Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:9]([OH:11])=O)=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].S(Cl)(Cl)=O.[CH2:16]([N:18](CC)[CH2:19]C)C.CNC>ClCCl.CN(C=O)C>[CH3:16][N:18]([CH3:19])[C:9]([C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:8][NH:7][N:6]=1)=[O:11]
Reactant: CCN(CC)CC
Reactant: O=C(O)c1n[nH]cc1[N+](=O)[O-]
Agent: CNC
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CN(C)C(=O)c1n[nH]cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 24 h
Yield: 29.7 %

Procedure:
A solution of 4-nitro-1H-pyrazole-3-carboxylic acid (1.0 g, 6.4 mmol) in dichloromethane (20 ml) was treated with thionyl chloride (1.4 ml, 19 mmol) and a drop of DMF at ambient temperature. The reaction mixture is stirred at 40° C. overnight whereupon another equivalent of thionyl chloride (0.46 ml, 6.4 mmol) was added and stirring was continued at 40° C. for another 24 h. All volatiles were removed and the acid chloride was suspended in dichloromethane (6 ml) and cooled to 0° C. Triethylamine (4.44 ml, 31.8 mmol) and dimethylamin (4.14 ml, 2M solution in THF) were added. The reaction mixture was allowed to warm-up to ambient temperature and stirring was continued for 3 h. The reaction mixture was partitioned between potassium hydrogen sulfate (20 ml, 10% aqueous solution) and ethyl acetate (40 ml) and extracted. The organic phase was washed with water and brine, dried and the solvent was evaporated. The crude product was triturated with diethylether, sucked off and dried to yield a light brown solid (0.35 g, 30%).
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:13]=[CH:14][C:15]3[C:21]([CH2:23][O:24][CH3:25])([CH3:22])[CH2:20][CH2:19][CH2:18][S:17][C:16]=3[CH:26]=2)=[CH:6][CH:5]=1.[OH-].[Na+]>C1COCC1.C(O)C>[CH3:25][O:24][CH2:23][C:21]1([CH3:22])[CH2:20][CH2:19][CH2:18][S:17][C:16]2[CH:26]=[C:12]([C:11]#[C:10][C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:27])=[O:2])=[CH:9][CH:8]=3)[CH:13]=[CH:14][C:15]1=2
Reactant: COCC1(C)CCCSc2cc(C#Cc3ccc(C(=O)OC)cc3)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COCC1(C)CCCSc2cc(C#Cc3ccc(C(=O)O)cc3)ccc21
Reaction time: 18 h
Yield: 92.7 %

Procedure:
316 mg (0.83 mmol) of 4-(5-methoxymethyl-5-methyl-2,3,4,5-tetrahydrobenzo[b]thiepin-8-ylethynyl)-benzoic acid methyl ester was dissolved in 8 ml of THF/EtOH (1/1) and treated with 1.38 ml of 3N NaOH (5 eq.). The reaction flask was kept in the dark and stirring continued for 18 h at room temperature. The mixture was then poured onto crushed ice/ HCl, extracted twice with diethylether, the organic phase was washed with brine, dried over magnesium sulfate, filtrated and evaporated to dryness. Crystallization of the residue from hexane/ethylacetate yielded 282 mg of the title product as white crystals of m.p. 182-183° C.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:9](=[O:10])[N:8]([CH3:11])[C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=2[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]1=2.[C:20](O)(=[O:24])[C@H:21]([CH3:23])[OH:22]>>[OH:22][C@@H:21]([CH3:23])[C:20]([NH:2][C@@H:3]1[C:9](=[O:10])[N:8]([CH3:11])[C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=2[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]1=2)=[O:24]
Reactant: CN1C(=O)[C@@H](N)c2ccccc2-c2ccccc21
Reactant: C[C@H](O)C(=O)O
Agent: Cl
Product: C[C@H](O)C(=O)N[C@@H]1C(=O)N(C)c2ccccc2-c2ccccc21

Procedure:
The title compound, MS: m/e=311.3 (M+H+), was prepared in analogy to example 1a) from (−)-(S)-7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one hydrochloride and L-(+)-lactic acid.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([CH2:8][C@H:9]([NH2:17])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7])([CH3:4])[CH3:3].[C:18]([O:22][C:23](=[O:52])[CH2:24][CH:25]([CH2:29][CH2:30][CH2:31][S:32][C:33]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:26](O)=[O:27])([CH3:21])([CH3:20])[CH3:19].C1C=CC2N(O)N=NC=2C=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:13]([O:12][C:10](=[O:11])[CH:9]([NH:17][C:26](=[O:27])[CH:25]([CH2:24][C:23]([O:22][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:52])[CH2:29][CH2:30][CH2:31][S:32][C:33]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[CH2:8][C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)CC(CCCSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)C[C@H](N)C(=O)OC(C)(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CC(CCCSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Yield: 86.4 %

Procedure:
To H-Asp (OtBu)-OtBu hydrochloride salt (28 mg, 0.10 mmol) in dry DMF (2 mL) was sequentially added at room temperature 2-(3-tritylsulfanyl-propyl)-succinic acid 4-tert-butyl ester (50 mg, 0.10 mmol), HOBt (14 mg, 0.10 mmol), PYBOP (56 mg, 0.11 mmol) and DIPEA (37 μL, 0.20 mmol). The usual aqueous work up yielded the title compound (62 mg, 86%) as a colorless residue: 1H NMR (CDCl3, 400 MHz) δ 7.41–7.38 (m, 6H), 7.29–7.25 (m, 6H), 6.60–6.57 (m, 1H), 4.68–4.56 (m, 1H), 3.18–3.14 (m, 2H), 2.89–2.80 (m, 1H), 2.74–2.52 (m, 2H), 2.43–2.36 (m, 1H), 2.32–2.19 (m, 1H), 2.12–2.07 (m, 2H), 1.83–1.80 (m, 2H), 1.60–1.53 (m, 1H), 1.45–1.40 (m, 27H); 13C (DEPT) (CDCl3, 100 MHz) δ 129.4, 127.7, 126.4, 49.0, 48.7, 46.1, 42.5, 37.8, 37.6, 37.2, 31.6, 31.5, 29.6, 27.9, 27.8, 27.7, 26.3, 26.2, 26.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=3)=[CH:14][CH:13]=2)=[O:10])=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30].[NH2:33][CH2:34][CH2:35][CH2:36][CH2:37][OH:38]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([NH:33][CH2:34][CH2:35][CH2:36][CH2:37][OH:38])[N:20]=3)=[CH:14][CH:13]=2)=[O:10])=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30]
Reactant: NCCCCO
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)n1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Oc2ccnc(NCCCCO)n2)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 216 mg (0.444 mmol) 1-(4-Chloro-3-trifluoromethyl-phenyl)-3-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-phenyl]-urea, 87.0 mg (0.976 mmol) 4-amino-butan-1-ol and 5 ml THF was stirred at r.t. for 12 h. The reaction mixture was evaporated and the residue purified by chromatography on silica (dichloromethane/ethanol 96:4). Yield 127 mg (58%) of the title compound.
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:6][C:5]=1[OH:16])([O-])=O.[N+](C1C=CC(O)=CC=1C1C=CN=CC=1)([O-])=O.[N+](C1C(C2C=CN=CC=2)=CC=CC=1O)([O-])=O>>[N:13]1[CH:14]=[CH:15][C:10]([C:7]2[CH:6]=[C:5]([OH:16])[CH:4]=[CH:9][CH:8]=2)=[CH:11][CH:12]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccncc2)cc1O
Agent: O=[N+]([O-])c1c(O)cccc1-c1ccncc1
Agent: O=[N+]([O-])c1ccc(O)cc1-c1ccncc1
Product: Oc1cccc(-c2ccncc2)c1

Procedure:
B-2. 2-Nitro-5-(4-pyridinyl)phenol--This compound along with two other isomers, namely, 4-nitro-3-(4-pyridinyl)phenol and 2-nitro-3-(4-pyridinyl)phenol (Example B-3), were all obtained when 3-(4-pyridinyl)phenol was nitrated as in Example B-1. To an ice cold mixture of 242 g. of 3-(4-pyridinyl)phenol and 1 liter of glacial acetic acid was added with stirring a solution containing 60 ml. of concentrated nitric acid in 200 ml. of glacial acetic acid over a 40 minutes period, maintaining the reaction temperature between 10°-15° C. The reaction mixture was stirred at room temperature for 1 hour, next gently heated on a steam bath for 4 hours and then allowed to stand at ambient temperature for 16 hours. The reaction mixture was concentrated on a rotary evaporator to remove about 700 ml. of acetic acid. The resulting slurry was poured into 1 liter of water and was neutralized by adding aqueous ammonium hydroxide. The resulting solid was collected, washed with water and dried at 80° C. It was crystallized from acetic acid (2 l.), collected and dried at 80° C. to produce 50.4 g. of 4-nitro-3-(4-pyridinyl)phenol, m.p.>300° C. The mother liquor was concentrated to give another 34 g. of crude 4-nitro-3-(4-pyridinyl)phenol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[C:9](=[N:15]O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.C(O)(=O)C.O>C(O)C.[Zn]>[NH2:15][CH:9]([C:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)=[O:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc(Br)cc1
Agent: [Zn]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(N)C(=O)c1ccc(Br)cc1
Temperature: 1 °C
Reaction time: 0.08 h

Procedure:
Step C″: Dissolve ethyl 3-(4-bromophenyl)-2-(hydroxyimino)-3-oxopropanoate (12.8 kg dry mass (15.75 kg wet), 42.65 mol, 1 eq, prepared in step B above) in ethanol (110 L) in a 400-L vessel at an internal temperature of 20° C. Cool the solution to an internal temperature of 1° C. over 20 min and add zinc dust (6.429 kg, 98.01 mol, 2.3 eq) portion-wise over 30 min at an internal temperature of 2 to 3° C. Prepare a solution of acetic acid (19.5 L), water (2.5 L), and ethanol (11.5 L) in a feeder. Add about 1 to 2% of the solution to the zinc suspension at 0° C. After 5 min, no exotherm is observed. Add another 1 to 2% of the solution. A rise of temperature could be observed. Add the rest of the solution, slowly in the beginning but continuously over 95 min at an internal temperature of −2 to 2° C. Cool the suspension to an internal temperature of −5° C. and stir for 15 min. to provide the title compound.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:17]([O-])=O)=[C:9]([CH:16]=1)[C:10]([O:12]C(C)C)=[O:11])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C>[CH:1]([O:4][C:5]1[CH:16]=[C:9]([C:10]([OH:12])=[O:11])[C:8]([NH2:17])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)c1cc(OC(C)C)ccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Oc1ccc(N)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
74.0 G. of 5-isopropoxy-2-nitrobenzoic acid, isopropyl ester was dissolved in 650 ml. of ethanol and 145 ml. of 4 N sodium hydroxide solution. This solution was allowed to stir at room temperature for 16 hours. The reaction mixture was diluted with 2.0 l. of water and washed three times with 1 l. of dichloromethane. The aqueous layer was then acidified to pH<2 with concentrated hydrochloric acid and extracted three times with 1.0 l. of ether. The combined ether extracts were washed with 1.0 l. of saturated brine, dried over anhydrous sodium sulfate, filtered through Celite and evaporated to an orange oil (65.9 g.) which solidified on cooling, mp 129°-131°. The above solid was dissolved in 1.0 l. of ethyl acetate and hydrogenated, using 3.1 g. of 10% palladium on carbon as catalyst. When hydrogen uptake had ceased, the catalyst was removed by filtration and the filtrate was evaporated to a yellow solid, 49.5 g. (mp 120°-122° ).
Reaction SMILES: [N:1]1([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5][CH:4]([C:7]([O:9]C)=[O:8])[CH2:3][CH2:2]1.[Li+].[OH-].CO.O>C1COCC1>[C:14]([O:13][C:11]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reaction time: 8 h
Yield: 100.3 %

Procedure:
A mixture of 1-tert-butyl 4-methyl piperidine-1,4-dicarboxylate (4.84 g 20 mmol), and LiOH (2.52 g, 60 mmol) in THF (90 mL)/MeOH (90 mL)/H2O (30 mL) was stirred at r.t overnight. Then the solvents were removed, and the pH of the residue was adjusted to 2 by using 2N HCl. The resulting mixture was extracted with EtOAc (3×20 mL). The combined organic layers were dried over Na2SO4, and concentrated to give 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (4.6 g, yield 100.0%).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[NH3:12]>CO>[N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[NH:12])([O-:3])=[O:2]
Reactant: N
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Solvent: CO
Product: N=Cc1ccccc1[N+](=O)[O-]
Yield: 75.3 %

Procedure:
To a solution of 15.1 g (0.1 mole) of 2-nitrobenzaldehyde and 40 ml of methanol a methanolic solution of 1.7 g (0.1 mole) of ammonia is added dropwise under stirring. The reaction mixture is stirred at room temperature for 20 hours, then cooled, the precipitated product is filtered, washed with methanol and dried. Thus 11.3 g of trimeric 2-nitro-benzaldehyde-imine are obtained, yield 75.3%, m. p.: 117°-119° C.
Reaction SMILES: [ClH:1].FC1C=C(C(C(NC2C=CC(F)=CC=2)=O)C(N)=O)C=CC=1[O:9][C:10]1[C:15]2=[C:16](C)[C:17](OCCN3CCOCC3)=[CH:18][N:14]2[N:13]=[CH:12][N:11]=1>C(N)=O>[Cl:1][C:16]1[CH:17]=[CH:18][N:14]2[C:15]=1[C:10](=[O:9])[NH:11][CH:12]=[N:13]2
Reactant: Cc1c(OCCN2CCOCC2)cn2ncnc(Oc3ccc(C(C(N)=O)C(=O)Nc4ccc(F)cc4)cc3F)c12
Reactant: Cl
Solvent: NC=O
Product: O=c1[nH]cnn2ccc(Cl)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.2 %

Procedure:
A solution of methyl 1-amino-3-chloro-1H-pyrrole-2-carboxylate (10.0 g, 57.3 mmol, WO 03/099286: Compound A of Example 9) in formamide (40 mL) was heated at 170° C. for 1 h and then at 190° C. for 1 h. Upon cooling to room temperature, the mixture solidified. The product was purified by recrystallization from ethyl acetate to give the title compound (6.53 g, 67%) as a white solid. 1H NMR (CDCl3) δ 10.24 (br s, 1H), 7.48 (d, 1H, J=3.6 Hz), 7.29 (d, 1H, J=2.8 Hz), 6.47 (d, 1H, J=2.8 Hz); MS(ESI+) m/z 170.1 (M+H)+.
Reaction SMILES: [Na].[OH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.F[C:10]1N=[CH:16][CH:15]=[CH:14][C:11]=1[C:12]#[N:13].[C:18](OCC)(=O)C.C([O-])(O)=O.[Na+]>CN(C)C=O>[N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][C:14]2[CH:15]=[CH:16][CH:18]=[CH:10][C:11]=2[C:12]#[N:13])[CH:4]=1
Reactant: Oc1cccnc1
Reactant: CCOC(C)=O
Reactant: N#Cc1cccnc1F
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: N#Cc1ccccc1Oc1cccnc1
Temperature: 100 °C

Procedure:
To a solution of 3-hydoxypyridine sodium salt (purchased from Acros) (2.54 g, 26.71 mmol) in N,N-dimethyl formamide (50 mL) was added 2-fluoronicotinonitrile (3.32 g, 26.68 mmol) dropwise and the solution was heated at 100° C. for 2 hours. To the reaction mixture was added ethyl acetate (100 mL) and 1M NaHCO3 (150 mL) and it was filtered to remove black tar. The filtrate was decolorized with activated charcoal and extracted with ethyl acetate (3×30 ml). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The crude product was purified by flash column chromatography on silica gel using dichloromethane to give the title compound. MS (ESI+) m/z 197 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH3:11])[C:3](=[O:10])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1.[Br:13]Br>>[Br:13][CH:4]([N:5]1[CH:9]=[N:8][CH:7]=[N:6]1)[C:3](=[O:10])[C:2]([CH3:12])([CH3:11])[CH3:1]
Reactant: CC(C)(C)C(=O)Cn1cncn1
Reactant: BrBr
Product: CC(C)(C)C(=O)C(Br)n1cncn1

Procedure:
Thus, for example, 3,3-dimethyl-1-(4-methoximino-methyl-phenoxy)-1-(1,2,4-triazol-1-yl)-butan-2-one formula ##STR11## can be prepared by reacting 3,3-dimethyl-1-(1,2,4-triazol-1-yl)-butan-2-one initially with bromine to form 1-bromo(1,2,4-triazol-1-yl)-3,3-dimethyl-butan-2-one and subsequently reacting this with 4-hydroxybenzaldehyde O-methyloxime ether in the presence of a base. This synthesis can be illustrated by the formulae as follows:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[NH2:6].C(=O)([O-])[O-].[K+].[K+].[CH2:18](O)[CH2:19]C>>[CH2:1]([O:2][C:3](=[O:11])[C:4]1[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[NH2:6])[CH2:18][CH3:19]
Reactant: COC(=O)c1ccccc1N
Reactant: CCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCOC(=O)c1ccccc1N
Yield: 0.2 %

Procedure:
453 parts of anthranilic acid methyl ester are reacted with 900 parts of n-propanol and 15 parts of potassium carbonate according to Example 1. The reaction lasts for about ten hours. There are obtained 495 parts of anthranilic acid-n-propyl ester (boiling point 128°-131° C. at 3-5 mm Hg; nD25 1,551; containing according to gas chromatography less than 0.2% of anthranilic acid methyl ester). The yield is 92% of the theory.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1.[OH-].[Na+].[CH3:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15]>CC(C)=O.O>[CH3:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([NH:1][C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1)=[O:15]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: Cc1cccc(N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: Cc1cccc(NC(=O)c2ccccc2C)c1
Temperature: 20 °C
Yield: 96.6 %

Procedure:
m-Toluidine (1772 g) is dissolved in acetone (3.5 L), and thereto is added a solution of sodium hydroxide (648 g) in water (6.25 L), and the mixture is cooled to around 20° C. To the mixture is added o-methylbenzoyl chloride (2507 g) over a period of about 20 minutes with stirring, by which the temperature of the reaction mixture raises to around 60° C. After stirring for about one hour, the reaction mixture is cooled around 10° C. and the resulting crystals are taken by filtration. The crystalline product is washed 2 times with methanol/water (4:1, 3.75 L), and dried at about 60° C. to give the desired product (3530 g, yield 96.62%).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=O)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[S:27]=[C:28]1[NH:32][C:31](=[O:33])[CH2:30][S:29]1>>[F:26][C:2]([F:1])([F:25])[C:3]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:17][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:30]3[S:29][C:28](=[S:27])[NH:32][C:31]3=[O:33])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: O=C1CSC(=S)N1
Reactant: O=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1
Product: O=C1NC(=S)SC1=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1

Procedure:
5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-thioxo-thiazolidin-4-one was prepared from 1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde and 2-thioxo-thiazolidin-4-one following General Procedure B.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=O)[O:4][C:2]2=[O:3].[N+:13]([C:16]1[CH:24]=[CH:23][C:19](C(Cl)=O)=[CH:18][CH:17]=1)([O-:15])=[O:14]>N1C=CC=CC=1>[N+:13]([C:16]1[CH:24]=[CH:23][C:19]([C:5]2[O:4][C:2](=[O:3])[C:1]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=2)=[CH:18][CH:17]=1)([O-:15])=[O:14]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: c1ccncc1
Product: O=c1oc(-c2ccc([N+](=O)[O-])cc2)nc2ccccc12
Temperature: 50 °C
Yield: 78.4 %

Procedure:
A 300 ml. flask equipped with a reflux condenser and a stirrer was charged with 16.3 g of isatoic anhydride and 150 ml of pyridine. They were stirred at about 50° C. to dissolve isatoic anhydride in pyridine. Then, 18.6 g of p-nitrobenzoylchloride was added in several portions over the course of about 10 minutes, and after the addition, the mixture was heated under reflux for 3 hours. The reaction mixture was cooled to 0° C. The precipitated crystals were separated by filtration, washed well with water, and dried at 120° C. for 4 hours by a hot air dryer. The resulting crystals were recrystallized from toluene to give 21 g of 2-p-nitrophenyl-3,1-benzoxazin-4-one.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[CH3:11][C:12]([O:15][C:16](=[O:27])[NH:17][CH2:18][CH2:19][C@@H:20]([OH:26])[C:21]1[S:22][CH:23]=[CH:24][N:25]=1)([CH3:14])[CH3:13].[H-].[Na+].C(OCC)(=O)C>CN(C)C=O.CCCC(C)C>[CH3:14][C:12]([O:15][C:16](=[O:27])[NH:17][CH2:18][CH2:19][C@@H:20]([O:26][C:4]1[CH:3]=[C:2]([Cl:1])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])[C:21]1[S:22][CH:23]=[CH:24][N:25]=1)([CH3:11])[CH3:13]
Reactant: N#Cc1ccc(Cl)cc1F
Reactant: CC(C)(C)OC(=O)NCC[C@@H](O)c1nccs1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCC(C)C
Product: CC(C)(C)OC(=O)NCC[C@@H](Oc1cc(Cl)ccc1C#N)c1nccs1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.6 %

Procedure:
To a solution of 4-chloro-2-fluorobenzonitrile (156 mg, 1 mmol) and [(3R)-3-hydroxy-3-(2-thiazolyl)propyl]carbamic acid 1,1-dimethylethyl ester (258 mg, 1 mmol) in dry dimethylformamide (3 ml), was added sodium hydride (60% dispersion in oil, 40 mg, 1 mmol) and the mixture was stirred at room temperature for 16 h. The reaction was quenched with methanol and partitioned between ethyl acetate and water. The combined extracts were washed with water (3×25 ml) and saturated brine solution, dried (magnesium sulphate) and concentrated in vacuo to leave a crude yellow gum. Flash chromatography (silica, 15% ethyl acetate in isohexane) gave 345 mg of a white solid (86%).
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9](=[O:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:12]([C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1)([CH3:14])[CH3:13].[OH-].[Na+].O>C(O)C>[CH:12]([C:15]1[CH:22]=[CH:21][C:18](/[CH:19]=[CH:10]/[C:9](=[O:11])/[CH:8]=[CH:7]/[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:17][CH:16]=1)([CH3:14])[CH3:13]
Reactant: CC(=O)/C=C/c1ccccc1
Reactant: CC(C)c1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)c1ccc(/C=C/C(=O)/C=C/c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 59 %

Procedure:
A mixture of 81.0 grams (0.555 mol) trans-4-phenyl-3-buten-2-one, 81.7 grams (0.552 mol) 4-isopropylbenzaldehyde, 12 mL of 10% sodium hydroxide, 150 mL water and 220 mL ethanol was stirred at ambient temperature for 15 hours. The crystalline product was collected by vacuum filtration to give 90.0 grams (59% of theoretical yield) of E,E-1-(p-isopropylphenyl)-5-phenyl-1,4-pentadien-3-one as a yellow solid. Melting point=76.0°-78.0° C. IR (KBr) 2960, 1655, 1595, 1345, 1195, 980, 820, 760, 695 cm-1 ; FDMS, m+ /z 276 (C20H2O). 1H NMR (CDCl3) d 7.74 (d, 2H, J=16 Hz), 7.59 (m, 2H) , 7.55 (d, 2H, J=8 Hz) , 7.39 (m, 3H) , 7.26 (d, 2H, J=8 Hz), 7.09 (d, 1H, J=16 Hz), 7.045 (d, 1H, J=16 Hz), 2.93 (septet, 1,H, J=7 Hz), 1.26 (d, 6H, J=7 Hz). Anal. Calcd. for C20H20O; C, 86.92;H, 7.29. Found: C, 86.87,H, 7.32.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:26])[CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24]Cl)=[CH:20][CH:19]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:27]([NH:34][CH2:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][CH2:16][C:15]([NH:14][C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)=[O:26])=[CH:19][CH:20]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NCc1ccccc1
Reactant: O=C(CCc1ccc(CCl)cc1)Nc1ccc(-c2ccc(Cl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(CCc1ccc(CNCc2ccccc2)cc1)Nc1ccc(-c2ccc(Cl)cc2)cc1
Reaction time: 24 h

Procedure:
A reaction mixture of 70 mg (0.18 mmol) of N-(4′-chlorobiphenyl-4-yl)-3-(4-chloromethylphenyl)propionamide, 16 mg (0.15 mmol) of benzylamine, and 41 mg (0.3 mmol) of potassium carbonate in 5 mL of acetone is agitated for 24 hours at reflux temperature. The reaction mixture is evaporated down. The residue is triturated with water and diisopropyl ether, suction filtered, and dried in the air. The residue is purified by column chromatography on silica gel (eluant: dichloromethane/ethanol/ammonia (30:1:0.1)). Yield: 23 mg (40% of theory); melting point: 176° C.; C29H27ClN2O (M=454.99); calc.: molecular ion peak (M+H)+: 455/57 (Cl); found: molecular ion peak (M+H)+: 455/57 (Cl).