Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]([F:10])[CH3:9])=[C:6]([Cl:11])[CH:5]=[CH:4][C:3]=1Br.[C:13]([NH:16][C:17]1[CH:22]=[C:21]([Sn](C)(C)C)[N:20]=[C:19]([C:27]([O:29][CH3:30])=[O:28])[C:18]=1[Cl:31])(=[O:15])[CH3:14].[F-].[Cs+].O>CN(C=O)C.[Cu](I)I.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>[C:13]([NH:16][C:17]1[CH:22]=[C:21]([C:3]2[CH:4]=[CH:5][C:6]([Cl:11])=[C:7]([CH:8]([F:10])[CH3:9])[C:2]=2[Cl:1])[N:20]=[C:19]([C:27]([O:29][CH3:30])=[O:28])[C:18]=1[Cl:31])(=[O:15])[CH3:14]
Reactant: COC(=O)c1nc([Sn](C)(C)C)cc(NC(C)=O)c1Cl
Reactant: CC(F)c1c(Cl)ccc(Br)c1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1nc(-c2ccc(Cl)c(C(C)F)c2Cl)cc(NC(C)=O)c1Cl

Procedure:
A solution of 2,4 dichloro-3-(1-fluoroethyl)-bromobenzene (3.4 g, 12.5 mmol), 4-acetylamino-3-chloro-6-trimethylstannyl-pyridine-2-carboxylic acid, methyl ester (4.7 g, 12.5 mmol), copper iodide (0.4 g, 2.1 mmol), cesium fluoride (3.6 g, 25 mmol) and dichlorobis(triphenylphosphine)palladium (0.14 g, 2 mmol) in DMF (50 mL) was heated to 70° C. for 2 hours. Water (100 mL) was added the mixture extracted with ethyl acetate (2×100 mL). The combined extracts were washed with brine, dried (sodium sulfate) and concentrated. The residue was purified by chromatography (15%-30% ethyl acetate in hexanes) to give 4-acetylamino-3-chloro-6-[2,4 dichloro-3-(1-fluoroethyl)phenyl]pyridine-2-carboxylic acid, methyl ester which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27]C)=[O:19])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:13][CH2:14][N:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[OH:27])=[O:19])[CH2:16][CH2:17]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: COc1ccccc1NC(=O)N1CCN(c2ccnc3cc(Cl)ccc23)CC1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(Nc1ccccc1O)N1CCN(c2ccnc3cc(Cl)ccc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4-(7-chloro-4-quinolinyl)-N-(2-methoxyphenyl)-1-piperazine carboxamide (40 mg, 0.1 mmol) in CH2Cl2 (6 mL) was added a solution of BBr3 (0.2 mL, 1.0 M) at rt. The reaction mixture was stirred at rt overnight, then quenched with 1 N NaOH solution. The reaction mixture was extracted with CH2Cl2, washed with brine, and dried over Na2SO4. Concentration in vacuo followed by flash chromatography afforded the title product. LC-MS 383 (M++1). 1H NMR (CDCl3) δ 8.75 (d, 1H), 8.05 (s, 1H), 7.95 (d, 1H), 7.45 (d, 1H), 7.05 (m, 3H), 6.85 (m, 2H), 6.70 (s, 1H), 3.85 (m, 4H), 3.30 (m, 4H).
Reaction SMILES: Cl.[C:2]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][NH2:31])=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)(=[O:4])[CH3:3].C(N(CC)CC)C.[C:39](OC(=O)C)(=[O:41])[CH3:40]>CN(C)C1C=CN=CC=1.C1COCC1>[C:2]([C:5]1[N:6]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([CH2:30][NH:31][C:39](=[O:41])[CH3:40])=[CH:28][CH:29]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)(=[O:4])[CH3:3]
Reactant: CC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(CN)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NCc1ccc(Cn2c(C(C)=O)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 92 %

Procedure:
To a solution of 3-acetyl-2-(4-aminomethylbenzyl)-6-bromo-4-phenyl-2H-isoquinolin-1-one hydrochloride (100 mg) and triethylamine (0.09 ml) and 4-dimethylaminopyridine (24 mg) in THF (5 ml) was added acetic anhydride (0.08 ml) and the mixture was stirred at room temperature for 12 hrs. The solvent was evaporated under reduced pressure, and partitioned between water and ethyl acetate. The ethyl acetate layer was washed with 1N hydrochloric acid, aqueous sodium hydrogen carbonate and brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/1→1/9) to give the title compound (93 mg, 92%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH2:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=2[O:20][CH3:21])=[C:4]([CH3:22])[N:3]=1.[CH2:23]([NH2:27])[CH2:24][CH2:25][CH3:26]>O1CCOCC1>[NH2:1][C:2]1[N:7]=[C:6]([NH:27][CH2:23][CH2:24][CH2:25][CH3:26])[C:5]([CH2:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=2[O:20][CH3:21])=[C:4]([CH3:22])[N:3]=1
Reactant: COC(=O)c1ccc(Cc2c(C)nc(N)nc2Cl)c(OC)c1
Reactant: CCCCN
Solvent: C1COCCO1
Product: CCCCNc1nc(N)nc(C)c1Cc1ccc(C(=O)OC)cc1OC
Temperature: 90 °C
Reaction time: 70 h

Procedure:
A stirred mixture of the product from step (i) (8 g) and butylamine (7.40 ml) in dioxane (100 ml) was heated at 90° C. for 72 h. More butylamine (7.40 ml) was added and the reaction mixture stirred for a further 70 hrs. The solvent was evaporated and the crude product was purified by chromatography (5% MeOH/DCM) to afford the subtitle compound as a tan solid, 4.5 g.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([Cl:9])=[N:7][OH:8])=[CH:4][CH:3]=1.[Cl:12][CH2:13][CH2:14][CH2:15][S:16](Cl)(=[O:18])=[O:17].C(N(CC)CC)C>C1C=CC=CC=1>[Cl:12][CH2:13][CH2:14][CH2:15][S:16]([O:8][N:7]=[C:6]([Cl:9])[C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:11][CH:10]=1)(=[O:18])=[O:17]
Reactant: Cc1ccc(C(Cl)=NO)cc1
Reactant: O=S(=O)(Cl)CCCCl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: Cc1ccc(C(Cl)=NOS(=O)(=O)CCCCl)cc1
Reaction time: 1 h
Yield: 54.5 %

Procedure:
To a solution of 8.5 g of 4-methylbenzohydroximoyl chloride and 8.8 g of 3-chloropropanesulfonyl chloride in 175 ml of benzene, 7.6 g of triethylamine was added dropwise during 8 minutes. The temperature of the reaction mixture rose to 35°. The reaction mixture was stirred for 1 hour and filtered, the filtrate was evaporated under reduced pressure, and the product was recrystallized twice from ethanol to give 8.4 g of N-(3-chloropropanesulfonyloxy)-4-methylbenzimidoyl chloride, m.p. 56°-58°. The ir spectrum was consistent with the assigned structure.
Reaction SMILES: I[C:2]#[C:3][CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[C:16]([OH:29])(=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]#[CH:27]>>[C:16]([OH:29])(=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]#[C:27][C:2]#[C:3][CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: C#CCOCCCCCCCC(=O)O
Reactant: CCCCCCCCCCOCC#CI
Product: CCCCCCCCCCOCC#CC#CCOCCCCCCCC(=O)O
Yield: 30.6 %

Procedure:
Following the procedure described in Singh, A. & Schnur, J. M., Synthetic Comm. 16, 847 (1986), 1-iodo-4-oxa-tetradecyne (10 mmol) was coupled with 9-oxa-11-dodecynoic acid (1.98 g, 10 mmol) to produce 1.2 g 9,16-dioxa-hexacosa-11,13-diynoic acid (31% yield). The 9-oxa-11-dodecynoic acid was dissolved in aqueous KOH solution (1.1 mol eq.). CuCl (0.25 mol eq.) in ethylamine (70% aq. solution) was added, followed by 15 mg±5 mg hydroxyl amine hydrochloride NH2OH.HCl crystals. To this solution (yellow) was then added, in small portions, the 1-iodo-4-oxa-tetradecyne dissolved in 10 ml of CH3OH--CH3CH2OCH2CH3 (1:1). On addition of 1-iodo-4-oxa-tetradecyne the reaction mixture turned blue, and then yellow on addition of a few drops of 10% aqueous NH2OH.HCl solution.
Reaction SMILES: C([O:4][CH:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:6][CH2:7][CH:8]1[N:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]C)=[O:20])[C:11](=[O:23])[CH2:10][S:9]1)(=O)C.[OH-].[Na+].CO>C(Cl)(Cl)Cl>[OH:4][CH:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:6][CH2:7][CH:8]1[N:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:11](=[O:23])[CH2:10][S:9]1
Reactant: CCCCCC(CCC1SCC(=O)N1CCCCCCC(=O)OC)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCCCC(O)CCC1SCC(=O)N1CCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 15 h
Yield: 72.7 %

Procedure:
A turbid mixture of methyl 7-[2-(3-acetyloxyoctyl)-4-oxo-3-thiazolidinyl]heptanoate (785 mg., 1.89 millimole), 2.5 N aqueous sodium hydroxide (2 ml.), and methanol (6 ml.) is stirred at 25° C. for 15 hours. After removing the solvents in vacuo below 50° C., the residual mass is acidified with 2 N hydrochloric acid and extracted twice with ether. The combined organic extract is washed with water, dried over magnesium sulfate, and filtered. In vacuo evaporation of the filtrate provides an oily residue which is applied to a silica gel column (20 g.) with chloroform. Elution with chloroform-acetic acid (50:1; v:v; 200 ml.) affords impure product; continued elution with the same eluant (600 ml.) provides the title compound as a pale yellow oil (494 mg., 73%); pmr (CDCl3) δ0.90 (3H, t), 2.34 (2H, t), 2.60-3.30 (H, m), 3.30-4.00 (4H, m, containing a singlet at 3.54), 4.53-4.93 (H, m) and 7.10 (2H, broad s, D2O exchangeable).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Cl[CH2:11][C:12]1[N:13]=[CH:14][N:15]([C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:17]([N:15]1[CH:16]=[C:12]([CH2:11][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[N:13]=[CH:14]1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: ClCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Temperature: 25 °C
Reaction time: 40 h
Yield: 51.8 %

Procedure:
1.22 g of p-hydroxybenzaldehyde and 4.08 g of 4-chloromethyl-1-tritylimidazole were dissolved in 40 ml of N,N-dimethylformamide, followed by adding 1.66 g of anhydrous potassium carbonate and subsequently stirring at room temperature for 40 hours. The thus prepared reaction solution were partitioned between water and benzene, and the resulting organic layer was concentrated to dryness. The resulting residue was purified by subjecting it to silica gel column chromatography using chloroform as an elution solvent, and the thus purified product was crystallized from a n-hexane/benzene solvent system. In this way, 2.3 g of the title compound was obtained.
Reaction SMILES: CI.[C:3]1([C:9]2([C:12]([OH:14])=[O:13])[CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:15](=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.[Cl-].[Na+].O>[C:3]1([C:9]2([C:12]([O:14][CH3:15])=[O:13])[CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)C1(c2ccccc2)CC1
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1(c2ccccc2)CC1
Reaction time: 1 h

Procedure:
Methyl iodide (2.8 mL, 0.045 mol) was added to a mixture of 1-phenylcyclopropane carboxylic acid (4.9 g, 0.030 mol) and potassium carbonate (8.3 g, 0.060 mol) in N,N-dimethylformamide (40 mL, 0.5 mol) at room temperature and then stirred for 1 hour. The mixture was diluted with ether,washed with water (×2) and brine successively, dried and concentrated to give the desired product.
Reaction SMILES: CC([O-])(C)C.[K+].[CH3:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1.C(O)(=O)C.C(=O)CC.C[N:26]1C(=O)[CH2:29][CH2:28][CH2:27]1>CCCCCCC.O>[CH3:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1.[CH3:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([N:26]=[CH:27][CH2:28][CH3:29])[CH:9]=1
Reactant: CN1CCCC1=O
Agent: CC(C)(C)[O-]
Agent: Cc1c[nH]c2ccccc12
Agent: [K+]
Solvent: CCCCCCC
Solvent: CCC=O
Solvent: O
Product: CCC=Nn1cc(C)c2ccccc21
Temperature: 20 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
A solution of 10 kg (76.2 mol) 3-methylindole in 50 kg NMP is prepared, and add an initial amount of 0.08–0.12 eq. KOtBu-solution to the 3-methylindole solution. The HOSA and the KOtBu solutions are added over a period of 120 min simultaneously and proportionally over mass flow meters at 20° C. to the reaction mixture. After the addition is completed, add to the resulting dark brown suspension 6.9 L (381 mol) water, 13.7 kg (228.6 mol) acetic acid (100%) and 7.5 kg (129.2 mol) propionaldehyde. Stir the mixture at 20° C. for ˜1 h, until completion of the reaction. The reaction mixture is then worked-up by adding 248 L water and 42 kg n-heptane. Unwanted salts precipitate from the reaction mixture. The resulting suspension is filtered and the phases are separated. The water phase is again extracted 3-times with 42 kg n-heptane. The combined organic phases are washed two times with 63 L water. The resulting brown heptane-solution is evaporated to dryness. This results in 11.6–12.5 kg 3-methyl-N-(propylidene)-1H-indol-1-amine (yield 81–90%) as a brown liquid.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[C:24]2[CH2:25][CH2:26][N:27]([CH2:29][C:30]#[CH:31])[CH2:28][C:23]=2[C:5]2[C:6]([OH:22])=[CH:7][C:8]([C:10]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)([CH3:14])[CH2:11][CH2:12][CH3:13])=[CH:9][C:4]=2[O:3]1.[ClH:33].[O:34]1[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][CH2:42][C:43](O)=[O:44])[CH2:36][CH2:35]1.C1(N=C=NC2CCCCC2)CCCCC1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.Cl>CCOCC.C(Cl)Cl>[ClH:33].[ClH:33].[CH3:32][C:2]1([CH3:1])[C:24]2[CH2:25][CH2:26][N:27]([CH2:29][C:30]#[CH:31])[CH2:28][C:23]=2[C:5]2[C:6]([O:22][C:43](=[O:44])[CH2:42][CH2:41][CH2:40][N:37]3[CH2:36][CH2:35][O:34][CH2:39][CH2:38]3)=[CH:7][C:8]([C:10]([C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)([CH3:14])[CH2:11][CH2:12][CH3:13])=[CH:9][C:4]=2[O:3]1
Reactant: O=C(O)CCCN1CCOCC1
Reactant: C#CCN1CCC2=C(C1)c1c(O)cc(C(C)(CCC)c3ccc(F)cc3)cc1OC2(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CCOCC
Solvent: ClCCl
Product: C#CCN1CCC2=C(C1)c1c(OC(=O)CCCN3CCOCC3)cc(C(C)(CCC)c3ccc(F)cc3)cc1OC2(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4.0 g. (10.1 mm.) of 5,5-dimethyl-10-hydroxy-8-(4-fluorophenyl-1-methylbutyl)-2-(2-propynyl)-1,2,3,4-tetrahydro-5H[1]benzopyrano[3,4-d]pyridine, 2.10 g. (10.1 mm.) of γ-morpholino-butyric acid hydrochloride and 2.18 g. (10.6 mm.) of dicyclohexylcarbodiimide are added to 200 ml. of methylene chloride. The reaction mixture is stirred at room temperature for 16 hours and after cooling, the by-product of dicyclohexylurea is removed by suction filtration. The mother liquor is evaporated to give a residue, which, after the usual workup, is converted to a dihydrochloride by the addition of an ether solution of hydrogen chloride. Recrystallization from methylene chloride/diethyl ether gives the final product.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:13]3[CH2:18][CH2:17][C:16](=O)[CH2:15][CH:14]=3)=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].CC(O)=O.Cl.[CH3:25][NH2:26].[OH-].[Na+]>ClCCCl>[CH3:25][NH:26][CH:16]1[CH2:17][CH2:18][C:13]([C:8]2[C:7]3[C:11](=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[NH:10][CH:9]=2)=[CH:14][CH2:15]1
Reactant: CN
Reactant: O=C1CC=C(c2c[nH]c3cc([N+](=O)[O-])ccc23)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CNC1CC=C(c2c[nH]c3cc([N+](=O)[O-])ccc23)CC1
Reaction time: 16 h
Yield: 88.8 %

Procedure:
A solution of compound 119 (0.5 g, 1.951 mmol) in 1,2-dichloroethane (10 mL) was treated with AcOH (0.11 mL, 1.951 mmol), methylamine hydrochloride (0.13 g, 1.951 mmol), NaBH(OAC)3 (0.62 g, 2.926 mmol) at room temperature and stirred for over night (16 h). The reaction was basified with 2 N NaOH (25 mL) and product was extracted into ethyl acetate (2×25 mL). The combined ethyl acetate layer washed with brine (15 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2M NH3 in MeOH:CH2Cl2, 1:9) to obtain compound 120 (0.47 g, 89%) as a solid. mp 170-172° C.; 1H NMR (DMSO-d6) δ 1.37-1.50 (m, 1H), 1.90-1.99 (m, 2H), 2.33 (s, 3H), 2.43-2.64 (m, 4H), 6.14 (brs, 1H), 7.80 (s, 1H), 7.86-7.96 (m, 2H), 8.30 (d, 1H, J=2.1 Hz); ESI-MS (m/z, %): 272 (MH+, 100), 241 (43).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[F:21][C:22]1[CH:23]=[C:24]([CH:36]=[C:37]([F:39])[CH:38]=1)[CH2:25][NH:26][C:27](=[O:35])[CH:28]([CH2:32][CH2:33][CH3:34])[C:29](O)=[O:30]>>[F:21][C:22]1[CH:23]=[C:24]([CH:36]=[C:37]([F:39])[CH:38]=1)[CH2:25][NH:26][C:27](=[O:35])[CH:28]([CH2:32][CH2:33][CH3:34])[C:29]([NH:1][CH:2]1[C:3](=[O:20])[N:4]([CH3:19])[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8]1)=[O:30]
Reactant: CCCC(C(=O)O)C(=O)NCc1cc(F)cc(F)c1
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Product: CCCC(C(=O)NCc1cc(F)cc(F)c1)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O

Procedure:
The title compound, MS: m/e=519.3 (M+H+), was prepared in analogy to example 16 from 3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and N-(3,5-difluoro-benzyl)-2-propyl-malonamic acid.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:18](=[N:20][NH:21][C:22]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[C:26]([N+:34]([O-:36])=[O:35])[CH:25]=2)=[O:23])[CH3:19])=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.[OH-].[Na+]>>[OH:1][C:2]1[C:3]([C:18](=[N:20][NH:21][C:22]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[C:26]([N+:34]([O-:36])=[O:35])[CH:25]=2)=[O:23])[CH3:19])=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:8]=[CH:9][C:10]([C:13]([F:15])([F:14])[F:16])=[CH:11][CH:12]=1
Reactant: COC(=O)c1ccc(C(=O)NN=C(C)c2nn(C)c(-c3ccc(C(F)(F)F)cc3)c2O)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Product: CC(=NNC(=O)c1ccc(C(=O)O)c([N+](=O)[O-])c1)c1nn(C)c(-c2ccc(C(F)(F)F)cc2)c1O
Yield: 71.9 %

Procedure:
From methyl 4-{[2-(1-{4-hydroxy-1-methyl-5-[4-(trifluoromethyl)phenyl]-1H-pyrazol-3-yl}ethylidene)hydrazino]carbonyl}-2-nitrobenzoate (0.30 mmol, 150 mg) and 1 M sodium hydroxide aqueous solution (1.48 mL, 1.48 mmol), 106.0 mg of the desired product was obtained in the same manner as in Synthetic Example 58 as a pale yellow solid (yield 73%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:26]C)=[C:6]2[C:10]=1[N:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17]CC3C=CC=CC=3)=[C:13]([F:25])[CH:12]=1)[N:8]=[CH:7]2>Br>[F:1][C:2]1[C:10]2[N:9]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([F:25])[CH:12]=3)[N:8]=[CH:7][C:6]=2[C:5]([OH:26])=[CH:4][CH:3]=1
Reactant: COc1ccc(F)c2c1cnn2-c1ccc(OCc2ccccc2)c(F)c1
Agent: Br
Product: Oc1ccc(-n2ncc3c(O)ccc(F)c32)cc1F
Temperature: 120 °C
Yield: 23 %

Procedure:
7-Fluoro-1-{3-fluoro-4-[(phenylmethyl)oxy]phenyl}-4-(methyloxy)-1H-indazole (D27) (280 mg, 0.764 mmol) was dissolved in HBr (48% aq., 15 mL) and refluxed at 120° C. under argon. After 2 hours the mixture was partitioned between DCM (50 mL)/water (50 mL), the pH adjusted to 7 by addition of a 2M solution of NaOH and the layers separated. The aqueous phase was extracted with DCM (3×50 mL) and the combined organics were washed with brine (50 mL), separated and dried over MgSO4, filtered and concentrated in vacuo. The crude material (198 mg) was purified by flash chromatography (Biotage SP4) with a gradient of 0-100% Et2O in hexane. The isolated material (75 mg) was further purified by MDAP to afford 46 mg of the title compound (E13).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:19]2[C:18](=[O:20])[NH:17][CH:16]=[N:15][C:14]=2[N:13]([CH3:21])[C:12](=[O:22])[CH:11]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+].Cl[C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][C:33]=1[N+:41]([O-:43])=[O:42]>CN(C=O)C>[N+:38]([C:35]1[CH:34]=[C:33]([N+:41]([O-:43])=[O:42])[CH:32]=[CH:37][C:36]=1[N:17]1[C:18](=[O:20])[C:19]2[C:10]([NH:9][C:3]3[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=3[F:1])=[CH:11][C:12](=[O:22])[N:13]([CH3:21])[C:14]=2[N:15]=[CH:16]1)([O-:40])=[O:39]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Cn1c(=O)cc(Nc2ccc(I)cc2F)c2c(=O)[nH]cnc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(=O)cc(Nc2ccc(I)cc2F)c2c(=O)n(-c3ccc([N+](=O)[O-])cc3[N+](=O)[O-])cnc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a mixture of 5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione 5F (41 mg, 0.1 mmol, 1 eq) and catalytic amount of potassium iodide in DMF (1 mL) was added potassium carbonate (21 mg, 0.15 mmol, 1.5 eq). The reaction mixture was stirred at ambient temperature for 5 minutes. 1-Chloro-2,4-dinitrobenzene (22 mg, 0.11 mmol, 1.1 eq) was then added and the reaction mixture was irradiated with microwave at 80° C. for 30 minutes and then at 100° C. for 30 minutes. The reaction mixture was filtered and the filtrate was purified by preparatory LC/MS (50-75% CH3CN in H2O) to give 3-(2,4-dinitrophenyl)-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione compound 24A as a yellow solid (18 mg, 31% yield). 1H NMR (400 MHz, CDCl3) δ ppm 3.78 (s, 3 H) 6.09 (s, 1 H) 7.17-7.24 (m, 1 H) 7.52 (d, J=8.34 Hz, 2 H) 7.72-7.80 (m, 1 H) 8.23 (s, 1 H) 8.75 (dd, J=8.46, 2.65 Hz, 1 H) 9.12 (d, J=2.53 Hz, 1 H) 9.83 (s, 1 H). [M+H] calc'd for C20H12FIN6O6, 579; found, 579.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:6]=[C:7](/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14])[CH:8]=[CH:9][CH:10]=1)=[O:4].[H][H]>[Pd].C(O)C.CN(C=O)C>[CH3:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:8]=[CH:9][CH:10]=1)=[O:4]
Reactant: [H][H]
Reactant: CNC(=O)c1cccc(/C=C/C(=O)OC)c1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCO
Product: CNC(=O)c1cccc(CCC(=O)OC)c1
Yield: 80.1 %

Procedure:
A solution of (E)-methyl 3-[3-(methylcarbamoyl)phenyl]prop-2-enoate (3.77 g, 17.20 mmol) and 10% palladium on carbon (0.458 g, 0.43 mmol) in a mixture of ethanol (100 mL) and DMF (10.00 mL) was stirred at room temperature for 18 h under a balloon of hydrogen. The reaction mixture was filtered through celite and evaporated to dryness to afford methyl 3-(3-(methylcarbamoyl)phenyl)propanoate (3.05 g, 80%) as a white solid. MS: m/z 222 (MH+).
Reaction SMILES: Cl.[CH:2]1([CH2:8][NH:9][C:10]2[CH:20]=[CH:19][C:13]([CH2:14][CH2:15][C:16](Cl)=[O:17])=[CH:12][CH:11]=2)[CH2:7][CH2:6][CH:5]=[CH:4][CH2:3]1.C(Cl)Cl.[OH:24][CH:25]([CH2:30][CH3:31])[C:26]([O:28][CH3:29])=[O:27].C(N(CC)CC)C>CCOCC>[CH:2]1([CH2:8][NH:9][C:10]2[CH:20]=[CH:19][C:13]([CH2:14][CH2:15][C:16]([O:24][CH:25]([C:26]([O:28][CH3:29])=[O:27])[CH2:30][CH3:31])=[O:17])=[CH:12][CH:11]=2)[CH2:7][CH2:6][CH:5]=[CH:4][CH2:3]1
Reactant: CCC(O)C(=O)OC
Reactant: O=C(Cl)CCc1ccc(NCC2CC=CCC2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: CCC(OC(=O)CCc1ccc(NCC2CC=CCC2)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 10.0 g. 4-(cyclohex-3-enylmethylamino)hydrocinnamoyl chloride hydrochloride in 200 ml. methylene chloride is added dropwise a solution of 3 g. methyl 2-hydroxybutyrate and 5 g. triethylamine in 100 ml. ether. After 17 hours stirring at room temperature, the precipitate is collected and washed with several portions of ether. The ether solution is washed with water, dried and evaporated to yield 1-(methoxycarbonyl)propyl 4-(cyclohex-3-enylmethylamino)hydrocinnamate as a white solid.