Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[CH3:7][O:8][C:9](=[O:35])[CH:10]([NH:14][C:15](=[O:34])[CH:16]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=1)[CH:11]([CH3:13])[CH3:12].[C:36]1(B(O)O)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C1(C)C=CC=CC=1.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:7][O:8][C:9](=[O:35])[CH:10]([NH:14][C:15](=[O:34])[CH:16]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:21][CH:20]=1)[CH:11]([CH3:13])[CH3:12]
Reactant: COC(=O)C(NC(=O)C(COc1ccc(Br)cc1)NC(=O)OC(C)(C)C)C(C)C
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)C(NC(=O)C(COC1=CCC(c2ccccc2)C=C1)NC(=O)OC(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 63.6 %

Procedure:
A solution of 2 M Na2CO3 (4 mL) was added at room temperature under an atmosphere of Argon to a mixture of the compound obtained in Example 22, step f (401 mg, 0.848 mmol), Pd(PPh3)2Cl2 (154 mg, 0.22 mmol) and phenylboronic acid (145 mg, 1.1872 mmol) in toluene (10 mL) and the reaction was heated to reflux. After 5 h, the reaction was cooled to room temperature. The mixture was diluted with EtOAc, and washed with brine. The combined organic layers were dried over anhydrous NaSO4 and concentrated under vacuum. The residue was purified by silica gel column chromatography which gave the title compound as a white solid (255 mg, 64%).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8]P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:28]([C:30]1[C:38]2[C:33](=[CH:34][C:35]([Cl:40])=[CH:36][C:37]=2[Cl:39])[NH:32][C:31]=1[C:41]([O:43][CH2:44][CH3:45])=[O:42])=O>>[C:1]([O:5][C:6]([CH:8]=[CH:28][C:30]1[C:38]2[C:33](=[CH:34][C:35]([Cl:40])=[CH:36][C:37]=2[Cl:39])[NH:32][C:31]=1[C:41]([O:43][CH2:44][CH3:45])=[O:42])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1C=O
Product: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1C=CC(=O)OC(C)(C)C
Yield: 67.8 %

Procedure:
A solution of tertbutoxycarbonylmethyltriphenylphosphorane (5.33 g) and ethyl 3-formyl-4,6-dichloroindole-2-carboxylate (3 g) in dioxanlacetonitrile (1;1; 60 ml) was stirred at 60° for 7 hours. The solvent was evaported under reduced pressure and the residual oil was purified by chromatography, eluting with cyclohexane and ethyl acetate 7/3, to obtain the title compound (2,73 g) tlc EA/CH: 3/7; Rf=0.35.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[N:11]([CH2:19][CH:20]2[CH2:22][CH2:21]2)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][CH:3]=1.[C:23]([NH:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl>CN(C=O)C>[C:23]([NH:31][C:32]1[CH:33]=[CH:34][C:35]([C:36]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]3[CH2:10][C@H:9]3[N:11]([CH2:19][CH:20]3[CH2:22][CH2:21]3)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][CH:3]=2)=[O:37])=[CH:39][CH:40]=1)(=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)N(CC1CC1)[C@@H]1C[C@H]1c1ccc(N)cc1
Reactant: O=C(O)c1ccc(NC(=O)c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CC1CC1)[C@@H]1C[C@H]1c1ccc(NC(=O)c2ccc(NC(=O)c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
To a solution of tert-butyl [trans-2-(4-aminophenyl)cyclopropyl](cyclopropylmethyl)carbamate (90.9 mg), 4-benzamidobenzoic acid (87 mg) and 1-hydroxybenzotriazole (60.9 mg) in DMF (1.5 mL) was added N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (86 mg). The reaction mixture was stirred at room temperature for 2 hr, and poured into 0.5N hydrochloric acid. The mixture was extracted with ethyl acetate, and the extract was washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was washed with ethyl acetate/diisopropyl ether to give the title compound (98.0 mg).
Reaction SMILES: [Na].[OH:2][C:3]1[CH:4]=[C:5]([OH:10])[CH:6]=[C:7]([Br:9])[CH:8]=1.Cl[CH2:12][CH:13]([O:16][CH3:17])[O:14][CH3:15].[Cl-].[NH4+]>O.CN(C)C=O>[CH3:15][O:14][CH:13]([O:16][CH3:17])[CH2:12][O:2][C:3]1[CH:4]=[C:5]([OH:10])[CH:6]=[C:7]([Br:9])[CH:8]=1
Reactant: Oc1cc(O)cc(Br)c1
Reactant: COC(CCl)OC
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: COC(COc1cc(O)cc(Br)c1)OC
Temperature: 90 °C

Procedure:
The monosodium salt of 3-hydroxy-5-bromophenol (0.05 mole) and dimethylformamide (75 ml) are charged under nitrogen gas into a glass reaction vessel equipped with a mechanical stirrer, thermometer and additional funnel. The mixture is stirred until dissolved, and 1-chloro-2,2-dimethoxyethane (0.05 mole) is added dropwise over a period of about 20 minutes. After the addition is completed, the reaction mixture is heated at about 90° C. with stirring for a period of about 48 hours. After this time water (200 ml) is added, and the reaction mixture is neutralized with ammonium chloride. The reaction mixture is then extracted with chloroform, and the organic phase is separated from the aqueous phase. The organic phase is then stripped of solvent, leaving an oil. This oil is distilled under reduced pressure to yield the desired product 3-(2,2-dimethoxyethoxy)-5-bromophenol.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.O.[NH2:20][NH2:21]>>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([NH:20][NH2:21])[CH:11]=1
Reactant: NN
Reactant: Clc1cc(-c2ccccc2Cl)c2ccccc2n1
Solvent: O
Product: NNc1cc(-c2ccccc2Cl)c2ccccc2n1

Procedure:
In the manner given in Example 1, 2-chloro-4-(o-chlorophenyl)quinoline is reacted with hydrazine hydrate at reflux to give 4-(o-chlorophenyl)-2-hydrazinoquinoline.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17](Cl)=[O:18])[CH:15]=3)[C:10]([CH3:20])=[CH:9]2)=[CH:5][CH:4]=1.Cl.[CH3:24][NH:25][O:26][CH3:27].N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:27][O:26][N:25]([CH3:24])[C:17]([C:14]1[CH:15]=[C:16]2[C:11]([C:10]([CH3:20])=[CH:9][N:8]2[CH2:7][C:6]2[CH:21]=[CH:22][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:12][CH:13]=1)=[O:18]
Reactant: CNOC
Reactant: COc1ccc(Cn2cc(C)c3ccc(C(=O)Cl)cc32)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(Cn2cc(C)c3ccc(C(=O)N(C)OC)cc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
A stirred solution of 1-(4-methoxybenzyl)-3-methyl-1H-indole-6-carbonyl chloride [2.8 g, Reference Example 42(b)] in chloroform (90 ml) at 0° C. was treated with N,O-dimethylhydroxylamine hydrochloride (0.982 g) and pyridine (1.55 ml). The solution was stirred at room temperature for 1 hour then evaporated. The residue was partitioned between dichloromethane (100 ml) and brine (50 ml). The organic layer was dried over sodium sulphate then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and hexane (1:2, v/v) to yield the title compound (2.8 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[C:7]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][N:23]=2)(=[O:21])=[O:20])[N:6]=[C:5]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([C:35]([OH:37])=[O:36])[CH:30]=2)[N:4]=1.[C:38](=[O:50])([O:46][CH:47](Cl)[CH3:48])[O:39][CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>>[CH:40]1([O:39][C:38]([O:46][CH:47]([O:36][C:35]([C:31]2[CH:30]=[C:29]([C:5]3[N:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[O:16][CH3:17])=[C:7]([NH:18][S:19]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][N:23]=4)(=[O:21])=[O:20])[N:6]=3)[CH:34]=[CH:33][N:32]=2)=[O:37])[CH3:48])=[O:50])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: CC(Cl)OC(=O)OC1CCCCC1
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccnc(C(=O)O)c2)nc1OC
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccnc(C(=O)OC(C)OC(=O)OC3CCCCC3)c2)nc1OC

Procedure:
In analogy to example 77, from 4-[4-methoxy-5-(2-methoxy-phenoxy)-6-(5-methyl-pyridine-2-sulfonylamino)-pyrimidin-2-yl]-pyridine-2-carboxylic acid, product of example 21, and cyclohexyl 1-chlorethyl carbonate (synthesis described by A. Riondel et al., Tetrahedron, 1988, Vol. 44, 1619) there was obtained 4-[4-methoxy-5-(2-methoxy-phenoxy)-6-(5-methyl-pyridine-2-sulfonylamino)-pyrimidin-2-yl]-pyridine-2-carboxylic acid 1-cyclohexyloxycarbonyloxy-ethyl ester as a white solid. ISN mass spectrum, m/e 692.1 (M−1 calculated for C33H35N5O10S: 692).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:15])=[C:4]([CH:7]=[C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:9]=1[OH:10])[CH:5]=O.[C:16](#[N:20])[CH2:17][C:18]#[N:19]>>[Br:1][C:2]1[C:3]([CH3:15])=[C:4]([CH:7]=[C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:9]=1[OH:10])[CH:5]=[C:17]([C:16]#[N:20])[C:18]#[N:19]
Reactant: N#CCC#N
Reactant: Cc1c(C=O)cc(C(C)(C)C)c(O)c1Br
Product: Cc1c(C=C(C#N)C#N)cc(C(C)(C)C)c(O)c1Br

Procedure:
In a similar manner as described in Example 2 reaction of 3-bromo-5-tert-butyl-4-hydroxy-2-methyl-benzaldehyde and malononitrile gave 3-bromo-5-tert-butyl-4-hydroxy-2-methylbenzylidenemalononitrile m.p. 144°.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[CH:23])[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.I[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[C:23][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][S:32]([CH3:35])(=[O:33])=[O:34])[CH:26]=4)[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C#CC1(c2ccc(OC)c(OC3CCCC3)c2)CCCC(=O)C1
Reactant: CS(=O)(=O)Nc1cccc(I)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COc1ccc(C2(C#Cc3cccc(NS(C)(=O)=O)c3)CCCC(=O)C2)cc1OC1CCCC1
Temperature: 80 °C
Yield: 58.4 %

Procedure:
To a solution of the compound from Example 3 (E1) (0.2 g, 0.64 mmol) and 1-iodo-3-methanesulfonamidobenzene (0.19 g, 0.64 mmol) in triethylamine (5 mL) under an argon atmosphere was added trace tetrakis(triphenylphosphine)palladium(0), copper(I) iodide and triphenylphosphine. The mixture was heated at 80° C. for 0.3 h, was cooled to room temperature and was concentrated in vacuo. The residue was purified by flash chromatography, eluting with 1:1 hexanes/ethyl acetate, to provide the title compound as a tan solid (0.18 g, 58%), m.p. 59°-62° C.
Reaction SMILES: CN(C)C[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH:14]([CH3:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:13])=[CH:8][CH:7]=1.[CH2:23](C(C1C=CC=CC=1)C(=O)C1C=CC(O)=CC=1)C>>[CH2:21]([CH:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:12](=[O:13])[C:9]1[CH:10]=[CH:11][C:6]([O:5][CH3:4])=[CH:7][CH:8]=1)[CH3:23]
Reactant: CCC(C(=O)c1ccc(O)cc1)c1ccccc1
Reactant: CC(C(=O)c1ccc(OCCN(C)C)cc1)c1ccccc1
Product: CCC(C(=O)c1ccc(OC)cc1)c1ccccc1

Procedure:
4-(β-Dimethylaminoethoxy)-α-ethyldesoxybenzoin (b.p. 162° C./0.075 mm.) may be obtained from α-ethyl-4-hydroxydesoxybenzoin by an analogous procedure to that described below for the preparation of 4-(β-dimethylaminoethoxy)-α-methyldesoxybenzoin, and α-ethyl-4-hydroxydesoxybenzoin itself (m.p. 122°-124° C.) may be obtained from α-ethyl-4-methoxydesoxybenzoin by an analogous procedure to that described below for the preparation of 4-hydroxy-α-methyldesoxybenzoin.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][NH:22][CH:23]2[CH3:26])=[CH:18][CH:17]=1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:22]3[CH2:21][CH2:20][C:19]4[C:24](=[CH:25][C:16]([O:15][CH3:14])=[CH:17][CH:18]=4)[CH:23]3[CH3:26])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: COc1ccc2c(c1)C(C)NCC2
Product: COc1ccc2c(c1)C(C)N(C(=O)c1cc3ncc(Cl)cn3n1)CC2

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-Methoxy-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[O:11])[CH:5]=1.O.[OH-].[Li+].Cl>C1COCC1>[CH3:16][S:13]([NH:12][C:10]([C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([OH:17])=[O:2])=[O:11])(=[O:15])=[O:14]
Reactant: COC(=O)c1cccc(C(=O)NS(C)(=O)=O)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)NC(=O)c1cccc(C(=O)O)c1

Procedure:
A mixture of Example 32A (627 mg, 2.43 mmol) and lithium hydroxide monohydrate (112 mg, 2.67 mmol) in THF (15 mL) was stirred for 12 hours at room temperature after which the pH was adjusted to 6 by addition of 1 M HCl solution (3 mL, 3 mmol). The mixture was concentrated under reduced pressure, and the residue was partitioned between dichloromethane (30 mL) and H2O (10 mL). The aqueous layer was extracted with ethyl acetate (2×20 mL), and the combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure to provide a white powder as the titled compound. MS (EST) m/e 244 (M+H)+, 242 (M−H)−; 1H NMR (500 MHz, CD3OD) δ ppm 3.38 (s, 3 H) 7.64 (t, 1 H) 8.11 (m, 1 H) 8.27 (m, 1 H) 8.54 (m, 1 H).
Reaction SMILES: C(N(CC)CC)C.S(=O)(=O)(O)O.[C:13](#[N:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[N-:21]=[N+:22]=[N-:23].[Na+]>C1(C)C=CC=CC=1>[C:14]1([C:13]2[NH:23][N:22]=[N:21][N:20]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: c1ccc(-c2nnn[nH]2)cc1
Yield: 98 %

Procedure:
Into the same device as used in Example 1 were placed 6.58 g (0.065 mole) of triethylamine and 52 ml of toluene. To the mixture were added 3.19 g (0.033 mole) of concentrated sulfuric acid with stirring. Further added were 5.16 g (0.050 mole) of benzonitrile and 4.23 g (0.065 mole) of sodiumazide. The mixture was heated to a temperature from 95° to 100° C. to undergo a reaction for 7 hours. The same subsequent treatment as in Example 1 was conducted, giving 7.11 g (0.049 mole) of 5-phenyl-1H-tetrazole (yield 97.3% based on benzonitrile).
Reaction SMILES: [CH2:1]([N:3]1[C:8](=[O:9])[C@@H:7]2[C@@H:10]([C:13]([F:16])([F:15])[F:14])[O:11][CH2:12][C@:6]2([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[N:5]=[C:4]1[NH:24]C(=O)OC(C)(C)C)[CH3:2].[OH-].[Na+].[N+:34]([O-])([OH:36])=[O:35]>>[NH2:24][C:4]1[N:3]([CH2:1][CH3:2])[C:8](=[O:9])[C@@H:7]2[C@@H:10]([C:13]([F:14])([F:16])[F:15])[O:11][CH2:12][C@:6]2([C:17]2[CH:22]=[C:21]([N+:34]([O-:36])=[O:35])[CH:20]=[CH:19][C:18]=2[F:23])[N:5]=1
Reactant: O=[N+]([O-])O
Reactant: CCN1C(=O)[C@@H]2[C@@H](C(F)(F)F)OC[C@]2(c2ccccc2F)N=C1NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Product: CCN1C(=O)[C@@H]2[C@@H](C(F)(F)F)OC[C@]2(c2cc([N+](=O)[O-])ccc2F)N=C1N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
tert-Butyl ((4aS,5S,7aS)-3-ethyl-7a-(2-fluorophenyl)-4-oxo-5-(trifluoromethyl)-3,4,4a,5,7,7a-hexahydrofuro[3,4-d]pyrimidin-2-yl)carbamate (300 mg, 0.67 mmol) was taken up in fuming nitric acid (2 mL) at RT. The mixture was stirred at RT for 24 h, then poured on to ice and basified slowly with 50% aq. NaOH (˜3 mL). The aqueous mixture was extracted with DCM (×4). The combined extracts were dried by passing through a hydrophobic frit and then evaporated to give the title compound (200 mg, pale yellow foam). 1H NMR (400 MHz, CDCl3) δ ppm 1.21 (t, J=7.20 Hz, 3H) 3.69-3.80 (m, 1H) 3.83-3.94 (m, 2H) 4.29 (dd, J=8.08, 1.77 Hz, 1H) 4.41-4.50 (m, 2H) 4.67 (br. s., 2H) 7.25 (dd, J=10.61, 9.09 Hz, 1H) 8.23 (ddd, J=8.84, 4.04, 2.78 Hz, 1H) 8.32 (dd, J=6.69, 2.91 Hz, 1H).
Reaction SMILES: [O-]CC.[Na+].C(O)C.[Na].[C:9]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:10][C:11]([O-:13])=O.[C:18]1([NH:24][C:25]2[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=2[C:27]#[N:28])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[NH2:28][C:27]1[C:26]2[C:25](=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:11](=[O:13])[C:10]=1[C:9]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: N#Cc1ccccc1Nc1ccccc1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)c1c(N)c2ccccc2n(-c2ccccc2)c1=O
Yield: 51.7 %

Procedure:
Into a sodium ethoxide/ethanol solution which had been prepared from 2.07 g (90 mmol) of metallic sodium and 75 ml of anhydrous ethanol, 14.4 g (90 mmol) of ethyl malonate were added dropwise at room temperature. After the resultant mixture was stirred for 30 minutes as was, 5.82 g (30 mmol) of 2-phenylaminobenzonitrile were added and the mixture so obtained was heated under reflux for 48 hours. The reaction mixture was concentrated under reduced pressure, followed by the addition of ethyl acetate. The resulting solution was washed with water and was then dried. The solvent was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column and was then recrystallized from chloroform/hexane, whereby 4.78 g of ethyl 4-amino-2-oxo-1-phenyl-1,2-dihydro-quinoline-3-carboxylate (Compound No. 1) were obtained (yield: 51.7%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[CH2:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10].[C:18]1(=[O:28])[NH:22][C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12.[K].CN(C)C=O>O>[O:23]=[C:21]1[C:20]2[C:19](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:18](=[O:28])[N:22]1[CH2:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[CH2:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10]
Reactant: CCOP(=O)(Cc1cccc(CBr)c1)OCC
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(Cc1cccc(CN2C(=O)c3ccccc3C2=O)c1)OCC
Temperature: 25 °C
Reaction time: 14 h
Yield: 78.3 %

Procedure:
A mixture of diethyl [3-(bromomethyl)benzyl]phosphonate (10 g), potassium phthalimide (5.77 g) and N,N-dimethylformamide (100 ml) was stirred at room temperature for 14 hrs. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated Recrystallization of the residue from ethyl acetate-hexane gave diethyl {3-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]benzyl}phosphonate (9.40 g, 78%) as colorless prism crystals. melting point: 100-101° C.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:8]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:20]=3[OH:28])[CH2:11][CH2:10]2)=[CH:7][C:6](=[O:29])[N:5]([CH3:30])[C:4]1=[O:31].[CH2:32](Br)[CH:33]=[CH2:34].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH3:2][N:3]1[C:8]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:20]=3[O:28][CH2:34][CH:33]=[CH2:32])[CH2:11][CH2:10]2)=[CH:7][C:6](=[O:29])[N:5]([CH3:30])[C:4]1=[O:31]
Reactant: Cn1c(N2CCN(CCCOc3cc([N+](=O)[O-])ccc3O)CC2)cc(=O)n(C)c1=O
Reactant: C=CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: C=CCOc1ccc([N+](=O)[O-])cc1OCCCN1CCN(c2cc(=O)n(C)c(=O)n2C)CC1
Yield: 77.4 %

Procedure:
1 g of 1,3-dimethyl-6-{4-[3-(2-hydroxy-5-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione (Compound 145--free form), 0.31 g of allyl bromide and 0.36 g of potassium carbonate were suspended in 10 ml of dry acetone and heated under reflux for 5 hours. The reaction mixture was poured into 60 ml of water and then extracted three times with 30 ml portions of chloroform. The extract was washed first with a 0.5 N aqueous solution of sodium hydroxide and then with water. The chloroform solution was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by chromatography on a silica gel column (eluent: chloroform/methanol=20/1, by volume). The resulting oily substance was crystallized from ethanol, thereby obtaining 0.78 g of 1,3-dimethyl-6-{4-[3-(2-allyloxy-5-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione as crystals.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[CH:4]=O.[CH2:12]([NH2:16])[CH2:13][CH2:14][CH3:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:12](/[N:16]=[CH:4]/[C:3]1[C:6]([F:11])=[CH:7][CH:8]=[C:9]([Cl:10])[C:2]=1[Cl:1])[CH2:13][CH2:14][CH3:15]
Reactant: CCCCN
Reactant: O=Cc1c(F)ccc(Cl)c1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCC/N=C/c1c(F)ccc(Cl)c1Cl

Procedure:
Butyl-[1-(2,3-dichloro-6-fluoro-phenyl)-meth-(E)-ylidene]-amine was prepared from 2,3-dichloro-6-fluorobenzaldehyde, N-butylamine and p-toluenesulphonic acid in analogy to Example 191a): brown oil; 1H-NMR (CDCl3): 0.96 (3H, t, CH3), 1.39 (2H, sextet, CH2), 1.73 (2H, quintet, CH2), 3.71 (2H, q, CH2), 7.02 (1H, dd, ArH), 7.44 (1H, dd, ArH), 8.44 (1H, s, CH═N).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:13]([CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:12]2[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=2[N:10]=1.[C:27]([C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=1)#[CH:28].C(N(CC)CC)C>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)=[C:2]([C:28]#[C:27][C:29]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=2)[CH:7]=1
Reactant: Fc1cc2nc(-c3ccc(Cl)cc3Br)n(CC3CCCCC3)c2cc1F
Reactant: C#Cc1ccc(C#N)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1ccc(C#Cc2cc(Cl)ccc2-c2nc3cc(F)c(F)cc3n2CC2CCCCC2)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 18 %

Procedure:
To a solution of 2-(2-bromo-4-chloro-phenyl)-1-cyclohexylmethyl-5,6-difluoro-1H-benzoimidazole (600 mg, 1.36 mmol) in tetrahydrofuran (20 ml) was added 4-ethynyl-benzonitrile (173.4 mg, 1.36 mmol; CAS Reg. No. 3032-92-6), bis(triphenylphosphine)palladium(ii) dichloride (57.2 mg, 0.08 mmol), copper iodide (7.7 mg, 0.04 mmol) and triethyl amine (20 ml) at 25° C. The resulting mixture was degassed and back-filled with nitrogen three times. It was then allowed to stir at 80° C. for 16 h. The reaction mixture was filtered through a bed of celite and solvents were removed under reduced pressure. The residue was purified by column chromatography over silica gel (10% ethyl acetate/n-hexane) to afford the desired compound as a yellow solid (18%). MS (Turbo Spray): m/z=485.6 (M+H).