL). The aqueous phase was separated and the organic phase was washed with 1 M citric acid, brine, satd aq NaHCO3, and brine. The organic phase was then dried with MgSO4, filtered and concentrated in vacuo to give 2.64 g of off-white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[OH-].[K+].[F:13][C:14]([F:18])=[C:15]([F:17])[Cl:16]>CN(C)C=O>[F:13][C:14]([F:18])([O:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[NH2:1])[CH:15]([F:17])[Cl:16]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: FC(F)=C(F)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Nc1cccc(OC(F)(F)C(F)Cl)c1
Temperature: 60 °C

Procedure:
139 grams (1 mole) of 3-nitro-phenol and 28 grams (0.5 mole) of potassium hydroxide were dissolved in 400 milliliters of dimethyl formamide, and 140 grams (1.2 mole) of trifluorochloroethylene were introduced in a gas pipe at 40°C; the mixture was then maintained at 60°C for 2hours. The main amount of dimethyl formamide was distilled off in vacuo. The residue was poured into ice water, separated, dried over Na2SO4 and distilled in vacuo.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].CO.[OH-].[Na+].S(=O)(=O)(O)O.[C:20](O)(=[O:36])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]CCCC>O>[C:20]([NH:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6])(=[O:36])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Reactant: CCCCCCCCCCCCCCCC(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCCCCCCCC(=O)N[C@@H](CCC(=O)O)C(=O)O

Procedure:
L-Glutamic acid 2.9 g was dissolved in 30 ml water and 30 ml methanol and 1.6 g of sodium hydroxide. To this solution was added 8.8 g of the crystal of palmitic acid sulfuric acid mixed anhydride and 10 N sodium hydroxide to keep pH 12 to 13, with stirring at 21° - 22°C. The reaction mixture was stirred for an additional 1 hour, and then treated by the same manner as in Example 1. N-Lauroyl-L-glutamic acid was obtained. Yield 6.4 g (96.9%). M.P. 101° - 104.5°C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:12])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](O)=[O:6].C(Cl)(=O)C([Cl:16])=O>ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:3]([F:12])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([Cl:16])=[O:6]
Reactant: O=C(O)c1ccc(F)c(Cl)c1F
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(F)c(Cl)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A quantity of 6.0 g of 3-chloro-2,4-difluorobenzoic acid is suspended in 20 ml of dichloromethane. A quantity of 2.99 ml of oxalyl chloride and 2 drops of DMF are then added. The suspension is stirred at room temperature overnight and the desired product is collected after evaporation of the solvent.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:35])[CH2:13][NH:14][C:15]([C:17]1[CH:18]=[C:19]([CH:23]2[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24]2)[CH:20]=[CH:21][CH:22]=1)=[O:16].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:35])[CH2:13][NH:14][C:15](=[O:16])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]2[CH2:27][CH2:26][NH:25][CH2:24]2)[CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(C(=O)NCC(O)CN3CCc4ccccc4C3)c2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCC(O)CN1CCc2ccccc2C1)c1cccc(C2CCNC2)c1
Temperature: 29 °C
Reaction time: 2 h
Yield: 25.1 %

Procedure:
To a solution of tert-butyl 3-(3-((3-(3, 4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl) carbamoyl)phenyl)pyrrolidine-1-carboxylate (400 mg, 0.83 mmol) in CH2Cl2 (5 mL) was added TFA (1 mL) at 29° C. The mixture was stirred for 2 h at 29° C. The mixture was concentrated and the residue was purified by prep-HPLC to give the title compound (79.1 mg, Yield 25.0%). 1H NMR (CD3OD, 400 MHz): δ 7.75-7.93 (m, 2H), 7.45-7.62 (m, 2H), 7.17-7.37 (m, 4H), 4.45-4.74 (m, 2H), 4.40 (dd, J=6.3, 3.3 Hz, 1H), 3.71-4.04 (m, 2H), 3.49-3.70 (m, 5H), 3.35-3.49 (m, 3H), 3.08-3.32 (m, 3H), 2.52 (qd, J=6.6, 4.2 Hz, 1H), 2.09-2.27 (m, 1H). LCMS (m/z): 380.2 (M+1).
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].O.[F:7][C:8]([F:20])([F:19])[C:9]1[CH:10]=[C:11]([C:15]#[C:16][C:17]#[N:18])[CH:12]=[CH:13][CH:14]=1>CO>[F:7][C:8]([F:19])([F:20])[C:9]1[CH:10]=[C:11]([C:15]2[O:3][N:2]=[C:17]([NH2:18])[CH:16]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: NO
Reactant: N#CC#Cc1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1cc(-c2cccc(C(F)(F)F)c2)on1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Hydroxylamine hydrochloride (1.6 grams), and sodium hydroxide (1.6 grams) were dissolved in 32 ml. of a 1:1 mixture of water and methanol at 0°-5° C. 3-(3-(Trifluoromethyl)phenyl)propiolonitrile (2.8 grams) in 10 ml. of methanol was added portionwise, and the reaction mixture was stirred overnight (about 18 hours) at 25° C. Solvent was evaporated; water was added to the residue and the product extracted with ether, washed with water, dried and evaporated, yield 1.4 grams. The identity of the desired product was confirmed by NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=2)=[C:19]2[C:14]([NH:15][C:16](=[O:29])[N:17]([CH3:28])[C:18]2=[O:27])=[N:13]1.Br[CH2:31][C:32]1[C:33]([CH3:38])=[N:34][O:35][C:36]=1[CH3:37].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=2)=[C:19]2[C:14]([N:15]([CH2:31][C:32]3[C:33]([CH3:38])=[N:34][O:35][C:36]=3[CH3:37])[C:16](=[O:29])[N:17]([CH3:28])[C:18]2=[O:27])=[N:13]1
Reactant: Cc1noc(C)c1CBr
Reactant: Cn1ccnc1-c1c2c(=O)n(C)c(=O)[nH]c2nn1Cc1c[nH]c2ccc(Cl)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1noc(C)c1Cn1c(=O)n(C)c(=O)c2c(-c3nccn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21

Procedure:
This compound was synthesized by the reaction of 2-[(5-chloro-1H-indol-3-yl)methyl]-5-methyl-3-(1-methyl-1H-imidazol-2-yl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione and 4-(bromomethyl)-3,5-dimethylisoxazole using potassium carbonate as a base in DMF at 80° C. Mass: 519.01 (M+H).
Reaction SMILES: [C:1]1([CH:7]2[C:16]3[O:15][C:14](=O)[NH:13][C:12](=[O:18])[C:11]=3[CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[NH4+:20]>>[C:1]1([CH:7]2[C:16]3[NH:20][C:14](=[O:15])[NH:13][C:12](=[O:18])[C:11]=3[CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=c1[nH]c(=O)c2c(o1)C(c1ccccc1)CCC2
Reactant: [NH4+]
Agent: [OH-]
Product: O=c1[nH]c2c(c(=O)[nH]1)CCCC2c1ccccc1
Yield: 100 %

Procedure:
A solution of 8-phenyl-5,6,7,8-tetrahydro-2H-benzo[e][1,3]oxazine-2,4(3H)-dione (415.0 mg, 1.706 mmol) in concentrated ammonium hydroxide (35 mL, 899 mmol) was stirred at 100° C. in a high-pressure vessel (75 mL) for 6 h. The formation of white precipitate was observed during the heating. The LC/MS analysis of the filtrate shows the presence of the product with the desired mass (M+H)=243.20. The solvent was removed in vacuum to provide 8-phenyl-5,6,7,8-tetrahydroquinazoline-2,4(1H,3H)-dione (435 mg, 1.706 mmol, 100% yield) as off-white solid. LC-MS (M+H)+=243.2. 1H NMR (500 MHz, DMSO-d6) δ ppm 10.2 (2H, br. s.), 7.34 (2H, t, J=7.5 Hz), 7.26 (1H, t, J=7.3 Hz), 7.14 (2H, d, J=7.3 Hz), 3.80 (1H, br. s.), 2.32-2.43 (1H, m), 2.15 (1H, ddd, J=16.9, 10.5, 6.1 Hz), 1.93-2.04 (1H, m), 1.67-1.75 (1H, m), 1.56 (1H, ddd, J=7.8, 5.2, 2.6 Hz), 1.36 (1H, dt, J=13.1, 2.7 Hz).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]([OH:12])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O[C:14]1[CH:15]=[C:16]([CH:21]=[C:22]([O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)[CH:23]=1)[C:17]([O:19][CH3:20])=[O:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[Si:1]([O:8][CH2:9][C@H:10]([CH3:11])[O:12][C:14]1[CH:15]=[C:16]([CH:21]=[C:22]([O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)[CH:23]=1)[C:17]([O:19][CH3:20])=[O:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@@H](O)CO[Si](C)(C)C(C)(C)C
Reactant: COC(=O)c1cc(O)cc(Oc2ccc(S(C)(=O)=O)cc2)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c1
Reaction time: 3 h
Yield: 87.3 %

Procedure:
(2R)-1-{[tert-Butyl(dimethyl)silyl]oxy}propan-2-ol (2.18 g, 11.47 mmol) was added to a solution of methyl 3-hydroxy-5-[4-(methylsulfonyl)phenoxy]benzoate (2.76 g, 8.57 mmol) in dry DCM (100 mL) followed by addition of polymer-supported triphenylphosphine (3.0 mmol/g (Fluka), 8.57 g, 25.71 mmol) and DIAD (3.37 mL, 17.1 mmol) at RT. The reaction was stirred for 3 h before filtration through diatomaceous earth and evaporation. Purification by column chromatography, eluting with 1:4 to 1:2 ethyl acetate:hexanes, afforded the title compound as a colourless oil (3.70 g, 87%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[C:6]([NH2:9])[CH:5]=[CH:4][N:3]=1.[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[N+](C1C=CC=CC=1)([O-])=O.O.[O-2].[O-2].[O-2].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.[Al+3].[Al+3]>>[Cl:1][C:2]1[C:7]2[N:8]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:9][C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccnc(Cl)c1N
Reactant: O=Cc1ccccc1
Agent: O=[Si]=O
Agent: [Al+3]
Agent: [O-2]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O
Product: Clc1nccc2[nH]c(-c3ccccc3)nc12
Temperature: 175 °C
Reaction time: 0.5 h

Procedure:
A mixture of 100 mg (0.696 mmol) of 2-chloropyridine-3,4-diamine [H. Dvorakova et al., Collect. Czech. Chem. Commun., 58, 629 (1993)], 0.086 mL (0.835 mmol) of benzaldehyde, and 2 mL of nitrobenzene was heated at 175° C. under microwave irradiation for 30 min. The cooled solution was treated with 500 mg of Montmorillonite K 10 clay, and microwave irradiation at 175° C. was continued for an additional 30 min. The cooled mixture was filtered through Celite, and the filter cake was washed with methanol. The combined filtrate and washings were concentrated to dryness. Flash chromatography of the residue on silica gel (0-5% methanol in dichloromethane) yielded the title compound as a foam. LC-MS 230 (M+1).
Reaction SMILES: [NH2:1]/[C:2](/[C:10]([F:13])([F:12])[F:11])=[C:3](/[F:9])\[C:4]([O:6]CC)=O.[Cl:14][C:15]1[C:20]([O:21][CH:22]([CH3:24])[CH3:23])=[CH:19][C:18]([N:25]=[C:26]=[O:27])=[C:17]([F:28])[CH:16]=1>>[Cl:14][C:15]1[C:20]([O:21][CH:22]([CH3:23])[CH3:24])=[CH:19][C:18]([N:25]2[C:4](=[O:6])[C:3]([F:9])=[C:2]([C:10]([F:11])([F:12])[F:13])[NH:1][C:26]2=[O:27])=[C:17]([F:28])[CH:16]=1
Reactant: CC(C)Oc1cc(N=C=O)c(F)cc1Cl
Reactant: CCOC(=O)/C(F)=C(\N)C(F)(F)F
Product: CC(C)Oc1cc(-n2c(=O)[nH]c(C(F)(F)F)c(F)c2=O)c(F)cc1Cl

Procedure:
using ethyl 3-amino-2,4,4,4-tetrafluorocrotonate and 4-chloro-2-fluoro-5-isopropoxyphenyl isocyanate there is obtained 3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-5-fluoro-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione, m.p. 133°-135° C.