Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].O=[C:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:8][CH2:9][C:10]([NH2:12])=[O:11].Cl.O>CO>[NH2:5][C:3]([NH:2][N:1]=[C:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:8][CH2:9][C:10]([NH2:12])=[O:11])=[S:4]
Reactant: NNC(N)=S
Reactant: NC(=O)CCC(=O)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CO
Product: NC(=O)CCC(=NNC(N)=S)c1ccccc1
Yield: 75 %

Procedure:
Thiosemicarbazide (1.38 g, 15.1 mmol) was added to a solution of 4-oxo-4-phenyl-butyramide (1.63 g, 9.22 mmol), prepared in the previous step, in 50 ml of methanol plus 2.5 ml of 1 N HCl plus 2.5 ml of water and the reaction stirred at room temperature for 28 hours. The solid formed was collected by filtration and dried to give 1.73 g of a purple solid. Recrystallization of the solid from methanol gave the title compound (1.34 g, 58%) as a purple solid, mp 186-188° C.
Reaction SMILES: [S:1](Cl)([C:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:9]([N:10]([CH3:12])[CH3:11])[C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH3:18][N:19]([CH3:36])[CH2:20][CH2:21][S:22][S:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]([OH:35])[C:31](F)(F)F)=[CH:26][CH:25]=1.C1N2CCN(CC2)C1.O>C(Cl)Cl>[CH3:18][N:19]([CH3:36])[CH2:20][CH2:21][S:22][S:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]([O:35][S:1]([C:4]2[C:16]3[C:8](=[C:9]([N:10]([CH3:12])[CH3:11])[CH:13]=[CH:14][CH:15]=3)[CH:7]=[CH:6][CH:5]=2)(=[O:3])=[O:2])[CH3:31])=[CH:26][CH:25]=1
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: CN(C)CCSSc1ccc(C(O)C(F)(F)F)cc1
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Solvent: O
Product: CC(OS(=O)(=O)c1cccc2c(N(C)C)cccc12)c1ccc(SSCCN(C)C)cc1
Reaction time: 4 h

Procedure:
Dansyl chloride (37.5 mg, 0.13 mmol) dissolved in dry CH2Cl2 (0.5 mL) was added to the crude 1-[4-(2-dimethylamino-ethyldisulfanyl)-phenyl]-2,2,2-trifluoro-ethanol obtained above. To this solution was added dropwise a solution of DABCO (157 mg, 1.4 mmol) dissolved in dry CH2Cl2 (0.25 mL). After 4 hours at room temperature, the reaction mixture was poured into H2O (30 mL) and extracted using ethyl acetate (3×30 mL). The combined organic phases were washed with H2O (3×30 mL), followed by brine (1×30 mL) and then dried over Na2SO4. The organic phase was collected by filtration and concentrated by rotary evaporation. The crude product thus formed was purified by using flash chromatography on silica gel using 0-2% CH2Cl2/MeOH to yield Compound 2 a yellow oil (8 mg). 1H NMR (400 MHz, CD3OD): δ 8.45 (m, 1H), 8.13 (m, 2H), 7.57 (m, 1H), 7.43 (m, 1H), 7.27 (m, 1H), 7.06 (m, 2H), 6.98 (d, J=8.47, 2H), 5.88 (q, J=6.5 Hz, 1H), 2.8 (s, 6H), 2.78 (m, 2H), 2.57 (m, 2H), 2.21 (s, 6H); 19F NMR (376 MHz, CH3OD): δ −78.1 (d, J=6.5 Hz).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:8][CH2:9][C:10]#[N:11])=[CH:3][CH:2]=1.[Li+].CC([N-]C(C)C)C.Cl[CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=[CH:30][CH:29]=1>C1COCC1>[C:7](=[N:8][CH:9]([CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=[CH:30][CH:29]=1)[C:10]#[N:11])([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N#CCN=C(c1ccccc1)c1ccccc1
Reactant: ClCc1ccnc2ccccc12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CC(Cc1ccnc2ccccc12)N=C(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 26.3 %

Procedure:
To N-(Diphenylmethylene) aminoacetonitrile (0.360 g, 1.633 mmol) in 10 ml of anhydrous THF and HMPA (hexamethyl phosphoramidite) (0.38 ml, 2.12 mmol), at −78° C., LDA (2.0 M, 1.06 ml, 2.12 mmol) was added dropwise over a period of 5 minutes. The color of solution turns from colorless to yellow to dark brown. It was then stirred at −78° C. for one hour. 4-Chloromethylquinoline (0.29 g, 1.63 mmol) was added dropwise over a period of 5 minutes and the reaction mixture was slowly brought to room temperature over a period of five minutes. The reaction mixture was quenched by addition of ice and partitioned between EtOAc (20 ml) and water (5 ml). The organic layer was dried over sodium sulfate, filtered concentrated and column purified (hexanes:EtOAc; 3.5:1.5) to give 0.155 g (26%) of the product as a syrup, which was used as such for the subsequent step.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:14]=[CH:13][C:9]2=[N:10][O:11][N:12]=[C:8]2[CH:7]=1)=[O:5].[CH3:16][Li]>C1COCC1>[N:10]1[O:11][N:12]=[C:8]2[CH:7]=[C:6]([C:4](=[O:5])[CH3:16])[CH:14]=[CH:13][C:9]=12
Reactant: [Li]C
Reactant: CON(C)C(=O)c1ccc2nonc2c1
Solvent: C1CCOC1
Product: CC(=O)c1ccc2nonc2c1
Reaction time: 1 h

Procedure:
To a solution of N-Methoxy-N-methyl-2,1,3-benzoxadiazole-5-carboxamide (630 mg, 3.04 mmol) in THF (5 mL) cooled to −40° C. was added methyl lithium solution (1.6M, 2.28 mL, 3.65 mmol). The reaction mixture was stirred at the same temperature for 1 h, then was quenched by addition of 1M HCl. The mixture was extracted with ethyl acetate and the organic layer was dried over MgSO4. Purification my flash chromatography afforded the title compound. 1H-NMR (500 MHz, CDCl3) δ ppm 8.48 (s, 1H), 8.02 (d, 1H), 7.91 (d, 1H), 2.72 (s, 3H).
Reaction SMILES: Br.[N:2]1([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[S:15][CH:16]=[C:17]([C:19]4[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=4)[N:18]=3)[CH2:10][CH2:9]2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[CH3:28][O:29][C:30]([C:32]1([NH2:38])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:31]>>[CH3:28][O:29][C:30]([C:32]1([NH:38][C:23]([C:22]2[CH:26]=[CH:27][C:19]([C:17]3[N:18]=[C:14]([N:11]4[CH2:10][CH2:9][N:8]([N:2]5[CH2:3][CH2:4][O:5][CH2:6][CH2:7]5)[CH2:13][CH2:12]4)[S:15][CH:16]=3)=[CH:20][CH:21]=2)=[O:24])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1)=[O:31]
Reactant: COC(=O)C1(N)CCCCC1
Reactant: O=C(O)c1ccc(-c2csc(N3CCN(N4CCOCC4)CC3)n2)cc1
Agent: Br
Product: COC(=O)C1(NC(=O)c2ccc(-c3csc(N4CCN(N5CCOCC5)CC4)n3)cc2)CCCCC1

Procedure:
4.50 g (9.90 mmol) of 4-[2-[4-(4-morpholinyl)-1-piperazinyl]-4-thiazolyl]benzoic acid hydrobromide was used instead of 4-[2-(4-methyl-1-piperazinyl)-4-thiazolyl]benzoic acid hydrobromide, and 1.57 g (9.90 mmol) of 1-aminocyclohexanecarboxylic acid methyl ester was used instead of 1-aminocyclohexanecarboxylic acid phenylmethyl ester in the process according to Reference Example 210 to obtain 5.08 g (quantitative) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[Br:16]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:16][CH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5]
Reactant: Cc1ccccc1C(=O)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(c1ccccc1)c1ccccc1CBr

Procedure:
A mixture of 2-methylbenzophenone (9.8 g), N-bromosuccinimide (8.9 g), benzoyl peroxide (0.5 g) and carbon tetrachloride (150 ml) was refluxed for 1 hour with light irradiation. The mixture was cooled, and then filtered to remove insoluble substances. The filtrate was concentrated to afford quantitatively the above-titled compound as an oily substance.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][NH2+:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.[CH3:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][N:32]=1)[C:27](O)=[O:28]>>[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][N:18]3[C:27]([C:26]3[CH:30]=[CH:31][N:32]=[C:24]([CH3:23])[CH:25]=3)=[O:28])=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:9])(=[O:10])[N:8]=1
Reactant: Cc1cc(C(=O)O)ccn1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCC[NH2+]3)c21
Agent: Cl
Product: Cc1cc(C(=O)N2CCCC[C@@H]2COc2cccc3c2C(N)=NS(=O)(=O)N3)ccn1

Procedure:
Prepared as in Example 15 from (R)-2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidinium hydrochloride (Example 15a) and 2-methylisonicotinic acid. 1H NMR (400 MHz, CD3OD) δ1.51-2.00 (m, 6H), 2.57 (s, 3H), 3.27 (m, 1H), 3.45 (m, 1H), 4.28 (m, 1H), 4.73 (t, 1H, J=10.5 Hz), 5.42 (m, 1H), 6.66 (d, 1H, J=8.1 Hz), 6.87 (d, 1H, J=8.1 Hz,), 7.22 (m, 1H), 7.26 (s, 1H), 7.48 (t, 1H, J=8.6 Hz), 8.50 (d, 1H, J=4.8 Hz). MS 430 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].[CH2:12]([CH:14]1[O:16][CH2:15]1)Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N+:8]([C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([O:11][CH2:12][CH:14]2[CH2:15][O:16]2)[C:2]=1[NH2:1])([O-:10])=[O:9]
Reactant: BrCC1CO1
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1c(OCC2CO2)cccc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
A solution of 2-amino-3-nitro-phenol (18.0 g, 0.117 mol) and epibromohydrin (21.0 g, 0.15 mol) in DMF (200 mL) containing potassium carbonate (20.7 g, 0.15 mol) was stirred at 70° C. overnight. The mixture was evaporated in vacuo, water was added to the residue and the mixture was then extracted with dichloromethane (2×300 mL), the combined organic layers were washed with saturated sodium chloride (300 mL), dried and concentrated. Purification by flash column chromatography (silica gel, methylene chloride) provided 15.0 g of the title compound as an orange solid. 1H NMR (DMSO-d6): δ 7.60 (dd, 1H); 7.11 (dd, 1H); 7.05 (s, 2H); 6.60 (dd, 1H); 4.40 (dd, 1H); 3.93 (dd, 1H); 3.42 (m, 1H); 2.87 (dd, 1H); 2.75 (dd, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=1.[C:11]1([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:17]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:18]=[CH:19][C:20]([O:23][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=2)=[CH:21][CH:22]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(COc2ccc(-c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.4 %

Procedure:
A solution of alpha-bromo-p-tolunitrile (5.00 g, 25.5 mmol), 4-phenylphenol (4.56 g, 26.8 mmol), and potassium carbonate (10.6 g, 76.5 mmol) in N,N-dimethylformamide (75 mL) was stirred vigorously for 16 hours at room temperature. Water (75 mL) was added and the mixture was stirred at room temperature for 1 hour. The precipitate was filtered off and washed with thoroughly with water. Drying in vacuo over night at 50° C. afforded 7.09 g (97%) of 4-(biphenyl-4-yloxymethyl)benzonitrile as a solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH2:8])=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:16][CH2:17][C:18](Cl)=[O:19]>ClCCl>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:18](=[O:19])[CH2:17][Cl:16])=[CH:3][CH:2]=1
Reactant: NCc1ccncc1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)NCc1ccncc1
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
The starting material was obtained as follows: A solution of 4-pyridylmethylamine (1.08 g) and triethylamine (1.0 g) in dichloromethane (25 ml) was added slowly over 30 minutes to a chilled, stirred solution of chloroacetyl chloride (1.2 g) in dichloromethane (7.5 ml). The reaction mixture was maintained at 0-5° C. throughout the addition, stirred for a further 30 minutes and allowed to warm to room temperature. The reaction mixture was washed with water (2×10 ml) and dried over MgSO4. Evaporation of the solvent under reduced pressure gave N-(4-pyridylmethyl)chloroacetamide as a brown oil, which was used immediately.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=[O:17])[CH:10]=[CH:11][C:12]=2[O:13]C)=[CH:5][CH:4]=[N:3]1.ClC(Cl)C.BrB(Br)Br>O>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH:15][C:16]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=3)=[O:17])[CH:10]=[CH:11][C:12]=2[OH:13])=[CH:5][CH:4]=[N:3]1
Reactant: COc1ccc(NC(=O)Nc2ccc(Cl)cc2)cc1-c1ccnn1C
Agent: BrB(Br)Br
Solvent: O
Solvent: CC(Cl)Cl
Product: Cn1nccc1-c1cc(NC(=O)Nc2ccc(Cl)cc2)ccc1O
Temperature: 25 °C

Procedure:
To a mixture of 1-[3-(2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(4-chloro-phenyl)-urea (6.35 g, 17.8 mmol) and dichloroethane (500 Lm), tribromoborane (10 mL, 106 mmol) was added. The mixture was allowed to warm to room temperature. After stirring over the weekend, the mixture was cooled in an ice bath and a mixture of ice cold ammonium hydroxide and water (ca. 100 mL) was added slowly. The mixture was transferred into a separatory funnel and extracted with methylene chloride and water. Solid in the water phase was filtered off and washed with water to give 1-[3-(2-methyl-2H-pyrazol-3-yl)-4-hydroxy-phenyl]-3-(4-chloro-phenyl)-urea as a white solid (4.92 g, 90% pure, 12.7 mmol, 71%). Combined organic phases were dried over MgSO4, filtered, and concentrated to afford additional 1-[3-(2-methyl-2H-pyrazol-3-yl)-4-hydroxy-phenyl]-3-(4-chloro-phenyl)-urea as a white solid (1.71 g, 4.99 mmol, 28%). Overall yield: 99%. LCMS m/z (%)=343.1 (M+H). 1H NMR (400 MHz, CDCl3) δ: 9.60 (br s, 1H), 8.78 (s, 1H), 8.53 (s, 1H), 7.48-7.42 (m, 31), 7.32-7.27 (m, 4H), 6.91-6.89 (m, 1H), 6.21 (d, J=1.8 Hz, 1H), 3.68 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:15]([C:16]#[N:17])=[CH:14][N:13]=[C:12]3[S:18][C:19]4[CH2:20][NH:21][CH2:22][CH2:23][C:24]=4[C:11]=23)[CH:5]=[CH:6][C:7]=1[F:8].Cl.[CH3:26][N:27]([CH3:34])[CH2:28]/[CH:29]=[CH:30]/[C:31](O)=[O:32]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:15]([C:16]#[N:17])=[CH:14][N:13]=[C:12]3[S:18][C:19]4[CH2:20][N:21]([C:31](=[O:32])/[CH:30]=[CH:29]/[CH2:28][N:27]([CH3:34])[CH3:26])[CH2:22][CH2:23][C:24]=4[C:11]=23)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN(C)C/C=C/C(=O)O
Reactant: N#Cc1cnc2sc3c(c2c1Nc1ccc(F)c(Cl)c1)CCNC3
Agent: Cl
Product: CN(C)C/C=C/C(=O)N1CCc2c(sc3ncc(C#N)c(Nc4ccc(F)c(Cl)c4)c23)C1

Procedure:
In analogy to Example 89, the title compound was prepared from 4-[(3-chloro-4-fluorophenyl)amino]-5,6,7,8-tetrahydrothieno[2,3-b:5,4-c′]dipyridine-3-carbonitrile from Example 55A (100 mg, 0.28 mmol) and (2E)-4-(dimethylamino)but-2-enoic acid hydrochloride from Example 1A (65 mg, 0.39 mmol) to yield 53 mg (40%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.[N:11]1(S(O)(=O)=O)[CH2:15][CH2:14][N:13]=[CH:12]1>C(O)C(C)C.ClCCl>[CH2:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][C:12]3[NH:13][CH2:14][CH2:15][N:11]=3)=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: O=S(=O)(O)N1C=NCC1
Reactant: Nc1ccc2c(c1)CCC2
Solvent: CC(C)CO
Solvent: ClCCl
Product: c1cc2c(cc1NC1=NCCN1)CCC2
Reaction time: 8 h
Yield: 72.9 %

Procedure:
A mixture of 5-aminoindan (200 mg, 1.50 mmol) and 2-imidazolinesulfonic acid (450 mg, 3.00 mmol) in isobutyl alcohol (5 mL) was heated at reflux for 3 h and then stirred overnight. The solvent was removed to give a dark oil. It was flash chromatographed over silica gel (EtOAc:MeOH:Et3N=6:2:1) to afford a yellow solid. The solid was redissolved in dichloromethane, and washed with saturated aqueous Na2CO3. The organic layer was cried and concentrated to give yellow crystals (220 mg, 73% yield): mp 41°-42° C.; EIMS m/z=201 (M+). Anal. Calcd. for C12H15N3 4/5H2O: C, 66.82; H, 7.74; N, 19.48. Found: C, 6.77; H, 7.31; N, 19.24.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:13])[C@H:8]([CH:10]([CH3:12])[CH3:11])[NH2:9])([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.[N+:21]([C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26]Cl)([O-:23])=[O:22]>CCO>[C:2]([O:6][C:7](=[O:13])[C@@H:8]([NH:9][CH2:26][C:25]1[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=1[N+:21]([O-:23])=[O:22])[CH:10]([CH3:11])[CH3:12])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)[C@H](N)C(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccccc1CCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)[C@H](NCc1ccccc1[N+](=O)[O-])C(=O)OC(C)(C)C
Reaction time: 20 h
Yield: 79.5 %

Procedure:
To a solution of valine tert-butyl ester hydrochloride (1.5 g, 7.15 mmol) in EtOH (10 mL) was added triethylamine (2.09 mL, 15 mmol), followed after 10 minutes by 2-nitrobenzyl chloride (1.227 g, 7.15 mmol). The mixture was then stirred for 20 h under reflux before it was evaporated. The residue was purified by flash chromatography (petrol/ethyl acetate, 85/15) to afford the sub-title compound as a colorless oil (1.753 g, 80%). 1H NMR (400 MHz CDCl3) δ 0.93 (6H, m), 1.48 (9H, s), 1.83-1.96 (2H, m), 2.82 (1H, d), 3.92 (1H, d), 4.11 (1H, d), 7.39 (1H, t), 7.57 (1H, t), 7.65 (1H, d), 7.89 (1H, d).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][C:8]([C:14]([O:16]CC)=[O:15])=[C:7]2[NH:19][C@H:20]1[CH2:23][C@@H:22]([O:24][CH3:25])[CH2:21]1>CO.C1COCC1>[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][C:8]([C:14]([OH:16])=[O:15])=[C:7]2[NH:19][C@H:20]1[CH2:23][C@@H:22]([O:24][CH3:25])[CH2:21]1
Reactant: CCOC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1C[C@@H](OC)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CO[C@H]1C[C@@H](Nc2c(C(=O)O)cnc3ccc(Br)cc23)C1
Temperature: 60 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
Sodium hydroxide (190 ml, 379.70 mmol) was added to ethyl 6-bromo-4-[(cis-3-methoxycyclobutyl)amino]quinoline-3-carboxylate (36 g, 94.92 mmol) in a mixture of MeOH (120 mL) and THF (120 mL) and the resulting mixture stirred at 60° C. for 3 h. The solvent was removed under reduced pressure and the mixture adjusted to pH 3 with 2M hydrochloric acid. The precipitate was collected by filtration, washed with water (300 mL) and dried under vacuum to afford the desired material (33.0 g, 99%) as a pale yellow solid, which was used without further purification. Mass Spectrum: m/z (ES+)[M+H]+=351.
Reaction SMILES: C(O[C:4]([C:6]1[C:7](=[O:21])[N:8]([CH3:20])[N:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH:11]=1)=[O:5])C.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1(C)C(C)=CC=CC=1>[CH2:22]([NH:29][C:4]([C:6]1[C:7](=[O:21])[N:8]([CH3:20])[N:9]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[CH:11]=1)=[O:5])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1cc(-c2ccc(OC)cc2)nn(C)c1=O
Reactant: NCc1ccccc1
Solvent: Cc1ccccc1C
Product: COc1ccc(-c2cc(C(=O)NCc3ccccc3)c(=O)n(C)n2)cc1
Yield: 94.2 %

Procedure:
In xylene, 4-ethoxycarbonyl-6-(4-methoxyphenyl)-2-methyl-2H-pyridazin-3-one and benzylamine were reacted at 140° C. for 1 hour. Post-treatments were conducted as in Example 68, whereby the title compound was obtained in a yield of 94.2%.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].C(O)(O)CC.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28](B(O)O)[CH:27]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:2]2[CH:10]=[C:9]3[C:5]([CH2:6][C:7](=[O:11])[NH:8]3)=[CH:4][CH:3]=2)[CH:27]=1
Reactant: O=C1Cc2ccc(Br)cc2N1
Reactant: OB(O)c1cccnc1
Agent: CCC(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1Cc2ccc(-c3cccnc3)cc2N1
Temperature: 100 °C
Yield: 42 %

Procedure:
To a solution of 6-bromo-2-oxindole (4 g, 26.3 mmol) dissolved in 60 mL of toluene and 60 mL of ethanol with stirring and a little heating tetrakis(triphenyl-phosphine)palladium(0) (2.3 g, 1.9 mmol) was added followed by a 2 M aqueous solution of sodium carbonate (50 mL, 100 mmol) and pyridine-3-boronic acid propane diol (5 g, 30.7 mmol). The mixture was heated in a 100° C. oil bath for 12 hours. The cooled reaction was diluted with ethyl acetate (500 mL), washed with saturated aqueous sodium bicarbonate (200 mL), water (200 mL) and brine (200 mL). The organic layer was dried with magnesium sulfate and concentrated to afford a brown solid. The residue was triturated with methylene chloride/diethyl ether to give 2.32 g (42%) of 6-pyridin-3-yl-1,3-dihydro-indol-2-one as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[C:10]([OH:14])(=[O:13])[CH:11]=[CH2:12]>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:12][CH2:11][C:10]([OH:14])=[O:13])=[CH:5][CH:4]=1
Reactant: C=CC(=O)O
Reactant: COc1ccc(N)cc1
Solvent: O
Product: COc1ccc(NCCC(=O)O)cc1

Procedure:
3-(4-Methoxyanilino)propionic acid is prepared in a manner similar to that described in Example 1 but starting from p-anisidine (61 g; 0.495 mole), acrylic acid (9.5 g; 0.132 mole) and water (12 cc). After recrystallisation in toluene, the pure product (11.7 g; 0.060 mole) is obtained in the form of a white powder which melts at 89° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:12])[CH:8]=2)[N:3]=1.[CH3:13][O:14][S:15]([O:18]C)(=[O:17])=[O:16]>>[CH3:13][O:14][S:15]([O-:18])(=[O:17])=[O:16].[CH3:13][N+:3]1[C:4]2[C:9](=[CH:8][C:7]([CH3:12])=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[CH3:1]
Reactant: Cc1ccc2nc(C)ccc2c1
Reactant: COS(=O)(=O)OC
Product: COS(=O)(=O)[O-]
Product: Cc1ccc2c(ccc(C)[n+]2C)c1
Yield: 190 %

Procedure:
2,6-Dimethylquinoline (4.78 g, 30 mmol) was alkylated with dimethylsulphate (3.78 g, 30 mmol) as above to give the title compound (7.9 g, 28.5 mmol, 95%).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[O:20][CH3:21])[C:9]([CH3:11])=[N:10][C:5]2=[CH:4][CH:3]=1.CN(C)[CH:24]=[O:25].C(N(CC)CC)C.[C]=O.[CH3:36][OH:37]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:8]2[C:6]3=[N:7][C:2]([C:36]([O:25][CH3:24])=[O:37])=[CH:3][CH:4]=[C:5]3[N:10]=[C:9]2[CH3:11])=[C:14]([O:20][CH3:21])[CH:15]=1
Reactant: CN(C)C=O
Reactant: COc1cc(Cl)ccc1Cn1c(C)nc2ccc(Br)nc21
Reactant: CO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [C]=O
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2nc(C)n(Cc3ccc(Cl)cc3OC)c2n1
Temperature: 85 °C
Reaction time: 18 h

Procedure:
To a solution of 5-bromo-3-(4-chloro-2-methoxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine (200 mg) in anhydrous methanol (1.8 ml) and an anhydrous N,N-dimethylformamide (2 ml) were added anhydrous triethylamine (129 mg), palladium acetate (35 mg) and 1,3-bis(diphenylphosiphino)propane (72 mg) and the mixture was placed in an autoclave. After replacing with carbon monoxide 4 times, the mixture was stirred at 85° C. and 10 atm. After 18 hr, the reaction mixture was cooled and water was added. The mixture was extracted with ethyl acetate. The organic layer was washed with water (three times) and saturated brine, then dried over anhydrous magnesium sulfate. The residue was subjected to flash silica gel chromatography (silica gel, 40 ml, eluent: dichloromethane-methanol=50-1) and crystallized from ethanol to give the objective compound (148 mg) as pale-yellow crystals.