Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:7](I)=[CH:6][N:5]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[N:4]=1)#[N:2].C([Li])CCC.[F:26][C:27]([F:33])([F:32])[C:28](OC)=[O:29].O>O1CCCC1>[C:1]([C:3]1[C:7]([C:28](=[O:29])[C:27]([F:33])([F:32])[F:26])=[CH:6][N:5]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[N:4]=1)#[N:2]
Reactant: COC(=O)C(F)(F)F
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1I
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C(=O)C(F)(F)F
Temperature: 25 °C

Procedure:
To a stirred solution of 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodopyrazole (4.62 g) in tetrahydrofuran (100 ml) at -75° C. under an atmosphere of nitrogen was added, at such a rate that the temperature of the reaction mixture did not exceed -75° C., n-butyllithium (4.7 ml of a 2.5M solution in hexanes). A solution of methyl trifluoroacetate (1.93 ml) in tetrahydrofuran (5 ml) was then added at such a rate that the temperature of the reaction mixture did not exceed -75° C. Upon completion of the addition the mixture was allowed to warm to room temperature. Water (100 ml) was added and the mixture extracted twice with ethyl acetate (80 ml). The combined organic layers were dried (Na2SO4) and evaporated to give a brown gum which was purified by column chromatography on silica gel (250 g) eluted with dichloromethane. Combination and evaporation of suitable fractions gave the title compound as a pale yellow solid, m.p. 124-125° C.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([OH:15])=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.[CH2:16](Br)[CH2:17][CH2:18][CH2:19][CH3:20].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1
Reactant: CCCCCBr
Reactant: Oc1ccc2c(c1)Cc1cc(Br)ccc1-2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCOc1ccc2c(c1)Cc1cc(Br)ccc1-2
Yield: 87.6 %

Procedure:
A mixture of 2-bromo-7-hydroxyfluorene (18 g), pentyl bromide (15.1 g), potassium carbonate (26.6 g) and dimethylformamide (200 mL) was heated for 3 hours while refluxing. 6M-hydrochloric acid (100 mL) was added to the reaction solution, and the solution was extracted with toluene. The toluene layer was washed with water and then dried on anhydrous magnesium sulfate, and it was concentrated under reduced pressure. This concentrate was recrystallized from acetone to obtain 2-bromo-7-pentyloxyfluorene (20 g) of colorless needle crystal.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([Cl:18])=[CH:10][C:9]=1[NH:19][C:20](=[O:36])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:18][C:11]1[C:12]([C:14]([F:17])([F:16])[F:15])=[CH:13][C:8]2[N:7]=[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=4)[CH:24]=3)[CH2:21][C:20](=[O:36])[NH:19][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(C(F)(F)F)c(Cl)cc1NC(=O)CC(=O)c1cccc(-c2ccncc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-c3ccncc3)c2)=Nc2cc(C(F)(F)F)c(Cl)cc2N1

Procedure:
The title compound was prepared from {4-chloro-2-[3-oxo-3-(3-pyridin-4-yl-phenyl)-propionylamino]-5-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M92) (0.44 g, 0.82 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light orange solid (120 mg, 35%).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1N1N=CC=N1)=[O:11].CC1C=C[C:28]([N:34]2[CH:38]=[CH:37][C:36](C)=[N:35]2)=C(C=1)C(O)=O>>[OH:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:37]1[CH:36]=[N:35][N:34]([CH3:28])[CH:38]=1)=[O:11]
Reactant: Cc1ccc(-n2ccc(C)n2)c(C(=O)O)c1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CO)c1
Product: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CO)c1

Procedure:
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(hydroxymethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone in Example A106 using 5-methyl-2-(3-methyl-1H-pyrazol-1-yl)benzoic acid. MS (ESI) 328 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([C:14](=O)[C:15]2[CH:20]=[CH:19][N:18]=[C:17]([Br:21])[CH:16]=2)=[CH:10][C:11]=1[O:12][CH3:13])[C:6](O)=[O:7].O.[NH2:24][NH2:25]>C(O)C>[Br:21][C:17]1[CH:16]=[C:15]([C:14]2[C:9]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:11]([O:12][CH3:13])[CH:10]=3)[C:6](=[O:7])[NH:25][N:24]=2)[CH:20]=[CH:19][N:18]=1
Reactant: COc1cc(C(=O)O)c(C(=O)c2ccnc(Br)c2)cc1OC
Reactant: NN
Solvent: CCO
Solvent: O
Product: COc1cc2c(-c3ccnc(Br)c3)n[nH]c(=O)c2cc1OC

Procedure:
3,4-Dimethoxy-6-(2-bromoisonicotinoyl)benzoic acid (15.2 g) and hydrazine monohydrate (15 ml) are added to ethanol (30 ml), and the mixture is heated under reflux for one hour. The reaction mixture is cooled with ice, and the precipitates are collected by filtration to give 2-bromo-4-(6,7-dimethoxyphthalazin-1(2H)-on-4-yl)pyridine (14.1 g).
Reaction SMILES: C(OC(N=NC(OC(C)C)=O)=O)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:34][C:35]1[CH:45]=[C:44]([O:46][CH2:47][CH:48]=[C:49]([Cl:51])[Cl:50])[CH:43]=[C:42]([Cl:52])[C:36]=1[O:37][CH2:38][CH2:39][CH2:40][OH:41].O[C:54]1[CH:59]=[CH:58][C:57]([CH2:60][C:61](=[O:63])[CH3:62])=[CH:56][CH:55]=1>O1CCCC1>[Cl:34][C:35]1[CH:45]=[C:44]([O:46][CH2:47][CH:48]=[C:49]([Cl:51])[Cl:50])[CH:43]=[C:42]([Cl:52])[C:36]=1[O:37][CH2:38][CH2:39][CH2:40][O:41][C:54]1[CH:59]=[CH:58][C:57]([CH2:60][C:61](=[O:63])[CH3:62])=[CH:56][CH:55]=1
Reactant: OCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: CC(=O)Cc1ccc(O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)Cc1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Reaction time: 0.5 h

Procedure:
P4.1) At 0-2° C., 4.3 g of azodicarboxylic acid diisopropyl ester are added dropwise to 5.6 g of triphenylphosphine in 100 ml of tetrahydrofuran. After 30 minutes' stirring, a solution of 6.7 g of 3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propan-1-ol and 2.9 g of 1-(4-hydroxy-phenyl)-propan-2-one in 100 ml of tetrahydrofuran is added dropwise at 0-2° C. in the course of 45 minutes. After 2 hours at from 0 to 2° C. and 6 hours at room temperature, the reaction mixture is concentrated and the residue is purified over silica gel. 1-(4-{3-[2,6-Dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propoxy}-phenyl)-propan-2-one is obtained. 1H-NMR (CDCl3) 300 MHz: 2.16 (s, 3H), 2.30 (m, 2H), 3.63 (s, 2H), 4.17 (t, 2H), 4.27 (t, 2H), 4.58 (d, 2H), 6.11 (t, 1H), 6.83 (s, 2H), 6.90 (d, 2H), 7.11 (d, 2H)
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Br:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1>CN(C)C=O>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:23])[NH:1][C:2]2[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)=[CH:17][CH:16]=1
Reactant: O=C=Nc1ccc(Br)cc1
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1csc(NC(=O)Nc2ccc(Br)cc2)n1

Procedure:
Following a procedure similar to that described in Preparation 1, the desired compound was prepared from 10 g of ethyl 2-aminothiazol-4-ylglyoxylate, 8.7 g of p-bromophenyl isocyanate and 80 ml of dimethylformamide, as yellow crystals having the following physical properties.
Reaction SMILES: [CH2:1]([CH:3]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:14](Cl)(Cl)Cl)[CH3:2].[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[OH:29].C(N(CC)CC)C>C(O)C>[CH2:1]([CH:3]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:14]1[O:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=1)[CH3:2]
Reactant: Nc1ccccc1O
Reactant: CCCCC(CC)Cn1c(C(Cl)(Cl)Cl)nc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCCC(CC)Cn1c(-c2nc3ccccc3o2)nc2ccccc21

Procedure:
28.2 g (0.12 mol) of 1-(2-ethylhexyl)-2-trichloromethylbenzimidazole (prepared by reacting N-2-ethylhexyl-o-phenylenediamine with trichloroacetamido methyl ester), 13.1 g (0.12 mol) of o-aminophenol and 39.4 g (0.38 mol) of triethylamine in 150 ml of ethanol are stirred at room temperature for 15 hours. The ethanol is subsequently removed on a rotary evaporator, ethyl acetate is added to the residue which remains, and the mixture is washed with water and dried over sodium sulfate. 35% of product is identified by HPLC in the product mixture thus obtained; isolation can be carried out, for example, by column chromatography.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:18]1[C:23]([I:24])=[C:22]([CH:25]([Cl:27])[CH3:26])[N:21]=[CH:20][N:19]=1>C1(C)C=CC=CC=1>[Cl:27][CH:25]([C:22]1[N:21]=[CH:20][N:19]=[C:18]([NH:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:23]=1[I:24])[CH3:26]
Reactant: CC(Cl)c1ncnc(Cl)c1I
Reactant: NCCc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(Cl)c1ncnc(NCCc2ccccc2)c1I
Temperature: 60 °C

Procedure:
In 20 ml of toluene were dissolved 2-phenylethylamine (0.6 g) and triethylamine (0.6 g), then, 4-chloro-6-(1-chloro-ethyl)-5-iodopyrimidine (1.5 g) was added to the solution, and the mixture was heated at about 60° C. for 3 hours while stirring.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]#[N:27])[CH:21]=1)=[O:19]>>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:17]=1[C:18](=[O:19])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]#[N:27])[CH:21]=1
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Reactant: N#Cc1cccc(C(=O)CBr)c1
Product: CCOC(=O)n1c(C(=O)c2cccc(C#N)c2)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 4-chloro-2-(ethoxycarbonylamino)benzonitrile (Example 1, step 1) and 2-bromo-3′-cyanoacetophenone. 1H-NMR (CDCl3) δ: 8.21 (1H , d, J=1.8 Hz), 8.03 (1H, s), 7.94 (1H, m), 7.80-7.72 (1H, m), 7.63-7.52 (2H, m), 7.32 (1H, dd, J=8.4, 1.8 Hz), 6.10 (2H, brs), 3.88 (2H, q, J=7.3 Hz), 0.95 (3H, t, J=7.3 Hz).
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[NH:8][C:7]2[CH:9]=[CH:10][C:11]([NH:13][NH2:14])=[CH:12][C:6]=2[N:5]=1.[C:15]1([S:21]([N:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[C:25]2[C:33]([C:35](=[CH:38]N(C)C)[C:36]#[N:37])=[O:34])(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[NH2:37][C:36]1[N:13]([C:11]2[CH:10]=[CH:9][C:7]3[NH:8][C:4]([CH3:3])=[N:5][C:6]=3[CH:12]=2)[N:14]=[CH:38][C:35]=1[C:33]([C:25]1[N:24]([S:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:23])=[O:22])[C:32]2[C:27]([CH:26]=1)=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:34]
Reactant: CN(C)C=C(C#N)C(=O)c1cc2ccccc2n1S(=O)(=O)c1ccccc1
Reactant: Cc1nc2cc(NN)ccc2[nH]1
Agent: Cl
Solvent: CCO
Product: Cc1nc2cc(-n3ncc(C(=O)c4cc5ccccc5n4S(=O)(=O)c4ccccc4)c3N)ccc2[nH]1
Temperature: 25 °C
Yield: 91 %

Procedure:
(2-Methyl-1H-benzimidazol-5-yl)-hydrazine dihydrochloride (830 mg) was added to an ethanol solution (15 ml) of crude 2-(1-benzenesulfonyl-1H-indole-2-carbonyl)-3-dimethylamino acrylonitrile (1.17 g). The reaction mixture was heated with stirring under reflux for four hours. After cooling to room temperature, the mixture was allowed to stand at room temperature. The precipitated solid was collected by filtration, and washed with ethanol to give [5-amino-1-(2-methyl-1H-benzimidazol-5-yl)-1H-pyrazol-4-yl]-(1-benzenesulfonyl-1H-indol-2-yl)-methanone was obtained as a yellow solid (1.5 g, with a two-step yield of 91%).
Reaction SMILES: [F:1][C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[N:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:16]([O:18]C)=[O:17])[C:8](=[O:24])[C:7]=1[Br:25].[OH-].[Na+].CC#N.Cl>O>[F:1][C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[N:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:16]([OH:18])=[O:17])[C:8](=[O:24])[C:7]=1[Br:25]
Reactant: COC(=O)c1ccc(C)c(-n2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: Cc1ccc(C(=O)O)cc1-n1c(C)cc(OCc2ccc(F)cc2F)c(Br)c1=O
Temperature: 60 °C
Yield: 87.1 %

Procedure:
Methyl 3-(4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1(2H)-yl)-4-methylbenzoate (3) (3.4 kg, 7.1 moles), 2.5M NaOH (3.1 L. 7.8 moles), CH3CN (12 L) and 8.6 L water were mixed together and heated to 60° C., under nitrogen. Once the mixture became homogeneous the mixture was stirred for an additional hour. The reaction mixture was cooled to 20° C. and then treated with 865 ml concentrated HCl at a rate such that the temperature was maintained below 25° C. After the HCl addition was completed the mixture was stirred for another hour. The product was filtered and washed with 12 L CH3CN, dried to give 2.87 kg (87%) adduct. 1H NMR (300 MHz, CD3OD) δ 7.87 (dd, J=7.8, 1.6 Hz, 1H), 7.82 (d, J=1.8 Hz, 1H), 7.69 (q, J=8.1 Hz, 1H), 7.57 (d, J=8.1 Hz, 1H), 7.09 (dt, J=2.2, 8.6 Hz, 1H), 6.7 (s, 1H), 5.4 (s, 2H), 2.14 (s, 3H), 2.02 (s, 3H) (d, J=2.4 Hz, 1H), 3.94 (s, 3H), 2.15 (s, 3H), 1.91 (s, 3H). ES-HRMS m/z 464.0275 (M+H calcd for C21H17BrF2NO4 requires 464.0304). Anal. Cald. for C21H16BrF2NO4: C, 54.33; H, 3.47; N, 3.02. Found: C, 54.40; H, 3.42; N, 3.17
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=[O:11].[N+:13]([O-])([OH:15])=[O:14]>OS(O)(=O)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:13]([O-:15])=[O:14])=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=[O:11]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)Cc1ccc(F)cc1F
Agent: O=S(=O)(O)O
Product: O=C(O)Cc1cc([N+](=O)[O-])c(F)cc1F
Temperature: 0 °C
Reaction time: 0.58 h
Yield: 88 %

Procedure:
A 0° C. solution of (2,4-difluoro-phenyl)acetic acid (14.5 g, 0.084 mol) in H2SO4 (60 mL) was treated drop-wise with 69% HNO3 (6 mL), stirred at 0° C. for 35 min, then poured into ice water. The aqueous layer was extracted with EtOAc, and the organic extracts were washed with brine, dried (Na2SO4), concentrated in vacuo and purified by silica gel chromatography to give (2,4-difluoro-5-nitro-phenyl)acetic acid (16 g, 88% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.30 (t, J=8.0 Hz, 1H), 7.68 (m, 1H), 3.75 (s, 2H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[N+:10]([O-:12])=[O:11].[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][N:23]([C:2]2[N:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=2[N+:10]([O-:12])=[O:11])[CH2:22][CH2:21]1
Reactant: Cc1nc(Br)c([N+](=O)[O-])c(=O)[nH]1
Reactant: Fc1ccccc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(N2CCN(c3ccccc3F)CC2)c([N+](=O)[O-])c(=O)[nH]1

Procedure:
In analogy to the procedure described in example 1, the 6-bromo-2-methyl-5-nitro-3H-pyrimidin-4-one (as prepared in Eur. Pat. Appl. EP 1 074 549 A2) was treated with the (2-fluoro-phenyl)-piperazine in N,N-dimethylformamide in the presence of potassium carbonate at room temperature to yield the 6-[4-(2-fluoro-phenyl)-piperazin-1-yl]-2-methyl-5-nitro-3H-pyrimidin-4-one as yellow amorphous solid; MS: [M+H]+=334.
Reaction SMILES: CS[C:3](SC)=[C:4]1[C:13](=[O:14])[C:12]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:15][CH2:16][CH2:17][CH3:18])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:23].[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:29][C:28]=1[S:41]([NH2:44])(=[O:43])=[O:42]>C1(C)C=CC=CC=1>[CH2:34]([O:33][C:30]1[CH:31]=[CH:32][C:27]2[NH:26][C:3]([C:4]3[C:13](=[O:14])[C:12]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:15][CH2:16][CH2:17][CH3:18])[C:11]4[C:6]([C:5]=3[OH:23])=[CH:7][CH:8]=[CH:9][CH:10]=4)=[N:44][S:41](=[O:42])(=[O:43])[C:28]=2[CH:29]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1S(N)(=O)=O
Reactant: CCCCC1(CCCC)C(=O)C(=C(SC)SC)C(=O)c2ccccc21
Solvent: Cc1ccccc1
Product: CCCCC1(CCCC)C(=O)C(C2=NS(=O)(=O)c3cc(OCc4ccccc4)ccc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Yield: 83.1 %

Procedure:
A solution of the product of Example 5C (52 mg, 0.14 mmol) and the product of Example 2D (38 mg, 0.14 mmol) in toluene (12 mL) was stirred at reflux for 6 hours, cooled to 25° C. and concentrated in vacuo. The residue was triturated with ether-hexane and collected by filtration to give the title compound (65 mg, 84%). 1H NMR (300 MHz, CDCl3): δ 16.66 (m, 1 H), 14.33 (s, 1 H), 8.27 (d, J=8.09 Hz, 1 H), 7.66 (m, 1 H), 7.38 (m, 10 H), 5.14 (s, 2 H), 2.35 (m, 2 H), 1.96 (m, 2 H), 1.12 (m, 4 H), 0.89 (m, 2 H), 0.70 (m, 6 H), 0.55 (m, 2 H).
Reaction SMILES: [CH:1]1[C:6](N)=[CH:5][CH:4]=[C:3]([NH2:8])[CH:2]=1.[C:9]([O:12][C:13](=[O:15])[CH3:14])(=[O:11])[CH3:10]>>[CH:1]1[C:13]([CH2:14][C:6]2[CH:1]=[CH:2][C:3]([NH2:8])=[CH:4][CH:5]=2)=[CH:5][CH:4]=[C:3]([NH2:8])[CH:2]=1.[C:9]([O:12][C:13](=[O:15])[CH3:14])(=[O:11])[CH3:10]
Reactant: Nc1ccc(N)cc1
Solvent: CC(=O)OC(C)=O
Product: Nc1ccc(Cc2ccc(N)cc2)cc1

Procedure:
In a similar manner, if one substitutes for the reaction product of p-phenylene diamine and acetic anhydride in the above reaction, the compound resulting from the reaction of 4,4'-diaminodiphenylmethane and acetic anhydride, i.e., ##SPC13##
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[CH2:5][CH2:6][N:7]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:8](=[O:32])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[CH3:2]>N1CCCCC1.CN(C)C=O>[CH2:1]([O:3][C:4](=[O:39])[CH2:5][CH2:6][N:7]([C:8](=[O:32])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH3:2]
Reactant: CCOC(=O)CCN(CC(=O)OCC)C(=O)CCCCCNC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: CCOC(=O)CCN(CC(=O)OCC)C(=O)CCCCCN
Reaction time: 1 h

Procedure:
3-{Ethoxycarbonylmethyl-[6-(9H-fluoren-9-ylmethoxycarbonylamino)-hexanoyl]-amino}-propionic acid ethyl ester AB (11.5 g, 21.3 mmol) was dissolved in 20% piperidine in dimethylformamide at 0° C. The solution was continued stirring for 1 h. The reaction mixture was concentrated under vacuum, water was added to the residue, and the product was extracted with ethyl acetate. The crude product was purified by conversion into its hydrochloride salt.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][NH:12]1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>C(OCC)(=O)C>[N+:8]([C:7]1[C:2]([N:12]2[CH2:13][CH2:14][C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:11]2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: c1ccc2c(c1)CCNC2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccnc1N1CCc2ccccc2C1
Temperature: 100 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
2-Chloro-3-nitropyridine (3.0 g, 18.92 mmol), 1,2,3,4-tetrahydroisoquinoline (2.37 ml, 18.92 mmol), and sodium carbonate (3.1 g, 28.62 mmol) were added to anhydrous N,N-dimethylformamide (30 ml). The reaction mixture was stirred for 1 hour at 100° C. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with water three times, and then washed with a saturated sodium chloride solution. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure to give 4.8 g of the titled compound as yellow oil. (Yield: 98%).
Reaction SMILES: Cl[C:2](Cl)(Cl)[C:3]([N:5]=[C:6]=[O:7])=[O:4].[NH2:10][C:11]1[C:15]([CH3:16])=[CH:14][S:13]C=1C(OC)=O>C(#N)C>[CH3:16][C:15]1[C:11]2[NH:10][C:6](=[O:7])[NH:5][C:3](=[O:4])[C:2]=2[S:13][CH:14]=1
Reactant: COC(=O)c1scc(C)c1N
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: CC#N
Product: Cc1csc2c(=O)[nH]c(=O)[nH]c12
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 57.8 %

Procedure:
Trichloroacetyl isocyanate (2.0 g) was added to a solution of methyl 3-amino-4-methylthiophene-2-carboxylate (1.3 g) in acetonitrile (10 mL) and the resulting mixture was stirred for 15 minutes. The solid, which crashed out, was collected by filtration and suspended in methanol (5 mL), a solution of ammonia in methanol (7 M, 5 mL) was then added and the resulting mixture was heated at 70° C. for 15 minutes. The reaction mixture was cooled, the solid formed was collected by filtration, dried under reduced pressure to give 0.8 g of 7-methyl-1H-thieno[3,2-d]pyrimidine-2,4-dione.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[C:14]([NH:17][CH:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])(=[O:16])[CH3:15].C[O-].[Na+]>CCO>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][C:4]=1[CH2:3][CH2:15][C:14]([NH:17][CH:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:16]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: ClCc1ccc2ccccc2n1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(NC(=O)CCc1ccc2ccccc2n1)C(=O)OCC
Yield: 99 %

Procedure:
To a solution of 2(chloromethyl)quinoline monohydrochloride (5.0 g, 23.4 mmol) and diethyl acetamidomalonate (10.1 g, 46.7 mmol) in EtOH (60 mL) was added sodium methoxide (3.78 g, 70 mmol). The reaction mixture was heated at reflux for 6 h. The reaction mixture was cooled, filtered, and concentrated. The residue was dissolved in EtOAc (400 mL) and extracted with cold 4N HCl (3×150 mL). The aqueous layer was neutralized with 10N NaOH and extracted with EtOAc (3×200 mL). The combined organic extract was washed with water, dried (anhydrous MgSO4), filtered, and concentrated to give the title compound (8.3 g).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH:7]=O.[CH3:9][C:10]1([CH3:17])[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])[O:11]1.[OH-].[Na+].[Cl-].[Na+]>C(O)C>[CH3:9][C:10]1([CH3:17])[C:14](=[O:15])[CH:13]=[C:12]([CH:16]=[CH:7][C:3]2[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=2)[O:11]1
Reactant: CC1=CC(=O)C(C)(C)O1
Reactant: Cn1cccc1C=O
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1cccc1C=CC1=CC(=O)C(C)(C)O1
Temperature: 70 °C
Yield: 64.6 %

Procedure:
To a solution of 1-methyl-2-pyrrolecarboxaldehyde (1.4 g, 12.7 mM) and 2,2,5-trimethyl-3(2H)-furanone (2.0 g, 15.9 mM) in ethanol (100 mL), was added 1N aqueous sodium hydroxide (1.6 mL, 1.6 mM). The reaction solution was heated at 70° C. for 48 hours. After the reaction solution was cooled to 0° C., saturated aqueous sodium chloride (400 mL) was added. The aqueous layer was extracted with ethyl acetate (3×100 mL). The combined ethyl acetate extracts were washed with saturated aqueous sodium chloride (50 mL), dried over MgSO4, filtered and concentrated to give a brown solid. The crude product was purified by chromatography (silica gel, pet. ether-ethyl acetate) to give orange crystals (1.8 g, 65% yield), m.p. 98.5°-100° C.