Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[O:23]1[C:28]2[CH:29]=[CH:30][C:31]([CH2:33][O:34][CH2:35][CH2:36][CH2:37][CH2:38]Br)=[CH:32][C:27]=2[O:26][CH2:25][CH2:24]1>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:38][CH2:37][CH2:36][CH2:35][O:34][CH2:33][C:31]3[CH:30]=[CH:29][C:28]4[O:23][CH2:24][CH2:25][O:26][C:27]=4[CH:32]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: BrCCCCOCc1ccc2c(c1)OCCO2
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCOCc2ccc3c(c2)OCCO3)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 4-((1,4-benzodioxan-6-yl)-methoxy)butyl bromide are reacted and treated in the same manner as in Example 168 to give 4-amino-5-chloro-N-((1-(4-((1,4-benzodioxan-6-yl)-methoxy)butyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11](=[O:14])[O:12][CH:13]=2)=[CH:5][CH:4]=1.[C:17]([O:21][CH3:22])(=[O:20])[CH:18]=[CH2:19]>C1(C)C=CC=CC=1>[O:14]=[C:11]1[NH:10][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][CH:7]=2)=[C:13]([CH2:19][CH2:18][C:17]([O:21][CH3:22])=[O:20])[O:12]1
Reactant: O=c1[nH]c(-c2ccc(C(F)(F)F)cc2)co1
Reactant: C=CC(=O)OC
Solvent: Cc1ccccc1
Product: COC(=O)CCc1oc(=O)[nH]c1-c1ccc(C(F)(F)F)cc1
Yield: 26.9 %

Procedure:
A mixture of 4-(4-trifluoromethylphenyl)-2-oxazolone (10.8 g), methyl acrylate (8.10 g), boron trifluoride diethyl ether complex (6.86 g) and toluene (50 ml) was stirred with heating under reflux for 3 hours. The reaction mixture was concentrated, and poured into ice water (200 ml). The solid precipitates were filtered, washed with water, and air-dried. Recrystallization from isopropyl alcohol-isopropyl ether gave methyl 3-[2-oxo-4-(4-trifluoromethylphenyl)-4-oxazolin-5-yl]propionate as pale yellow prisms (4.00 g, 27%). Melting point 156-157° C.
Reaction SMILES: [O:1]1[CH2:5][CH:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:3]2[CH:12]=[CH:13][CH:14]=[CH:15][C:2]1=2.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1(C)C=CC=CC=1>[O:1]1[CH:5]=[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:3]2[CH:12]=[CH:13][CH:14]=[CH:15][C:2]1=2
Reactant: CCOC(=O)CC1COc2ccccc21
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1coc2ccccc12
Yield: 74.5 %

Procedure:
A toluene solution under N2 atmosphere containing ethyl 2,3-dihydrobenzo[b]furan-3-acetate (9.80 g, 47.6 mmol) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (12.97 g, 57.1 mmol) was heated at reflux for ~8 h. The reaction was filtered and the filtrate concentrated in vacuo. Silica gel chromatography (97:3 Hexane:EtOAc) of the residue afforded the title compound (7.24 g, 75%) as an orange oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.ClCCCOC1C=C(C2C3SC=CC=3ON=2)C=CC=1.[NH2:39][CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][C:45]([S:48]([NH2:51])(=[O:50])=[O:49])=[CH:44][CH:43]=1.C(=O)([O-])[O-].[K+].[K+]>>[O:14]1[C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:12]([C:8]2[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=2)[O:5][CH2:4][CH2:3][CH2:2][NH:39][CH2:40][CH2:41][C:42]2[CH:43]=[CH:44][C:45]([S:48]([NH2:51])(=[O:49])=[O:50])=[CH:46][CH:47]=2)=[N:13]1
Reactant: NCCc1ccc(S(N)(=O)=O)cc1
Reactant: BrCCCOc1cccc(-c2noc3ccsc23)c1
Agent: ClCCCOc1cccc(-c2noc3ccsc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: NS(=O)(=O)c1ccc(CCNCCCOc2cccc(-c3noc4ccsc34)c2)cc1
Yield: 35 %

Procedure:
The title compound is prepared from a mixture of 3-[3-(3-bromo-propoxy)-phenyl]-thieno[2,3-d]isoxazole, 3-[3-(3-chloro-propoxy)-phenyl]-thieno[2,3-d]isoxazole, 4-(2-aminoethyl) benzenesulfonamide and potassium carbonate essentially as described above in example 4 except that the column is eluted using a graded solvent mixture of dichloromethane:methanol (90:10). Combine the appropriate fractions and concentrate to give the title compound (0.16 g, 35% Yield) as a solid. Purity by LC/MS (APCI)=96% area, [M+H]+=458 m/e.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([CH2:18][CH2:19][CH2:20][OH:21])=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26].C(N(CC)CC)C>C(Cl)Cl>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([CH2:18][CH2:19][CH2:20][O:21][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: OCCCc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.7 %

Procedure:
360 mg (1.07 mmol) 3-[3-(4-Trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-propan-1-ol in 3 ml CH2Cl2 were treated with 100 μl (1.29 mmol) methanesulfonic acid chloride and 450 μl (3.23 mmol) triethylamine at 0° C. The solution was stirred at RT for 2 h, diluted with CH2Cl2 and washed with 1N HCl and dried over Na2SO4. Evaporation gave 350 mg (79%) crude Methanesulfonic acid 3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-propyl ester, which was directly subjected to the following reaction.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[C:6](O)(=[O:14])[C:7]1[C:8](=[CH:10][CH:11]=[CH:12][CH:13]=1)[NH2:9].Cl>ClCCl>[CH2:2]([C:1]1[O:4][C:6](=[O:14])[C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)[CH3:3]
Reactant: Nc1ccccc1C(=O)O
Reactant: CCC(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: CCc1nc2ccccc2c(=O)o1
Yield: 78.2 %

Procedure:
Propanoyl chloride (6.2 g, 67 mmol) was added to a solution of anthranilic acid (1 g, 7.3 mmol) in dichloromethane (20 mL). The reaction medium was kept under reflux and agitation, with the end of the reaction being monitored by CG/MS. After the end of the reaction, a hydrochloric acid solution was added (20 mL, 1M), and the resulting mixture was extracted with ethyl acetate (100 mL), the extract was dried with magnesium sulfate and the solvent was evaporated. Acetic anhydride (15 mL) was added to the residue and the reaction medium was taken to reflux and accompanied through CG/MS in order to monitor cyclization. After the end of the reaction, the reaction medium spin dried at a temperature of 65° C. using portions of toluene to facilitate the elimination of the anhydride. 1.0 g of the raw product 2-ethyl-4H-3,1-benzoxazin-4-one was obtained, which was used directly in the stage subsequent to reaction.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:13]([C@H:16]2[CH2:21][CH2:20][C@H:19]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][CH2:17]2)[CH2:14][CH3:15])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[H-].[Na+].[CH3:32]I>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([C@H:16]2[CH2:17][CH2:18][C@H:19]([N:22]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH3:32])[CH2:20][CH2:21]2)[CH2:14][CH3:15])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: CI
Reactant: CCN(c1cc(Br)cc(C(=O)OC)c1C)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(c1cc(Br)cc(C(=O)OC)c1C)[C@H]1CC[C@H](N(C)C(=O)OC(C)(C)C)CC1
Reaction time: 0.33 h

Procedure:
To a stirred solution of methyl 5-bromo-3-(((trans)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(ethyl)amino)-2-methylbenzoate (3 g, 6.41 mmol, see, e.g., WO2012142504) in THF (30 mL), NaH (0.184 g, 7.69 mmol) was added at 0° C. and stirred it at same temperature for 20 min. Then methyl iodide (9.10 g, 64.10 mmol) was added at 0° C. and reaction was stirred for overnight at room temperature. On completion, reaction was quenched with ice water and extracted with dichloromethane. The combined organic layers were washed with water, dried, concentrated under reduced pressure. The crude compound was purified by column chromatography to afford the crude title compound that was used without further purification (3 g, 97.4% yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[N:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([NH2:27])=[O:26])=[CH:20][CH:19]=1>>[CH:12]1([C:4]2[N:3]=[C:2]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:24][C:25]([NH2:27])=[O:26])=[CH:22][CH:23]=3)[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: FC(F)(F)c1cc(Cl)nc(C2CCCC2)n1
Reactant: NC(=O)Cc1ccc(N)cc1
Product: NC(=O)Cc1ccc(Nc2cc(C(F)(F)F)nc(C3CCCC3)n2)cc1
Yield: 65.2 %

Procedure:
Following general procedure A1, 4-chloro-2-cyclopentyl-6-(trifluoromethyl)pyrimidine (0.100 g, 0.40 mmol) was reacted with 2-(4-aminophenyl)acetamide (0.072 g, 0.48 mmol) to afford the title compound (0.095 g, 65%) as a white solid. MW=364.36. 1H NMR (DMSO-d6, 500 MHz) δ 9.97 (s, 1H), 7.69-7.57 (m, 2H), 7.42 (s, 1H), 7.25 (d, J=8.0 Hz, 2H), 6.93 (s, 1H), 6.85 (s, 1H), 3.34 (s, 2H), 3.20 (quin, J=8.0 Hz, 1H), 2.05-1.97 (m, 2H), 1.89-1.59 (m, 6H); APCI MS m/z 365 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[O:6][C@H:5]([CH2:7][O:8][C:9]2[C:18]([CH3:19])=[CH:17][C:12]([C:13]([NH:15][OH:16])=[NH:14])=[CH:11][C:10]=2CC)[CH2:4][O:3]1.[Cl:23]C1C=C(C=C(C)C=1O)C#N>>[Cl:23][C:10]1[CH:11]=[C:12]([CH:17]=[C:18]([CH3:19])[C:9]=1[O:8][CH2:7][C@@H:5]1[CH2:4][O:3][C:2]([CH3:22])([CH3:1])[O:6]1)[C:13]([NH:15][OH:16])=[NH:14]
Reactant: Cc1cc(C#N)cc(Cl)c1O
Reactant: CCc1cc(C(=N)NO)cc(C)c1OC[C@@H]1COC(C)(C)O1
Product: Cc1cc(C(=N)NO)cc(Cl)c1OC[C@@H]1COC(C)(C)O1

Procedure:
The title compound is obtained as a colorless oil (1.39 g) in analogy to (R)-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-3-ethyl-N-hydroxy-5-methyl-benzamidine starting from 3-chloro-4-hydroxy-5-methyl-benzonitrile and L-α,β-isopropyliden glycerol; LC-MS: tR=0.66 min, [M+H]+=314.96.
Reaction SMILES: [CH2:1]([C:5]1[C:9](/[CH:10]=[CH:11]/[C:12]2[S:13][C:14]([C:18]([OH:20])=O)=[C:15]([CH3:17])[N:16]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[NH2:22][C@H:23]([CH2:26][CH3:27])[CH2:24][OH:25]>>[OH:25][CH2:24][C@H:23]([NH:22][C:18]([C:14]1[S:13][C:12](/[CH:11]=[CH:10]/[C:9]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][O:7][C:8]=2[CH3:21])=[N:16][C:15]=1[CH3:17])=[O:20])[CH2:26][CH3:27]
Reactant: CC[C@@H](N)CO
Reactant: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)O)s1
Product: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)N[C@H](CC)CO)s1
Yield: 80 %

Procedure:
As described for example 104, 2-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-4-methyl-thiazole-5-carboxylic acid (153 mg, 0.5 mmol) was converted, using (R)-2-amino-1-butanol instead of rac-2-amino-1-butanol, to the title compound (151 mg, 80%) which was obtained as a light yellow solid after purification by chromatography (silica, 50 to 100% ethyl acetate in heptane) and recrystallization from ethyl acetate/heptane. MS: m/e=378.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[C:20](=[O:21])[N:19]([CH3:22])[C:12]3[N:13]=[C:14](SC)[N:15]=[CH:16][C:11]=3[CH:10]=2)=[CH:4][C:3]=1[NH:23][C:24]([NH:26][C:27]1[O:31][N:30]=[C:29]([CH:32]([CH3:34])[CH3:33])[CH:28]=1)=[O:25].[CH3:35][NH2:36].C1COCC1>>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[C:20](=[O:21])[N:19]([CH3:22])[C:12]3[N:13]=[C:14]([NH:36][CH3:35])[N:15]=[CH:16][C:11]=3[CH:10]=2)=[CH:4][C:3]=1[NH:23][C:24]([NH:26][C:27]1[O:31][N:30]=[C:29]([CH:32]([CH3:34])[CH3:33])[CH:28]=1)=[O:25]
Reactant: CSc1ncc2cc(-c3cc(NC(=O)Nc4cc(C(C)C)no4)c(F)cc3C)c(=O)n(C)c2n1
Reactant: CN
Solvent: C1CCOC1
Product: CNc1ncc2cc(-c3cc(NC(=O)Nc4cc(C(C)C)no4)c(F)cc3C)c(=O)n(C)c2n1
Yield: 20.9 %

Procedure:
Using a procedure analogous to Example A1, 1-(2-fluoro-4-methyl-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(3-isopropylisoxazol-5-yl)urea (0.203 g, 0.421 mmol, 1.00 eq) and 2.00M MeNH2/THF (2.10 ml, 4.21 mmol, 10.00 eq,) were combined to afford 1-(2-fluoro-4-methyl-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(3-isopropylisoxazol-5-yl)urea (41 mg, 21% yield) as a pale yellow powder. 1H NMR (400 MHz, DMSO-d6) δ 10.28 (s, 1H), 8.67 (brs, 1H), 8.60 (s, 1H), 7.88 (d, J=8.0 Hz, 1H), 7.81 (brq, J=4.0 Hz, 1H), 7.67 9s, 1H), 7.17 (d, J=12.8 Hz, 1H), 5.96 (s, 1H), 3.59 (s, 3H), 2.90 (d, J=4.8 Hz, 3H), 2.89 (septet, J=7.2 Hz, 1H), 2.08 (s, 3H), 1.16 (d, J=7.2 Hz, 6H); MS (ESI) m/z: 466.0 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[H-].[Na+].[H][H].Cl[CH2:14][CH2:15][O:16][CH3:17]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:14][CH2:15][O:16][CH3:17])=[N:6][CH:7]=1
Reactant: [H][H]
Reactant: COCCCl
Reactant: Nc1ccc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCNc1ccc(Br)cn1
Temperature: 2.5 °C
Reaction time: 0.83 h
Yield: 52.8 %

Procedure:
5-Bromo-pyridin-2-ylamine (29-1, 1.43 g, 8.27 mmol) was dissolved in anhydrous DMF (20 mL) under N2. The solution was cooled to 0-5° C. and added with NaH (>1.0 equiv) until no hydrogen was formed. The solution was added with 1-chloro-2-methoxy-ethane (2.5 ml, 14 mmol) dropwisely at 0-5° C. The reaction mixture was stirred at 0° C. for 50 min. The solution was quenched with methanol and saturated aqueous NH4Cl. The solution was concentrated under reduced pressure and distributed between water, brine, and dichloromethane. The aqueous phase was then extracted with dichloromethane and the combined organic phases were dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel to give 5-bromo-N-(2-methoxyethyl)pyridin-2-amine (29-2, 1.01 g) as brown solids in 53% yield: 1H NMR (500 MHz, CDCl3) δ 8.01 (d, 1 H), 7.57 (d, 1 H), 6.57 (d, 1 H), 3.97 (t, 2 H), 3.49 (t, 2 H), 3.35 (s, 3 H). ESI-MS: m/z 231.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[NH:12]1[CH:16]=[CH:15][N:14]=[CH:13]1.O>CN(C)C=O>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([C:13]2[NH:12][CH:16]=[CH:15][N:14]=2)[N:3]=1
Reactant: c1c[nH]cn1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc(-c2ncc[nH]2)ccc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 8 h
Yield: 79.5 %

Procedure:
In 80 ml of N,N-dimethylformamide were dissolved 4.00 g of 2-amino-6-chloro-3-nitropyridine and 15.69 g of imidazole, and the solution was stirred at 120° C. overnight. After spontaneous cooling to room temperature, 100 ml of water was added and the resulting crystals were collected by filtration. The crystals were rinsed with a small amount of water and dried under reduced pressure to provide 3.76 g of 2-amino-6-imidazolyl-3-nitropyridine. Physicochemical properties:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=O)[CH2:8][C:9]([O:11]CC)=O)=[N:3][CH:2]=1.N1C=CC(C(=O)CC(OCC)=O)=CC=1.Cl.[NH:30]=[C:31]1[CH:37]([N:38]2[C:46](=[O:47])[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39]2=[O:48])[CH2:36][CH2:35][CH2:34][CH2:33][NH:32]1>>[O:11]=[C:9]1[N:32]2[CH2:33][CH2:34][CH2:35][CH2:36][CH:37]([N:38]3[C:46](=[O:47])[C:45]4[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=4)[C:39]3=[O:48])[C:31]2=[N:30][C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][N:3]=2)=[CH:8]1
Reactant: N=C1NCCCCC1N1C(=O)c2ccccc2C1=O
Reactant: CCOC(=O)CC(=O)c1ccncn1
Agent: CCOC(=O)CC(=O)c1ccncc1
Agent: Cl
Product: O=C1c2ccccc2C(=O)N1C1CCCCn2c1nc(-c1ccncn1)cc2=O

Procedure:
By analogy with the method described in example 1 (step 1.3), using ethyl 3-(4-pyrimidinyl)-3-oxopropionate (prepared by analogy to the method described in patent DE 2705582) in place of ethyl 3-(pyridin-4-yl)-3-oxopropionate and using 2-(2-iminoazepan-3-yl)-1H-isoindole-1,3(2H)-dione hydrochloride (1:1), the compound was obtained as a white powder.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Br[CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14].C(=O)([O-])[O-].[K+].[K+]>>[CH3:16][O:15][C:13](=[O:14])[CH2:12][CH2:11][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CCN2
Reactant: COC(=O)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)CCN1CCc2ccccc21

Procedure:
A solution of indoline (6.15 g), methyl 3-bromopropionate (13 g), potassium carbonate (21 g) in 150 mL of acetonitrie was refluxed fro 16 h. The reaction mixture was concentrated, mixed with 300 mL of ether. The mixed reaction solution was filtered, concentrated down to afford compound UUA (8 g). MS: 206 (M+1)+.
Reaction SMILES: C[O:2][C:3](=[O:42])[CH2:4][CH2:5][NH:6][C:7](=[O:41])[C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH2:38][CH:39]=[CH2:40])([CH2:18][O:19][C:20]2[CH:25]=[C:24]([CH3:26])[C:23]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)=[C:22]([CH3:37])[CH:21]=2)[CH2:15][CH:16]=[CH2:17])=[CH:10][CH:9]=1.[Li+].[OH-].Cl>C1COCC1.O>[CH2:15]([C:14]([C:11]1[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:42])=[O:2])=[O:41])=[CH:13][CH:12]=1)([CH2:18][O:19][C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[C:22]([CH3:37])[CH:21]=1)[CH2:38][CH:39]=[CH2:40])[CH:16]=[CH2:17]
Reactant: C=CCC(CC=C)(COc1cc(C)c(-c2ccc(C(F)(F)F)cc2)c(C)c1)c1ccc(C(=O)NCCC(=O)OC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C=CCC(CC=C)(COc1cc(C)c(-c2ccc(C(F)(F)F)cc2)c(C)c1)c1ccc(C(=O)NCCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.6 %

Procedure:
A solution of 3-{4-[1-allyl-1-(2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-yloxymethyl)-but-3-enyl]-benzoylamino}-propionic acid methyl ester (0.0438 g, 0.0756 mmol) in THF (1.0 mL) is treated with 1N LiOH (1.0 mL) and stirred overnight at room temperature. The reaction mixture is acidified with 1N HCl (1.1 mL), diluted with water (5 mL), and extracted with EtOAc (3×10 mL). The combined extracts are dried over MgSO4, filtered, and concentrated to provide 0.0105 g (24%) of the title compound as a white solid. MS (ES): 566.4 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[C:9]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:36])[O:17][CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][N:26]([C:28](=[O:35])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][NH2:34])[CH3:27])[CH2:20][CH2:19]1.C(N(CC)CC)C>C(O)CCC>[C:9]1([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:36])[O:17][CH:18]1[CH2:19][CH2:20][N:21]([CH2:24][CH2:25][N:26]([C:28](=[O:35])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:5]2[N:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)[CH3:27])[CH2:22][CH2:23]1
Reactant: Clc1ncc(Br)cn1
Reactant: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCN
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCNc1ncc(Br)cn1
Yield: 74.6 %

Procedure:
5-Bromo-2-chloropyrimidine (124 mg, 0.643 mmol) and the compound (300 mg, 0.643 mmol) obtained in Example 1a were dissolved in n-butanol (5 mL), triethylamine (0.134 mL, 0.965 mmol) was added, and the mixture was stirred with heating to reflux for 19 hours. The solvent was evaporated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=1:1→0:100, v/v) to give the title compound (299 mg; yield, 75%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][C:11](=[O:13])[N:10]=[C:9]2[NH:14][CH3:15])=[CH:4][CH:3]=1.S(OC)(O[CH3:20])(=O)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][C:11](=[O:13])[N:10]([CH3:20])[C:9]2=[N:14][CH3:15])=[CH:6][CH:7]=1
Reactant: CNC1=NC(=O)CN1c1ccc(Cl)cc1
Reactant: COS(=O)(=O)OC
Product: CN=C1N(C)C(=O)CN1c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
3 g. of 1-(p-chlorophenyl)-2-methylamino-4-oxo-2-imidazoline and 9 ml. dimethyl sulfate were heated slowly to 120° C. with stirring. The reaction mixture, cooled to room temperature, was filtered. The clear filtrate diluted with 150 ml. H2O was extracted once with 200 ml. ether. The aqueous layer was separated and made basic with 5N NaOH and cooling. The precipitate was filtered and recrystallized once with acetonitrile. Thin-layer chromatography gave a single spot. The yield of product, m.p. 150°-152° C., was 1.6 g. (50%).
Reaction SMILES: [C:1]([N:4]1[CH:10]([CH3:11])[CH2:9][C:8]2[CH:12]=[C:13]([Cl:17])[C:14]([Cl:16])=[CH:15][C:7]=2[C:6]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[C:20]([CH3:27])[CH:19]=2)=[N:5]1)(=[O:3])[CH3:2].O.NN>CO.ClCCl.[Ni]>[C:1]([N:4]1[CH:10]([CH3:11])[CH2:9][C:8]2[CH:12]=[C:13]([Cl:17])[C:14]([Cl:16])=[CH:15][C:7]=2[C:6]([C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([CH3:27])[CH:19]=2)=[N:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1N=C(c2ccc([N+](=O)[O-])c(C)c2)c2cc(Cl)c(Cl)cc2CC1C
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CC(=O)N1N=C(c2ccc(N)c(C)c2)c2cc(Cl)c(Cl)cc2CC1C
Reaction time: 0.75 h
Yield: 86.9 %

Procedure:
4.06 g (10 mmoles) of (±)-3-acetyl-4,5-dihydro-7,8-dichloro-1-(3-methyl-4-nitrophenyl)-4-methyl-3H-2,3-benzodiazepine are dissolved in a mixture of 55 cm3 of methanol and 55 cm3 of dichloromethane, then 3.0 g of wet Raney nickel catalyst and, under vigorous stirring, 1.7 cm3 (35 mmoles) of 98% hydrazine hydrate are added. The reaction mixture is stirred for further 45 minutes, the catalyst is filtered, washed with dichloromethane, the filtrate is evaporated, and the residue is rubbed with 50 cm3 of water to obtain solid matter. The crude product is recrystallized from a mixture of ethyl acetate and hexane. Thus, 3.27 g (87%) of the title compound are obtained in the form of yellow ochre solids melting at 127–129° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH:11]([NH2:21])[C:12]([N:14]3[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]3)=[O:13])=[CH:9][C:4]=2[N:3]=[CH:2]1.[N+:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1)([O-:24])=[O:23]>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH:11]([NH:21][S:37]([C:34]3[CH:33]=[CH:32][C:31]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[N+:22]([O-:24])=[O:23])=[CH:36][CH:35]=3)(=[O:38])=[O:39])[C:12]([N:14]3[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]3)=[O:13])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1CCN(C(=O)C(N)Cc2ccc3[nH]cnc3c2)CC1
Product: CC1CCN(C(=O)C(Cc2ccc3[nH]cnc3c2)NS(=O)(=O)c2ccc(-c3ccccc3[N+](=O)[O-])cc2)CC1

Procedure:
Prepared from 1-(1H-benzimidazol-5-yl-methyl)-2-(4-methyl-piperidin-1-yl)-2-oxo-ethylamine and 2'-nitro-4-biphenylyl-sulphonic acid chloride analogously to Example 2.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[O:13][C:12]([C:14]3[C:15]([O:29]CC[Si](C)(C)C)=[N:16][C:17]([NH:20][CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=4)=[N:18][CH:19]=3)=[N:11][N:10]=2)[CH2:4][CH2:3]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>C1COCC1>[OH:29][C:15]1[C:14]([C:12]2[O:13][C:9]([CH2:8][N:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)=[N:10][N:11]=2)=[CH:19][N:18]=[C:17]([NH:20][CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=2)[N:16]=1
Reactant: CN1CCN(Cc2nnc(-c3cnc(NCCc4ccncc4)nc3OCC[Si](C)(C)C)o2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CN1CCN(Cc2nnc(-c3cnc(NCCc4ccncc4)nc3O)o2)CC1
Reaction time: 5 h
Yield: 56 %

Procedure:
To 80 mL of THF, 5-[5-(4-methylpiperazinyl)methyl[1,3,4]oxadiazol-2-yl]-2-[2-(4-pyridyl)ethylamino]-4-(2-trimethylsilylethoxy)pyrimidine (3.83 g, 7.71 mmol) obtained in Step 3 was dissolved, then TBAF-THF solution (1.0 mol/L, 15.8 mL, 15.8 mmol) was added thereto, followed by stirring at a temperature between room temperature and 50° C. in total of 5 hours. After completion of the reaction was confirmed by thin-layer chromatography, the reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/methanol). Then, the residue was crystallized from hexane/ethyl acetate to give 4-hydroxy-5-[5-(4-methylpiperazinyl)methyl[1,3,4]oxadiazol-2-yl]-2-[2-(4-pyridyl)ethylamino]pyrimidine [Compound (AB) in which R2B is [2-(4-pyridyl)ethylamino] and —X—Y—Z— is